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Novel Macromolecular IV to Oral Delivery Conversion Pathway: Anti-thrombolytic post-surgical - Catalent OptiGel Bio™ Technology

Reporter: Aviva Lev-Ari, PhD, RN

Case Study

OptiGel BioTechnology Enables IV to Oral Therapy Conversion

Executive Summary

An early-stage biotechnology company had developed a novel macromolecular intravenous (IV) therapy for an anti-thrombolytic post-surgical indication. While the therapy had shown complete absorption via IV, the dose form was not ideal due to a number of factors including manufacturing costs, compliance, and ease of use, as well as as well as the long term treatment requirements. This case study demonstrates how Catalent OptiGel Bio™ technology can provide a pathway for an IV to oral delivery conversion, resulting in enhanced therapies for patients.

The Challenges

Though soluble, the macromolecule presented a number of permeability challenges, which hindered delivery of an active therapeutic dose across the lumen of the small intestine to achieve the desired therapeutic effect.

*Salamat-Miller N et al. , Pharmaceutical Research, 2005, 22(2):245-254

By incorporating OptiGel Bio™ technology and our formulation expertise, an optimized oral therapy was developed combining permeation enhancement and targeted delivery.

physiochemical properties High molecular weight (>2500 Da)Strong negative charge*

Rigid, inflexible geometry*

targeted delivery Functional API must be delivered to the small intestine in order to achieve bioavailability
permeability Mucus layer physical barrierRandom and limited transcellular pathways

“Fence and gate” function of tight junctions

pharmacokinetic profile Oral delivery must reach exposure within therapeutic range

The Catalent Solution

enhanced permeability The first challenge to overcome in development was enhancing the permeability of the macromolecule. A stepwise screening approach utilizing both in vitro and in vivo models yielded lead formulation candidates for further evaluation.

The Catalent Solution

https://kapost-files-prod.s3.amazonaws.com/uploads/direct/1382388405-22-3748/274-01_CaseStudy_OptiGelBio.pdf

enhanced permeability The first challenge to overcome in development was enhancing the permeability of the macromolecule. A stepwise screening approach utilizing both in vitro and in vivo models yielded lead formulation candidates for further evaluation.

Conclusion

Using OptiGel Bio™ technology, we overcame the challenges traditionally associated with the oral delivery of macromolecules and enabled conversion from an IV to a more efficient, more convenient and less invasive oral dose form while maintaining an effective pK profile. Through a multi-step drug delivery screening process and our OptiGel Bio™ technology, we can enable enhanced therapies—resulting in better treatments and more value for innovators, healthcare professionals and patients.

SOURCE

https://kapost-files-prod.s3.amazonaws.com/uploads/direct/1382388405-22-3748/274-01_CaseStudy_OptiGelBio.pdf

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Biomaterials Technology: Models of Tissue Engineering for Reperfusion and Implantable Devices for Revascularization

Author and Curator: Larry H Bernstein, MD, FACP

and

Curator: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/5_04_2013/bernstein_lev-ari/Bioengineering_of_Vascular_and_Tissue_Models

This is the THIRD of a three part series on the evolution of vascular biology and the studies of the effects of biomaterials
in vascular reconstruction and on drug delivery, which has embraced a collaboration of cardiologists at Harvard Medical School , Affiliated Hospitals, and MIT,
requiring cardiovascular scientists at the PhD and MD level, physicists, and computational biologists working in concert, and
an exploration of the depth of the contributions by a distinguished physician, scientist, and thinker.

The FIRST part – Vascular Biology and Disease – covered the advances in the research on

Drug Eluting Stents: On MIT’s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES

  • vascular biology,
  • signaling pathways,
  • drug diffusion across the endothelium and
  • the interactions with the underlying muscularis (media),
  • with additional considerations for type 2 diabetes mellitus.

The SECOND part – Stents and Drug Delivery – covered the

Vascular Repair: Stents and Biologically Active Implants

  • purposes,
  • properties and
  • evolution of stent technology with
  • the acquired knowledge of the pharmacodynamics of drug interactions and drug distribution.

In this THIRD part, on Problems and Promise of Biomaterials Technology, we cover the biomaterials used and the design of the cardiovascular devices, extension of uses, and opportunities for improvement

Biomaterials Technology: Tissue Engineering and Vascular Models -

Problems and Promise

We have thus far elaborated on developments in the last 15 years that have led to significant improvements in cardiovascular health.

First, there has been development of smaller sized catheters that can be introduced into

  • not only coronary arteries, but into the carotid and peripheral vasculature;

Second, there has been specific design of coated-stents that can be placed into an artery

  • for delivery of a therapeutic drug.

This began with a focus on restenosis, a serious problem after vascular repair, beginning
with the difficult problem of  control of heparin activity given intravenously, and was
extended to modifying the heparan-sulfate molecular structure

  • to diminish vascular endothelial hyperplasia,
  • concurrent with restriction of the anticoagulant activity.

Third, the ability to place stents with medicated biomaterials locally has extended to

  • the realm of chemotherapy, and we shall see where this progresses.

The Engineered Arterial Blood Flow Models

Biomedical engineers, in collaboration with physicians, biologists, chemists, physicists, and
mathematicians, have developed models to predict vascular repair by knowledge of

  • the impact of interventions on blood flow.

These models have become increasingly sophisticated and precise, and they propel us
toward optimization of cardiovascular therapeutics in general and personalizing treatments
for patients with cardiovascular disease. (1)
The science of vascular biology has been primarily stimulated by the clinical imperative to

  • combat complications that ensue from vascular interventions.

Thus, when a novel vascular biological finding or cardiovascular medical/surgical technique
is presented, we are required to ask the 2-fold question:

  • what have we learned about the biology of the blood vessel?
  • how might this knowledge be used to enhance clinical perspective and treatment?

The innovative method of engineering arterial conduits presented by Campbell et al. in
Circulation Research presents us with just such a challenge, and we deal with it’s biological and clinical ramifications.

Each of four pivotal studies in vascular tissue engineering has been an important advance
in the progression to a tissue-engineered blood vessel that can serve as a

  • living graft, responsive to the biological environment as
  • a self-renewing tissue with an inherent healing potential.
  • Weinberg and Bell taught us that a tissue-engineered graft could be constructed
  • and could be composed of human cells.

L’heureux et al demonstrated that the mechanical strength of such a material

  • derived in major part from the extracellular matrix and
  • production of matrix and integrity of cellular sheets
  • could be enhanced by alterations in culture conditions.

Niklason et al. noted that grafts are optimally formed

  • when incubated within environmental conditions that they will confront in vivo
  • or would have experienced if formed naturally.

Campbell et al. now demonstrate that it is possible to remove

  • the immune reaction and acute rejection that may follow cell-based grafting
  • by culturing tissues in the anticipated host and
  • address a fundamental issue of whether cell source or site of cell placement
  • dictates function after cell implantation.

It appears that the vascular matrix can be remodeled by the body according to the needs of the environment. It may
very well be that the ultimate configuration of autologous cell-based vascular graft need not be determined at
outset by the cells that comprise the device, but rather

  • by a dynamics that is established by environmental needs, wherein the body molds
  • tissue-engineered constructs to meet
    • local flow,
    • metabolic, and
    • inflammatory requirements.

In other words, cell source for tissue reconstruction may be secondary to
cell pliability to environmental influence.

Endothelial and smooth muscle cells from many, perhaps any,

  • vascular bed can be used to create new grafts and will then
  • achieve secondary function once in place in the artery.

The environmental remodeling observed after implantation

  • may modify limitations of grafts that are composed of nonvascular peritoneal cells whose initial structure
    is not either venous or arterial. (2)
  • The trilaminate vascular architecture provides biochemical regulation and mechanical integrity.
  • Yet regulatory control can be regained after injury without recapitulating tertiary structure.

Tissue-engineered (TE) endothelium controls repair even when

  • placed in the perivascular space of injured vessels.

It remains unclear from vascular repair studies whether endothelial implants recapitulate the vascular
epithelial lining
or expose injured tissues to endothelial cells (ECs) with unique healing potential because

  • ECs line the vascular epithelium and the vasa vasorum.

Authors examined this issue in a nonvascular tubular system, asking whether airway repair is controlled by

  • bronchial epithelial cells (EPs) or by
  • Endothelial Cells (ECs) of the perfusing bronchial vasculature.

Localized bronchial denuding injury

  • damaged epithelium, narrowed bronchial lumen, and led to
  • mesenchymal cell hyperplasia, hypervascularity, and inflammatory
  • cell infiltration. Peribronchial TE constructs embedded with

EPs or ECs limited airway injury, although optimum repair was obtained

  • when both cells were present in TE matrices.

EC and EP expression of

  • PGE2, TGF1, TGF2, GM-CSF, IL-8, MCP-1, and soluble VCAM-1
  • and ICAM-1 was altered by matrix embedding,

but expression was altered most significantly when both,

  • EC and EP,  cells were present simultaneously.

EPs may provide for functional control of organ injury and fibrous response, and

ECs may provide for preservation of tissue perfusion and the epithelium in particular.

Together the two cells

  • optimize functional restoration and healing, suggesting that
  • multiple cells of a tissue contribute to the differentiated biochemical function and repair
    of a tissue, but 
    need not assume
  • a fixed, ordered architectural relationship, as in intact tissues, to achieve these effects. (3)

Matrix-embedded Endothelial Cells (MEECs) Implants

The implantation of matrix-embedded endothelial cells (MEECs)

  • is considered to have therapeutic potential in controlling the vascular response to injury and
  • maintaining patency in arteriovenous anastomoses.

Authors considered the 3-dimensional microarchitecture of the tissue engineering scaffold to be
a key regulator of endothelial behavior in MEEC constructs.

Notably, Authors found that

  • ECs in porous collagen scaffold had a markedly altered cytoskeletal structure with oriented actin
    fibers
    and rearranged focal adhesion proteins, in comparison to cells grown on 2D surfaces.

Examining the immunomodulatory capabilities of MEECs revealed, MEECs were able to reduce the recruitment
of monocytes
to an inflamed endothelial monolayer by 5-fold compared to EC on 2D surfaces.

An analysis of secreted factors from the cells revealed

  • an 8-fold lower release of Monocyte Chemotactic Protein-1 (MCP-1) from MEECs.

Differences between 3D and 2D cultured cells were abolished in the presence of

  • inhibitors to the focal adhesion associated signaling molecule Src, suggesting that
  • adhesion-mediated signaling is essential in controlling the potent immunomodulatory
    effects of MEEC. (4)

Cardiogenesis is regulated by a complex interplay between transcription factors. How do these interactions
regulate the transition from mesodermal precursors to cardiac progenitor cells (CPCs)?

Yin Yang 1 (YY1), a member of the GLI-Kruppel

  • family of DNA-binding zinc finger transcription factor (TF), can
  • activate or inhibit transcription in a context-dependent manner.

Bioinformatic-based Transcription Factor Genome-wide Sequencing Analysis

These investigators performed a bioinformatic-based transcription factor genome-wide sequencing analysis

  • binding  site analysis on upstream promoter regions of genes that are enriched in embryonic stem cell–derived CPCs
  • to identify novel regulators of mesodermal cardiac lineage

From 32 candidate transcription factors screened, they found that

  • Yin Yang 1 (YY1), a repressor of sarcomeric gene expression, is present in CPCs.

They uncovered the ability of YY1 to transcriptionally activate Nkx2.5,

  • Nkx2.5 as a key marker of early cardiogenic commitment.
  • YY1 regulates Nkx2.5 expression via a 2.1-kb cardiac-specific enhancer as demonstrated by in vitro
  1. luciferase-based assays,
  2. in vivo chromatin immunoprecipitation,
  3. and genome-wide sequencing analysis.

Furthermore, the ability of YY1 to activate Nkx2.5 expression depends on its cooperative interaction with Gata4.

Cardiac mesoderm–specific loss-of-function of YY1 resulted in early embryonic lethality.

This was corroborated in vitro by embryonic stem cell–based assays which showed the

  • overexpression of YY1 enhanced the cardiogenic differentiation of embryonic stem cells into CPCs.

The results indicate an essential and unexpected role for YY1

  • to promote cardiogenesis as a transcriptional activator of Nkx2.5
  • and other CPC-enriched genes. (5)

Proportional Hazards Models to Analyze First-onset of Major
Cardiovascular Disease Events

Various measures of arterial stiffness and wave reflection are considered to be cardiovascular risk markers.

Prior studies have not assessed relations of a comprehensive panel of stiffness measures to prognosis

Authors used Proportional Hazards Models to analyze first-onset of major cardiovascular disease events 

  • myocardial infarction,
  • unstable angina,
  • heart failure, or
  • stroke

In relation to arterial stiffness measured by

  • pulse wave velocity [PWV]
  • wave reflection
  • augmentation index [AI]
  • carotid-brachial pressure amplification [PPA]
  • and central pulse pressure [CPP]

in 2232 participants (mean age, 63 years; 58% women) in the Framingham Heart Study.

During median follow-up of 7.8 (range, 0.2 to 8.9) years,

  • 151 of 2232 participants (6.8%) experienced an event.

In multivariable models adjusted for

  • age,
  • sex,
  • systolic blood pressure,
  • use of antihypertensive therapy,
  • total and high-density lipoprotein cholesterol concentrations,
  • smoking, and
  • presence of diabetes mellitus,

Higher aortic PWV was associated with a 48% increase in

  • cardiovascular disease risk
    (95% confidence interval, 1.16 to 1.91 per SD; P0.002).

After PWV was added to a standard risk factor model,

  • integrated discrimination improvement was 0.7%
    (95% confidence interval, 0.05% to 1.3%; P < 0.05).

In contrast, AI, CPP, and PPA were not related to

  • cardiovascular disease outcomes in multivariable models.

(1) Higher aortic stiffness assessed by PWV is associated with

  • increased risk for a first cardiovascular event.

(2) Aortic PWV improves risk prediction when added to standard risk factors

  • and may represent a valuable biomarker of CVD risk in the community. (6)

1. Engineered arterial models to correlate blood flow to tissue biological response. J Martorell, P Santoma, JJ Molins,
AA Garcıa-Granada, JA Bea, et al.  Ann NY Acad Sci 2012: 1254:51–56. (Issue: Evolving Challenges in Promoting
Cardiovascular Health)    http://dx.doi.org/10.1111/j.1749-6632.2012.06518.x

2.  Vascular Tissue Engineering. Designer Arteries. Elazer R. Edelman. Circ Res. 1999; 85:1115-1117
http://www.circresaha.org  http://dx.doi.org/10.1161/01.RES.85.12

3.  Tissue-engineered endothelial and epithelial implants differentially and synergistically regulate airway repair.
BG Zani, K Kojima, CA Vacanti, and ER Edelman.   PNAS 13, 2008; 105(19):7046–7051.
http://www.pnas.org/cgi/doi/10.1073/pnas.0802463105

4.  The role of scaffold microarchitecture in engineering endothelial cell immunomodulation.
L Indolfi, AB Baker, ER Edelman. Biomaterials 2012; http://dx.doi.org/10.1016/j.biomaterials.2012.06.052

5.  Essential and Unexpected Role of Yin Yang 1 to Promote Mesodermal Cardiac Differentiation. S Gregoire, R Karra,
D Passer, Marcus-André Deutsch, et al.  Circ Res. 2013;112:900-910. http://dx.doi.org/10.1161/CIRCRESAHA.113.259259
http://circres.ahajournals.org/doi:10.1161/CIRCRESAHA.113.259259

6.  Arterial Stiffness and Cardiovascular Events. The Framingham Heart Study.
GF Mitchell, Shih-Jen Hwang, RS Vasan, MG Larson, et al.  Circulation. 2010;121:505-511.
http://circ.ahajournals.org/doi/10.1161/CIRCULATIONAHA.109.886655

Cardiology Diagnosis of ACS and Stents – 2012

The Year in Cardiology 2012: Acute Coronary Syndromes.

Nick E.J. West      http://www.medscape.com/viewarticle/779039

The European Society of Cardiology (ESC) produced updated guidance on management of STEMI in 2012.
It also produced a third version of the Universal Definition of Myocardial Infarction.
The importance of early diagnosis is stressed, with first ECG in patients

  • with suspected STEMI recommended within 10 min of first medical contact (FMC)
  • and primary percutaneous coronary intervention (PPCI) for STEMI
  • ideally within 90 min (rated ‘acceptable’ out to a maximum of 120 min).

The guidance highlights the importance of collaborative networks

  • to facilitate achievement of such targets.
  • the importance of prompt assessment
  • management of atypical presentations not always considered under the umbrella of STEMI, including
    • left bundle branch block (LBBB),
    • paced rhythms, and
    • isolated ST-segment elevation in lead aVR,

especially when accompanied by symptoms consistent with myocardial ischaemia.

Therapeutic hypothermia is now recommended for

  • all resuscitated patients with STEMI complicated by cardiac arrest
  •  immediate coronary angiography with a view to follow-on PPCI
  • when the ECG demonstrates persistent ST-segment elevation.

In the light of recently published studies and meta-analyses,

  • including that of Kalesan et al., drug-eluting stents (DES) are
  • now routinely preferred to bare metal stents (BMS) in view of
  • the reduced need for repeat revascularization and the lack of
  • previously perceived hazard for stent thrombosis.

The more potent antiplatelet agents prasugrel and ticagrelor are also preferred

  • to clopidogrel for all STEMI cases, with duration of dual antiplatelet therapy (DAPT)
  • ideally for 1 year, but reduced to a strict
  • minimum of 6 months for patients receiving DES.

The Third Universal Definition of Myocardial Infarction was published
simultaneously with the STEMI guidance. This guideline endorses

  • cardiac troponin as the biomarker of choice to detect myocardial necrosis
  • with spontaneously occurring myocardial infarction (MI) defined as an
  • elevation above the 99th percentile upper reference value for the assay.

There is further development and clarification of MI in different settings

  • to allow standardization across trials and registries

in particular after revascularization procedures: after CABG with normal baseline troponin

  • MI is defined as a rise to a value 10 times greater than baseline in the first 48 h, and
  • a rise to 5 times greater than 99th percentile upper reference after PCI

in patients with a normal baseline level (or a 20% rise when troponin is elevated and stable or falling pre-procedure).

ACCF/AHA  updated guidance on the management of unstable angina/non-STEMI:

angiography with a view to revascularization

  • is now recommended within 12–24 h of presentation, with
  • DAPT pre-loading prior to PCI procedures also now advocated.

Ticagrelor and prasugrel are cited as acceptable alternatives to clopidogrel.
The maintenance dose of aspirin recommended for the majority of cases is 81 mg daily.
This guideline brings about transatlantic agreement in most areas.

Risk Stratification

Identification and appropriate triage of patients presenting to emergency departments
with acute chest pain remains a difficult dilemma:

  • many are low-risk and have a non-cardiac origin
  • a significant minority with coronary artery disease may not be picked up
    on clinical grounds even when accompanied by appropriate tests,

    • including ECG and biomarker estimation used in conjunction
    • with a clinical risk score (e.g. GRACE, TIMI).

As endorsed in ESC guidance, there has been increasing interest in

  • non-typical ECG patterns for the diagnosis of STEMI; although LBBB is
  • an accepted surrogate

Widimsky et al.  retrospectively analysed 6742 patients admitted to hospital with acute MI

  • in patients presenting with right bundle branch block, a blocked epicardial vessel was
  • more common (51.7 vs. 39.4%; P < 0.001) and incidence of both shock and mortality
  • comparable with LBBB (14.3 vs. 13.1%; P = NS; and 15.8 vs. 15.4%; P = NS, respectively).

Wong et al. demonstrated the importance of ST-elevation in lead aVR,

  • often viewed as indicative of left main stem occlusion, having increased mortality
  • in patients presenting with both inferior and anterior infarction.

Perhaps the most important data regarding the ECG in 2012 were also the most simple:

  • Antoni et al. highlighted a powerful and very simple method of risk stratification;
  •  heart rate measured on a 12-lead ECG at discharge after Primary PCI (PPCI) is an
  • independent predictor of mortality at 1 and 4 years of follow-up.

Patients with a discharge heart rate of ≥70 b.p.m. had a two-fold higher mortality at both follow-up
time points, with every increase of 5 b.p.m. in heart rate

  • equating to a 29% increase in mortality at 1 year and 24% at 5 years.

These findings have important implications for the optimization of patient therapies after MI (including the use of
rate-limiting agents such as beta-blockers, calcium channel-blockers, and ivabradine), although large randomized
trials are needed to confirm that

  • interventions to reduce heart rate will replicate the benefits observed in this study.

http://img.medscape.com/article/779/039/779039-thumb1.png

Figure 1.  Kaplan–Meier time-to-event plots for heart rate at discharge divided by quartiles and all-cause mortality
(A and C) and cardiovascular mortality (B and D) at 1-year (A and B) and 4-year (C and D) follow-up,
demonstrating relationship between discharge heart rate and mortality after PPCI for STEMI.
Modified from Antoni et al.

Coronary Intervention and Cardioprotection in Acute Coronary Syndromes

Microvascular obstruction during PCI for ACS/STEMI is associated with increased infarct size and adverse prognosis;
its pathophysiology is thought to be a combination of

  • mechanical distal embolization of thrombus and plaque constituents during PCI,  coupled with
  • enhanced constriction/hyperreactivity of the distal vascular bed.

The most novel Strategy to Reduce Infarct Size

is the use of a Bare Metal Stent (BMS) covered on its outer surface with a mesh micronet designed to
trap and hold potentially friable material that might embolize distally at the time of PCI.

The MASTER study randomized 433 STEMI patients to PPCI

  • with conventional BMS or DES at the operator’s discretion vs.
  • the novel MGuard stent (InspireMD, Tel Aviv, Israel);

the primary endpoint of complete ST-segment resolution was better

  • in patients receiving MGuard (57.85 vs. 44.7%; P = 0.008), as was
  • the achievement of TIMI grade 3 flow in the treated vessel (91.7 vs. 82.9%; P = 0.006).

Nevertheless, median ST-segment resolution did not differ

  • between treatment groups,
  • myocardial blush grade was no different, and
  • safety outcomes at 30 days (death, adverse events) as well as
  • overall MRI-determined infarct mass.

Higher TVR rates may accrue with a BMS platform when compared with

  • current-generation DES (as now endorsed for PPCI in ESC guidance).

In comparing the four studies in cardioprotection, there remains little to choose between strategies as evidenced by

  • the relatively minor differences between surrogate endpoints employed regardless of
  • therapeutic intervention chosen (Figure 2).

http://img.medscape.com/article/779/039/779039-fig2.jpg

Figure 2.  Comparison of study endpoints for reduction in infarct size in STEMI.
Study endpoints listed on the x-axis. STR, ST-segment resolution; TIMI 3, thrombolysis in
myocardial infarction grade 3 antegrade flow; myocardial blush grade 2/3 (MBG 2/3).

Recent advances in

  • PCI equipment,
  • peri-procedural pharmacology,
  • technique, and safety, as well as
  • convergence of national guidance,

are leading to the point where

  • even in the highest risk patients such as those presenting with ACS, small improvements
  • may be difficult to discern despite large well-designed and -conducted studies.

References

  1. a. The Task Force on the management of ST-segment elevation acute myocardial infarction
    of the European Society of Cardiology. ESC guidelines for the management of acute
    myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J
    2012;33:2569–2619.  b. Management of acute myocardial infarction in patients presenting
    with ST-segment elevation. The Task Force on the Management of Acute Myocardial
    Infarction of the European Society of Cardiology.  Eur Heart J 2003; 24 (1): 28-66.
    http://dx.doi.org/10.1093/eurheartj/ehs215
  2. ESC Guidelines for the management of acute coronary syndromes in patients presenting
    without persistent ST-segment elevation: The Task Force for the management of acute
    coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation
    of the European Society of Cardiology (ESC).  http://dx.doi.org/10.1093/eurheartj/ehr236
  3. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BS, White HD. The Writing Group on
    behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of
    Myocardial Infarction. Third universal definition of myocardial infarction.
    Eur Heart J 2012;33:2551–2567.  http://dx.doi.org/10.1093/eurheartj/ehm355
  4. Kalesan B, Pilgrim T, Heinimann K, Raber L, Stefanini GG, et al. Comparison of drug-eluting
    stents with bare metal stents in patients with ST-segment elevation myocardial infarction.
    Eur Heart 2012;33:977–987.
  5. Jneid H, Anderson JL, Wright RS, Adams CS, et al. 2012 ACCF/AHA Focused Update of the
    Guideline for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial
    Infraction (Updating the 2007 Guideline and Replacing the 2011 Focused Update). A Report
    of the American College of CardiologyFoundation/American Heart Association Task Force
    on Practice Guidelines. J Am Coll Cardiol 2012;60:645–681.
  6. Widimsky P, Rohác F, Stásek J, Kala P, Rokyta R, et al. Primary angioplasty in acute myocardial
    infarction with right bundle branch block: should new onset right bundle branch block be added
    to future guidelines as an indication for reperfusion therapy? Eur HeartJ 2012;33:86–95.
  7. Wong CK, Gao W, Stewart RA, French JK, and the HERO-2 Investigators. The prognostic meaning of
    the full spectrum of aVR ST-segment changes in acute myocardial infarction.
    Eur Heart J 2012;33:384–392.
  8. Antoni L, Boden H, Delgado V, Boersma E, et al. Relationship between discharge heart rate and mortality
    in patients after myocardial infarction treated with primary percutaneous coronary intervention.
    Eur Heart J 2012;33:96–102.
  9. Stone GW, Abizaid A, Silber S, Dizon JM, Merkely B, et al. Prospective, randomised, multicenter evaluation
    of a polyethylene terephthalate micronet mesh-covered stent (MGuard) in ST-segment elevation myocardial
    infarction. The MASTER Trial. J Am Coll Cardiol. doi:pii:S0735-1097(12)04506-8. 10.1016/j.jacc.2012.09.004. 
  10. Zhou C, Yao Y, Zheng Z, Gong J, Wang W, Hu S, Li L. Stenting technique, gender, and age are associated with
    cardioprotection by ischaemic postconditioning in primary coronary intervention: a systematic review of
    10 randomized trials. Eur Heart J 2012;33:3070–3077.

Resistant Hypertension.

Robert M. Carey.
Hypertension. 2013;61:746-750.  http://dx.doi.org/10.1161/HYPERTENSIONAHA.111.00601

Resistant hypertension is defined as failure to achieve goal blood pressure (BP) <140/90 mm Hg
(or <130/80 mm Hg in patients with diabetes mellitus or chronic kidney disease) in patients with

  • hypertension who are compliant with maximum tolerated doses of an appropriate antihypertensive drug regimen consisting of a minimum of 3 agents of different classes, including a diuretic.
  • Patients who meet the criteria for resistant hypertension but whose BP can be controlled on maximum tolerated
    doses of ≥4 antihypertensive agents are classified as having controlled resistant hypertension.

Although the number of failed antihypertensive drugs required for the classification of resistant hypertension is arbitrary,

  • this diagnosis identifies patients at high risk for having a potentially curable form of hypertension, and
  • those who may benefit from specific therapeutic approaches to lower BP.

Summary

The first portion of this document shows the impact that ER Edelman and his peers have had in the development
of interventional cardiology, and in carrying out studies to test, validate, or reject assumptions about the interaction of
biomaterials with

  • vascular and smooth muscle tissue in the repair of injured vessels, by
  1. trauma
  2. inflammatory injury
  3. stent placement.

In the second portion of this discussion, I introduce current views about complications in implanted devices, evolving
standards, and the current definitions of stable, unstable, and previously unclassified ACS risk.

Pushing Drug-Eluting Stents Into Uncharted Territory

Simpler Than You Think—More Complex Than You Imagine

Campbell Rogers, MD; Elazer R. Edelman, MD, PhD.  Circulation 2006; 113: 2262-2265.
http://dx.doi.org/10.1161/​CIRCULATIONAHA.106.623470

Mechanical failure is a characteristic of a material or a device and not necessarily an indication of inadequacy. All devices
will fail under some specific stress. It is only failure at the lowest levels of stress that may represent inadequacy. Stress on
a material, for example, rises with strain until a critical load is exceeded, at which point the material fatigues and loses
mechanical integrity. Failure analysis, the science by which these conditions are rigorously defined, is an important
component of device design, development, and use. Once the transition point to failure is identified, material use can be
restricted to the zone of safety or modified so as to have this zone expanded. Just as the characterization of a material is
incomplete unless pushed to the limits of load bearing, characterization of an implantable device is incomplete unlesspreclinical and clinical environments test the limits of device functionality. It was in this light in 1999 that the Authors noted the impossibility of defining the functional limits of novel bare metal stents in head-to-head trials, which, by necessity, could only include lesions into which the predicate device (the Palmaz-Schatz stent, Cordis, Warren, NJ) could have be placed.

New School Percutaneous Interventions

Over the past 5 years, the number of percutaneous interventions has grown by 40%. This expansion derives from an
increased breadth of cases, as percutaneous interventions are now routinely performed in diabetic, small-vessel, multilesion,diffuse disease, and acute coronary syndrome settings. Contemporaneously, widespread adoption of drug-eluting stents has emboldened clinicians and provided greater security in the use of these devices in lesions or patients previously thought to

Head-to-head randomized trial data have accumulated so that analysis may demonstrate differences among drug-eluting stents. The playing field for prospective randomized trials could enhance the weight of evidence to unanswered questions about what underlying factors determine device failure.

Complexity Simplified

Drug-eluting stent “failure” can be defined operationally in the same way as material failure:

  • inadequate function in the setting of a given load or strain.

The inability to withstand stress may take many forms that can change over time. Failure may be manifest acutely as

  • the inability to deliver a stent to the desired location,
  • subacutely as stent thrombosis or
  • postprocedural myonecrosis, and later as
  • restenosis

“Simple lesions” are those in which few devices should fail;“Complex” lesions have a heightened risk of failure. To be of value, each scale of advancing complexity must provoke higher failure rates.  For any device may fail sooner than another along one such “complexity” scale and later along another. As advanced drug-eluting stent designs have enhanced deliverability and reduced restenosis rates, 7 randomized trials comparing directly the two Food and Drug Administration (FDA)-approved drug-eluting stents, Cypher (Cordis-Johnson and Johnson) and Taxus (Boston Scientific, Boston, Mass), have been reported.  These trials report a broad range of restenotic failure as evidenced by the need for revascularization. Across these trials, driven by a variety of factors, revascularization rates vary quite widely.

The clinical end point of target lesion revascularization (TLR) becomes

  • a single measure of device failure.

When the 7 trials are depicted in order of increasing TLR, the rate of failure increases more slowly with 1 device than
the other.  This gives two regression plots for Taxus vs Cypher with different slopes, as complexity increases, and the

  • separation between the failure rates of the two devices broadens plotted against “degree of complexity” assigned by the  slopes of the lines.

Finally, the correlation between TLR rates for Taxus and Cypher stents indicates that trial-specific events and conditions determined TLR (with a sharp slope of Taxus vs Cypher (r-sq = 0.85).  The ratio of TLR (the slope) wasgreater than 3, suggesting that although both devices are subject to increasing failure as complexity increases,

  • one device becomes ever-more likely than the other to fail when applied in settings with ever-higher TLR risk.

In other words, composite medical devices with a wide range of

  • structural,
  • geometric, and
  • pharmacological differences
    • can be shown to produce different clinical effects
    • as the environments in which they are tested become increasingly complex.

What the Individual Trials Cannot Tell Us

The progressive difference between the performances of the 2 FDA-approved drug-eluting stents as they are pushed into
more complex settings is precisely what one would anticipate from medical devices with different performance signatures.
Most randomized trials, even if they include high complexity, are unable to identify predictors of failure because of the low numbers of patients enrolled, and the problem gets worse as the number of subsets increase. Consequently, device development, and clinical practice, knowing which patient or lesion characteristics confer higher failure rates is critical.
This analysis has centered on restenosis. Other failure modes to be considered are

  • stent thrombosis,
  • postprocedural myonecrosis
  • late plaque rupture
  • vascular disease away from the site
  • heightened inflammatory reaction
    • are no less critical and may be determined by
    • completely different device or patient characteristics.

Well-executed registry or pooled data

It is in this light that the registry report of Kastrati et al. in the current issue of Circulation is of greatest value. There are
two ways in which well-executed registry or pooled data can be most complementary to randomized trials.

First, large numbers of patients provide a higher incidence of rare failure modes as well as allow more granular determination of lesion- or patient-specific predictors of failure (meta-analysis or better, combined data file). A pooled analysis of several head-to-head randomized bare metal stent trials allowed identification of clear risk factors for stent thrombosis that had eluded analysis of the individual (smaller) trials.

Second, registry or pooled data may incorporate a broader range of patient characteristics, allowing greater discrimination between devices. The report of Kastrati et al may fall into this category as well, as it includes “high risk” populations from several randomized trials. They report on more than 2000 lesions in 1845 patients treated with either Taxus or Cypher drug-eluting stents at two hospitals.  The study population is from a series of randomized trials comparing Taxus and Cypher stents.   Using multivariate analysis to identify what lesion and patient characteristics predict failure (restenosis), they identified risk factors that included

  • prior history of coronary bypass surgery
  • calcification
  • smaller vessel size
  • greater degree of prestent and poststent stenosis.

Use of a Cypher rather than Taxus stent was independently associated with lower restenosis risk.

An interesting negative finding was the absence of diabetes as a significant predictor, at odds with strong suggestions from several other analyses. A better understanding from preclinical or clinical studies of the effect of diabetic states on restenosis is critical.

Author’s opinion voiced:

This Author (LHB), considers the study underpowered to answer that question because of further partitioning with several variables. Pooled data with

  • rigorous ascertainment and
  • careful statistical methodology, taken
  • together with randomized trial data, open a door to device choice based on the knowledge that risk of failure (complexity) does vary, and
  • the higher the complexity, the greater the incremental benefit of choosing one device over another.

A decision algorithm is therefore possible, whereby multiple failure modes and risk factors are weighed, and

  • an optimum stent choice made which balances
  • safety and efficacy based on the totality of evidence, rather than anecdote and loose comparisons of disparate subgroups from individual trials.

Evaluating Clinical Trials

The subject of trial(s) is difficult… the aim and meaning of all the trials… is

  • to let people know what they ought to do or what they must believe

It was perhaps naïve to imagine that devices as different one from another as the two current FDA-approved drug-eluting
stents would produce identical clinical results. If so, it ought not to come as a surprise that head-to-head randomized trial
data from many different countries in complex settings are now indicating just how differently the 2 devices may perform.

Future trials should be designed and evaluated to examine why these differences exist. Trials residing
only in previous safety and complexity domains

  • are unlikely to offer deeper insights into
    1. device performance,
    2. patient care decisions, or
    3. discrimination of alternative therapies.

We look forward to more trials that will examine what we currently believe to be the limits of

  • drug-eluting stents and interventional cardiology and to

help define in simple terms differences

  • between complex devices applied to complex problems.

This 2009 article was an excellent demonstration of comparing two commonly used coated-stents, and then extending the argument to the need for more data to further delineated the factors that explain the differences they found. In the previous article, the SECOND in the three article series,  Stents and Drug Delivery

Vascular Repair: Stents and Biologically Active Implants

we concentrated on stents and drug delivery, and not on stent failure.  But the following article in J Control Release,

was published the following year, and is another example of this method of explanatory approach to the problem.

Lesion Complexity Determines Arterial Drug Distribution After Local Drug Delivery

AR Tzafriri,  N Vukmirovic, VB Kolachalama, I Astafieva, ER Edelman. J Control Release. 2010; 142(3): 332–338.
http://:dx. doi:.org/10.1016/j.jconrel.2009.11.007       PMCID: PMC2994187

Local drug delivery from endovascular stents has transformed how we treat coronary artery disease. Yet, few drugs are in fact effective when delivered from endovascular implants and those that possess a narrow therapeutic window. The width of this window is predicated to a great degree upon the extent of drug deposition and distribution through the arterial wall.

  • Drugs that are retained within the blood vessel are far more effective than those that are not.

Thus, for example, heparin regulates virtually every aspect of the vascular response to injury, but it is so soluble and diffusible that it simply cannot stay in the artery for more than minutes after release.

  • Heparin has no effect on intimal hyperplasia when eluted from a stent.
  • Paclitaxel and sirolimus in contradistinction are far smaller compounds with perhaps more narrow and specific effects than heparin.

These drugs bind tenaciously to tissue protein elements and specific intracellular targets and remain beneath stent struts long after release.

The clinical efficacy of paclitaxel and sirolimus at reducing coronary artery restenosis rates following elution from stents appears incontrovertible. Emerging clinical and preclinical data suggest that the benefit of the local release of these drugs is beset by significant complications, that rise with lesion complexity as

  • the native composition and layered ultrastructure of the native artery is more significantly disrupted.

Virmani and others have hypothesized that the attraction of lipophilic drugs like paclitaxel and sirolimus to fat should affect their retention within and effects upon atheromatous lesions.

Though stents are deployed in diseased arteries drug distribution has only been quantified in intact, non-diseased vessels.

Authors @ MIT, correlated steady-state arterial drug distribution with tissue ultrastructure and composition in abdominal aortae from atherosclerotic human autopsy specimens and rabbits

  • with lesions induced by dietary manipulation and controlled injury.

Drug and compositional metrics were quantified and correlated at a compartmental level, in each of the tunica layers, or at an intra-compartmental level. All images were processed to

  • eliminate backgrounds and artifacts, and
  • pixel values between thresholds were extracted for all zones of interest.

Specific algorithms analyzed each of the histo/immuno-stained arterial structures. Intra-compartmental analyses were

  • performed by sub-dividing arterial cross-sections into 2–64 equal sectors and
  • evaluating the pixel-average luminosity for each sector.

Linear regression of drug versus compositional luminosities asymptotically approached steady state after subdivision into 16 sectors. This system controlled delivered dose and removed the significant unpredictability in release that is imposed by variability

  • in stent position relative to the arterial wall,
  • inflation techniques and stent geometry.
As steady state tissue distribution results were obtained under constant source conditions, without washout by flowing blood,
  • they constitute upper bounds for arterial drug distribution
  • following transient modes of in vivo drug delivery wherein
  • only a fraction of the eluted dose is absorbed by the artery

Paclitaxel, everolimus, and sirolimus deposition in human aortae was maximal in the media and scaled inversely with lipid content.

Net tissue paclitaxel and everolimus levels were indistinguishable in mildly injured rabbit arteries independent of diet. Yet, serial sectioning of cryopreserved arterial segments demonstrated

  • a differential transmural deposition pattern that was amplified with disease and
  • correlated with expression of their intracellular targets, tubulin and FKBP-12.

Tubulin distribution and paclitaxel binding increased with

  • vascular injury and macrophage infiltration, and
  • were reduced with (reduced) lipid content.

Sirolimus analogues and their specific binding target FKBP-12 were less sensitive to alterations of diet
in mildly injured arteries, presumably reflecting a faster transient response of FKBP-12 to injury.

The idea that drug deposition after balloon inflation and stent implantation within diseased, atheromatous and sclerotic vessels tracks so precisely with specific tissue elements is

  • an important consideration of drug-eluting technologies and
  • may well require that we consider diseased rather than naïve tissues in preclinical evaluations.

Another publication in the same year reveals the immense analytical power used in understanding the complexities
of drug-eluting stents.

Luminal Flow Amplifies Stent-Based Drug Deposition in Arterial Bifurcations

Kolachalama VB, Levine EG, Edelman ER.    PLoS ONE 2009; 4(12): e8105.
 http://dx.doi.org/10.1371/journal.pone.0008105

Treatment of arterial bifurcation lesions using drug-eluting stents (DES) is now common clinical practice.
Arterial drug distribution patterns become challenging to analyze if the lesion involves more than a vessel
such as in the case of bifurcations.  As use extends to nonstraightforward lesions and complex geometries,
questions abound

  • regarding DES longevity and safety

Indeed, there is no consensus on best stent placement scenario, no understanding as to

  • whether DES will behave in bifurcations as they do in straight segments, and
  • whether drug from a main-branch (MB) stent can be deposited within a side-branch (SB).

It is not evident how to

  • efficiently determine the efficacy of local drug delivery and
  • quantify zones of excessive drug that are
  • harbingers of vascular toxicity and thrombosis,
  • and areas of depletion that are associated
  • with tissue overgrowth and
  • luminal re-narrowing.

Geometry modeling and governing equations

Authors @MIT constructed two-phase computational models of stent-deployed arterial bifurcations

  • simulating blood flow and drug transport to investigate the
  • factors modulating drug distribution when the main-branch (MB) was treated using a DES.

The framework for constructing physiologically realistic three dimensional computational models of single
and bifurcated arterial vessels was SolidWorks (Dassault Systemes) (Figs. 1A–1B, Movie S1). The geometry
generation algorithm allowed for controlled alteration of several parameters including

  • stent location
  • strut dimensions
  • stent-cell shape
  • lumen diameter to arterial tissue thickness ratio
  • lengths of the arterial branches
  • extent of stent apposition and
  • the bifurcation angle.

For the current study, equal lengths (2LS) were assumed for the proximal and distal sections of the MB from the bifurcation. The SB was constructed at an angle of 300. The inlet conditions were based on

  • mean blood flow and
  • diameter measurements

obtained from human left anterior descending coronary artery (LAD).

The diameter of the lumen (DMB) and thickness (TMB) for the MB were defined such that DMB=TMB~10 and

  • this ratio was also maintained for the SB.

Schematics of the computational models used for the study. A stent of length LS is placed at the upstream section of the arterial vessel in the (A) absence and in the (B) presence of a bifurcation, respectively.

  • Insets in (B) denote delta wing stent design (i),
  • strut thickness (d) (ii), and
  • the outlets of the side-branch in (iii) and
  • and the main-branch in (iv).

A delta wing-shaped cell design belonging to the class of slotted-tube stents was used for all simulations.
The length (LS) and diameter (DS) were

  • fixed at 9|10-2 m and 3|10-2 m, respectively, for the MB stent.

All stents were assumed to be perfectly apposed to the lumen of MB and the intrinsic strut shape was modeled as

  • square with length 10-4 m.

The continuity and momentum equations were solved within the arterial lumen, where

vf , rho~1060 kg=m3, P and m are

  • velocity
  • density
  • pressure and the
  • viscosity of blood.

In order to capture boundary layer effects at the lumen-wall (or mural) surface, a Carreau model was employed for

  • all the simulations to account for shear thinning behavior of blood at low shear rates

In the arterial lumen, drug transport followed advection-diffusion process.  Similar to the momentum transport in the arterial lumen, the continuity equation was solved within the arterial wall by assuming it as a porous medium.

A finite volume solver (Fluent, ANSYS Inc.) was utilized to perform the coupled flow and drug transport simulations. The semi-implicit method for pressure-linked equations-consistent (SIMPLEC) algorithm was used with second order spatial accuracy. A second order discretization scheme was used to solve the pressure equation and second order  upwind schemes were used for the momentum and concentration variables.

Simulations for each case were performed

  • for at least 2500 iterations or
  • until there was a 1028 reduction in the mass transport residual.

Drug distribution in non-bifurcating vessels

Constant flow simulations generate local recirculation zones juxtaposed to the stent which in turn act as

  • secondary sources of drug deposition and
  • induce an asymmetric tissue drug distribution profile in the longitudinal flow direction.

Our3D computational model predicts a far more extensive fluid mechanic effect on drug deposition than previously appreciated in two-dimensional (2D) domains.

Within the stented region, drug deposition on the mural interface quantified as

  • the area-weighted average drug concentration (AWAC)
  • in the distal segment of the stent is 12% higher than the proximal segment

Total drug uptake in the arterial wall denote as volume-weighted average concentration (VWAC) is highest in the middle segment of the stent and 5% higher than the proximal stent region

Increased mural drug deposition along the flow direction in a non-bifurcating arterial vessel.

Inset shows a high magnification image of drug pattern in the distal stent segment outlined by black dashed line.
The entire stent is divided into three equal sections denoted as proximal, middle and distal sections, respectively
and the same notation is followed for subsequent analyses.

http://dx.doi.org/10.1371/journal.pone.0008105.g002

These observations indicate that the flow-mediated effect induced by the presence of the stent in the artery

  • is maximal on the mural surface and
  • increases in the longitudinal flow direction.

Further, these results suggest that transmural diffusion-mediated transport sequesters drug from both

  • the proximal and distal portions of the stent
  • into the central segment of the arterial wall beneath the stent.

Predicted levels of average drug concentration varied exponentially

  • with linear increments of inlet flow rate

but maintained similar relationship between the inter-segment concentration levels within the stented region.

Stent position influences drug distribution in bifurcated beds

The location of the stent directly modulates

  • the extent to which drug is deposited on the arterial wall as well as
  • spatial gradients that are established in arterial drug distribution.

Similar to the non-bifurcating vessel case,

  • peaks in drug deposition occur directly beneath the stent struts regardless of the relative location of the SB with respect to the stent. However,
  • drug distribution and corresponding spatial heterogeneity within inter-strut regions depend on the stent location with respect to the flow divider.
  • Mural drug deposition is a function of relative stent position with respect to the side-branch and Reynolds number in arterial bifurcations.

Impact of flow on drug distribution in bifurcations

One can appreciate how blood flow and flow dividers affect arterial drug deposition, and especially on inter-strut drug deposition.

  • Drug deposition within the stented-region of MB  and the entire SB significantly decreases with flow acceleration regardless of stent placement.

Simulations predicted

Local endovascular drug delivery was long assumed to be governed by diffusion alone. The impact of flow was
thought to be restricted to systemic dilution.

  • 2D computational models suggested a complex interplay between the stent and blood flow
  1. Arterial drug deposition is a function of stent location.   http://dx.doi.org/10.1371/journal.pone.0008105.g005
  2. Arterial drug deposition is mediated by flow in bifurcated beds.
    http://dx.doi.org/10.1371/journal.pone.0008105.g006
  • extensive flow-mediated drug delivery in bifurcated vascular beds where the drug distribution patterns are heterogeneous and sensitive to relative stent position and luminal flow.

A single DES in the MB coupled with large retrograde luminal flow on the lateral wall of the side-branch (SB) can provide drug deposition on the SB lumen-wall interface, except

  • when the MB stent is downstream of the SB flow divider.
  • the presence of the SB affects drug distribution in the stented MB.

Fluid mechanic effects play an even greater role than in the SB

  • especially when the DES is across and downstream to the flow divider
  • and in a manner dependent upon

    the Reynolds number.

Summary

We presented the hemodynamic effects on drug distribution patterns using a

  • simplified uniform-cell stent design, though our methodology is adaptable to
    several types of stents with variable design features.

Variability in arterial drug distribution due to other geometric and morphologic aspects such as

  • bifurcation angle, arterial taper as well as presence of a trifurcation can also be understood using our computational framework.

Further, performance of a candidate DES using other commonly used stenting procedures for bifurcation lesions such as culotte and crush techniques can be quantified based on their resulting drug distribution patterns.

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Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production

Aviva Lev-Ari, PhD, RN 7/19/2012

http://pharmaceuticalintelligence.com/2012/07/19/cardiovascular-disease-cvd-and-the-role-of-agent-alternatives-in-endothelial-nitric-oxide-synthase-enos-activation-and-nitric-oxide-production/

Resident-cell-based Therapy in Human Ischaemic Heart Disease: Evolution in the PROMISE of Thymosin beta4 for Cardiac Repair

Aviva Lev-Ari, PhD, RN 4/30/2012

http://pharmaceuticalintelligence.com/2012/04/30/93/

Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes

Aviva Lev-Ari, PhD, RN 5/29/2012

http://pharmaceuticalintelligence.com/2012/05/29/445/

Macrovascular Disease – Therapeutic Potential of cEPCs: Reduction Methods for CV Risk

Aviva Lev-Ari, PhD, RN 7/2/2012

http://pharmaceuticalintelligence.com/2012/07/02/macrovascular-disease-therapeutic-potential-of-cepcs-reduction-methods-for-cv-risk/

Mitochondria Dysfunction and Cardiovascular Disease – Mitochondria: More than just the “powerhouse of the cell”

Aviva Lev-Ari, PhD, RN 7/9/2012

http://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/

Bystolic’s generic Nebivolol – positive effect on circulating Endothelial Proginetor Cells endogenous augmentation

Aviva Lev-Ari, PhD, RN 7/16/2012

http://pharmaceuticalintelligence.com/2012/07/16/bystolics-generic-nebivolol-positive-effect-on-circulating-endothilial-progrnetor-cells-endogenous-augmentation/

Arteriogenesis and Cardiac Repair: Two Biomaterials – Injectable Thymosin beta4 and Myocardial Matrix Hydrogel

Aviva Lev-Ari, PhD, RN 2/27/2013

http://pharmaceuticalintelligence.com/2013/02/27/arteriogenesis-and-cardiac-repair-two-biomaterials-injectable-thymosin-beta4-and-myocardial-matrix-hydrogel/

Cardiac Surgery Theatre in China vs. in the US: Cardiac Repair Procedures, Medical Devices in Use, Technology in Hospitals, Surgeons’ Training and Cardiac Disease Severity”

Aviva Lev-Ari, PhD, RN 1/8/2013

http://pharmaceuticalintelligence.com/2013/01/08/cardiac-surgery-theatre-in-china-vs-in-the-us-cardiac-repair-procedures-medical-devices-in-use-technology-in-hospitals-surgeons-training-and-cardiac-disease-severity/

Heart Remodeling by Design – Implantable Synchronized Cardiac Assist Device: Abiomed’s Symphony

Aviva Lev-Ari, PhD, RN 7/23/2012

http://pharmaceuticalintelligence.com/2012/07/23/heart-remodeling-by-design-implantable-synchronized-cardiac-assist-device-abiomeds-symphony/

Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI

Aviva Lev-Ari, PhD, RN 3/10/2013

http://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/

Dilated Cardiomyopathy: Decisions on implantable cardioverter-defibrillators (ICDs) using left ventricular ejection fraction (LVEF) and Midwall Fibrosis: Decisions on Replacement using late gadolinium enhancement cardiovascular MR (LGE-CMR)

Aviva Lev-Ari, PhD, RN 3/10/2013
http://pharmaceuticalintelligence.com/2013/03/10/dilated-cardiomyopathy-decisions-on-implantable-cardioverter-defibrillators-icds-using-left-ventricular-ejection-fraction-lvef-and-midwall-fibrosis-decisions-on-replacement-using-late-gadolinium/

The Heart: Vasculature Protection – A Concept-based Pharmacological Therapy including THYMOSIN

Aviva Lev-Ari, PhD, RN 2/28/2013
http://pharmaceuticalintelligence.com/2013/02/28/the-heart-vasculature-protection-a-concept-based-pharmacological-therapy-including-thymosin/

FDA Pending 510(k) for The Latest Cardiovascular Imaging Technology

Aviva Lev-Ari, PhD, RN 1/28/2013
http://pharmaceuticalintelligence.com/2013/01/28/fda-pending-510k-for-the-latest-cardiovascular-imaging-technology/

PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity

Aviva Lev-Ari, PhD, RN 1/10/2013
http://pharmaceuticalintelligence.com/2013/01/10/pci-outcomes-increased-ischemic-risk-associated-with-elevated-plasma-fibrinogen-not-platelet-reactivity/

The ACUITY-PCI score: Will it Replace Four Established Risk Scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX

Aviva Lev-Ari, PhD, RN 1/3/2013
http://pharmaceuticalintelligence.com/2013/01/03/the-acuity-pci-score-will-it-replace-four-established-risk-scores-timi-grace-syntax-and-clinical-syntax/

Coronary artery disease in symptomatic patients referred for coronary angiography: Predicted by Serum Protein Profiles

Aviva Lev-Ari, PhD, RN 12/29/2012
http://pharmaceuticalintelligence.com/2012/12/29/coronary-artery-disease-in-symptomatic-patients-referred-for-coronary-angiography-predicted-by-serum-protein-profiles/

Heart Renewal by pre-existing Cardiomyocytes: Source of New Heart Cell Growth Discovered

Aviva Lev-Ari, PhD, RN 12/23/2012
http://pharmaceuticalintelligence.com/2012/12/23/heart-renewal-by-pre-existing-cardiomyocytes-source-of-new-heart-cell-growth-discovered/

Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis.

Aviva Lev-Ari, PhD, RN 10/30/2012
http://pharmaceuticalintelligence.com/2012/10/30/cardiovascular-risk-inflammatory-marker-risk-assessment-for-coronary-heart-disease-and-ischemic-stroke-atherosclerosis/

To Stent or Not? A Critical Decision

Aviva Lev-Ari, PhD, RN 10/23/2012
http://pharmaceuticalintelligence.com/2012/10/23/to-stent-or-not-a-critical-decision/

New Definition of MI Unveiled, Fractional Flow Reserve (FFR)CT for Tagging Ischemia

Aviva Lev-Ari, PhD, RN 8/27/2012
http://pharmaceuticalintelligence.com/2012/08/27/new-definition-of-mi-unveiled-fractional-flow-reserve-ffrct-for-tagging-ischemia/

Ethical Considerations in Studying Drug Safety — The Institute of Medicine Report

Aviva Lev-Ari, PhD, RN 8/23/2012
http://pharmaceuticalintelligence.com/2012/08/23/ethical-considerations-in-studying-drug-safety-the-institute-of-medicine-report/

New Drug-Eluting Stent Works Well in STEMI

Aviva Lev-Ari, PhD, RN 8/22/2012
http://pharmaceuticalintelligence.com/2012/08/22/new-drug-eluting-stent-works-well-in-stemi/

Expected New Trends in Cardiology and Cardiovascular Medical Devices

Aviva Lev-Ari, PhD, RN 8/17/2012
http://pharmaceuticalintelligence.com/2012/08/17/expected-new-trends-in-cardiology-and-cardiovascular-medical-devices/

Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents

Aviva Lev-Ari, PhD, RN 8/13/2012

http://pharmaceuticalintelligence.com/2012/08/13/coronary-artery-disease-medical-devices-solutions-from-first-in-man-stent-implantation-via-medical-ethical-dilemmas-to-drug-eluting-stents/

Percutaneous Endocardial Ablation of Scar-Related Ventricular Tachycardia

Aviva Lev-Ari, PhD, RN 7/18/2012

http://pharmaceuticalintelligence.com/2012/07/18/percutaneous-endocardial-ablation-of-scar-related-ventricular-tachycardia/

Competition in the Ecosystem of Medical Devices in Cardiac and Vascular Repair: Heart Valves, Stents, Catheterization Tools and Kits for Open Heart and Minimally Invasive Surgery (MIS)

Aviva Lev-Ari, PhD, RN 6/22/2012

http://pharmaceuticalintelligence.com/2012/06/22/competition-in-the-ecosystem-of-medical-devices-in-cardiac-and-vascular-repair-heart-valves-stents-catheterization-tools-and-kits-for-open-heart-and-minimally-invasive-surgery-mis/

Global Supplier Strategy for Market Penetration & Partnership Options (Niche Suppliers vs. National Leaders) in the Massachusetts Cardiology & Vascular Surgery Tools and Devices Market for Cardiac Operating Rooms and Angioplasty Suites

Aviva Lev-Ari, PhD, RN 6/22/2012

http://pharmaceuticalintelligence.com/2012/06/22/global-supplier-strategy-for-market-penetration-partnership-options-niche-suppliers-vs-national-leaders-in-the-massachusetts-cardiology-vascular-surgery-tools-and-devices-market-for-car/

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Vascular Repair: Stents and Biologically Active Implants

Author and Curator: Larry H Bernstein, MD, FACP
and
Curator: Aviva Lev-Ari, RN, PhD

This is the second article of a three part series recognizing the immense contribution of Elazer Edelman, MD, PhD, and his laboratory group at MIT to vascular biology, cardiovascular disease studies, and the bioengineering, development, and use of stenting technology for drug delivery, vascular repair, and limitation of vessel damage caused by stent placement.

The first article, published on this Open Access Online Scientific Journal
was concerned with vascular biology, and largely on both the impact of drug delivery design and placement on the endothelium of the vessel wall, and on the kinetics of drug delivery based on the location of stent placement versus intravascular injection as well as the metabolic events taking place in the arterial endothelium, intima, and muscularis.
This second article, is concerned with stents and drug delivery as it has evolved since the last decade of the 20th century based on biomaterials development and vascular biology principles to minimize inherent injury risk over this period.
The third. will be concerned with the lessons from biomaterials and stent mechanics going forward.
Heart care is in the midst of a transformation. Patients who once required heart surgery are treated with a stent, catheters for repair of valves, rhythm abnormalities, and a growing number of heart or vascular distrbances.
The catheters are threaded in through the femoral artery, and sometimes through the radial artery. The American College of Cardiology annual meeting highlights research on these devices.  The procedure allows patients to leave the hospital after a day or two post-implant, but the initial cost of the novel devices is high.  Not everyone qualifies for the treatment, and it will take a few years to compare the long term results with the benefits from surgery. But these procedures have allowed many patients treatment alternatives to surgery, and they offer an option for people who cannot be successfully managed by conservative medical therapy.

The effects of stent placement on vascular injury and the initiation of an inflammatory response

Leukocytes are recruited early and abundantly to experimentally injured vessels,

  • in direct proportion to cell proliferation and intimal growth.
Activated circulating leukocytes and Mac-1 (CD11 by CD18, aMb2) (monocytic) expression are
  • markers of restenosis risk in patients undergoing angioplasty.
Angioplastied vessels lack endothelium but have extensive fibrin(ogen) and platelet deposition.  Consequently, Mac-1-dependent adhesion to fibrin(ogen)  would be expected to
  • signal leukocyte recruitment and function, thereby
  • promote intimal growth
In this study
  • M1/70, an anti-CD11b blocking mAb, was  administered to rabbits before, and every 48 hr for 3, 6, or 14 days after iliac artery balloon denudation.
  • M1/70 was bound to isolated rabbit monocytes.

The result was

  • Mac-1-mediated dose-dependent
  • inhibition of fibrinogen binding in vitro, thereby,
  • reducing by half leukocyte recruitment at 3, 6, and 14 days after injury.
Neointimal growth 14 days after injury was markedly attenuated by treatment with M1/70 –
intimal area after balloon injury, 0.12+0.09 mm2, compared with
  •  0.32+0.08 mm2 in vehicle treated controls, P<0.01, and
  •  0.38+0.08mm2 in IgG-treated controls, P<0.005;
intimal area after stent injury, 0.56+0.16 mm2, compared with
  •  0.84+ 0.13 mm2 in vehicle-treated controls, P <0.05, and
  •  0.90+0.15 mm2 in IgG-treated controls, P <0.02).
Mac-1 blockade reduces experimental neointimal thickening. These findings suggest that
  • leukocyte recruitment to and
  • infiltration of injured arteries

may be a valid target for preventing intimal hyperplasia. (1) Emerging data indicate that the inflammatory response after mechanical arterial injury

  • correlates with the severity of neointimal hyperplasia in animal models
  • and post angioplasty restenosis in humans.
The present study was designed to examine whether a nonspecific
  • stimulation of the innate immune system,
  • induced in close temporal proximity to the vascular injury,
  • would modulate the results of the procedure.
A LPS dose was chosen to be sufficient to induce systemic inflammation but not septic shock. Key markers of inflammation increased after LPS administration were:
  • serum interleukin-1 levels, and
  • monocytic stimulation (CD14 levels on monocytes)
Arterial macrophage infiltration at 7 days after injury was
  • 1.7+1.2% of total cells in controls and
  • 4.2+1.8% in LPS-treated rabbits (n=4, P<0.05).
The injured arteries 4 weeks after injury had significantly increased
  • luminal stenosis:   38+4.2% versus 23+2.6%, mean+SEM; n=8, P<0.05; and
  • neointima-to-media ratio:  1.26+0.21 versus 0.66+0.09, P<0.05 in LPS-treated animals compared with controls.
This effect was abolished by anti-CD14 Ab administration. Serum Il-1 levels and monocyte CD14 expression were significantly increased
  • in correlation with the severity of intimal hyperplasia.
  • LPS treatment increased neointimal area after stenting
    • from 0.57+0.07 to 0.77+0.1 mm2, and
  • stenosis from 9+1% to 13+1.7% (n=5, P<0.05).
Nonspecific systemic stimulation of the innate immune system
  • concurrently with arterial vascular injury
  • facilitates neointimal formation, and conditions associated with
  • increased inflammation may increase restenosis.(2)
Millions of patients worldwide have received drug-eluting stents
  • to reduce their risk for in-stent restenosis.
The efficacy and toxicity of these local therapeutics depend upon
  • arterial drug deposition,
  • distribution, and
  • retention.
To examine how administered dose and drug release kinetics control arterial drug uptake, a model was created using principles of
  • computational fluid dynamics and
  • transient drug diffusion–convection.
The modeling predictions for drug elution were validated using
  • empiric data from stented porcine coronary arteries.
Inefficient, minimal arterial drug deposition was predicted when a bolus of drug was released and depleted within seconds.
Month-long stent-based drug release
  • efficiently delivered nearly continuous drug levels, but
  • the slow rate of drug presentation limited arterial drug uptake.
Uptake was only maximized when
  • the rates of drug release and absorption matched,
  • which occurred for hour-long drug release.
Of the two possible means for increasing the amount of drug on the stent,
  • modulation of drug concentration potently impacts
  • the magnitude of arterial drug deposition,
  • while changes in coating drug mass affect duration of release.
We demonstrate the importance of drug release kinetics and administered drug dose
  • in governing arterial drug uptake and suggest
  • novel drug delivery strategies for controlling spatio-temporal arterial drug distribution.(3)
Arterial drug concentrations determine local toxicity. Therefore, the emergent safety concerns surrounding drug-eluting stents mandate an investigation of the factors contributing to fluctuations in arterial drug uptake.
  • Drug-eluting stents were implanted into porcine coronary arteries, arterial drug uptake was followed and modeled using 2-dimensional computational drug transport.
Arterial drug uptake in vivo occurred faster than predicted by free drug diffusion, thus
  • an alternate, mechanism for rapid transport has been proposed involving carrier-mediated transport.
Though there was minimal variation in vivo in release kinetics from stent to stent,
  • arterial drug deposition varied by up to 114% two weeks after stent implantation.
  • extent of adherent mural thrombus fluctuated by 113% within 3 days.
The computational drug transport model predicted that focal and diffuse thrombi
  • elevate arterial drug deposition in proportion to the thrombus size
  • by reducing drug washout subsequently increasing local drug availability.
Variable peristrut thrombus can explain fluctuations in arterial drug uptake even in the face of a narrow range of drug release from the stent. The mural thrombus effects on arterial drug deposition may be circumvented by forcing slow rate limiting arterial transport, that cannot be further hindered by mural thrombus. (4)
1.  A mAb to the b2-leukocyte integrin Mac-1 (CD11byCD18) Reduces Intimal Thickening after Angioplasty or Stent Implantation in Rabbits. C Rogers, ER Edelman, and DI Simon. PNAS Aug 1998; 95: 10134–10139.
2.  Formation After Balloon and Stent Injury in Rabbits Systemic Inflammation Induced by Lipopolysaccharide increases Neointimal Formation After Balloon and Stent Injury in Rabbits. HD Danenberg, FGP Welt, M Walker, III, P Seifert, et al. Circulation 2002;105;2917-2922; http://dx.doi.org/10.1161/01.CIR.0000018168.15904.BB
3.  Intravascular drug release kinetics dictate arterial drug deposition, retention, and distribution.
B Balakrishnan, JF Dooley, G Kopia, ER Edelman. J Controlled Release  2007;123:100–108.
http://dx. doi.org/10.1016/j.jconrel.2007.06.025.
4.  Thrombus causes fluctuations in arterial drug delivery from intravascular stents. B Balakrishnan, J Dooley, G Kopia, ER Edelman. J Control Release 2008. http://dx.doi.org/10.1016/j.jconrel.2008.07.027

Perivascular Graft Repair

Heparin remains the gold-standard inhibitor of the processes involved in the vascular response to injury. Though this compound has profound and wide-reaching effects on vascular cells, its clinical utility is unclear. It is clear that the mode of heparin delivery is critical to its potential and it may well be that
  • routine forms of administration are insufficient
  • to observe benefit given the heparin’s short half-life and complex pharmacokinetics.
When ingested orally, heparin is degraded to inactive oligomer fragments while systemic administration
  • is complicated by the need for continuous infusion
  • and the potential for uncontrolled hemorrhage.
Thus alternative heparin delivery systems have been proposed to maximize regional effects while limiting systemic toxicity. Yet, as heparin is such a potent antithrombotic compound and since existing local delivery systems lack the ability to
  • precisely regulate release kinetics,
  • even site-specific therapy is prone to bleeding.
Authors now describe the design and development of a novel biodegradable system for the perivascular delivery of heparin to the blood vessel wall with well-defined release kinetics.
This system consists of heparin-encapsulated
  • poly(DL lactide-co-glycolide) (pLGA) microspheres sequestered in an alginate gel.
Controlled release of heparin from this heterogeneous system is obtained for a period of 25 days.
The experimental variables affecting heparin release from these matrices were investigated by
  • gel permeation chromatography (GPC) and scanning electron microscopy (SEM)
  • to monitor the degradation process and correlated well with the release kinetics.
Heparin-releasing gels inhibited growth in tissue culture of
  • bovine vascular smooth muscle cells in a dose-dependent manner.
  • and also controlled vascular injury in denuding and
  • interposition vascular graft animal models of disease even when uncontrolled bleeding was evident with standard matrix-type release.
This system provided an effective means of examining
  • the effects of various compounds in
  • the control of smooth muscle cell proliferation in accelerated arteriopathies and also
  • shed light on the biologic nature of these processes.(1)
Soft tissue adhesives are employed to repair and seal many different organs that range in both
  • tissue surface chemistry and
  • mechanical effects during organ function.
This complexity motivates the development of tunable adhesive materials with
  • high resistance to uniaxial or multiaxial loads
  • dictated by a specific organ environment.
Co-polymeric hydrogels comprising
  • aminated star polyethylene glycol and
  • dextran aldehyde (PEG:dextran)
are materials exhibiting physico-chemical properties that can be modified
Here we report that resistance to failure
  • under specific loading conditions, as well as
  • tissue response at the adhesive material–tissue interface, can be modulated through regulation of
  • the number and density of adhesive aldehyde groups.
Author found that atomic force microscopy (AFM) can
  • characterize the material aldehyde density available for tissue interaction,
  • facilitating rapid, informed material choice.

Further, the correlation between AFM quantification of nanoscale unbinding forces

  • with macroscale measurements of adhesion strength
  • by uniaxial tension or multiaxial burst pressure allows the design of materials with specific cohesion and adhesion strengths.
However, failure strength alone does not predict optimal in vivo reactivity. The development of adhesive materials is significantly enabled when
  • experiments are integrated along length scales to consider
  • organ chemistry and mechanical loading states concurrently
  • with adhesive material properties and tissue response. (2)
Cell culture and animal data support the role of endothelial cells and endothelial-based compounds in regulating vascular repair after injury.
Authors describe a long-term study in pigs in which the biological and immunological
  • responses to endothelial cell implants were investigated 3 months after angioplasty,
  • approximately 2 months after the implants have degraded.
Confluent porcine or bovine endothelial cells grown in polymer matrices were implanted adjacent to 28 injured porcine carotid arteries.
Porcine and bovine endothelial cell implants significantly
  • reduced experimental restenosis compared to control by 56 and 31%, respectively.
Host humoral responses were investigated by detection of an increase in serum antibodies that bind to the bovine or porcine cell strains used for implantation.
A significant increase in titer of circulating antibodies to the bovine cells was observed
  • after 4 days in all animals implanted with xenogeneic cells.
Detected antibodies returned to presurgery levels after Day 40.
No significant increase in titer of antibodies to the porcine cells was observed during the experiment in animals implanted with porcine endothelial cells.
No implanted cells, Gelfoam, or focal inflammatory reaction could be detected
  • histologically at any of the implant sites at 90 days.

Suggesting that tissue engineered endothelial cell implants

  • may provide long term control of vascular repair after injury,
  • rather than simply delaying lesion formation and that
  • allogeneic implants are able to provide a greater benefit than xenogeneic implants. (3)
Vascular access complications are a major problem in hemodialysis patients. Native arteriovenous fistulae, historically the preferred mode of access, have a patency rate of only 60% at 1 year.
The most common mode of failure is due to progressive stenosis at the anastomotic site.
Authors have previously demonstrated that perivascular endothelial cell implants
  • inhibit intimal thickening following acute balloon injury in pigs, and now seek to determine if these
  • implants provide a similar benefit in the chronic and more complex injury model of arteriovenous anastomoses.
Side-to-side femoral artery-femoral vein anastomoses were created in 24 domestic swine.
  • toxicological,
  • biological and
  • immunological responses

were investigated 3 days and 1 and 2 months postoperatively to allogeneic endothelial cell implants . The anastomoses were wrapped with polymer matrices containing

  • confluent porcine aortic endothelial cells (PAE; n = 14) or
  • control matrices without cells (n = 10).
PAE implants significantly reduced intimal hyperplasia at the anastomotic sites
  • compared to controls by 68% (p ! 0.05) at 2 months.
The beneficial effects of the PAE implants were not due to
  • differences in the rates of reendothelialization between the groups.
No significant immunological response to the allogeneic endothelial cells that impacted on efficacy was detected in any of the pigs.
No apparent toxicity was observed in any of the animals treated with endothelial implants.
These data suggest that perivascular endothelial cell implants
  • are safe and reduce early intimal hyperplasia in a porcine model of arteriovenous anastomoses. (4)
1.  Perivascular graft heparin delivery using biodegradable polymer wraps. ER Edelman, A Nathan,
M Katada, J Gates, MJ Karnovsky. Biomaterials 2000; 21:2279 -2286.
onlinelibrary.wiley.com/doi/10.1002/anie.200461360/full
2.  Tuning adhesion failure strength for tissue-specific applications. N Artzi, A Zeiger, F Boehning,
A bon Ramos, K Van Vliet, ER Edelman.  Acta Biomateriala 2010.
http://dx.doi.org/10.1016/j.actbio.2010.07.008.
3. Endothelial Implants Provide Long-Term Control of Vascular Repair in a Porcine Model of Arterial Injury. HM Nugent, ER Edelman. J Surg Res 2001; 99:228–234.  http://dx.doi.org/10.1006/jsre.2001.6198
4.  Perivascular Endothelial Implants Inhibit Intimal Hyperplasia in a Model of Arteriovenous Fistulae: A Safety and Efficacy Study in the Pig. HM Nugent, A Groothuis, P Seifert, et al. J Vasc Res 2002;39:524–533.

Luminal Flow and Arterial Drug Delivery

Endovascular stents reside in a dynamic flow environment and yet the impact of flow
  • on arterial drug deposition after stent-based delivery is only now emerging.
Authors employed computational fluid dynamic modeling tools to investigate
  • the influence of luminal flow patterns on arterial drug deposition and distribution.
Flow imposes recirculation zones distal and proximal to the stent strut that extend
  • the coverage of tissue absorption of eluted drug and
  • induce asymmetry in tissue drug distribution.
Our analysis now explains how the disparity in
  • sizes of the two recirculation zones and
  • the asymmetry in drug distribution are determined by a complex interplay of local flow and strut geometry.
When temporal periodicity was introduced as a model of
  • pulsatile flow,
  • the net luminal flow served as an index of flow-mediated spatiotemporal tissue drug uptake.
Dynamically changing luminal flow patterns are intrinsic to the coronary arterial tree. Coronary drug-eluting stents should be appropriately considered where
  • luminal flow,
  • strut design and
  • pulsatility
have direct effects on tissue drug uptake after local delivery.(1)
The efficacy of drug-eluting stents (DES) requires delivery of potent compounds directly to the underlying arterial tissue.
The commercially available DES drugs rapamycin and paclitaxel bind specifically to
  • their respective therapeutic targets, FKBP12 and polymerized microtubules,
  • while also associating in a more general manner with other tissue elements.
As it is binding that provides biological effect, the question arises as to whether other
  • locally released or systemically circulating drugs can
  • displace DES drugs from their tissue binding domains.
Specific and general binding sites for both drugs are distributed across the media and adventitia with higher specific binding associated with the binding site densities in the media.
The ability of rapamycin and paclitaxel to compete for specific protein binding and general tissue deposition
  • was assessed for both compounds simultaneously and
  • in the presence of other commonly administered cardiac drugs.
Drugs classically used to treat standard cardiovascular diseases, such as hypertension and hypercoaguability,
  • displace rapamycin and paclitaxel from general binding sites, possibly
  • decreasing tissue reserve capacity for locally delivered drugs.
Paclitaxel and rapamycin do not affect the other’s binding
  • to their biologically relevant specific protein targets, but
  • can  displace each other from tissue at three log order molar excess,
  • decreasing arterial loads by greater than 50%.
Local competitive binding therefore should not limit the placement of rapamycin and paclitaxel eluting stents in close proximity.(2)
Stent thrombosis is a lethal complication of endovascular intervention. There is concern about the inherent risk associated with specific stent designs and drug-eluting coatings
Authored examined whether drug-eluting coatings are inherently thrombogenic and whether the response to these materials was determined to any degree
  • by stent design and
  • stent deployment with custom-built stents.
Drug/polymer coatings uniformly reduce rather than increase thrombogenicity relative to matched bare metal counterparts (0.65-fold; P 0.011).
Thick-strutted (162 m) stents were 1.5-fold more thrombogenic than otherwise
  • identical thin-strutted (81 m) devices in ex vivo flow loops (P< 0.001),
commensurate with 1.6-fold greater thrombus coverage
  • 3 days after implantation in porcine coronary arteries (P 0.004).
When bare metal stents were deployed in
  • malapposed or overlapping configurations, thrombogenicity increased compared with apposed, length-matched controls (1.58-fold, P < 0.001; and 2.32-fold, P <0.001).
The thrombogenicity of polymer-coated stents with thin struts was
  • lowest in all configurations and remained insensitive to incomplete deployment.
Computational modeling– based
  • predictions of stent-induced flow derangements
  • correlated with spatial distribution of formed clots.
Drug/polymer coatings do not inherently increase acute stent clotting;
  • they reduce thrombosis.
However, strut dimensions and positioning relative to the vessel wall
  • are critical factors in modulating stent thrombogenicity.
Optimal stent geometries and surfaces, as demonstrated with thin stent struts,
  • help reduce the potential for thrombosis
  • despite complex stent configurations and variability in deployment. (Circulation. 2011;123:1400-1409.) (3)
1. Luminal flow patterns dictate arterial drug deposition in stent-based delivery.
VB Kolachalama, AR Tzafriri, DY Arifin, ER Edelman. J Control Release 2009; 133:24–30.
2. Local and systemic drug competition in drug-eluting stent tissue deposition properties.
AD Levin, M Jonas, Chao-Wei Hwang, ER Edelman.  J Control Release 2005; 109:236-243.
3. Stent Thrombogenicity Early in High-Risk Interventional Settings Is Driven by
Stent Design and Deployment and Protected by Polymer-Drug Coatings
Kumaran Kolandaivelu, Rajesh Swaminathan, William J. Gibson,.. ER Edelman

Management of Obstructive Coronary Artery Disease

Multiple studies have shown that diabetes mellitus (DM) can affect the
  • efficacy of revascularization therapies and subsequent clinical outcomes.
Selecting the appropriate myocardial revascularization strategy is critically important
  • in the setting of multivessel coronary disease.
Optimal medical therapy is an appropriate first-line strategy in patients with DM and mild symptoms. When medical therapy does not adequately control symptoms,
  • revascularization with either PCI or CABG may be used.
In patients with treated DM, moderate to severe symptoms and complex multivessel coronary disease,
  • coronary artery bypass graft surgery provides better survival,
  • fewer recurrent infarctions and
  • greater freedom from re-intervention.
Decisions regarding revascularization in patients with DM must take into account multiple factors and as such require a multidisciplinary team approach (‘heart team’). (1)
An incomplete understanding of the transport forces and local tissue structures
  • that modulate drug distribution has hampered
  • local pharmacotherapies in many organ systems.
These issues are especially relevant to arteries, where stent-based delivery allows fine control of locally directed drug release.
Local delivery produces tremendous drug concentration gradients
  • these are in part derived from transport forces,
  • differences in deposition from tissue to tissue

This suggests that tissue ultrastructure also plays an important role.

Authors measured the equilibrium drug uptake and the penetration and diffusivity of
  • dextrans (a model hydrophilic drug similar to heparin) and albumin
  • in orthogonal planes in arteries explanted from different vascular beds.
Authors found significant variations in drug distribution with
  • geometric orientation and
  • arterial connective tissue content.
Drug diffusivities parallel to the connective tissue sheaths were
  • one to two orders of magnitude greater than across these sheaths.
This diffusivity difference remained relatively constant for drugs up to 70 kDa
  • before decreasing for larger drugs.
Drugs also distributed better into elastic arteries, especially at lower molecular weights,
  • with almost 66% greater transfer into the thoracic aorta
  • than into the carotid artery.
Arterial drug transport is thus highly anisotropic and
  • dependent on arterial tissue content.
The role of the local composition and geometric organization of arterial tissue
  • in influencing vascular pharmacokinetics
is likely to become a critical consideration for local vascular drug delivery (2)
Radiolabeled drug-eluting stents have been proposed
  • to potentially reduce restenosis in coronary arteries.
A P-32 labeled oligonucleotide (ODN) loaded on a polymer coated stent
  • is slowly released in the arterial wall to deliver a therapeutic dose to the target tissue.
A relatively low proportion of drugs is transferred to the arterial wall (< 2%– 5% typically). This raises questions about the degree to which radiolabeled drugs eluted from the stent
  • can contribute to the total radiation dose delivered to tissues.
A three-dimensional diffusion-convection transport model is used
  • to model the transport of a hydrophilic drug released
  • from the surface of a stent to the arterial media.
Large drug concentration gradients are observed
  • near the stent struts giving rise to a
  • non-uniform radiation activity distribution for the drug
  • in the tissues as a function of time.
A voxel-based kernel convolution method is used to calculate the radiation dose rate
  • resulting from this activity build-up in the arterial wall
  • based on the medical internal radiation dose formalism.
Measured residence time for the P-32 ODN in the arterial wall and
  • at the stent surface obtained from animal studies
  • are used to normalize the results in terms of absolute dose to tissue.
The results indicate radiation due to drug eluted from the stent
  • contributes only a small fraction of the total radiation delivered to the arterial wall,
  • the main contribution comes from the activity embedded in the stent coating.
For hydrophilic compounds with rapid transit times in arterial tissue and minimal binding interactions,
  • the activity build-up in the arterial wall contributes only a small fraction
  • to the total dose delivered by the P-32 ODN stent.
For these compounds, it is concluded that radiolabeled drug-eluting stent
  • would not improve the performance of radioactive stents in treating restenosis.
Also, variability in the efficacy of drug delivery devices
  • makes accurate dosimetry difficult and
  • the drug washout in the systemic circulatory system
may yield an unnecessary activity build-up and dose to healthy organs. (3)
The first compounds considered for stent-based delivery,
  • such as heparin have failed to stop restenosis clinically.
More recent compounds, such as paclitaxel, are of a different sort.
They are hydrophobic, and their effects after local release seem far more profound.
This dichotomy raises the question of whether drugs that have an effect when released from a stent do so because of
  • differences in biology or differences in physicochemical properties and targeting.
Authored applied continuum pharmacokinetics to examine the effects of
  • transport forces and device geometry on
the distribution of stent-delivered hydrophilic and hydrophobic drugs.
Stent-based delivery leads to large concentration gradients.
Drug concentrations range from nil to several times the
  • mean tissue concentration over a few micrometers.
Concentration variations were a function of the Peclet number (Pe),
  • the ratio of convective to diffusive forces.
Although hydrophobic drugs exhibit greater variability than hydrophilic drugs,
  • they achieve higher mean concentrations and
  • they remain closer to the intima.
Inhomogeneous strut placement influences hydrophilic drugs
  • more negatively than hydrophobic drugs, and notably
  • affect local concentrations without changing mean concentrations.
Local concentrations and gradients are inextricably linked to biological effect. Therefore,
  • these results provide a potential explanation for the variable success of stent-based delivery.
Authors conclude that mere proximity of delivery devices to tissues
  • does not ensure adequate targeting,
  • because physiological transport forces cause
  • local concentrations to deviate significantly from mean concentrations. (4)
1.  Role of CABG in the management of obstructive coronary arterial disease in patients with diabetes mellitus. D Aronson, ER Edelman.  Curr Opin Pharmacol 2012, 12:134–141. Issue on Cardiovascular and renal. [Eds: JY Jeremy, K Zacharowski, N Shukla, S Wan].  http://dx.doi.org/10.1016/j.coph.2012.01.011
2.  Arterial Ultrastructure Influences Transport of Locally Delivered Drugs. Chao-Wei Hwang, ER Edelman. Circ Res. 2002; 90:826-832. http://www.circresaha.org/dx.doi.org/10.1161/01.RES.0000016672.26000.9E
3.  Dose model for stent-based delivery of a radioactive compound for the treatment of restenosis in coronary arteries. C Janickia, Chao-Wei Hwang, ER Edelman.  Med Phys 2003; 30(10), 2622-7.    http://dx.doi.org/10.1118/1.1607506
4.  Physiological Transport Forces Govern Drug Distribution for Stent-Based Delivery. Chao-Wei Hwang, D Wu, ER Edelman. Circulation. 2001;104(5) :600-605; e14 – e9010.     http://dx.doi.org/10.1161/hc3101.09221
Stent-Versus-Stent Equivalency Trials. Are Some Stents More Equal Than Others? Elazer R. Edelman, Campbell Rogers Circulation. 1999; 100(9): 896-898; e47 – e47.  http://dx.doi.org/10.1161/01.CIR.100.9.896
New endovascular stent designs are displacing tried and-true devices for use in an ever-broader array of lesions. There is disagreement as to which device is most advantageous and whether design determines outcome. Preclinical research says that this should be the case. Clinical trials have failed to validate design dependence. Can the divergent results be reconciled? More than 50 different stent configurations are available. The processes of industrial development and federal regulatory evaluation support the importance of design.
Stents are made from
  • a spectrum of materials
  • a range of manufacturing techniques, and have
    • variable surfaces,
    • dimensions,
    • surface coverage, and
    • strut configurations.
The number of parameters involved may doom the number of subsets to approach the number of designs. Moreover, each device seems to have a unique optimal mode of placement.  Differences have been reported in
  • flexibility,
  • tracking ability,
  • expansion,
  • radiovisibility,
  • side-branch access, and
  • resistance to compression and recoil for different devices.
Regulatory approval includes standards for safety:
  • toxicity,
  • biocompatibility,
  • structural and material analysis, and
  • fatigue testing
It has been suggested that
  • hoop strength,
  • surface cracking,
  • uniformity of expansion, and
  • other features become standardized as well.
Four different direct comparisons of first-generation Palmaz-Schatz slotted-tube stents and
second-generation stents have been made. In several studies there were no significant differences
in restenosis at follow-up, including
  • minimal luminal diameter (MLD),
  • percent diameter stenosis,
  • late loss, or
  •  binary restenosis rate.
In the fourth study, restenosis was far greater for the Gianturco-Roubin II (GR-II) stent (Cook) than
  • the Palmaz-Schatz stent (Cordis-Johnson & Johnson).
The data for all stents bunch across trials: with the exception of the GR-II stent,
variability between the test stent groups was no greater than
  • the variability between the Palmaz-Schatz stent groups in the different trials.
Three distinct possibilities exist to explain the absence of clinical evidence that different designs behave differently:
(1) no differences in clinical outcomes exist between devices;
(2) differences exist but are so slight as to be clinically meaningless; and
(3) differences exist that may be clinically meaningful, but trials performed to date were not designed to detect them.
Schematic representation of device performance plotting outcome against indication indicates that
  • complication rates rise as lesion complexity increases.
When 2 devices are clinically different, their curves are displaced, and when they are indistinguishable, their curves overlap.
Clinical trials that restrict the test population to lesions low on the complexity scale
  • ensure safety for all patients but are not the ideal venues in which to detect differences between devices.
Thus, although stents 1 and 2 may have different clinical outcomes, in a restricted-criteria equivalency trial with low complexity, they appear identical. It is only when the test device performs worse than the standard, that differences can be appreciated.
In contrast, an open registry will not only show when a test stent is worse than the standard stent but also when it is better.

Equivalency Trials

Stent-versus-stent trials are equivalency trials, designed to show that a test device performs “as well as” a standard, currently acceptable device.  This is a valid regulatory threshold but
  • not the means to evaluate the full potential of a device.
Equivalency trials must by definition commence with a patient population for whom the standard device is safe. Trials with currently approved devices as the standard necessitate that
  • patient entry and lesion selection be determined by
  • limitations of the standard, not the device.
to observe a difference in such a trial
  •  the test device performs worse
For the test device to perform better, both the test and the standard must be challenged.
This was not the case for the trials in which
  • the average reference vessel size was 3.0+0.05 mm and
  • American College of Cardiology type B2 and C lesions accounted for only ~65% of lesions.
These lesions are those for which the Palmaz-Schatz stent is approved and technically suited, but
  • they represent only a minority of those lesions now receiving stents

Complexity, Equivalence, and Better

In truth, it may be most appropriate to think about parameters of device success and safety as a continuum, describing a correlation between events such as
  • thrombosis or restenosis and
  • a continuous measure of indication,
  • vessel dimension, or lesion complexity (Figure).
A given device may be represented by a characteristic response over a range of indications.
When there is a lateral offset to the curves,
  • differences in potential performance are anticipated.
Curves might even cross, rather than run parallel, indicating that devices might be matched
to lesions and indications. Open trials would consider the entire range of the curves.
  • equivalency trials are limited to a small region of the curve.
The first-generation stents were a major innovation in interventional cardiology, and their place in medical history and biotechnology is unassailable.
Demonstration that new stents are better than old will require that evaluations be
  • performed in lesions for which current devices have marginal or limited application.
Complex or acutely unstable lesions, small arteries, and diseased bypass grafts are
  • the next great challenges of interventional cardiology.
Perhaps in these settings, future stent trials will provide firm evidence that
  • the manner in which blood vessels are manipulated dictates biological sequelae.
Proof that stent design can alter clinical outcomes may then unleash the potential
  • to change the way in which we consider design, approval, and use of new devices.
REFERENCES

Menichelli, M. (2006). Sirolimus Stent vs. Bare Stent in Acute Myocardial Infarction Trial. Presented at The European Paris Course on Revascularization (EuroPCR), May 16-19, 2006, Paris, France Paris, France.http://www.medscape.com/viewprogram/5505?rss

Pfisterer, P.E. (2006). Basel Stent Cost-effectiveness Trial-Late Thrombotic events (BASKET LATE) Trial. Presented at American College of Cardiology 55th Annual Scientific Session, March 11 – 14, 2006, Atlanta, Georgia.http://www.medscape.com/viewprogram/5185 

Rogers, C. Edelman E.R. (2006). Pushing drug-eluting stents into uncharted territory, Simpler then you think – more complex than you imagine. Circulation,113, 2262-2265.

Shirota, T., Yasui, H., Shimokawa, H. & Matsuda, T. (2003). Fabrication of endothelial progenitor cell (EPC)-seeded intravascular stent devices and in vitro endothelialization on hybrid vascular tissue. Biomaterials 24(13), 2295–2302.

Simonton, C. (2006). The STENT Registry: A real-world look at Sirolimus- and Pacitaxel-Eluting Stents. Cath Lab Digest, 14 (1), 1-10.

Turco, M. (2006). TAXUS ATLAS Trial – 9-Month results: Evaluation of TAXUS Liberte vs. TAXUS Express. Presented at The European Paris Course on Revascularization (EuroPCR), May 16-19, 2006, Paris, France Paris, France.http://www.medscape.com/viewprogram/5505?rss

Verma, S. and Marsden, P.A. (2005). Nitric Oxide-Eluting Polyurethanes – Vascular Grafts of the Future? New England Journal Medicine, 353 (7), 730-731.

Wood, S. (2006). Guidant suspends release of Xience V everolimus-eluting stent due to manufacturing standards http://www.theheart.org/article/679851.do 

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http://pharmaceuticalintelligence.com/2012/08/27/new-definition-of-mi-unveiled-fractional-flow-reserve-ffrct-for-tagging-ischemia/

Ethical Considerations in Studying Drug Safety — The Institute of Medicine Report

Aviva Lev-Ari, PhD, RN 8/23/2012
http://pharmaceuticalintelligence.com/2012/08/23/ethical-considerations-in-studying-drug-safety-the-institute-of-medicine-report/

New Drug-Eluting Stent Works Well in STEMI

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http://pharmaceuticalintelligence.com/2012/08/22/new-drug-eluting-stent-works-well-in-stemi/

Expected New Trends in Cardiology and Cardiovascular Medical Devices

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http://pharmaceuticalintelligence.com/2012/08/17/expected-new-trends-in-cardiology-and-cardiovascular-medical-devices/

Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents

Aviva Lev-Ari, PhD, RN 8/13/2012

http://pharmaceuticalintelligence.com/2012/08/13/coronary-artery-disease-medical-devices-solutions-from-first-in-man-stent-implantation-via-medical-ethical-dilemmas-to-drug-eluting-stents/

Percutaneous Endocardial Ablation of Scar-Related Ventricular Tachycardia

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http://pharmaceuticalintelligence.com/2012/07/18/percutaneous-endocardial-ablation-of-scar-related-ventricular-tachycardia/

Competition in the Ecosystem of Medical Devices in Cardiac and Vascular Repair: Heart Valves, Stents, Catheterization Tools and Kits for Open Heart and Minimally Invasive Surgery (MIS)

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http://pharmaceuticalintelligence.com/2012/06/22/competition-in-the-ecosystem-of-medical-devices-in-cardiac-and-vascular-repair-heart-valves-stents-catheterization-tools-and-kits-for-open-heart-and-minimally-invasive-surgery-mis/

Global Supplier Strategy for Market Penetration & Partnership Options (Niche Suppliers vs. National Leaders) in the Massachusetts Cardiology & Vascular Surgery Tools and Devices Market for Cardiac Operating Rooms and Angioplasty Suites

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Drug Eluting Stents: On MIT’s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES


Drug Eluting Stents: On MIT‘s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES

Author: Larry H Bernstein, MD, FACP

and 

Curator: Aviva Lev-Ari, PhD, RN
http://PharmaceuticalIntelligence.com/2013/04/25/Contributions
-to-vascular-biology/

This is the first of a three part series on the evolution of vascular biology and the studies of the effects of biomaterials in vascular reconstruction and on drug delivery, which has embraced a collaboration of cardiologists at Harvard Medical School , Affiliated Hospitals, and MIT,
requiring cardiovascular scientists at the PhD and MD level, physicists, and computational biologists working in concert, and
an exploration of the depth of the contributions by a distinguished physician, scientist, and thinker.

The first part – Vascular Biology and Disease – will cover the advances in the research on

  • vascular biology,
  • signaling pathways,
  • drug diffusion across the endothelium and
  • the interactions with the underlying muscularis (media),
  • with additional considerations for type 2 diabetes mellitus.

The second part – Stents and Drug Delivery – will cover the

  • purposes,
  • properties and
  • evolution of stent technology with
  • the acquired knowledge of the pharmacodynamics of drug interactions and drug distribution.

The third part – Problems and Promise of Biomaterials Technology – will cover the shortcomings of the cardiovascular devices, and opportunities for improvement

Vascular Biology and Cardiovascular Disease

Early work on endothelial injury and drug release principles

The insertion of a catheter for the administration of heparin is not an innocuous procedure. Heparin is infused to block coagulation, lowering the risk of a dangerous

  • clot formation and
  • dissemination.

It was shown experimentally that the continuous infusion of heparin

  • suppresses smooth muscle proliferation after endothelial injury. It may lead to
  • hemorrhage as a primary effect.

The anticoagulant property of heparin was removed by chemical modification without loss of the anti-proliferative effect.

In this study, MIT researches placed ethylene-vinyl acetate copolymer matrices containing standard and modified heparin adjacent to rat carotid arteries at the time of balloon deendothelialization.

Matrix delivery of both heparin compounds effectively diminished this proliferation in comparison to controls without producing systemic anticoagulation or side effects.

This mode of therapy appeared more effective than administering the agents by either

  • intravenous pumps or
  • heparin/polymer matrices placed in a subcutaneous site distant from the injured carotid artery

This indicated that the site of placement at the site of injury is a factor in the microenvironment, and is a preference for avoiding restenosis after angioplasty and other interventions.

This raised the question of why the proliferation of vascular muscle occurs in the first place.
 Edelman, Nugent and Karnovsky  (1) showed that the proliferation required first the denudation of vascular surface endothelium. This exposed the underlayer to the effect of basic fibroblast growth factor, which stimulates mitogenesis of the exposed cell, explained by the endothelium as a barrier from circulating bFGF.

To answer this question, they compared the effect of

  • 125I-labelled bFGF intravenously given with perivascular controlled bFGF release.
  • Polymeric controlled release devices delivered bFGF to the extravascular space without transendothelial transport. 
Deposition within the blood vessel wall was rapidly distributed circumferentially and was substantially greater than that observed following intravenous injection.

The amount of bFGF deposited in arteries adjacent to the release devices was 40 times that deposited in similar arteries in animals who received a single intravenous bolus of bFGF.

The presence of intimal hyperplasia increased deposition of perivascularly released bFGF 2.4-fold but decreased the deposition of intravenously injected bFGF by 67%.

  • bFGF was 5- to 30-fold more abundant in solid organs after intravenous injection than it was following perivascular release, and
  • bFGF deposition was greatest in the kidney, liver, and spleen and was substantially lower in the heart and lung.

This result indicated that vascular deposition of bFGF is independent of endothelium, and

  • bFGF delivery is effectively perivascular. (2)

Drug activity studies have to be done in well controlled and representative conditions.
 Edelsman’s Lab researchers studied the

  • dose response of injured arteries to exogenous heparin in vivo by providing steady and predictable arterial levels of drug.
  • Controlled-release devices were fabricated to direct heparin uniformly and at a steady rate to the adventitial surface of balloon-injured rat carotid arteries.

Researchers predicted the distribution of heparin throughout the arterial wall using computational simulations and correlated these concentrations with the biologic response of the tissues.

Researchers determined from this process that an in vivo arterial concentration of 0.3 mg/ml of heparin is required to maximallyinhibit intimal hyperplasia after injury.

This estimation of the required tissue concentration of a drug is

  • independent of the route of administration and
  • applies to all forms of drug release.

In this way the Team was able to

  • evaluate the potential of  widely disparate forms of drug release and, to finally
  • create some rigorous criteria by which to guide the development of particular delivery strategies for local diseases. (3)

Chiefly, the following three effects:

(1) Effect of controlled adventitial heparin delivery on smooth muscle cell proliferation following endothelial injury. ER Edelman, DH Adams, and MJ Karnovsky. PNAS May 1990; 87: 3773-3777.


(2) Perivascular and intravenous administration of basic fibroblast growth factor: Vascular and solid organ deposition. ER Edelman, MA Nugent, and MJ Karnovsky. PNAS Feb 1993; 90: 1513-1517.


(3) Tissue concentration of heparin, not administered dose, correlates with the biological response of injured arteries in vivo. MA Lovich and ER Edelman. PNAS Sep 1999; 96: 11111–11116.

Vascular Injury and Repair

Perlecan is a heparin-sulfate proteoglycan that might be critical for regulation of vascular repair by inhibiting the binding and mitogenic activity of basic fibroblast growth factor-2 (bFGF-2) in vascular smooth muscle cells .

The Team generated

  • Clones of endothelial cells expressing an antisense vector targeting domain III of perlecan. The transfected cells produced significantly less perlecan than parent cells, and they had reduced bFGF in vascular smooth muscle cells.
  • Endothelial cells were seeded onto three-dimensional polymeric matrices and implanted adjacent to porcine carotid arteries subjected to deep injury.
  • The parent endothelial cells prevented thrombosis, but perlecan deficient cells were ineffective.

The ability of endothelial cells to inhibit intimal hyperplasia, however, was only in part suppressed by perlecan. The differential regulation by perlecan of these aspects of vascular repair may clarify why control of clinical clot formation does not lead to full control of intimal hyperplasia.

The use of genetically modified tissue engineered cells provides a new approach for dissecting the role of specific factors within the blood vessel wall.(1) Successful implementation of local arterial drug delivery requires transmural distribution of drug. The physicochemical properties of the applied compound govern its transport and tissue binding.

  • Hydrophilic compounds are cleared rapidly.
  • Hydrophobic drugs bind to fixed tissue elements, potentially prolonging tissue residence and biological effect.

Local vascular drug delivery provides

  • elevated concentrations of drug in the target tissue while
  • minimizing systemic side effects.

To better characterize local pharmacokinetics the Team examined the arterial transport of locally applied dextran and dextran derivatives in vivo.

Using a two-compartment pharmacokinetic model to correct

  • The measured transmural flux of these compounds for systemic
  • Redistribution and elimination as delivered from a photo-polymerizable hydrogel.
  • The diffusivities and the transendothelial permeabilities were strongly dependent on molecular weight and charge
  • For neutral dextrans, the diffusive resistance increased with molecular weightapproximately 4.1-fold between the molecular weights of 10 and 282 kDa.
  • Endothelial resistance increased 28-fold over the same molecular weight range.
  • The effective medial diffusive resistance was unaffected by cationic charge as such molecules moved identically to neutral compounds, but increased approximately 40% when dextrans were negatively charged.

Transendothelial resistance was 20-fold lower for the cationic dextrans, and 11-fold higher for the anionic dextrans, when both were compared to neutral counterparts.

These results suggest that, while

  • low molecular weight drugs will rapidly traverse the arterial wall with the endothelium posing a minimal barrier,
  • the reverse is true for high molecular weight agents.

The deposition and distribution of locally released vascular therapeutic compounds might be predicted based upon chemical properties, such as molecular weight and charge. (2)

Paclitaxel is hydrophobic and has therapeutic potential against proliferative vascular disease.
 The favorable preclinical data with this compound may, in part, result from preferential tissue binding.
 The complexity of Paclitaxel pharmacokinetics required in-depth investigation if this drug is to reach its full clinical potential in proliferative vascular diseases.

Equilibrium distribution of Paclitaxel reveals partitioning above and beyond perfusate concentration and a spatial gradient of drug across the arterial wall.

The effective diffusivity (Deff) was estimated from the Paclitaxel distribution data to

  • facilitate comparison of transport of Paclitaxel through arterial parenchyma with that of other vasoactive agents and to
  • characterize the disparity between endovascular and perivascular application of drug.

This transport parameter described the motion of drug in tissues given an applied concentration gradient and includes, in addition to diffusion,

  • the impact of steric hindrance within the arterial interstitium;
  • nonspecific binding to arterial elements; and, in the preparation used here,
  • convective effects from the applied transmural pressure gradient.

At all times, the effective diffusivity for endovascular delivery exceeded that of perivascular delivery. The arterial transport of Paclitaxel was quantified through application ex vivo and measurement of the subsequent transmural distribution.

  • Arterial Paclitaxel deposition at equilibrium varied across the arterial wall.
  • Permeation into the wall increased with time, from 15 minutes to 4 hours, and
  • varied with the origin of delivery.

In contrast to hydrophilic compounds, the concentration in tissue exceeded the applied concentration and the rate of transport was markedly slower. Furthermore, endovascular and perivascular Paclitaxel application led to differences in deposition across the blood vessel wall.

This leads to a conclusion that Paclitaxel interacts with arterial tissue elements  as it moves under the forces of

  • diffusion and
  • convection and
  • can establish substantial partitioning and spatial gradients across the tissue. (3)

Endovascular drug-eluting stents have changed the practice of  cardiovascular vascularization, and yet it is unclear how they so dramatically reduce restenosis

We don’t know how to distinguish between the different formulations available.
 Researchers are now questioning whether individual properties of different drugs beyond lipid avidity effect arterial transport and distribution.

In bovine internal carotid segments, tissue-loading profiles for

  • Hydrophobic Paclitaxel and Rapamycin are indistinguishable, reaching load steady state after 2 days.
  • Hydrophilic dextran reaches equilibrium in hours.

Paclitaxel and Rapamycin bind to the artery at 30–40 times bulk concentration, and bind to specific tissue elements.

Transmural drug distribution profiles are markedly different for the two compounds.

  • Rapamycin binds specifically to FKBP12 binding protein and it distributes evenly through the artery,
  • Paclitaxel binds specifically to microtubules, and remains primarily in the subintimal space.

The binding of Rapamycin and Paclitaxel to specific intracellular proteins plays an essential role in

  • determining arterial transport and distribution and in
  • distinguishing one compound from another.

These results offer further insight into the

  • mechanism of local drug delivery and the
  • specific use of existing drug-eluting stent formulations. (4)

The Role of Amyloid beta (A) in Creation of Vascular Toxic Plaque

Amyloid beta (A) is a peptide family produced and deposited in neurons and endothelial cells (EC).
It is found at subnanomolar concentrations in the plasma of healthy individuals.
 Simple conformational changes produce a form of A-beta , A-beta 42, which creates toxic plaque in the brains of Alzheimer’s patients.

Oxidative stress induced blood brain barrier degeneration has been proposed as a key factor for A-beta 42 toxicity.

This cannot account for lack of injury from the same peptide in healthy tissues.
Researchers hypothesized that cell state mediates A-beta’s effect.
 They examined the viability in the presence of A-beta secreted from transfected
Chinese hamster ovary cells (CHO) of

  • aortic Endothelial Cells (EC),
  • vascular smooth muscle cells (SMC) and
  • epithelial cells (EPI) in different states

A-beta was more toxic to all cell types when they were subconfluent.
 Subconfluent EC sprouted and SMC and EPI were inhibited by A-beta.
Confluent EC were virtually resistant to A-beta and suppressed A-beta production by A-beta +CHO.

Products of subconfluent EC overcame this resistant state, stimulating the production and toxicity of A-beta 42. Confluent EC overgrew >35% beyond their quiescent state in the presence of A-beta conditioned in media from subconfluent EC.

These findings imply that A-beta 42 may well be even more cytotoxic to cells in injured or growth states and potentially explain the variable and potent effects of this protein.

One may now need to consider tissue and cell state in addition to local concentration of and exposure duration to A-beta.

The specific interactions of A-beta and EC in a state-dependent fashion may help understand further the common and divergent forms of vascular and cerebral toxicity of A-beta and the spectrum of AD. (5)

(1) Perlecan is required to inhibit thrombosis after deep vascular injury and contributes
to endothelial cell-mediated inhibition of intimal hyperplasia. MA Nugent, HM Nugent,
RV Iozzoi, K Sanchack, and ER Edelman. PNAS Jun 2000; 97(12): 6722-6727


(2) Correlation of transarterial transport of various dextrans with their physicochemical properties.
O Elmalak, MA Lovich, E Edelman. Biomaterials 2000; 21: 2263-2272


(3) Arterial Paclitaxel Distribution and Deposition. CJ Creel, MA Lovich, ER Edelman. Circ Res. 2000;86:879-884


(4) Specific binding to intracellular proteins determines arterial transport properties for rapamycin and Paclitaxel.
AD Levin, N Vukmirovic, Chao-Wei Hwang, and ER Edelman. PNAS Jun 2004; 101(25): 9463–9467.
www.pnas.org/cgi/doi/10.1073/pnas.0400918101

(5) Amyloid beta toxicity dependent upon endothelial cell state. M Balcells, JS Wallins, ER Edelman.
Neuroscience Letters 441 (2008) 319–322

Endothelial Damage as an Inflammatory State

Autoimmunity may drive vascular disease through anti-endothelial cell (EC) antibodies. This raises a question about whether an increased morbidity of cardiovascular diseases in concert with systemic illnesses may involve these antibodies.

Matrix-embedded ECs act as powerful regulators of vascular repair accompanied by significant reduction in expected systemic and local inflammation.

The Lab researchers compared the immune response against free and matrix-embedded ECs in naive mice and mice with heightened EC immune reactivity. Mice were presensitized to EC with repeated subcutaneous injections of saline-suspended porcine EC (PAE) (5*10^5 cells).

On day 42, both naive mice (controls) and mice with heightened EC immune reactivity received 5*10^5 matrix-embedded or free PAEs. Circulating PAE-specific antibodies and effector T-cells were analyzed 90 days after implantation for -

  • PAE-specific antibody-titers,
  • frequency of CD4+-effector cells, and
  • xenoreactive splenocytes

These were 2- to 4-fold lower (P<0.0001) when naıve mice were injected with matrix-embedded instead of saline-suspended PAEs.

Though basal levels of circulating antibodies were significantly elevated after serial PAE injections (2210+341 mean fluorescence intensity, day 42) and almost doubled again 90 days after injection of a fourth set of free PAEs, antibody levels declined by half in recipients of matrix-embedded PAEs at day 42 (P<0.0001), as did levels of CD4+-effector cells and xenoreactive splenocytes.

A significant immune response to implantation of free PAE is elicited in naıve mice, that is even more pronounced in mice with pre-developed anti-endothelial immunity.

Matrix-embedding protects xenogeneic ECs against immune reaction in naive mice and in mice with heightened immune reactivity.

Matrix-embedded EC might offer a promising approach for treatment of advanced cardiovascular disease. (1)

Researchers examined the molecular mechanisms through which

mechanical force and hypertension modulate

endothelial cell regulation of vascular homeostasis.

Exposure to mechanical strain increased the paracrine inhibition of vascular smooth muscle cells (VSMCs) by endothelial cells.

Mechanical strain stimulated the production by endothelial cells of perlecan and heparan-sulfate glycosaminoglycans. By inhibiting the expression of perlecan with an antisense vector researchers demonstrated that perlecan was essential to the strain-mediated effects on endothelial cell growth control.

Mechanical regulation of perlecan expression in endothelial cells was

  • governed by a mechano-transduction pathway
  • requiring transforming growth factor (TGF-β) signaling and
  • intracellular signaling through the ERK pathway.

Immunohistochemical staining of the aortae of spontaneously hypertensive rats
demonstrated strong correlations between

  • endothelial TGF-β,
  • phosphorylated signaling intermediates, and
  • arterial thickening.

Studies on ex vivo arteries exposed to varying levels of pressure demonstrated that

ERK and TGF-beta signaling were required for pressure-induced upregulation of endothelial HSPG.

The Team’s findings suggest a novel feedback control mechanism in which

  • net arterial remodeling to hemodynamic forces is controlled by a dynamic interplay between growth stimulatory signals from vSMCs and
  • growth inhibitory signals from endothelial cells. (2)

Heparan-sulfate proteoglycans (HSPGs) are potent regulators of vascular remodeling and repair.
 The major enzyme capable of degrading HSPGs is heparanase, which led us to examine
the role of heparanase in controlling

  • arterial structure,
  • mechanics, and
  • remodeling.

In vitro studies suggested heparanase expression in endothelial cells serves as a negative regulator of endothelial inhibition of vascular smooth muscle cell (vSMC) proliferation.

ECs inhibit vSMC proliferation through the interplay between

  • growth stimulatory signals from vSMCs and
  • growth inhibitory signals from ECs.

This would be expected if ECs had HSPGs that are degraded by heparanase.
Arterial structure and remodeling to injury is modified by heparanase expression.
Transgenic mice overexpressing heparanase had

  • increased arterial thickness,
  • cellular density, and
  • mechanical compliance.

Endovascular stenting studies in Zucker rats demonstrated increased heparanase expression in the neointima of obese, hyperlipidemic rats in comparison to lean rats.

The extent of heparanase expression within the neointima strongly correlated with the neointimal thickness following injury. To test the effects of heparanase overexpression on arterial repair, researchers developed a novel murine model of stent injury using small diameter self-expanding stents.

Using this model, researchers found that increased

  • neointimal formation and
  • macrophage recruitment occurs in transgenic mice overexpressing heparanase.
  • Taken together, these results support a role for heparanase in the regulation of arterial structure, mechanics, and repair. (3)

The first host–donor reaction in transplantation occurs at the blood–tissue interface.
When the primary component of the implant (donor) is the endothelial cells, it incites an immunologic reaction. Injections of free endothelial cell implants elicit a profound major histocompatibility complex (MHC) II dominated immune response.

Endothelial cells embedded within three-dimensional matrices behave like quiescent endothelial cells.

Perivascular implants of such embedded ECs cells are the most potent inhibitor of intimal hyperplasia and thrombosis following controlled vascular injury, but without any immune reactivity.

Allo- and even exenogenic endothelial cells evoke no significant humoral or
cellular immune response in immune-competent hosts when embedded within matrices.
 Moreover,  endothelial implants are immune-modulatory, reducing the extent of the memory response to previous free cell implants.

Attenuated immunogenicity results in muted activation of adaptive and innate immune cells. These findings point toward a pivotal role of matrix–cell-interconnectivity for

  • the cellular immune phenotype and might therefore assist in the design  of
  • extracellular matrix components for successful tissue engineering. (4)

Because changes in subendothelial matrix composition are associated with alterations of the endothelial immune phenotype, researchers sought to understand if

  • cytokine-induced NF-κB activity and
  • downstream effects depend on substrate adherence of endothelial cells (EC).

The team compared the upstream

  • phosphorylation cascade,
  • activation of NF-ĸβ, and
  • expression/secretion

of downstream effects of EC grown on tissue culture polystyrene plates (TCPS) with EC embedded within collagen-based matrices (MEEC).

Adhesion of natural killer (NK) cells was quantified in vitro and in vivo.

  • NF-κβ subunit p65 nuclear levels were significantly lower and
  • p50 significantly higher in cytokine-stimulated MEEC than in EC-TCPS.

Despite similar surface expression of TNF-α receptors, MEEC had significantly decreased secretion and expression of IL-6, IL-8, MCP-1, VCAM-1, and ICAM-1.

Attenuated fractalkine expression and secretion in MEEC (two to threefold lower than in EC-TCPS; p < 0.0002) correlated with 3.7-fold lower NK cell adhesion to EC (6,335 ± 420 vs. 1,735 ± 135 cpm; p < 0.0002).

Furthermore, NK cell infiltration into sites of EC implantation in vivo was significantly reduced when EC were embedded within matrix.

Matrix embedding enables control of EC substratum interaction.

This in turn regulates chemokine and surface molecule expression and secretion, in particular – of those compounds within NF-κβ pathways,

  • chemoattraction of NK cells,
  • local inflammation, and
  • tissue repair. (5)

Monocyte recruitment and interaction with the endothelium is imperative to vascular recovery.

Tie2 plays a key role in endothelial health and vascular remodeling.
Researchers studied monocyte-mediated Tie2/angiopoietin signaling following interaction of primary monocytes with endothelial cells and its role in endothelial cell survival.

The direct interaction of primary monocytes with subconfluent endothelial cells

resulted in transient secretion of angiopoietin-1 from monocytes and

the activation of endothelial Tie2. This effect was abolished by preactivation of monocytes with tumor necrosis factor-α (TNFα).

Although primary monocytes contained high levels of

  • both angiopoietin 1 and 2,
  • endothelial cells contained primarily angiopoietin 2.

Seeding of monocytes on serum-starved endothelial cells reduced caspase-3 activity by 46+5.1%, and 52+5.8% after TNFα treatment, and it decreased single-stranded DNA levels by 41+4.2% and 40+ 3.5%, respectively.

This protective effect of monocytes on endothelial cells was reversed by Tie2 silencing with specific short interfering RNA.

The antiapoptotic effect of monocytes was further supported by the

  • activation of cell survival signaling pathways involving phosphatidylinositol 3-kinase,
  • STAT3, and
  • AKT.

Monocytes and endothelial cells form a unique Tie2/angiopoietin-1 signaling system that affects endothelial cell survival and may play critical a role in vascular remodeling and homeostasis. (6)

(1) Cell–Matrix Contact Prevents Recognition and Damage of Endothelial Cells in States of Heightened Immunity.
H Methe, ER Edelman. Circulation. 2006;114[suppl I]:I-233–I-238.
http://www.circulationaha.org/DOI/10.1161/CIRCULATIONAHA.105.000687

(2) Endothelial Cells Provide Feedback Control for Vascular Remodeling Through a Mechanosensitive Autocrine
TGFβ Signaling Pathway. AB Baker, DS Ettenson, M Jonas, MA Nugent, RV Iozzo, ER Edelman.
Circ. Res. 2008;103;289-297   http://dx.doi.org/10.1161/CIRCRESAHA.108.179465http://circres.ahajournals.org/cgi/content/full/103/3/289

(3) Heparanase Alters Arterial Structure, Mechanics, and Repair Following Endovascular Stenting in Mice.
AB Baker, A Groothuis, M Jonas, DS Ettenson…ER Edelman.   Circ. Res. 2009;104;380-387;
http://dx.doi.org/10.1161/CIRCRESAHA.108.180695  http://circres.ahajournals.org/cgi/content/full/104/3/380

(4) The effect of three-dimensional matrix-embedding of endothelial cells on the humoral and cellular immune response.
H Methe, S Hess, ER Edelman. Seminars in Immunology 20 (2008) 117–122. http://dx.doi.org/10.1016/j.smim.2007.12.005

(5) NF-kB Activity in Endothelial Cells Is Modulated by Cell Substratum Inter-actions and Influences Chemokine-Mediated
Adhesion of Natural Killer Cells.  S Hess, H Methe, Jong-Oh Kim, ER Edelman.
Cell Transplantation 2009; 18: 261–273


(6) Primary Monocytes Regulate Endothelial Cell Survival Through Secretion of Angiopoietin-1 and Activation of Endothelial Tie2.
SY Schubert, A Benarroch, J Monter-Solans and ER Edelman. Arterioscler Thromb Vasc Biol 2011;31;870-875
http://dx.doi.org/10.1161/ATVBAHA.110.218255

Neointimal Formation, Shear Stress, and Remodelling with Reference to Diabetes

Innate immunity is of major importance in vascular repair. The present study evaluated whether

  • systemic and transient depletion of monocytes and macrophages with
  • liposome-encapsulated bisphosphonates inhibits experimental in-stent neointimal formation.

The Experiment

Rabbits fed on a hypercholesterolemic diet underwent bilateral iliac artery balloon denudation and stent deployment.

Liposomal alendronate (3 or 6 mg/kg) was given concurrently with stenting.

  • Monocyte counts were reduced by 90% 24 to 48 hours aftera single injection of liposomal alendronate, returning to basal levels at 6 days.

This treatment significantly reduced

  • intimal area at 28 days, from 3.88+0.93 to 2.08+0.58 and 2.16 +0.62 mm2.
  • Lumen area was increased from 2.87+0.44 to 3.57­+0.65 and 3.45+0.58 mm2, and
  • arterial stenosis was reduced from 58 11% to 37 8% and 38 7% in controls, in rabbits treated with 3 mg/kg, and with 6 mg/kg, respectively (mean+SD, n=8 rabbits/group, P< 0.01 for all 3 parameters).

No drug-related adverse effects were observed.
Reduction in neointimal formation was associated with

  • reduced arterial macrophage infiltration and proliferation at 6 days and with an
  • equal reduction in intimal macrophage and smooth muscle cell content at 28 days after injury.

Conversely, drug regimens ineffective in reducing monocyte levels did not inhibit neointimal formation.
Researchers have shown that a

  • single liposomal bisphosphonates injection concurrent with injury reduces in-stent neointimal formation and
  • arterial stenosis in hypercholesterolemic rabbits, accompanied by systemic transient depletion of monocytes and macrophages. (1)

Diabetes and insulin resistance are associated with increased disease risk and poor outcomes from cardiovascular interventions.

Even drug-eluting stents exhibit reduced efficacy in patients with diabetes.
Researchers reported the first study of vascular response to stent injury in insulin-resistant and diabetic animal models.

Endovascular stents were expanded in the aortae of

  • obese insulin-resistant and
  • type 2 diabetic Zucker rats,
  • in streptozotocin-induced type 1 diabetic Sprague-Dawley rats, and
  • in matched controls.

Insulin-resistant rats developed thicker neointima (0.46+0.08 versus 0.37+0.06 mm2, P 0.05), with  decreased lumen area (2.95+0.26 versus 3.29+0.15 mm2, P 0.03) 14 days after stenting compared with controls, but without increased vascular inflammation (tissue macrophages).

Insulin-resistant and diabetic rat vessels did exhibit markedly altered signaling pathway activation 1 and 2 weeks after stenting, with up to a 98% increase in p-ERK (anti-phospho ERK) and a 54% reduction in p-Akt (anti-phospho Akt) stained cells. Western blotting confirmed a profound effect of insulin resistance and diabetes on Akt and ERK signaling in stented segments. p-ERK/p-Akt ratio in stented segments uniquely correlated with neointimal response (R2 = 0.888, P< 0.04) , but not in lean controls.

Transfemoral aortic stenting in rats provides insight into vascular responses in insulin resistance and diabetes.

Shifts in ERK and Akt signaling related to insulin resistance may reflect altered tissue repair in diabetes accompanied by a

  • shift in metabolic : proliferative balance.

These findings may help explain the increased vascular morbidity in diabetes and suggest specific therapies for patients with insulin resistance and diabetes. (2)

Researchers investigated the role of Valsartan (V) alone or in combination with Simvastatin (S) on coronary atherosclerosis and vascular remodeling, and tested the hypothesis that V or V/S attenuate the pro-inflammatory effect of low endothelial shear stress (ESS).

Twenty-four diabetic, hyperlipidemic swine were allocated into Early (n = 12) and Late (n=12) groups.
Diabetic swine in each group were treated with Placebo (n=4), V (n = 4) and V/S (n = 4) and  followed for 8 weeks in the Early group and 30 weeks in the Late group.

Blood pressure, serum cholesterol and glucose were similar across the treatment subgroups.
ESS was calculated in plaque-free subsegments of interest (n = 109) in the Late group at week 23.
Coronary arteries of this group were harvested at week 30, and the subsegments of interest were identified, and analyzed histopathologically.

Intravascular geometrically correct 3-dimensional reconstruction of the coronary arteries of 12 swine was performed 23 weeks after initiation of diabetes mellitus and a hyperlipidemic diet. Local endothelial shear stress was calculated

  • in plaque-free subsegments of interest (n=142) with computational fluid dynamics, and
  • the coronary arteries (n=31) were harvested and the same subsegments were identified at 30 weeks.

V alone or with S

  • reduced the severity of inflammation in high-risk plaques.
Both regimens attenuated the severity of enzymatic degradation of the arterial wall, reducing the severity of expansive remodeling.
  • attenuated the pro-inflammatory effect of low ESS.
V alone or with S
  • exerts a beneficial effect of reducing and stabilizing high-risk plaque characteristics independent of a blood pressure- and lipid-lowering effect. (3)

This study tested the hypothesis that low endothelial shear stress  augments the

  • expression of matrix-degrading proteases, promoting the
  • formation of thin-capped atheromata.

Researchers assessed the messenger RNA and protein expression, and elastolytic activity of selected elastases and their endogenous inhibitors.

Subsegments with low endothelial shear stress at week 23 showed

  • reduced endothelial coverage,
  • enhanced lipid accumulation, and
  • intense infiltration of activated inflammatory cells at week 30.

These lesions showed increased expression of messenger RNAs encoding

  • matrix metalloproteinase-2, -9, and -12, and cathepsins K and S
  • relative to their endogenous inhibitors and
  • increased elastolytic activity.

Expression of these enzymes correlated positively with the severity of internal elastic lamina fragmentation.

Thin-capped atheromata in regions with

  • lower preceding endothelial shear stress had
  • reduced endothelial coverage,
  • intense lipid and inflammatory cell accumulation,
  • enhanced messenger RNA expression and
  • elastolytic activity of MMPs and cathepsins with
  • severe internal elastic lamina fragmentation.

Low endothelial shear stress induces endothelial discontinuity and

  • accumulation of activated inflammatory cells, thereby
  • augmenting the expression and activity of elastases in the intima and
  • shifting the balance with their inhibitors toward matrix breakdown.

Team’s results provide new insight into the mechanisms of regional formation of plaques with thin fibrous caps. (4)

Elevated CRP levels predict increased incidence of cardiovascular events and poor outcomes following interventions. There is the suggestion that CRP is also a mediator of vascular injury.

Transgenic mice carrying the human CRP gene (CRPtg) are predisposed to arterial thrombosis post-injury.

Researchers examined whether CRP similarly modulates the proliferative and hyperplastic phases of vascular repair in CRPtg when thrombosis is controlled with daily aspirin and heparin at the time of trans-femoral arterial wire-injury.

Complete thrombotic arterial occlusion at 28 days was comparable for wild-type and CRPtg mice (14 and 19%, respectively). Neointimal area at 28d was 2.5 fold lower in CRPtg (4190±3134 m2, n = 12) compared to wild-types (10,157±8890 m2, n = 11, p < 0.05).

Likewise, neointimal/media area ratio was 1.10±0.87 in wild-types and 0.45±0.24 in CRPtg (p < 0.05).

  • Seven days post-injury, cellular proliferation and apoptotic cell number in the intima were both less pronounced in CRPtg than wild-type.
  • No differences were seen in leukocyte infiltration or endothelial coverage.
CRPtg mice had significantly reduced p38 MAPK signaling pathway activation following injury.

The pro-thrombotic phenotype of CRPtg mice was suppressed by aspirin/heparin, revealing CRP’s influence on neointimal growth after trans-femoral arterial wire-injury.

  • Signaling pathway activation,
  • cellular proliferation, and
  • neointimal formation

were all reduced in CRPtg following vascular injury.
 Increasingly the Team was aware of CRP multipotent effects.
 Once considered only a risk factor, and recently a harmful agent, CRP is a far more complex regulator of vascular biology. (5)

(1) Liposomal Alendronate Inhibits Systemic Innate Immunity and Reduces In-Stent Neointimal
Hyperplasia in Rabbits. HD Danenberg, G Golomb, A Groothuis, J Gao…, ER Edelman.
Circulation. 2003;108:2798-2804


(2) Vascular Neointimal Formation and Signaling Pathway Activation in Response to Stent Injury
in Insulin-Resistant and Diabetic Animals. M Jonas, ER Edelman, A Groothuis, AB Baker, P Seifert, C Rogers.
Circ. Res. 2005;97;725-733.        http://dx.doi.org/10.1161/01.RES.0000183730.52908.C6
http://circres.ahajournals.org/cgi/content/full/97/7/725

(3) Attenuation of inflammation and expansive remodeling by Valsartan alone or in combination with
Simvastatin in high-risk coronary atherosclerotic plaques. YS Chatzizisis, M Jonas, R Beigel, AU Coskun…
ER Edelman, CL Feldman, PH Stone.  Atherosclerosis 203 (2009) 387–394


(4) Augmented Expression and Activity of Extracellular Matrix-Degrading Enzymes in Regions of Low
Endothelial Shear Stress Colocalize With Coronary Atheromata With Thin Fibrous Caps in Pigs.
YS Chatzizisis, AB Baker, GK Sukhova,…P Libby, CL Feldman, ER Edelman, PH Stone
Circulation 2011;123;621-630     http://dx.doi.org/10.1161/CIRCULATIONAHA.110.970038
http://circ.ahajournals.org/cgi/content/full/123/6/621


(5) Neointimal formation is reduced after arterial injury in human crp transgenic mice
HD Danenberg, E Grad, RV Swaminathan, Z Chenc,…ER Edelman
Atherosclerosis 201 (2008) 85–91

A Rattle Bag of Science and the Art of Translation

Science Translational Medicine – A rattle bag of science and the art of translation
E. R. Edelman, G. A. FitzGerald.
Sci.Transl. Med. 3, 104ed3 (2011). http://dx.doi.org/10.1126/scitranslmed.3002131

Elazer R. Edelman is the Thomas D. and Virginia W. Cabot Professor of Health Sciences and Technology at MIT,
Professor of Medicine at Harvard Medical School, a coronary care unit cardiologist at the Brigham and Women’s
Hospital, and Director of the Harvard-MIT Biomedical Engineering Center. E-mail: ere@mit.edu

Garret A. FitzGerald is the McNeil Professor in Translational Medicine and Therapeutics, Chair of the Department of
Pharmacology, and Director of the Institute for Translational Medicine & Therapeutics, University of Pennsylvania.
E-mail: garret@upenn.edu

In 2011, the American Association for the Advancement of Science (AAAS)  founded Science Translational Medicine (STM)
to disseminate interdisciplinary science integrating basic and clinical research that defines and fosters new therapeutics, devices, and diagnostics.

Conceived and nourished under the creative vision of Elias Zerhouni and Katrina Kelner, the journal has attracted widespread attention.
Now, as we assume the mantle of co-chief scientific advisors, we look back on the journal’s early accomplishments, restate our mission, and make clear the kinds of manuscripts we seek and accept for publication.

STM’s mission, as articulated by Elias and Katrina, was to

“promote human health by providing a forum for communication and cross-fertilization among basic, translational, and clinical research practitioners and trainees from all relevant established and emerging disciplines.”

This statement remains relevant and accurate today.
 With this mission on our masthead, STM now receives ~25 manuscripts (full-length research articles) per week and publishes ~10% of them. Roughly half of the submissions are deemed inappropriate for the journal and are returned without review within 8 to 10 days of receipt.

Of those papers that undergo full peer review,

decisions to reject are made within 48 days and

the mean time to acceptance (including the revision period) is 125 days.

There is now an average wait of only 24 days between acceptance and publication.

Defining TRANSLATIONAL Medicine

In accord with the journal’s broad readership, the ideal manuscript meets five criteria: It
(i) reports a discovery of translational relevance with high-impact potential;
(ii) has a conceptual focus with interdisciplinary appeal;
(iii) elucidates a biological mechanism;
(iv) is innovative and novel; and
(v) is presented in clear, broadly accessible language.
 STM seeks to publish research that describes

  • how innovative concepts drive the creative biomedical science
  • that ultimately improves the quality of people’s lives—

This is the broadest of our journal’s criteria but is the one that sets us apart as well.
Translational relevance does not require demonstration of benefit in humans but does require the evident potential to advance clinical medicine, thus impacting the direction of our culture and the welfare of our communities. Conceptual focus and mechanistic emphasis discriminate our papers from those that contain observational descriptions of technical findings for which value is restricted to a specific discipline.

However, innovation and novelty may apply to a fundamental scientific discovery or to the nature of its application and relevance to the translational process. Criteria enable the journal to consider versatile technological advances that apply new and creative thinking but may not necessarily offer fresh insights into biological mechanisms. Finally, while the subsequent additional efforts of the STM editorial staff are not to be discounted, the clarity of writing and coherence of argument presented within a submitted manuscript are likely to facilitate its progress through the challenge of peer review.

On Causes - Hippocrates, Aristotle, Robert Koch, and the Dread Pirate Roberts

Elazer R. Edelman
Circulation 2001;104:2509-2512

The idea of risk factors for vascular disease has evolved

  • from a dichotomous to continuous hazard analysis and
  • from the consideration of a few factors to
  • mechanistic investigation of many interrelated risks.

However, confusion still abounds regarding issues of association and causation. Originally, the simple presence of

  • tobacco abuse, hypertension, and/or hypercholesterolemia were tallied, and
  • the cumulative score was predictive of subsequent coronary artery disease.

Since then, dose responses have been defined for these and other factors and it has been suggested that almost 300 factors place patients at risk; these factors include elevations in plasma homocysteine.
 Recent studies shed interesting light on the mechanism of this potentially causal relationship, which was first noted in 1969.

Aside from putative effects on vessel wall dynamics, there is now direct evidence that homocysteine is atherogenic. Twenty-fold increases in plasma homocysteine achieved by dietary manipulation of apoE–/– mice increased aortic root lesion size 2-fold and produced a prolonged chronic inflammatory mural response accompanied by elevations in vascular cell adhesion molecule-1 (VCAM) and tumor necrosis factor-a (TNF-a).

In long term followup, homocysteine levels elevated by

  • dietary supplementation with methionine or homocysteine
  • promoted lesion size and plaque fibrosis in these
  • atherosclerosis-prone mice early in life, but without influencing ultimate plaque burden as the animals aged.

A number of mechanisms were proposed by which homocysteine achieved this effect, including

  • promotion of inflammation,
  • regulation of lipoprotein metabolism, and
  • modification of critical biochemical pathways and
  • metabolites including nitric oxide (NO).

See p 2569
In the present issue of Circulation,

Stühlinger et al 7 advance these mechanistic insights one critical step further by defining homocysteine’s effects at an enzymatic level.

The group led by Lentz published an association between levels of the

  • endogenous inhibitor of Nirtic Oxide synthase,
  • asymmetric dimethyl arginine (ADMA), and
  • homocysteine in cultured endothelial cells and in the serum of cynomolgus monkeys.

Such an association is interesting because the L-arginine–NO synthase pathway seems to be a critical component in the full range of endothelial cell biology and vascular dysfunction.

Stühlinger et al 7  now show that increased cultured endothelial cell elaboration of ADMA by homocysteine and its precursor L-methionine is associated with a dose-dependent impairment of the activity of endothelial dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that degrades ADMA. Homocysteine directly inhibited DDAH activity in a cell-free system by targeting a critical sulfhydryl group on this enzyme.

Thus, one could envision that the balance of cardiovascular health and disease could well be determined by the ability of an intact Nirtic Oxide synthase system to overcome environmental, dietary, and even genetic factors.

In patients with altered enzymatic defense systems,

  • elevated homocysteine,
  • oxidized lipoproteins,
  • inflammation, and other
  • vasotoxins

may dominate even the most potent defense mechanisms.
These studies raise a number of issues.
Do we need to add to our list of established cardiovascular risk factors to accommodate new findings and associations?
Is there a final common pathway for all risk factors or perhaps even a unified factor theory into which all potential risks can be grouped?
And, as always, should we consider Nirtic Oxide at the core of this universality?
Finally, should we change our focus altogether and speak not of risk factors but of

  • genetic predisposition,
  • extent of biochemical aberration, and
  • degree of physical damage?

Some would view these remarkable success stories and the repeated association of hyperhomocyst(e)inemia with coronary, cerebral, and peripheral vascular disease and simply advocate for increased folic acid intake for all.

Indeed, this intervention of negligible cost and

  • insignificant side effect is already partially in place;
  • many foods are fortified with folate to prevent congenital neural tube defects.

This reader considers the seminal work by Vernon Young and Yves Ingenbleek on the relationship between

  • S8 and regions distant from lava flows in Asia and Indian subcontinents,
  • where they have determined hyperhomocysteinemia and the consequence associated with:
  • veganism (not voluntary)
  • impaired methyl donor reactions and transsulfuration pathways (not corrected by B12, folate)
  • loss of lean body mass due to the constant relationship of S:N (insufficient from plant sources)

What happens, when we fail to continue to pursue causality,

  • the linkage of biological significance or scientific plausibility with
  • epidemiologically or statistically significant association?

In medicine, risk becomes the likelihood that people without a disease will acquire the disease through contact with factors thought to increase disease risk.

All of these risk factors are then, by nature, imprecise and nonspecific.
 They are stochastic measures of what will happen to normal people who fall into particular measures of these parameters.

The daring may be willing to accept these risks, citing friend and foe who live well beyond or for far lesser times than anticipated by risk alone. Such concerns may well become moot if we can simultaneously identify patients at risk

  • by linking phenotype with genotype,
  • gene expression with protein elaboration, and
  • environmental exposures with the biochemical consequences and
  • direct anatomic aberrations they induce.

This kind of characterization may well replace a family history of arterial disease as a rough estimate of

  • genotype,
  • serum cholesterol as an indirect measure of the health of lipoprotein metabolism,
  • serum glucose as a crude determinant of the ravages of diabetes mellitus,
  • blood pressure measurement as a marker of long-standing endogenous exposure to altered flow, and
  • tobacco abuse as a maker of long-standing exposure to exogenous toxins.

Rather than identifying patients on the basis of their serum cholesterol, we will have a direct measure of their

  • LDL receptor number,
  • internalization rate,
  • macrophage content in the blood vessel wall,
  • metalloproteinase activity, etc.
  • insulin receptor metabolism,
  • oxidative state, and
  • glycated burden.
  • Serum glucose will similarly give way to these tests

Evaluating a new way to open clogged arteries: Computational model offers insight into mechanisms of drug-coated balloons.

A new study from MIT analyzes the potential usefulness of a new treatment that combines the benefits of angioplasty balloons and drug-releasing stents, but may pose fewer risks. With this new approach, a balloon is inflated in the artery for only a brief period, during which it releases a drug that prevents cells from accumulating and clogging the arteries over time.
While approved for limited use in Europe, these drug-coated balloons are still in development in the United States and have not received FDA approval. The MIT study, which models the behavior of the balloons, should help scientists optimize their performance and aid regulators in evaluating their effectiveness and safety.
“Until now, people who evaluate such technology could not distinguish hype from promise,” says Elazer Edelman, the Thomas D. and Virginia W. Cabot Professor of Health Sciences and Technology and senior author of the paper describing the study, which appeared online recently in the journal Circulation.
Lead author of the paper is Vijaya Kolachalama, a former MIT postdoc who is now a principal member of the technical staff at the Charles Stark Draper Laboratory.
Edelman’s lab is investigating a possible alternative to the current treatments: drug-coated balloons. “We’re trying to understand how and when this therapy could work and identify the conditions in which it may not,” Kolachalama says. “It has its merits; it has some disadvantages.”

Modeling drug release

The drug-coated balloons are delivered by a catheter and inflated at the narrowed artery for about 30 seconds, sometimes longer. During that time, the balloon coating, containing a drug such as Zotarolimus, is released from the balloon. The properties of the coating allow the drug to be absorbed in the body’s tissues. Once the drug is released, the balloon is removed.
In their new study, Kolachalama, Edelman and colleagues set out to rigorously characterize the properties of the drug-coated balloons. After performing experiments in tissue grown in the lab and in pigs, they developed a computer model that explains the dynamics of drug release and distribution. They found that factors such as the size of the balloon, the duration of delivery time, and the composition of the drug coating all influence how long the drug stays at the injury site and how effectively it clears the arteries.
One significant finding is that when the drug is released, some of it sticks to the lining of the blood vessels. Over time, that drug is slowly released back into the tissue, which explains why the drug’s effects last much longer than the initial 30-second release period.
“This is the first time we can explain the reasons why drug-coated balloons can work,” Kolachalama says. “The study also offers areas where people can consider thinking about optimizing drug transfer and delivery.”

http://circ.ahajournals.org/content/127/20/2047.short  
http://www.mit.edu/people/vbk/Circulation_2013.pdf 
http://www.sciencedaily.com/…13/05/130521121513.ht…    
Circulation, 2013; 127 (20): 2047 – 2055
http://dx.doi.org/10.1161/CIRCULATIONAHA.113.002051;

 

Conclusion

MIT’s Edelman’s Lab conducted the pioneering work in Vascular biology, animal models of drug eluting stents and was at the forefront of Empirical Molecular Cardiology in its studies in vascular physiology, biology and biomaterials for medical devices.

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Suppression of JAK2/STAT3 Signaling Reduces End-to-End Arterial Anastomosis Induced Cell Proliferation in Common Carotid Arteries of Rats (plosone.org)

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The Heart Revolution By Kilmer McCully, Martha McCully

HarperCollinsPublishers, 1969

http://books.google.com/books?id=iYLbuZFxEt8C&pg=PR20&dq=New+York+Times+homocysteine+and+Cholesterol&hl=en&sa=X&ei=_0F7UfDRA8zB4APozIHQAQ&ved=0CEMQ6AEwAg

 

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http://pharmaceuticalintelligence.com/2013/02/27/arteriogenesis-and-cardiac-repair-two-biomaterials-injectable-thymosin-beta4-and-myocardial-matrix-hydrogel/

Cardiac Surgery Theatre in China vs. in the US: Cardiac Repair Procedures, Medical Devices in Use, Technology in Hospitals, Surgeons’ Training and Cardiac Disease Severity”

Aviva Lev-Ari, PhD, RN 1/8/2013

http://pharmaceuticalintelligence.com/2013/01/08/cardiac-surgery-theatre-in-china-vs-in-the-us-cardiac-repair-procedures-medical-devices-in-use-technology-in-hospitals-surgeons-training-and-cardiac-disease-severity/

Heart Remodeling by Design – Implantable Synchronized Cardiac Assist Device: Abiomed’s Symphony

Aviva Lev-Ari, PhD, RN 7/23/2012

http://pharmaceuticalintelligence.com/2012/07/23/heart-remodeling-by-design-implantable-synchronized-cardiac-assist-device-abiomeds-symphony/

Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI

Aviva Lev-Ari, PhD, RN 3/10/2013

http://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/

Dilated Cardiomyopathy: Decisions on implantable cardioverter-defibrillators (ICDs) using left ventricular ejection fraction (LVEF) and Midwall Fibrosis: Decisions on Replacement using late gadolinium enhancement cardiovascular MR (LGE-CMR)

Aviva Lev-Ari, PhD, RN 3/10/2013
http://pharmaceuticalintelligence.com/2013/03/10/dilated-cardiomyopathy-decisions-on-implantable-cardioverter-defibrillators-icds-using-left-ventricular-ejection-fraction-lvef-and-midwall-fibrosis-decisions-on-replacement-using-late-gadolinium/

The Heart: Vasculature Protection – A Concept-based Pharmacological Therapy including THYMOSIN

Aviva Lev-Ari, PhD, RN 2/28/2013
http://pharmaceuticalintelligence.com/2013/02/28/the-heart-vasculature-protection-a-concept-based-pharmacological-therapy-including-thymosin/

FDA Pending 510(k) for The Latest Cardiovascular Imaging Technology

Aviva Lev-Ari, PhD, RN 1/28/2013
http://pharmaceuticalintelligence.com/2013/01/28/fda-pending-510k-for-the-latest-cardiovascular-imaging-technology/

PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity

Aviva Lev-Ari, PhD, RN 1/10/2013
http://pharmaceuticalintelligence.com/2013/01/10/pci-outcomes-increased-ischemic-risk-associated-with-elevated-plasma-fibrinogen-not-platelet-reactivity/

The ACUITY-PCI score: Will it Replace Four Established Risk Scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX

Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/01/03/the-acuity-pci-score-will-it-replace-four-established-risk-scores-timi-grace-syntax-and-clinical-syntax/

Coronary artery disease in symptomatic patients referred for coronary angiography: Predicted by Serum Protein Profiles

Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2012/12/29/coronary-artery-disease-in-symptomatic-patients-referred-for-coronary-angiography-predicted-by-serum-protein-profiles/

Heart Renewal by pre-existing Cardiomyocytes: Source of New Heart Cell Growth Discovered

Aviva Lev-Ari, PhD, RN 12/23/2012
http://pharmaceuticalintelligence.com/2012/12/23/heart-renewal-by-pre-existing-cardiomyocytes-source-of-new-heart-cell-growth-discovered/

Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis.

Aviva Lev-Ari, PhD, RN 10/30/2012
http://pharmaceuticalintelligence.com/2012/10/30/cardiovascular-risk-inflammatory-marker-risk-assessment-for-coronary-heart-disease-and-ischemic-stroke-atherosclerosis/

To Stent or Not? A Critical Decision

Aviva Lev-Ari, PhD, RN 10/23/2012
http://pharmaceuticalintelligence.com/2012/10/23/to-stent-or-not-a-critical-decision/

New Definition of MI Unveiled, Fractional Flow Reserve (FFR)CT for Tagging Ischemia

Aviva Lev-Ari, PhD, RN 8/27/2012
http://pharmaceuticalintelligence.com/2012/08/27/new-definition-of-mi-unveiled-fractional-flow-reserve-ffrct-for-tagging-ischemia/

Ethical Considerations in Studying Drug Safety — The Institute of Medicine Report

Aviva Lev-Ari, PhD, RN 8/23/2012
http://pharmaceuticalintelligence.com/2012/08/23/ethical-considerations-in-studying-drug-safety-the-institute-of-medicine-report/

New Drug-Eluting Stent Works Well in STEMI

Aviva Lev-Ari, PhD, RN 8/22/2012
http://pharmaceuticalintelligence.com/2012/08/22/new-drug-eluting-stent-works-well-in-stemi/

Expected New Trends in Cardiology and Cardiovascular Medical Devices

Aviva Lev-Ari, PhD, RN 8/17/2012
http://pharmaceuticalintelligence.com/2012/08/17/expected-new-trends-in-cardiology-and-cardiovascular-medical-devices/

Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents

Aviva Lev-Ari, PhD, RN 8/13/2012

http://pharmaceuticalintelligence.com/2012/08/13/coronary-artery-disease-medical-devices-solutions-from-first-in-man-stent-implantation-via-medical-ethical-dilemmas-to-drug-eluting-stents/

Percutaneous Endocardial Ablation of Scar-Related Ventricular Tachycardia

Aviva Lev-Ari, PhD, RN 7/18/2012

http://pharmaceuticalintelligence.com/2012/07/18/percutaneous-endocardial-ablation-of-scar-related-ventricular-tachycardia/

Competition in the Ecosystem of Medical Devices in Cardiac and Vascular Repair: Heart Valves, Stents, Catheterization Tools and Kits for Open Heart and Minimally Invasive Surgery (MIS)

Aviva Lev-Ari, PhD, RN 6/22/2012

http://pharmaceuticalintelligence.com/2012/06/22/competition-in-the-ecosystem-of-medical-devices-in-cardiac-and-vascular-repair-heart-valves-stents-catheterization-tools-and-kits-for-open-heart-and-minimally-invasive-surgery-mis/

Global Supplier Strategy for Market Penetration & Partnership Options (Niche Suppliers vs. National Leaders) in the Massachusetts Cardiology & Vascular Surgery Tools and Devices Market for Cardiac Operating Rooms and Angioplasty Suites

Aviva Lev-Ari, PhD, RN 6/22/2012

http://pharmaceuticalintelligence.com/2012/06/22/global-supplier-strategy-for-market-penetration-partnership-options-niche-suppliers-vs-national-leaders-in-the-massachusetts-cardiology-vascular-surgery-tools-and-devices-market-for-car/

Blood_Vessels

Blood_Vessels (Photo credit: shoebappa)

Visceral Myopathy in Statins

Visceral Myopathy in Statins (Photo credit: Snipergirl)

Medical science has advanced significantly sin...

Medical science has advanced significantly since 1507, when Leonardo da Vinci drew this diagram of the internal organs and vascular systems of a woman. (Photo credit: Wikipedia)

English: Lee Hood, MD, PhD, President and Co-f...

English: Lee Hood, MD, PhD, President and Co-found of the Institute for Systems Biology (Photo credit: Wikipedia)

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Author: Tilda Barliya PhD

Peripheral nerve lacerations are common injuries and often cause long lasting disability (1a) due to pain, paralyzed muscles and loss of adequate sensory feedback from the nerve receptors in the target organs such as skin, joints and muscles (1b).

Nerve injuries are common and typically affect young adults with the majority of injuries occur from trauma or complication of surgery. Traumatic injuries can occur due to stretch, crush, laceration (sharps or bone fragments), and ischemia, and are more frequent in wartime, i.e., blast exposure. Domestic or occupational accidents with glass, knifes of machinery may also occur.

Statistics show that peripheral nervous system (PNS) injuries were 87% from trauma and 12% due to surgery (one-third tumor related, two-thirds non– tumor related). Nerve injuries occurred 81% of the  time in the upper extremities and 11% in the lower extremities, with the balance in other locations (4).

Injury to the PNS can range from severe, leading to major loss of function or intractable neuropathic pain, to mild, with some sensory and/or motor deficits affecting quality of life.

Functional recovery after nerve injury involves a complex series of steps, each of which may delay or impair the regenerative process. In cases involving any degree of nerve injury, it is useful initially to categorize these regenerative steps anatomically on a gross level. The sequence of regeneration may be divided into anatomical zones (4):

  1. the neuronal cell body
  2. the segment between the cell body and the injury site
  3. the injury site itself
  4. the distal segment between the injury site and the end organ
  5. the end organ itself

A delay in regeneration or unsuccessful regeneration may be attributed to pathological changes that impede normal reparative processes at one or more of these zones.

Nanotechnology for regenerative nerves: by Gunilla Elam

Repairing nerve defects with large gaps remains one of the most operative challenges for surgeons. Incomplete recovery from peripheral nerve injuries can produce a diversity of negative outcomes, including numbness, impairment of sensory or motor function, possibility of developing chronic pain, and devastating permanent disability.

In the past few years several techniques have been used to try and repair nerve defects and include:

  • Coaptation
  • Nerve autograph
  • Biological or polymeric nerve conduits (hollow nerve guidance conduits)

For example, When a direct repair of the two nerve ends is not possible, synthetic or biological nerve conduits are typically used for small nerve gaps of 1 cm or less. For extensive nerve damage over a few centimeters in length, the nerve autograft is the “gold standard” technique. The biggest challenges, however, are the limited number and length of available donor nerves, the additional surgery associated with donor site morbidity, and the few effective nerve graft alternatives.

Degeneration of the axonal segment in the distal nerve is an inevitable consequence of disconnection, yet the distal nerve support structure as well as the final target must maintain efficacy to guide and facilitate appropriate axonal regeneration. There is currently no clinical practice targeted at maintaining fidelity of the distal pathway/target, and only a small number of researchers are investigating ways to preserve the distal nerve segment, such as the use of electrical stimulation or localized drug delivery. Thus development of tissue-engineered nerve graft may be a better matched alternative (6,7,9).

The guidance conduit serves several important roles for nerve regeneration such as:
a) directing axonal sprouting from the regenerating nerve
b) protecting the regenerating nerve by restricting the infiltration of fibrous tissue
c) providing a pathway for diffusion of neurotropic and neurotophic factors

Early guidance conduits were primarily made of silicone due to its stability under physiological conditions, biocompatibility, flexibility as well as ease of processing into tubular structures. Although silicone  conduits have proven reasonably successful as conduits for small gap lengths in animal models (<5 mm). The non-biodegradability of silicone conduits has limited its application as a strategy for long-term repair and recovery. Tubes also eventually become encapsulated with fibrous tissue, which leads to nerve compression, requiring additional surgical intervention to remove the tube. Another limiting factor with inert guidance conduits is that they provide little or no nerve regeneration for gap lengths over 10 mm in the PNS unless exogenous growth factors are used (6,7).

In animal studies, biodegradable nerve guidance conduits have provided a feasible alternative, preventing neuroma formation and infiltration of fibrous tissue. Biodegradable conduits have been fabricated from natural or synthetic materials such as collagen, chitosan and poly-L-lactic acid.

Nanostructured Scaffolds for Neural Tissue Engineering: Fabrication and Design

At the micro- and nanoscale, cells of the CNS/PNS reside within functional microenvironments consisting of physical structures including pores, ridges, and fibers that make up the extracellular matrix (ECM) and plasma membrane cell surfaces of closely apposed neighboring cells. Cell-cell and cell-matrix interactions contribute to the formation and function of this architecture, dictating signaling and maintenance roles in the adult tissue, based on a complex synergy between biophysical (e.g. contact-mediated signaling, synapse control), and biochemical factors (e.g. nutrient support and inflammatory protection). Neural tissue engineering scaffolds are aimed toward recapitulating some of the 3D biological signaling that is known to be involved in the maintenance of the PNS and CNS and to facilitate proliferation, migration and potentially differentiation during tissue repair (9).

Nanotechnology and tissue engineering are based on two main approaches:

  • Electrospinning (top-down) - involves the production of a polymer filament using an electrostatic force. Electrospinning is a versatile technique that enables production of polymer fibers with diameters ranging from a few microns to tens of nanometers.
  • Molecular self-assembly of peptides (bottom-up) - Molecular self-assembly is mediated by weak, non-covalent bonds, such as van der Waals forces, hydrogen bonds, ionic bonds, and hydrophobic interactions. Although these bonds are relatively weak, collectively they play a major role in the conformation of biological molecules found in nature.


Pfister et al (6) very nicely summarized the various polymeric fibers been used to achieve the goal of nerve regeneration, even in humans. These material include a wide array of polymers from silica to PLGA/PEG and Diblock copolypeptides.

Many of these approaches also enlist many trophic factors that have been investigated in nerve conduits

Currently there are three general biomaterial approaches for local factor delivery:

  1. Incorporation of factors into a conduit filler such as a hydrogel
  2. Designing a drug release system from the conduit biomaterial such as microspheres
  3. Immobilizing factors on the scaffold that are sensed in place or liberated upon matrix degradation.

Maeda et al had a  creative approach to bridge larger gaps by using the combination of nerve grafts and open conduits in an alternating “stepping stone” assembly, which may perform better than an empty conduit alone (8).

Summary

Peripheral nerve repair is a growing field with substantial progress being made in more effective repairs. Nanotechnology and biomedical engineering have made significant contributions; from surgical instrumentation to the development of tissue engineered grafting substitutes.  However, to date the field of neural tissue engineering has not progressed much past the conduit bridging of small gaps and has not come close to matching the autograf. Much more studies are needed to understand the cell behaviour that can promote cell survival, neurite outgrowth, appropriate re-innervation and consequently the functional recovery post PNS/CNS injuries. This is since understanding of the cellular response to the combination of these external cues within 3D architectures is limited at this stage.

Ref:

1a. Jaquet JB, Luijsterburg AJ, Kalmijn S, Kuypers PD, Hofman A, Hovius SE.  Median, ulnar, and combined median-ulnar nerve injuries:functional outcome and return to productivity. J Trauma 2001 51: 687-692. http://www.ncbi.nlm.nih.gov/pubmed/11586160

1b. Lundborg G, Rosen B. Hand function after nerve repair. Acta Physiol (Oxf) 2007 189: 207-217. http://www.ncbi.nlm.nih.gov/pubmed/17250571

1. Chang WC., Kliot M and Stretavan DW. Microtechnology and Nanotechnology in Nerve Repair. Neurological Research 2008; vol 30: 1053-1062. http://vision.ucsf.edu/sretavan/sretavanpdfs/2008b-Chang%20&%20Sretavan.pdf

2. Biazar E., Khorasani MT and Zaeifi D. Nanotechnology for peripheral nerve regeneration. Int. J. Nano. Dim. 2010 1(1): 1-23.  http://www.ijnd.ir/doc/2010-v1-i1/2010-V1-I1-1.pdf

3. Albert Aguayo. Nerve regeneration revisited. Nature Reviews Neuroscience 7, 601 (August 2006).

http://www.nature.com/nrn/journal/v7/n8/full/nrn1974.html

4. Burnett MG and  Zager EL. Pathophysiology of Peripheral Nerve Injury: A Brief Review. Neurosurg Focus. 2004;16(5) .

http://www.medscape.com/viewarticle/480071_5

5. Dag Welin. Neuroprotection and axonal regeneration after peripheral nerve injury. MEDICAL DISSERTATIONS

Welin, D., Novikova, L.N., Wiberg, M., Kellerth, J-O. and Novikov, L.N. Survival and regeneration of cutaneous and muscular afferent neurons after peripheral nerve injury in adult rats. Experimental Brain Research, 186, 315-323, 2008.

http://link.springer.com/article/10.1007%2Fs00221-007-1232-5

6. Pfister BJ., Gordon T., Loverde JR., Kochar AS., Mackinnon SE and Cullen Dk. Biomedical Engineering Strategies for Peripheral Nerve Repair: Surgical Applications, State of the Art, and Future Challenges. Critical Reviews™ in Biomedical Engineering 2011, 39(2):81–124. http://www.med.upenn.edu/cullenlab/user_documents/2011Pfisteretal-PNIReviewArticleCritRevBME.pdf

7. Zhou K, Nisbet D, Thouas G,  Bernard C and Forsythe J. Bio-nanotechnology Approaches to Neural Tissue Engineering. Intechopen. Com. http://cdn.intechopen.com/pdfs/9811/InTech-Bio_nanotechnology_approaches_to_neural_tissue_engineering.pdf

8. Maeda T, Mackinnon SE, Best TJ, Evans PJ, Hunter DA, Midha RT. Regeneration across ‘stepping-stone’ nerve grafts. Brain Res. 1993;618(2):196–202. http://www.ncbi.nlm.nih.gov/pubmed/?term=Maeda+T+and+regeneration+across+stepping+stone

9. Sedaghati T., Yang SY., Mosahebi A., Alavijeh MS and Seifalian AM. Nerve regeneration with aid of nanotechnology and cellular engineering. Biotechnol Appl Biochem. 2011 Sep-Oct;58(5):288-300. http://www.ncbi.nlm.nih.gov/pubmed/21995532

 

 

 

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Author: Tilda Barliya PhD

Ocular drug delivery is a very challenging field for pharmaceutical scientists.  The unique structure of the eye restricts the entry of drug molecules at the required site of action. The eye and its drugs are classically divided into : Anterior and Posterior segments (1).

Conventional systems like eye drops, suspensions and ointments cannot be considered optimal in  the treatment of vision threatening ocular diseases yet  more than 90% of the marketed ophthalmic formulations are in the form of eye drops.

In the majority of these topical  formulations which target the anterior chamber (the front of the eye) are washed off from the eye by various mechanisms:

  • lacrimation,
  • tear dilution
  • tear turnover
  • Moreover, human cornea comprising of epithelium, substantia propria and endothelium also restricts the ocular entry of drug molecules

Under normal condition the human eye can hold about 25–30 μl of an ophthalmic solution; however after a single blink the volume is reduced to 7–10 μl through nasolacrimal drainage which cause the drug to be systemically absorbed across the nasal mucosa or the gastrointestinal tract. A significant systemic loss from topically applied drugs also occurs from conjunctival absorption into the local circulation (4)

Thus resulting in low ocular  bioavailability of drugs with less than 5% of the drugs entering the eye.   Recently many drug efflux pumps have been identified and significant  enhancement in ocular drug absorption was achieved following their inhibition or evasion. But prolonged use of such inhibitors may result in undesirable effects.

Targeting the posterior chamber is even more difficult due to the tight junctions  of blood retinal barrier (BRB) restrict the entry of systemically administered drugs into the retina. Drugs are therefore delivered to the posterior chamber via:

  • Intravitreal injections
  • Implants
  • periocular injections

Here’s an illustration of the several ocular drug and their administration path

The success of nanoparticle systems for ocular drug delivery may depend on optimizing lipophilic-hydrophilic properties of the polymer-drug system, optimizing rates of biodegradation, and safety. Polymers used for the preparation of nanoparticles should be mucoadhesive and biocompatible. The choice of polymer plays an important role in the release kinetics of the drug from a nanoparticle system (4).

The choice of polymer plays an important role in the release kinetics of the drug from a nanoparticle system. Ocular bioavailability from a mucoadhesive dosage form will depend on the polymer’s bioadhesion characteristics, which are affected by its swelling properties, hydration time, molecular weight, and degree of crosslinking. The binding of drug depends on the physicochemical properties of the molecule as well as of the nanoparticle polymer, and also on the manufacturing process for these nanoparticle systems (4).

Other areas in which nanotechnology may be used is the use as biosensors, cell delivery and scaffolds etc (2)

Delivery of a drug via nanotechnology based product fulfills mainly three  objectives as follows:

  1. enhances drug permeation
  2. controls the release of drug
  3. targets drug

Tiwari et al (1) nicely covered different ocular delivery systems available. In this section we’ll review only few of the these drug products:

Viscosity improver:

The viscosity enhancers used are hydrophilic polymers such as cellulose, polyalcohol and polyacrylic acid. Sodium carboxy methyl cellulose is one of the most important mucoadhesion polymers having mono adhesive strength. Viscosity vehicles increases the contact time and no marked sustaining effect are seen.

Prodrugs:

Prodrugs enhance comeal drug permeability through modification of the hydrophilic or lipophilicity of the drug . The method includes modification of chemical structure of the drug molecule, thus making it selective, site specific and a safe ocular drug delivery system. Drugs with increased penetrability through prodrug formulations are epinephrine1, phenylephrine, timolol, and pilocarpine. The main indication of these drugs is to treat glaucoma thought epinephrine1 and phenylephrine are also being used to treat redness of the eye  and/or part of dialing eye-drops.

Colloidal Carriers:
Nanoparticles  provide sustained release-and prolonged therapeutic activity when retained in the cul-de-sac after  topical administration and the entrapped drug must be released from the particles at an appropriate rate. Most commonly used polymers are venous poly (alkyl cyanoacrylates), poly Scaprolactone and polylactic-co-glycolic acid, which undergo hydrolysis in tears. Enhanced permeation across the cornea was also observed when poly (epsilon-caprolactone) nanoparticles were coated with polyethylene glycol.

Liposomes:

Liposomes are lipid vesicles containing aqueous core which have been widely exploited in ocular delivery for various drug molecules.Liposomes are favorable for lipophilic drugs and not for-hydrophilic drugs. liposomes has an affinity to bind to, ocular surfaces, and release contents at optimal rates. Coating with bioadhesive polymers to liposomes, prolong the  precomea retention of liposomes. Carbopol 1342-coated pilocarpine containing liposomes were  shown to produce a longer duration of action. Ciprofloxacin (CPFX) was also formulated in  liposomal environmental which lowered tear-driven dilution in the conjunctival sac.  Multilamellar vesicles from lecithin and alpha-L-dipalmithoyl-phosphatidylcholine were used to prepare liposome containing CPFX. This approach produced sustained release of the drug  depending on the nature of the lipid composition selected.

There are many other known forms used in the industry to enhance drug penetration and bioavailability such as dendrimers, bioadhesive polymers, niosomes and microemulsions which will be discussed elsewhere.

Summary:

Drug delivery by topical and intravitreal routes cannot always be considered safe, effective and patient friendly. Drug delivery by periocular route can potentially overcome many of these limitations and also can provide sustained drug levels in  ocular pathologies affecting both segments. Transporter targeted delivery can be a promising  strategy for many drug molecules. Colloidal carriers can substantially improve the current therapy and may emerge as an alternative following their periocular administration. Ophthalmic drug delivery, more than any other route of administration, may benefit to a full extent from the characteristics of nano-sized drug particles. Other aspect of nanotechnology and ocular drug delivery will be discussed in the next chapter.

REFERENCES

1. Tiwari A and Shukla KR. Novel ocular drug delivery systems: An overview. J. Chem. Pharm. Res., 2010, 2(3):348-355

http://jocpr.com/vol2-iss3-2010/JOCPR-2010-2-3-348-355.pdf

2. Kalishwaralal K., Barathmanikanth S., Pandian SR, Deepak V and Gurunathan S.  Silver nano-a trove for retinal therapies. J Control Release  2010 Jul 14;145(2):76-90. http://www.ncbi.nlm.nih.gov/pubmed/20359511

3.Cholkar K., Patel SP., Vadlapudi AD and Mitra AK. Novel Strategies for Anterior Segment Ocular Drug Delivery. J Ocul Pharmaco Ther  2012 Dec 5. [Epub ahead of print]

4. Bucolo C., Drago F and Salomone S. Ocular drug delivery: a clue from nanotechnology. Front Pharmacol. 2012; 3: 188.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486627/

5. Vega E., Gamisans F., García M. L., Chauvet A., Lacoulonche F., Egea M. A. (2008). PLGA nanospheres for the ocular delivery of flubiprofen: drug release and interactions. J. Pharm. Sci.97, 5306–5317.

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Author: Tilda Barliya PhD

Metastasis, the spread of cancer cells from a primary tumour to seed secondary tumours in distant sites, is one of the greatest challenges in cancer treatment today. For many patients, by the time cancer is detected, metastasis  has already occurred. Over 80% of patients diagnosed  with lung cancer, for example, present with metastatic  disease. Few patients with metastatic cancer are cured by surgical intervention, and other treatment modalities are limited. Across all cancer types, only one in five patients diagnosed with metastatic cancer will survive more than 5 years. (1,2).

Metastatic Cancer 

  • Metastatic cancer is cancer that has spread from the place where it first started to another place in the body.
  • Metastatic cancer has the same name and same type of cancer cells as the original cancer.
  • The most common sites of cancer metastasis are the lungs, bones, and liver.
  • Treatment for metastatic cancer usually depends on the type of cancer and the size, location, and number of metastatic tumors.

How do cancer cells spread (3)

  • Local invasion: Cancer cells invade nearby normal tissue.
  • Intravasation: Cancer cells invade and move through the walls of nearby lymph vessels or blood vessels.
  • Circulation: Cancer cells move through the lymphatic system and the bloodstream to other parts of the body.

The ability of a cancer cell to metastasize successfully depends on its individual properties; the properties of the noncancerous cells, including immune system cells, present at the original location; and the properties of the cells it encounters in the lymphatic system or the bloodstream and at the final destination in another part of the body. Not all cancer cells, by themselves, have the ability to metastasize. In addition, the noncancerous cells at the original location may be able to block cancer cell metastasis. Furthermore, successfully reaching another location in the body does not guarantee that a metastatic tumor will form. Metastatic cancer cells can lie dormant (not grow) at a distant site for many years before they begin to grow again, if at all.

Although cancer therapies are improving, many drugs are not reaching the sites of metastases, and doubt  remains over the efficacy of those that do. Methods  that are effective for treating large, well-vascularized tumours may be inadequate when dealing with small clusters of disseminated malignant cells.

We expect that the expanding capabilities of nanotechnology, especially in targeting, detection and particle trafficking, will enable  novel approaches to treat cancers even after metastatic dissemination.

Lymph nodes, which are linked by lymphatic vessels, are distributed throughout the body and have an integral role in the immune response. Dissemination of cancer cells through the lymph network is thought to be an important route for metastatic spread. Tumor proximal lymph nodes are often the first site of metastases, and the presence of lymph node metastases signifies further metastatic spread and poor patient survival.

As such, lymph nodes have been targeted using cell-based nanotechnologies

Lymph nodes are small, bean-shaped organs that act as filters along the lymph fluid channels. As lymph fluid leaves the organ (such as breast, lung etc) and eventually goes back into the bloodstream, the lymph nodes try to catch and trap cancer cells before they reach other parts of the body. Having cancer cells in the lymph nodes suggests an increased risk of the cancer spreading. It is thus very important to evaluate the involvement of lymph nodes when choosing the best possible treatment for the patient.

Although current mapping methods are available such as CT and MRI scans, PET scan, Endobronchial Ultrasound, Mediastinoscopy and lymph node biopsy, sentinel lymph node (SLN) mapping and nodal treatment in lung cancer remain inadequate for routine clinical use. 

Certain characteristics are associated with preferential (but not exclusive) nanoparticle trafficking to lymph nodes following intravenous administration.

Targeting is often an indirect process, as receptors on the surface of leukocytes bind nanoparticles and transfer them to lymph nodes as part of a normal immune response. Several strategies have been used to enhance nanoparticle uptake by leukocytes in circulation. Coating iron-oxide nanoparticles with carbohydrates, such as dextran, results in the increased accumulation of these nanoparticles in lymph nodes. Conjugating peptides and antibodies, such as immunoglobulin G (IgG), to the particle surface also increases their accumulation in the lymphatic network. In general, negatively charged particles are taken up at faster rates than positively charged or uncharged particles. Conversely, ‘stealth’ polymers, such as polyethylene glycol (PEG), on the surface of nanoparticles, can inhibit uptake by leukocytes, thereby reducing accumulation in the lymph nodes.

Lymph node targeting may be achieved by other routes of administration. Tsuda and co-workers reported that non-cationic particles with a size range of 6–34nm, when introduced to the lungs (intrapulmonary administration), are trafficked rapidly (<1 hour) to local lymph nodes. Administering particles <80 nm in size subcutaneously also results in trafficking to lymph nodes. Interestingly, some studies have indicated that non-pegylated particles exhibit enhanced accumulation in the lymphatics and that pegylated particles tend to appear in the circulation several hours after administration.

Over the last twenty years, sentinel lymph node (SLN) imaging has revolutionized the treatment of several malignancies, such has melanoma and breast cancer, and has the potential to drastically improve treatment in other malignancies, including lung cancer. Several attempts at developing an easy, reliable, and effective method for SLN mapping in lung cancer have been unsuccessful due to unique difficulties inherent to the lung and to operating in the thoracic cavity.

An inexpensive method offering rapid, intraoperative identification of SLNs, with minimal risk to both patient and provider, would allow for improved staging in patients. This, in turn, would permit better selection of patients for adjuvant therapy, thus reducing morbidity in those patients for whom adjuvant treatment is inappropriate, and ensuring that those who need this added therapy actually receive it. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109504/)

Current methods for SLN identification involve the use of radioactivity-guided mapping with technetium-99m sulfur colloid and/or visual mapping using vital blue dyes. Unfortunately these methods can be inadequate for SLN mapping in non-small cell lung cancer (NSCLC) The use of vital blue dyes is limited in vivo by poor visibility, particularly in the presence of anthracotic mediastinal nodes, thereby decreasing the signal-to-background ratio (SBR) that enables nodal detection. Similarly, results with technetium-99m sulfur colloid have been mixed when used in the thoracic cavity, where hilar structures and aberrant patterns of lymphatic drainage make detection more difficult.

Although Nomori et al. have reported an 83% nodal identification rate following a preoperative injection of technetium-99 colloid, there is an associated increased risk of pneumothorax and bleeding with this method. Further, the recently completed CALGB 140203 multicenter Phase 2 trial investigating the use of intraoperative technetium-99m colloid found an identification rate of only 51% with this technique.  Clearly a technology with greater accuracy, improved SBR, and less potential risk to surgeon and patient would be welcome in the field of thoracic oncology.

Near-infrared (NIR) fluorescence imaging has the potential to meet this difficult challenge.

Near-Infrared Light

NIR light is defined as that within the wavelength range of 700 to 1000 nm. Although NIR light is invisible to the naked eye, it can be thought of as “redder” than UV and visible light.

  • Absorption, scatter, and autofluorescence are all significantly reduced at redder wavelengths. For instance, Hemoglobin, water, lipids, and other endogenous chromophores, such as melanin, have their lowest absorption within the NIR spectrum, which permits increased photon depth penetration into tissues
  • In addition, imaging can also be affected by photon scatter, which describes the reflection and/or deflection of light when it interacts with tissue. Scatter, on an absolute scale, is often ten-times higher than absorption. However, the two major types of scatter, Mie and Rayleigh, are both reduced in the NIR, making the use of NIR wavelengths especially important for the reduction of photon attenuation.
  • living tissue has extremely high “autofluorescence” in the UV and visible wavelength ranges due to endogenous fluorophores, such as NADH and the porphyrins. Therefore, UV/visible fluorescence imaging of the intestines, bladder, and gallbladder is essentially precluded. However, in the NIR spectrum, autofluorescence is extremely low, providing the black imaging background necessary for optimal detection of a NIR fluorophore within the surgical field
  • Additionally, optical imaging techniques, such as NIR fluorescence, eliminate the need for ionizing radiation. This, combined with the availability of a NIR fluorophore already FDA-approved for other indications and having extremely low toxicity (discussed below), make this a potentially safe imaging modality.

The main disadvantage is that it’s invisible to the human eye, requiring special imaging-systems to “see” the NIR fluorescence.

Currently there are three intraoperative NIR imaging systems in various stages of development:

  • The SPY system (Novadaq, Canada) - utilizes laser light excitation in order to obtain fluorescent images. The Spy system has been studied for imaging patency of vascular anastamoses following CABG and organ transplantation
  • The Photodynamic Eye(Hamamatsu, Japan) - is presently available only in Japan
  • The Fluorescence-Assisted Resection and Exploration (FLARE) system ()- developed by the authors’ laboratory utilizes NIR light-emitting diode (LED) excitation, eliminating the need for a potentially harmful laser. Additionally, the FLAREsystem has the advantage of being able to provide simultaneous color imaging, NIR fluorescence imaging, and color-NIR merged images, allowing the surgeon to simultaneously visualize invisible NIR fluorescence images within the context of surgical anatomy.

Near-Infrared Fluorescent Nanoparticle Contrast Agents

The ideal contrast agent for SLN mapping would be anionic and within 10–50 nm in size in order to facilitate rapid uptake into lymphatic vessels with optimal retention within the SLN.

Due to the lack of endogenous NIR tissue fluorescence, exogenous contrast agents must be administered for in vivo studies. The most important contrast agents that emit within the NIR spectrum are the heptamethine cyanines fluorophores, of which indocyanine green (ICG) is the most widely used, and fluorescent semiconductor nanocrystals, also known as quantum dots (QDs).

  • ICG is an extremely safe NIR fluorophore, with its only known toxicity being rare anaphylaxis. The dye was FDA approved in 1958 for systemic administration for indicator-dilution studies including measurements of cardiac output and hepatic function. Additionally, it is commonly used in ophthalmic angiography. When given intravenously, ICG is rapidly bound to plasma albumin and cleared from the blood via the biliary system. Peak absorption and emission of ICG occur at 780 nm and 830 nm respectively, within the window where in vivo tissue absorption is at its minimum. ICG has a relatively neutral charge, has a hydrodynamic diameter of only 1.2 nm, and is relatively hydrophobic. Unfortunately, this results in rapid transport out of the SLN and relatively low fluorescence yield, thereby decreasing its efficacy in mapping techniques. However, noncovalent adsorption of ICG to human serum albumin (HSA), as occurs within plasma, results in an anionic nanoparticle with a diameter of 7.3 nm and a three-fold increase in fluorescence yield markedly improving its utility in SLN mapping.
  • QDs consist of an inorganic heavy metal core and shell which emit within the NIR spectrum. This structure is then surrounded by a hydrophilic organic coating which facilitates aqeuous solubility and lymphatic distrubtion. QDs have been extensively studied and are ideal for SLN mapping as their hydrodynamic diameter can be customized to the appropriate size within a narrow distribution (15–20 nm), they can be engineered to have an anionic surface charge, and exhibit an extremely high SBRs with significant photostability. Unfortunately, safety concerns due to the presence of heavy metals within the QDs so far have precluded clinical application

Human Clinical Trials and NIR SLN mapping

Several studies have investigated the clinical use of indocyanine green without adsorption to HSA for NIR fluorescence-guided SLN mapping in breast and gastric cancer with good success (9-13).

Kitai et al. first examined this technique in 2005 in breast cancer patients, and was able to identify a SLN node in 17 of 18 patients using NIR fluorescence rather than the visible green color of ICG (9). Sevick-Muraca et al. reported similar results using significantly lower microdoses of ICG (10 – 100 μg), successfully identifying the SLN in 8 of 9 patients (11). Similar to these subcutaneous studies, 56 patients with gastric cancer underwent endoscopic ICG injection into the submucosa around the tumor 1 to 3 days preoperatively or injection directly into the subserosa intraoperatively with identification of the SLN in 54 patients (13).

Recently, Troyan et al. have completed a pilot phase I clinical trial examining the utility of NIR imaging the ICG:HSA nanoparticle fluorophore for SLN mapping/biopsy in breast cancer using the FLAREsystem. In this study, 6 patients received both 99mTc-sulfur colloid lymphoscintigraphy along with ICG:HSA at micromolar doses. SLNs were identified in all patients using both methods. In 4 of 6 patients the SLNs identified were the same, while in the remaining two, lymphoscintigraphy identified an additional node in one patient and ICG:HSA identified an additional SLN in the other. Irrespective, this study demonstrates that NIR SLN mapping with low dose ICG:HSA is a viable method for intraoperative SLN identification.

Nanotechnology and Drug Delivery in Lung cancer

We previously explored Lung cancer and nanotechnology aspects as polymer nanotechnology has been an area of significant research over the past decade as polymer nanoparticle drug delivery systems offer several advantages over traditional methods of chemotherapy delivery

see: (15) http://pharmaceuticalintelligence.com/2012/11/08/lung-cancer-nsclc-drug-administration-and-nanotechnology/                (16) http://pharmaceuticalintelligence.com/2012/12/01/diagnosing-lung-cancer-in-exhaled-breath-using-gold-nanoparticles/

As the importance of micrometastatic lymphatic spread of tumor becomes clearer, there has been much interest in the use of nanoparticles for lymphatic drug delivery. The considerable focus on developing an effective method for SLN mapping for lung cancer is indicative of the importance of nodal spread on overall survival.

Our lab is investigating the use of image-guided nanoparticles engineered for lymphatic drug delivery. We have previously described the synthesis of novel, pH-responsive methacrylate nanoparticle systems (14). Following a simple subcutaneous injection of NIR fluorophore-labeled nanoparticles 70 nm in size, we have shown that we can deliver paclitaxel loaded within the particles to regional draining lymph nodes in several organ systems of Yorkshire pigs while simultaneously confirming nodal migration using NIR fluorescent light. Future studies will need to investigate the ability of nanoparticles to treat and prevent nodal metastases in animal cancer models. Additionally, the development of tumor specific nanoparticles will potentially allow for targeting of chemotherapy to small groups of metastatic tumor cells further limiting systemic toxicities by narrowing the delivery of cytotoxic drugs.

Ref:

1. http://www.nature.com.rproxy.tau.ac.il/nrc/journal/v12/n1/pdf/nrc3180.pdf

2. http://www.nature.com/nrc/focus/metastasis/index.html

3. http://www.cancer.gov/cancertopics/factsheet/Sites-Types/metastatic

4. http://www.cancerresearchuk.org/cancer-help/about-cancer/what-is-cancer/body/the-lymphatic-system

5. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Lymphnodessecondary/Secondarycancerlymphnodes.aspx

6. Khullar O, Frangioni JV and Colson YL. Image-Guided Sentinel Lymph Node Mapping and Nanotechnology-Based Nodal Treatment in Lung Cancer using Invisible Near-Infrared Fluorescent Light. Semi Thorac Cardiovasc Surg 2009 :21 (4);  309-315. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109504/

7. Stacker SA, Achen MG, Jussila L,  Baldwin ME and Alitalo K. Metastasis: Lymphangiogenesis and cancer metastasis.  Nature Reviews Cancer 2002 2, 573-583. http://www.nature.com/nrc/journal/v2/n8/full/nrc863.html

8. Schroeder A., Heller DA., Winslow MM., Dahlman JE., Pratt GW., Langer R., Jacks T and Anderson DG.. Nature Reviews Cancer 2012; 12(1), 39-50. Treating metastatic cancer with nanotechnology. http://www.nature.com.rproxy.tau.ac.il/nrc/journal/v12/n1/pdf/nrc3180.pdf

http://www.nature.com.rproxy.tau.ac.il/nrc/journal/v12/n1/full/nrc3180.html

9. Kitai T, Inomoto T, Miwa M, et al. Fluorescence navigation with indocyanine green for detecting sentinel lymph nodes in breast cancer. Breast Cancer. 2005;12:211–215.

10. Ogasawara Y, Ikeda H, Takahashi M, et al. Evaluation of breast lymphatic pathways with indocyanine green fluorescence imaging in patients with breast cancer. World journal of surgery.2008;32:1924–1929.

11. Sevick-Muraca EM, Sharma R, Rasmussen JC, et al. Imaging of lymph flow in breast cancer patients after microdose administration of a near-infrared fluorophore: feasibility study. Radiology.2008;246:734–741.

12. Miyashiro I, Miyoshi N, Hiratsuka M, et al. Detection of sentinel node in gastric cancer surgery by indocyanine green fluorescence imaging: comparison with infrared imaging. Ann Surg Oncol.2008;15:1640–1643.

13. Tajima Y, Yamazaki K, Masuda Y, et al. Sentinel node mapping guided by indocyanine green fluorescence imaging in gastric cancer. Ann Surg. 2009;249:58–62.

14. Griset AP, Walpole J, Liu R, et al. Expansile nanoparticles: synthesis, characterization, and in vivo efficacy of an acid-responsive drug delivery system. J Am Chem Soc. 2009;131:2469–2471

15. http://pharmaceuticalintelligence.com/2012/11/08/lung-cancer-nsclc-drug-administration-and-nanotechnology/

16.  http://pharmaceuticalintelligence.com/2012/12/01/diagnosing-lung-cancer-in-exhaled-breath-using-gold-nanoparticles/

 

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English: Schematic sketch showing the transpor...

English: Schematic sketch showing the transport types at the blood-brain barrier. Deutsch: Schematische Darstellung der Transportmechanismen an der Blut-Hirn-Schranke. Français : Schéma des types de transport à travers la barrière hémato-encéphalique (Photo credit: Wikipedia)

Larry H Bernstein, MD
Reporter

Provided without comment.  Quite interesting.

novel protease resistant peptide shuttles able to cross the blood-brain barrier (BBB) by binding to a specific brain receptor

Description

A Catalan Research Institute based in Barcelona (Spain) has identified novel protease resistant peptide shuttles able to cross the blood-brain barrier (BBB) by binding to a specific brain receptor. These shuttles are a powerful alternative to carry a wide variety of small and large molecules as cargos. This represents a novel opportunity to develop new delivery carriers able to cross actively a range of biological barriers.

New and innovative aspects

These compounds are novel drug delivery carriers that provide a non-invasive, non-antigenic, stable and receptor-specific way to transport drugs across the Blood-Brain Barrier and into the Central Nervous System.

These compounds show high permeability, biocompatibility, good solubility in water and resistance to proteases.

Specifications

The treatment of most neurological disorders has not been fully addressed mainly because of the neuroprotective role of the blood-brain barrier (BBB) that hinders the delivery of many diagnostic and therapeutic agents into the brain. Consequently, therapeutic molecules and genes that might otherwise be effective in diagnosis and therapy do not cross the BBB in adequate amounts: 98% of compounds smaller than 400Da and 100% of larger ones do not reach further drug development stages.

Most central nervous system (CNS) diseases, however, are complex disorders with difficult molecular targets that require larger, safer and more selective drugs. As a result, brain tumors, neurodegenerative diseases such as Parkinson’s and Alzheimer’s, and central nervous system (CNS) diseases such as schizophrenia are not successfully treated. Therefore, finding an efficient CNS delivery system is one of the major challenges in neurological treatment and one our technology can potentially overcome.

One of the best approaches for drug delivery to the brain is the use of endogenous transport mechanisms, such as receptor-mediated transcystosis. Peptides are biocompatible molecules able to transport cargos (i.e. therapeutic compounds) to specific tissues such as the brain. However, one of the main limitations of peptides as therapeutic agents is their low stability in plasma.

The use of non-natural amino acids in peptidic sequences can circumvent this problem because they are resistant to human serum proteases. Using this approach, we obtained several modified peptides. Two of them were selected based on their protease resistance and transport capacity across the blood-brain barrier, using a specific endogenous receptor. Both peptides showed enhanced membrane permeability in vitro in comparison to standard peptides and even greater stability in plasma (over 24h).

Main advantages of its use

Novel delivery technology that provides a non-invasive, non-antigenic, permeable, stable, soluble and receptor-specific way to transport drugs across the BBB and into the CNS.

This technology may ultimately allow the delivery of therapeutic agents, even large ones, across the BBB and other biological barriers, thus increasing the effectiveness of existing or new drugs.

Potential of application in a wide number of fields and in transport through various biological barriers.

Applications

Biotechnological and Pharmaceutical companies specialized in drug discovery, drug delivery, neurological disorders, tools to cross the Blood-brain barrier. The final aim is to increase the efficiency of existing molecules for the treatment of neurological disorders.

Molecule and treatment design, drug manufacture, treatment of neurological disorders, drug delivery across the blood-brain barrier (BBB).

Intellectual property status

This invention is protected by a priority application in Spain and we plan to apply for a PCT in due time.

 

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