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

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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

luciferase-based assays,
in vivo chromatin immunoprecipitation,
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

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
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
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
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 J 2012;33:977–987.
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.
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.
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.
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.
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.
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

trauma
inflammatory injury
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 unless preclinical 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

device performance,
patient care decisions, or
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).

http://dx.doi.org/10.1371/journal.pone.0008105.g001

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

Arterial drug deposition is a function of stent location. http://dx.doi.org/10.1371/journal.pone.0008105.g005
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.

Peripheral Nerve Repair: Use of Nanotechnology and Tissue engineering

Posted in Bio Instrumentation in Experimental Life Sciences Research, BioSimilars, Drug Delivery Platform Technology, Innovations in Neurophysiology & Neuropsychology, Medical Devices R&D Investment, Nanotechnology for Drug Delivery, Pain: Etiology, Genetics & Innovations in Treatment, Technology Transfer: Biotech and Pharmaceutical, tagged Drug delivery, electrospinning, hydrogel, molecular self-assembly, Nanostructure scaffolds, Nerve autograph, nerve regeneration, neuronal injury, neuronal tissue engineering, Peripheral nerve repair, polymeric nerve conduits, silicone conduits, Tissue engineering on April 3, 2013| 7 Comments »

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):

the neuronal cell body
the segment between the cell body and the injury site
the injury site itself
the distal segment between the injury site and the end organ
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:

Incorporation of factors into a conduit filler such as a hydrogel
Designing a drug release system from the conduit biomaterial such as microspheres
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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Introduction to Tissue Engineering; Nanotechnology applications

Posted in Bio Instrumentation in Experimental Life Sciences Research, BioSimilars, Cardiac & Vascular Repair Tools Subsegment, Cell Biology, Signaling & Cell Circuits, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Nanotechnology for Drug Delivery, Pharmaceutical R&D Investment, Technology Transfer: Biotech and Pharmaceutical, tagged 3D, ECM, Extracellular matrix, nanocomposites, nanostructure, nanotopographic, scaffold, Tissue engineering on January 1, 2013| 8 Comments »

Introduction to Tissue Engineering; Nanotechnology applications

Author, Editor and Curator: Tilda Barliya, PhD

Tissue Engineering is an emerging multidisciplinary field involving biology, medicine, and engineering that is likely to revolutionize the ways we improve the health and quality of life for millions of people by restoring, maintaining, or enhancing tissue and organ function. Tissue engineering emerged as organ transplantation is limited by the number of available donors and high cost process, leaving thousands of people each year on the transplant waiting lists in the United States alone. Many die before an organ donor becomes available. Dr. Tal Dvir from the Langer’s lab at MIT have summarized this topic in his review (2. http://nextbigfuture.com/2011/01/nanotechnology-strategies-for-tissue.html)

Tissue engineering aims at developing functional substitutes for damaged tissues and organs, a process that involves the use of a combination of cells, engineering and material methods, including suitable biochemical and chemical factors to improve or replace biological functions. Rather than simply introducing cells into a diseased area to repopulate a defect and/or restore function, in tissue engineering the cells are often seeded in or onto biomaterials (scaffolds) before transplantation.

These biomaterial scaffold allows cells to attach and reorganize to form functional tissue by proliferating, synthesizing extracellular matrix, and migrating along the implant path (1,2,3) Figure 1.

Until recently, it was believed that the macroporous features of scaffolds used in tissue engineering mimicked the dimension scale of the extracellular matrix (ECM), and that the matrix itself (natural or artificial) only served as a support for the cells; morphogenesis was controlled passively by defining tissue boundaries. Emphasis was placed on critical engineering and material issues, such as improving mass transfer into the core of the cell constructs and designing biocompatible and biodegradable scaffolds with mechanical properties suitable for engineering various tissues. As the field evolved, attention focused on the biology of the scaffolds and how they affect various cell types.

Tissue engineers had recognized that some of the widely used scaffolds do not fairly recapitulate the cell microenvironment and that the ECM is a dynamic and hierarchically organized nanocomposite that regulates essential cellular functions such as:

morphogenesis,
differentiation
proliferation
adhesion
migration

Nanotechnological tools for tissue engineering may help design advanced nanocomposite scaffolds that can better mimic the ECM and eventually assemble more complex and larger functional tissues. In order to generate a functional tissue, effective organization of cells in the tissue is required with similar morphology and physiology of the parental tissue.

Morphogenesis in the three-dimensional (3D) scaffold should occur in a similar way to natural organ development. The cells reorganize owing to interaction with the ECM on the basis of:

topography,
mechanical properties (such as matrix stiffness, elasticity and viscosity)
concentration gradients of immobilized growth factors
ECM molecules.

Recently, Ott and co-workers (4) reported a study emphasizing the importance of the ECM structure in guiding the seeded cells and promoting morphogenesis. Rat hearts were decellularized by perfusion of detergents to preserve the underlying ECM and then reseeded with cardiac and endothelial cells (4). The cells migrated and self-organized in their natural location in the matrix and by day 8, under physiological load and electrical stimulation, the constructs were able to generate pump function (4). The importance of the ECM was shown for:

Heart
Lung
Arteries
Liver
Bone
Nerve

So why is the Extracellular Martix (ECM) so important?

The ECM is composed of an intricate interweaving of protein fibres such as fibrillar collagens and elastins, ranging from 10 to several hundreds of nanometres. The mesh is covered with nanoscale adhesive proteins such as laminin and fibronectin that provide specific binding sites for cell adhesion (interacting with integrins, cadherins and so forth) and have been shown to regulate important cell behaviours such as growth, shape, migration and differentiation. Polysaccharides such as hyaluronic acid and heparan sulphate fill the interstitial space between the fibres and act as a compression buffer against the stress placed on the ECM or serve as a growth factor depot (Figure 2).

Scaffold design considerations

The ECMs of various tissues in the body differ in the composition and spatial organization of the collagens, elastins, proteoglycans and adhesion molecules, to maintain specific tissue morphologies and organ specific shape and function, and to supply specific instructive cues. Therefore, the design considerations for scaffolds should vary according to the desired engineered tissue. For example, the biochemical, electrical and mechanical functions of the heart are uniquely dependent on their biological nanostructures. The heart’s 3D ECM network is composed of an intricate, micro- and nanoscale interweaving pattern of fibrillar collagen and elastin bundles that form a dense, elastic network with proteoglycans and with adhesive and non-adhesive molecules. In this defined mesh, the cardiomyocytes are forced to couple mechanically to each other, to form elongated and aligned cell bundles that interact with each other or with neighbouring capillaries and nerves.

Post-isolation cells lose their ultrastructural elongated morphology and their interaction with their surroundings, and they adopt a random distribution on the flat surface of the scaffold, which compromises many of their physiological properties. Therefore, the structure and support of the ECM is crucial. See Figure 2.

Limitations of the ECM:

Weak mechanical properties
Lack of electrical conductivity
Absence of adhesive and micoenvironment- defining moieties
Inability of cells to self-assemble to 3D tissue structure.

The rational behind incorporating nanostructures is to compensate for other scaffold limitations (Table 2) Ref.2

The Heart for example requires more than alignment and mechanical support (Boyang Zhang, Ref 5)

cell responses to micro- and nanopatterned topographical cues
cell responses to patterned biochemical cues
controlled 3D scaffolds
patterned tissue vascularization
electromechanical regulation (conductivity). of tissue assembly and function

Nanostructures can be used to record the electronic signals that are transmitted through cells such as neurons and cardiomyocytes. One way to record these signals is by lithographically defining nanostructures as field-effect transistors, which are sensitive to local electric field changes. In particular, silicon nanowire transistors are useful for measuring extracellular signals because they exhibit particularly exquisite field-effect sensitivity compared with conventional, planar devices; they are just tens of nanometres in diameter and can therefore interface with cells and tissue at a subcellular level; and they show nanotopographic features that encourage tight interfaces with biological systems.

Summary:

This introduction reviewed some of the aspects required for tissue engineering with the affiliation to nanotechnology. In the next post, we will dive deeper into a specific tissue organ, the bioengineering aspect and how nanotechnology strategies may improve the design and outcome.

Ref

1. http://www.nanotech-now.com/news.cgi?story_id=35168

2. Dvir T., Timko BR., Kohane DS., and Langer R. Nanotechnological strategies for engineering complex tissues. Nature Nanotechnology 2010; 12():. http://nextbigfuture.com/2011/01/nanotechnology-strategies-for-tissue.html

3. http://www.nature.com/nnano/journal/v6/n1/abs/nnano.2010.246.html

4. Ott, H. C. et al. Perfusion-decellularized matrix: Using nature’s platform to engineer a bioartificial heart. Nature Med. 14, 213–221 (2008).

5. Boyang Zhang, Yun Xiao, Anne Hsieh, Nimalan Thavandiran and Milica Radisic. Micro- and nanotechnology in cardiovascular tissue engineering. Nanotechnology 2011; 22(49): 494003

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Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, HTN, Human Immune System in Health and in Disease, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Resident-cell-based, Scientist: Career considerations, Stem Cells for Regenerative Medicine, Systemic Inflammatory Response Related Disorders, Technology Transfer: Biotech and Pharmaceutical, tagged Biology, Biotechnology, Blood vessel, Cardiovascular Biology, Cedars-Sinai Medical Center, Cell Biology, Endothelium, Stem cell, Tissue engineering, vascular biology on August 24, 2012| 17 Comments »

Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs

Curator and Author: Aviva Lev-Ari, PhD, RN

Classification of Fast Acting Therapies for Patients at High Risk for Macrovascular events

Macrovascular Disease – Therapeutic Potential of cEPCs

The two leading therapy classes are:

Cell-based Therapies for angiogenesis and myocardial regeneration
Intracoronary Delivery of Autologous Bone Marrow originating cells to restore Ischemic Tissue

The European Meeting on Vascular Medicine and Biology is a biannual international conference. The 3rd European Meeting on Vascular Medicine and Biology, took place in September 2005 and the next conference will be in 2007. All abstract presentations are published in Supplement 2, JOURNAL OF VASCULAR RESEARCH, Volume 42, 2005.

Review of 355 abstracts of posters presented at the conference has identified the following twenty Research Frontiers in Vascular Biology and Vascular Disease.

One abstract is of special interest to the line of research which focus on endogenous augmentation of cEPCs and to reduction of CVD risk by endogenous induction of regression of atherosclerotic plaques. It was selected by being judged to have the highest potential for commercialization and the potential to replace several therapeutic agents with higher efficacy.

P119 IgG1 antibodies against oxLDL epitopes induce regression of advanced atherosclerotic plaques in LDLR-/- APOBEC mice.

A. Schiopu1, B. Jansson2, P.K. Shah3, R. Carlsson3, J. Nilsson1, G. Nordin Fredrikson1Department of Medicine, Malmö University Hospital, Lund University, Malmö, SE; 2 BioInvent International AB, Lund, SE; 3 Atherosclerosis Research Center, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, US.

Objective: The purpose of our study was to assess the effects of recombinant human IgG1 antibodies against specific oxLDL epitopes on advanced atherosclerotic lesions in mice.

Methods: We have tested 2 recombinant human IgG1 antibodies directed to malondialdehyde (MDA)-modified ApoB-100 peptide sequences. Three weekly 1 mg antibody doses were injected intraperitoneally starting at 25 weeks in LDLR-/-Apobec mice, which were then sacrificed at 29 weeks of age. IgG1 antibodies directed against fluorescein isothiocyanate, which do not bind to either native or oxidized LDL, and a

baseline group sacrificed at 25 weeks of age, to asses plaque status before immunization, were used as controls.

Results: Both antibodies induced a significant regression of already present atherosclerotic plaques in the descending aorta as compared to baseline. This effect was not present in the isotype control group. The changes did not depend on alterations in weight, cholesterol or triacylglycerol content in mice plasma.

Conclusions: The present study suggests that antibody treatment has the ability to reduce the extent of already present, advanced atherosclerotic lesions. Passive immunization with antibodies directed against oxLDL epitopes might constitute a future fast acting therapy for patients at high risk for acute cardiovascular events.

Twenty Research Frontiers in Vascular Medicine of Human Endothelium

Research Frontiers in Vascular Biology and Vascular Disease	International Research Projects
Stem Cell biology	Embryonic stem cells in cardiovascularrepairEarly differentiation of human endothelial progenitor cellsVessels transmigration of stem cells depends on activation of the endothelium. Interaction of embryonal endothelial progenitor cells with platelets Role of smooth muscle cell progenitors on atherosclerotic plaque development and stability.
Ischemia and Reperfusion	Connexin 43 and myocardial ischemia/reperfusioninjuryEndothelialreperfusion injuryA possible role for hypoxia-inducible factor 1• in protection against reperfusion injury
Genetic Basis of Vascular Disease	Cardiovascular genomics and oxidative stressNox1 mediates basic fibroblast growth factor induced vascular smooth muscle cell migrationReactive oxygen species upregulate NOX4, but not NOX2, in endothelial cells Induction of prolyl hydroxylase 2 by nitric oxide interferes with the hypoxia induced feedback loop of HIF-1• regulation Protein disulfide isomerase is a central regulator of NADPH oxidase activity
Inflammation	Inflammatory mediatorsofvascularInflammationIsoprostanes inhibit in vitro migration and tube formation of endothelial cells via the thromboxane A2 receptor. Heme oxygenase-1-dependent and -independent regulation of angiogenic and inflammatory genes expression in human microvascular endothelial cells
Tissue Engineering	Engineered heart tissueEndothelial tissue engineeringBlood vessel growth and remodeling in in-vivo tissue engineering The effects of cyclic strain on the cytoskeleton of vascular smooth muscle cells
Atherosclerosis Imaging Experimental	In vivo imaging ofatherosclerosisHoming ofCD34+ progenitor cells to sites ofangiogenic tube formation using real-time video microscopy.Relation between lipoprotein(a) and fibrinogen and serial intravascular ultrasound plaque progression in left main stems Cardiovascular Development Controlled by Fluid Shear Stress. A Functionomic Approach. Dynamics in microvascular alterations in UCP/DTA mice in vivo – from metabolic syndrome to diabetes mellitus type 2
Vascular Cell Signaling	TGF-beta in endothelial cell functionandvascular developmentVEGF signaling
Atherosclerosis (Clinical / In Vivo)	Pathophysiology of cigarette smoking-inducedatherosclerosisThe homeostatic benefits of plaque ruptureEarly coronary atherogenesis as a consequence of chronic in-vivo proteasome inhibition.
Renin-Angiotensin System	ACE inhibitorsstimulate endothelialCOX-2expression by aJNK-dependent ACE signalling pathway.A new ACE on the table: ACE2 expression in human atherosclerosis Role of the ACE gene in renal and vascular complications of diabetes mellitus, experimental study in the mouse. Bone marrow molecular alterations after myocardial infarction: impact on endothelial progenitor cells and modulation by ACE inhibition or statin treatment. Anti-inflammatory properties of Ramiprilat: reduction of monocyte adhesion to angiotensin II-stimulated endothelium is associated with AT1 downregulation. Activation of phospholipase D by angiotensin II in HUVECS and HMVECS
Pathogenesis of Atherosclerosis	Metalloproteinases in vascular pathologywhat we know and what we don’t know.
Stem Cell Therapy	Functional assessment of circulatingcellsHuman fetal vascular progenitor cellsaccelerate the healing of ischemic diabetic ulcers Peri-infarct gene transfer of human tissue kallikrein gene prevents left ventricle dysfunction by stimulating angiogenesis/arteriogenesis and cardiac stem cell activation and by inhibiting cardiomyocyte apoptosis.
Genomics / Proteomics in Vascular Biology	Genomic analysis of animal modelsforatherosclerosis.Differential gene expression analysis of tube forming and non-tube forming microvascular endothelial cells in vitro, separated by differences in morphology Proteomic and metabolomic analysis of atherosclerotic vessels in ApoE-/- mice Hypoxic angiogenic transcriptome in human keratinocytes and microvascular endothelial cells: macroarray and real-time PCR analysis. Gene expression profiling of human red blood cells.
Oxidant and Lipid Signaling	Lipid modifications in atherogenesis.Epoxyeicosatrienoic acids in vascularHomeostasis Oxidized phospholipids as modulators of Inflammation
Chemokines — Cell-Cell Interactions	Endothelial cell-to-celljunctionsInterplay ofchemokines and platelets invascular cell recruitment
Vascular Development	Embryonic vesseldeterminationVascular remodeling: differentiation ofarteries, veins and lymph vessels
Vascular Aneurysms and VascularDegradation	MMP in aneurysmdevelopmentFurin-likeproproteinconvertases regulate membrane type-1 matrixmetalloproteinase in atherosclerosisNon-viral, electroporation mediated gene transfer of TIMP-1.ATF, a cell-surface directed MMP inhibitor, suppresses intimal hyperplasia in vein grafts more efficiently than TIMP-1 in vivo. EMMPRIN regulates MMP activity in cardiovascular cells. Implications in Acute Myocardial Infarction. NF-kB promotes monocyte adhesion in vessels exposed to high intraluminal pressure
Diabetes Mellitus and InsulinResistance	The endothelial cellglycocalyx indiabetesVasocrine signaling and insulin resistanceEarly arteriogenic defects in a diabetic ischemic hindlimb model Diabetes-induced overproduction of reactive oxygen species impairs post-ischemic neovascularization
Microparticles / Platelets	The significance of membranemicroparticles in vascular pathophysiology andintercellularcommunication.Influences of nuclear receptors on platelet function. Cellular origin of microparticles in human atherosclerotic plaques Apoptotic microparticles derived from endothelial cells, smooth muscle cells and monocytes induce thrombin generation via different pathways
Smooth Muscle Cells	Role of epigenetic mechanisms in control of SMC differentiation in development anddiseaseThe cytoskeletal proteinzyxin is amechanosensitive signaltransducer in vascular smooth muscle cells.Leukotriene-induced migration and proliferation of vascular smooth muscle cells: implications for atherosclerosis and restenosis
Stem Cells	Transfer of stem cell-derived endothelial cells retardedneointimal lesions in the injured artery.Stimulation ofreendothelialization viarecruitment of endothelial progenitor cells with selective antibodies against progenitor cell surface markers Caspase-8 activity is essential for endothelial progenitor cell adherence

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Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs

Classification of Fast Acting Therapies for Patients at High Risk for Macrovascular events

Macrovascular Disease – Therapeutic Potential of cEPCs

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Proportional Hazards Models to Analyze First-onset of Major
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