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3D BioPrinted Carbon Nanotubes used to Stimulate Bone Regrowth
Reporter: Irina Robu, PhD
Bone disorders are of significant concern due to increase in the median age of our population and at this present time bone grafts have are used to restore damaged bone. However, synthetic biomaterials are now being used as bone graft substitutes and they are selected for structural restoration based on their biomechanical properties. Lately, scaffolds are engineered to be bioactive to enhance tissue growth. These scaffolds are usually porous, made of biodegradable factors, drugs or stem cells.
The research group led by Dr. Maria Vallet-Regi at Faculty of Pharmacy-Universidad Complutense de Madrid showed that carbon nanotubes to the mix to create 3D electrical network within the bone tissue can stimulate bone cell regrowth. The polymer they used was polycarpolactone (PCL), which is rather easy to 3D print. According to Mercedes Vila, the Principal Investigator in charge of the project, the carbon nanotubes were added to the bio-printable material mixture to create a three-dimensional electrical conducting network all through the volume of the scaffold, which would allow the application of this stimulation to the scaffold once implanted on the damaged bone site.
“In this sense, electrical stimulation has been explored since the discovery of the presence of electrical potentials in mechanically loaded bones,” Mercedes pointed out. “Certain types of cell behavior, such as adhesion and differentiation, can be affected by the application of electrical stimulation. Thus, the creation of a permanent charge on the material surface, positive or negative, as well as a direct electrical stimulation can promote the attraction of charged ions from the environment to the cells. This would modify their protein adsorption with the subsequent influence on the cells’ metabolic activity. Therefore, the use of electrical stimulation after biomaterial implantation to favor cell adhesion and differentiation and, consequently, induce bone healing seems a smart approach to accelerate the osteointegration process.”
Adding CNTs into the bio-printed polymer and mineral prosthetic bone can stimulate regrowth of the actual bone cells. However, bio-printing CNTs created no extra difficulties, as they are so thin that they can be extruded with ease through any pneumatic syringe. Most of the complications are related to finding the correct viscosity in the combination of CPL and hydroxypatite.
“Finding the right right viscosity to be extruded through the syringe while keeping enough robustness to get the 3D scaffold printed at room temperature, was complicated,” Mercedes admitted. “At the same time as the slurry was prepared in dichloromethane solution for diluting the PCL, achieving the right viscosity while evaporating the solvent was tricky. Moreover, once the PCL and the hydroxyapatite were mixed together, the addition of the CNTs was performed and reaching a proper dispersion took a bit of stirring time.”
Using EnvisionTEC’s 3D bioplotter, the researchers were able to create very complex 3D structures which would enhance the future for tissue replacements as it allows tailored solutions by capturing the anatomical information of the patient’s wound by computed tomography and magnetic resonance, for example, to obtain a personalized and unique implant.
As with many other 3D printing applications, it appears we are only starting to scratch the surface of the possibilities that are ahead for bioprinting.
CELLINK and RoosterBio developed cellular bio-ink kits. These kits will enable printing of living cellular constructs by combining RoosterBio’s stem cell systems with the universal bioinks that have been created by CELLINK. This combination provides the materials needed for the creation of human tissue needed for research and testing. These kits represent the first commercially available, plug-and-play living cellular bioinks and are available for both commercial and academic use. Erik Gatenholm from CELLINK stated that “this revolutionary, cost effective, and elegantly simple-to-use Bioprinting Kit is exactly what innovators and early adopters worldwide need to propel their research in the tissue-engineering field. By offering a complete package of the right bioink together with the right cells we can finally establish the first standard in the bioprinting industry.”
These kits will minimize the time needed for optimizing a biomaterial-stem cell combination in preparation for research and development.
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
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)
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.
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 asa 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
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
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.
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
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. EurHeartJ 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. EurHeartJ2012;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. EurHeartJ 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 Cardiol2012;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? EurHeartJ2012;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. EurHeartJ2012;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. EurHeartJ2012;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. EurHeartJ2012;33:3070–3077.
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
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
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
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 complexityas
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
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.
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.
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 heterogeneitywithin 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
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.
Other Related Articles that were published on this Open Access Online Scientific Journal include the following:
Hypertriglyceridemia concurrent Hyperlipidemia: Vertical Density Gradient Ultracentrifugation a Better Test to Prevent Undertreatment of High-Risk Cardiac Patients
Fight against Atherosclerotic Cardiovascular Disease: A Biologics not a Small Molecule – Recombinant Human lecithin-cholesterol acyltransferase (rhLCAT) attracted AstraZeneca to acquire AlphaCore
High-Density Lipoprotein (HDL): An Independent Predictor of Endothelial Function & Atherosclerosis, A Modulator, An Agonist, A Biomarker for Cardiovascular Risk
Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes
Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?
Inhibition of ET-1, ETA and ETA-ETB, Induction of NO production, stimulation of eNOS and Treatment Regime with PPAR-gamma agonists (TZD): cEPCs Endogenous Augmentation for Cardiovascular Risk Reduction – A Bibliography
Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral
Cardiovascular Outcomes: Function of circulating Endothelial Progenitor Cells (cEPCs): Exploring Pharmaco-therapy targeted at Endogenous Augmentation of cEPCs
Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs
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”
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)
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
English: Cardiovascular disease: PAD therapy with stenting Deutsch: PAVK Therapie: Kathetertherapie mit stenting (Photo credit: Wikipedia)
Endoscopic image of self-expanding metallic stent in esophagus. Photograph released into public domain on permission of patient. — Samir धर्म 07:38, 2 June 2006 (UTC) (Photo credit: Wikipedia)
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