Vascular Repair: Stents and Biologically Active Implants
Author and Curator: Larry H Bernstein, MD, FACP
and
Curator: Aviva Lev-Ari, PhD, RN
This is the second article of a three part series recognizing the immense contribution of Elazer Edelman, MD, PhD, and his laboratory group at MIT to vascular biology, cardiovascular disease studies, and the bioengineering, development, and use of stenting technology for drug delivery, vascular repair, and limitation of vessel damage caused by stent placement.
The first article, published on this Open Access Online Scientific Journal
was concerned with vascular biology, and largely on both the impact of drug delivery design and placement on the endothelium of the vessel wall, and on the kinetics of drug delivery based on the location of stent placement versus intravascular injection as well as the metabolic events taking place in the arterial endothelium, intima, and muscularis.
This second article, is concerned with stents and drug delivery as it has evolved since the last decade of the 20th century based on biomaterials development and vascular biology principles to minimize inherent injury risk over this period.
The third. will be concerned with the lessons from biomaterials and stent mechanics going forward.
Heart care is in the midst of a transformation. Patients who once required heart surgery are treated with a stent, catheters for repair of valves, rhythm abnormalities, and a growing number of heart or vascular distrbances.
The catheters are threaded in through the femoral artery, and sometimes through the radial artery. The
American College of Cardiology annual meeting highlights research on these devices. The procedure allows patients to leave the hospital after a day or two post-implant, but the initial cost of the novel devices is high. Not everyone qualifies for the treatment, and it will take a few years to compare the long term results with the benefits from surgery. But these procedures have allowed many patients treatment alternatives to surgery, and they offer an option for people who cannot be successfully managed by conservative medical therapy.
The effects of stent placement on vascular injury and the initiation of an inflammatory response
Leukocytes are recruited early and abundantly to experimentally injured vessels,
- in direct proportion to cell proliferation and intimal growth.
Activated circulating leukocytes and
Mac-1 (CD11 by CD18, aMb2) (monocytic) expression are
- markers of restenosis risk in patients undergoing angioplasty.
Angioplastied vessels lack endothelium but have extensive fibrin(ogen) and platelet deposition. Consequently, Mac-1-dependent adhesion to fibrin(ogen) would be expected to
- signal leukocyte recruitment and function, thereby
- promote intimal growth
In this study
- M1/70, an anti-CD11b blocking mAb, was administered to rabbits before, and every 48 hr for 3, 6, or 14 days after iliac artery balloon denudation.
- M1/70 was bound to isolated rabbit monocytes.
The result was
- Mac-1-mediated dose-dependent
- inhibition of fibrinogen binding in vitro, thereby,
- reducing by half leukocyte recruitment at 3, 6, and 14 days after injury.
Neointimal growth 14 days after injury was markedly attenuated by treatment with M1/70 –
intimal area after balloon injury, 0.12+0.09 mm2, compared with
- 0.32+0.08 mm2 in vehicle treated controls, P<0.01, and
- 0.38+0.08mm2 in IgG-treated controls, P<0.005;
intimal area after stent injury, 0.56+0.16 mm2, compared with
- 0.84+ 0.13 mm2 in vehicle-treated controls, P <0.05, and
- 0.90+0.15 mm2 in IgG-treated controls, P <0.02).
Mac-1 blockade reduces experimental neointimal thickening. These findings suggest that
- leukocyte recruitment to and
- infiltration of injured arteries
may be a valid target for preventing intimal hyperplasia. (1) Emerging data indicate that the inflammatory response after mechanical arterial injury
- correlates with the severity of neointimal hyperplasia in animal models
- and post angioplasty restenosis in humans.
The present study was designed to examine whether a nonspecific
- stimulation of the innate immune system,
- induced in close temporal proximity to the vascular injury,
- would modulate the results of the procedure.
A LPS dose was chosen to be sufficient to induce systemic inflammation but not septic shock. Key markers of inflammation increased after LPS administration were:
- serum interleukin-1 levels, and
- monocytic stimulation (CD14 levels on monocytes)
Arterial macrophage infiltration at 7 days after injury was
- 1.7+1.2% of total cells in controls and
- 4.2+1.8% in LPS-treated rabbits (n=4, P<0.05).
The injured arteries 4 weeks after injury had significantly increased
- luminal stenosis: 38+4.2% versus 23+2.6%, mean+SEM; n=8, P<0.05; and
- neointima-to-media ratio: 1.26+0.21 versus 0.66+0.09, P<0.05 in LPS-treated animals compared with controls.
This effect was abolished by anti-CD14 Ab administration. Serum Il-1 levels and monocyte CD14 expression were significantly increased
- in correlation with the severity of intimal hyperplasia.
- LPS treatment increased neointimal area after stenting
- from 0.57+0.07 to 0.77+0.1 mm2, and
- stenosis from 9+1% to 13+1.7% (n=5, P<0.05).
Nonspecific systemic stimulation of the innate immune system
- concurrently with arterial vascular injury
- facilitates neointimal formation, and conditions associated with
- increased inflammation may increase restenosis.(2)
- to reduce their risk for in-stent restenosis.
The efficacy and toxicity of these local therapeutics depend upon
- arterial drug deposition,
- distribution, and
- retention.
To examine how administered dose and drug release kinetics control arterial drug uptake, a model was created using principles of
- computational fluid dynamics and
- transient drug diffusion–convection.
The modeling predictions for drug elution were validated using
- empiric data from stented porcine coronary arteries.
Inefficient, minimal arterial drug deposition was predicted when a bolus of drug was released and depleted within seconds.
Month-long stent-based drug release
- efficiently delivered nearly continuous drug levels, but
- the slow rate of drug presentation limited arterial drug uptake.
Uptake was only maximized when
- the rates of drug release and absorption matched,
- which occurred for hour-long drug release.
Of the two possible means for increasing the amount of drug on the stent,
- modulation of drug concentration potently impacts
- the magnitude of arterial drug deposition,
- while changes in coating drug mass affect duration of release.
We demonstrate the importance of drug release kinetics and administered drug dose
- in governing arterial drug uptake and suggest
- novel drug delivery strategies for controlling spatio-temporal arterial drug distribution.(3)
Arterial drug concentrations determine local toxicity. Therefore, the emergent safety concerns surrounding drug-eluting stents mandate an investigation of the factors contributing to fluctuations in arterial drug uptake.
- Drug-eluting stents were implanted into porcine coronary arteries, arterial drug uptake was followed and modeled using 2-dimensional computational drug transport.
Arterial drug uptake in vivo occurred faster than predicted by free drug diffusion, thus
- an alternate, mechanism for rapid transport has been proposed involving carrier-mediated transport.
Though there was minimal variation in vivo in release kinetics from stent to stent,
- arterial drug deposition varied by up to 114% two weeks after stent implantation.
- extent of adherent mural thrombus fluctuated by 113% within 3 days.
The computational drug transport model predicted that focal and diffuse thrombi
- elevate arterial drug deposition in proportion to the thrombus size
- by reducing drug washout subsequently increasing local drug availability.
Variable peristrut thrombus can explain fluctuations in arterial drug uptake even in the face of a narrow range of drug release from the stent. The mural thrombus effects on arterial drug deposition may be circumvented by forcing slow rate limiting arterial transport, that cannot be further hindered by mural thrombus. (4)
1. A mAb to the b2-leukocyte integrin Mac-1 (CD11byCD18) Reduces Intimal Thickening after Angioplasty or Stent Implantation in Rabbits. C Rogers, ER Edelman, and DI Simon. PNAS Aug 1998; 95: 10134–10139.
2. Formation After Balloon and Stent Injury in Rabbits Systemic Inflammation Induced by Lipopolysaccharide increases Neointimal Formation After Balloon and Stent Injury in Rabbits. HD Danenberg, FGP Welt, M Walker, III, P Seifert, et al. Circulation 2002;105;2917-2922;
http://dx.doi.org/10.1161/01.CIR.0000018168.15904.BB3. Intravascular drug release kinetics dictate arterial drug deposition, retention, and distribution.
Perivascular Graft Repair
Heparin remains the gold-standard inhibitor of the processes involved in the vascular response to injury. Though this compound has profound and wide-reaching effects on vascular cells, its clinical utility is unclear. It is clear that the mode of heparin delivery is critical to its potential and it may well be that
- routine forms of administration are insufficient
- to observe benefit given the heparin’s short half-life and complex pharmacokinetics.
When ingested orally, heparin is degraded to inactive oligomer fragments while systemic administration
- is complicated by the need for continuous infusion
- and the potential for uncontrolled hemorrhage.
Thus alternative heparin delivery systems have been proposed to maximize regional effects while limiting systemic toxicity. Yet, as heparin is such a potent antithrombotic compound and since existing local delivery systems lack the ability to
- precisely regulate release kinetics,
- even site-specific therapy is prone to bleeding.
Authors now describe the design and development of a novel biodegradable system for the perivascular delivery of heparin to the blood vessel wall with well-defined release kinetics.
This system consists of heparin-encapsulated
- poly(DL lactide-co-glycolide) (pLGA) microspheres sequestered in an alginate gel.
Controlled release of heparin from this heterogeneous system is obtained for a period of 25 days.
The experimental variables affecting heparin release from these matrices were investigated by
- gel permeation chromatography (GPC) and scanning electron microscopy (SEM)
- to monitor the degradation process and correlated well with the release kinetics.
Heparin-releasing gels inhibited growth in tissue culture of
- bovine vascular smooth muscle cells in a dose-dependent manner.
- and also controlled vascular injury in denuding and
- interposition vascular graft animal models of disease even when uncontrolled bleeding was evident with standard matrix-type release.
This system provided an effective means of examining
- the effects of various compounds in
- the control of smooth muscle cell proliferation in accelerated arteriopathies and also
- shed light on the biologic nature of these processes.(1)
Soft tissue adhesives are employed to repair and seal many different organs that range in both
- tissue surface chemistry and
- mechanical effects during organ function.
This complexity motivates the development of tunable adhesive materials with
- high resistance to uniaxial or multiaxial loads
- dictated by a specific organ environment.
Co-polymeric hydrogels comprising
- aminated star polyethylene glycol and
- dextran aldehyde (PEG:dextran)
are materials exhibiting physico-chemical properties that can be modified
Here we report that resistance to failure
- under specific loading conditions, as well as
- tissue response at the adhesive material–tissue interface, can be modulated through regulation of
- the number and density of adhesive aldehyde groups.
Author found that atomic force microscopy (AFM) can
- characterize the material aldehyde density available for tissue interaction,
- facilitating rapid, informed material choice.
Further, the correlation between AFM quantification of nanoscale unbinding forces
- with macroscale measurements of adhesion strength
- by uniaxial tension or multiaxial burst pressure allows the design of materials with specific cohesion and adhesion strengths.
However, failure strength alone does not predict optimal in vivo reactivity. The development of adhesive materials is significantly enabled when
- experiments are integrated along length scales to consider
- organ chemistry and mechanical loading states concurrently
- with adhesive material properties and tissue response. (2)
Cell culture and animal data support the role of endothelial cells and endothelial-based compounds in regulating vascular repair after injury.
Authors describe a long-term study in pigs in which the biological and immunological
- responses to endothelial cell implants were investigated 3 months after angioplasty,
- approximately 2 months after the implants have degraded.
Confluent porcine or bovine endothelial cells grown in polymer matrices were implanted adjacent to 28 injured porcine carotid arteries.
Porcine and bovine endothelial cell implants significantly
- reduced experimental restenosis compared to control by 56 and 31%, respectively.
Host humoral responses were investigated by detection of an increase in serum antibodies that bind to the bovine or porcine cell strains used for implantation.
A significant increase in titer of circulating antibodies to the bovine cells was observed
- after 4 days in all animals implanted with xenogeneic cells.
Detected antibodies returned to presurgery levels after Day 40.
No significant increase in titer of antibodies to the porcine cells was observed during the experiment in animals implanted with porcine endothelial cells.
No implanted cells, Gelfoam, or focal inflammatory reaction could be detected
- histologically at any of the implant sites at 90 days.
Suggesting that tissue engineered endothelial cell implants
- may provide long term control of vascular repair after injury,
- rather than simply delaying lesion formation and that
- allogeneic implants are able to provide a greater benefit than xenogeneic implants. (3)
Vascular access complications are a major problem in hemodialysis patients. Native arteriovenous fistulae, historically the preferred mode of access, have a patency rate of only 60% at 1 year.
The most common mode of failure is due to progressive stenosis at the anastomotic site.
Authors have previously demonstrated that perivascular endothelial cell implants
- inhibit intimal thickening following acute balloon injury in pigs, and now seek to determine if these
- implants provide a similar benefit in the chronic and more complex injury model of arteriovenous anastomoses.
Side-to-side femoral artery-femoral vein anastomoses were created in 24 domestic swine.
- toxicological,
- biological and
- immunological responses
were investigated 3 days and 1 and 2 months postoperatively to allogeneic endothelial cell implants . The anastomoses were wrapped with polymer matrices containing
- confluent porcine aortic endothelial cells (PAE; n = 14) or
- control matrices without cells (n = 10).
PAE implants significantly reduced intimal hyperplasia at the anastomotic sites
- compared to controls by 68% (p ! 0.05) at 2 months.
The beneficial effects of the PAE implants were not due to
- differences in the rates of reendothelialization between the groups.
No significant immunological response to the allogeneic endothelial cells that impacted on efficacy was detected in any of the pigs.
No apparent toxicity was observed in any of the animals treated with endothelial implants.
These data suggest that perivascular endothelial cell implants
- are safe and reduce early intimal hyperplasia in a porcine model of arteriovenous anastomoses. (4)
1. Perivascular graft heparin delivery using biodegradable polymer wraps. ER Edelman, A Nathan,
2. Tuning adhesion failure strength for tissue-specific applications. N Artzi, A Zeiger, F Boehning,
3. Endothelial Implants Provide Long-Term Control of Vascular Repair in a Porcine Model of Arterial Injury. HM Nugent, ER Edelman. J Surg Res 2001; 99:228–234.
http://dx.doi.org/10.1006/jsre.2001.61984. Perivascular Endothelial Implants Inhibit Intimal Hyperplasia in a Model of Arteriovenous Fistulae: A Safety and Efficacy Study in the Pig. HM Nugent, A Groothuis, P Seifert, et al. J Vasc Res 2002;39:524–533.
Luminal Flow and Arterial Drug Delivery
Endovascular stents reside in a dynamic flow environment and yet the impact of flow
- on arterial drug deposition after stent-based delivery is only now emerging.
Authors employed computational fluid dynamic modeling tools to investigate
- the influence of luminal flow patterns on arterial drug deposition and distribution.
Flow imposes recirculation zones distal and proximal to the stent strut that extend
- the coverage of tissue absorption of eluted drug and
- induce asymmetry in tissue drug distribution.
Our analysis now explains how the disparity in
- sizes of the two recirculation zones and
- the asymmetry in drug distribution are determined by a complex interplay of local flow and strut geometry.
When temporal periodicity was introduced as a model of
- pulsatile flow,
- the net luminal flow served as an index of flow-mediated spatiotemporal tissue drug uptake.
Dynamically changing luminal flow patterns are intrinsic to the coronary arterial tree. Coronary drug-eluting stents should be appropriately considered where
- luminal flow,
- strut design and
- pulsatility
have direct effects on tissue drug uptake after local delivery.(1)
The efficacy of drug-eluting stents (DES) requires delivery of potent compounds directly to the underlying arterial tissue.
The commercially available DES drugs rapamycin and paclitaxel bind specifically to
- their respective therapeutic targets, FKBP12 and polymerized microtubules,
- while also associating in a more general manner with other tissue elements.
As it is binding that provides biological effect, the question arises as to whether other
- locally released or systemically circulating drugs can
- displace DES drugs from their tissue binding domains.
Specific and general binding sites for both drugs are distributed across the media and adventitia with higher specific binding associated with the binding site densities in the media.
The ability of rapamycin and paclitaxel to compete for specific protein binding and general tissue deposition
- was assessed for both compounds simultaneously and
- in the presence of other commonly administered cardiac drugs.
Drugs classically used to treat standard cardiovascular diseases, such as hypertension and hypercoaguability,
- displace rapamycin and paclitaxel from general binding sites, possibly
- decreasing tissue reserve capacity for locally delivered drugs.
Paclitaxel and rapamycin do not affect the other’s binding
- to their biologically relevant specific protein targets, but
- can displace each other from tissue at three log order molar excess,
- decreasing arterial loads by greater than 50%.
Local competitive binding therefore should not limit the placement of rapamycin and paclitaxel eluting stents in close proximity.(2)
Stent thrombosis is a lethal complication of endovascular intervention. There is concern about the inherent risk associated with specific stent designs and drug-eluting coatings
Authored examined whether drug-eluting coatings are inherently thrombogenic and whether the response to these materials was determined to any degree
- by stent design and
- stent deployment with custom-built stents.
Drug/polymer coatings uniformly reduce rather than increase thrombogenicity relative to matched bare metal counterparts (0.65-fold; P 0.011).
Thick-strutted (162 m) stents were 1.5-fold more thrombogenic than otherwise
- identical thin-strutted (81 m) devices in ex vivo flow loops (P< 0.001),
commensurate with 1.6-fold greater thrombus coverage
- 3 days after implantation in porcine coronary arteries (P 0.004).
When bare metal stents were deployed in
- malapposed or overlapping configurations, thrombogenicity increased compared with apposed, length-matched controls (1.58-fold, P < 0.001; and 2.32-fold, P <0.001).
The thrombogenicity of polymer-coated stents with thin struts was
- lowest in all configurations and remained insensitive to incomplete deployment.
Computational modeling– based
- predictions of stent-induced flow derangements
- correlated with spatial distribution of formed clots.
Drug/polymer coatings do not inherently increase acute stent clotting;
However, strut dimensions and positioning relative to the vessel wall
- are critical factors in modulating stent thrombogenicity.
Optimal stent geometries and surfaces, as demonstrated with thin stent struts,
- help reduce the potential for thrombosis
- despite complex stent configurations and variability in deployment. (Circulation. 2011;123:1400-1409.) (3)
1. Luminal flow patterns dictate arterial drug deposition in stent-based delivery.
VB Kolachalama, AR Tzafriri, DY Arifin, ER Edelman. J Control Release 2009; 133:24–30.
2. Local and systemic drug competition in drug-eluting stent tissue deposition properties.
AD Levin, M Jonas, Chao-Wei Hwang, ER Edelman. J Control Release 2005; 109:236-243.
3. Stent Thrombogenicity Early in High-Risk Interventional Settings Is Driven by
Stent Design and Deployment and Protected by Polymer-Drug Coatings
Kumaran Kolandaivelu, Rajesh Swaminathan, William J. Gibson,.. ER Edelman
Management of Obstructive Coronary Artery Disease
Multiple studies have shown that diabetes mellitus (DM) can affect the
- efficacy of revascularization therapies and subsequent clinical outcomes.
Selecting the appropriate myocardial revascularization strategy is critically important
- in the setting of multivessel coronary disease.
Optimal medical therapy is an appropriate first-line strategy in patients with DM and mild symptoms. When medical therapy does not adequately control symptoms,
- revascularization with either PCI or CABG may be used.
In patients with treated DM, moderate to severe symptoms and complex multivessel coronary disease,
- coronary artery bypass graft surgery provides better survival,
- fewer recurrent infarctions and
- greater freedom from re-intervention.
Decisions regarding revascularization in patients with DM must take into account multiple factors and as such require a multidisciplinary team approach (‘heart team’). (1)
An incomplete understanding of the transport forces and local tissue structures
- that modulate drug distribution has hampered
- local pharmacotherapies in many organ systems.
These issues are especially relevant to arteries, where stent-based delivery allows fine control of locally directed drug release.
Local delivery produces tremendous drug concentration gradients
- these are in part derived from transport forces,
- differences in deposition from tissue to tissue
This suggests that tissue ultrastructure also plays an important role.
Authors measured the equilibrium drug uptake and the penetration and diffusivity of
- dextrans (a model hydrophilic drug similar to heparin) and albumin
- in orthogonal planes in arteries explanted from different vascular beds.
Authors found significant variations in drug distribution with
- geometric orientation and
- arterial connective tissue content.
Drug diffusivities parallel to the connective tissue sheaths were
- one to two orders of magnitude greater than across these sheaths.
This diffusivity difference remained relatively constant for drugs up to 70 kDa
- before decreasing for larger drugs.
Drugs also distributed better into elastic arteries, especially at lower molecular weights,
- with almost 66% greater transfer into the thoracic aorta
- than into the carotid artery.
Arterial drug transport is thus highly anisotropic and
- dependent on arterial tissue content.
The role of the local composition and geometric organization of arterial tissue
- in influencing vascular pharmacokinetics
is likely to become a critical consideration for local vascular drug delivery (2)
Radiolabeled drug-eluting stents have been proposed
- to potentially reduce restenosis in coronary arteries.
A P-32 labeled oligonucleotide (ODN) loaded on a polymer coated stent
- is slowly released in the arterial wall to deliver a therapeutic dose to the target tissue.
A relatively low proportion of drugs is transferred to the arterial wall (< 2%– 5% typically). This raises questions about the degree to which radiolabeled drugs eluted from the stent
- can contribute to the total radiation dose delivered to tissues.
A three-dimensional diffusion-convection transport model is used
- to model the transport of a hydrophilic drug released
- from the surface of a stent to the arterial media.
Large drug concentration gradients are observed
- near the stent struts giving rise to a
- non-uniform radiation activity distribution for the drug
- in the tissues as a function of time.
A voxel-based kernel convolution method is used to calculate the radiation dose rate
- resulting from this activity build-up in the arterial wall
- based on the medical internal radiation dose formalism.
Measured residence time for the P-32 ODN in the arterial wall and
- at the stent surface obtained from animal studies
- are used to normalize the results in terms of absolute dose to tissue.
The results indicate radiation due to drug eluted from the stent
- contributes only a small fraction of the total radiation delivered to the arterial wall,
- the main contribution comes from the activity embedded in the stent coating.
For hydrophilic compounds with rapid transit times in arterial tissue and minimal binding interactions,
- the activity build-up in the arterial wall contributes only a small fraction
- to the total dose delivered by the P-32 ODN stent.
For these compounds, it is concluded that radiolabeled drug-eluting stent
- would not improve the performance of radioactive stents in treating restenosis.
Also, variability in the efficacy of drug delivery devices
- makes accurate dosimetry difficult and
- the drug washout in the systemic circulatory system
may yield an unnecessary activity build-up and dose to healthy organs. (3)
The first compounds considered for stent-based delivery,
- such as heparin have failed to stop restenosis clinically.
More recent compounds, such as paclitaxel, are of a different sort.
They are hydrophobic, and their effects after local release seem far more profound.
This dichotomy raises the question of whether drugs that have an effect when released from a stent do so because of
- differences in biology or differences in physicochemical properties and targeting.
Authored applied continuum pharmacokinetics to examine the effects of
- transport forces and device geometry on
the distribution of stent-delivered hydrophilic and hydrophobic drugs.
Stent-based delivery leads to large concentration gradients.
Drug concentrations range from nil to several times the
- mean tissue concentration over a few micrometers.
Concentration variations were a function of the Peclet number (Pe),
- the ratio of convective to diffusive forces.
Although hydrophobic drugs exhibit greater variability than hydrophilic drugs,
- they achieve higher mean concentrations and
- they remain closer to the intima.
Inhomogeneous strut placement influences hydrophilic drugs
- more negatively than hydrophobic drugs, and notably
- affect local concentrations without changing mean concentrations.
Local concentrations and gradients are inextricably linked to biological effect. Therefore,
- these results provide a potential explanation for the variable success of stent-based delivery.
Authors conclude that mere proximity of delivery devices to tissues
- does not ensure adequate targeting,
- because physiological transport forces cause
- local concentrations to deviate significantly from mean concentrations. (4)
1. Role of CABG in the management of obstructive coronary arterial disease in patients with diabetes mellitus. D Aronson, ER Edelman. Curr Opin Pharmacol 2012, 12:134–141. Issue on Cardiovascular and renal. [Eds: JY Jeremy, K Zacharowski, N Shukla, S Wan].
http://dx.doi.org/10.1016/j.coph.2012.01.0113. Dose model for stent-based delivery of a radioactive compound for the treatment of restenosis in coronary arteries. C Janickia, Chao-Wei Hwang, ER Edelman. Med Phys 2003; 30(10), 2622-7.
http://dx.doi.org/10.1118/1.16075064. Physiological Transport Forces Govern Drug Distribution for Stent-Based Delivery. Chao-Wei Hwang, D Wu, ER Edelman. Circulation. 2001;104(5) :600-605; e14 – e9010.
http://dx.doi.org/10.1161/hc3101.09221New endovascular stent designs are displacing tried and-true devices for use in an ever-broader array of lesions. There is disagreement as to which device is most advantageous and whether design determines outcome. Preclinical research says that this should be the case. Clinical trials have failed to validate design dependence. Can the divergent results be reconciled? More than 50 different stent configurations are available. The processes of industrial development and federal regulatory evaluation support the importance of design.
Stents are made from
- a spectrum of materials
- a range of manufacturing techniques, and have
- variable surfaces,
- dimensions,
- surface coverage, and
- strut configurations.
The number of parameters involved may doom the number of subsets to approach the number of designs. Moreover, each device seems to have a unique optimal mode of placement. Differences have been reported in
- flexibility,
- tracking ability,
- expansion,
- radiovisibility,
- side-branch access, and
- resistance to compression and recoil for different devices.
Regulatory approval includes standards for safety:
- toxicity,
- biocompatibility,
- structural and material analysis, and
- fatigue testing
It has been suggested that
- hoop strength,
- surface cracking,
- uniformity of expansion, and
- other features become standardized as well.
Four different direct comparisons of first-generation Palmaz-Schatz slotted-tube stents and
second-generation stents have been made. In several studies there were no significant differences
in restenosis at follow-up, including
- minimal luminal diameter (MLD),
- percent diameter stenosis,
- late loss, or
- binary restenosis rate.
In the fourth study, restenosis was far greater for the Gianturco-Roubin II (GR-II) stent (Cook) than
- the Palmaz-Schatz stent (Cordis-Johnson & Johnson).
The data for all stents bunch across trials: with the exception of the GR-II stent,
variability between the test stent groups was no greater than
- the variability between the Palmaz-Schatz stent groups in the different trials.
Three distinct possibilities exist to explain the absence of clinical evidence that different designs behave differently:
(1) no differences in clinical outcomes exist between devices;
(2) differences exist but are so slight as to be clinically meaningless; and
(3) differences exist that may be clinically meaningful, but trials performed to date were not designed to detect them.
Schematic representation of device performance plotting outcome against indication indicates that
- complication rates rise as lesion complexity increases.
When 2 devices are clinically different, their curves are displaced, and when they are indistinguishable, their curves overlap.
Clinical trials that restrict the test population to lesions low on the complexity scale
- ensure safety for all patients but are not the ideal venues in which to detect differences between devices.
Thus, although stents 1 and 2 may have different clinical outcomes, in a restricted-criteria equivalency trial with low complexity, they appear identical. It is only when the test device performs worse than the standard, that differences can be appreciated.
In contrast, an open registry will not only show when a test stent is worse than the standard stent but also when it is better.
Equivalency Trials
Stent-versus-stent trials are equivalency trials, designed to show that a test device performs “as well as” a standard, currently acceptable device. This is a valid regulatory threshold but
- not the means to evaluate the full potential of a device.
Equivalency trials must by definition commence with a patient population for whom the standard device is safe. Trials with currently approved devices as the standard necessitate that
- patient entry and lesion selection be determined by
- limitations of the standard, not the device.
to observe a difference in such a trial
- the test device performs worse
For the test device to perform better, both the test and the standard must be challenged.
This was not the case for the trials in which
- the average reference vessel size was 3.0+0.05 mm and
- American College of Cardiology type B2 and C lesions accounted for only ~65% of lesions.
These lesions are those for which the Palmaz-Schatz stent is approved and technically suited, but
- they represent only a minority of those lesions now receiving stents
Complexity, Equivalence, and Better
In truth, it may be most appropriate to think about parameters of device success and safety as a continuum, describing a correlation between events such as
- thrombosis or restenosis and
- a continuous measure of indication,
- vessel dimension, or lesion complexity (Figure).
A given device may be represented by a characteristic response over a range of indications.
When there is a lateral offset to the curves,
- differences in potential performance are anticipated.
Curves might even cross, rather than run parallel, indicating that devices might be matched
to lesions and indications. Open trials would consider the entire range of the curves.
- equivalency trials are limited to a small region of the curve.
The first-generation stents were a major innovation in interventional cardiology, and their place in medical history and biotechnology is unassailable.
Demonstration that new stents are better than old will require that evaluations be
- performed in lesions for which current devices have marginal or limited application.
Complex or acutely unstable lesions, small arteries, and diseased bypass grafts are
- the next great challenges of interventional cardiology.
Perhaps in these settings, future stent trials will provide firm evidence that
- the manner in which blood vessels are manipulated dictates biological sequelae.
Proof that stent design can alter clinical outcomes may then unleash the potential
- to change the way in which we consider design, approval, and use of new devices.
REFERENCES
Menichelli, M. (2006). Sirolimus Stent vs. Bare Stent in Acute Myocardial Infarction Trial. Presented at The European Paris Course on Revascularization (EuroPCR), May 16-19, 2006, Paris, France Paris, France.http://www.medscape.com/viewprogram/5505?rss
Pfisterer, P.E. (2006). Basel Stent Cost-effectiveness Trial-Late Thrombotic events (BASKET LATE) Trial. Presented at American College of Cardiology 55th Annual Scientific Session, March 11 – 14, 2006, Atlanta, Georgia.http://www.medscape.com/viewprogram/5185
Rogers, C. Edelman E.R. (2006). Pushing drug-eluting stents into uncharted territory, Simpler then you think – more complex than you imagine. Circulation,113, 2262-2265.
Shirota, T., Yasui, H., Shimokawa, H. & Matsuda, T. (2003). Fabrication of endothelial progenitor cell (EPC)-seeded intravascular stent devices and in vitro endothelialization on hybrid vascular tissue. Biomaterials 24(13), 2295–2302.
Simonton, C. (2006). The STENT Registry: A real-world look at Sirolimus- and Pacitaxel-Eluting Stents. Cath Lab Digest, 14 (1), 1-10.
Turco, M. (2006). TAXUS ATLAS Trial – 9-Month results: Evaluation of TAXUS Liberte vs. TAXUS Express. Presented at The European Paris Course on Revascularization (EuroPCR), May 16-19, 2006, Paris, France Paris, France.http://www.medscape.com/viewprogram/5505?rss
Verma, S. and Marsden, P.A. (2005). Nitric Oxide-Eluting Polyurethanes – Vascular Grafts of the Future? New England Journal Medicine, 353 (7), 730-731.
Wood, S. (2006). Guidant suspends release of Xience V everolimus-eluting stent due to manufacturing standards http://www.theheart.org/article/679851.do
Other Related Articles that were published on this Open Access Online Scientific Journal include the following:
Modeling Targeted Therapy
Larry H Bernstein, MD, FACP 3/2/2013
Quantum Biology And Computational Medicine
Larry H Bernstein, MD, FACP 4/3/2013
Virtual Biopsy – is it possible?
Larry H Bernstein, MD, FACP 3/3/2013
Reprogramming cell fate 3/2/2013
Larry H Bernstein, MD, FACP
How Methionine Imbalance with Sulfur-Insufficiency Leads to Hyperhomocysteinemia
Larry H Bernstein, MD, FACP 4/4/2013
http://pharmaceuticalintelligence.com/2013/04/04/sulfur-deficiency-and-hyperhomocusteinemia/
Amyloidosis with Cardiomyopathy
Larry H Bernstein, MD, FACP 3/31/2013
http://pharmaceuticalintelligence.com/2013/03/31/amyloidosis-with-cardiomyopathy/
Nitric Oxide, Platelets, Endothelium and Hemostasis
Larry H Bernstein, MD, FACP 11/8/2012
http://pharmaceuticalintelligence.com/2012/11/08/nitric-oxide-platelets-endothelium-and-hemostasis/
Mitochondrial Damage and Repair under Oxidative Stress
Larry H Bernstein, MD, FACP 10/28/2012
http://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/
Endothelial Function and Cardiovascular Disease
Larry H Bernstein, MD, FACP 10/25/2012
http://pharmaceuticalintelligence.com/2012/10/25/endothelial-function-and-cardiovascular-disease/
Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease –Therapeutic Potential of cEPCs
Aviva Lev-Ari, PhD, RN 8/27/2012
Revascularization: PCI, Prior History of PCI vs CABG
Aviva Lev-Ari, PhD, RN 4/25/2013
http://pharmaceuticalintelligence.com/2013/04/25/revascularization-pci-prior-history-of-pci-vs-cabg/
Cholesteryl Ester Transfer Protein (CETP) Inhibitor: Potential of Anacetrapib to treat Atherosclerosis and CAD
Aviva Lev-Ari, PhD, RN 4/7/2013
http://pharmaceuticalintelligence.com/2013/04/07/cholesteryl-ester-transfer-protein-cetp-inhibitor-potential-of-anacetrapib-to-treat-atherosclerosis-and-cad/
Hypertriglyceridemia concurrent Hyperlipidemia: Vertical Density Gradient Ultracentrifugation a Better Test to Prevent Undertreatment of High-Risk Cardiac Patients
Aviva Lev-Ari, PhD, RN 4/4/2013
http://pharmaceuticalintelligence.com/2013/04/04/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
Aviva Lev-Ari, PhD, RN 4/3/2013
http://pharmaceuticalintelligence.com/2013/04/03/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
Aviva Lev-Ari, PhD, RN 3/31/2013
http://pharmaceuticalintelligence.com/2013/03/31/high-density-lipoprotein-hdl-an-independent-predictor-of-endothelial-function-artherosclerosis-a-modulator-an-agonist-a-biomarker-for-cardiovascular-risk/
Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI
Aviva Lev-Ari, PhD, RN 3/10/2013
http://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/
Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013
Lev-Ari, A. and L H Bernstein 3/7/2013
http://pharmaceuticalintelligence.com/2013/03/07/genomics-genetics-of-cardiovascular-disease-diagnoses-a-literature-survey-of-ahas-circulation-cardiovascular-genetics-32010-32013/
The Heart: Vasculature Protection – A Concept-based Pharmacological Therapy including THYMOSIN
Aviva Lev-Ari, PhD, RN 2/28/2013
http://pharmaceuticalintelligence.com/2013/02/28/the-heart-vasculature-protection-a-concept-based-pharmacological-therapy-including-thymosin/
Arteriogenesis and Cardiac Repair: Two Biomaterials – Injectable Thymosin beta4 and Myocardial Matrix Hydrogel
Aviva Lev-Ari, PhD, RN 2/27/2013
http://pharmaceuticalintelligence.com/2013/02/27/arteriogenesis-and-cardiac-repair-two-biomaterials-injectable-thymosin-beta4-and-myocardial-matrix-hydrogel/
Coronary artery disease in symptomatic patients referred for coronary angiography: Predicted by Serum Protein Profiles
Aviva Lev-Ari, PhD, RN 12/29/2012
http://pharmaceuticalintelligence.com/2012/12/29/coronary-artery-disease-in-symptomatic-patients-referred-for-coronary-angiography-predicted-by-serum-protein-profiles/
Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment
Bernstein, HL and Lev-Ari, A. 11/28/2012
http://pharmaceuticalintelligence.com/2012/11/28/special-considerations-in-blood-lipoproteins-viscosity-assessment-and-treatment/
Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes
Aviva Lev-Ari, PhD, RN 11/13/2012
http://pharmaceuticalintelligence.com/2012/11/13/peroxisome-proliferator-activated-receptor-ppar-gamma-receptors-activation-pparγ-transrepression-for-angiogenesis-in-cardiovascular-disease-and-pparγ-transactivation-for-treatment-of-dia/
Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?
Aviva Lev-Ari, PhD, RN 10/19/2012
http://pharmaceuticalintelligence.com/2012/10/19/clinical-trials-results-for-endothelin-system-pathophysiological-role-in-chronic-heart-failure-acute-coronary-syndromes-and-mi-marker-of-disease-severity-or-genetic-determination/
Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation
Aviva Lev-Ari, PhD, RN 10/4/2012
http://pharmaceuticalintelligence.com/2012/10/04/endothelin-receptors-in-cardiovascular-diseases-the-role-of-enos-stimulation/
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
Aviva Lev-Ari, PhD, RN 10/4/2012
http://pharmaceuticalintelligence.com/2012/10/04/inhibition-of-et-1-eta-and-eta-etb-induction-of-no-production-and-stimulation-of-enos-and-treatment-regime-with-ppar-gamma-agonists-tzd-cepcs-endogenous-augmentation-for-cardiovascular-risk-reduc/
Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral
Aviva Lev-Ari, PhD, RN 8/29/2012
http://pharmaceuticalintelligence.com/2012/08/29/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
Aviva Lev-Ari, PhD, RN 8/28/2012
http://pharmaceuticalintelligence.com/2012/08/28/cardiovascular-outcomes-function-of-circulating-endothelial-progenitor-cells-cepcs-exploring-pharmaco-therapy-targeted-at-endogenous-augmentation-of-cepcs/
Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease – Therapeutic Potential of cEPCs
Aviva Lev-Ari, PhD, R N 8/27/2012
http://pharmaceuticalintelligence.com/2012/08/27/endothelial-dysfunction-diminished-availability-of-cepcs-increasing-cvd-risk-for-macrovascular-disease-therapeutic-potential-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
Aviva Lev-Ari, PhD, RN 8/24/2012
http://pharmaceuticalintelligence.com/2012/08/24/vascular-medicine-and-biology-classification-of-fast-acting-therapy-for-patients-at-high-risk-for-macrovascular-events-macrovascular-disease-therapeutic-potential-of-cepcs/
Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production
Aviva Lev-Ari, PhD, RN 7/19/2012
http://pharmaceuticalintelligence.com/2012/07/19/cardiovascular-disease-cvd-and-the-role-of-agent-alternatives-in-endothelial-nitric-oxide-synthase-enos-activation-and-nitric-oxide-production/
Resident-cell-based Therapy in Human Ischaemic Heart Disease: Evolution in the PROMISE of Thymosin beta4 for Cardiac Repair
Aviva Lev-Ari, PhD, RN 4/30/2012
http://pharmaceuticalintelligence.com/2012/04/30/93/
Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes
Aviva Lev-Ari, PhD, RN 5/29/2012
http://pharmaceuticalintelligence.com/2012/05/29/445/
Macrovascular Disease – Therapeutic Potential of cEPCs: Reduction Methods for CV Risk
Aviva Lev-Ari, PhD, RN 7/2/2012
http://pharmaceuticalintelligence.com/2012/07/02/macrovascular-disease-therapeutic-potential-of-cepcs-reduction-methods-for-cv-risk/
Mitochondria Dysfunction and Cardiovascular Disease – Mitochondria: More than just the “powerhouse of the cell”
Aviva Lev-Ari, PhD, RN 7/9/2012
http://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/
Bystolic’s generic Nebivolol – positive effect on circulating Endothelial Proginetor Cells endogenous augmentation
Aviva Lev-Ari, PhD, RN 7/16/2012
http://pharmaceuticalintelligence.com/2012/07/16/bystolics-generic-nebivolol-positive-effect-on-circulating-endothilial-progrnetor-cells-endogenous-augmentation/
Arteriogenesis and Cardiac Repair: Two Biomaterials – Injectable Thymosin beta4 and Myocardial Matrix Hydrogel
Aviva Lev-Ari, PhD, RN 2/27/2013
http://pharmaceuticalintelligence.com/2013/02/27/arteriogenesis-and-cardiac-repair-two-biomaterials-injectable-thymosin-beta4-and-myocardial-matrix-hydrogel/
Cardiac Surgery Theatre in China vs. in the US: Cardiac Repair Procedures, Medical Devices in Use, Technology in Hospitals, Surgeons’ Training and Cardiac Disease Severity”
Aviva Lev-Ari, PhD, RN 1/8/2013
http://pharmaceuticalintelligence.com/2013/01/08/cardiac-surgery-theatre-in-china-vs-in-the-us-cardiac-repair-procedures-medical-devices-in-use-technology-in-hospitals-surgeons-training-and-cardiac-disease-severity/
Heart Remodeling by Design – Implantable Synchronized Cardiac Assist Device: Abiomed’s Symphony
Aviva Lev-Ari, PhD, RN 7/23/2012
http://pharmaceuticalintelligence.com/2012/07/23/heart-remodeling-by-design-implantable-synchronized-cardiac-assist-device-abiomeds-symphony/
Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI
Aviva Lev-Ari, PhD, RN 3/10/2013
http://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/
Dilated Cardiomyopathy: Decisions on implantable cardioverter-defibrillators (ICDs) using left ventricular ejection fraction (LVEF) and Midwall Fibrosis: Decisions on Replacement using late gadolinium enhancement cardiovascular MR (LGE-CMR)
Aviva Lev-Ari, PhD, RN 3/10/2013
http://pharmaceuticalintelligence.com/2013/03/10/dilated-cardiomyopathy-decisions-on-implantable-cardioverter-defibrillators-icds-using-left-ventricular-ejection-fraction-lvef-and-midwall-fibrosis-decisions-on-replacement-using-late-gadolinium/
The Heart: Vasculature Protection – A Concept-based Pharmacological Therapy including THYMOSIN
Aviva Lev-Ari, PhD, RN 2/28/2013
http://pharmaceuticalintelligence.com/2013/02/28/the-heart-vasculature-protection-a-concept-based-pharmacological-therapy-including-thymosin/
FDA Pending 510(k) for The Latest Cardiovascular Imaging Technology
Aviva Lev-Ari, PhD, RN 1/28/2013
http://pharmaceuticalintelligence.com/2013/01/28/fda-pending-510k-for-the-latest-cardiovascular-imaging-technology/
PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity
Aviva Lev-Ari, PhD, RN 1/10/2013
http://pharmaceuticalintelligence.com/2013/01/10/pci-outcomes-increased-ischemic-risk-associated-with-elevated-plasma-fibrinogen-not-platelet-reactivity/
The ACUITY-PCI score: Will it Replace Four Established Risk Scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX
Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2013/01/03/the-acuity-pci-score-will-it-replace-four-established-risk-scores-timi-grace-syntax-and-clinical-syntax/
Coronary artery disease in symptomatic patients referred for coronary angiography: Predicted by Serum Protein Profiles
Aviva Lev-Ari, PhD, RN
http://pharmaceuticalintelligence.com/2012/12/29/coronary-artery-disease-in-symptomatic-patients-referred-for-coronary-angiography-predicted-by-serum-protein-profiles/
Heart Renewal by pre-existing Cardiomyocytes: Source of New Heart Cell Growth Discovered
Aviva Lev-Ari, PhD, RN 12/23/2012
http://pharmaceuticalintelligence.com/2012/12/23/heart-renewal-by-pre-existing-cardiomyocytes-source-of-new-heart-cell-growth-discovered/
Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis.
Aviva Lev-Ari, PhD, RN 10/30/2012
http://pharmaceuticalintelligence.com/2012/10/30/cardiovascular-risk-inflammatory-marker-risk-assessment-for-coronary-heart-disease-and-ischemic-stroke-atherosclerosis/
To Stent or Not? A Critical Decision
Aviva Lev-Ari, PhD, RN 10/23/2012
http://pharmaceuticalintelligence.com/2012/10/23/to-stent-or-not-a-critical-decision/
New Definition of MI Unveiled, Fractional Flow Reserve (FFR)CT for Tagging Ischemia
Aviva Lev-Ari, PhD, RN 8/27/2012
http://pharmaceuticalintelligence.com/2012/08/27/new-definition-of-mi-unveiled-fractional-flow-reserve-ffrct-for-tagging-ischemia/
Ethical Considerations in Studying Drug Safety — The Institute of Medicine Report
Aviva Lev-Ari, PhD, RN 8/23/2012
http://pharmaceuticalintelligence.com/2012/08/23/ethical-considerations-in-studying-drug-safety-the-institute-of-medicine-report/
New Drug-Eluting Stent Works Well in STEMI
Aviva Lev-Ari, PhD, RN 8/22/2012
http://pharmaceuticalintelligence.com/2012/08/22/new-drug-eluting-stent-works-well-in-stemi/
Expected New Trends in Cardiology and Cardiovascular Medical Devices
Aviva Lev-Ari, PhD, RN 8/17/2012
http://pharmaceuticalintelligence.com/2012/08/17/expected-new-trends-in-cardiology-and-cardiovascular-medical-devices/
Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents
Aviva Lev-Ari, PhD, RN 8/13/2012
http://pharmaceuticalintelligence.com/2012/08/13/coronary-artery-disease-medical-devices-solutions-from-first-in-man-stent-implantation-via-medical-ethical-dilemmas-to-drug-eluting-stents/
Percutaneous Endocardial Ablation of Scar-Related Ventricular Tachycardia
Aviva Lev-Ari, PhD, RN 7/18/2012
http://pharmaceuticalintelligence.com/2012/07/18/percutaneous-endocardial-ablation-of-scar-related-ventricular-tachycardia/
Competition in the Ecosystem of Medical Devices in Cardiac and Vascular Repair: Heart Valves, Stents, Catheterization Tools and Kits for Open Heart and Minimally Invasive Surgery (MIS)
Aviva Lev-Ari, PhD, RN 6/22/2012
http://pharmaceuticalintelligence.com/2012/06/22/competition-in-the-ecosystem-of-medical-devices-in-cardiac-and-vascular-repair-heart-valves-stents-catheterization-tools-and-kits-for-open-heart-and-minimally-invasive-surgery-mis/
Global Supplier Strategy for Market Penetration & Partnership Options (Niche Suppliers vs. National Leaders) in the Massachusetts Cardiology & Vascular Surgery Tools and Devices Market for Cardiac Operating Rooms and Angioplasty Suites
Aviva Lev-Ari, PhD, RN 6/22/2012
http://pharmaceuticalintelligence.com/2012/06/22/global-supplier-strategy-for-market-penetration-partnership-options-niche-suppliers-vs-national-leaders-in-the-massachusetts-cardiology-vascular-surgery-tools-and-devices-market-for-car/
Related Articles
Image via CrunchBase
Diagram showing the location of vascular smooth muscle cells (Photo credit: Wikipedia)
English: simplified diagram of the human Arterial system in anterior view. Français : Diagramme simplifié du système artériel humain en vue antérieure (en anglais). (Photo credit: Wikipedia)
Read Full Post »
| 
2012pharmaceutical
sjwilliamspa