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Recent alternative approaches of vascular drug-eluting stents
Abstract
Vascular stent is tubular shaped medical device designed to treat occluded circulatory or digestive systems by opening the blocked vascular sites. Originally stents were made of bare metals, such as stainless steel and cobalt–chromium alloys, due to their inherent corrosion resistance and good mechanical properties. Damage of intimal layer during expansion of stent, however, have caused neointimal hyperplasia resulting in in-stent restenosis which is one of main complications of vascular stent treatment. Drug-eluting stents (DESs) were introduced to alleviate this restenosis by local delivery of anti-proliferative drugs to the implanted or inserted site. The DES systems have been developed over the years by making changes in its main component, namely, drug, polymeric coating layer and expandable scaffold. Nevertheless, late thrombosis caused by drugs themselves and polymeric coating layer still remains as a serious problem of DES systems. Numerous studies, therefore, consistently focus on more advanced DES systems to solve the current issues. In this mini review article, we cast an opinion on how to improve the potential of DES system by means of (i) summarizing the history of DES system developed so far and (ii) updating current advances for the future generation of DES system.
... The appearance of drugliberating stents (DES), that release antiproliferative drugs in the implanted site, was an efficient form to overcome this problem. However, released drugs themselves and polymeric coating layer may cause subsequent thrombosis and yet they remain a problem [51]. In this sense, the work realized by Chin-Quee et al. showed that the fluorinated copolymer PVDF-HFP and the phosphorylcholine polymer, both commercially available drug-eluting stents, had similar effects, giving both acute thrombotic responses [52]. ...
This chapter presents a general description of the most common synthetic and semi-synthetic polymers, ranging from macro to nanoscopic sizes that have been used in the preparation of different pharmaceutical dosage. The polymers represent an important component of several pharmaceutical formulations. It is well-known that the formulation and clinical performance of pharmaceutical dosage forms depend on the physicochemical properties of the used polymers. Therefore, the impact of polymers is a consequence of the great advances in chemical synthesis and the analysis of their properties.
In the different sections of this chapter, the most used synthetic methodologies for obtaining synthetic and semi-synthetic polymers with some representative examples of their pharmaceutical applications will be presented.
... Reprinted with permission from Elsevier metallic, there has been a growing interest to incorporate polymers in the fabrication of stents to augment the stent's drug-holding potential and increase their biocompatibility. As such, polymer-coated stents emerged where the metal backbone afforded the required mechanical support and the polymer coat provided a biocompatible, and if needed, drug-laden layer (63)(64)(65)(66). Recently, researchers' efforts have been directed toward composing purely polymeric expandable implants. ...
Implantable drug delivery systems, such as drug pumps and polymeric drug depots, have emerged as means of providing predetermined drug release profiles at the desired site of action. While initial implants aimed at providing an enduring drug supply, developments in polymer chemistry and pharmaceutical technology and the growing need for refined drug delivery patterns have prompted the design of sophisticated drug delivery implants such as on-demand drug-eluting implants and personalized 3D printed implants. The types of cargo loaded into these implants range from small drug molecules to hormones and even therapeutic cells. This review will shed light upon recent advances in materials and composites used for polymeric implant fabrication, highlight select approaches employed in polymeric implant fabrication, feature medical applications where polymeric implants have a significant impact, and report recent advances made in these areas.
... As a consequence, focus was set on the development of drug-eluting stents (DES) [591-,592,593]. These systems carry an antiproliferative drug, which is incorporated into a polymer coating of the BMS [594]. The drugs are directly released at the injured sites to prevent the ISR by the suppression of the neointimal growth [595]. ...
A series of dexamethasone (DEX)-loaded polydioxanone (PDO) monofilaments drawn at different draw ratios through a melt spinning process was developed to investigate changes in drug release behavior, mechanical properties, and biodegradation. Drawn PDO monofilaments presented decreased diameters, increased tensile strengths, and reduced elongation at break. The XRD analysis of DEX-loaded PDO monofilament showed changes in crystallinity due to the drawing process. The drawing process also changed behaviors of degradation and drug release, showing reduced degradation rates and long-term sustained release rates at higher draw ratios. Taken together, obtained characteristic properties and their controllability are expected to be favorable for practical applications requiring invasive and longer implantation such as non-vascular stents, surgical sutures, and face-lifting materials.
While absorbable magnesium (Mg) based vascular stents show promise, more progress is needed to fulfil suitable durability, fast endothelialization, anti‐restenosis, and anti‐inflammation. To design a multifunctional stent, the authors screen a common oral atorvastatin calcium (ATVC) loaded into a surface‐eroding poly(1,3‐trimethylene carbonate) (PTMC) on a Mg alloy material (AZ31 wire) to achieve well‐controllable degradation rate, target drug delivery, and vascular remodeling. Moreover, to reduce cytocompatibility discrepancy between in vitro static culture and in vivo tests for Mg‐based materials, a microfluidic model is developed to mimic the microenvironment of an early‐stage stented vessel for the study of endothelial cell responses to Mg. The PTMC and PTMC‐ATVC coatings effectively reduce degradation rate of the Mg alloy in the static immersion, electrochemical measurement, microfluidic chip, and in vivo tests. The PTMC‐ATVC‐coated wires perform an outstanding growth and migration of endothelial cells in the microfluidic chip at a flow rate of 10 µL min⁻¹, compared with uncoated and PTMC‐coated wires. In vivo rat test, the PTMC‐ATVC coating positively regulate endothelial cells and smooth muscle cells, reduce intimal hyperplasia and inflammation. The target atorvastatin delivery by PTMC coating show a promising dual‐function for improving the durability and early endothelialization of Mg‐based stents.
This review focuses on describing new generations of drug-eluting stents (DES) based on the use of novel stent platforms, coatings, and carrier systems, developed to enhance DES safety. Examples of various DES classes among the most clinically-used DES are briefly discussed.
Background:
Recent evidence suggests that bioresorbable vascular scaffolds (BVS) are associated with an excess of thrombotic complications compared with metallic everolimus-eluting stents (EES).
Objective:
We sought to investigate the comparative effectiveness of the FDA approved Absorb BVS versus metallic EES in patients undergoing percutaneous coronary intervention at longest available follow-up.
Methods:
We searched MEDLINE, Scopus and web sources for randomized trials comparing the BVS and EES. The primary efficacy and safety endpoints were target lesion failure and definite/probable stent thrombosis, respectively. This study is registered with PROSPERO, number CRD42017059993.
Results:
Seven trials were included: in sum, 5,583 patients were randomized to receive either the study Absorb BVS (n=3,261) versus EES (n=2,322). Median time of follow-up was 2 years (range 2 to 3 years). Compared with metallic EES, risk of target lesion failure (9.6% vs. 7.2%, absolute risk difference [ARD] = +2.4%, relative risk [RR]: 1.32, 95% confidence interval [CI]: 1.10 to 1.59, number needed to harm [NNH] = 41, p=0.003, I(2)=0%) and stent thrombosis (2.4% vs. 0.7%, ARD: +1.7%, RR: 3.15, 95% CI: 1.87 to 5.30, NNH = 60, p<0.0001, I(2)=0%) were both significantly higher with BVS. There were no significant differences in all-cause or cardiovascular mortality between groups. The increased risk for ST associated with BVS was concordant across the early (< 30 days), late (30 days to 1 year) and very-late (> 1 year) periods (pinteraction=0.49).
Conclusion:
Compared with metallic EES, the Absorb BVS appears to be associated with both lower efficacy and higher thrombotic risk over time.
Objective To report the long-term safety and efficacy data of a third generation drug eluting stent (DES) with biodegradable polymer in the complex patient population of diabetes mellitus after a follow-up period of 5 years. Background After percutaneous coronary intervention patients with diabetes mellitus are under higher risk of death, restenosis and stent thrombosis (ST) compared to non-diabetic patients. Methods In 126 centers worldwide 3067 patients were enrolled in the NOBORI 2 registry, 888 patients suffered from diabetes mellitus (DM), 213 of them (14%) being insulin dependent (IDDM). Five years follow-up has been completed in this study. ResultsAt 5 years, 89.3% of the patients were available for follow-up. The reported target lesion failure (TLF) rates at 5 years were 12.39% in DM group and 7.34% in non-DM group; (p < 0.0001). In the DM group, the TLF rate in patients with IDDM was significantly higher than in the non-IDDM subgroup (17.84 vs. 10.67%; p < 0.01). The rate of ST at 5 years was not different among diabetic versus non-diabetic patients or IDDM versus NIDDM. Only 10 (<0.4%) very late stent thrombotic events beyond 12 months occurred. Conclusions
The Nobori DES performed well in patients with DM. As expected patients with DM, particularly those with IDDM, had worse outcomes. However, the very low rate of very late stent thrombosis in IDDM patients might have significant clinical value in the treatment of these patients.Clinical trial registration ISRCTN81649913; http://www.controlled-trials.com/isrctn/search.html?srch=81649913&sort=3&dir=desc&max=10
Controlled drug delivery systems are an encouraging solution to some drug disadvantages such as reduced solubility, deprived biodistribution, tissue damage, fast breakdown of the drug, cytotoxicity, or side effects. Self-ordered nanoporous anodic alumina is an auspicious material for drug delivery due to its biocompatibility, stability, and controllable pore geometry. Its use in drug delivery applications has been explored in several fields, including therapeutic devices for bone and dental tissue engineering, coronary stent implants, and carriers for transplanted cells. In this work, we have created and analyzed a stimuli-responsive drug delivery system based on layer-by-layer pH-responsive polyelectrolyte and nanoporous anodic alumina. The results demonstrate that it is possible to control the drug release using a polyelectrolyte multilayer coating that will act as a gate.
Electronic supplementary material
The online version of this article (doi:10.1186/s11671-016-1585-4) contains supplementary material, which is available to authorized users.
Coronary stents represent a key development for the treatment of obstructive coronary artery disease since the introduction of percutaneous coronary intervention. While drug-eluting stents gained wide acceptance in contemporary percutaneous coronary intervention practice, further developments in bare-metal stents remain crucial for patients who are not candidates for drug-eluting stents, or to improve metallic platforms for drug elution. Initially, stent platforms used biologically inert stainless steel, restricting stent performance due to limitations in flexibility and strut thickness. Later, cobalt chromium stent alloys outperformed steel as the material of choice for stents, allowing latest generation stents to be designed with significantly thinner struts, while maintaining corrosion resistance and radial strength. Most recently, the introduction of the platinum chromium alloy refined stent architecture with thin struts, high radial strength, conformability, and improved radiopacity. This review will provide an overview of the novel platinum chromium bare-metal stent platforms available for coronary intervention. Mechanical properties, clinical utility, and device limitations will be summarized and put into perspective.
A synergistic impact of research in the fields of post-angioplasty restenosis, drug-eluting stents and vascular gene therapy over the past 15 years has shaped the concept of gene-eluting stents. Gene-eluting stents hold promise of overcoming some biological and technical problems inherent to drug-eluting stent technology. As the field of gene-eluting stents matures it becomes evident that all three main design modules of a gene-eluting stent: a therapeutic transgene, a vector and a delivery system are equally important for accomplishing sustained inhibition of neointimal formation in arteries treated with gene delivery stents. This review summarizes prior work on stent-based gene delivery and discusses the main optimization strategies required to move the field of gene-eluting stents to clinical translation.
Metal-based drug-eluting stents (DESs) have severe drawbacks such as peeling-off and cracking of the coated polymer. To prevent the fracture of polymer-coated layer and improve the durability of DES, poly(l-lactide) (PLLA) brushes were synthesized onto cobalt-chromium (Co-Cr or CC) surface through atom transfer radical polymerization (ATRP) of 2-hydroxyethylmethacrylate (HEMA) followed by surface-initiated ring opening polymerization (SI-ROP) of l-lactide. The polymer brushes were then characterized by attenuated total reflection-Fourier transform infrared (ATR-FTIR), water contact angle, ellipsometry, X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), and scanning electron microscopy (SEM). All of the unmodified and modified Co-Cr surfaces were coated with a matrix of poly(d,l-lactide) (PDLLA) and sirolimus (SRL). The in vitro drug release profile was measured for 70 days. The PLLA-modified Co-Cr showed a biphasic release pattern in the initial burst followed by a slow release. On the other hand, the unmodified Co-Cr showed fast drug release and detachment of the coated polymer layer due to the instability of the polymer layer on Co-Cr surface. In comparison, the PLLA-modified Co-Cr preserved a uniform coating without detachment even after 6 weeks of degradation test. The platelet morphology and low density of platelet adhered on the modified layer and the SRL-in-PDLLA coated Co-Cr surfaces demonstrated that these samples would be blood compatible. Therefore, the introduction of PLLA brush onto Co-Cr surface is proved to dramatically improve the durability of the coating layer, and it is a promising strategy to prevent the coating defects found in DESs.
Coating stability is increasingly recognized as a concern impacting the long-term effectiveness of drug eluting stents (DES). In particular, unstable coatings have been brought into focus by a recently published report (Denardo et al 2012 J. Am. Med. Assoc. 307 2148–50). Towards the goal of overcoming current challenges of DES performance, we have developed an endothelium mimicking nanomatrix coating composed of peptide amphiphiles that promote endothelialization, but limit smooth muscle cell proliferation and platelet adhesion. Here, we report a novel water evaporation based method to uniformly coat the endothelium mimicking nanomatrix onto stents using a rotational coating technique, thereby eliminating residual chemicals and organic solvents, and allowing easy application to even bioabsorbable stents. Furthermore, the stability of the endothelium mimicking nanomatrix was analyzed after force experienced during expansion and shear stress under simulated physiological conditions. Results demonstrate uniformity and structural integrity of the nanomatrix coating. Preliminary animal studies in a rabbit model showed no flaking or peeling, and limited neointimal formation or restenosis. Therefore, it has the potential to improve the clinical performance of DES by providing multifunctional endothelium mimicking characteristics with structural integrity on stent surfaces.
Endoglin/CD105 is an accessory protein of the transforming growth factor-β receptor system that plays a critical role in proliferation of endothelial cells and neovasculature. Here, we aimed to assess the effect of novel stents coated with antibodies to endoglin (ENDs) on coronary neointima formation. Thirty ENDs, thirty sirolimus-eluting stents (SESs), and thirty bare metal stents (BMSs) were randomly assigned and placed in the coronary arteries in 30 juvenile pigs. Histomorphometric analysis and scanning electron microscopy were performed after stent implantation. Our results showed that after 7 days, there was no difference in the neointimal area and percent area stenosis in ENDs compared with SMSs or BMSs. After 14 days, the neointima area and percent area stenosis in ENDs were markedly decreased than those in BMSs or SESs (P < 0.05). Moreover, the percentage of reendothelialization was significantly higher in ENDs than that in SESs or BMSs (P < 0.01) at 7 and 14 days. The artery injury and the inflammation scores were similar in all groups at 7 and 14 days. In conclusion, our results demonstrated for the first time to our knowledge that endoglin antibody-coated stents can markedly reduce restenosis by enhancing reendothelialization in the porcine model and potentially offer a new approach to prevent restenosis.
Background:
CCR5 is the major coreceptor for human immunodeficiency virus (HIV). We investigated whether site-specific modification of the gene ("gene editing")--in this case, the infusion of autologous CD4 T cells in which the CCR5 gene was rendered permanently dysfunctional by a zinc-finger nuclease (ZFN)--is safe.
Methods:
We enrolled 12 patients in an open-label, nonrandomized, uncontrolled study of a single dose of ZFN-modified autologous CD4 T cells. The patients had chronic aviremic HIV infection while they were receiving highly active antiretroviral therapy. Six of them underwent an interruption in antiretroviral treatment 4 weeks after the infusion of 10 billion autologous CD4 T cells, 11 to 28% of which were genetically modified with the ZFN. The primary outcome was safety as assessed by treatment-related adverse events. Secondary outcomes included measures of immune reconstitution and HIV resistance.
Results:
One serious adverse event was associated with infusion of the ZFN-modified autologous CD4 T cells and was attributed to a transfusion reaction. The median CD4 T-cell count was 1517 per cubic millimeter at week 1, a significant increase from the preinfusion count of 448 per cubic millimeter (P<0.001). The median concentration of CCR5-modified CD4 T cells at 1 week was 250 cells per cubic millimeter. This constituted 8.8% of circulating peripheral-blood mononuclear cells and 13.9% of circulating CD4 T cells. Modified cells had an estimated mean half-life of 48 weeks. During treatment interruption and the resultant viremia, the decline in circulating CCR5-modified cells (-1.81 cells per day) was significantly less than the decline in unmodified cells (-7.25 cells per day) (P=0.02). HIV RNA became undetectable in one of four patients who could be evaluated. The blood level of HIV DNA decreased in most patients.
Conclusions:
CCR5-modified autologous CD4 T-cell infusions are safe within the limits of this study. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00842634.).
Controlled delivery of multiple growth factors (GFs) holds great potential for the clinical treatment of ischemic diseases and might be more therapeutically effective to reestablish vasculature than the provision of a single GF. Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are two potent angiogenic factors. However, due to rapid degradation and dilution in the body, their clinical potential will rely on an effective mode of delivery. A coacervate, composed of heparin and a biodegradable polycation, which protects GFs from proteolysis and potentiates their bioactivities, is developed. Here, the coacervate incorporates VEGF and HGF and sustains their release for at least three weeks. Their strong angiogenic effects on endothelial cell proliferation and tube formation in vitro are confirmed. Furthermore, it is demonstrated that coacervate-based delivery of these factors has stronger effects than free application of both factors and to coacervate delivery of each GF separately.
Despite development of new coronary stent technologies, in-stent restenosis and stent thrombosis are still clinically relevant. Interactions of blood and tissue cells with the implanted material may represent an important cause of these side effects. We hypothesize material-dependent interaction of blood and tissue cells. The aim of this study is accordingly to investigate the impact of vascular endothelial cells, smooth muscle cells, and platelets with various biodegradable polymers to identify a stent coating or platform material that demonstrates excellent endothelial-cell-supportive and non-thrombogenic properties.
Human umbilical venous endothelial cells, human coronary arterial endothelial cells, and human coronary arterial smooth muscle cells were cultivated on the surfaces of two established biostable polymers used for drug-eluting stents: poly(ethylene-co-vinylacetate) (PEVA) and poly(butyl methacrylate) (PBMA). We performed comparison to new biodegradable polyesters poly(L-lactide) (PLLA), poly(3-hydroxybutyrate) (P(3HB)), poly(4-hydroxybutyrate) (P(4HB)) and a polymeric blend of PLLA/P(4HB) in a ratio of 78/22 % (w/w). Biocompatibility tests were performed under static and dynamic conditions.
Measurement of cell proliferation, viability, glycocalix width, eNOS and PECAM-1 mRNA expression revealed strong material dependency among the six polymer samples investigated. Only the polymeric blend of PLLA/P(4HB) achieved excellent endothelial markers of biocompatibility. Data show that PLLA and P(4HB) tend to a more thrombotic response, whereas the polymer blend is characterized by a lower thrombotic potential.
These data demonstrate material-dependent endothelialization, smooth muscle cell growth and thrombogenicity. Although polymers such as PEVA and PBMA are already commonly used for vascular implants, they did not sufficiently meet criteria for biocompatibility. The investigated biodegradable polymeric blend PLLA/P(4HB) evidently represents a promising material for vascular stents and stent coatings.
Drug-eluting stents have reduced the risk of in-stent restenosis and have broadened the application in percutaneous coronary intervention in coronary artery disease. However, the concept of using a permanent metallic endovascular device to restore the patency of a stenotic artery has inherited pitfalls, namely the presence of a foreign body within the artery causing vascular inflammation, late complications such as restenosis and stent thrombosis, and impeding the restoration of the physiologic function of the stented segment. Bioresorbable scaffolds (BRS) were introduced to potentially overcome these limitations, as they provide temporary scaffolding and then disappear, liberating the treated vessel from its cage. Currently, several BRSs are available, undergoing evaluation either in clinical trials or in preclinical settings. The aim of this review is to present the new developments in BRS technology, describe the mechanisms involved in the resorption process, and discuss the potential future prospects of this innovative therapy.
Background:
Drug-eluting stents successfully reduce restenosis at the cost of delayed re-endothelialization. A novel concept to enhance re-endothelialization is the use of antibody-coated stents which capture circulating progenitor cells. A CD34-positive-cell-capturing stent was recently developed with conflicting clinical results. CD133 is a glycoprotein expressed on circulating hematopoietic and putative endothelial-regenerating cells and may be superior to CD34.
Objective:
The aim of our study was to develop a CD133-cell-capturing bare-metal stent and investigate feasibility, safety, and efficacy of CD133-stents in terms of re-endothelialization and neointima inhibition.
Methods and results:
Anti-human CD133-antibodies were covalently attached to bare-metal stents. In vitro, binding capacity of CD133-stents was studied, revealing a significantly higher affinity of human CD133-positive cells to CD133-stents compared with mononuclear cells (MNCs). In vivo, 15 landrace pigs received BMS and CD133-stents in either RCX or LAD (n = 30 stents). Re-endothelialization was examined on day 1 (n = 4), 3 (n = 4) and day 7 (n = 4) using scanning electron microscopy. In histology, injury and inflammatory scores, as well as diameter restenosis were evaluated after day 7 (n = 3), 14 (n = 4), and 28 (n = 2). Overall no reduction in re-endothelialization, diameter stenosis or inflammatory score was seen with CD133-stents.
Conclusion:
Stent coating with anti-human CD133-antibodies was successfully achieved with effective binding of CD133-positive cells. However, in vivo, no difference in re-endothelialization or neointima formation was evident with the use of CD133-stents compared with BMS. The low number of circulating CD133-positive cells and an increase in unspecific binding of MNCs over time may account for the observed lack of efficacy.
The sustained or controlled release of nitric oxide (NO) can be the most promising approach for the suppression or prevention of restenosis and thrombosis caused by stent implantation. The aim of this study is to investigate the feasibility in the potential use of layer-by-layer (LBL) coating with a NO donor-containing liposomes to control the release rate of NO from a metallic stent. Microscopic observation and surface characterizations of LBL-modified stents demonstrate successful LBL coating with liposomes on a stent. Release profiles of NO show that the release rate is sustained up to 5 d. In vitro cell study demonstrates that NO release significantly enhances endothelial cell proliferation, whereas it markedly inhibits smooth muscle cell proliferation. Finally, in vivo study conducted with a porcine coronary injury model proves the therapeutic efficacy of the NO-releasing stents coated by liposomal LBL technique, supported by improved results in luminal healing, inflammation, and neointimal thickening except thrombo-resistant effect. As a result, all these results demonstrate that highly optimized release rate and therapeutic dose of NO can be achieved by LBL coating and liposomal encapsulation, followed by significantly efficacious outcome in vivo.
Despite all the benefits of drug-eluting stents (DES), concerns have been raised over their long-term safety, with particular reference to stent thrombosis. In an effort to address these concerns, newer stents have been developed that include: DES with biodegradable polymers, DES that are polymer free, stents with novel coatings, and completely biodegradable stents. Many of these stents are currently undergoing pre-clinical and clinical trials; however, early results seem promising. This paper reviews the current status of this new technology, together with other new coronary devices such as bifurcation stents and drug-eluting balloons, as efforts continue to design the ideal coronary stent.
Background:
Current monotherapy drug-eluting stents are associated with impaired healing, neoatherosclerosis, and late stent thrombosis. The healing profile and neointimal transformation of the first dual-therapy endothelial progenitor cell-capturing sirolimus-eluting stent are unknown.
Methods and results:
In this prospective, single-center study, 61 patients treated with the Combo stent had optical coherence tomography at baseline, early follow-up (4 monthly groups in a 1:2:2:1 ratio from 2 to 5 months), 9 months, and 24 months. Optical coherence tomography early strut coverage increased from 77.1% to 92.5% to 92.7% to 94.9% between 2 and 5 months. At 9 months, the major adverse cardiac event rate was 1.64%, and angiographic in-stent late loss was 0.24 mm (0.08-0.40). The 36-month major adverse cardiac event rate was 3.3%. From 9 to 24 months, neointimal regression was confirmed by optical coherence tomography: neointimal thickness (median [first quartile and third quartile]), 0.14 mm (0.08 and 0.21) versus 0.12 mm (0.07 and 0.19), P<0.001; neointimal volume, 29.9 mm(3) (22.1 and 43.2) versus 26.2 mm(3) (19.6 and 35.8), P=0.003; and percent neointimal volume, 17.8% (12.2 and 21.2) versus 15.7% (11.2 and 19.4), P=0.01. No definite or probable late stent thrombosis was recorded.
Conclusions:
With additional endothelial progenitor cell-capturing technology, the Combo stent exhibits a unique late neointimal regression (from 9 to 24 months) that has not been reported in any drug-eluting stents, translating into good 36-month clinical results with minimal restenosis and no late stent thrombosis. This is the first study testing the concept of using a longitudinal sequential optical coherence tomography protocol to continuously document early healing profile and late neointimal transformation, predicting long-term outcomes of a new novel stent platform.
Clinical trial registration:
URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01274234, NCT01756807, and NCT02263313.
The aim of this study was to evaluate the optimal method for coating a double-layer polymer coronary stent with sirolimus and alpha-lipoic acid (ALA) in a porcine coronary overstretch restenosis model. Pigs were randomized into three groups, in which the coronary arteries (10 in each group) were stented with a dual-layer stent with an inner layer of ALA and an outer layer of sirolimus (IAOS, n=10), a dual-layer stent with an inner layer of sirolimus and an outer layer of ALA (ISOA, n=10), or a commercial drug-eluting stent (biolimus-eluting stent, BES, n=10). Histopathological analysis was performed 28 days after stenting. There were no significant differences among the three groups in injury and inflammation scores. There were significant differences among the three groups in neointimal area (1.1±0.16 mm2 for IAOS vs. 1.3±0.41 mm2 for ISOA vs. 1.9±0.50 mm2 for BES, p<0.0001), and percentage of stenosis area (21.4±3.08% for IAOS vs. 29.9±7.72% for ISOA vs. 38.2±9.08% for BES, p<0.0001). Regarding the percentage of stenosis area, microcomputed tomography revealed significant differences between the three groups (23.8±3.51% for IAOS vs. 28.9±4.65% for ISOA vs. 36.4±8.07% for BES, p<0.05). Compared with commercial stent placement, both IAOS and ISOA resulted in significant inhibition of neointimal formation in a porcine coronary restenosis model. In addition, IAOS was more effective than ISOA in preventing anti-neointimal hyperplasia after stenting.
Statement of significance:
Stents have been developed from bare metal stent to advanced forms such as drug-eluting stents (DESs). However, even DESs can still cause in-stent restenosis as long-term outcomes. This paper demonstrated a novel DES using spatio-temporal coating by dopamine-mediated hyaluronic acid coating (HA-DA) before asymmetric coating of sirolimus-in-poly(D,L-lactide) (P+S). It showed stable coating surface and prevented crack formation after ballooning. HA-DA coating also had an inhibitive effect on adhesion of platelets and maintained cell viability of endothelial cells even under the existence of sirolimus. Additionally, in vivo neointima area and inflammation score of HA-DA/P+S stent significantly decreased than those of BMS. We expected that this novel type of DES can be effectively applied to introduce diverse anti-proliferative drugs and bioactive molecules.
At present there is much excitement about drug-eluting stents, which hold promise for the treatment of coronary artery disease. This ingenious therapy involves coating the outside of a standard coronary stent with a thin polymer containing medication that can prevent scarring at the site of coronary intervention. Early trials with sirolimus coated stents showed that they might prevent coronary artery restenosis, but later studies, involving more complex coronary lesions, did not show a complete absence of restenosis. Recent studies have demonstrated the long term cost effectiveness of drug-eluting stents as they have reduced the need for revascularisation procedures. At present there are few data on the safety and effectiveness of stents over follow up periods exceeding two years, and data obtained from animal models of stenting might not be completely applicable to humans. There are concerns that drug-eluting stents might delay, rather than inhibit, restenosis. Also there is concern regarding the inflammation caused by the polymer substrate. This article reviews the present data on drug-eluting stents and their benefits, shortcomings, and concerns.
Rapid re-endothelialization of damaged vessel lining efficiently prevents restenosis and thrombosis and restores original vascular functions. In this study, we designed a novel metallic stent with a heparin-modified surface and used different methods, including 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and divinyl sulfone (DVS), to load growth factors. First we loaded heparin into a dopamine-conjugated hyaluronic acid (HA) coating to serve as a growth factor reservoir. In a second step, we took advantage of the heparin-binding domain of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) to gain advanced re-endothelialization capabilities. We demonstrated that DVS technique offered higher amount of growth factor loading. In vitro assessment also showed better capillary-like structure formation and localized gap junctions when DVS coating was employed. This study suggested that growth factor loaded stent modified by HA and heparin provided the advantage to rapid and tight restoration of endothelium.
The restoration of a damaged endothelium might be a fascinating way to reduce significantly late-thrombosis and restenosis in the stent treatment. It has been recently reported that the recruitment of endothelial progenitor cells (EPCs), capable for repairing a damaged endothelium, can be important in the vascular stent application. Therefore, we focused on the hypothesis that stromal cell-derived factor-1α (SDF-1α) acts as a key chemokine for the mobilization and recruitment of EPCs to the damaged endothelium lesion. In this study, the effect of SDF-1α released from a cobalt-chromium alloy (Co-Cr) plate, vascular stent material, was investigated on the recruitment of EPCs in vitro. Dopamine-conjugated heparin was synthesized to introduce heparin onto Co-Cr. Heparin-coated Co-Cr surfaces were examined by water contact angle and attenuated total reflectance-Fourier transform infrared (ATRFTIR) to prove successful coating of heparin. Finally, SDF-1α was bound to the coated heparin derivative. Amounts of loaded and released SDF-1α were measured by ELISA, and the recruited EPC by released SDF-1α was evaluated using two different migration assays. The quantity of SDF-1α bound to the heparin-modified surface increased in a concentration-dependent manner and SDF-1α was released over 28 days. Transwell migration assay revealed that soluble SDF-1α released from the heparin-coated Co-Cr induced significantly more EPC recruitment than bare Co-Cr and heparin-coated Co-Cr. More importantly, fibrin gel migration assay further demonstrated that EPCs evidently respond to heparin-based substrate with SDF-1α and this type of behaviors was surprisingly found at as low level as less 1 ng/day of SDF-1α. These results are strongly encouraging for further in vitro and in vivo studies.[Figure not available: see fulltext.] © 2015, The Polymer Society of Korea and Springer Sciene+Business Media Dordrecht.
Two kinds of magnesium hydroxide (Mg(OH)2) rods (Mg-Rod, 150 and 350 nm in size) and plates (Mg-PL, 60 and 300 nm) were prepared, and blended with poly(L-lactide) (PLLA) to obtain PLLA/Mg(OH)2 composites to investigate the effect of the shape and size of Mg(OH)2 particles. The structure, morphology, pH change, thermal and mechanical properties, cytotoxicity, and inflammation of Mg(OH)2 control and PLLA/Mg(OH)2 composites were evaluated. PLLA/Mg-Rod150 (30%) composite showed a 50% higher tensile strength and a 45% improved modulus as compared with PLLA/Mg-PL300 30% composite. Although Mg-Rods displayed similar cell viability (above 80%) as compared to Mg-PLs, the expression levels of TNF-α from Mg-PL60 gradually increased with increasing concentrations from 1 to 300 μg. This indicates that Mg-PL60 had a potential cytotoxicity due to endocytosis. In addition, the byproduct of PLLA/Mg-Rods composite was more effectively neutralized than that of the PLLA/Mg-PLs composite, but cell viability and the expression levels of TNF-α were similar. Therefore, the use of our PLLA/Mg-Rod composite system would be a promising strategy to prevent the current fatal problems in biomedical applications including biodegradable implants such as stents.
Recent clinical trials of gene therapy have shown remarkable therapeutic benefits and an excellent safety record. They provide evidence for the long-sought promise of gene therapy to deliver 'cures' for some otherwise terminal or severely disabling conditions. Behind these advances lie improved vector designs that enable the safe delivery of therapeutic genes to specific cells. Technologies for editing genes and correcting inherited mutations, the engagement of stem cells to regenerate tissues and the effective exploitation of powerful immune responses to fight cancer are also contributing to the revitalization of gene therapy.
Background
In patients with coronary artery disease who receive metallic drug-eluting coronary stents, adverse events such as late target-lesion failure may be related in part to the persistent presence of the metallic stent frame in the coronary-vessel wall. Bioresorbable vascular scaffolds have been developed to attempt to improve long-term outcomes.
Methods
In this large, multicenter, randomized trial, 2008 patients with stable or unstable angina were randomly assigned in a 2:1 ratio to receive an everolimus-eluting bioresorbable vascular (Absorb) scaffold (1322 patients) or an everolimus-eluting cobalt–chromium (Xience) stent (686 patients). The primary end point, which was tested for both noninferiority (margin, 4.5 percentage points for the risk difference) and superiority, was target-lesion failure (cardiac death, target-vessel myocardial infarction, or ischemia-driven target-lesion revascularization) at 1 year.
Results
Target-lesion failure at 1 year occurred in 7.8% of patients in the Absorb group and in 6.1% of patients in the Xience group (difference, 1.7 percentage points; 95% confidence interval, −0.5 to 3.9; P=0.007 for noninferiority and P=0.16 for superiority). There was no significant difference between the Absorb group and the Xience group in rates of cardiac death (0.6% and 0.1%, respectively; P=0.29), target-vessel myocardial infarction (6.0% and 4.6%, respectively; P=0.18), or ischemia-driven target-lesion revascularization (3.0% and 2.5%, respectively; P=0.50). Device thrombosis within 1 year occurred in 1.5% of patients in the Absorb group and in 0.7% of patients in the Xience group (P=0.13).
Conclusions
In this large-scale, randomized trial, treatment of noncomplex obstructive coronary artery disease with an everolimus-eluting bioresorbable vascular scaffold, as compared with an everolimus-eluting cobalt–chromium stent, was within the prespecified margin for noninferiority with respect to target-lesion failure at 1 year. (Funded by Abbott Vascular; ABSORB III ClinicalTrials.gov number, NCT01751906.)
Background:
There is a paucity of data reporting the clinical outcomes of biodegradable polymer biolimus-eluting stent (BP-BES) compared with durable polymer everolimus-eluting stent (DP-EES) beyond 1 year after stent implantation when the polymer is fully degraded.
Methods and results:
The NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial (NEXT) is a prospective, multicenter, randomized, open-label, noninferiority trial comparing BP-BES with DP-EES in patients scheduled for percutaneous coronary intervention using drug-eluting stent (DES) without any exclusion criteria among 98 participating centers in Japan. The trial was designed to evaluate noninferiority of BP-BES relative to DP-EES in terms of any target-lesion revascularization at 1 year and death or myocardial infarction at 3 years. Between May and October 2011, 3235 patients were randomly assigned to receive either BP-BES (1617 patients) or DP-EES (1618 patients). Complete 3-year follow-up was achieved in 97.6% of patients. At 3 years, the primary safety end point of death or myocardial infarction occurred in 159 patients (9.9%) in the BP-BES group and in 166 patients (10.3%) in the DP-EES group, demonstrating noninferiority of BP-BES relative to DP-EES (P noninferiority<0.0001 and P superiority=0.7). Cumulative incidence of target-lesion revascularization was not significantly different between the 2 groups (7.4% versus 7.1%; P=0.8). By a landmark analysis at 1 year, the cumulative incidences of death or myocardial infarction and target-lesion revascularization were also not significantly different between the 2 groups (4.6% versus 5.2%; P=0.46 and 3.3% versus 2.7%; P=0.39, respectively).
Conclusions:
Safety and efficacy outcomes of BP-BES were non inferior to those of DP-EES 3 years after stent implantation.
Clinical trial registration:
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01303640.
Opinion statement:
The development of bare metal stent (BMS) was a major advancement over plain old balloon angioplasty (POBA) in the management of symptomatic coronary artery disease. BMS prevented restenosis by attenuating early arterial recoil and contraction; both seen commonly after POBA. However, the rate of clinically indicated target lesion repeat revascularization due to a process of in-stent restenosis (ISR) at 1 year remained relatively high (10 to 20 %), often due to excessive neointimal growth (Fischman et al. N Engl J Med. 331:496, 1994; Serruys et al. N Engl J Med. 331:489, 1994; Cutlip et al. J Am Coll Cardiol 40:2082, 2002). Stents with drug elution technology (DES) were developed to reduce the relatively high rate of ISR and subsequent repeat revascularization seen with BMS. Clinical trials have confirmed a reduction of as much as 50 to 70 % in target lesion revascularization by DES compared to BMS. These findings have led to the preferential use of DES in the majority of percutaneous coronary intervention (PCI). However, as DES require a longer period of dual antiplatelet therapy (DAPT) to prevent stent thrombosis, DES are not appropriate for all patients.
Clinical evaluations have proven the efficacy of drug-elution stents (DES) in reduction of in-stent restenosis rates as compared to drug-free bare metal stents (BMS). Typically, DES are metal stents that are covered with a polymer film loaded with anti-inflammatory or antiproliferative drugs that are released a sustained manner. However, although favorable effects of the released drugs have been observed, the polymer coating as such has been associated with several adverse clinical effects, such as late stent thrombosis. Elimination of the polymeric carrier of DES may therefore potentially lead to safer DES. Several technologies have been developed to design polymer-free DES, such as the use of microporous stents and inorganic coatings that can be drug loaded. Several drugs, including sirolimus, tacrolimus paclitaxel and probucol have been used in the design of carrier free stents. Due to the function of the polymeric coating to control the release kinetics of a drug, polymer-free stents are expected to have a faster drug elution rate, which may affect the therapeutic efficacy. However, several polymer-free stents have shown similar efficacy and safety as the first-generation DES although the superiority of polymer-free DES have not been established in clinical trials.
Background— We recently reported delayed angiographic restenosis in 15 patients who received 7-hexanoyltaxol (QP2)–eluting polymer stents (QuaDS) for the treatment of in-stent restenosis. This study presents the histological findings of atherectomy specimens from a subset of these patients receiving implants.
Methods and Results— Between October and December 2001, 5 patients treated with QuaDS-QP2 stents underwent directional coronary atherectomy at 11.2±1.0 months for recurrent in-stent restenosis. Restenotic lesion composition was assessed with special stains, immunohistochemistry with quantitative image analysis, and, in one specimen, transmission electron microscopy. Atherectomy specimens contained fibrin interspersed in a smooth muscle cell–rich neointima with proteoglycan matrix. In 2 of 5 specimens, large aggregates of macrophages and T-lymphocytes were noted. These areas of active inflammation demonstrated a relatively high proliferation index by Ki-67 antibody staining, whereas the proliferation index in smooth muscle cell–rich restenotic areas was low.
Conclusion— Restenotic lesions from QuaDS-QP2–eluting stents at 12 months show persistent fibrin deposition with varying degrees of inflammation. These pathological changes, representing delayed healing, are usually observed up to only 3 months in human coronary arteries with stainless steel balloon-expandable stents. The nonreabsorbable polymer alone may have induced chronic inflammation.
Aims:
To assess the safety and performance of the Nobori drug-eluting stent with biodegradable polymer versus the TAXUS drug-eluting stent with permanent polymer, in the treatment of patients with de novo coronary artery lesions.
Methods and results:
NOBORI 1 was a multicentre, randomised (2:1), prospective, controlled, clinical trial which enrolled 363 patients (238 Nobori and 125 TAXUS) with up to two de novo lesions in two epicardial vessels. The primary endpoint was in-stent late loss at nine months, while secondary endpoints included safety and efficacy up to five years. At five years, clinical data were available for 350 patients (96%). There were no differences in the composite of death and myocardial infarction (10.9% vs. 11.2%) and target lesion failure (9.2% and 10.4%), while ischaemia- and non-ischaemia-driven target lesion revascularisations were less frequent in the Nobori (6.3%) than in the TAXUS arm (16.0%). The rates of stent thrombosis (definite and probable according to the ARC definitions) were 0.0% and 3.2%, in the Nobori and TAXUS stents, respectively (p=0.014).
Conclusions:
Five years after implantation, the Nobori DES resulted in durable treatment effects with very low TLR and no stent thrombosis. The study was not powered to assess the differences in clinical endpoints. These data are hypothesis-generating.
Films of 1:1 blend and films non-blended were prepared from poly(l-lactic acid) (PLLA) and poly(d-lactic acid) (PDLA) with a solution casting method, and the mechanical properties and morphology of the films were investigated using tensile tests, dynamic mechanical relaxation measurements, polarizing optical microscopy, differential scanning calorimetry (DSC) and X-ray diffractometry. The tensile strength, Young’s modulus, and the elongation-at-break of 1:1 blend films were found to be higher than those of non-blended films when their weight-average molecular weight (Mw) was in the range 1×105–1×106. The enthalpy of melting for stereocomplex crystallites in 1:1 blend films was higher than that of homo-crystallites when Mw of polymers was below 2×105, while this relationship was reversed when MW increased to 1×106. Spherulites formation was suppressed in 1:1 blend films, whereas large-sized spherulites with radii of 100–1000 μm were formed for non-blended PLLA and PDLA films, irrespective of Mw. The mechanical properties of 1:1 blend films superior to those of non-blended films were ascribed to the micro-phase structure difference generated as a result of formation of many stereocomplex crystallites which acted as intermolecular cross-links during solvent evaporation of blend solution. On the contrary, non-blended films had larger-sized spherulites of less contacting area with the surrounding spherulites.
Biodegradable polymers such as poly(l-lactide) (PLLA) have been widely utilized as materials for biomedical applications. However, the relatively poor mechanical properties of PLLA and its acid-induced cell inflammation brought about by the acidic byproducts during biodegradation pose severe problems. In this study, these drawbacks of PLLA are addressed using a stereocomplex structure, where oligo-d-lactide-grafted magnesium hydroxide (MgO-ODLA) is synthesized by grafting d-lactide onto the surface of magnesium hydroxide, which is then blended with a PLLA film. The structure, morphology, pH change, thermal and mechanical properties, in-vitro cytotoxicity, and inflammation effect of the MgO-ODLAs and their PLLA composites are evaluated through various analyses. The PLLA/MgO70-ODLA30 (0–20 wt%) composite with a stereocomplex structure shows a 20% increase in its tensile strength and an improvement in the modulus compared to its oligo-l-lactide (PLLA/MgO70-OLLA30) counterpart. The interfacial interaction parameter of PLLA/MgO70-ODLA30 (5.459) has superior properties to those of PLLA/MgO70-OLLA30 (4.013) and PLLA/Mg(OH)2 (1.774). The cell cytotoxicity and acid-induced inflammatory response are suppressed by the neutralizing effect of the MgO-ODLAs. In addition, the inflammatory problem caused by the rapid acidification of the stereocomplex structure is also addressed. As a result, the stereocomplex structure of the MgO-ODLA/PLLA composite can be used to overcome the problems associated with the biomedical applications of PLLA films.
The potential association between arterial stiffening and circulating endothelial progenitor cells (EPCs) in patients with essential hypertension was investigated. Pulse wave velocity (PWV) was used to evaluate arterial stiffness in 24 patients with essential hypertension and 19 healthy controls. Blood samples were taken and immunostained with antibodies against the cell surface markers CD34, CD45, and CD133. Using flow cytometry, EPCs as a population of CD45−/CD34+/CD133+ cells were measured. Hypertensive patients were not found to have higher levels of circulating CD45−/CD34+/CD133+ compared with the control group (0.0026%±0.0031% vs 0.0023%±0.0023%, respectively; P=.7). Correlation analysis revealed a strong association between the number of CD45−/CD34+/CD133+ cells and PWV (r=0.58, P<.001), indicating that hypertensive patients with increased PWV have a greater percentage of CD45−/CD34+/CD133+ cells. Data showed a correlation between the number of circulating CD45−/CD34+/CD133+ cells and arterial stiffness, suggesting that those cells might have a role in arterial remodeling.
Most drug-eluting stents currently available are coated with anti-proliferative drugs on both abluminal (toward blood vessel wall) and luminal (toward lumen) surfaces to prevent neointimal hyperplasia. While the abluminal delivery of anti-proliferative drugs is useful for controlling neointimal hyperplasia, the luminal delivery of such drugs impairs or prevents endothelialization which causes late stent thrombosis. This research is focused on developing a bidirectional dual drug-eluting stent to co-deliver an anti-proliferative agent (paclitaxel – PAT) and an endothelial cell promoting agent (nitric oxide – NO) from abluminal and luminal surfaces of the stent, respectively. Phosphonoacetic acid, a polymer-free drug delivery platform, was initially coated on the stents. Then, the PAT and NO donor drugs were co-coated on the abluminal and luminal stent surfaces, respectively. The co-coating of drugs was collectively confirmed by the surface characterization techniques such as Fourier transform infrared spectroscopy, scanning electron microscopy (SEM), 3D optical surface profilometry, and contact angle goniometry. SEM showed that the integrity of the co-coating of drugs was maintained without delamination or cracks formation occurring during the stent expansion experiments. In vitro drug release studies showed that the PAT was released from the abluminal stent surfaces in a biphasic manner, which is an initial burst followed by a slow and sustained release. The NO was burst released from the luminal stent surfaces. Thus, this study demonstrated the co-delivery of PAT and NO from abluminal and luminal stent surfaces, respectively. The stent developed in this study has potential applications in inhibiting neointimal hyperplasia as well as encouraging luminal endothelialization to prevent late stent thrombosis.
Stents occupy an important place in the medical field for their widespread application. They have been used in vascular as well as non-vascular organs for various reasons. Among vascular stents, development of coronary drug eluting stents (DES's) have completely revolutionised the percutaneous coronary intervention. Similarly, attempts have been made to make use of this modality in non-vascular organs. This paper focuses on the preclinical and clinical experience with drug-eluting non-vascular stents with emphasis on drug delivery systems and regulatory requirements for their development.
Biodegradable polymers, such as poly(L-lactide) (PLLA), are very useful in many biomedical applications. However, their degradation by-products have been much of a concern as they are the sources of inflammatory reactions in the body. In this work, we suggest a novel composite system composed of PLLA and oligolactide-grafted magnesium hydroxide (Mg-OLA) that can overcome drawbacks caused by poor mechanical properties and inflammatory response of PLLA for biomedical applications. Mg-OLAs were synthesized by ring opening polymerization and the structure, morphology, pH change, thermal, and mechanical properties were analyzed using FTIR, SEM, pH meter, TGA, and UTM. In particular, the tensile strength and modulus of PLLA/Mg80-OLA20 (0–20 wt%) were higher than those of PLLA/magnesium hydroxide. The PLLA/Mg80-OLA20 composite was also very effective in neutralizing the acidic environment caused by the degradable by-product of the PLLA matrix. In vitro cell viability and the expression levels of COX-2 and IL-6 proteins in the PLLA composites were also evaluated. Cell viability increased to around 100% with increasing the amount of Mg80-OLA20 from 0 to 20 wt%. The expression levels of IL-6 and COX-2 were reduced dramatically when increasing the proportion of Mg80-OLA20 from 0 to 50 wt%. As a result, the incorporation of Mg-OLAs into the PLLA matrix could reinforce the mechanical properties as well as reduce the inflammatory response of the hybrid PLLA. Therefore, this hybrid composite system blending oligomer-grafted magnesium hydroxide in biodegradable polymers would be a promising strategy for avoiding current fatal problems in biomedical applications.
It was reported previously that Mg(OH)2 nanoplatelets are effective antibacterial agent [1]. This paper further studied the mechanism study of Mg(OH)2 nanoplatelets against Escherichia coli. Both experimental results and SEM analysis indicated that the membrane of the bacterial cell was destroyed by the direct contact with the Mg(OH)2 nanoplatelets, leading to the cell death. In addition, UV illumination could further improve the antibacterial efficiency of Mg(OH)2 nanoplatelets. Compared with other nanoparticles, it was also found that Mg(OH)2 nanoplatelets have higher antibacterial efficiency, implicating their great potential application in biological control.
Stents are structural implants with widespread clinical use in vascular intervention to re-open stenotic vessels for the treatment of coronary artery disease and peripheral arterial occlusive disease. Apart from their mechanical function, current drug-eluting stents (DES) utilize local drug delivery from a drug-incorporated permanent polymer coating to prevent in-stent restenosis. This delayed closure of the stented vessel is considered one of the major limitations of conventional bare metal stents (BMS). The long-term safety of DES, however, is still under debate, with reported cases of delayed healing, late thrombosis and hypersensitivity demanding further evolution in this field. A promising approach to circumvent the limitations of first generation DES is the application of degradable polymer coatings in second generation DES, and fully absorbable polymer stents. From a materials and engineering perspective, this paper provides a mini-review of current clinically relevant DES technology and recent advancements in the development of stents from degradable polymeric materials as an alternative to permanent BMS and DES. This review, includes work on degradable stents and coatings based on blends of polylactic acid and the microbially-produced poly(4-hydroxybutyrate). Copyright © 2009 Society of Chemical Industry
All materials intended for application in humans as biomaterials, medical devices, or prostheses undergo tissue responses when implanted into living tissue. This review first describes fundamental aspects of tissue responses to materials, which are commonly described as the tissue response continuum. These actions involved fundamental aspects of tissue response including injury, inflammatory and wound healing responses, foreign body reactions, and fibrous encapsulation of the biomaterial, medical device, or prosthesis. The second part of this review describes then in vivo evaluation of tissue responses to biomaterials, medical devices, and prostheses to determine intended performance characteristics and safety or biocompatibility considerations. While fundamental aspects of tissue responses to materials are important from research and development perspectives, the in vivo evaluation of tissue responses to these materials is important for performance, safety, and regulatory reasons.
Percutaneous coronary intervention is one of the most frequently performed therapeutic procedures in medicine. This review provides an overview of currently available devices, summarizes randomized evidence, and outlines clinical indications for use.