Polymeric heart valves: new materials, emerging hopes.

Heart valve (HV) replacements are among the most widely used cardiovascular devices and are in rising demand. Currently, clinically available devices are restricted to slightly modified mechanical and bioprosthetic valves. Polymeric HVs could represent an attractive alternative to the existing prostheses, merging the superior durability of mechanical valves and the enhanced haemodynamic function of bioprosthetic valves. After early unsatisfactory clinical results, polymeric HVs did not reach commercialization, mainly owing to their limited durability. Recent advances in polymers, nanomaterials and surface modification techniques together with the emergence of novel biomaterials have resulted in improved biocompatibility and biostability. Advances in HV design and fabrication methods could also lead to polymeric HVs that are suitable for long-lasting implantation. Considering all these progresses, it is likely that the new generation of polymeric HVs will find successful long-term clinical applications in future.

Percutaneous heart valve replacement: an update.

Valvular heart disease continues to be an important health care problem. Although surgical valve replacement remains the standard treatment, minimally invasive approaches for valve repair and replacement are becoming attractive alternatives among physicians and patients. In fact, percutaneous procedures can extend treatment to the increasing population of elderly patients with severe comorbidities who cannot withstand the stress of open heart surgery and to the younger patients at the early stage of valve disease, who are not treated until older ages to avoid multiple invasive surgeries. Feasibility of this technique has been shown in the first clinical experiences, and the early results are promising. However, it is clear that percutaneous valve replacement therapy is still at the early stage of development and requires enhanced implantation procedures and substantial design improvements as well as long-term follow-up to show the safety and effectiveness of this new treatment modality.

Effect of cell density on osteoblastic differentiation and matrix degradation of biomimetic dense collagen scaffolds.

Plastic compression of hyperhydrated collagen gels produces tissue-like scaffolds of enhanced biomechanical properties. By increasing collagen density, these scaffolds could be developed into highly Biomimetic cell-seeded templates. When utilizing three-dimensional (3-D) scaffold systems for tissue repair, and indeed when investigating the cytocompatibility of two-dimensional (2-D) surfaces, the cell seeding density is often overlooked. In this study, we investigated this potentially critical parameter using MG-63 cells seeded in the dense collagen scaffolds. This is conducted within the overall scope of developing these scaffolds for bone repair. Cell proliferation, osteoblastic differentiation, and matrix remodelling capacity in relation to various seeding densities, ranging from 10(5) to 10(8) cells/ml compressed collagen, were evaluated in vitro. This was performed using the AlamarBlue assay, quantitative polymerase chain reaction (qPCR), and tensile mechanical analysis respectively. Variations in cell seeding density significantly influenced cell proliferation where lower initial seeding density resulted in higher proliferation rates as a function of time in culture. Gene transcription levels for alkaline phosphatase (ALPL), runt-related transcription factor 2 (RUNX2), and osteonectin (SPARC) were also found to be dependent on the cell density. While ALPL transcription was down-regulated with culturing time for all seeding densities, there was an increase in RUNX2 and SPARC transcription, particularly for scaffolds with cell densities in the range 10(6)-10(7) cells/ml collagen. Furthermore, this range of seeding density affected cell capacity in conducting collagenous matrix degradation as established by analyzing matrix metalloproteinase 1 (MMP1) transcription and scaffold mechanical properties. This study has shown that the seeded cell population in the three-dimensional dense collagen scaffolds clearly affected the degree of osteoblastic cell proliferation, differentiation, and some aspects of matrix remodelling activity. The seeding density played a major role in influencing the corresponding cell differentiation and cell-matrix interaction.

Flow behaviour of a POSS biopolymer solution.

A non-biodegradable polyhedral oligomeric silsesquioxane (POSS) nanocomposite biopolymer has been developed for fabrication of medical devices and for tissue engineering human organs. The polymer in solution, containing 2 wt% of POSS, has been synthesized, characterized and investigated to determine its key rheological properties. Thus, the variation of shear stress and viscosity as a function of shear rate has been determined at ambient temperature to estimate yield stress and the index of pseudoplasticity, respectively. The temperature dependence of viscosity and the effect of ageing on the viscosity of the polymer have also been investigated. Results are compared with those of a conventional polycarbonate urethane (PCU) polymer solution. The POSS-PCU polymer solution shows near-Newtonian behaviour in the shear rate range to 1000 s(-1), having an apparent viscosity of approximately 3000 mPa s and a pseudoplasticity index of 0.90, decreasing slightly as the polymer solution is aged over 9 months. The temperature dependence of viscosity of the POSS polymer is extremely low and does not change with ageing but the yield strength increases from 2.7 Pa to 8.3 Pa.

Incorporation of a lauric acid-conjugated GRGDS peptide directly into the matrix of a poly(carbonate-urea)urethane polymer for use in cardiovascular bypass graft applications.

Gly-Arg-Gly-Asp-Ser (GRGDS) was modified by conjugation to lauric acid (LA) to facilitate incorporation into the matrix of a poly(carbonate-urea)urethane (PCU) used in vascular bypass grafts. GRGDS and LA-GRGDS were synthesized using solid phase Fmoc chemistry and characterized by high performance liquid chromatography and Fourier transform infrared spectroscopy. LA-GRGDS was passively coated and incorporated as nanoparticle dispersion on the PCU films. Biocompatibility of the modified surfaces was investigated. Endothelial cells seeded on LA-GRGDS coated and incorporated PCU showed after 48 h and 72 h a significant (p < 0.05) increase in metabolism compared with unmodified PCU. The platelet adhesion and hemolysis studies showed that the modification of PCU had no adverse effect. In conclusion, LA-conjugated RGD derivatives, such as LA-GRGDS, that permit solubility into solvents used in solvent casting methodologies should have wide applicability in polymer development for use in coronary, vascular, and dialysis bypass grafts, and furthermore scaffolds utilized for tissue regeneration and tissue engineering.

Is there an alternative to systemic anticoagulation, as related to interventional biomedical devices?

To reduce the toxic effects, related clinical problems and complications such as bleeding disorders associated with systemic anticoagulation, it has been hypothesized that by coating the surfaces of medical devices, such as stents, bypass grafts, extracorporeal circuits, guide wires and catheters, there will be a significant reduction in the requirement for systemic anticoagulation or, ideally, it will no longer be necessary. However, current coating processes, even covalent ones, still result in leaching followed by reduced functionality. Alternative anticoagulants and related antiplatelet agents have been used for improvement in terms of reduced restenosis, intimal hyperphasia and device failure. This review focuses on existing heparinization processes, their application in clinical devices and the updated list of alternatives to heparinization in order to obtain a broad overview, it then highlights, in particular, the future possibilities of using heparin and related moieties to tissue engineer scaffolds.

Interactions between endothelial cells and a poly(carbonate-silsesquioxane-bridge-urea)urethane.

We have recently developed a polymer which contains silsesquioxane in the form of nano-bridges poly(carbonate-silsesquioxane-bridge-urea)urethane (PCBSU) for cardiovascular device applications. The polymer has been characterised and the durability has been confirmed with long-term in vivo tests. The aim of this study was to test the cytocompatibility of the new polymer and to investigate any potential cytotoxic effects. To assess the effect of direct contact with PCBSU sections of polymer material were cut and placed into a 24-well plate. Six discs were seeded with 2 x 10(5) human umbilical vein cells (HUVEC). As a positive control, six wells were seeded with the same number of HUVEC. In a further experiment to assess indirect contact with PCBSU a sample of the polymer was powdered using a Micro-Dismembrator. Cell culture medium was exposed to powdered polymer (1-100 mg/ml) for a period of 7 days. HUVEC seeded as above were then exposed to the treated cell culture medium for 24 and 96 h. Finally, cell proliferation was studied over 16 days by seeding 2 x 10(5) HUVEC on films of PCBSU cast in glass Petri dishes. Cell viability and growth were assessed using Alamar blue, lactate dehydrogenase and Pico green assays and morphology was studied by Toluidine blue staining and scanning electron microscopy. Viable cells were demonstrated to be present after 16 days seeded on PCBSU. Exposing cells to PCBSU-treated cell culture medium resulted in no apparent damage to the cells at concentrations of 1 or 10 mg/ml, and only a slight reduction at 100 mg/ml after 96 h exposure. This study demonstrates that PCBSU can support the growth of endothelial cells for a prolonged period and does not demonstrate any significant toxic effects to cells. Thus it has the potential to be used both as a medical device and as scaffolding in tissue engineering applications.

The anti-calcification potential of a silsesquioxane nanocomposite polymer under in vitro conditions: potential material for synthetic leaflet heart valve.

Calcification currently represents a major cause of failure of biological tissue heart valves. It is a complex phenomenon influenced by a number of biochemical and mechanical factors. Recent advances in material science offer new polymers with improved properties, potentially suitable for synthetic leaflets heart valves manufacturing. In this study, the calcification-resistance efficacy and mechanical and surface properties of a new nanocomposite polymeric material (polyhedral oligomeric silsesquioxane-poly(carbonate-urea)urethane; POSS-PCU) which has been developed by our group are assessed by means of in vitro testing. In particular, thin sheets of nanocomposite, glutaraldehyde-fixed bovine pericardium (BP) and polyurethane (PU) were exposed to a calcium solution into a specially designed in vitro accelerated physiological pulsatile pressure system for a period of 31days and a total of 4×10(7) cycles. The samples were investigated for signs of calcification after exposure to calcium solution by means of X-ray, microscopic and chemical inspections. Mechanical and surface properties were also studied using stress-strain behaviour and surface morphology and hydrophobicity. Comparison shows that, in the experimental conditions, the level of calcification for the nanocomposite is considerably lower than for the fixed BP (p=0.008) and PU samples (p=0.015). Also, mechanical properties were unchanged in POSS-PCU, while there was a significant deterioration in PU samples (p<0.05). Hydrophobicity was significantly reduced in both the POSS-PCU and PU samples (p<0.0001). However, the POSS-PCU nanocomposite remained more hydrophobic than the PU sample (p<0.0001). Less platelet adhered to the POSS-PCU compared to the PU (p<0.0001). These results indicate that the use of this nanocomposite in synthetic leaflets heart valves may lead to potential advantages in terms of long-term performances and durability.

Current developments and future prospects for heart valve replacement therapy.

Valve replacement is the most common surgical treatment in patients with advanced valvular heart disease. Mechanical and bio-prostheses have been the traditional heart valve replacements in these patients. However, currently the heart valves for replacement therapy are imperfect and subject patients to one or more ongoing risks, including thrombosis, limited durability, and need for re-operations due to the lack of growth in pediatric populations. Furthermore, they require an open heart surgery, which is risky for elderly and young children who are too weak or ill to undergo major surgery. This article reviews the current state of the art of heart valve replacements in light of their potential clinical applications. In recent years polymeric materials have been widely studied as potential prosthetic heart valve material being designed to overcome the clinical problems associated with both mechanical and bio-prosthetic valves. The review also addresses the advances in polymer materials, tissue engineering approaches, and the development of percutaneous valve replacement technology and discusses the future prospects in these fields.

A novel nanocomposite polymer for development of synthetic heart valve leaflets.

A novel nanocomposite polymer with a polycarbonate soft segment (PCU) and polyhedral oligomeric silsesquioxanes (POSS) nanoparticle (POSS-PCU) has been selected for a synthetic heart valve due to its superior biocompatibility and in vivo biostability. However, the development of synthetic heart valves from polymeric materials requires an understanding of the basic mechanical and surface properties of the polymer. In this study, the mechanical properties of POSS-PCU, including tensile strength, tear strength and hardness, were tested and compared to control (PCU). The surface property was analyzed using contact angle measurement and the resistance to platelet adhesion was also investigated. POSS-PCU (hardness 84+/-0.8 Shore A) demonstrated significantly higher tensile strength 53.6+/-3.4 and 55.9+/-3.9Nmm(-2) at 25 and 37 degrees C, respectively) than PCU (33.8+/-2.1 and 28.8+/-3.4Nmm(-2) at 25 and 37 degrees C, respectively). Tensile strength and elongation at break of POSS-PCU was significantly higher than PCU at both 25 and 37 degrees C (P<0.001). POSS-PCU showed a relatively low Young's modulus (25.9+/-1.9 and 26.2+/-2.0Nmm(-2)) which was significantly greater in comparison with control PCU (9.1+/-0.9 and 8.4+/-0.5Nmm(-2)) at 25 and 37 degrees C, respectively, with 100mum thickness. There was no significant difference (P>0.05) in tear strength between POSS-PCU and PCU at 25 degrees C. However, tear strength increased significantly (P<0.001) (at 37 degrees C) as the thickness increased from 100microm (51.0+/-3.3Nmm(-1)) to 200microm (63+/-1.5Nmm(-1)). The surface of POSS-PCU was significantly less hydrophilic than that of PCU.

Anticoagulant and antiplatelet agents: their clinical and device application(s) together with usages to engineer surfaces.

An essential aspect of the treatment of patients with cardiovascular disease is the use of anticoagulant and antiplatelet agents for the prevention of further ischaemic events and vascular death resulting from thrombosis. Aspirin and heparin have been the standard therapy for the management of such conditions to date. Recently, numerous more potent platelet inhibitors together with anticoagulant agents have been developed and tested in randomized clinical trials. This article reviews the current state of the art of antiplatelet and anticoagulant therapy in light of its potential clinical efficacy. It then focuses on the usages of these agents in order to improve the performance of clinical devices such as balloon catheters, coronary stents, and femoropopliteal bypass grafting and extra corporeal circuits for cardiopulmonary bypass. The article then goes on to look at the usage of these agents more specifically heparin, heparan, hirudin, and coumarin in the development of more biocompatible scaffolds for tissue engineering.