Asmeret G. Kidane

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.

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 Youngs 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.

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.

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.

Magnetic beads (Dynabead™) toxicity to endothelial cells at high bead concentration: Implication for tissue engineering of vascular prosthesis

Magnetic beads (Dynabeads™) have been used for the purification of endothelial cells. One application for this procedure may be for single-stage seeding of bypass grafts. The number of endothelial cells (EC) isolated is crucial and therefore to increase the number of cells extracted, a higher number of Dynabeads™ per cell may need to be used. The effect of large numbers of CD31 Dynabeads™ on cell proliferation/metabolism is unknown. We undertook this study using CD31-coated Dynabeads™ and EC from human umbilical vein. EC were coated at concentrations of 4, 10, or 50 beads per cell. The cells were cultured for 6 days with control being normal EC. Cellular proliferation was assessed by trypsinization of cells and metabolism assessed with an Alamar blue™ viability assay. In a further experiment a compliant polyurethane graft was single-stage seeded with both coated Dynabeads™ and normal EC. The results showed that using a higher number of beads per cell resulted in a reduction in cell proliferation and a reduction in cell metabolism. The total number of Dynabeads™-coated cells in culture compared to controls (%) by day 6 were 30.7±2.56, 41.3±9.8 and 59.2±7.3 for 50, 10, and 4 beads per cell, respectively. The corresponding results for Alamar blue were 43.7±1.2, 61.8±1.4, and 72.1±4.3. The seeded grafts showed reduced metabolism with the Dynabeads™-coated EC. In conclusion, high numbers of beads per cell have a late detrimental effect on cell proliferation and metabolism. Therefore for single-stage seeding lower numbers of Dynabeads™ will need to be used with resultant reduction in the number of available EC.

Extraction of cells for single-stage seeding of vascular-bypass grafts

Experimental data are reported for the seeding of prosthetic vascular grafts with either mesothelial or endothelial cells as part of a research strategy in tissue engineering with the aim of improving graft patency and developing new techniques for single‐stage cell extraction and seeding that would give a step reduction in surgery time. New data are reported for two different sources of cells, peritoneal lavage and subcutaneous fat. All experiments were undertaken in patients undergoing abdominal aortic aneurysm repair. Cells extracted from peritoneal lavage were insufficient for a single‐stage seeding process. Subcutaneous fat was processed using either a positive cell‐extraction method using CD31 Dynabeads or by a negative extraction method using CDw90‐coated magnetic beads. Only positive cell extraction gave reliably sufficient numbers of endothelial cells as a source for single‐stage seeding of vascular grafts.

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.

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.

Synthesis and evaluation of amphiphilic RGD derivatives: Uses for solvent casting in polymers and tissue engineering applications

Derivatives containing arginine-glycine-aspartic acid (RGD) inhibit fibrinogen binding to activated platelets and promote endothelial and smooth muscle cell attachment. An amphiphilic derivative of RGD that can be dissolved in an organic solvent has potential in the development of non-thrombogenic biomaterials. Such a derivative, LA-GRGD, was synthesised by coupling glycine-arginine-glycine-aspartic acid (GRGD) with lauric acid (LA). Its solubility and antithrombotic, cytotoxic and cell-binding effects were then evaluated in comparison with heparin (which is used clinically) and a fibronectin-engineered protein polymer (FEPP). Thromboelastography (TEG) was used to measure blood clotting time using fresh whole blood from healthy volunteers. Tissue factor (TF) activity was measured using plasma with a standard prothrombin time assay (PT). Cytotoxicity was assessed on human umbilical cord endothelial cells (HUVECs) using an Alamar blue assay. Solubility of the conjugate was assessed in a co-solvent. These techniques were used to study LA-GRGD, using heparin and FEPP as controls. The amphiphilic property of LA-GRGD, using heparin and FEPP as controls. The amphiphilic GRGD was soluble in acetone:water and water. LA-GRGD inhibited TF by >90% and prolonged TEG-r by 8.2±3.3 min (200 μg ml−1). Heparin inhibited TF by >90%, but prolonged TEG-r by 97.4±1.6 min (1 U ml−1) FEPP inhibited TF by >90% (100μg ml−1) and prolonged TEG-r by 73.7±8.4 min (10μg ml−1). Heparin had no cytotoxic effect on EC metabolism and viability at the concentrations studied (0.1–100 U ml−1). No significant cytotoxic effect was produced by LA-GRGD or FEPP at concentrations ranging from 0.1 μg ml−1, to 50 μg ml−1, but, at higher concentrations (100 μg ml−1 and 200 μg ml−1), a detrimental effect was observed. Cell binding studies showed that LA-GRGD bound 29% of ECs compared with FEPP (60%) and heparin (22%). This new approach for synthesising amphiphilic RGD and its analogues has potential as a drug delivery system for the manufacture of new polymer formulations for use in bypass grafts and other tissue-engineered devices.