Congratulations to Professor Sacks; he and his collaborators have received four new awards with a total value of $1.75 million from the National Institutes of Health (NIH) to fund research aimed at various heart related tissue-engineered and biomaterial projects. The research includes investigations on heart valve prostheses and biomechanical properties research, development of techniques to analyze muscle derived stem cells, and the calcification of fabricated heart valves. These grants are in partnership with other researchers from the University of Pittsburgh and faculty from other universities throughout the United States. The new grant summaries follow:
- “Fluid-Structure Simulation for Prosthetic Heart Valves”;
NIH/NHLBI; Co-investigator with K.B. Chandran, U. Iowa
Summary: Mechanical and biological tissue valve prostheses have been used as replacement for diseased natural heart valves for over four decades. Even though patients with implanted valves lead a relatively normal life, thrombus deposition and subsequent embolic complications encountered with mechanical valve implants require the patients to have long-term anticoagulant therapy. Implanted tissue valves fail due to calcification and fatigue failure and require replacement after an average of 10-12 years with associated risks of multiple surgeries. In vitro experimental studies and flow simulations published to date have yielded valuable information on possible relationship between the dynamic stresses developed during the valve function and the associated problems, but the knowledge gained is still incomplete. With the advent of high-speed computational capabilities and development of computational fluid dynamic and structural analysis capabilities, computational simulation of valve function can provide valuable information on the valve dynamics and abnormal stresses developed during a cardiac cycle and such detailed information is otherwise unavailable with experimental tools alone. The long-term goal of these studies is to develop an accurate, robust, and physiologically realistic numerical model capable of simulating tissue valve dynamics. The model can aid in design changes and the development of new designs in order to improve the functional characteristics of the valves. The simulation can also be potentially extended to analyze the optimal function of the native human aortic and mitral valves. An understanding of the stresses developed on the leaflets and the nature of flow dynamics past the native valves will have potential applications in the development of tissue engineered heart valves as well.
- “Biocompatible Heterograft Biomaterials”; NIH/NHLBI;
Co-investigator with R.J. Levy, U. Penn
Summary: The Sacks’ group has shown that ethanol pretreatment inhibits calcification of glutaraldehyde pretreated bioprosthetic heart valves fabricated from either porcine aortic valves or bovine pericardium. The most common cause of bioprosthetic heart valve failure in clinical implants is cuspal calcification. Our ethanol discoveries have led to a successful new anti-calcification approach that is currently in clinical use. An ethanol pretreated stent mounted bioprosthesis using our technology has been approved for clinical use in Europe, and similarly two novel stentless ethanol pretreated bioprostheses are in multi-center clinical trials in the United States. However, ethanol pretreatment does not completely inhibit bioprosthetic cuspal calcification, and has no effect on bioprosthetic aortic wall calcification, a complication affecting stentless valve designs. To address this problem, research in the Sacks’ laboratory has led to the synthesis of a novel protein cross linking reagent, triglycidyl amine (TGA), for preparing calcification resistant bioprostheses. Thus, the overall hypothesis of this proposal is that TGA cross linking and related reactions, including those with bisphosphonates, inhibits bioprosthetic calcification due to major modifications of the structural proteins of the extracellular matrix (ECM). This results in cell-ECM interactions that confer not only calcification resistance, but enhanced biocompatibility, and stabile biomechanical properties.
- “Functional Tissue Engineering for Stress Incontinence”;
NIH; Co-investigator with Michael B. Chancellor
Summary: Utilizing techniques developed in the Sacks’ laboratory, the study will mount a systematic in vitro and in vivo physiological and biomechanical analysis of muscle stem cell based tissue engineering treatment of stress urinary incontinence (SUI). SUI is a significant medical problem affecting approximately 25 million American women1. Despite the high prevalence of SUI, there is very little treatment-oriented research utilizing tissue engineering techniques. The research will develop a truly physiologic sling, not from synthetic or cadaveric tissue, but rather an engineered, functional stem cell muscle scaffold that can be implanted to repair a damaged urethral sphincter. By reengineering the deficient urinary sphincter through functional tissue engineering, we plan to significantly improve the treatment of SUI. We want to strongly emphasize that our research is in complete compliance with the federal guidelines on embryonic stem cell research. These stem cells have not been obtained from embryos (animal or human) or cell lines of embryonic stem cells.
- “Cardiopulmonary Organ Engineering – Core C (Biomechanics)”;
NIH/NHLBI; Co-investigator with William Wagner
Summary: The aim of this proposal is to design solutions for vascular, cardiac, and pulmonary organ failure by building interactive teams of researchers focused on specific aspects of cardiopulmonary organ engineering. We will focus our efforts on three projects: a tissue engineered blood vessel, a myocardial patch, and a biohybrid lung. The assembled research teams will function as cores of expertise that address common tasks associated with all three projects. Five research cores will be established in the following areas: 1) matrix synthesis and surface modification, 2) precursor cell isolation and characterization, 3) biomechanical testing and conditioning, 4) animal model development, and 5) construct assessment.