This Phase II proposal seeks support to continue the development of a heart valve scaffold created from the extracellular matrix (ECM) of the porcine urinary bladder. Phase I studies have been successfully completed and showed that all goods were either met or exceeded. It was determined that a lyophilized form of the urinary bladder ECM (U- ECM) supported the in vitro growth of human microvascular endothelial cells (HMECs) and promoted growth and differentiation of this cell type. It was also found that the suture retention strength for a bilaminate form of the U-ECM exceeded that of normal heart tissue. Finally, an in vivo study in a dog model showed that the bilaminate form of the U-ECM induced constructive remodeling of the anterior leaflet of the pulmonic valve with complete endothelialization, repopulation by host mesenchymal cells, and neo-matrix deposition in an organized fashion. The work described in the Phase B proposal will: (1) establish quality assurance methods for raw material (ECM) acquisition in partial fulfillment for FDA certification of a manufacturing plant, (2) support the completion of ISO-9001/tripartite guideline tests to establish uniformity of product manufacturing and safety of the implantable ECM device, and (3) conduct definitive preclinical animal studies in two separate species (dog and sheep). The pulmonic valve will be replaced by ACell's U-ECM heart valve device and the animals will be followed for periods of time ranging from 6 months to 1 year. The measured endpoints of this study will include function testing (echocardiography, angiography, pressure gradient studies) and morphology. The proposed studies will be conducted by an experienced interdisciplinary team of tissue engineers and cardiovascular surgeons. Criteria for success of each study in this proposal are established, and a time line for completion of the work is delineated. This technology addresses a clinically important problem in an innovative fashion and offers the hope for permanent replacement of damaged and diseased heart valves without the associated morbidity of life-long anticoagulation or the need for subsequent surgery.
There are up to 80,000 heart valves replaced in the United States alone each year. A valve that eliminates the need for anticoagulation and does not calcify over time would likely capture a major share of the market within a short period of time.