SBIR-STTR Award

This Phase I SBlR application seeks support to develop and evaluate the use of an extracellular matrix (ECM) bioscaffold derived from the urinary bladder submucosa (UBS) for the repair and reconstruction of heart valves. Porcine-derived UBS-ECM represents an acellular biodegradable scaffold material which supports cell attachment, migration, proliferation, differentiation, and wound healing. The hydrated form of single sheets of UBS and other ECMs have shown excellent remodeling capabilities in both preclinical animal studies and early human clinical studies for noncardiac applications. We propose to conduct three studies. Study #1 will evaluate two different forms of the UBS-ECM, both a dehydrated form and a lyophilized form, for their ability to support human microvascular endothelial cell (HMEC) growth and differentiation in vitro. Study #2 will determine the suture retention strength of these two different forms of UBS. We will select a preferred form of the UBS-ECM, either dehydrated or lyophilized, for utilization in a preliminary dog study (Study #3) in which one leaflet of the pulmonic valve will be replaced with the UBS-ECM. Currently, the options for heart valve replacement include mechanical valves or biologic tissue valves. Mechanical valves suffer from problems such as hemolysis and the need for life-long anticoagulation. Biologic tissue valves are usually cross-linked with agents such as glutaraldehyde and eventually mineralize with subsequent loss of desirable mechanical properties. Successful completion of the three specific aims identified for this Phase I project will provide the necessary information to decide whether or not this UBS scaffold should be evaluated further as a biomaterial for heart valve repair (i.e., Phase II studies). Each objective/specific aim has well- defined endpoints and criteria for success. The proposed studies will be conducted by an experienced and knowledgeable research team. A time line for the proposed work is provided, and the technology involves an innovative tissue engineering approach in a medical field with significant unmet needs. PROPOSED COMMERCIAL APPLICATIONS: The use of UBS-ECM for tissue engineering applications of heart valve replacement provides a potential alternative to mechanical valves and cross-linked biologic valves. More than 175,000 heart valves are replaced annually, and the ability of a naturally-occurring scaffold to be used as a heart valve replacement material would obviate the need for anticoagulation or concerns about mineralization with loss of needed mechanical properties. ACell, Inc. is targeting this field as one of its markets in the field of tissue engineering.

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. PROPOSED COMMERCIAL APPLICATIONS: 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.