The goal of the proposed project is to develop and evaluate a biocompatible implant capable of preserving cardiac function following ischemic injury. By facilitating restoration of functional heart tissue, this implant will significantly improve healing and recovery after heart attack. The implant will be fabricated as a reinforced hydrogel (the cardiac patch), easily securable to the heart and capable of storing and releasing growth factors into the injured tissue. Functional tissue restoration will be achieved through the growth of a new capillary network surrounding the injured tissue in response to the implant.
Currently, 920,000 heart attacks (myocardial infarction) occur annually in the US. Inadequate blood supply to the injured heart tissue is a critical limitation to healing. Development of mature microvessel networks in the damaged tissue can therefore provide a major advance towards restoring heart function. The cardiac patch will consist of a novel composite biomaterial composed of electrospun silk fibers dispersed through a covalently crosslinked, thiol-modified hyaluronic acid and heparin-based gel, creating a synthetic extracellular matrix. Mature microvessel networks will be induced by controlled, sequential release of multiple growth factors from the gel and by synergistic interactions of those growth factors with hyaluronic acid. In the proposed project, we will test the hypothesis that heparin-regulated growth factor release can dramatically improve the revascularization of damaged myocardium, eliciting functional, perfused vessels that restore cardiac function after ischemic injury. Physico-chemical properties of the composite will be evaluated in vitro and its composition optimized with regard to specified design criteria. The angiogenic capacity of patches pre-loaded with selected growth factors then sutured onto ischemic hearts will be quantified by measurement of microvessel proliferation and maturity in heart samples post-implantation. The functionality of elicited vessels will then be determined by non-invasive magnetic resonance imaging in live animals over time. Such imaging will also allow determination of improvements in heart function.
Broader impact
By supporting restoration of functionality to diseased heart tissue, this implant will significantly reduce the burden of suffering associated with ischemic heart damage. The proposed investigations will establish protocols for design and fabrication of silk and hyaluronic acid-based hydrogels that restore functional cardiac tissue in diseased heart tissue by eliciting the growth of new capillary blood vessels into diseased tissue through sustained growth factor delivery. By developing a superior matrix, our results can in due course significantly impact therapeutic treatment of heart disease.
Furthermore, as is described in the proposal text, the PIs have a long history of significant commitment to education, training and mentorship of students. The proposed project will permit us to continue to engage undergraduate as well as graduate students in our ongoing research efforts, expanding the research training, educational experience and opportunities available to the students involved. As part of the process of recruitment of students into the project, full attention will be given to the infrastructure in place in our institutions for recruiting and retaining women and underrepresented minorities in research. These include the New England Board of Higher Education Excellence through Diversity Program, a major forum for recruitment of underrepresented minority students for programs and for disseminating information about the opportunities, and the Tufts University School of Medicine minority outreach program. For the last ten years, these programs have been highly successful in attracting underrepresented undergraduate students to spend summers at Tufts involved in biomedical science research.
