Collaborative Research: Engineering an Angiogenic Cardiac Patch

0932456/0933470Peattie/FirpoIntelligence优点拟议项目的目标是开发和评估一种能够在缺血损伤后保留心功能的生物相容性植入物。通过促进功能心脏组织的恢复，这种植入物将显著改善心脏病发作后的愈合和恢复。这种植入物将被制造成一种增强的水凝胶(心脏补片)，很容易被心脏保护，并能够将生长因子储存和释放到受损组织中。功能性组织修复将通过在受损组织周围生长一个新的毛细血管网络来实现，以响应植入。目前，美国每年发生92万例心脏病发作(心肌梗死)。损伤心脏组织的血液供应不足是愈合的关键限制因素。因此，在受损组织中发展成熟的微血管网络可以为恢复心脏功能提供重大进展。心脏补片将由一种新型的复合生物材料组成，该材料由电纺丝纤维通过共价交联的硫醇修饰的透明质酸和基于肝素的凝胶分散而成，形成一种合成的细胞外基质。成熟的微血管网络将通过受控的、顺序的从凝胶中释放多种生长因子以及这些生长因子与透明质酸的协同作用来诱导。在拟议的项目中，我们将检验这样一个假设，即肝素调节的生长因子释放可以显著改善受损心肌的血运重建，引发功能性的、灌流的血管，恢复缺血损伤后的心功能。复合材料的物理化学性能将在体外进行评估，其组成将根据指定的设计标准进行优化。通过测量移植后心脏样本中微血管的增殖和成熟度，可以量化预载有特定生长因子的补片在缺血心脏上的血管生成能力。随着时间的推移，将通过活体动物的非侵入性磁共振成像来确定被激发的血管的功能。这种成像还可以确定心脏功能的改善。更广泛的影响通过支持对患病心脏组织功能的恢复，这种植入物将显著减少与缺血性心脏损伤相关的痛苦负担。这项拟议的研究将建立基于丝素和透明质酸的水凝胶的设计和制造方案，这种水凝胶通过持续输送生长因子，诱导新的毛细血管生长到病变组织中，从而恢复病变心脏组织中的功能心脏组织。通过开发一个更好的矩阵，我们的结果将在适当的时候显著影响心脏病的治疗。此外，正如提案文本中所描述的那样，私人投资者在对学生的教育、培训和指导方面有着悠久的历史。拟议的项目将使我们能够继续让本科生和研究生参与我们正在进行的研究工作，扩大参与的学生可以获得的研究培训、教育经验和机会。作为该项目招收学生过程的一部分，将充分关注我们各机构现有的基础设施，以招募和留住妇女和在研究中代表性不足的少数群体。其中包括新英格兰高等教育卓越委员会通过多样性计划，一个主要的论坛，招收代表不足的少数族裔学生参加项目，并传播有关机会的信息，以及塔夫茨大学医学院少数族裔外联计划。在过去的十年里，这些项目非常成功地吸引了未被充分代表的本科生在塔夫茨大学从事生物医学科学研究的暑假。

0932456/0933470Peattie/FirpoIntellectual meritThe 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 impactBy 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.