Collaborative Research: Engineering an Angiogenic Cardiac Patch

合作研究：设计血管生成心脏补片

• 批准号: 1332149
• 负责人: Robert Peattie
• 金额: $ 0.96万
• 依托单位: Tufts Medical Center, Inc
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1332149&HistoricalAwards=false
• 关键词: Collaborative; Research; Engineering; Angiogenic; Cardiac

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.

0932456/0933470 Peattie/Firpo智力优点拟议项目的目标是开发和评价能够在缺血性损伤后保留心脏功能的生物相容性植入物。 通过促进功能性心脏组织的恢复，这种植入物将显着改善心脏病发作后的愈合和恢复。 植入物将被制成一种增强的水凝胶（心脏补片），很容易固定在心脏上，并能够储存和释放生长因子到受伤的组织中。 功能性组织恢复将通过响应于植入物在受损组织周围生长新的毛细血管网络来实现。 目前，美国每年发生920，000例心脏病发作（心肌梗死）。 对受伤的心脏组织的血液供应不足是愈合的关键限制。 因此，在受损组织中发育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复合生物材料组成，该材料由分散在共价交联、巯基修饰的透明质酸和肝素基凝胶中的静电纺丝纤维组成，从而形成合成的细胞外基质。 成熟的微血管网络将通过多种生长因子从凝胶中的受控、顺序释放以及这些生长因子与透明质酸的协同相互作用来诱导。 在这个项目中，我们将检验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，诱导功能性灌注血管在缺血性损伤后恢复心脏功能的假设。 将在体外评价复合材料的物理化学性质，并根据指定的设计标准对其组成进行优化。 将通过测量植入后心脏样本中的微血管增殖和成熟度来量化预加载有选定生长因子然后缝合到缺血心脏上的贴片的血管生成能力。 然后将通过活体动物随时间推移的非侵入性磁共振成像来确定诱发血管的功能。 更广泛的影响通过支持患病心脏组织的功能恢复，这种植入物将显著减轻与缺血性心脏损伤相关的痛苦负担。 拟议的研究将建立设计和制造基于丝和透明质酸的水凝胶的方案，通过持续的生长因子递送诱导新的毛细血管生长到患病组织中来恢复患病心脏组织中的功能性心脏组织。 通过开发一个上级矩阵，我们的结果可以在适当的时候显着影响心脏病的治疗。此外，正如建议文本所述，首席执行官长期以来一直致力于教育，培训和指导学生。 拟议的项目将使我们能够继续从事本科生以及研究生在我们正在进行的研究工作，扩大研究培训，教育经验和机会提供给有关学生。 作为该项目招收学生过程的一部分，将充分重视我们各机构现有的基础设施，以招收和留住从事研究的妇女和代表性不足的少数民族。 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，为招聘代表性不足的少数民族学生的方案和传播有关机会的信息，以及塔夫茨大学医学院少数民族外展计划。 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进行生物医学科学研究。