Engineered Cardiac Morphogenesis-Stem Cells and Scaffolds

描述(申请人提供)：每年有数百万人死于心肌梗塞。解决这种心肌破坏的临床策略基本上是姑息性的或无效的。在生物工程研究伙伴关系的第二阶段(第6-10年)，我们利用在第1-5年获得的知识，并将其应用于开发用于临床修复受损心肌的工程系统。具体地说，我们使用增殖的人心肌细胞和一种新型的促血管生成的多孔支架(两者都是在该计划的第1-5年开发的)来设计直径300？m的心肌棒(RCM)或心肌颗粒(PCM)，这些心肌棒或心肌颗粒可以被注射到心肌梗死区，促进心肌的功能修复。心肌的体外组织工程本身虽然是重要的一步，但还不够--这种新的肌肉必须存活、生长、整合到心脏中，并最终增强收缩功能。我们的工程系统工程方法将演变出解决这些问题的综合治疗策略。我们设想，在心肌梗死后，将尽早实施一系列微创干预措施，以减少纤维化，促进血管生成，并限制进一步的心脏损害。然后，RCM或PCM将被植入这个“预置”的梗塞区。这些心肌结构的缺血性死亡将通过植入物的几何形状、使心肌细胞对缺血损伤“硬化”的策略以及诱导快速血管生成的新方法来最小化。植入物的电气集成是必不可少的，因此我们将优化该结构的电生理特性。该合作伙伴关系开发这种心肌修复系统的努力围绕四个主要目标展开：(1)使用合理设计的多孔支架和来自人类胚胎干细胞的增殖心肌细胞进行组织工程心肌棒和微粒(批准株GEO01.07；WA01，07，14)，(2)通过控制细胞外基质成分和诱导血管形成，启动梗死部位以准备接受植入的组织床，(3)开发将组织工程杆或颗粒输送到梗死区的外科方法，以及(4)评估对梗死心脏的结构和功能益处。这一全面的心肌修复方法将由一个协作的多学科团队实施，该团队密切整合了工程师、科学家和临床医生。

DESCRIPTION (provided by applicant): Myocardial infarction leads to millions of deaths per year. Clinical strategies to address this heart muscle destruction are essentially palliative or ineffective. For phase 2 (years 6-10) of this Bioengineering Research Partnership, we take knowledge gained in years 1-5 and apply this to developing an engineering system for clinical repair of damaged heart muscle. Specifically, we use proliferating human cardiomyocytes and a novel pro-angiogenic porous scaffold (both developed in years 1-5 of this program) to engineer 300?m diameter rods of cardiac muscle (RCM) or particles of cardiac muscle (PCM) that can be injected into a heart infarct zone and facilitate functional repair of cardiac muscle. The in vitro tissue engineering of cardiac muscle by itself, though an important step, is insufficient - this new muscle must survive, grow, integrate into the heart and, ultimately, enhance systolic function. Our engineering systems approach will evolve an integrated therapeutic strategy addressing these issues. We envision that, as early as possible after a myocardial infarction, a series of minimally invasive interventions will be implemented to reduce fibrosis, promote angiogenesis and limit further heart damage. RCM or PCM then will be implanted in this "primed" infarct. Ischemic death of these myocardial constructs will be minimized via the geometry of the implant, strategies to "harden" cardiomyocytes to ischemic injury, and novel approaches to induce rapid angiogenesis. Electrical integration of the implant is essential, and therefore we will optimize the electrophysiologic properties of the construct. The partnership's efforts to develop this heart muscle repair system are centered around four broad aims: (1) the tissue engineering of heart muscle rods and particles using rationally designed porous scaffolds and proliferating cardiomyocytes derived from human embryonic stem cells (approved lines GEO01.07; WA01, 07, 14), (2) priming the infarct site to prepare the tissue bed to accept the implant by controlling extracellular matrix components and inducing blood vessel formation, (3) developing surgical approaches to deliver the tissue-engineered rods or particles into the infarct and molecular approaches to promote implant survival, and (4) assessing structural and functional benefit to the infarcted heart. This comprehensive approach to heart muscle repair will be implemented by a collaborative, multidisciplinary team closely integrating engineers, scientists and clinicians.