Engineered Cardiac Morphogenesis-Stem Cells and Scaffolds

描述（由申请人提供）：心肌梗死每年导致数百万人死亡。解决这种心肌破坏的临床策略基本上是姑息或无效的。对于该生物工程研究合作伙伴关系的第2阶段（6-10年），我们利用1-5年获得的知识，并将其应用于开发用于受损心肌临床修复的工程系统。具体而言，我们使用增殖的人心肌细胞和一种新的促血管生成的多孔支架（均在本计划的1-5年开发）工程师300？m直径的心肌棒（RCM）或心肌颗粒（PCM），其可以被注射到心脏梗塞区中并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，融入心脏，并最终增强收缩功能。我们的工程系统方法将发展一个综合的治疗策略来解决这些问题。我们设想，在心肌梗死后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伤。然后将RCM或PCM植入该“引发的”梗死中。这些心肌结构的缺血性死亡将通过植入物的几何形状、使心肌细胞对缺血性损伤“硬化”的策略以及诱导快速血管生成的新方法来最小化。植入物的电气集成至关重要，因此我们将优化结构的电生理特性。该合作伙伴开发这种心肌修复系统的努力围绕着四个广泛的目标：（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心肌棒和颗粒的组织工程（核准的GEO01.07行; WA 01，07，14），（2）通过控制细胞外基质成分和诱导血管形成，引发梗塞部位以制备组织床以接受植入物，（3）开发将组织工程化杆或颗粒递送到梗塞中的手术方法和促进植入物存活的分子方法，以及（4）评估对梗塞心脏的结构和功能益处。这种全面的心肌修复方法将由一个紧密结合工程师，科学家和临床医生的协作，多学科团队实施。

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.