Bio-printing stem cell based and oxygen releasing tissue grafts for myocardial in

描述(申请人提供)：估计有8000万美国成年人(三分之一)患有一种或多种心血管疾病(CVD)；7900,000,000人有心肌梗塞病史(美国心脏协会)。干细胞治疗是一种很有前途的心肌梗死修复方法，利用干细胞修复受损的心脏是当前心脏研究的主流。不幸的是，到目前为止，将干细胞直接注射到梗死心脏纤维化区的成功有限，可能是因为干细胞在坏死区的保留率和存活率较低，以及移植细胞在宿主心脏组织内的心脏原性分化和功能整合有限。为了解决这些问题，最近提出了一种组织工程支架方法，包括使用人工合成的组织支架，将干细胞种植并随后嵌入到生物工程移植物框架中。然而，由于合成支架与干细胞结合的经验不足，以及对如何改善支架的几何形状和组成以促进血管重建和改善移植物微环境以提高干细胞的活性、生长和分化的了解有限，因此取得的成功有限。我们的建议通过一种新的策略来解决这些限制，该策略结合使用可生物降解的弹性体和释放氧气的支架进行间充质干细胞治疗。为此，我们将使用我们的聚合物静电纺丝和微喷细胞打印的混合生物打印技术来制造一种持久的基于干细胞的多层三维心脏贴片。在这种生物工程结构中，支架是一种有效的干细胞载体和三维弹性物理结构，用于心肌细胞的生长和机电耦合。在我们的支架中加入过氧化钙释氧纳米颗粒可以改善微环境，以增强干细胞的存活及其与受损心脏组织的整合。因此，我们提出了4个具体目标：1.心脏补片支架材料的制备和表征。2.优化氧释放颗粒在支架中的掺入，以实现最大的氧气输送和最小的毒性。3.采用混合制造技术制作复合心脏补片。4.对生物工程心脏补片进行体外评价。综上所述，拟议的项目将通过为细胞提供稳定的输送工具和顺从的局部环境来改善目前对心肌梗死的干细胞治疗，以增强和调节细胞的增殖和分化，以促进基于细胞的组织再生和修复。此外，这项工作承诺通过生物打印关键信号肽和其他分子来改进未来的方法学，这些分子用于修复软组织损伤的支架。 公共卫生相关性：估计有8000万美国成年人(三分之一)患有一种或多种心血管疾病；7900,000人有心肌梗塞病史(美国心脏协会)。干细胞治疗是一种很有前途的心肌梗死修复方法，利用干细胞修复受损的心脏是当前心脏研究的主流。拟议的项目将通过为细胞提供稳定的输送载体和顺从的局部环境来改善目前对心肌梗死的干细胞治疗，以增强和调节细胞的增殖和分化，以促进基于细胞的组织再生和修复。

DESCRIPTION (provided by applicant): An estimated 80,000,000 American adults (one in three) have one or more types of cardiovascular disease (CVD); 7,900,000 have a history of myocardial infarction (American Heart Association). Stem cell therapy is a promising approach for myocardial infarction repair, and the use of stem cells to repair a damaged heart is now mainstream in current cardiac research. Unfortunately, thus far direct injection of stem cells into the fibrotic area of infarcted hearts has met with limited success, probably due to the low retention and survival of stem cells in the necrotic areas, together with the limited cardiogenic differentiation and functional integration of delivered cells within the host heart tissue. To solve these problems, a tissue engineered scaffolding method has recently been proposed, involving the use of synthetic tissue scaffoldings with stem cells seeded and subsequently embedded within the bioengineered graft framework. However, limited success has been achieved due to inadequate experience in combining synthetic scaffolds with stem cells and limited knowledge of how to improve the geometry and composition of scaffolding to favor revascularization and improve the graft microenvironment for enhanced viability, growth, and differentiation of stem cells. Our proposal addresses these limitations with a new strategy that combines use of biodegradable elastomeric and oxygen-releasing scaffoldings for mesenchymal stem cell therapy. To this aim, we will use our hybrid bio-printing technology of polymer electrospinning and microjet cell printing to fabricate a durable stem cell based multilayered 3-D cardiac patch. In this bioengineered construct, the scaffold serves as an efficient stem cell carrier and 3-D elastomeric physical structure for myocyte growth and electro-mechanical coupling. The inclusion of calcium peroxide oxygen-releasing nanoparticles in our scaffoldings improves the microenvironment for enhanced survival of stem cells and their integration with the injured cardiac tissue. Therefore, we propose 4 Specific Aims: 1. Prepare and characterize scaffold materials for a cardiac patch. 2. Optimize incorporation of oxygen releasing particles into scaffolds for maximum oxygen delivery and minimal toxicity. 3. Fabricate a composite cardiac patch by using the hybrid fabrication biotechnology. 4. Conduct in vitro evaluation of the bio- engineered cardiac patch. Taken together, the proposed project will improve current stem cell therapy for myocardial infarct by providing cells with a stable delivery vehicle and an amenable local environment that enhances and regulates their proliferation and differentiation for cell-based tissue regeneration and repair. In addition, this effort promises future methodological improvements by bio-printing critical signaling peptides and other molecules for use in scaffolds designed to repair soft tissue injuries. PUBLIC HEALTH RELEVANCE: An estimated 80,000,000 American adults (one in three) have one or more types of cardiovascular disease (CVD); 7,900,000 have a history of myocardial infarction (American Heart Association). Stem cell therapy is a promising approach for myocardial infarction repair, and the use of stem cells to repair a damaged heart is now mainstream in current cardiac research. The proposed project will improve current stem cell therapy for myocardial infarct by providing cells with a stable delivery vehicle and an amenable local environment that enhances and regulates their proliferation and differentiation for cell-based tissue regeneration and repair.