Anisotropic Human Mesenchymal Stem Cell Patch with Oriented Vasculature

患病组织的替换要求植入材料不仅具有适当的机械强度，而且还必须具有功能性血液分布网络（脉管系统;静脉、毛细血管），并且这些通常难以制造。这个项目将试图了解和模拟三维（3D）心脏组织的结构和血管。目标是设计一种机械强度和功能性的细胞贴片，用于受损心脏组织的再生。拟议的研究还将为本科生和研究生以及代表性不足的社区学院学生提供参与跨学科干细胞和组织工程研究的机会。此外，还将举办一系列研讨会，以提高密歇根州UP（上半岛）卫生界和公众对干细胞和组织工程的认识。该项目的总体目标是创建对齐的纳米纤维天然细胞外基质（ECM）支架，用于预血管化各向异性干细胞贴片的生物支架，并阐明体内微环境中微血管取向的机制。人骨髓间充质干细胞（hMSCs）具有免疫调节、再生、有效促进心肌再生，并作为周细胞稳定内皮细胞（EC）形成的微血管。这些独特的性质使得hMSC能够与ECM支架和EC联合收割机组合以生物制造现成的或患者特异性的预血管化补片，其中hMSC将发挥稳定由EC在体外形成的脉管系统和在植入后协调死亡心脏组织的再生的双重作用。在这个项目中，hMSCs将与内皮细胞在纳米纤维ECM支架中共培养，以形成对齐的毛细血管样脉管系统，并将研究对齐的纳米纤维对微血管的密度，方向和成熟的影响。预血管化的hMSC片层将是多层的，并在灌注生物反应器中进一步成熟，并且将评估生理间质流对3D仿生组织平台内现有微血管的互连、对齐和成熟的作用。如果成功，该项目可能会导致开发个性化或现成的心脏组织贴片，从而大大提高治疗与心脏病发作相关的死亡心肌的成功率。

Replacement of diseased tissue requires that the implanted material not only have the proper mechanical strength, but it must also have a functioning blood distribution network (vasculature; veins, capillaries), and these are often difficult to manufacture. This project will seek to understand and mimic the structure and vasculature of three-dimensional (3D) cardiac tissue. The goal is to engineer a mechanically strong and functional cell patch for the regeneration of damaged heart tissue. The proposed research will also provide opportunities for undergraduate and graduate students, as well as underrepresented community college students, to be involved in interdisciplinary stem cell and tissue engineering research. In addition, a series of seminars will be hosted to increase stem cell and tissue engineering awareness among the health community and public in the UP (Upper Peninsula) of Michigan. The overall objective of the project is to create aligned nanofibrous natural extracellular matrix (ECM) scaffolds for the biofabrication of a prevascularized anisotropic stem cell patch and elucidate the mechanism of microvessel orientation within the in vivo microenvironment. Human mesenchymal stem cells (hMSCs) are immunoregulatory, regenerative, effective in promoting myocardial regeneration, and function as pericytes to stabilize the microvessels formed by endothelial cells (ECs). These unique properties enable hMSCs to combine with ECM scaffolds and ECs to biofabricate an off-the-shelf or patient-specific prevascularized patch, in which hMSCs will play a dual role of stabilizing vasculature formed by ECs in vitro and orchestrating the regeneration of dead cardiac tissue after implantation. In this project, hMSCs will be co-cultured with ECs in a nanofibrous ECM scaffold to form an aligned capillary-like vasculature, and the effects of aligned nanofibers on the density, orientation and maturation of the microvessels will be investigated. The prevascularized hMSC sheets will be multi-layered and further matured in a perfusion bioreactor, and the role of physiological interstitial flow on the inter-connections, alignment and maturation of the existing microvessels within the 3D biomimetic tissue platform will be evaluated. If successful, this project could lead to the development of personalized or off-the-shelf cardiac tissue patches that could dramatically increase the success rate for the treatment of dead cardiac muscle associated with heart attacks.