Bio-Fabrication of Tissue Engineering Scaffolds

简介：数百万人遭受组织/器官损伤，包括外周神经损伤、脊髓损伤、骨关节炎和心脏病发作。组织/器官移植是治疗这些类型损伤的黄金标准，但由于供体组织/器官的可用性有限，作为一种选择受到严重限制。其他治疗方法包括手术重新排列神经末梢，抗炎甲基强的松龙治疗，用钢或其他人造材料制成的假体植入物替换关节，以及血栓破坏药物和血管成形术。然而，这些治疗后的恢复水平是高度可变的，功能的恢复几乎从未完成。组织工程（TE）是一个新兴领域，旨在生产可以与患者一起生长的组织/器官替代品或支架，最终提供永久性解决方案，从而改善当前的治疗方法。组织支架的设计和制造已被证明是一项具有挑战性的任务，其显著限制了临床应用的进展。一个重要的障碍是不能制造具有模拟天然组织/器官的结构和细胞组织的支架。[*]酒店：该研究计划的长期目标是推进TE应用的生物制造支架的理论和实践基础，通过该支架，活细胞在制造过程中被纳入支架中。在接下来的五年里，该研究旨在开发新的方法或工具，以解决支架生物制造方面的三个关键问题。具体而言，短期目标是：（1）开发提高细胞活力的方法，以便更多的细胞在该过程中存活并在随后的愈合过程中发挥作用;（2）操纵多种材料/细胞以模拟天然组织/器官的复杂结构;以及（3）开发新方法，允许在支架制造期间在支架内创建图案化的血管网络。目标1建立在我以前的NSERC发现资助期间进行的工作的基础上，认识到细胞受到持续的过程诱导力（例如，剪切应力），因此可能无法在该过程中存活。目标2解决了现有方法缺乏以可控方式操纵材料/细胞的能力的事实，因此，支架制造在很大程度上限于简单结构。目标3认识到支架内的血管化对于为细胞提供氧气和营养以及运输细胞的废物是至关重要的;然而，通过现有方法在支架内形成的血管是不够的，这显著限制了支架在愈合过程中的功能，特别是在修复心脏等厚而大的组织/器官中。** 影响：这项研究将导致新技术和工具的开发，以推进细胞封装支架的生物制造，以及新型支架，用于广泛的TE应用，包括外周神经修复，关节软骨修复，脊髓损伤修复和心脏病发作的治疗。因此，主要利益攸关方是大量遭受组织/器官损伤的加拿大公民以及相关领域的卫生研究人员和从业人员及行业伙伴。这项研究还将涉及研究生的培训，以满足TE对高素质人才日益增长的需求。

INTRODUCTION: Millions of people suffer from tissue/organ injuries, including peripheral nerve injuries, spinal cord injury, osteoarthritis, and heart attacks. Tissue/organ transplantation is the gold standard to treat some of these types of injuries but is severely restricted as an option due to the limited availability of donor tissues/organs. Other treatment approaches include surgically realigning nerve endings, anti-inflammatory methylprednisolone therapy, replacing joints with prosthetic implants made from steel or other artificial materials, and clot-busting medicines and angioplasty. However, the level of recovery following these treatments is highly variable and the return of function is almost never complete. Tissue engineering (TE) is an emerging field that aims to produce tissue/organ substitutes or scaffolds that can grow with patients, ultimately providing a permanent solution and thus improving upon current treatment approaches. The design and fabrication of tissue scaffolds has proven to be a challenging task that has significantly limited progress towards clinical applications. An important barrier is the inability to fabricate scaffolds with structures and cell organizations that mimic those of native tissues/organs. **OBJECTIVES: The long-term goal of this research program is to advance the theoretical and practical basis of bio-fabricating scaffolds for TE applications, by which living cells are incorporated into the scaffolds during their fabrication. Over the next five years, the research aims to develop novel methods or tools to address three key issues with respect to scaffold bio-fabrication. Specifically, the short-term objectives are to: (1) develop methods to improve cell viability so that more cells survive the process and play a role in the subsequent healing process; (2) manipulate multiple materials/cells for mimicking the complicated structure of native tissues/organs; and (3) develop novel methods that allow for the creation of patterned vascular networks within scaffolds during their fabrication. Objective 1 builds on work conducted during my previous NSERC Discovery grant, recognizing that cells are subjected to sustained process-induced forces (e.g., shear stress) during biofabrication and, as a result, may not survive the process. Objective 2 addresses the fact that existing approaches lack the ability to manipulate materials/cells in a controllable manner and, as a result, scaffold fabrication is largely limited to simple structures. Objective 3 recognizes that vascularization within scaffolds is critical to supply cells with oxygen and nutrients and to transport the waste products of cells; however, the vasculatures formed within scaffolds by existing methods are inadequate, and this has significantly limited the function of scaffolds in the healing process, particularly in the repair of such thick and large tissues/organs as hearts. **IMPACT: This research will lead to the development of new techniques and tools to advance the bio-fabrication of cell-encapsulated scaffolds, as well as novel scaffolds, for wide TE applications including peripheral-nerve repair, articular-cartilage repair, spinal-cord-injury repair, and treatment of heart attack. As such, the primary stakeholders are the large number of Canadian citizens who suffer from tissue/organ injuries as well as health researchers and practitioners and industry partners in related areas. This research will also involve the training of graduate students to meet the increasing demand for highly qualified personnel in TE.