Bio-Fabrication of Tissue Engineering Scaffolds

简介：数以百万计的人遭受组织/器官损伤，包括周围神经损伤、脊髓损伤、骨关节炎和心脏病发作。组织/器官移植是治疗其中一些类型损伤的黄金标准，但由于供体组织/器官的可获得性有限，作为一种选择受到严格限制。其他治疗方法包括手术重新调整神经末梢，抗炎甲基强的松龙治疗，用钢铁或其他人工材料制成的假体替换关节，以及溶栓药物和血管成形术。然而，这些治疗后的恢复程度是高度可变的，功能的恢复几乎永远不会完成。组织工程(TE)是一个新兴的领域，旨在生产组织/器官替代品或支架，可以随着患者的生长而生长，最终提供永久的解决方案，从而改进现有的治疗方法。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，极大地限制了临床应用的进展。一个重要的障碍是无法制造出具有模仿天然组织/器官的结构和细胞组织的支架。**目的：本研究计划的长期目标是为TE应用的生物构建支架提供理论和实践基础，在支架制造过程中将活细胞掺入支架中。在接下来的五年里，这项研究的目标是开发新的方法或工具来解决与支架生物制造有关的三个关键问题。具体来说，短期目标是：(1)开发提高细胞活力的方法，以便更多的细胞在这个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)开发新的方法，允许在支架制造过程中在支架内创建图案化的血管网络。目标1建立在我上一次NSERC发现资助期间进行的工作基础上，认识到细胞在生物制造过程中受到持续的过程诱导力(例如剪切力)，因此可能无法存活。目标2解决了这样一个事实，即现有的方法缺乏以可控的方式操纵材料/细胞的能力，因此，支架的制造在很大程度上限于简单的结构。目标3认识到支架内的血管形成是为细胞提供氧气和营养物质以及运输细胞废物的关键；然而，现有方法在支架内形成的血管是不够的，这严重限制了支架在愈合过程中的功能，特别是在修复像心脏这样厚而大的组织/器官方面。**影响：这项研究将导致开发新的技术和工具，以促进细胞包裹支架的生物制造，以及新型支架的广泛应用，包括周围神经修复、关节软骨修复、脊髓损伤修复和心脏病发作的治疗。因此，主要利益攸关方是遭受组织/器官损伤的大量加拿大公民以及相关领域的卫生研究人员和从业者以及行业合作伙伴。这项研究还将涉及培养研究生，以满足日益增长的对高素质人才的需求。

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.