Converging biomechanical and biophysical approaches toward ligament and tendon regeneration

融合生物力学和生物物理方法实现韧带和肌腱再生

• 批准号: RGPIN-2022-04233
• 负责人: Rosenzweig, Derek
• 金额: $ 2.26万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=765818
• 关键词: Converging; biomechanical; biophysical; approaches; toward

The overall goal of my research program is leverage biofabrication, bioengineering and biophysical approaches to drive human mesenchymal stem cell differentiation towards ligament and tendon for tissue engineering. Tendon and ligament injuries account for approximately 50% of the 33 million musculoskeletal injuries reported in the United States. These tissues have limited self-healing capacities, and the current gold-standard of autografts have high failure rates, showing the need for improved repair strategies. Tendon tissue engineering aims to provide alternative to autografts by providing a biocompatible material to act as a scaffold for cell remodelling in vitro or in vivo to fabricate a tendon-like tissue. However, the most suitable cell type, scaffold design and biomaterial remain to be determined for optimal tendon-like tissue growth. Mesenchymal stem cells (MSCs) are multipotent and self-renewing cells, which have shown great potential within regenerative medicine. Although the optimal type of MSCs for ligament repair remains to be identified. Furthermore, ligament/tendon tissues require mechanical stimulation for extracellular matrix gene expression, yet it remains unlcear whether tissue engineered ligament constructs could benefit from mechanical activation. To successfully promote cell differentiation and matrix deposition for tendon/ligament healing, we propose that MSCs or MSC-seeded scaffolds should undergo mechanoactivation and cellular alignemnt for optimal cell signaling and gene expression. We will apply novel 3D printing technologies to generate unique geometric scaffolds with biophysical and topographical properties not achievable in other platforms. Our group has been at the forefront of biofabrication for tissue engineering and in vitro human tissue modeling applications. We also have extensive expertise in mechanical/dynamic culture of primary human cells using unique cell cutlure platforms. These approaches will be applied in the following aims: Objectives: 1) Asses impact of nanopatterned 3D printed scaffolds on stem cell seeding, and tendon/ligament differentiation. 2) Determine the effects of mechanically dynamic 2D cell culture on priming stem cells for tendon and ligament differentiation. 3) Determine impact of long term mechanically active bioreactor culture on tendon matrix depostion and remodeling. Multidisciplinary approaches including biomaterials science, bioengineering, and cell biology expertise are used to generate a unique technology platform for tissue modeling and tissue engineering. The availability of such biofabricaton technology will directly allow for rapid scaffold design testing and better understanding of how biophysics and mechanics can drive ligament cell differentiation. Finally, this research program may open up avenues to intellectual properties, commercialization and interactions with industry partners.

我的研究计划的总体目标是利用生物织物，生物工程和生物物理方法来驱动人类间充质干细胞向韧带和肌腱分化，用于组织工程。肌腱和韧带损伤约占美国报告的3300万肌肉骨骼损伤的50%。这些组织具有有限的自我修复能力，并且当前自体移植的金标准具有高失败率，这表明需要改进修复策略。肌腱组织工程旨在通过提供生物相容性材料作为支架，在体外或体内进行细胞重塑，以制造肌腱样组织，从而提供自体移植物的替代品。然而，最合适的细胞类型，支架设计和生物材料仍有待确定最佳肌腱样组织生长。间充质干细胞（MSCs）是一种具有自我更新能力的多能细胞，在再生医学领域显示出巨大的潜力。尽管用于韧带修复的最佳MSC类型仍有待确定。此外，韧带/肌腱组织需要机械刺激以使细胞外基质基因表达，但组织工程化韧带构建物是否可以受益于机械活化仍不清楚。为了成功地促进肌腱/韧带愈合的细胞分化和基质沉积，我们建议MSC或MSC接种的支架应进行机械活化和细胞排列，以获得最佳的细胞信号传导和基因表达。我们将应用新的3D打印技术来生成独特的几何支架，这些支架具有其他平台无法实现的生物物理和地形特性。我们的团队一直处于组织工程和体外人体组织建模应用的生物织物的最前沿。我们还拥有使用独特的细胞培养平台进行原代人类细胞机械/动态培养的广泛专业知识。这些方法将应用于以下目的：目的：1）评估纳米图案化3D打印支架对干细胞接种和肌腱/韧带分化的影响。2)确定机械动态2D细胞培养对引发肌腱和韧带分化的干细胞的影响。3)确定长期机械活性生物反应器培养对肌腱基质沉积和重塑的影响。包括生物材料科学，生物工程和细胞生物学专业知识在内的多学科方法用于生成组织建模和组织工程的独特技术平台。这种生物制造技术的可用性将直接允许快速支架设计测试和更好地理解生物物理学和力学如何驱动韧带细胞分化。最后，这项研究计划可能会开辟知识产权，商业化和与行业合作伙伴互动的途径。