EiR: Thermo-sensitive Therapeutic Laden Hydrogels to Induce Cartilage Tissue Regeneration

非技术：软骨是在人类关节中发现的结缔组织。随着时间的推移，软骨造成的损害对数百万美国人来说是一个巨大的挑战，并最终助长了骨关节炎的发展。鉴于减轻软骨损伤的这一重要需求，为人类关节开发新的治疗性植入性材料至关重要。为了发现、理解并最终利用新的生物材料，需要了解这些材料在复杂的机械应力和生物环境中的行为的基本知识。该奖项将支持研究生和本科生在软骨组织修复新治疗材料的准备和评估方面的培训，并将加深我们对它们在导致骨关节炎的压力环境下的反应的理解。此外，莫尔豪斯学院的学生将制作短片，让社会参与生物材料科学的学习，同时还为当地亚特兰大公立学校的学生举办外联活动。这项活动将促进从K-12、本科生、研究生到成人的学习者社区的发展。技术：关节软骨是一种高度有序的无血管结缔组织，排列在关节内，能承受巨大的生物力学负荷，具有无摩擦的表面，可获得最佳的移动性。然而，关节软骨在疾病或损伤后修复自身的能力是有限的。在损伤或疾病开始时，低氧(低氧)会破坏无血管结构，导致活性氧物种的存在，从而阻止健康的关节软骨细胞在三维软骨组织基质中增殖。目前还没有在低氧条件下促进健康3D细胞培养和增殖的生物材料。本项目的目标是开发温度敏感的治疗负载型水凝胶，并研究低氧对细胞活力和3D打印生物墨水制备的水凝胶结构和功能的影响。这项研究包括温度响应型载水凝胶的制备、表征、3D打印、生化分析和空间定位，为再生组织工程提供了一种新的途径。在3D培养中，使用混合治疗水凝胶来改善细胞微环境和促进健康的细胞外基质尤其令人感兴趣。该项目的主导假说是由混合治疗负载水凝胶的配方驱动的，该凝胶具有坚固的结构完整性、更高的氧气扩散系数，以及通过3D打印生物墨水模仿关节软骨区的结构，以在低氧条件下为软骨形成提供细胞保护。使用混合治疗负载水凝胶，首席研究员和研究团队评估低氧诱导的活性氧物种如何减轻细胞命运、细胞外基质数量和影响生物材料的性能。杂化治疗水凝胶中化学修饰的效果以及结构和功能的影响因改进的组织工程策略而被注意到。研究小组的方法包括使用化学和聚合物合成制备杂化治疗水凝胶，材料表征，使用基于流动的直接墨水写入的3D打印，在低氧和常氧条件下关节软骨细胞和间充质干细胞的静态细胞培养，以及机械刺激制度来评估化学结构的相变化，以及细胞外基质蛋白的时间和空间定位。最后，从这项研究中将获得新的知识，通过改善生物材料的性能以在病理生理条件下耐受，为开发用于软骨组织工程和再生的新型治疗性水凝胶做出贡献。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Non-Technical: Cartilage is the firm connective tissue found in human joints. The damage attributed to cartilage over time presents a tremendous challenge for millions of Americans, and ultimately fosters the development of osteoarthritis. Given this important need to mitigate the damage to cartilage, it is critical that new therapeutic implantable materials are developed for human joints. In order to discover, understand, and ultimately utilize new biomaterial, fundamental knowledge of the behavior of these materials in a complex mechanical stress and biological environment is required. This award will support graduate and undergraduate training on the preparation and evaluation of new therapeutic materials for cartilage tissue repair and will further our understanding of how they respond under stressed environments that lead to osteoarthritis. Additionally, students at Morehouse College will prepare short films to engage society into learning about biomaterial science while also hosting outreach activities for local Atlanta Public School students. This activity will facilitate the development of a community of learners ranging from K-12, undergraduate, post graduate, to adults. Technical: Articular cartilage is a highly ordered avascular connective tissue that lines the articular joints and is known to withstand enormous biomechanical loads having a frictionless surface for optimal mobility. However, articular cartilage is limited in its ability to repair itself after defects from disease or injury. At the onset of injury or disease, hypoxia (low oxygen) disrupt the avascular architecture giving rise to the presence of reactive oxygen species that prevent healthy articular cartilage cell proliferation throughout the three-dimensional cartilage tissue matrix. Biomaterials that promote healthy 3D cell culture and proliferation under hypoxia are currently not available. The objective of this project focuses on the development of thermo-sensitive therapeutic laden hydrogels and the study of hypoxia on cell viability and hydrogel structure and function prepared from 3D printed bio-inks. This research entails the preparation, characterization, 3D printing, biochemical analysis, and spatial mapping of thermo-responsive therapeutic laden hydrogels that provide a new approach to regenerative tissue engineering. The use of hybrid therapeutic hydrogels to improve cell microenvironments and promote healthy extracellular matrix in 3D culture is of particular interest. The governing hypothesis of this project is driven by formulations of hybrid therapeutic laden hydrogels with robust structural integrity, higher oxygen diffusion coefficients, and the structural mimicry of articular cartilage zones via 3D printed bio-inks to provide cellular-protection under hypoxia towards chondrogenesis. Using hybrid therapeutic laden hydrogels, the Principal Investigator and research team evaluate how hypoxic induced reactive oxygen species mitigate cell fate, ECM amounts, and effect biomaterial properties. The effect of chemical modifications and the impact of structure and function in hybrid therapeutic hydrogels are noted for improved tissue engineering strategies. The research team approaches include using chemical and polymer synthesis of preparation of hybrid therapeutic hydrogels, material characterization, 3D-printing using flow-based direct ink write, static cell culture of articular chondrocytes and mesenchymal stem cells under hypoxia and normoxia, and mechanical stimulation regimes to assess chemical structure phase changes, along with temporal and spatial localization of extra cellular matrix proteins. Finally, new knowledge will be gained from this research by contributions to the development of novel therapeutic hydrogels for cartilage tissue engineering and regeneration by improving biomaterial properties to endure under pathophysiological conditions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.