Hydrogels with Tunable Stress Relaxation and Mobility for Enhancing Articular Cartilage Regeneration

关节软骨的急性损伤是常见的，并且可以显著增加个体发展成关节炎的风险。 骨关节炎，但仍然缺乏有效的再生疗法。Carbohydrate有一个有限的自我能力- 由于低细胞性和缺乏脉管系统而导致的再生。软骨修复的一个有前途的策略是使用 间充质干细胞（MSCs）可注射的水凝胶载体对于MSC递送是特别理想的， 它们可以在微创手术中应用于软骨缺损。水凝胶设计的灵感来自于 天然软骨组织特性，如硬度和生化配体，已被广泛研究 in the context背景of MSC软骨genesis生成in 3D.软骨也是粘弹性的，表明应力松弛 对施加压力的反应。使用藻酸盐水凝胶作为模型系统， 显示更快的应力松弛增强了基于软骨细胞的软骨产生。然而， 粘弹性调节基于MSC的软骨再生在很大程度上仍是未知的。 我们的实验室以前曾报道过滑动水凝胶（SG）与移动的交联，可以滑动沿着PEG 聚合物骨架，与非移动相比，其在3D中显著加速MSC软骨形成， 共价交联的水凝胶。与藻酸盐水凝胶不同，SG通过不可逆共价键交联 并且不表现出应力松弛。基于先前在SG和藻酸盐水凝胶系统中的发现， 我推测，将粘弹性引入SG将进一步加速基于MSC的软骨再生 在体外和体内通过增强的机械转导以剂量依赖性的方式。为了验证这个假设， 我建议：（1）开发和表征具有可调应力松弛的自适应滑动水凝胶（ASG）， 通过动态交联的掺入形成3D干细胞龛;（2）评估应力松弛的效果 在ASG对MSC软骨形成的体外研究中， （3）通过优化应力松弛来验证ASG在加速机械传导信号传导中的功效。 使用大鼠骨软骨缺损模型的基于MSC的体内软骨再生。与海藻酸盐相比 基于PEG的ASG是一种更清洁的系统，可为细胞提供高度受控的生态位 线索这些结果将填补粘弹性影响MSC的方式方面的知识空白 3D软骨形成，开创了具有粘弹性的动态水凝胶在软骨中的体内翻译 再生我将由一个基础和临床科学家团队指导，他们在以下方面具有互补的专业知识： 生物材料和组织工程，高分子化学，机械传导，成像和动物模型。的 结果将填补粘弹性影响MSC软骨形成的知识的关键空白， 在3D和验证适应性滑动水凝胶作为一种新的生物材料，加速MSC为基础的软骨 再生

Acute injury to articular cartilage is common and can significantly increase an individual’s risk for developing osteoarthritis, yet effective regenerative therapies remain lacking. Cartilage has a limited capacity for self- regeneration due to low cellularity and lack of vasculature. One promising strategy for cartilage repair is the use of mesenchymal stem cells (MSCs). Injectable hydrogel carriers are particularly desirable for MSC delivery as they can be applied to cartilage defects in minimally invasive procedures. Hydrogel design can be inspired by native cartilage tissue properties such as stiffness and biochemical ligands, which have been extensively studied in the context of MSC chondrogenesis in 3D. Cartilage is also viscoelastic, demonstrating stress relaxation behavior in response to applied stresses. Using alginate hydrogels as a model system, it has been recently shown that faster stress-relaxation enhances chondrocyte-based cartilage production. However, the way viscoelasticity modulates MSC-based cartilage regeneration remains largely unknown. Our lab has previously reported sliding hydrogels (SG) with mobile crosslinks that can slide along the PEG polymer backbone, which significantly accelerated MSC chondrogenesis in 3D compared to non-mobile, covalently crosslinked hydrogels. Unlike alginate hydrogels, SG is crosslinked by irreversible covalent bonds and does not exhibit stress relaxation. Based on previous findings in both the SG and alginate hydrogel systems, I hypothesize that introducing viscoelasticity to SG would further accelerate MSC-based cartilage regeneration in a dose-dependent manner through enhanced mechanotransduction in vitro and in vivo. To test this hypothesis, I propose to: (1) Develop and characterize adaptable sliding hydrogels (ASG) with tunable stress relaxation as a 3D stem cell niche through the incorporation of dynamic crosslinks; (2) Evaluate the effect of stress relaxation in ASG on MSC chondrogenesis in vitro and elucidate the underlying mechanisms by characterizing mechanotransduction signaling; (3) Validate the efficacy of ASG with optimized stress relaxation in accelerating MSC-based cartilage regeneration in vivo using a rat osteochondral defect model. Compared to alginate hydrogels, the proposed PEG-based ASG is a cleaner system that presents cells with highly controlled niche cues. The outcomes will fill a critical gap in knowledge about the way viscoelasticity influences MSC chondrogenesis in 3D and pioneer the in vivo translation of dynamic hydrogels with viscoelasticity for cartilage regeneration. I will be mentored by a team of basic and clinical scientists with complementary expertise in biomaterials and tissue engineering, polymer chemistry, mechanotransduction, imaging and animal models. The outcomes will fill a critical gap in knowledge about the way that viscoelasticity influences MSC chondrogenesis in 3D and validate adaptable sliding hydrogels as a new biomaterial for accelerating MSC-based cartilage regeneration.