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

具有可调应力松弛和活动能力的水凝胶可增强关节软骨再生

• 批准号: 10750831
• 负责人: SARAH JANE JONES
• 金额: $ 4.77万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2026-09-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750831
• 关键词: 3-Dimensional; Acceleration; Acute; Alginates; Animal Model; Behavior; Biochemical; Biocompatible Materials; Biological Assay; Biological Models; Breathing; Calcium; Cartilage; Catabolic Process; Cell Volumes; Cells; Cellularity; Chemicals; Chondrocytes; Chondrogenesis; Clinical; Cues; Cyclodextrins; Data; Defect; Degenerative polyarthritis; Deposition; Disease; Doctor of Philosophy; Dose; Elasticity; Exhibits; Faculty; Histology; Hydrogels; Image; Imaging Device; In Vitro; Individual; Injectable; Injury; Knowledge; Life; Ligands; Medical Imaging; Mentors; Mentorship; Mesenchymal Stem Cells; Methods; Modeling; Morbidity - disease rate; Natural regeneration; Optical Coherence Tomography; Outcome; Patients; Polymer Chemistry; Polymers; Positioning Attribute; Procedures; Production; Property; Quality of life; Rattus; Relaxation; Reporting; Risk; Scientist; Signal Transduction; Site; Slide; Speed; Stress; Structure; System; Testing; Time; Tissue Engineering; Tissues; Translations; Vertebral column; Work; animal imaging; articular cartilage; cartilage regeneration; cartilage repair; covalent bond; crosslink; design; efficacy validation; experimental study; hydrogel scaffold; improved; improved mobility; in vivo; in vivo regeneration; innovation; mechanotransduction; minimally invasive; novel; osteochondral tissue; prevent; regenerative therapy; repaired; response; self-renewal; stem cell delivery; stem cell niche; stem cells; tool; viscoelasticity

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.

关节软骨的急性损伤很常见，并且可能会大大增加个人发展的风险 骨关节炎，但仍缺乏有效的再生疗法。软骨的自我能力有限 软骨维修的一种承诺策略是使用 间充质干细胞（MSC）。可注射的水凝胶载体特别需要MSC输送 它们可以在微创程序中应用于软骨缺陷。水凝胶设计可以灵感来自 天然软骨组织特性，例如刚度和生化配体，已广泛研究 在3D中的MSC软骨形成的背景下。软骨也是粘弹性的，表明应力松弛 响应应用应力的行为。使用藻酸盐水凝胶作为模型系统，最近它是 表明，更快的应力 - 浮肿可增强基于软骨细胞的软骨产生。但是，路 粘弹性调节基于MSC的软骨再生仍然未知。 我们的实验室以前已经报道了具有移动交联的滑动水凝胶（SG），可以沿着PEG滑动 聚合物主链，与非摩托相比，3D的MSC软骨发生显着加速了 共价交联的水凝胶。与藻酸盐水凝胶不同，SG通过不可逆的共价键交联 并且不存在压力放松。根据SG和藻酸盐氢系统的先前发现， 我假设将粘弹性引入SG将进一步加速基于MSC的软骨再生 通过增强的体外和体内机械转导的剂量依赖性方式。为了检验这一假设， 我建议：（1）以可调的应力放松为 通过动态交联的结合结构的3D干细胞生态位； （2）评估压力放松的影响 在体外MSC软骨发生的ASG中，通过表征来阐明基本机制 机械转导信号传导； （3）在加速度中以优化的应力松弛验证ASG的效率 使用大鼠骨软骨缺损模型在体内基于MSC的软骨再生。与藻酸盐相比 水凝胶是一种基于PEG的ASG的水凝胶，是一个更清洁的系统，它为具有高度控制的细分市场提供了细胞 提示。结果将填补有关粘弹性如何影响MSC的知识的关键差距 3D和先驱的软骨发生，具有软骨的粘弹性动态水凝胶的体内翻译 再生。我将由具有完善专业知识的基础和临床科学家团队的组成 生物材料和组织工程，聚合物化学，机械转导，成像和动物模型。 结果将填补有关粘弹性影响MSC软骨发生方式的知识的关键空白 在3D和验证适应性滑水凝胶作为加速基于MSC软骨的新生物材料中 再生。