Matrix-reinforcing and cell-instructive smart hydrogel for cartilage preservation

用于软骨保存的基质强化和细胞指导智能水凝胶

• 批准号: 10543437
• 负责人: Jay M Patel
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543437
• 关键词: Actins; Affect; Aftercare; Anabolism; Anti-Inflammatory Agents; Articulation; Behavior; Biochemical; Biocompatible Materials; Biophysics; Cartilage; Cartilage injury; Catabolism; Cells; Chemicals; Chondrocytes; Coupled; Cues; Cytoskeletal Modeling; Cytoskeleton; Defect; Degenerative polyarthritis; Deposition; Deterioration; Environment; Equilibrium; Exhibits; Feedback; Formulation; Genotype; Goals; Growth Factor; Health; Homeostasis; Hyaluronic Acid; Hydrogels; In Vitro; Inflammation; Inflammatory; Injury; Instruction; Interleukin-1 Receptors; Intra-Articular Injections; Joints; Knowledge; Lead; Libraries; MADH2 gene; MAP Kinase Gene; Mechanics; Mentors; Miniature Swine; Modeling; Molecular Biology Techniques; Morphology; Nature; Outcome; Pain; Palliative Care; Pathway interactions; Penetration; Peptides; Phenotype; Positioning Attribute; Predisposition; Process; Production; Property; Psychological reinforcement; Quality of life; Regulation; Rehabilitation therapy; Replacement Arthroplasty; Research; Route; Services; Shapes; Signal Transduction; Site; Steroids; Structure; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Thick; Time; Tissue Preservation; Tissues; Training; Trauma; Up-Regulation; Veterans; Work; active duty; antagonist; articular cartilage; biomechanical test; career; cartilage cell; cartilage degradation; cell behavior; crosslink; cytokine; experience; fortification; improved; in vivo; inflammatory milieu; injured; innovation; knee replacement arthroplasty; mechanotransduction; military veteran; multimodality; novel; novel therapeutic intervention; peptidomimetics; preservation; prevent; response; skills; tissue degeneration; transmission process

Cartilage damage is extremely common in the active-duty and Veteran populations, both by trauma and wear- and-tear. These initial injuries compromise the biophysical and biochemical environment around cells, characterized by softening of the surrounding microenvironment and production of pro-inflammatory cytokines. The softer cellular microenvironment leads to volumetric and morphological changes of the cartilage cells, or chondrocytes, and the pro-inflammatory signaling leads to the continued degradation of the surrounding matrix. Combined, these early degenerative changes lead to aberrant cell behavior and a vicious deteriorative process, leading to progressive cartilage wear with time and culminating in osteoarthritis (OA). OA is a significant burden on the Veteran population, causing pain, discomfort, and reduced quality of life. Halting the degenerative process early in its progression, by specifically rehabilitating the cell and its surrounding environment, represents an impactful and innovative approach to preventing or delaying the onset of OA. Thus, the overarching goal of this proposal is to utilize a novel hyaluronic acid (HA) hydrogel system to both fortify damaged cartilage tissue and provide persistent presentation of inflammation-inhibiting peptides, all with the goal of preventing the progression of OA. This goal will be tested with the following specific aims: Aim 1: Determine the restorative effect of PCM fortification on chondrocyte cytoskeletal organization and mechano-transduction. First, a library of HA formulations and applications will be developed and tested on damaged cartilage tissue to achieve 3-4 levels of PCM fortification. Then, in a cartilage explant culture model, the impact of fortification on chondrocyte volume regulation, morphology, cytoskeletal composition and organization, and mechano-transductive properties will be determined and compared to healthy cells. Aim 2: Establish whether the combination of PCM fortification and persistent inflammatory inhibition prevents catabolism and restores chondrocyte homeostasis. HA will be conjugated with cell-instructive peptides that mimic an active sequence of IL-1 receptor antagonist (inhibits inflammation). In cartilage explants, the relative effects of fortification and inflammatory-inhibiting peptide, and their combination, will be tested on inflammatory cytokine release, matrix breakdown and loss, and matrix synthesis. Specifically, focus will be maintained on restoring the balance of matrix synthesis and deposition (anabolism) with degradation (catabolism). Aim 3: Evaluate the in vivo therapeutic effect of combined reinforcement and anti-inflammatory peptide presentation on cartilage deterioration. In a Yucatan minipig model, partial-thickness defects will be treated with fortification or a combination of fortification and anti-inflammatory peptide. Functional multi-scale biomechanical testing and matrix retention and quality will be assessed at 1- and 3-months post-treatment, to characterize whether early markers of cartilage deterioration were prevented or reduced. This research will enhance knowledge and understanding of the early degenerative changes to chondrocytes and their surrounding matrix, and directly develops a novel therapeutic strategy to mechanically stabilize cartilage and deliver cell-instructive cues to prevent, or even reverse, aberrant chondrocyte behavior. Furthermore, the multi-scale, multi-modal nature of the proposed work uses these cell-level outcomes to drive tissue-scale function and rehabilitation. Such a therapy would be monumental in the cartilage injury and osteoarthritis treatment in the Veteran population, improving activity levels and quality of life, and delaying or preventing the need for total joint replacement. Finally, the proposed CDA-2 research combined with the proposed mentoring and training plan, will allow Dr. Patel to acquire a plethora of new skills and knowledge, and position him well for a transition to a successful VA-based, independent research career.

软骨损伤在现役军人和退伍军人中非常常见，既有创伤，也有磨损。 还有-眼泪。这些最初的损伤损害了细胞周围的生物物理和生化环境， 以周围微环境的软化和促炎细胞因子的产生为特征。 较软的细胞微环境导致软骨细胞体积和形态的变化，或 软骨细胞和促炎信号导致周围基质的持续降解。 结合起来，这些早期的退化变化会导致细胞行为异常和恶性的退化过程， 导致软骨随着时间的推移而逐渐磨损，最终导致骨关节炎(OA)。办公自动化是一个沉重的负担 对退伍军人群体造成痛苦、不适和生活质量下降。停止退化过程 在其发展的早期，通过专门恢复细胞及其周围环境，代表了一种 预防或延缓骨性关节炎发病的有效和创新的方法。因此，这一计划的首要目标是 建议利用一种新型的透明质酸(HA)水凝胶系统来加固受损的软骨组织和 提供持续的炎症抑制多肽，所有的目的都是为了防止进展 对于办公自动化来说。这一目标将通过以下具体目标进行测试： 目的1：测定强化PCM对软骨细胞骨架组织的修复作用。 机械转导。首先，将开发和测试HA配方和应用程序库 受损软骨组织达到3-4级PCM加固。然后，在软骨移植培养模型中， 强化对软骨细胞体积调节、形态、细胞骨架组成及功能的影响 组织和机械传导特性将被确定，并与健康细胞进行比较。 目的2：确定强化PCM和持续的炎症抑制相结合是否可以防止 分解新陈代谢，恢复软骨细胞动态平衡。HA将与模拟细胞的指示多肽偶联 IL-1受体拮抗剂的活性序列(抑制炎症)。在软骨移植中，相对的影响 增强剂和炎性抑制肽及其组合将在炎性细胞因子上进行测试 释放、基质分解和损失以及基质合成。具体而言，将继续把重点放在恢复 基质合成和沉积(合成代谢)与降解(分解代谢)的平衡。 目的3：评价补益联合抗炎肽的体内治疗效果 表现为软骨退化。在尤卡坦小型猪模型中，部分厚度缺陷将被 防御剂或防御剂和抗炎肽的组合。功能多尺度生物力学 检测和基质保留和质量将在治疗后1个月和3个月进行评估，以确定 软骨退化的早期标志是否被预防或减少。 这项研究将增进对软骨细胞早期退行性变化的认识和理解 及其周围基质，并直接开发出一种新的治疗策略，以机械稳定 并提供细胞指导信号，以防止甚至逆转软骨细胞的异常行为。 此外，拟议工作的多尺度、多模式性质使用这些单元级结果来推动 组织尺度功能和康复。这种疗法对软骨损伤和 退伍军人中的骨关节炎治疗，改善活动水平和生活质量，并延迟或 避免了完全关节置换的需要。最后，拟议的CDA-2研究结合了 拟议的指导和培训计划，将使Patel博士获得过多的新技能和知识，以及 为他过渡到以退伍军人事务部为基础的成功的独立研究生涯做好准备。