Hydrogel Delivery of Extracellular Vesicles to Treat Osteoarthritis

水凝胶递送细胞外囊泡治疗骨关节炎

• 批准号: 10631851
• 负责人: Robert L Mauck
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10631851
• 关键词: Activities of Daily Living; Address; Adrenal Cortex Hormones; Adult; Affect; Affinity; Aging; Animal Model; Area; Articular Range of Motion; Award; Behavior; Biomedical Engineering; Cartilage; Cells; Clinic; Clinical; Collaborations; Custom; Data; Defect; Degenerative polyarthritis; Development; Diffusion; Disease; Disease Progression; Encapsulated; Engineering; Engraftment; Ensure; Evaluation; FDA approved; Family suidae; Formulation; Gel; Genetic Materials; Goals; Growth Factor; Histology; Hyaluronic Acid; Hydrogels; In Situ; In Vitro; Incidence; Inflammation; Injectable; Injection of therapeutic agent; Injections; Injury; Investigation; Joints; Kinetics; Label; Lead; Magnetic Resonance Imaging; Measures; Mechanics; Mediator of activation protein; Miniature Swine; Modeling; Monitor; Motion; Motivation; Non-Steroidal Anti-Inflammatory Agents; Orthopedics; Pain; Pain-Free; Paracrine Communication; Patients; Polymers; Process; Property; Protease Inhibitor; Proteins; Regenerative Medicine; Source; Structure; Surface; Surface Properties; Surgeon; Symptoms; Syringes; System; Techniques; Therapeutic; Thinness; Time; Tissue Engineering; Tissues; Translating; Traumatic injury; Veterans; Water; Work; articular cartilage; associated symptom; base; biomaterial development; cartilage degradation; clinical application; clinically relevant; crosslink; density; disability; efficacy testing; experience; extracellular vesicles; functional outcomes; healing; in vivo; interest; knee replacement arthroplasty; mechanical force; mesenchymal stromal cell; military veteran; new technology; novel; novel therapeutics; paracrine; reconstruction; repair strategy; stem cell delivery; symptom treatment; translational model

Articular cartilage has limited intrinsic healing capacity, and as a result, any injury, as well as the natural aging process, may lead to osteoarthritis (OA). Various reconstructive techniques are being employed for treatment of focal defects; however, there are few approaches being developed to address damage across cartilage surfaces with OA and to alter the progression of the disease. Although there are therapeutic molecules that may be of interest to treat OA, their systemic application is limited due to off-target concerns and local injection has limited efficacy due to short half-lives. To address these concerns, injectable hydrogels may be used to locally delivery and sustain the release of therapeutics to the joint. The objective of this study is to develop an injectable hydrogel for the delivery of therapeutic extracellular vesicles (EVs) and to evaluate the EV/hydrogel therapy in a minipig model of OA. Two Aims will be pursued towards this goal. In Aim 1 we will use our experience in biomaterial development to engineer a shear-thinning and self-healing hydrogel based on hyaluronic acid (HA). We will use dynamic covalent crosslinks to obtain these desired properties and will encapsulate and release EVs isolated from pig mesenchymal stromal cells (MSCs). The MSC EVs will be characterized for size, surface properties, and content before and after release and the release kinetics will be monitored with fluorescent labeling from hydrogels with a range of crosslink densities. This Aim will identify one hydrogel formulation that releases EVs over several weeks that can be used for in vivo assessment in Aim 2. In Aim 2 we will test the efficacy of our engineered hydrogel therapies in an in vivo setting. Using our Yucatan minipig model of OA, we will evaluate functional outcomes (histology, MRI) after injection of our hydrogels containing EVs. This evaluation will include activity measures (steps/day) and joint range of motion using custom motion tracking systems that we previously developed. Upon completion, we will have developed an injectable hydrogel therapeutic that is applied through a simple process similar to viscosupplements to deliver therapeutics to alter the progression of disease with OA. This therapy could be translated to the clinic for treatment of the large number of OA patients in the Veteran population who have few treatment options and could limit the number of total knee replacements performed.

关节软骨的内在愈合能力有限，因此任何损伤以及 自然衰老过程，可能导致骨关节炎（OA）。各种重建技术 用于治疗局灶性缺陷；然而，方法很少 正在开发用于解决 OA 软骨表面损伤并改变 疾病的进展。尽管有一些治疗分子可能会引起人们的兴趣 治疗 OA，由于脱靶问题和局部注射，其全身应用受到限制 由于半衰期短，疗效有限。为了解决这些问题，可注射水凝胶可能是 用于局部输送和维持治疗药物向关节的释放。的目标 这项研究旨在开发一种可注射水凝胶，用于输送治疗性细胞外药物 囊泡 (EV) 并评估 EV/水凝胶疗法在小型猪 OA 模型中的作用。两个目标 将朝着这个目标不断努力。在目标 1 中，我们将利用我们在生物材料方面的经验 开发基于透明质酸的剪切稀化和自修复水凝胶 （哈）。我们将使用动态共价交联来获得这些所需的特性，并将 封装并释放从猪间充质基质细胞 (MSC) 中分离的 EV。 MSC 电动汽车在发布前后将对其尺寸、表面特性和含量进行表征 释放动力学将通过水凝胶的荧光标记进行监测 交联密度。该目标将确定一种水凝胶配方，可在超过 几周的时间可用于目标 2 中的体内评估。在目标 2 中，我们将测试 我们的工程水凝胶疗法在体内环境中的功效。使用我们的尤卡坦迷你猪 OA 模型，我们将在注射我们的药物后评估功能结果（组织学、MRI） 含有 EV 的水凝胶。该评估将包括活动测量（步数/天）和 使用我们之前开发的定制运动跟踪系统的关节运动范围。 完成后，我们将开发出一种可注射的水凝胶疗法，可应用于 通过类似于粘稠补充剂的简单过程来提供治疗以改变 OA 疾病的进展。这种疗法可以转化为临床治疗 退伍军人群体中大量 OA 患者几乎没有治疗选择 并且可能会限制膝关节置换术的总数量。