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，任何伤害以及 自然衰老过程可能导致骨关节炎（OA）。各种重建技术 正在用于治疗局灶性缺陷；但是，方法很少 开发以解决使用OA跨软骨表面的损坏并改变 疾病的进展。尽管有治疗分子可能感兴趣 治疗OA，由于脱离目标的问题，他们的系统应用受到限制，局部注射已有 由于半衰期短，有限的功效。为了解决这些问题，可注射的水凝胶可能是 用于局部交付并维持将治疗剂释放到关节中。目的 这项研究是开发一种可注射的水凝胶，用于提供细胞外的治疗性水凝胶 囊泡（EV）并评估OA的Minipig模型中的EV/水凝胶治疗。两个目标 将追求这个目标。在AIM 1中，我们将利用生物材料的经验 开发基于透明质酸的剪切稀释和自我修复水凝胶 （哈）。我们将使用动态共价交联获得这些所需的属性，将会 封装并释放从猪间充质基质细胞（MSC）中分离出的EV。 MSC 电动汽车将以尺寸，表面特性和释放前后的内容为特征 并且将使用来自具有范围的水凝胶的荧光标记来监测释放动力学 交联密度。这个目标将确定一种水凝胶配方，可释放电动汽车 可以在AIM 2中用于体内评估的几周。在AIM 2中，我们将测试 我们工程水凝胶疗法在体内环境中的功效。使用我们的Yucatan Minipig OA的模型，我们将评估注入我们的功能结果（组织学，MRI） 含有电动汽车的水凝胶。该评估将包括活动措施（步骤/天）和 我们先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应用的注射水凝胶治疗性 通过与Viscosupplements类似的简单过程，以提供治疗剂以改变 OA的疾病进展。该疗法可以转化为诊所以进行治疗 资深人口中的大量OA患者几乎没有治疗选择 并可能限制执行的总膝盖替代者的数量。