Hydrogel Delivery of Extracellular Vesicles to Treat Osteoarthritis

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，可能会导致骨关节炎(OA)。各种重建技术 正被用于治疗局灶性缺陷；然而，几乎没有方法 正在开发，以解决跨软骨表面的损伤与骨关节炎，并改变 疾病的发展。尽管有一些治疗分子可能会对 治疗骨性关节炎，由于非靶点的考虑和局部注射，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到关节的释放。的目标是 本研究旨在开发一种可注射的水凝胶，用于治疗细胞外药物的释放。 并在小型猪骨性关节炎模型中评价EV/水凝胶疗法。两个目标 将朝着这一目标努力。在目标1中，我们将利用我们在生物材料方面的经验 基于透明质酸的工程剪切变稀自愈水凝胶的研制 (HA)。我们将使用动态共价交联来获得这些所需的属性，并将 包裹并释放从猪间充质基质细胞(MSCs)分离的EVS。海事局 电动汽车将在发布前后对尺寸、表面属性和内容进行表征 释放动力学将通过水凝胶的荧光标记进行监测 交联剂的密度。这一目标将确定一种释放电动汽车的水凝胶配方 目标2中可用于体内评估的几周。在目标2中，我们将测试 我们的工程水凝胶疗法在活体环境中的有效性。用我们的尤卡坦小型猪 我们将评估注射OUR后的功能结果(组织学、MRI)。 含有电动汽车的水凝胶。这项评价将包括活动措施(步骤/天)和 使用我们先前开发的自定义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水凝胶疗法，并应用于 通过一个类似粘性补充的简单过程来提供治疗药物来改变 随着骨性关节炎的疾病进展。这种疗法可以移植到临床上用于治疗 退伍军人群体中的大量OA患者几乎没有治疗选择 并可能限制进行膝关节置换的总次数。

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.