Preventing Recurrent Capsular Contracture in Traumatic Elbow Injuries

预防肘部外伤中复发性包膜挛缩

• 批准号: 9891331
• 负责人: EDWARD A SANDER
• 金额: $ 16.46万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891331
• 关键词: Actins; Actomyosin; Adherens Junction; Adopted; Affect; Animal Model; Animals; Ankle; Articular Range of Motion; Behavior; Biochemical; Bioreactors; Bone Tissue; Cell Membrane Permeability; Cellularity; Chemicals; Clinical; Collagen; Complex; Complication; Contracts; Contracture; Cues; Cytoskeleton; Data; Deposition; Dose; Elbow; Elbow Injury; Elbow joint structure; Extracellular Matrix; Feedback; Fibroblasts; Fibrosis; Fingers; Generations; Human; In Vitro; Injectable; Injections; Injury; Intercellular Junctions; Interruption; Intervention; Joint Capsule; Joints; Kinetics; Knee; Knowledge; Length; Mechanics; Microfilaments; Minor; Modeling; Myofibroblast; Myosin Type II; Normal Range; Operative Surgical Procedures; Outcome; Outcome Study; Pathologic; Patients; Pharmaceutical Preparations; Physical therapy; Postoperative Period; Prevention; Preventive measure; Process; Production; Rattus; Recurrence; Risk; Safety; Series; Site; Smooth Muscle Actin Staining Method; Soft Tissue Injuries; Splint Device; System; Testing; Tissues; Trauma; Treatment Effectiveness; Wound models; base; blebbistatin; capsule; controlled release; cost; efficacy testing; experimental study; healing; improved; in vitro Model; inhibitor/antagonist; joint injury; joint mobilization; joint stiffness; mechanical force; non-muscle myosin; particle; poly(lactide); prevent; response; small molecule; small molecule inhibitor; treatment effect; treatment strategy; wound; wound healing

PROJECT SUMMARY/ABSTRACT Post-traumatic elbow contracture is a debilitating complication characterized by joint immobility and caused by thickening and stiffening of the joint capsule. Surgical capsular release is performed when contractures do not respond to nonsurgical intervention. Capsular release, however, generally only improves (but not normalize) elbow range of motion. Furthermore, additional fibrosis and contraction often recurs, all of which necessitates the need to develop better treatment strategies. Joint capsules from post-traumatic elbow contractures have been found to contain activated myofibroblasts expressing alpha smooth muscle actin (α-SMA) and increased collagen deposition. In other wound healing scenarios, myofibroblasts exert contractile forces on the ECM and synthesize collagen in a manner that is modulated in part by mechanical forces and biochemical factors present in and around the wound. These components interact with the myofibroblasts in a reciprocal and dynamic manner, such that wound healing proceeds as a mechano-chemical feedback loop that resolves with either normal or pathological healing. We hypothesize that this feedback loop is also operational in the injured joint capsule and contributes to capsule thickening and contracture. Our strategy is to interrupt this feedback loop by temporarily blocking NMMII-actin engagement, and thus the ability of myofibroblasts to generate and sense force at critical points during wound healing by delivering the drug blebbistatin (or its derivatives) to the wound site via poly(lactide-co-gylcolide) (PLGA) particles. This project has two major aims that are centered on developing a mechanistic understanding of the feedback loop in the joint capsule and assessing the feasibility of using small molecules to interrupt this feedback loop and reduce/eliminate fibrosis and contracture. In aim 1, we will perform a series of in vitro experiments where we compare blebbistatin and para-nitroblebbistatin PLGA particle compositions and release kinetics to remodeling outcomes, such as myofibroblast activation, force generation, myofibroblast activation, collagen production, and ECM remodeling/tissue stiffness. In aim 2, we will test the ability of blebbistatin or para-nitroblebbistatin to mitigate joint capsule thickening/stiffening, contracture, and fibrosis in a validated rat model of elbow joint contracture. We envision that inhibition of NMMII activity with blebbistatin/para-blebbistatin can be used adjunctively to capsule release surgery. We hypothesize that the controlled-release of drug will temper myofibroblast behavior so that more normal healing follows and larger gains in post-operative ROM are maintained. The knowledge gained here will also have implications for other joints (e.g., knee, ankle, finger) and fibrotic conditions.

项目摘要/摘要 创伤性肘关节挛缩症是一种衰弱的并发症，其特征是关节不能活动，由 关节囊增厚、僵硬。当肌挛缩不发生时，施行手术包膜松解术 对非手术干预有反应。然而，胶囊释放通常只会改善(但不会正常化) 肘关节的运动范围。此外，更多的纤维化和收缩经常复发，所有这些都是必要的 需要制定更好的治疗策略。创伤性肘关节痉挛的关节囊有 已发现含有表达α-平滑肌肌动蛋白(α-SMA)的激活的肌成纤维细胞，并增加 胶原蛋白沉积。在其他伤口愈合方案中，肌成纤维细胞对ECM施加收缩力量，并 以一种部分受机械力和存在的生化因素调节的方式合成胶原 在伤口内和伤口周围。这些成分与肌成纤维细胞相互作用，相互作用，相互作用。 以这种方式，伤口愈合就像机械力-化学反馈循环一样进行，它可以解决 正常愈合或病理性愈合。我们假设这个反馈环在受伤的关节中也是可操作的。 包膜，有助于包膜增厚和收缩。我们的策略是通过以下方式中断反馈循环 暂时阻止NMMII-肌动蛋白的参与，从而阻止肌成纤维细胞产生和感知力的能力 在伤口愈合过程中的临界点，通过以下途径将药物blbbistatin(或其衍生物)输送到伤口部位 聚(丙交酯-乙交酯)(PLGA)微粒。该项目有两个主要目标，主要是开发一个 了解关节囊内反馈环的机理，并评估使用Small的可行性 分子中断这一反馈循环，减少/消除纤维化和肌挛缩。在目标1中，我们将表演 一系列的体外实验，我们比较了白球抑素和对亚硝酸白球白斑抑素PLGA颗粒 成分和释放动力学对重塑结果的影响，如肌成纤维细胞的激活，力的产生， 肌成纤维细胞激活、胶原生成和细胞外基质重塑/组织僵硬。在目标2中，我们将测试 可减轻关节囊增厚/僵硬、肌挛缩和 肘关节挛缩症大鼠模型中的纤维化。我们设想，通过抑制NMMII活性 泡抑素/类泡抑素可作为胶囊释放手术的辅助用药。我们假设 药物的控释将缓和肌成纤维细胞的行为，从而使更多的正常愈合随之而来，更大 术后活动度的增加保持不变。在这里获得的知识也将对其他 关节(如膝盖、脚踝、手指)和纤维性疾病。