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; 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 创伤后的肘部签发是一种令人衰弱的并发症，其特征是固定性，由 关节囊的增厚和僵硬。当签发不进行手术囊膜释放 应对非手术干预。然而，囊状释放通常只会改善（但不正常） 肘部运动范围。此外，额外的纤维化和收缩经常出现，所有这些都需要 需要制定更好的治疗策略。创伤后肘部闭合的关节胶囊有 发现包含表达α平滑肌肌动蛋白（α-SMA）的活化的肌纤维细胞并增加 胶原蛋白沉积。在其他伤口愈合的情况下，肌纤维细胞在ECM上施加收缩力和 以机械力和生化因子的一部分调节胶原蛋白的合成胶原蛋白 伤口和周围。这些成分与相互和动态的肌纤维细胞相互作用 方式，使伤口愈合作为一种机械化学反馈回路进行，以两种方式解决 正常或病理康复。我们假设此反馈循环也在受伤的关节中运行 胶囊并有助于胶囊增厚和染色。我们的策略是通过 暂时阻止Nmmii-actin的互动，因此肌纤维细胞产生和感觉力的能力 在伤口愈合期间的关键点通过将药物泡泡蛋白（或其衍生物）传递到伤口部位 聚（乳酸 - 乙酰乳酸）（PLGA）颗粒。该项目的两个主要目标集中于开发 对关节胶囊中反馈回路的机械理解，并评估使用小的可行性 分子中断此反馈回路并减少/消除纤维化和染色。在AIM 1中，我们将表演 一系列的体外实验，我们比较了blebbistatin和para-nitroblebbistatin plga粒子 组成和释放动力学以重塑结果，例如肌纤维细胞激活，力产生， 肌纤维细胞激活，胶原蛋白产生和ECM重塑/组织刚度。在AIM 2中，我们将测试 布莱比抗抑素或para-nitroblebistatin的能力减轻关节囊增厚/僵硬，染色和 肘关节合同的验证大鼠模型中的纤维化。我们设想对NMMII活性的抑制 Blebbistatin/para-Blebbistatin可以辅助地用于胶囊释放手术。我们假设 药物释放的释放将调节肌纤维细胞行为，以便更正常的愈合和更大的愈合 维持术后ROM的收益。这里获得的知识也将对其他 关节（例如膝盖，脚踝，手指）和纤维化条件。