Biomaterial Implants for the Treatment of Disuse Muscle Atrophy

残疾继发于长期固定是一个主要原因的发病率和升级 VA的医疗费用。制动是许多情况的并发症（例如肢体损伤、卧床 休息）并导致骨骼肌的机械卸载。响应于机械卸载， 肌肉经历称为废用性萎缩的快速质量损失。废用性萎缩 康复期，增加了无法实现完全功能恢复的风险。当前 废用性萎缩的康复过程包括抗阻运动模式， 促进肌肉生长，但许多患有萎缩的VA患者年龄较大，过于虚弱， 顺利完成培训。无法恢复将刺激一个恶性循环， 活动和丧失流动性，影响生活质量。因此，恢复萎缩的肌肉仍然是一个 高度相关的治疗靶点。全身递送胰岛素样生长因子1（IGF-1），以及 其他因子（如瘦素和脂联素），增加肌肉质量;然而，全身递送， 受到成本、脱靶效应和患者对给药方案的依从性的阻碍。最近， 生物工程师正在解决这些问题的药物输送系统，使本地化，持续 释放治疗剂。虽然这些设备可能在某种程度上证明是成功的，但最大限度地 功能恢复可能需要更复杂的因素组合， 在生理时间尺度上的生理浓度，这是难以实现的电流 技术.为了解决这些局限性，这项工作将开发设备，工程脂肪 组织，一个容易获得的组织来源，以最理想的比例释放因子， 萎缩的肌肉生长。事实上，脂肪组织分泌的生物分子作用于全身 水平为了调节脂肪分泌组，我们开发了组织工程支架 用于使用可生物降解的聚合物聚（丙交酯-共-乙交酯）植入脂肪组织。这 材料用于FDA批准的器械，包括缝线和接骨螺钉。支架植入 小鼠内脏脂肪增加IGF-1表达。与此同时，参与肌肉的基因表达 腓肠肌中的生长被激活。这些数据激发了一个假设， 设计的支架植入脂肪后可以促进肌肉支持性分泌蛋白， 方法将增强废用性萎缩小鼠的功能恢复。拟议工作的目标1 将通过研究支架的改变来提高我们对支架功能的理解。 脂肪分泌蛋白是生物材料特异性的。这一目标也将促进支架的翻译 相关性通过确定当植入部位被植入时是否存在肌肉再生分泌蛋白质组来确定。 皮下脂肪目的2将确定是否支架植入具有萎缩肌肉的老年小鼠中， 后肢制动可促进腿部负重后的功能恢复。功能恢复是 使用计算机监测的活动笼进行定量。肌肉结构、功能和炎症将 也是复苏的指标。这种小鼠模型概括了一种常见的表现形式， 在VA中观察到多种病因的表型，并结合活动监测， 相对高通量的测试和概念研究的证明需要推进支架 技术.这种创新策略具有很高的临床翻译潜力，因为材料具有 已建立的人体安全记录和拟议的器械将是互补和添加的 目前的康复策略。这种新的方法有望改善 成千上万的患者患有废用性萎缩继发的长期残疾或面临长期残疾的风险。

Disabilities secondary to long term immobilization are a major cause of morbidity and escalating healthcare costs for the VA. Immobilization is a complication of many conditions (e.g. limb injury, bed rest) and results in mechanical unloading of skeletal muscles. In response to mechanical unloading, muscles undergo a rapid loss of mass, referred to as disuse atrophy. Disuse atrophy prolongs the rehabilitation period, increasing the risk that full functional recovery will not be achieved. The current rehabilitation course for disuse atrophy encompasses resistance exercise paradigms designed to promote muscle growth, but many VA patients with atrophy are advanced aged and too frail to successfully complete the training. The inability to rehabilitate will spur a vicious cycle of decreased activity and loss of mobility, impacting quality of life. Thus, rehabilitating atrophied muscle remains a highly relevant therapeutic target. Systemic delivery of insulin-like growth factor 1 (IGF-1), as well as other factors (e.g. leptin and adiponectin), increases muscle mass; however, systemic delivery is hindered by cost, off target effects, and patient compliance with the dosing schedule. Recently, bioengineers are addressing these issues with drug delivery systems that enable localized, sustained release of a therapeutic. While these devices may prove successful to some extent, maximal functional recovery is likely to require a more complex combination of factors delivered at physiological concentrations over physiological timescales, which is difficult to achieve with current technologies. To address these limitations, this work will develop devices to engineer the adipose tissue, a readily available tissue source, to release factors in the most ideal proportions that promote growth of atrophied muscle. Indeed, adipose tissues secrete biomolecules that act at the systemic level. In order to modulate the adipose secretome, we have developed tissue engineering scaffolds for implant into the adipose tissue using the biodegradable polymer poly(lactide-co-glycolide). This material is used in FDA approved devices including sutures and bone screws. Scaffold implant into visceral fat of mice elevates IGF-1 expression. Concurrently, gene expression involved in muscle growth is activated in the gastrocnemius. This data motivates the hypothesis that specifically designed scaffolds can promote a muscle-supportive secretome when implanted into fat and this approach will enhance functional recovery in mice with disuse atrophy. Aim 1 of the proposed work will improve our understanding of how the scaffold functions by investigating if alterations in the adipose secretome is biomaterial specific. This aim will also advance the scaffold’s translational relevance by determining if a muscle regenerative secretome exists when the implant site is subcutaneous fat. Aim 2 will determine if scaffold implant in aged mice with atrophied muscle from hindlimb immobilization enhances functional recovery after the leg is reloaded. Functional recovery is quantified using computer monitored activity cages. Muscle structure, function, and inflammation will also serve as indices of recovery. This mouse model recapitulates a common presentation and phenotype of multiple etiologies seen in the VA and, combined with activity monitoring, allows for relatively high throughput testing and proof of concept studies needed to advance the scaffold technology. This innovative strategy has high potential for clinical translation as the materials have an established safety record in humans and the proposed devices would be complementary and additive to current rehabilitation strategies. This novel approach is expected to improve the rehabilitation of hundreds of thousands of patients with, or at risk for long-term disability secondary to disuse atrophy.