Biomaterial Implants for the Treatment of Disuse Muscle Atrophy

长期制动后继发的残疾是发病率上升的主要原因。 退伍军人管理局的医疗费用。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， 肌肉会迅速失去质量，这就是所谓的废用性萎缩。废用性萎缩延长 康复期，增加了无法实现完全功能恢复的风险。海流 废用性萎缩的康复课程包括旨在 促进肌肉生长，但许多退伍军人退化症患者年事已高，身体虚弱，无法 顺利完成培训。不能恢复将会刺激一种恶性循环 活动和丧失行动能力，影响生活质量。因此，恢复萎缩的肌肉仍然是一种 高度相关的治疗靶点。胰岛素样生长因子1(IGF-1)的系统递送，以及 其他因素(如瘦素和脂联素)会增加肌肉质量；然而，全身分娩是 受制于成本、偏离目标的影响和患者对剂量计划的遵守情况。最近， 生物工程师正在用药物输送系统来解决这些问题，这种系统能够使本地化、可持续 释放一种治疗药物。虽然这些设备可能在某种程度上被证明是成功的，但最大的 功能恢复可能需要更复杂的因素组合才能实现 生理时间尺度上的生理集中，这是用电流很难实现的 技术。为了解决这些限制，这项工作将开发出设计脂肪的设备 组织，一种容易获得的组织来源，以最理想的比例释放促进 萎缩肌肉的生长。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聚合物聚(丙交酯-乙交酯)植入脂肪组织。这 材料用于FDA批准的设备，包括缝合线和骨螺钉。脚手架植入 小鼠内脏脂肪可促进IGF-1的表达。同时，涉及肌肉的基因表达 腓肠肌的生长是激活的。这一数据激发了一种假设，即 设计的支架可以促进肌肉支持的分泌体植入脂肪中，这 该方法可促进废用性萎缩小鼠的功能恢复。拟议工作的目标1 将通过研究支架的变化来提高我们对支架如何工作的理解 脂肪分泌组是生物材料特有的。这一目标也将推动脚手架的翻译 通过确定植入部位是否存在肌肉再生分泌组的相关性 皮下脂肪。目标2将确定支架植入老年小鼠的肌肉萎缩是否来自 后肢制动可增强腿部重载后的功能恢复。功能恢复是 使用计算机监控的活动笼子进行量化。肌肉的结构、功能和炎症将 也可以作为经济复苏的指标。此鼠标模型概括了一个常见的演示文稿和 VA中可见的多种病因的表型，结合活动监测，允许 推进脚手架所需的相对较高的吞吐量测试和概念验证研究 技术这一创新策略在临床翻译中具有很高的潜力，因为材料具有 已建立的人体安全记录和拟议的设备将是互补和相加的 到目前的康复策略。这一新的方法有望改善老年人的康复 数十万患有或有长期残疾风险的患者继发于废用萎缩。

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.