Biomaterial Implants for the Treatment of Disuse Muscle Atrophy

用于治疗废用性肌肉萎缩的生物材料植入物

基本信息

批准号：
10476990
负责人：
Robert Michael Gower
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10476990
关键词：
Activities of Daily Living Address Adipose tissue Affect Aging Atrophic Basal metabolic rate Bed Occupancy Bed rest Biocompatible Materials Biomedical Engineering Blast Injuries Body fat Bone Screws Chronic Disease Complement Complex Complication Data Device Designs Devices Disuse Atrophy Dose Drug Delivery Systems Elderly Engineering Etiology Exercise FDA approved Fatty acid glycerol esters Formulation Foundations Fracture Frequencies Gastrocnemius Muscle Gene Expression Glycolic-Lactic Acid Polyester Goals Growth Growth Factor Health Care Costs Healthcare Systems Hindlimb Hindlimb Suspension Home Hospitalization Hospitals Human Immobilization Impairment Implant Individual Inflammation Injury Innovative Therapy Insulin Resistance Insulin-Like Growth Factor I Lead Leg Leptin Life Limb structure Location Mechanics Metabolism Minor Monitor Morbidity - disease rate Mus Muscle Muscle function Muscular Atrophy Nutritional Support Outcome Pain Patients Phenotype Physical therapy Physiological Process Production Quality of life Recovery Recovery of Function Rehabilitation therapy Research Risk Safety Schedule Secondary to Site Skeletal Muscle Skin Source Spinal cord injury Supervision Surgical sutures Technology Testing Therapeutic Time Tissue Engineering Tissues Training Trauma Visceral fat Work adipokines adiponectin aged biodegradable polymer biomaterial compatibility clinical translation compliance behavior computer monitor cost design disability functional disability functional loss implantable device improved indexing injury recovery innovation limb injury mouse model multiplex assay muscle form muscle metabolism muscular structure novel novel strategies physically handicapped polycaprolactone reduced muscle strength regenerative rehabilitation strategy release factor resistance exercise response sarcopenia scaffold skeletal muscle wasting skeletal unloading strength training subcutaneous synergism therapeutic target

项目摘要

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.

长期固定的残疾是发病率和升级的主要原因 VA的医疗保健费用。固定是许多条件的并发症（例如，肢体损伤，床休息），并导致骨骼肌的机械卸载。响应机械卸载，肌肉会迅速丧失肿块，被称为废除萎缩。废除萎缩可以延长康复期，增加将无法实现全功能恢复的风险。电流废除萎缩的康复课程包括抗抵抗运动范式促进肌肉生长，但许多萎缩率的VA患者已经衰老，过于脆弱，无法成功完成培训。无法康复将刺激恶性循环活动和流动性丧失，影响生活质量。那，康复的萎缩肌肉仍然是高度相关的治疗靶点。胰岛素样生长因子1（IGF-1）的全身传递以及其他因素（例如瘦素和脂联素）增加肌肉质量；但是，全身交付是受到成本，关闭目标效果和患者遵守给药时间表的阻碍。最近，生物工程师正在通过药物输送系统来解决这些问题，这些问题使局部，持续释放疗法。尽管这些设备可能在某种程度上成功，但最大功能恢复可能需要更复杂的组合在物理时间尺度上的生理浓度，当前很难实现技术。为了解决这些限制，这项工作将开发以设计脂肪的设备组织是一种易于使用的组织来源，以最理想的比例释放因子萎缩肌肉的生长。实际上，脂肪时机在系统性上作用的秘密生物分子等级。为了调节脂肪秘密，我们开发了组织工程脚手架使用可生物降解的聚合物聚（乳酸 - 糖苷）植入脂肪组织中。这材料用于FDA认可的设备，包括缝合线和骨螺钉。脚手架植入小鼠的内脏脂肪升高IGF-1表达。同时，肌肉中涉及的基因表达在胃病中激活生长。该数据激发了以下假设当植入脂肪中时，设计的脚手架可以促进肌肉支持的分泌组方法将增强残疾萎缩小鼠的功能恢复。拟议工作的目标1 将通过研究是否在脂肪分泌组为生物材料特异性。这个目标还将推动脚手架的翻译通过确定植入物位置时是否存在肌肉再生性分泌物的相关性皮下脂肪。 AIM 2将确定在老年小鼠的脚手架植入物中是否具有萎缩的肌肉固定后，固定化可以增强腿后的功能恢复。功能恢复是使用计算机监控的活动笼进行量化。肌肉结构，功能和炎症将也是恢复指标。该鼠标模型概括了常见的表现和在VA中看到的多种病因的表型，并结合活动监测，允许相关的高吞吐量测试和概念研究证明，以推动脚手架技术。这种创新策略具有临床翻译的高潜力，因为材料具有在人类和拟议的设备中建立的安全记录将是完整的和附加的目前的康复策略。这种新颖的方法有望改善成千上万的患者患有或有长期残疾的危险，继发于萎缩。