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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.

继发于长期固定的残疾是发病和不断升级的主要原因