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.
When mobility is limited, such as during severe illness or injury, muscles undergo a rapid loss in mass called disuse atrophy. Atrophy decreases muscle strength and hinders the patient?s ability to rehabilitate, leading to functional disability. We are developing biodegradable, biocompatible devices for implant into fat tissue under the skin. The devices are designed to promote the release of biomolecules that enhance muscle metabolism and growth. This innovative approach complements current rehabilitation strategies (e.g. physical therapy, nutritional support) and is expected to maximize functional recovery in many types of patients, including those rehabilitating from blast injury, chronic illness, or spinal cord injury.
