PI Fabrisia Ambrosio, PhD
Co-PI Stephen F. Badylak DVM, PhD, MD
Title Mechanical loading as a critical determinant for functional skeletal muscle formation with a biological scaffold
Description Purpose: The purpose of this project is to investigate the effect of mechanical loading on remodeling of bioscaffolds composed of extracellular matrix, when used for skeletal muscle reconstruction.
Background: Technological advancements in body armor are keeping our servicemen and women alive, but limb injuries are exacting a high toll. In the case of volumetric muscle and tendon loss, there is a paucity of effective therapeutic interventions to restore lost function. The use of biologic scaffolds comprised of extracellular matrix (ECM) holds great promise for reducing disability following these injuries. Although there is mounting evidence that mechanical loading plays an important role in the functional incorporation of implanted ECM, there is little evidence to guide the rationale design of targeted and specific post-operative protocols.
Methods: Four to 6 month old female wild type mice will be divided into 3 groups (n=10 each): 1) Injury + normal cage activity (control group), 2. Injury + hindlimb unloading (HU) and 3. Injury + treadmill running (TM).
All animals will receive ECM scaffold implantation at the time of muscle injury. We have decided not to include non-implanted control groups for 2 primary reasons: 1) the study will be evaluating the effect of loading on remodeling of the scaffold, not remodeling of skeletal muscle per se; and 2) extensive studies have already clearly demonstrated a beneficial effect of ECM implantation for skeletal muscle remodeling, when compared to controls.
Injury: A 10mm segment of the gastrocnemius will be excised to create a volumetric muscle loss.
Hindlimb unloading (HU): HU will be performed as previously described (McCarthy et al, 1997).
Treadmill running (TM) : Animals in the TM group, will complete a running protocol 3x/week for up to 30 days.
Outcome variables: Thirty or 90 days after surgery, animals will complete in situ contractile testing to quantify strength, resistance to a fatiguing protocol, and recovery from fatigue. Histological variables will include: myofiber regeneration index, myofiber area, number of embryonic myosin heavy chain positive cells, vascularity and fibrosis.
Expected Results: We anticipate that the addition of a running protocol following ECM implantation will result in a significantly increased functional strength recovery and increased fatigue resistance, when compared to normal cage activity and HU counterparts. We further anticipate that improvement in functional capacity will be positively correlated with an increased histological evidence of regeneration.
Relevance to Rehabilitation: With the ever-increasing translation of regenerative medicine approaches to the clinic, there is a concurrent increased need to better understand how rehabilitation may play a role to maximize the therapeutic benefit of these therapies. Completion of this study will provide important information to guide the development of post-operative rehabilitation programs following ECM implantation into severely injured skeletal muscle.
Source National Skeletal Muscle Research Center at the University of California, San Diego
Term 08/01/2012- 05/31/2013