Fight Aging!

In this open access paper, researchers explore the utility of decellularized muscle grafts to repair severe injury. Decellularization is the process by which a donor tissue is cleared of cells, leaving behind the extracellular matrix. This intricate structure includes capillary networks and chemical cues to guide cells, line items that the research community has yet to reliably recreate when building tissue from scratch. Over the past decade, researchers have demonstrated the ability to repopulate decellularized tissue with patient-derived cells, a capacity that in principle allows for the production of patient-matched donor organs. This is an important stepping stone on the path towards fully tissue engineered organs grown from a cell sample, and offers the potential for incremental improvement over the present situation for organ donation and transplantation. It can expand the donor pool to include tissues that would be rejected, allow the possibility of transplantation across species, and greatly improve patient prognosis by near eliminating transplant rejection issues.

Injuries to the extremities affect soft and hard tissues and can result in permanent loss of skeletal muscle mass, termed volumetric muscle loss (VML). Treatments for VML include muscle transfers or stem cell injections, but they are not effective procedures to restore muscle function and can require additional surgeries and tissue harvest. Extensive research has been done to identify more effective VML treatments using animal models with severe functional deficits. In these models, VML typically exceeds 20% of the affected muscle mass and results in reduced muscle function. Wounds this large are far beyond the natural healing capacity, making them a gold standard for regenerative medicine research.

Extracellular matrix (ECM) structure and chemistry are key elements involved in muscle regeneration and taking advantage of those elements is important to restore function in VML injuries. Muscle ECM is a matrix rich in laminin, fibronectin, collagens, proteoglycans, and growth factors, which play a role in myoblast differentiation and muscle fiber formation. Biomaterials derived from soft tissues can retain these ECM components and have already shown promise. Several decellularized allogenic and xenogenic matrices are currently available for clinical use, but are exclusively produced from thin tissues such as the skin, small intestine submucosa, and bladder. Those thin-walled tissues do not possess specific properties found in skeletal muscle such as alignment and muscle-specific chemistry.

Decellularized muscle matrices (DMMs) retain the native morphology of muscle ECM, support muscle healing, and promote a proregenerative immune response. These matrices release factors in vivo that promote constructive remodeling of tissue by macrophages and suppress a cytotoxic T cell response, resulting in implant integration and tissue regeneration. Properties like these are critical to elicit a regenerative response that activates muscle progenitors (satellite cells and myoblasts) to differentiate into myocytes, and fuse together to form muscle fibers. Without ECM cues to direct muscle progenitors, muscle healing is delayed.

We compared the ability of DMM, autologous muscle grafts (clinical standard), and type I collagen plugs (negative control) to support muscle regeneration. DMM supported regeneration over a 56-day period in 1×1 cm and 1.5×1 cm gastrocnemius muscle defects in rats. Muscle function tests demonstrated improved muscle recovery in rats with DMM grafts when compared to collagen. DMM supported muscle regeneration with less fibrosis and more de novo neuromuscular receptors than either autograft or collagen. Overall, our results indicate that DMM may be used as a muscle replacement graft based on its ability to improve muscle function recovery, promote muscle regeneration, and support new neuromuscular junctions.

Link: https://doi.org/10.1089/ten.tea.2017.0386