Magnetically Responsive Biomaterials for Enhanced Skeletal Muscle Regeneration

Abstract

Skeletal muscle comprises a large percentage of the human body mass and plays an essential role in locomotion, postural support, and breathing. Unfortunately, severe muscle injuries can lead to extensive and irreversible fibrosis, scarring, and loss of function without therapeutic intervention. In these cases, the repair of damaged muscle may be improved by a material system capable of on-demand, spatiotemporally controlled biologic delivery. The hypothesis guiding this thesis is that the regeneration of injured skeletal muscle can be controlled by an active ferrogel scaffold that provides a microenvironment suitable for myogenic cell survival and is capable of delivering these cells to injured muscle tissue in a noninvasive and precisely timed manner. In this thesis, a new magnetically responsive biomaterial capable of triggered drug and cell delivery was developed to enhance the regeneration of severely injured skeletal muscle. By redistributing the iron oxide content of the conventional monophasic ferrogel, biphasic ferrogels were fabricated that were appropriate in size and mechanical properties for in vivo implantation and on-demand triggered release in small animal models. Strikingly, magnetic actuation of empty biphasic ferrogel scaffolds resulted in uniform cyclic compressions that enhanced muscle regeneration without the use of cells or growth factors. Reduced fibrous capsule formation around the implant, as well as reduced fibrosis and inflammation in the injured muscle, demonstrated a potential immunomodulatory role for ferrogel-driven cyclic compressions. Biphasic ferrogel scaffolds were also used to deliver cells and growth factors precisely timed with inflammation in vivo to enhance functional muscle regeneration. Cells and growth factors were delivered by ferrogel scaffold to severely injured muscle immediately following injury and at delayed time points. Significant reductions in fibrosis and increases in angiogenesis were observed following delayed delivery. More importantly, delayed scaffold treatment of injured muscle led to enhanced engraftment efficiency and functional muscle regeneration. Together, these results demonstrate the therapeutic potential of this new magnetically responsive biomaterial.