Muscle degeneration in chronic massive rotator cuff tears of the shoulder: Addressing the real problem using a graphene matrix.

Massive rotator cuff tears (MRCTs) of the shoulder cause disability and pain among the adult population. In chronic injuries, the tendon retraction and subsequently the loss of mechanical load lead to muscle atrophy, fat accumulation, and fibrosis formation over time. The intrinsic repair mechanism of muscle and the successful repair of the torn tendon cannot reverse the muscle degeneration following MRCTs. To address these limitations, we developed an electroconductive matrix by incorporating graphene nanoplatelets (GnPs) into aligned poly(l-lactic acid) (PLLA) nanofibers. This study aimed to understand 1) the effects of GnP matrices on muscle regeneration and inhibition of fat formation in vitro and 2) the ability of GnP matrices to reverse muscle degenerative changes in vivo following an MRCT. The GnP matrix significantly increased myotube formation, which can be attributed to enhanced intracellular calcium ions in myoblasts. Moreover, the GnP matrix suppressed adipogenesis in adipose-derived stem cells. These results supported the clinical effects of the GnP matrix on reducing fat accumulation and muscle atrophy. The histological evaluation showed the potential of the GnP matrix to reverse muscle atrophy, fat accumulation, and fibrosis in both supraspinatus and infraspinatus muscles at 24 and 32 wk after the chronic MRCTs of the rat shoulder. The pathological evaluation of internal organs confirmed the long-term biocompatibility of the GnP matrix. We found that reversing muscle degenerative changes improved the morphology and tensile properties of the tendon compared with current surgical techniques. The long-term biocompatibility and the ability of the GnP matrix to treat muscle degeneration are promising for the realization of MRCT healing and regeneration.

Electroconductivity, a regenerative engineering approach to reverse rotator cuff muscle degeneration.

Muscle degeneration is one the main factors that lead to the high rate of retear after a successful repair of rotator cuff (RC) tears. The current surgical practices have failed to treat patients with chronic massive rotator cuff tears (RCTs). Therefore, regenerative engineering approaches are being studied to address the challenges. Recent studies showed the promising outcomes of electroactive materials (EAMs) on the regeneration of electrically excitable tissues such as skeletal muscle. Here, we review the most important biological mechanism of RC muscle degeneration. Further, the review covers the recent studies on EAMs for muscle regeneration including RC muscle. Finally, we will discuss the future direction toward the application of EAMs for the augmentation of RCTs.

Biomimetic electroconductive nanofibrous matrices for skeletal muscle regenerative engineering.

The regeneration of the muscles of the rotator cuff represents a grand challenge in musculoskeletal regenerative engineering. Several types of matrices have been proposed for skeletal muscle regeneration. However, biomimetic matrices to promote muscle regeneration and mimic native muscle tissue have not been successfully engineered. Besides topographical cues, an electrical stimulus may serve as a critical cue to improve interactions between materials and cells in scenarios fostering muscle regeneration. In this in vitro study, we engineered a novel stimuli-responsive conductive nanocomposite matrix, and studied its ability to regulate muscle cell adhesion, proliferation, and differentiation. Electroconductive nanocomposite matrices demonstrated tunable conductivity and biocompatibility. Under the optimum concentration of conductive material, the matrices facilitated muscle cell adhesion, proliferation, and differentiation. Importantly, conductive aligned fibrous matrices were effective in promoting myoblast differentiation by upregulation of myogenic markers. The results demonstrated promising potential of aligned conductive fibrous matrices for skeletal muscle regenerative engineering.

Emergence of the Stem Cell Secretome in Regenerative Engineering.

The secretome is defined as the set of molecules and biological factors that are secreted by cells into the extracellular space. In the past decade, secretome-based therapies have emerged as a promising approach to overcome the limitations associated with cell-based therapies for tissue and organ regeneration. Considering the growing number of recent publications related to secretome-based therapies, this review takes a step-by-step engineering approach to evaluate the role of the stem cell secretome in regenerative engineering. We discuss the functional benefits of the secretome, the techniques used to engineer the secretome and tailor its therapeutic effects, and the delivery systems and strategies that have been developed to use the secretome for tissue regeneration.

Nanofiber-based matrices for rotator cuff regenerative engineering.

The rotator cuff consists of a cuff of soft tissue responsible for rotating the shoulder. Rotator cuff tendon tears are responsible for a significant source of disability and pain in the adult population. Most rotator cuff tendon tears occur at the bone-tendon interface. Tear size, patient age, fatty infiltration of muscle, have a major influence on the rate of retear after surgical repair. The high incidence of retears (up to 94% in some studies) after surgery makes rotator cuff injuries a critical musculoskeletal problem to address. The limitations of current treatments motivate regenerative engineering approaches for rotator cuff regeneration. Various fiber-based matrices are currently being investigated due to their structural similarity with native tendons and their ability to promote regeneration. This review will discuss the current approaches for rotator cuff regeneration, recent advances in fabrication and enhancement of nanofiber-based matrices and the development and use of complex nano/microstructures for rotator cuff regeneration. STATEMENT OF SIGNIFICANCE: Regeneration paradigms for musculoskeletal tissues involving the rotator cuff of the shoulder have received great interest. Novel technologies based on nanomaterials have emerged as possible robust solutions for rotator cuff injury and treatment due to structure/property relationships. The aim of the review submitted is to comprehensively describe and evaluate the development and use of nano-based material technologies for applications to rotator cuff tendon healing and regeneration.