Repairing Volumetric Muscle Loss in the Ovine Peroneus Tertius Following a 6-Month Recovery.

Tissue-engineered skeletal muscle is a promising novel therapy for the treatment of volumetric muscle loss (VML). Our laboratory has developed tissue-engineered skeletal muscle units (SMUs) and engineered neural conduits (ENCs), and modularly scaled them to clinically relevant sizes for the treatment of VML in a large animal (sheep) model. In a previous study, we evaluated the effects of the SMUs and ENCs in treating a 30% VML injury in the ovine peroneus tertius muscle after a 3-month recovery period. The goal of the current study was to expand on our 3-month study and evaluate the SMUs and ENCs in restoring muscle function after a 6-month recovery period. Six months after implantation, we found that the repair groups with the SMU (VML+SMU and VML+SMU+ENC) restored muscle mass to a level that was statistically indistinguishable from the uninjured contralateral muscle. In contrast, the muscle mass in the VML-Only group was significantly less than groups repaired with an SMU. Following the 6-month recovery from VML, the maximum tetanic force was significantly lower for all VML injured groups compared with the uninjured contralateral muscle. However, we did demonstrate the ability of our ENCs to effectively regenerate nerve between the distal stump of the native nerve and the repair site in 14 of the 15 animals studied. Impact Statement Volumetric muscle loss (VML) is a clinically relevant problem for which current treatment options are lacking and for which tissue-engineered skeletal muscle presents a promising novel therapeutic option. However, the fabrication of tissues of clinically relevant sizes is necessary for advancement of the technology to the clinic. This study aimed to evaluate the efficacy of our scaled-up tissue-engineered skeletal muscle to treat VML in a large animal (sheep) model after a 6-month recovery.

Repairing Volumetric Muscle Loss in the Ovine Peroneus Tertius Following a 3-Month Recovery.

Much effort has been made to fabricate engineered tissues on a scale that is clinically relevant to humans; however, scale-up remains one of the most significant technological challenges of tissue engineering to date. To address this limitation, our laboratory has developed tissue-engineered skeletal muscle units (SMUs) and engineered neural conduits (ENCs), and modularly scaled them to clinically relevant sizes for the treatment of volumetric muscle loss (VML). The goal of this study was to evaluate the SMUs and ENCs in vitro, and to test the efficacy of our SMUs and ENCs in restoring muscle function in a clinically relevant large animal (sheep) model. The animals received a 30% VML injury to the peroneus tertius muscle and were allowed to recover for 3 months. The animals were divided into three experimental groups: VML injury without a repair (VML only), repair with an SMU (VML+SMU), or repair with an SMU and ENC (VML+SMU+ENC). We evaluated the SMUs before implantation and found that our single scaled-up SMUs were characterized by the presence of contracting myotubes, linearly aligned extracellular matrix proteins, and Pax7+ satellite cells. Three months after implantation, we found that the repair groups (VML+SMU and VML+SMU+ENC) had restored muscle mass and tetanic force production to a level that was statistically indistinguishable from the uninjured contralateral muscle after 3 months in vivo. Furthermore, we demonstrated the ability of our ENCs to effectively bridge the gap between native nerve and the repair site by eliciting a muscle contraction through direct electrical stimulation of the re-routed nerve. Impact statement The fabrication of tissues of clinically relevant sizes is one of the largest obstacles preventing engineered tissues from achieving widespread use in the clinic. This study aimed to combat this limitation by developing a fabrication method to scale-up tissue-engineered skeletal muscle for the treatment of volumetric muscle loss in a large animal (sheep) model and evaluating the efficacy of the tissue-engineered constructs after a 3-month recovery.

Tissue-engineered tendon constructs for rotator cuff repair in sheep.

Current rotator cuff repair commonly involves the use of single or double row suture techniques, and despite successful outcomes, failure rates continue to range from 20 to 95%. Failure to regenerate native biomechanical properties at the enthesis is thought to contribute to failure rates. Thus, the need for technologies that improve structural healing of the enthesis after rotator cuff repair is imperative. To address this issue, our lab has previously demonstrated enthesis regeneration using a tissue-engineered graft approach in a sheep anterior cruciate ligament (ACL) repair model. We hypothesized that our tissue-engineered graft designed for ACL repair also will be effective in rotator cuff repair. The goal of this study was to test the efficacy of our Engineered Tissue Graft for Rotator Cuff (ETG-RC) in a rotator cuff tear model in sheep and compare this novel graft technology to the commonly used double row suture repair technique. Following a 6-month recovery, the grafted and contralateral shoulders were removed, imaged using X-ray, and tested biomechanically. Additionally, the infraspinatus muscle, myotendinous junction, enthesis, and humeral head were preserved for histological analysis of muscle, tendon, and enthesis structure. Our results showed that our ETC-RCs reached 31% of the native tendon tangent modulus, which was a modest, non-significant, 11% increase over that of the suture-only repairs. However, the histological analysis showed the regeneration of a native-like enthesis in the ETG-RC-repaired animals. This advanced structural healing may improve over longer times and may diminish recurrence rates of rotator cuff tears and lead to better clinical outcomes. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:289-299, 2018.