A Renewed Sense of Optimism: A Brave New World of Biologics in Orthopaedics

Commentary Patients with a rotator cuff tear typically present with limited motion and function after weeks of nonoperative care, with eventual magnetic resonance imaging demonstrating that some amount of muscular atrophy is present. Often, insurance criteria will require them to undergo further physical therapy before undergoing a repair. The problem is that, despite receiving adequate care, our patients often present with contracted, atrophied tissues that impede repair and make for a longer recovery. Even if this process is expedited, there is still the reflexive avoidance of pain that, combined with the surgery and the period of recovery, results in considerable disuse atrophy of the rotator cuff. Patients with atrophy and massive tears have been shown to have worse outcomes1,2. Research investigating the causes of atrophy has shown that insult to myocytes results in increased oxidative stress and can lead to a disruption in mitochondrial function and in the overall efficiency of the cell. This dysfunction leads to fatty infiltration, immune-mediated inflammatory changes, fibrosis, and, ultimately, atrophy of the muscle3. This pathway represents an opportunity to prevent muscular compromise in the injured. Xu et al. have forged a new potential direction in orthopaedics with their unique translational study on improving the quality of muscle perioperatively with the use of mitochondrial transplantation in rotator cuff repair. Their study showed that the incorporation of transferred mitochondria rejuvenated myocytes in rats, replenishing cellular metabolism and reducing oxidative stress. This has previously been observed in cardiac tissues, in which injured cells took up transferred mitochondria and demonstrated the properties of healthier cells4. Additionally, tunneling nanotubes in cardiac tissue have been reported to aid in the exchange of mitochondria with neighboring cells4. The same process may occur in injured skeletal myocytes and other tissues as well. In the study by Xu et al., rotator cuff muscles that received mitochondrial therapy were demonstrated to have an enhanced muscle fiber cross-sectional area and reduced fibrosis and oxidative stress. The therapeutic benefits of mitochondrial transfer are likely not exclusive to rotator cuff tears; rather, they likely extend throughout the body and may have broader clinical applications. Think of the potential use in anterior cruciate ligament (ACL) injury and reconstruction, in which quadriceps recovery is one of the largest hurdles to overall recovery, or the potential application in a patient with polytrauma, in whom atrophy may occur as a result of direct injuries, prolonged immobilization, or limited weight-bearing while recovering. If this therapy could be applied at the time of injury, imagine the potential for improved recovery if the involved muscles were less atrophied. Mitochondrial transplantation may even have uses in arthroplasty, in which the time to recover function is muscle-dependent, with different durations for the abductors in total hip arthroplasty, the quadriceps in knee arthroplasty, and the deltoids in shoulder arthroplasty. Even if muscle strength is lacking initially, the reduced atrophy and fibrosis may improve muscle compliance and decrease the tension on repairs, which may result in earlier range of motion and improved comfort during rehabilitation. Mitochondrial transfer may even give rise to improvements in nonoperative treatments. Obviously, there are more avenues to explore. Mitochondrial transfer, in conjunction with advances in biologic scaffolds for severe tendinopathy, may augment our improvements in fixation and muscle-sparing approaches in our quest for better, faster recovery. There is still room to explore improvements to tissue vascularity, neuromuscular rehabilitation strategies, and biologic scaffolds that are augmented with stem cells or growth factors. This is an exciting time in orthopaedics, as we can finally begin to embrace these technologies with a better understanding of the needs of tissues with regard to healing. In a time of increased demand for a faster recovery time and more scrutiny of patient outcomes, there has been limited evidence of the utility of first-generation biologics despite their potential benefits. This fact, paired with the expense associated with biologics, has led to a lack of coverage from insurers, which has created frustration over the limited accessibility of these treatments5. This has largely made many physicians “gun-shy” regarding the application of biologics and may have created a jaded perspective of biologics in orthopaedics. However, it appears that, with additional study, mitochondrial transplantation has the potential to impact the recovery of our patients and may represent a paradigm shift in the repairability of rotator cuff tears (even those that we have traditionally believed to be irreparable), as well as in the rehabilitation and recovery of the injured patient in many other conditions.