cartilage, and functional status.
Another group of clinical trials have utilized bone marrow concentrate (BMC) as a potential source of stem cells. Surgical treatment was the choice method of implantation for the majority of the BMC clinical trials. However, only one study utilized a control group method of treatment, ACI, in order to attempt to compare the effectiveness of treatment. This study utilized BMC with platelet-rich fibrin as a scaffold and hyaluronic acid, which is used commonly in attempts to treat osteoarthritis. Researchers found positive results in the regeneration of cartilage in both groups that were not significantly different from one another. Three additional surgical treatment clinical studies were performed and found positive results in clinical scores and growth of cartilage with BMC treatment.
A potential problem of overgrowth of cartilage, hypertrophy, was seen in a small number of the patients treated. A study assessing the effectiveness of injection treatment of BMC with debridement, a common therapy currently used to stimulate regrowth, was tested against a control group that underwent debridement alone. This study found shortened stay in the hospital and improvement of symptoms with the BMC injection.
A third group of clinical trials utilized adipose-derived mesenchymal stem cells (ADMSCs) as a source. The benefit of using ADMSCs is that they are very easily obtainable by clinicians, which makes it an attractive candidate for treatment. All three of the studies that used ADMSCs chose injection implantation as a route of delivery. Two of these studies utilized additional modifiers such as hyaluronic acid, the corticosteroid dexamethasone, and platelet-rich plasma in order to aid in the healing. All three of these studies had positive findings relating to cartilage thickness and clinical results.
Synovial-derived mesenchymal stem cells have been seen as a hopeful source of MSCs to stimulate cartilage regeneration. Synovial-derived mesenchymal cells have a greater chondrogenic than osteogenic potential. Therefore, the stem cells would have a greater likelihood of differentiating into cartilage rather than bone. This could increase the effect of treatment as well as potentially decrease negative side effects.
Although there were many positive findings signifying the effectiveness of MSCs on regeneration of cartilage, all of these early studies have low sample sizes and lack adequate randomization needed for definitive findings. Large randomized control studies will need to be conducted in order to prove the efficacy of MSCs in cartilage regeneration. In addition, more analysis will need to be conducted in order to determine benefits and risks of both surgical and injection treatments, as well as to determine the most appropriate methods of treatment.
Tendons and Ligaments
As individuals age and grow, their tendons and ligaments decrease their aerobic metabolic rates and shift their energy production to predominantly anaerobic methods. The ability to produce energy in conditions that lack oxygen allows our tendons and ligaments to maintain their strength throughout long periods of activity. However, due to the fact that anaerobic metabolism generates far less energy than aerobically, tendons and ligaments struggle with repair. Unfortunately, there is currently no standardized treatment method to aid the healing of tendons. These factors make MSC utilization an attractive method to aid in the repair of tendons and ligaments. There have been several preclinical trials that found positive results for the treatment of tendon and ligament injury in rat, rabbit, pig, and horse models.
Due to the positive findings in the preclinical models, there were in 2014 six active clinical trials analyzing the effect of utilizing MSCs in the regeneration of damaged ligaments and tendons. Trials are at this writing being conducted to assess the effect on rotator cuff tears, Achilles tendinopathy, and damage to ligaments and tendons caused by rheumatoid arthritis and osteoarthritis. Positive outcomes from these studies have the potential to be a breakthrough in tendon and ligament regeneration and treatment for adults.
Current Research Challenges
Due to the early positive results, there were over 13 clinical trials taking place (in 2014) to identify the most effective method for utilization of MSCs for cartilage, tendon, and ligament regeneration. These next studies will attempt to clarify the therapeutic potential. First, these studies will attempt to more clearly identify the most appropriate MSC source that will lead to the most effective treatment for cartilage, tendon, or ligament conditions. Once the source is identified, there may be challenges associated with extraction and purification of the MSCs. Next, studies will have to identify the appropriate scaffolding and growth and transcription factors needed for treatment that will lead to the highest effectiveness.
In addition, there is potential for unplanned negative outcomes such as cardiomyopathy, neoplasm, and other side effects of treatment. While gaining an understanding of the most effective method of cartilage, tendon, and ligament regeneration, safety of treatment will have to be studied in depth.
Krishna S. Vyas
Brad St. Martin
University of Kentucky College of Medicine
See Also: Cartilage, Tendons, and Ligaments: Current Research on Isolation or Production of Therapeutic Cells; Cartilage, Tendons, and Ligaments: Development and Regeneration Potential; Cartilage, Tendons, and Ligaments: Existing or Potential Regenerative Medicine Strategies; Cartilage, Tendons, and Ligaments: Major Pathologies.
Further Readings
Agnieszka, Arthur, Andrew Zannettino, and Stan Gronthos. “The Therapeutic Applications of Multipotential Mesenchymal/Stromal Stem Cells in Skeletal Tissue Repair.” Journal of Cellular Physiology, v.218 (2009).
Alberton, Paolo, Cvetan Popov, Markus Pragert, et al. “Conversion of Human Bone Marrow Derived Mesenchymal Stem Cells Into Tendon Progenitor Cells by Ectopic Expression of Scleraxis.” Stem Cells and Development, v.21 (2012).
Filardo, Giuseppe and Henning Madry. “Mesenchymal Stem Cells for the Treatment of Cartilage Lesions From Preclinical Findings to Clinical Applications in Orthopaedics.” Knee Surgery, Sports Traumatology Arthroscopy, v.21 (2013).
Jo, Chris Hyunchul, Young Gil Lee,Won Hyoung Shin, et al. “Intra-Articular Injection of Mesenchymal Stem Cells for the Treatment of Osteoarthritis of the Knee: A Proof-of-Concept Clinical Trial.” Stem Cells, v.32 (2014).
Krampera, Mauro, Giovanni Pizzolo, Giuseppe Aprili, and Massimo Franchini. “Mesenchymal Stem Cells for Bone, Cartilage, Tendon, and Skeletal Muscle Repair.” Bone, v.39 (2006).
Longo, Umile Giuseppe, Alfredo Lamberti, Nicola Maffulli. and Vincenzo Denaro. “Tissue Engineered Biological Augmentation for Tendon Healing: A Systematic Review.” British Medical Bulletin, v.98 (2011).
Sharma, Pankaj and Nicola Maffulli. “Tendon Injury and Tendinopathy: Healing and Repair.” Journal of Bone and Joint Surgery, v.87-A/1 (2005).
Case Western Reserve University/Cleveland Clinic
Case Western Reserve University/Cleveland Clinic
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Case Western Reserve University/Cleveland Clinic
A multidisciplinary medical center, the Cleveland Clinic is one of the top hospitals in the United States, and is affiliated with the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. It was founded in 1921 by four physicians in Cleveland who shared a medical practice and had served together in World War I, to provide medical research, education, and patient care; it has become one of the largest medical centers in the world, treating millions of patients a year. There are about 2,800 staff physicians and scientists and 1,300 residents from among 120 specialties.
Specialties in which the Cleveland Clinic is ranked among the top 10 hospitals in the nation by U.S. News and World Report include cardiology and cardiac surgery, gastroenterology, urology, rheumatology, orthopedic surgery, nephrology, pulmonology, neurology, neurosurgery,