The Efficacy of Stem Cell Treatment for Musculoskeletal Conditions

By Ayesha Abdeen, MD

The current standard treatments for musculoskeletal injuries and degenerative conditions rely on methods to encourage existing structures and tissues to heal and using modalities such as rest, ice, physical therapy, bracing, and anti-inflammatory medications to reduce pain and improve function during the healing phase. If tissues are not able to heal themselves or if conservative treatments fail to provide relief, then surgical intervention may be indicated. Examples of this include anterior cruciate ligament (ACL) surgery, whereby the ligament is reconstructed with tissue from elsewhere in the patient such as their quadriceps or hamstrings or patellar tendon, or repair of a rotator cuff with sutures or replacement of a hip or knee with a metal and plastic implant. Although surgical intervention has excellent outcomes, all surgical procedures have associated risks, albeit low, and complications such as infection, blood loss, blood clots/pulmonary embolism, scar tissue, chronic pain, and joint stiffness.

A desire to replenish damaged tissues with new, biologic tissue, beyond that which the body can do independently with scar tissue, has inspired the field of Regenerative Medicine. Techniques in Regenerative Medicine include the use of stem cells to regenerate damaged human tissues. Human stem cells have the potential to differentiate into a variety of cell types and therefore are appealing as an option to regenerate damaged tissue due to trauma, overuse, or degenerative conditions of the bones, joints, and ligaments. However, this ability also leads to the potential for uncontrolled growth or the formation of a potentially harmful neoplasm (new growth) of cells. Therefore, research in this field is focused on guiding the stem cells to differentiate into the desired cell type and avoiding uncontrolled growth of unwanted tissue.

Some stem cell techniques have emerged that show promise in the treatment of many musculoskeletal conditions due to inflammation and damaged cartilage; however, long-term studies have not yet proven such techniques to be superior or safer to conventional treatments and other alternatives. Many of the techniques in regenerative medicine, as applied to the musculoskeletal system, are in the laboratory or in-vitro stages. There are some modalities in the early clinical phases that show some encouraging data. However, evidence regarding long-term outcomes, indications, and adverse effects remain limited, and thus, these techniques have not yet supplanted conventional treatments as the gold standard of care in the treatment of musculoskeletal conditions.

Osteoarthritis (OA) is one of the leading causes of joint disease. OA affects more than 10% of the world’s population over the age of 60. In OA, the smooth cartilage in the joint becomes worn out and eventually may get to the stage where bone is touching bone in the joint. This causes pain due to friction of the rough surfaces. OA is also associated with inflammation within the joint. The standard treatment of OA of the knee is a nonsteroidal anti-inflammatory medication and cortisone injections or viscosupplementation (an injection of hyaluronic acid meant to lubricate the joint and replenish cartilage, thus reducing or eliminating pain). Physical therapy can also be helpful. However, the nonsurgical treatments are directed toward pain reduction and improved function exclusively and do not reverse the arthritic process or cure the damaged cartilage. If these conventional nonsurgical methods do not help, the gold standard treatment is joint replacement, which involves removing the damaged cartilage and replacing it with a smooth surface of metal and plastic/polyethylene. This is an extremely successful operation. Complications occur in less the 1% of cases; however, when they do occur, complications can be serious and include knee infection, nerve or vessel injury, bleeding, hematoma, fracture, stiffness or instability of the knee, and risk of anesthetic. The potential for surgical complication (although rare) and the interest in replacing damaged tissue with biologic tissue rather than artificial devices has driven the investigation into stem cells as a treatment to replace damaged cartilage in arthritis. Growth factors, blood derivatives, such as platelet concentrates, and mesenchymal adult stem cells are emerging as the most promising tool for the treatment of OA, especially in the early phases. Primarily targeted towards focal cartilage defects, these biological agents have recently showed promising results to relieve pain and reduce inflammation in patients with more advanced OA, with the aim of halting the progression of the disease and the need for joint replacement. However, despite several satisfactory in-vitro and pre-clinical studies, the evidence is still limited to support their clinical efficacy in OA.

Platelet-rich plasma (PRP): PRP involves taking a sample of a patient’s own blood and spinning it in a centrifuge to isolate the platelet cells. The remaining supernatant is a fluid rich in platelet cells, which is then injected into the knee joint to create a healing response in damaged cartilage. The growth factors released by the platelets are claimed to possess multiple regenerative properties. In the knee, PRP has been used in patients with articular cartilage damage and ligamentous and meniscal injuries. In the early stages after an acute ligament, there are a number of growth factors that are released in the inflammatory phase during the first week. PRP can increase these growth factors and thus is thought to potentially be beneficial in the initial inflammatory phase of the healing process. PRP has also been shown in some studies to improve healing of an ACL graft after surgery. PRP is also being used for meniscal injuries of the knee, as laboratory experiments have shown that PRP has a positive effect on meniscal cells. PRP may provide growth factors that enhance the meniscus healing through cell proliferation and regeneration of the blood supply to this structure. For the meniscus to heal, there needs to be good blood supply. The inner part of the meniscus that is prone to injury lacks a good blood supply. PRP may be helpful in the healing of meniscal injuries by supplying the growth factors that induce return of the blood supply/revascularization. Again, these benefits remain theoretical and PRP has not been proven to heal meniscal tears. In the meantime, repair with sutures or debridement remains the standard of care for symptomatic lesions that cause locking of the knee.

There is an emerging body of literature that PRP may also help reduce and eliminate symptoms of cartilage lesions and osteoarthritis of the knee. In-vitro laboratory studies have shown that chondrocytes (cartilage cells) stimulated with PRP can increase the production of molecules called proteoglycans and collagen that make up normal cartilage. PRP also contains growth factors that can potentially treat small, focal areas of cartilage damage or defects within the cartilage. Early clinical studies have shown improved pain scores after 6 months and improved function at one year following injection of PRP in patients with knee arthritis. However, MRI studies have not shown reconstitution of the cartilage at one year in the majority of patients treated with PRP for knee arthritis. Whether this process truly results in halting and reversal of the arthritic process remains uncertain.

Adipose-derived mesenchymal stem cells (ASC): Osteoarthritis involves, among other things, the loss of functional cartilage cells/chondrocytes. The use of mesenchymal stem cells (MSC) are being investigated for the regeneration of joint cartilage. Subcutaneous fat from the abdomen as well as the fat pads around the knee cap inside the knee joint are an accessible source of adipose-derived mesenchymal stem cells. ASC-based treatments for cartilage damage/knee arthritis are being tested in clinical trials. The regenerative properties of fat cells in abdominal fat and the knee (suprapatellar and infrapatellar fat pads) have been demonstrated in in-vitro studies and found to be chondrogenic and osteogenic (cartilage and bone producing). Chemically-induced arthritis in mouse models have been treated with ASC-transplanted cells, and cartilage-like tissue was found to be restored. From a technical standpoint in translating this research to humans, it can be challenging to find a method for the cells to remain in the area of interest long enough to allow formation of cartilage. Some techniques involve suturing a membrane over the cells to keep them centered on the damaged cartilage. Early studies with one-year follow up are encouraging regarding improvement in symptoms and function; however, whether the treatment results in restoration of cartilage tissue remains undetermined.

Stem cell therapy remains an avenue of research in the treatment of many musculoskeletal conditions including ACL injuries, meniscal injuries, cartilage lesions, and osteoarthritis. Treatments, including PRP and mesenchymal or multipotent stem cells, have shown regenerative properties in vitro and have also shown some promising clinical results. However, there remains a paucity of high-level evidence that support the clinical use of these therapies. Long-term results remain undetermined and significantly more data needs to be obtained before these techniques supplant current standard treatments.

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