Newer therapies show promise
Prevention of degenerative joint disease and the restoration of articular cartilage through minimally invasive means is a major focus of basic science and orthopaedic sports research. That research has led to advances in technology that enable the long-term storage of cartilage and the replication of “chondroinductive” cells, resulting in cartilage restoration procedures that may potentially set a new standard of care in orthopaedic clinical practice.

For example, there is ongoing research into new options including methods for harvest and transplantation of tissue-forming cells. When combined with bioactive scaffold matrix materials and bioactive molecules, these stem and progenitor cells can differentiate into the appropriate cell lineage for specific tissue repair. Available cell-based strategies may utilize local cells, transplantated autogenous connective tissue progenitor cells derived from bone marrow or other tissues, or autologous growth factors obtained from a patient’s own platelets.

Injections—challenging the status quo
Corticosteroid and hyaluronic acid (HA) injections—the predominant minimally invasive treatments for symptomatic osteoarthritis—are often the bar against which new injectable agents are measured. Corticosteroids work by reducing inflammation and suppressing the immune response within damaged tissue. Often combined with a local anesthetic, steroid injections are inexpensive, reach their peak effectiveness within 4 weeks of injection, and are indicated in treatment of many joint and soft tissue disorders.

HA injections, primarily used for knee arthritis, attempt to replace articular fluid while acting as a shock-absorber and lubricant. Although HA injections provide good pain relief compared to placebo treatment within 8 weeks of injection, they are costly and results are not superior to corticosteroid injections. Although both corticosteroids and HA provide temporary pain relief, neither have been shown in long-term studies to regenerate articular cartilage or delay the onset of arthritis.

Platelet-rich plasma (PRP) is derived from autologous blood in which platelets have been concentrated to 2 to 8 times. The regenerative potential of PRP depends on the amount and viability of the inherent growth factors present in the delivered materials. Large variations exist between the 40 plus commercially available systems; therefore, each system needs to be tested individually for growth factor and cytokine expression. The final platelet concentration of any PRP product depends on several factors, including the initial volume of whole blood to be processed and the platelet recovery efficiency of the chosen technique. Recent randomized control trials support the use of PRP injections in the treatment of mild osteoarthritis disease. As a result, PRP has been used to treat osteoarthritis in the clinical setting. Compared to HA or steroid injections, data suggest that PRP injections may offer better pain relief over a longer period in patients with mild arthritis.

Although mesenchymal stem cell (MSC) therapy is a burgeoning area of interest, it is also controversial due to misrepresentation and misunderstanding among patients, physicians, and distributors. To date, very few high-quality studies support the use of MSC injections to improve joint pain.

Adipose- and bone marrow-derived MSCs have chondrogenic potential and have demonstrated promising results in comparison to HA injections for mild knee arthritis. Some studies have shown bone marrow-derived MSC injection during ligament reconstruction to improve graft incorporation and overall pain scores. However, many purveyors of MSC preparations do not disclose contents of their products or expected yield.

Similarly, bone marrow aspirate concentrate (BMAC), marrow centrifuged to enhance its concentration of MSCs and other trophic factors, has been trialed as an intraarticular injection to treat arthritis with inconclusive results. BMAC preparations vary widely and MSCs make up less than 0.01 percent of cells in the final product, making it difficult to standardize treatment or analyze outcomes. Due to the scarcity of double-blinded, randomized control trials or long-term studies on outcomes of treatment of osteoarthritis or osteochondral defects with MSC injections, it is unclear whether these injections provide any regenerative benefit to articular cartilage over time.

Advertisements regarding expected benefits of MSC injections may mislead patients who often believe the injections will repair their severe degenerative joint disease (DJD) and prevent the need for arthroplasty. Current data is inconclusive regarding the use of MSC or BMAC injections for treatment of DJD or osteochondral defects, and overall, there is insufficient evidence to support the routine use of MSC injections for treating articular cartilage pathology. Further study is needed before definitive conclusions can be drawn and recommendations made.

Procedures—old and new
Microfracture is one of the oldest, most inexpensive, and commonly used procedures for treating osteochondral defects. Microfracture, through marrow stimulation using small perforations into subchondral bone, produces a fibrin clot and brings pluripotent stem cells to form fibrocartilage in damaged articular tissue. Although evidence suggests that microfracture improves pain, its use should be restricted to small chondral defects, and pain relief often peaks then wanes after 2 years. Compared to microfracture, newer treatments with autologous and allograft chondral implantation have wider indications and improved outcomes at long-term follow-up.

Osteochondral autograft transplantation (OAT) is one of the oldest cartilage transplant procedures still practiced today for the treatment of osteochondral defects. In a one-stage procedure, osteochondral autografts are obtained from less–weight-bearing sections of articular cartilage in small diameter “plugs” that are then placed directly into the chondral defect. Defects larger than 8 mm may require multiple plugs for coverage (mosaicplasty). This method is useful in addressing small chondral defects where deep subchondral damage, untreatable by microfracture, is present.

Autologous chondrocyte implantation (ACI) has been used to treat larger shallow defects (1 cm – 3 cm) and bypasses the problem of donor size by taking a small arthroscopic biopsy of healthy cartilage and expanding it ex-vivo for up to 6 weeks. The area of damaged cartilage is addressed in a second procedure with débridement, placement of a membrane or patch over the lesion, and an injection of the cultured chondrocytes underneath the patch (Fig. 1).

Like ACI, matrix-induced autologous chondrocyte implantation (MACI) requires a two-stage procedure where autologous chondrocytes are harvested, expanded, and implanted on a collagen scaffold, which is then placed into an articular defect. Both ACI and MACI have similar results with good integration of “hyaline-like” tissue in the defect and long-term functional results that are improved compared to microfracture.

BMAC is also used in a similar fashion to ACI and MACI. Marrow is harvested, most often from the iliac crest (Fig. 2), and then placed into or under a scaffold/membrane on the débrided defect site. Despite the final centrifuged bone marrow having few MSCs, results are similar to ACI and MACI with good medium-term outcomes. The predominant drawback to the use of BMAC involves the technical aspects of aspiration to obtain a threshold number of progenitor cells.

Osteochondral allografts obviate the need for staged repair and can address large diameter osteochondral defects with fresh or preserved donor tissue. The recipient wound bed is size-matched to donor tissue that is shaped to fit the defect during the surgery. These allografts can treat subchondral defects up to 1 cm deep, with the added benefit of bone integration that provides support for the hyaline cartilage after implantation. Unlike blood products or glandular tissue, osteochondral allografts do not need to be screened for immune compatibility as long as the marrow elements are removed prior to transplant. These grafts perform well at medium-term follow-up, are particularly well-suited for use in the femoral condyles and patellofemoral joint, and have also found use in disorders such as spontaneous osteonecrosis of the knee. The success of these procedures has encouraged research into complete and partial allograft joint replacement surgery.

Summary
Biologic treatments such as PRP, which have the potential to augment tissue regeneration, are changing the face of orthopaedics. However, due to a lack of a standardized harvest and treatment algorithm, efficacy of these new therapies is difficult to quantify. In the absence of long-term evidence, further research is needed to investigate the ultimate risks and cost benefit ratio of biologic treatments for cartilage disease (Table 1).

Rivka C. Ihejirika, MD, is a PGY-2 research resident in the department of orthopaedic surgery at NYU Langone Orthopedic Hospital and a member of the AAOS Biologic Implants Committee.

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