PRP, BMAC, Stem Cells, and Other Adjuvants and How They Affect Repair: Clinical Outcome Studies

Introduction

Biological-based therapies are emerging as a promising alternative for treating articular cartilage degenerative defects and early osteoarthritis (OA). These treatments can reduce symptoms, restore joint function, and possibly prevent the progression of OA by delaying the need for metal resurfacing. Numerous biologic agents are currently used in clinical practice, ranging from platelet concentrates to minimally manipulated mesenchymal stromal cells (MSCs). These have been mostly successful for the intra-articular treatment of degenerative joint disease, in particular knee OA. However, because of their potential to improve cartilage healing, biologics are also being used for augmentation in cartilage repair techniques, to enhance clinical outcomes and possibly improve cartilage repair tissue quality.

Platelet-Rich Plasma

Platelet-rich plasma (PRP) is being used to improve the healing of tissues with low healing potential, such as cartilage. There has been growing interest in PRP because of the high content of cytokines, growth factors, and bioactive molecules stored in platelet α-granules, which play a role in the homeostasis, healing process, and immunoregulation of articular cartilage. PRP is widely used in clinical practice because of its safety, low cost, and the simple preparation technique needed to obtain its biologically active content and it has given promising results as a treatment for several orthopedic diseases, in particular cartilage degeneration and OA.

Until now, research has focused on the effectiveness of delivering PRP through intra-articular injections in the treatment of knee OA, a minimally invasive approach that seems to provide increased functional improvement and reduced pain-related symptoms for up to 12 months. Moreover, some evidence suggests that some patients notice a clinical improvement provided by PRP beyond 24 months, although this benefit gradually wanes over time. Despite the placebo effect of intra-articular injections, in particular when dealing with new orthobiologics such as PRP, a recent meta-analysis on 34 randomized controlled trials (RCTs) concluded that PRP injections offered a statistically and clinically significant improvement in patients with knee OA compared with saline injections at 12-month follow-up, without increasing the risk of adverse events. Moreover, PRP injections provided better results than other commonly used injectable options such as corticosteroids or hyaluronic acid. Although this benefit was not significant at earlier follow-ups, it increased over time and was clinically significant after 6–12 months. However, this improvement (greater than what is considered to be the minimal clinically important difference [MCID]) was partial and is supported by a low level of evidence. This partial improvement has also recently been highlighted in a study by Altamura et al. in a cohort of sport-active patients suffering from knee cartilage degeneration and OA. In this relatively young population (mean age 41 years), PRP injective treatment provided good clinical outcomes, but results were less satisfactory in terms of return to sport since only half of the patients achieved the same competitive level as before the onset of symptoms. Other authors underlined the potential of PRP for the injective treatment of hip OA and some investigated the potential of intra-articular PRP injections as a conservative treatment for patients with focal osteochondral lesions of the talus and ankle OA. The ability of PRP to reduce pain and improve function for up to 12 months has also been documented in these patients, although more data are needed to elucidate the real effects of these PRP applications.

The use of PRP has also been extended to cartilage repair procedures, with the aim of exploiting its potential to improve repair tissue quality. Indeed, growth factors released by the activated platelets can support the proliferation of chondrocytes and the production of extracellular matrix. Several preclinical studies have confirmed that PRP can promote chondrocyte proliferation and the differentiation of MSCs from subchondral bone into the chondrogenic line after microfracture surgery. These preclinical results prompted researchers to evaluate the effect of PRP augmentation to microfracture in clinical practice. A recent meta-analysis on seven clinical comparative studies revealed that PRP augmentation improved the clinical outcome offered by microfractures in patients affected by knee or ankle cartilage defects for up to 24 months of follow-up. Although PRP augmentation was safe and showed the potential to improve the results of microfractures, the comparative analysis also showed that this improvement did not reach the MCID and thus was not clinically perceivable by all patients. Besides the clinical results, Papalia et al. provided a magnetic resonance imaging (MRI) evaluation of patients with knee cartilage lesions treated with microfractures alone or combined with PRP or platelet-rich fibrin (PRF) in a retrospective comparative study at 5-year follow-up. The authors reported better results in terms of the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score for the groups treated with platelet concentrates compared with the microfracture alone group, thus confirming the possible role of PRP in improving cartilage repair.

PRP-augmented scaffolds have also been investigated for cartilage defects. In particular, scaffolds can be soaked in PRP with the aim of supplying localized growth factors that facilitate cell infiltration, proliferation, and differentiation. Several preclinical studies have reported that PRP-augmented scaffolds are beneficial in the articular cartilage repair process. Thus, different scaffolds have been used in clinical practice combined with PRP to treat articular cartilage defects and have shown promising clinical results. In autologous matrix-induced chondrogenesis (AMIC), a porcine collagen type I/III membrane has been used with fibrin glue and autologous serum or PRP to cover the microfractured defect: Dhollander et al. reported the successful clinical combination of PRP and AMIC for the treatment of patellar cartilage defects in a small number of patients at 24-month follow-up. Newer approaches favor the use of synthetic scaffolds, such as textile polyglycolic acid–hyaluronan (PGA-HA) implants for covering microfractured defects. Siclari et al. evaluated 52 patients treated with PRP-augmented PGA/HA scaffolds for articular cartilage defects of the knee. They reported a statistically significant clinical improvement at 12-month follow-up, with histological evaluation showing a homogenous hyaline-like cartilage repair tissue.

Overall, PRP research seems promising for cartilage repair, but many questions remain unanswered. In particular, the most suitable type of concentrate is still being debated. Different preparation methods for PRP can yield products with different compositions and characteristics, and different features in terms of content of platelets and leukocytes, volume of whole blood harvested, storage procedures, exogenous activation of platelets, and formation of a fibrin matrix. All this makes it very difficult to merge and analyze clinical results from different studies and gain a full understanding of the actual benefits of this biological approach. Further studies will be required to investigate these aspects to gain a better understanding of the potential and limitations of PRP for the treatment of cartilage defects and OA.