Orthobiologics for knee osteoarthritis: A review of current practice and future directions

Orthobiologics: Why are they necessary?

The osteoarthritic knees have a diminished regenerative potential due to ongoing degenerative changes such as age- related decrease in glycosaminoglycan and proteoglycan levels and poor ability to repair focal cartilage lesions such as softening/fissuring.^[2,4] Conservative measures such as activity modification, patient education, and lower limb physiotherapy regimen and injectables such as corticosteroids and hyaluronic acid can aim to tackle early stages of OA [Figure 1]. Nonetheless, these methods can only provide symptomatic relief but can’t alter the natural progression of OA. “Cell based” orthobiologic therapies are then tried as the next line of management as they possess the ability to change joint microenvironment through their chondroprotective and tissue regenerative properties. These orthobiologics merely supplement the body’s inherent healing responses to halt the ongoing pathophysiology of OA. It is rather necessary to boost the natural healing process since the tissue anabolic cascades are weakened in geriatric knees.^[3,5]

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Figure 1:

Role of orthobiologics in preventing the progression of osteoarthritis.

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PRP

PRP is a regenerative concentrate derived from the patient’s own blood through a process of centrifugation. It effectively contains a high concentration of platelets suspended in plasma making it rich in growth factors which are responsible for its tissue reparative and anabolic action. PRP also holds the potential to counteract catabolic cascades at the cellular levels through its anti-inflammatory cytokines such as transforming growth factor-b (TGF-b), Interleukin (IL)-10, and IL- 13.^[7] Over the course of years, PRP has widely emerged as the most commonly used orthobiologic agent for knee OA since it can act directly on cartilage microenvironment by up regulating the anabolic signals and down regulating the catabolic signals which influence cartilage degeneration. PRP is believed to stimulate the body’s natural healing responses, promoting tissue regeneration, counter acting inflammation, and potentially slowing down the progression of degenerative conditions like OA.^[7,8] PRP contains a high concentration of many growth factors such as platelet-derived growth factor; insulin-like growth factor; fibroblast growth factor; and TGF-b.^[1-3,5] The earliest publications discussing PRP therapy for knee OA began to emerge in the mid-2000s. Patel et al.^[5] did one of the initial randomized controlled trials to compare the effects of intra-articular PRP to saline placebo injection. They reported clinically significant improvement in WOMAC scores at sequential follow-up visits and concluded that PRP injections can exhibit short-term effectiveness (up to 6 months for a single dose) in early knee OA. Bansal et al.^[7] compared the effects of hyaluronate injection with a PRP injection containing higher platelet count (10 billion) and reported clinically significant results at 1 year follow-up duration.

Even though there is surmounting evidence on the clinical supremacy of PRP injections for knee OA; yet there are numerous variables which remain elusive. Some examples are leukocyte rich versus poor PRP; PRP without or without an activator;^[9] low dose versus superdose PRP formulation; single-spin or double-spin centrifugation methods for PRP preparation; and multiple PRP injections versus a single PRP injection. We believe that future studies should focus on evaluation of these variables in an effort to define the ideal PRP formulation that can exist.

The therapeutic use of PRP has many advantages such as the ease of availability of commercial kits; minimal risk of allergic reactions; good patient compliance; and flexibility to choose the required therapeutic dose. Although most of commercially available kits yield 3–5 mL of injectable PRP, recently published literature has also focused on the beneficial effects of a higher volume of PRP (7–8 mL of final product) which contains a relatively higher platelet count (>5 billion absolute platelet numbers).^[10] The analogy of “superdose” PRP especially holds true for the knee, since 7–8 mL of injectable drug can diffuse easily inside such a large joint.

BMAC

BMAC has become a crucial biological tool for orthopedic surgeons, being among the few methods approved by the Food and Drug Administration for delivering stem cells and growth factors.^[11] BMAC is another “cellular” orthobiologic injectable derived from patient’s own blood through a specialized aspiration needle. BMAC intra-articular injections have shown encouraging results for the treatment of early knee OA and focal cartilage defects.^[11,12] BMAC is prepared by collecting marrow aspirate from an easily accessible site such as the anterior superior iliac spine or the posterior superior iliac spine, followed by centrifugation at a high speed (3200 rpm for 15 min) to yield an ultra- filtrate rich in pluripotent MSCs which can differentiate into chondroblastic lineage to hasten and upregulate the cartilage repair cascades inside the knee joint.^[11,13] However, in bone marrow aspirates, MSCs make up only a minute fraction (<0.01%) of mononuclear cells after density gradient centrifugation to eliminate red blood cells, granulocytes, immature myeloid precursors, and platelets.^[14] By virtue of its high content of growth factors, bioactive proteins, and cartilage precursor cells, BMAC holds enormous potential to alter the course of OA rather than just control pain. However, the existing literature on BMAC is scarce and varies widely in terms of indications, timing, and outcomes.

Kim et al.^[12] evaluated the effect of BMAC in 75 knees suffering from OA ranging from Kellgren Lawrence grade I– IV, through visual analog scale (VAS) score; International knee documentation committee (IKDC) score; Knee injury and osteoarthritis outcome score (KOOS); and Lysholm Knee questionnaire. They concluded that BMAC injections led to clinically significant improvement in score values at 6 and 12 months, more so for K.L grades I–III. Shapiro et al.^[15] studied the effect of BMAC in a placebo-controlled trial by injecting one knee with BMAC and the other knee with saline placebo injection in 25 patients suffering from bilateral OA. Osteoarthritis research society international (OARSI) and VAS pain scores decreased significantly in both groups at 1 week, 3 months, and 6 months follow-up, but no difference was found between the two groups. Some other studies have reported clinically significant outcome of BMAC for focal cartilage defects when used to augment other treatment options such as microfracture creation.^[16]

ACS

IL-1 is a key mediator of pathophysiology of degenerative changes in knee OA and its high levels have been detected in synovial fluid of such knees. The chondrocytes and fibroblasts in an osteoarthritic knee express higher levels of IL-1 receptor type 1. The endogenous inhibitor of IL-1, known as the IL-1 receptor antagonist (IL-1Ra), holds the potential to restrict the intra-articular effects of IL-1 and shield cartilage from matrix metalloproteinase (MMP).^[17,18] Numerous researchers have documented the efficacy of IL-1Ra through intra- articular administration in studies involving dogs (Pelletier et al.) affiicted with OA and in initial human trials.^[19]

ACS is prepared from patient’s own blood, which has recently gained attention as a potential treatment for knee OA. ACS contains a high level of IL-1Ra. The research on ACS can be dated back to early 2000s. Meijer et al. observed that when blood comes into contact with glass beads, it triggers a robust and swift rise in the production of various anti-inflammatory cytokines, including IL-1Ra.^[20] This finding forms the foundation for generating ACS, which is administered into the joint through a course of six intra-articular injections, given twice weekly over a span of 3 weeks. At present, this treatment is accessible for human patients in multiple European nations, and its application is even more prevalent for managing equine OA.^[21]

Baltzer et al.^[22] conducted a placebo controlled trial on a total of 376 patients, to compare the effects of ACS, hyaluronate, and placebo (saline) as three separate groups. This was the first ever conducted clinical trial on ACS; they evaluated the outcomes based on WOMAC index, VAS score, and SF-8 at 7, 13, and 26 weeks. The outcomes of ACS treatment showed greater efficacy compared to both hyaluronate and saline across all evaluated parameters and time intervals, with improvements reaching clinically significant levels. Notably, there was no discernible difference in efficacy between hyaluronate and saline.

Future advancements in biotechnology can pave the path for improved ACS formulations that optimize growth factor concentrations and biological activity.

A2M

A2M is a broad-spectrum protease inhibitor which primarily works as an anti-inflammatory mediator to prevent the progression of knee OA. A2M is present in both serum as well as synovial fluid, but its intra-articular levels are low in OA. As we have already mentioned, there is a heightened expression of proinflammatory cytokines such as IL-1, IL-6, tumor necrosis factor-alpha, and IL-8 in the synovial fluid of osteoarthritic knees.^[23,24] A2M acts as a scavenger protein since it possesses the ability to target proteinase inhibitors such as MMP-13 and adam metallopeptidase with thrombospondin type 1 (ADAMTS-1) to form immune complexes to render these enzymes functionally inactive.^[23-26] These immune complexes are subsequently cleared off by synovial cells and macrophages. A2M is prepared by subjecting PRP to a process of ultra-centrifugation to removed platelets and other small molecules, leaving behind plasma which has a high concentration of A2M which is relatively larger molecule.

Wang et al.^[26] demonstrated in their study that rats subjected to anterior cruciate ligament transection and treated with intra-articular A2M exhibited reduced MMP-13 levels and a slower progression of OA. Their findings suggest that additional intra-articular A2M could potentially protect chondral tissue in cases of post-traumatic OA.

Klein et al.^[27] conducted an RCT to compare intra-articular injections of steroids, PRP, and A2M in 75 patients by evaluating VAS score, WOMAC score, KOOS score, and Lysholm scores. Patient reported outcomes were recorded at 6 weeks and 12 weeks. The A2M group exhibited the highest decrease in VAS score at 6 weeks follow-up. They reported a mildly better effect of steroid and A2M as compared to PRP, but the results were not statistically significant.

Moving forward, personalized therapies utilizing autologous A2M enrichment technology are poised for clinical implementation. This approach allows OA patients to utilize A2M extracted from their own plasma to reduce inflammation levels within their knee joints. Looking ahead, advancements in molecular engineering and biological technology may enable the development of highly effective variants of A2M, akin to the progress seen with synthetic insulin, offering enhanced quality and quantity.

MSCs

Gene therapy

Gene therapy is an upcoming treatment option for management of knee OA. This technique involves intra-articular delivery of the drug which directly targets the genes involved in the pathogenesis of OA.^[33] Their mechanism is of action involves blocking the inflammatory cascade inside the affect joint. Gene therapy can broadly be divided into in vivo and ex vivo treatment arms. The rationale behind gene therapy lies in its potential to address underlying disease mechanisms rather than merely alleviating symptoms. Various delivery systems are being explored to facilitate intra-articular gene transfer, including viral vectors (e.g., lentivirus) and non-viral vectors (e.g., nanoparticles).^[34] The in vivo delivery system involves the direct transfer of vector carrying the gene to the target region, often by intra-articular injections. The ex vivo is a rather complicated process since it involves extraction of chondrocytes and other mesenchymal pluripotent cells from the joint. The second step allows their genetic modification outside the body in a sterile environment followed by repeat transfer into the targeted joint by another intra-articular injection. Out of the two delivery systems, “ex vivo” transfer was the first one to be introduced but gradually it was less favored after introduction of the “in vivo” process. The in vivo process allows for increased local gene expression inside the joint, and thus, it can directly act on the pathophysiology of OA at the genomic level.^[34] The adeno-associated virus has shown promising results as a vector for in vivo gene transfer.^[34,35]

Current research into gene therapy for knee OA is in its early phases, primarily emphasizing safety, feasibility, and initial effectiveness. Addressing challenges such as vector immunogenicity and determining optimal dosing schedules is crucial for ensuring the safety and sustained efficacy of this treatment method. Gene therapy aims to target the fundamental molecular processes involved in the disease, potentially offering treatments that modify its progression. Continued exploration and development are essential to fully realize the therapeutic potential of gene therapy in clinical practice.

Future perspectives

Limitations

Despite the potential for significant advancements in orthobiologics’ related research, several limitations still persist. Many studies suffer from small sample sizes, which restrict their statistical power and the generalizability of their results. In addition, the lack of standardization in the preparation and administration of orthobiological formulations leads to variability in reported outcomes. Inconsistent reporting of adverse events further complicates the comprehensive assessment of orthobiologics’ safety profile. Moreover, only a few studies have made direct comparisons between different orthobiologic treatments or between orthobiologics and placebos, hindering the determination of their relative efficacy.

To provide more conclusive evidence on the efficacy and safety of orthobiologics in clinical practice, it is crucial to address these limitations through well-designed, large-scale studies that utilize standardized protocols and include longer follow-up periods.