Introduction
Osteoarthritis (OA) is a debilitating condition that can lead to chronic pain, disability, decreased quality of life and inability to perform activities of daily living. Authors have reported that OA and diabetes are responsible for the largest increase in years lived with disability at the global population level, in part because of the obesity epidemic and aging populations. It has been reported that patients with symptomatic knee or hip OA have a 55% greater all-cause mortality compared with the general population. There are more than 30 million Americans affected by OA. Others have stated that at least one in four people may develop symptomatic OA in his or her lifetime. , The most commonly affected joints include the knee, hand and hip. , Annually the treatment of OA puts significant strain on the healthcare system and has wider socioeconomic as our populaces age. Published numbers attribute medical costs in excess of US$140 billion to arthritis-related care and more than US$450 billion in costs when account for costs to the economy and lost wages. The mainstay first-line treatments for symptomatic OA are nonsurgical, such as activity modification, nonsteroidal antiinflammatory medications, weight optimisation and low-impact exercise and strengthening programs. Alternative medications such as tramadol have historically been used for palliation in OA patients but 2019 Cochrane evidence suggests that tramadol alone or in conjunction with Tylenol has ‘no important benefit on mean pain or function in people with osteoarthritis’. When patients fail to improve with other conservative measures, providers may turn to injection therapies or surgical intervention. Surgical options differ depending on the stage of OA and the joint involved but may involve arthroscopy with debridement for palliation or arthroplasty. Although total joint arthroplasty has been shown to be highly effective definitive management for OA especially of the hip and knee, that is not always a viable option depending on patient age, surgical risk and medical comorbidities. As such, nonsurgical injection therapies have been developed in an attempt to achieve durable symptomatic relief and ideally offer disease-modifying benefits.
For more than 100 years now, intraarticular injections have been used as potentially therapeutic substances of OA, specifically of the knee. , Many of the early injection strategies were abandoned because of risks to the patient with minimal benefits seen. Corticosteroids became more commonplace in the 1950s and continue to be used via intraarticular injection therapy for OA. , Despite frequent use of corticosteroid agents for OA, the American Academy of Orthopedic Surgeons (AAOS) Clinical Practice Guidelines approved in 2013 gave an ‘inconclusive’ evidence and state ‘we are unable to recommend for or against the use of intraarticular (IA) corticosteroids for patients with symptomatic osteoarthritis of the knee’. The highest quality, Level I to II literature regarding intraarticular corticosteroid use in OA patients reports underwhelming results. After the advent of widespread corticosteroid use, hyaluronic acid (HA) was approved by the US Food and Drug Administration (FDA), but it too has not delivered the disease-altering affects that are desired. Given the lack of consistent, positive benefits of HA compared with placebo or corticosteroids in clinical trials, the AAOS guidelines offer a ‘strong’ recommendation that they cannot recommend using HA for symptomatic OA. As the AAOS guideline authors note, although meta-analyses have demonstrated improved Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, function and stiffness subscales, none of the improvements met minimal clinically important improvement thresholds.
The limitations seen with both and corticosteroids have spawned research into novel biological intraarticular injection therapies – specifically, platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC) and adipose-derived mesenchymal stem cells (AD-MSCs), among others. These biological agents, known to many as orthobiologics , represent a shifting paradigm in treatment as the pathophysiology of OA continues to be better understood to target complex cellular signalling pathways that play a role in disease progression. To date, the existing human literature is most robust regarding PRP and BMAC, with few studies being published regarding AD-MSCs. Legislation that has lessened restriction through the US Public Health Section Act Section 361 Pathway has expedited the pathway from development to the marketplace for orthobiologics. Although interest and demand from both patients and providers is high for improved nonsurgical treatment options for OA, patients have been exposed to direct-to-consumer marketing campaigns that may inaccurately frame products in testimonials instead of touting peer-reviewed research. As authors have reported, the number of US clinics offering unproved stem cell therapies has at least doubled each year from 2009–14. As clinics have seen a boom in patients looking for biological treatments and subsequently clinics offering those treatments, there remain significant concerns regarding costs of these products. , Most major insurance companies do not cover orthobiologic treatments, citing a lack of high-quality evidence demonstrating their efficacy and cost-effectiveness. Orthobiologics have gain widespread public awareness through marketing campaigns and treatment of professional athletes. The use of buzzwords in the media such as ‘stem cells’ to represent minimally manipulated, multipotent mesenchymal cells can be misleading and confusing to patients. To be clear, the adult MSCs found in cell therapies such as BMAC and AD-MSC preparations originate from the mesoderm and have a limited array of cells they may become. These cells include chondrocytes, osteoblasts, myoblasts and adipocytes, all of which have been shown to be impactful paracrine signal cells to mediate cellular recruitment, immune system modulation and regeneration. , These orthobiologic agents are the focus of this review. In this chapter we detail the indications for these injection modalities; discuss each injection, including different preparations and current clinical outcomes evidence; and review published statements by AAOS and orthopaedic subspecialty groups regarding biologics use for OA.
Indications
Although adults or elderly populations have the highest prevalence of OA, young, active people may be affected, leading to decreased functionality and quality of life. Many demographic, activity and medical history factors have been found to be associated with OA, including genetics, obesity, previous joint injury, recreational activities, occupation, gender and race. The indications for orthobiologics have not been uniformly described, but generally these modalities are for patients who lead an active lifestyle and do not have radiographic evidence of Kellgren-Lawrence (KL) grade 4 OA or advanced imaging evidence of diffuse, full-thickness articular cartilage loss. How age affects treatment efficacy of orthobiologics is an active area of research to better define indications because PRP, BMAC and AD-MSCs are all autologous products. The metabolic activity and paracrine effects of MSCs present specifically in BMAC and AD-MSCs may be affected by the age of the patient. For example, several authors have reported a reduction in the absolute number of MSCs within BMAC and decreased proliferative capacity with age. , Further considerations when discussing treatment options should include a thorough evaluation for concomitant meniscal, ligamentous and malalignment pathological conditions. Many of these concomitant pathological conditions may be driving factors in OA disease progression, and without correction orthobiologics may be limited in their efficacy.
Platelet-Rich Plasma
PRP, or autologous conditioned plasma, is autologous plasma that has undergone centrifugation to concentrate platelets, growth factors and cytokines postulated to aid in tissue healing and anabolism. , Although the exact concentration of what platelet concentration constitutes PRP has not been universally agreed on, PRP typically contains at least 3 to 5 times physiological platelet levels but can reach as high as 9.3 times. , Specific growth factors such as platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) have been shown to collectively have a chemotactic effect on MSCs. The attraction of MSCs is thought to be important in helping conduct increased proteoglycan and cartilage production. Further effects of these proteins and growth factors include antiinflammatory properties through modifying gene expression and limiting production of matrix metalloproteinases and nuclear factor–κB. ,
Protocols
PRP preparation protocols vary widely, with more than 100 publications describing various PRP preparations for treatment of knee OA alone. Despite the variation in retrieval, preparation and injection protocols, the basic steps remain the same. Whole blood is first obtained through standard venepuncture technique, usually in an arm. The blood is then placed in a centrifuge where the blood components are separated into three distinct layers based on density. The most superficial or least dense layer is the PRP. The densest or bottom layer consists of red blood cells, whereas the middle layer contains white blood cells known as the buffy coat .
Preparations differ between being leucocyte poor (LP-PRP) or leucocyte rich (LR-PRP) depending on if the buffy coat is incorporated. LR-PRP contains the entire buffy coat layer, whereas LP-PRP contains only the superficial layer of the buffy coat ( Fig. 24.1 ). The number of centrifuge cycles differs in the literature; whereas many preparation protocols call for a single round of centrifugation, others perform two mainly while trying to isolate LP-PRP to remove any remaining white and red blood cells.
For the treatment of OA, LP-PRP is thought to be superior because leucocytes found within LR-PRP are postulated to stimulate the release of interleukin-1β (IL-1β) and tumour necrosis factor-α, leading to an inflammatory response. The exclusion of leucocytes from PRP is believed to limit the inflammatory response elicited by the injection. Preparation of a PRP injection typically takes 15 to 20 minutes.
A 2019 systematic review reported that at least 32 commercially available PRP concentration systems exist. A study by Castillo et al. compared PRP platelet, red blood cell, white blood cell, fibrinogen, active TGF-β, several different PDGFs and VEGF concentrations among three different commercial systems and found significant differences. The adage ‘more is always better’ may not necessarily apply to platelet concentration because data have been reported noting that platelet concentrations greater than 1,000,000 platelets/μL do not afford additional benefits. In summary, variation in PRP preparation protocols vary to a large degree in the literature, making it difficult to define optimal concentrations and preparation techniques and compare clinical outcomes.
Clinical Outcomes
Johal et al. summated the PRP literature for pain relief in orthopaedic surgery in a systematic review and meta-analysis. The authors identified 78 randomised controlled trials (RCTs) including 5308 patients. Interestingly, 44% of studies used PRP as an adjunct during surgical treatment. The data pertaining to OA demonstrated moderate-quality evidence to support a reduction in pain at 1 year regardless of PRP preparation type. In 2016 Smith published a doubled-blind, FDA-sanctioned RCT evaluating the efficacy of LP-PRP for treatment of knee OA compared with saline control. This was a single-centre study that included 30 patients between ages 30 and 80, with KL grades 2 to 3 symptomatic knee OA who had failed conservative measures of at least 6 weeks duration. Fifteen patients were randomly allocated to three weekly injections of 3 to 8 mL of LP-PRP and 15 patients were randomly allocated to three weekly injections of 3 to 8 mL of phosphate-buffered saline. There were no adverse events in the PRP group. Smith reported that compared with preinjection or baseline WOMAC scores, the WOMAC scores at 1 week after injection were significantly decreased, and at final follow-up 12 months after injection, WOMAC scores in the PRP group were improved by 78% from baseline. In contrast, the saline placebo group saw a 7% improvement in WOMAC scores at 12 months. The efficacy of LP-PRP compared with LR-PRP and HA for treatment of symptomatic knee OA was examined in a systematic review and meta-analysis of RCT (Level I) and prospective comparative studies (PCS; Level II) by Riboh et al. In total, nine studies (six RCT and three PCS) with 1055 patients met inclusion criteria. No differences in adverse events were identified between LP-PRP and LR-PRP; however, both versions of PRP were found to have a higher incidence of adverse events than HA. The authors also reported significantly better WOMAC scores in LP-PRP compared with HA or placebo but no difference compared with LR-PRP. Earlier this year, a randomised, doubled-blinded, triple-parallel, placebo-controlled trial comparing intraarticular injections of LP-PRP, HA and normal saline (sham) was performed in 87 patients aged 20 to 80 years with grade 1 to 3 symptomatic OA. The authors randomly allocated patients to one of the three groups receiving three weekly injections and had 12-month follow-up. All three groups showed significant improvements in WOMAC and International Knee Documentation Committee (IKDC) subjective scores at 1 month after final injection, but only the LP-PRP group sustained the improvement in scores out to 12 months and met the minimal clinically important difference (MCID) threshold in the WOMAC score at all postinjection follow-up visits. Of note, younger patient age was found to be associated with significantly better outcomes.
Many authors have performed systematic reviews, and meta-analyses summated this Level I and II evidence regarding PRP for treatment of symptomatic OA predominantly of the knee. , In a systematic review evaluating four separate biological injection therapies for knee OA including PRP, Delanois et al. identified 11 Level I studies including patients from KL grade 0 to 3 OA. The authors concluded that PRP may reduce pain and lead to modest improvements in function, as was reported in the majority, but not all, of the studies; however, no study to date has demonstrated the ability of PRP to slow or review the OA process. Likewise in a meta-analysis of 10 RCTs including 1069 patients, Dai et al. found significantly improved pain relief and function in patients treated with PRP at 6 months and 12 months postinjection. Specifically, at 12 months the effect sizes of the WOMAC pain and function scores exceeded the previously validated MCID thresholds (–0.79 for WOMAC pain and –2.85 for WOMAC function). However, the authors found that only 2 of the 10 included studies had a low risk of bias using validated instruments to rate bias. This point clearly demonstrates one of the major flaws to date of the PRP literature in that despite the nobility of blinded, prospective designs of these Level I studies, the majority suffer from high levels of bias, whether it be to industry, patient selection or something else, and thus the results may not truly reflect the underlying efficacy. The majority of PRP injection studies for treatment of OA suffer from small sample sizes, short follow-up intervals and varying preparation protocols. Given these data, PRP may best be used as an adjunct or as nonsurgical treatment to achieve short-term pain relief and possible improvement in function without altering disease progression. Although there has been an exponential increase in research into the utility of PRP for treatment of OA, there remains a significant amount of work to be done to better elucidate optimal preparation and processing techniques, injection schedules and patient indications.
Bone Marrow Aspirate Concentrate
BMAC has emerged as a source of growth factors, cytokines and minimally manipulated MSCs that several authors have shown to be efficacious in early knee OA treatment. BMAC is isolated from bone marrow aspirate, which contains a mixture of cellular components, including platelets, white blood cells, red blood cells, hematopoietic precursors, adipose cells and nonhematopoietic precursors, through centrifugation. Bone marrow aspirate–derived mesenchymal stem cells (BM-MSCs) were first isolated in 1999 by Pittenger et al. from bone marrow taken from the iliac crest. These BM-MSCs have been shown to be able to differentiate into osteocytes and chondrocytes, although it is unclear if culture expansion improves this ability compared with minimally manipulated cells. , However, studies have demonstrated that BM-MSCs comprise merely 0.001% to 0.01% of mononuclear cells within bone marrow aspirate after density gradient centrifugation to remove granulocytes, red blood cells and immature myeloid precursors. , Numerous growth factors are present within BMAC, including the TGF-β superfamily of factors, which have been linked to chondrocyte proliferation; PDGF, thought to promote wound healing, collagen synthesis and suppression of inflammatory mediators like IL-1β; insulin growth factor-1 (IGF-1); fibroblast growth factor-18 (FGF-18); and bone morphogenic protein-2 (BMP-2) and BMP-7, among others. , Although many of these factors are also found in PRP, studies have identified higher concentration of IL-1 receptor antagonist (IL-1Ra), which inhibits IL-1β diminishing the catabolic and proinflammatory effects. ,
Bone marrow aspirate may be extracted from many regions of the body. The most commonly used sites include the iliac crest ( Fig. 24.2 ), distal femur, proximal tibia, proximal humerus and the calcaneus. Bone marrow aspirate taken from the posterior iliac crest has been reported to yield the highest concentration of BM-MSCs. There are at least eight commercially available systems that can be used to harvest bone marrow aspirate, all of which require at a minimum 30 mL but preferably 60 mL. These systems include the Arthrex Angel cPRP & Bone Marrow Processing System (Arthrex Inc., Naples, FL, USA), BMAC2 Harvest Device (Harvest Tech/Terumo BCT, Lakewood, CO, USA), CellPoint Concentrated Bone Marrow Aspirate System (Drikot Medical, Oakdale, MN, USA), BioCUE Platelet Concentration System (Biomet Biologics, Warsaw, IN, USA), Magellan Autologous Platelet Separator System (Arteriocyte Medical Systems, Inc./ISTO Technologies, Hopkinton, MA, USA), PureBMC device (EmCyte Corp., Fort Myers, FL, USA), ART BMAC (Celling Biosciences, Austin, TX, USA) and Exactech Biologics Preparation Technique (Exactech Biologics, Gainesville, FL, USA).
