Abstract
Osteoarthritis has emerged as one of the major public health problems with a burden of disease that significantly affects the world’s aging population. Osteoarthritis is a progressive degeneration of articular cartilage caused by a plethora of etiologies. The traditional nonoperative pharmacologic agents have limited effect on disease progression, let alone, cartilage regeneration. The emergence of biologics such as platelet-rich plasma or stem cells has provoked an unprecedented opportunity to stop, prevent, and reverse cartilage demise provoked by osteoarthritis. This chapter will discuss the current biologic options available to the clinician and will explore the literature supporting their use.
Keywords
Biologics, Mesenchymal stem cells, Osteoarthritis, PRP, Stem cells
Introduction
The development of osteoarthritis (OA) precipitates an irreversible cascade of degenerative changes affecting the hyaline articular cartilage. It is projected to affect more than 20% of adults in North America and Europe by 2020. The burden of disease of OA on the affected patient population ranges from pain to severe functional limitation. With the increased prevalence of OA in the aging population, more than one-third of adults older than 60 years have radiographic evidence of knee OA. Currently, nonsurgical treatments such as topical or oral nonsteroidal antiinflammatory drugs (NSAIDs), intraarticular steroid injection, or hyaluronic acid (HA) have produced mixed results in pain reduction and functional improvement. These pharmacologic treatments target the catabolic cytokines and inflammatory mediators that are integral to OA’s pathophysiologic process of degrading cartilage, synovium, and bone. Although these treatment modalities have proven to be effective in short-term symptom relief, they have not been shown to stop, prevent, or reverse disease progression. A thorough evaluation of the current literature surrounding the role of biologics in OA will be discussed in the following section, which is included to help the treating physician understand how to appropriately utilize this new treatment option.
The Clinical Challenge
The articular hyaline cartilage is composed of chondrocytes and the extracellar matrix (ECM), which mainly includes type II collagen, proteoglycan, and water. The irreversible loss of type II collagen observed during OA progression is attributed to the absence of vasculature and innervation to its microstructure. There is a need to transcend the current symptom relief treatment modalities and provide opportunities to stop and possibly reverse the OA process. Novel biologic treatment modalities have emerged to provide alternative process in decreasing inflammation and cytokines and possibly reverse the collagen and cell population lost. These new biologic treatment options include platelet-rich plasma (PRP) and stem cells and express potential regenerative properties and antiinflammatory modulating effects.
Orthobiologics
Platelet-Rich Plasma
Over the past few years, the advances in our understanding of the pathophysiology of OA have peaked, stimulating a growing interest in biological aids to disease modulation. The biologic factors recently studied to alter articular cartilage degeneration mainly focused on stem cells and PRP. PRP has been used to enhance soft tissue repairs such as Achilles tendon and rotator cuff repair and also to aid in the treatment of osteoarthritis and cartilage pathology. PRP provides a unique treatment modality given that it has been shown to have a successful modulatory effect on inflammation and healing through molecules such as interleukin 1B and of TGF-B. Over the last decade, the preparation of PRP has been greatly simplified and is often done in clinical setting.
The procedure consists on drawing whole blood from the patient with a venipuncture. The whole blood is then put through a centrifugation process that effectively concentrates the platelets. The supernatant contains a high concentration of platelets (150,000–350,000), which release a numerous amount of growth factors upon activation. This process concentrates growth factors and cytokines modulator above physiologic levels, which can then be sterilely injected in the joint. The sizable amount of signaling proteins, growth factors, and chemokines are theorized to potentiate and enhance tissue repair process. More specifically, PRP modulates inflammation and vascular pathology and is a precursor to cell migration, proliferation, and differentiation.
In the adult joint, the chondrocyte in cartilage do not have the capacity to divide or proliferate leading to an incapacity to regenerate after injury or demise. Cartilage regeneration is therefore contingent on cell migration of precursor cells to the articular surface with the capacity to differentiate into the appropriate ECM structure. These precursor cells have been found in surrounding soft tissue, such as the synovium, fat pad, and the subchondral bone.
Outcomes
The application of PRP in the clinical setting to treat OA has been extensively studied and shown to be efficacious at symptoms relief. In a study of 115 osteoarthritic knees treated with three intraarticular injections of PRP, Kon et al. showed an improvement in the posttreatment clinical scores at 6 and 12 months. They found the maximal symptom relief at 6 months with a subsequent significant, but reduced, improvement at 12 months post PRP injections. In a randomized double-blind trial of Duif et al. 58 knees were randomized to either intraarticular PRP during arthroscopy versus control. They found initial improvements in pain and assessment of life quality (SF-36) at 6 months but equal results at 12 months. In a midterm follow-up, Gobbi et al. performed a prospective randomized control trial of 119 knees, which either receive one cycle of three intraarticular injections of PRP or two cycles, 1 year apart, of three PRP injections. They found a significant reduction in pain and improvement in function at 12 months post PRP injection, and they also found continued improvement at 18 months by annual repetition of the PRP intraarticular treatment.
Furthermore, in a systematic review of overlapping meta-analysis, Campbell et al. demonstrated that intraarticular injection of PRP in the treatment of OA provides symptoms relief up to 12 months. In addition, they concluded that PRP injections should be considered in patients with early knee OA. While intraarticular injections of PRP have been shown to provide short-term symptomatic relief and improvement of function, there is little evidence demonstrating that PRP reverses osteoarthritis degeneration of bone and cartilage. To investigate if PRP had molecular intraarticular effect beyond inflammation modulation, Sundman et al. performed a laboratory analysis of soft tissue harvested from OA knees, which were subjected to PRP or HA. They found PRP to be effective at both stimulating endogenous HA production and decreasing cartilage catabolism.
Other evidence supports the role of PRP as modulator of the intraarticular inflammatory response. Furthermore, recent evidence has promoted the use of leukocyte-poor PRP to decrease the damaging effect of cytokines and proteases releases by the white cells.
Stem Cells
Stem cell–based treatment approaches aimed to create, replace, repair, or improve diseased tissue have recently emerged. The stems cells are generally characterized by undifferentiated cells expressing an ability to self-renew and also to differentiate into specific cell types; this allows maintenance of tissue homeostasis through repair. The multipotent stems such as mesenchymal stems cells (MSCs) have the capacity to differentiate into particular cell lineage and are widely used in research secondary to regulations. MSCs have been utilized and implanted both in an autologous and in an allograft setting. MSCs can be harvested from bone marrow aspirate, synovium, periosteum, adipose tissue, and postnatal umbilical cords. Furthermore, the MSCs are precursor cells that can differentiate into chondrogenic, osteogenic, and adipogenic cells and are theorized to improve intrinsic regenerative and reparative functions of tissue such as cartilage.
The MSCs are thought to potentiate reparative healing and regeneration of tissue through a plethora of characteristics such as cellular proliferation, antiinflammatory modulation, antiapoptosis, and antimicrobial. The regenerative and antiinflammatory properties of MSCs have stimulated the investigation of novel approaches in altering the normal disease progression in OA.
The utilization of stem cells as a treatment approach in cartilage injury is increasing both in basic science and in clinical studies. The basic science setting has demonstrated that stem cells can be effectively delivered to the knee cartilage either through implantation with a scaffold or from direct intraarticular injection. Fortier et al. have shown in an equine model that stem cells from bone marrow concentrate injected intraarticularly were superior in knee cartilage regeneration than microfracture alone.
In the clinical setting, Wong et al. investigated autologous bone marrow-derived MSCs in unicompartmental OA of the knees undergoing high tibial osteotomies and microfracture. In the randomized controlled trial, they investigated 58 knees in which 28 knees received MSCs 3 weeks postoperatively. They found an improvement in both clinical scores at 2 years and healing imaging scores at 1 year in knee treated with MSCs. In another study evaluating the role of MSCs in OA, Koh et al. performed intraarticular injection of MSCs into 30 elderly patients. They saw a significant improvement in all clinical outcomes measures at 12 months and 2 years post treatment. Another randomized control trial investigated the use of intraarticular injection of allograft stem cells in patients with OA unresponsive to conservative treatment. They found that, at 12 months, the MSCs-retreated knees had better pain score and functional outcomes score than the control knees. Lastly, Saw et al. investigated in a randomized control trial the regenerative properties of cartilage subjected to autologous blood-derived stem cells. At 2 years’ follow-up, the intraarticular stem cell injection in combination with HA produced an improvement in imaging scoring cartilage regeneration.
The safety of injecting stem cell in the intraarticular environment has been well studied. Hendrich et al. performed intraarticular injection of autologous bone marrow stem cells in 101 consecutive patients and found no complications or malignant transformation. Malignant transformation of stem cells has been observed in prolonged culture of MSCs; short-term culture has proven to be neoplastic free. Centeno et al. found no neoplastic occurrence after intraarticular injection of limited cultured MSCs in knee at 15 months.
Bone Morphogenic Protein
Another biologic that has been widely studied is bone morphogenic protein-7 (BMP-7). It came under scientific scrutiny because of a theorized anabolic effect on cartilage synthesis and ECM components while inhibiting catabolic molecules such as interleukin-1(IL-1). Badlani et al. demonstrated less cartilage degradation in rabbit anterior cruciate ligament (ACL)–injured knee compared with controls. In a double-blind multicenter controlled trial, Hunter et al. evaluated four cohorts of patients with knee OA found a trend toward a dose-dependent improvement in pain.
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