Posttraumatic osteoarthritis (PTOA) is responsible for about 12% of the 21 million Americans thought to be suffering from osteoarthritis at any given time. The economic impact of PTOA is estimated to be approximately $3B annually.1 The treatment of articular cartilage injuries is evolving as scientists and clinicians gain a better and broader understanding of the actual extent of these injuries including the widespread response that occurs throughout the joint, surrounding tissues, and systemically. The ideal treatment regimen for articular cartilage injuries would address each of these factors including the restoration of joint congruity, stability, and mitigation of the negative cellular and molecular changes that compromise in many cases the outcome of these injuries. The injury to the articular cartilage maybe as subtle as a superficial scuff, crack, or fissure, with or without an associated underlying “bone bruise,” or as devastating as an open intraarticular fracture with loss of bone and articular cartilage with or without an associated ligamentous rupture.
This article reviews the cellular and molecular response that takes place after an articular cartilage injury. It will also review the importance of articular incongruity and joint instability in the development of PTOA, the role of chondrocyte apoptosis in the cartilage's response to injury, the emergence of cellular and growth factors in the treatment of articular cartilage injury, as well as recent advances in articular regeneration and its potential role in the salvage of these injured joints.
ARTICULAR INCONGRUITY AND JOINT INSTABILITY IN THE DEVELOPMENT OF POSTTRAUMATIC OSTEOARTHRITIS
Despite the paucity of fundamental research into the causes of PTOA, the subject is enjoying a renewed interest among investigators because of its ideal nature for investigation.2,3 There are 3 aspects of PTOA that make this a good subject for research: (1) the time of disease onset is known in most cases; (2) the disease tends to progress rapidly relative to other arthritis types; and (3) no disease-modifying drugs are currently available for treatment.
The idea that an anatomic restoration of the articular surface is critical to the survival of the injured/fractured join is long engrained in orthopaedic surgery. The work of Rudei and Allgower, as well as that of others, have highlighted the importance of obtaining an accurate articular surface restoration.4,5 The investigation of articular injuries without fracture such as cruciate ligament ruptures have also identified the importance of restoring joint stability to minimize abnormal shear on the injured cartilage to prevent or delay the onset of PTOA.6 A variety of reviews in the past 2 decades have assessed the importance of an anatomic reduction on long-term outcome in articular fractures. Marsh and Giannoudis reviewed published outcomes of articular injuries in relation to articular reduction.7,8 Several investigators have found that certain joints are more tolerant of injury and residual articular incongruity. For example, tibial plateau fractures are capable of withstanding up to 5 mm of articular displacement without significant long-term effects as long as joint stability, limb alignment, and an adequate amount of meniscal tissue have been preserved.7 By contrast, the acetabulum is one of the most highly sensitive surfaces to articular reduction. It has been reported that more than 1 mm of articular displacement within the superior, weight-bearing portion of the acetabulum can result in a significant increased risk for early development of PTOA.9
There are subtle hints in the literature that articular reduction, although important, may not always be the dominant parameter influencing long-term outcome after articular injuries. McKinley et al best showed this in reviewing a series of fractures, specifically, tibial plateau and acetabular fractures, over a 50-year period.10 In this review, they identified that during a period in which there were improvements in articular imaging techniques and implants for joint surgery, the overall outcomes from these injuries did not improve dramatically. This observation strongly suggests that there are other factors at play.
A variety of articular mechanics investigations have been performed. Olson et al9 identified that reconstruction of the articular surface of the acetabulum resulted in the loss of the shared peripheral loading across the joint into more of a centered superior “dome” loading scenario. McKinley et al11 showed that peak contact joint stresses demonstrable with articular incongruity were increased significantly in the setting of joint instability.
A variety of in vivo animal models to study PTOA have been developed. These models range from anterior cruciate ligament transection and destabilization of the meniscus to closed intraarticular fracture models.12 Such works have helped identify that the early injury response and inflammation plays an important role in the development of PTOA. Recent work comparing closed intraarticular fractures in Black-6 mice (which routinely develop posttraumatic osteoarthritis after fracture) and MRL/MpJ mice (MRL/MpJ which do not develop PTOA after injury) found that residual incongruity of the articular surface was highly correlated with the development of PTOA in the Black-613 mice but essentially has no correlation with the development of PTOA in MRL/MpJ mice. These findings imply that there is an in vivo biologic aspect to the development of PTOA after an injury.
Although our understanding of the multitude of factors as well as overall basic science of intraarticular fractures and joint injuries needs to increase, the need to care for articular fractures clinically continues. Clearly, methods to accurately reduce articular surfaces while minimizing soft tissue injury, and to visualize these reductions intraoperatively and provide sufficient fracture stability to promote healing, are critically important. In addition, joint stability throughout the range of motion is a skill that orthopaedic trauma surgeons will need to continue to develop. What seems to be lacking are the biologic interventions that will protect these injured surfaces from additional deterioration after open reduction internal fixation.
THE MOLECULAR RESPONSE TO ARTICULAR CARTILAGE INJURY
The molecular and cellular responses that occur in each of the joint tissues as a result of articular cartilage, and joint injury, are becoming better understood. These responses to a variable degree are known to occur with or without the presence of an intraarticular fracture and can ultimately lead to the joint's articular surfaces. It is important to understand these responses, to develop successful intervention strategies to treat and ultimately prevent the development of PTOA after a joint injury. This response is now recognized as a multifaceted process, and has been found to include the articular cartilage itself and its resident cell the chondrocyte, with the synovium playing a very prominent role in this largely inflammatory response, as well as to a lesser extent the joint ligaments and subchondral bone. This response is typically inflammatory in nature and if left unchecked can ultimately lead to the development of PTOA (Fig. 1).
In the acute postinjury phase, an abundance of inflammatory mediators such as IL-1β, IL-6, IL-8, TNF-α, and NO can be found to a greater extent than normal in the surrounding tissues and synovial fluid. IL-1β and TNF-α have been found to be key cytokines, which drive the production of inflammatory mediators and matrix-degrading enzymes. These proinflammatory cytokines bind to their respective cell surface receptors and activate inflammatory signaling pathways culminating with the activation of nuclear factor (NF-κB), a factor that has been shown to be triggered by a host of stress-related stimuli including excessive mechanical stress and extracellular matrix degradation products. Once activated, NF-κB has been shown to affect expression of other cytokines, chemokines, adhesion molecules, inflammatory mediators, and matrix-degrading enzymes. Therefore, proinflammatory cytokines, their cell surface receptors, NF-κB, and downstream signaling pathways are potential therapeutic targets to prevent the development of PTOA. In addition, anti-inflammatory molecules, including IL-10, IL-4, IL-1ra, can also be readily identified in the tissues and synovial fluid of the injured joint. Chondrocyte necrosis and chondrocyte apoptosis also occur as a result of injury and play a role in the articular cartilage response to injury and development of PTOA.14–16
In the subacute phase, alarmins, also referred to as “danger signals,” are released into the extracellular milieu from dying and necrotic cells, and activated immune cells. These endogenous molecules interact with cellular receptors (TLRs) to further stimulate signaling pathways that initiate innate/adaptive immune responses, which can trigger either additional joint inflammation or can help to initiate tissue repair.17,18
In the chronic phase after articular cartilage and joint injury, metalloproteinases, aggrecanases, reactive oxidative species, nitric oxide (NO), and vascular endothelial growth factor have been found to be upregulated and play an important role in maintaining a detrimental response to injury also contribute to the development of PTOA. These chronic phase reactants can also serve as targets for intervention to mitigate joint degeneration.17,18
At this time, there is ample evidence that the joint tissue's response to injury is complex and multifaceted. This response involves each of the tissues of an injured diarthrodial joint. These responses occur in a series of in phases along a continuum. The acute phase involves a substantial inflammatory response, as well as the production of anti-inflammatory mediators. A subacute phase includes primarily chondrocyte cell death and distress leading to the release of alarmins that play a role in supporting chronic inflammation leading to additional cartilage destruction. Ultimately, if this sequence of events is allowed to continue unchecked, there is osteocyte involvement, angiogenesis, osteophyte formation, additional cell death, and the advancement of joint degeneration.17,18
CHONDROCYTE APOPTOSIS AND ITS ROLE IN THE DEVELOPMENT OF POSTTRAUMATIC OSTEOARTHRITIS
Osteoarthritis is characterized by chronic, progressive, and irreversible degradation of the articular cartilage associated with joint inflammation and a reparative bone response. More than 100 million people are affected by this condition worldwide with significant health and welfare costs. Available treatment options are extremely limited, particularly after fractures and development of posttraumatic osteoarthritis.
After a traumatic event and an intraarticular injury, extracellular matrix damage occurs, with chondrocytes undergoing apoptosis and necrosis.19,20 Secondary damage may also take place due to the unfriendly (hypoxic) local environment that develops as a result of inflammatory insults related to surgery and the postoperative sequelae.
Lately, research to prevent chondrocyte apoptosis in PTOA has been focused on modulation of inflammation, administration of growth factors, pharmacological factors, herbs, antioxidants, and targeting of specific molecular pathways (Wnt antagonist, caspase inhibitors, P53 molecule, and NO inhibitors).21 However, most of the studies used animal cells (in vitro) and animal models. There are distinct differences between human and animal cells in terms of molecular pathways and the cellular responses. In addition, the animal's joint cartilage makeup is different. Moreover, in experiments where osteoarthritis (OA) is induced chemically, the underlying pathophysiological processes diverge compared with humans.21
In general terms, due to the limitations of the available experimental research, mapping the pathogenesis of posttraumatic osteoarthritis to undisputable human conditions has been proven to be rather problematic. Challenges identified hindering potential curative tactics include the induction of an anabolic phenotype, reversal of catabolic responses, maintenance of subchondral bone, and successful regulation of the joint inflammation among others. Currently, it can be argued that it is difficult to make any robust recommendations for a particular clinical application or a potential pathway that will reverse the apoptosis of chondrocytes after a cartilage injury. Consequently, a comprehensive approach involving all systemic and local biological factors upregulated and contributing to the development of OA seems to be the most appealing strategy. Some methods of attack would be delivery of molecules capable of downregulating inflammation; blocking the metabolic changes occurring within the joint; arresting chondrocyte senescence and apoptosis; facilitating induction of chondrocyte proliferation and differentiation; blocking osteoclastic activity; improving osteogenesis; reversing of catabolic and apoptotic signals; and enriching the numbers of chondrocytes locally through the application of either culture expanded chondrocytes or mesenchymal stem cells.22–24
To gain momentum and a deeper understanding of the molecular events involved, future research should center on human biology. Finally, a combined approach including molecules acting on different aspects of chondrocyte physiology and OA pathogenesis seems to be an attractive approach.
CELLULAR AND GROWTH FACTORS FOR TREATMENT OF ARTICULAR CARTILAGE INJURY
Well-defined cartilage defects have been treated with marrow stimulation techniques (eg, microfracture), or with autologous osteochondral transplantation (OCT), also known as mosaicplasty. However, these approaches suffer from limitations. For instance, instead of producing hyaline cartilage, microfracture normally results in fibrocartilage that can start deteriorating within 2 years after intervention.25 OCT is associated with donor-site morbidity and can be technically demanding.26 Consequently, various therapies based on cell or growth factor delivery have been investigated to develop more effective treatment options.
AUTOLOGOUS CHONDROCYTE IMPLANTATION
Autologous chondrocyte implantation (ACI) is certainly the most established cell-based therapy for articular cartilage defects. In this technique, chondrocytes are isolated from a cartilage biopsy, collected from a low load-bearing region of the joint, and expanded in vitro.26 During a second surgery, a periosteal flap (ACI-P) is sutured over the debrided defect and chondrocytes are injected into the newly created space. However, because graft hypertrophy is a common complication of ACI-P, defects have been covered alternatively with collagen membranes (ACI-C). Chondrocytes in culture can also be seeded on a scaffold that is delivered to the defect a few days later, a procedure called matrix-induced chondrocyte implantation (MACI).25 Despite the knowledge that monolayer culture is known to affect chondrocyte phenotype, the ACI/MACI strategies can improve pain and functional scores and produce a tissue with hyaline characteristics.25–27
A definitive consensus on the comparative effectiveness of ACI/MACI and standard treatments still needs to be reached. In the long term, microfracture and ACI-P have led to similar mixed outcomes (14–15 years of follow-up).28 MACI is technically easier to perform than ACI, and no clear differences have been noticed in the short term (≤2 years).27 A recent meta-analysis of randomized controlled trials compared ACI-P/C, MACI, microfracture, and OCT for cartilage repair in the knee.29 Short-term clinical scores did not differ between treatments but ACI-C demonstrated lower long-term reoperation rates than OCT or microfracture. Overall, based on the reoperation rate, presence of hyaline cartilage, graft hypertrophy, and clinical scores, ACI-C was ranked as the best option, followed by OCT and MACI. These conclusions were unfortunately limited by the paucity of data for some techniques, outcomes, or time points and in each case, only localized, well-defined areas of injured cartilage were being addressed. These studies have not been performed in injured joints at high risk of developing PTOA.
MESENCHYMAL STEM CELLS
Mesenchymal stem cells (MSCs) have been attracting interest primarily due to their ability to differentiate into chondrocytes.30,31 MSCs can be expanded in vitro and implanted in a fashion mimicking ACI or MACI. Clinical trials have also shown the therapeutic potential of bone marrow–derived MSCs (BMSCs). A cohort study comparing ACI-P and BMSCs delivered with a periosteal flap resulted in similarly improved clinical scores up to 2 years after surgery.32 Although BMSCs can be isolated without intervening in the affected joint, they are associated with other limitations. For instance, their differentiation potential decreases with increasing time in culture, and various shortcomings can occur after cell delivery (eg, fibrocartilage formation, osteophyte formation, and calcifying cartilage).30 A one-step technique using bone marrow aspirate concentrate can also be performed and thereby reduce costs.29 In cohort studies, this procedure provided outcomes at least similar to MACI (≥3 years of follow-up) but was superior to microfracture after 5 years.33,34 Adipose-derived MSCs (ASCs) have also demonstrated beneficial effects on cartilage repair in animal and human studies.30,31,35 Their harvest is easier and less painful than BMSCs, and a higher yield can be reached. In culture, ASCs maintain their phenotype better than BMSCs but they may have a lower chondrogenic potential. Like their bone marrow counterparts, ASCs can either be expanded in vitro or delivered through a one-step procedure using the stromal vascular fraction, which is obtained after adipose tissue processing. Other stem/progenitor cells have also attracted interest, such as peripheral blood–derived MSCs.31 Synovium-derived MSCs are particularly interesting because they have a high chondrogenic potential, and chondrocytes derived from articular cartilage and synovial MSCs share a similar gene expression profile.36
A thorough evaluation of cell-based therapies for injured cartilage is, however, impeded by the lack of optimal or standardized injury models, protocols, and materials (eg, cell culture, cell dose, and scaffold). In addition, BMSCs and ASCs have often been tested in combination with other procedures, such as microfracture or platelet-rich plasma (PRP), and only short-/mid-term outcomes are generally reported. Because treatments may only provide temporary repair, longer follow-ups are essential to fully assess effectiveness.
GROWTH FACTORS AND PLATELET-RICH PLASMA/FIBRIN
Various growth factor candidates have been considered, including insulin-like growth factor-1 and several members of the transforming growth factor (TGF)-β superfamily or the fibroblast growth factor (FGF) family.37 Potential benefits have been documented but deleterious side-effects have also been observed. For instance, osteophyte formation and/or synovial fibrosis could occur with the use of TGF-β1, FGF-2, or bone morphogenetic protein-2. Moreover, most conclusions are based on in vitro and animal studies.
Because a combination of growth factors is presumably more effective at treating cartilage defects, autologous PRP and its derivatives have become appealing options.38 PRP is rich in various growth factors that can stimulate migration, proliferation, and differentiation of stem/progenitor cells. In most cases, animal and clinical studies have reported favorable effects using PRP but firm statements can hardly be made.39 In addition to interindividual variations; multiple preparation protocols, formulations, or delivery modes have been used. Similar to MSC-based therapies, adjunct treatments, limited follow-ups, or inconsistent etiologies among studies further interfere with our understanding.
In summary, cell-based and growth factor–based therapies are promising possibilities in the treatment of injured cartilage. However, there is still a crucial need for high-quality and long-term studies with comparisons to current standard treatments. Factors potentially affecting outcomes, cost-effectiveness, and regulatory considerations should be thoroughly investigated to facilitate clinical decision making.
REGENERATING ARTICULAR CARTILAGE
Regenerating articular cartilage in the laboratory is the goal of many researchers. This is of particular importance because articular cartilage once injured or lost, has very limited healing capacity. There are many challenges that have thus far prevented our ability to regenerate articular cartilage. These challenges have been both scientific in nature as well as regulatory. The development of engineered articular cartilage requires a combination of the appropriate biologic materials or scaffolds, pluripotent cell lines, and stimulating factors.40
Scaffolds are a critically important component in that they provide the appropriate 3-dimensional environment for development of articular cartilage. They can be made of either natural biomaterial or synthetics. Numerous materials have been investigated including molded hydrogels, injectable hydrogels, woven fibers, porous meshes, and composites. At this time, there is no universal consensus as to the best material to function as the ideal scaffold.40
The next critical ingredient in cartilage generation is the cell. Many sources and types of cells have been investigated. Chondrocytes have been frequently used from a number of sources, including costal cartilage, auricular cartilage, nasal cartilage, and actual articular cartilage. Each of these behaves somewhat differently. Stem cells, from a number of different sources, have also been investigated as to their ability to make articular cartilage in the proper setting. The types of cells that have been studied include bone marrow cells, adipocytes, synovial cells, umbilical cord, and placenta-derived cells. These cells are pluripotent and differentiate down several different pathways. Their chondrogenic potential have shown to be highly influenced by the presence of certain growth factors or stimulating agents in the growth environment. Some investigators have attempted to engineer cartilage with the use of fibroblasts.40 Another critical ingredient is stimulating or growth factors. A number of different materials have been investigated. These include transforming growth factor-β, bone morphogenetic proteins, FGFs 2 and 18, insulin growth factors, the Wingless family, and the Hedgehog family.40 All of these have a different influence and each has the potential for stimulating the growth of articular cartilage in the appropriate setting.
The final important factor in regenerating articular cartilage is the biophysical stimuli. Environment and physical stimulation can cause the engineered tissue to begin to take on the characteristics of hyaline cartilage. The use of bioreactors and various stimuli such as hydrostatic pressure, compression, shear forces, and oxygen tension may be the most critical step. Our lead researcher at the Thompson Laboratory for Regenerative Medicine at the University of Missouri refers to this step as “taking the engineered cartilage running” (James Cook, PhD, September 2016, personal communication).
The science of regenerating articular cartilage has developed tremendously in the past 10 years. Unfortunately, the regulatory environment has become increasingly challenging over the same period, slowing the performance of transitional research. If these regulatory hurdles can be overcome, engineered cartilage may become a reality for the treatment of articular defects, and perhaps PTOA, in the years to come.
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