Current Applications of Growth Factors for Knee Cartilage Repair and Osteoarthritis Treatment
Purpose of Review
The decreased contact area, edge loading, and increased stress in the adjacent area cartilage resulting from chondral defects are believed to predispose this tissue to degenerative changes that have significant economic implications, especially when considering its progression to osteoarthritis of the knee. Growth factors are considered therapeutic possibilities to enhance healing of chondral injuries and modify the progression to degenerative arthritis. Thus, the purposes of this review are to first to summarize important points for defect preparation and recent advances in techniques for marrow stimulation and second, and to identify specific growth factors and cytokines that have the capacity to advance cartilage regeneration and the treatment of osteoarthritis in light of recent laboratory and clinical studies.
TGF-β, BMP-2, BMP-7, IGF-1, as IL-1 receptor antagonist, and recombinant human FGF-18 are some of the promising growth factor/cytokine treatments with pioneering and evolving clinical developments. The bulk of the review describes and discusses these developments in light of fundamental basic science. It is crucial to also understand the other underlying advances made in the surgical management of cartilage defects prior to onset of OA. These advances are in techniques for defect preparation and marrow stimulation, a common cartilage repair procedure used in combination with growth factor/cytokine augmentation.
Multiple growth factor/cytokine modulation therapies are currently undergoing clinical trial investigation including Invossa (currently in phase III study), Kineret (currently in phase I study), and Sprifermin (currently in phase II study) for the treatment of symptomatic osteoarthritis.
The treatment of articular cartilage defects of the knee remains an enduring struggle facing an orthopedic surgeon. These lesions are widespread with studies of consecutive knee arthroscopies demonstrating an incidence of chondral defects ranging from 60 to 66% [1–3]. Articular cartilage, devoid of vascularity, relies on diffusion to obtain nutrients and oxygen, thus making intrinsic repair of defects remarkably difficult in vivo . Untreated cartilage injuries (> 12 months duration of symptoms) may create an unfavorable chemical environment for later cartilage repair . Early surgical intervention for articular cartilage injury is particularly important in the athlete’s knee for the successful return to sports participation . Defects in the weight-bearing portion of the femoral condyle results in increased rim stress concentration and chondral wear at the lesion rim . The decreased contact area, edge loading, and increased stress in the adjacent area cartilage resulting from full-thickness chondral defects are believed to predispose this tissue to degenerative changes.  Lesions in articular cartilage can cause considerable musculoskeletal morbidity with significant economic implications, especially when considering its progression to osteoarthritis (OA) of the knee .
Growth factors are being considered as therapeutic possibilities to enhance healing of chondral injuries and modify the progression to degenerative arthritis. Multiple studies have confirmed that growth factors and chemotactic cytokines promote the migration of pluripotent mesenchymal stromal cells (MSCs) (nonhematopoietic adult cell population with a capability to differentiate into different lineages) from the marrow into the defect [10–12]. The goal of growth factor application is to stimulate differentiation of MSCs to create a phenotype that is closer in appearance to normal articular cartilage with similar biomechanical properties . Some suggest that cartilage repair is exclusively mediated by the proliferation and differentiation of mesenchymal cells [13, 14]. Most commonly, marrow substrates including MSCs, growth factors, and cytokines are introduced through marrow stimulation (MS) , although newer techniques have utilized bone marrow aspirate concentrate (BMAC) and adipose tissue (ADSC). Given the vast collection of growth factors that are required for proper cartilage expansion and homeostasis, it is doubtful that any single growth factor will lead to complete cartilage repair, but rather a multifaceted course will be required.
Exciting developments have been made in the field of growth factors, and it is crucial to also understand the other underlying advances made in the surgical management of cartilage defects prior to onset of OA. These advances are in techniques for defect preparation and marrow stimulation, a common cartilage repair procedure used in combination with growth factor/cytokine augmentation. Thus, the purposes of this review are to first to summarize important points for defect preparation and recent advances in marrow stimulation and second, to identify specific growth factors and cytokines that have the capacity to advance cartilage regeneration and OA treatment in light of recent laboratory and clinical studies.
There is importance in the individual surgical steps of defect preparation with critical technical details that help optimize clinical results [16, 17]. Many factors have been suspected for the limited potential of vertical and horizontal integration of the peripheral healthy cartilage into the repair tissue. Chondrocyte immobility in the extracellular matrix has been speculated to be a significant limiting factor in the repair capacity , but chondrocytes are motile and can move through the extracellular matrix once adequate signals are present . Incision through the cartilage tissue has been shown to induce chondrocyte motility producing neocartilage around the edges [20•]. Bos et al. [20•] reported that the deep zone of articular cartilage contains chondrocytes capable of proliferation while retaining their cartilage phenotype. These cells are able to form new cartilage tissue [20•] and possibly improve the peripheral integration of the repair tissue. These studies highlight the importance of the creation of healthy, vertical walls at the defect edge  to maximize the tissue response . A second critical step of defect preparation is debridement of the calcified cartilage which may allow the ingrowth of bone marrow-derived cells . In vitro studies have shown that successful removal of the calcified cartilage layer results in improved neocartilage integration [24•]. Yet, significant variability has been shown in a surgeon’s ability to reliably remove the calcified cartilage layer [25••]. However, care must be taken as excessive debridement of the calcified cartilage may stimulate subchondral bone overgrowth, which can be associated with clinical failure after MS [26•].
Marrow Stimulation Innovations: Technique and Instrumentation
Marrow stimulation (common cartilage repair procedure in combination with growth factor/cytokine augmentation) improvements have been developed to increase the concentration of MSCs as well as increase the amount of growth factors and chemotactic cytokines . Basic science principles elucidated in recent years, namely (1) depth of subchondral penetration, (2) diameter of awl, and (3) number of subchondral perforations, are thought to help solve the subchondral bone structure/overgrowth and MSC access issues. First, depth of subchondral perforation influences the outcomes of cartilage repair and repairing/remodeling of subchondral bone (6 mm > 2 mm). [28, 29•] Improvement in overall tissue repair quantity (defect fill) and quality (histologic parameters) was found to be significantly better with deep (6 mm) versus shallow (2 mm) microdrilling [29•]. Second, diameter of awl used in MS has been correlated with repair tissue quality. Eldracher et al. [30•] demonstrated the application of 1.0-mm diameter subchondral drill holes (compared with 1.8-mm drill holes) led to significantly improved histological matrix staining, cellular morphological characteristics, subchondral bone reconstitution, and average total histological score. Third, increased number of subchondral perforations may improve MSC access. A thin and sharp awl has been shown to produce a statistically higher percentage for marrow access than a beveled tip awl . Min et al.  demonstrated the number of MSCs increased with an increase in the number of perforations in the defect (3 or 5 versus 1 perforation; p < 0.05) and concluded as the size of the total exposed area increased, so did the number of MSCs obtained .