Current Applications of Growth Factors in Knee Arthritis and Cartilage Repair

Courtesy: Sarav Shah MD, Consultant Shoulder Surgeon, New England Baptist Hospital, Boston, Massachussets, USA

Articular Cartilage Defects of the Knee

Articular cartilage is avascular and depends entirely on diffusion from synovial fluid for the supply of nutrients and oxygen.
Due to the absence of blood vessels, nerves, and lymphatics, the intrinsic repair capacity of articular cartilage is extremely limited in vivo.
Untreated cartilage injuries with symptom duration exceeding twelve months may create an unfavorable biochemical and mechanical environment, reducing the success of subsequent cartilage repair procedures.
Full-thickness chondral defects reduce the contact surface area and lead to edge loading with increased stress on the surrounding cartilage.
These altered biomechanical forces are believed to accelerate degeneration of the adjacent cartilage, predisposing the joint to early osteoarthritis.

Role of Growth Factors and Chemotactic Cytokines in Chondrogenesis

Growth factors and chemotactic cytokines play a critical role in promoting chondrogenesis by attracting and activating reparative cells.
Cartilage repair is primarily mediated through the migration, proliferation, and differentiation of pluripotent mesenchymal stem cells.
These biological mediators are commonly introduced through bone marrow stimulation techniques.
Newer biological strategies include the use of bone marrow aspirate concentrate and adipose-derived stem cells to enhance the local regenerative environment.

Growth Factors as Therapeutic Modalities

Growth factors aim to enhance the healing of chondral injuries and modify the progression toward degenerative osteoarthritis through the following mechanisms:

Promotion of mesenchymal stem cell migration to the site of cartilage injury.
Stimulation of mesenchymal cell proliferation and differentiation into chondrocytes.
Augmentation of biological substrates introduced through marrow stimulation techniques.

Step One: Defect Preparation and Bone Marrow Stimulation Innovations

Defect Preparation

Proper defect preparation is a critical determinant of clinical outcomes in cartilage repair surgery.

Creation of Stable and Vertical Defect Margins
- Healthy, vertical cartilage walls should be created at the edges of the defect.
- Incision through cartilage tissue has been shown to stimulate chondrocyte motility, leading to neocartilage formation at the defect margins.
- These migrating chondrocytes may improve peripheral integration of the repair tissue with the surrounding native cartilage.
Debridement of the Calcified Cartilage Layer
- Removal of the calcified cartilage layer has been shown in in vitro studies to improve integration between repair tissue and subchondral bone.
- Considerable variability exists among surgeons in achieving complete and consistent removal of this layer.
- Excessive debridement must be avoided, as it may stimulate subchondral bone overgrowth, which has been associated with clinical failure following bone marrow stimulation procedures.

Innovations in Bone Marrow Stimulation

Recent basic science studies have clarified several technical parameters that improve access to mesenchymal stem cells and reduce adverse subchondral bone changes.

Depth of Subchondral Bone Penetration
- The depth of subchondral perforation significantly influences cartilage repair outcomes.
- Deeper perforations, approximately six millimeters in depth, have demonstrated superior defect fill and improved histological repair quality compared to shallow perforations of approximately two millimeters.
Diameter and Design of the Perforation Instrument
- Subchondral drill holes with a diameter of one millimeter result in improved histological matrix staining, cellular morphology, and subchondral bone reconstitution compared to larger diameter holes.
- Thin, sharp awls produce significantly greater marrow access compared to beveled-tip awls.

Step Two: Growth Factor Augmentation Strategies

Transforming Growth Factor Beta

Transforming growth factor beta isoforms one, two, and three induce Sox-9 expression and increase production of cartilaginous extracellular matrix.
Inhibition of transforming growth factor beta signaling has been shown to impair autonomous cartilage-like tissue formation from expanded chondrocytes.
Scaffolds seeded with mesenchymal stem cells and loaded with transforming growth factor beta one demonstrate increased expression of type two collagen, aggrecan, and Sox-9 compared to scaffolds containing mesenchymal stem cells alone.
Scaffolds cross-linked with transforming growth factor beta three facilitate mesenchymal stem cell proliferation and abundant extracellular matrix production, with evidence of chondrogenic differentiation in animal models.
Invossa (TissueGene-C)
- A cell-based gene therapy consisting of genetically engineered chondrocytes virally transduced with transforming growth factor beta one.
- Preclinical studies demonstrated increased deposition of type two collagen and formation of hyaline-like cartilage.

Bone Morphogenetic Protein Two

Bone morphogenetic protein two induces both cartilage and bone formation, making it particularly attractive for regeneration of the osteochondral unit.
Mesenchymal stem cells combined with bone morphogenetic protein two demonstrate increased extracellular matrix production and elevated Sox-9 expression compared to mesenchymal stem cells alone.
Chondral defects treated with bone morphogenetic protein two show superior histological grading scores compared to untreated defects at twenty-four weeks.
Microfracture combined with bone morphogenetic protein two results in higher glycosaminoglycan content and increased type two collagen deposition compared to microfracture alone.

Recombinant Human Fibroblast Growth Factor Eighteen

Recombinant human fibroblast growth factor eighteen primarily activates fibroblast growth factor receptor three on chondrocytes.
This growth factor stimulates chondrocyte proliferation and Sox-9 expression while suppressing type one collagen production.
Mechanical testing has demonstrated improved adhesive strength and larger contact areas between native and repair cartilage, indicating enhanced lateral integration.
Chondral defects treated with microfracture and intra-articular recombinant human fibroblast growth factor eighteen administered as three weekly injections showed significant improvement in International Cartilage Repair Society scores and modified O’Driscoll scores at six months compared to microfracture alone.

Interleukin One Receptor Antagonist

Inflammatory cytokines such as interleukin one contribute to proteoglycan degradation in articular cartilage.
Interleukin one receptor antagonist reduces cartilage catabolism and preserves proteoglycan content.
Interleukin one–exposed cartilage demonstrated complete reversal of proteoglycan loss when treated with insulin-like growth factor one and interleukin one receptor antagonist gene therapy.
Joints treated with microfracture followed by interleukin one receptor antagonist and insulin-like growth factor one gene therapy showed more intense staining for aggrecan and type one collagen compared to microfracture alone.
Anakinra
- A pharmacologic interleukin one receptor antagonist developed as a chondroprotective and anti-inflammatory agent.
- Phase one clinical studies are currently evaluating the safety of intra-articular anakinra in patients with moderate knee osteoarthritis.

Platelet-Rich Plasma

Platelet-rich plasma contains platelet concentrations exceeding one million platelets per milliliter of plasma, approximately five times baseline levels.
Platelets release alpha granules rich in growth factors, including platelet-derived growth factor, transforming growth factor beta, insulin-like growth factor, and vascular endothelial growth factor.
Platelet-rich plasma has been shown to stimulate chondrocyte proliferation and promote chondrogenic differentiation of mesenchymal stem cells in vitro.
Lack of standardization in preparation methods has contributed to variable clinical outcomes.

Bone Marrow Aspirate Concentrate

Bone marrow aspirate concentrate contains mesenchymal stem cells and a high concentration of growth factors, including platelet-derived growth factor and transforming growth factor beta.
These biological components play a critical role in inducing effective chondrogenesis.

Basic Science Evidence

Application of bone marrow aspirate concentrate combined with thrombin following microfracture resulted in significantly higher macroscopic and histological cartilage repair scores at eight months compared to microfracture alone.
Magnetic resonance imaging demonstrated a statistically significant increase in defect fill in treated joints.

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