Biomaterials for cartilage regeneration.

Abstract

Osteoarthritis (OA), rheumatoid arthritis (RA) or cartilage damage resulting from severe injuries are among the most prevalent chronic conditions that may lead to disability, resulting in high healthcare costs and a major economic burden to society.1 Current articular or hyaline cartilage repair therapies include nonsteroidal anti-inflammatory drugs, such as cyclooxygenase-2 inhibitors, for pain relief; chondroprotective agents to stimulate chondrogenesis and chondrocyte synthesis of collagen and proteoglycans (eg, hyaluronan, chondroitin sulfate, glucosamine);2 and surgical approaches (eg, microfracture, mosaicplasty, osteochondral autologous transplantation, autologous chondrocyte implantation, matrix-induced autologous chondrocyte implantation).3,4 The major challenge in selecting a cartilage regeneration technique for clinical applications is to find a method that demonstrates significant advantage over the others for improving joint function. However, so far, clinical outcomes have not produced histologically comparable cartilage that mimics the complex zonal architecture of native hyaline cartilage with optimal long-term implications.4-7 Ideally, cartilage regeneration techniques must be cost effective, single stage, and patient friendly.4 Biomaterials are an interesting choice because they not only provide in situ three dimensional space-filing properties to facilitate regeneration in medium- or large-sized cartilage defects, but they also can be tailored to increase cell-anchorage sites by incorporating biophysical/biochemical cues for cell guidance.1,5 In addition, mechanical compatibility is another crucial criterion that plays an integral role in stimulating chondrocytes to deposit cartilaginous extracellular matrix (ECM). Therefore, scaffolds are valuable in maintaining the mechanical integrity of constructs during the regeneration process. Furthermore, functional scaffolds have been designed to induce chondrogenic differentiation through a cascade of signaling events and regulatory cytokines.1 All of these key factors demonstrate that biomaterials possess advantageous characteristics that set them apart from other competitors in the field of articular cartilage regeneration. Biomaterials for Cartilage Regeneration Research on tissue-engineered products for hyaline cartilage regeneration is ongoing. In 2011, the market size of surgical procedures for cartilage regeneration reached €25 billion (US$33.5 billion) worldwide.8 In the United States alone, 250,000 to 300,000 symptomatic cartilage injuries receive surgical treatment every year; 70% of these injuries are treated with lavage/débridement, 20% with microfracture, and 10% with other methods (eg, autologous chondrocyte implantation, allografts, autografts).9,10 To date, collagen, alginate, fibrin, chitosan, hyaluronic acid (HA), and synthetic polymers have been the main components of commercial products used for cartilage regeneration. Therefore, based on their success rate, collagen-based scaffolds, commercially known as Carticel (collagen I/III; Genzyme) and CaReS (collagen I; Arthrokinetics) have been widely used to improve the structural and biologic performance of grafts.11,12 HA alone as a chondroprotective agent has excellent viscoelastic properties, with the ability to promote chondrocyte phenotype via CD44 molecular markers; nonetheless, when injected into the defect site, it degrades rapidly. However, commercially available HA-based biomaterials, including Hyalograft-C (Anika Therapeutics) and Hyalgan (Fidia Pharma), have been shown to promote the regeneration of cartilage with improved mobility.5,13 Cartipatch (Xizia Biotech), composed of alginate/agarose hydrogel, has been clinically proven to regenerate hyaline cartilage.14 In addition, synthetic polymers, such as the TruFit plug (composed of poly[lactic-co-glycolic acid]/calcium sulfate/polyglycolic acid [PGA] fibers; Smith & Nephew) and Chondrotissue (composed of PGA/HA sponge; BioTissue) have been used for filling osteochondral defects with satisfactory outcomes. All the above-mentioned commercial products are approved by the FDA and the Medical Devices Directorate in the EU. Unmet Expectations of Biomaterials and Future Perspectives Biomaterials are designed to be flexible in order to take the shape and size of the defect site upon implantation or injection.5 Apart from satisfying the fundamental requirement of biocompatibility, scaffolds must also mimic the in-depth heterogeneity of native cartilage and simultaneously promote cell adhesion, proliferation, and ECM deposition in situ.15 Hydrogels and sponges have been shown to have interconnected pores or fibers (optimum pore size, 150 to 250 µm),16 through which diffusion of nutrients and other biologic signaling molecules can facilitate complete integration with the host cartilage and subchondral bone.17 Lack of integration may deteriorate regenerated cartilage.18 In addition, altering mechanical properties (including strength, stiffness, and roughness) has also been shown to have an effect on the stability of the scaffold.19,20 Various studies have shown cell-seeded scaffolds to aid deposition of cartilaginous ECM; however, lack of maturation has led to inferior qualities and subsequent clinical failure. Summary Although researchers have been successful in restoring the surface of articular cartilage via preloaded growth factors (eg, transforming growth factor–β) and cells in situ, constructing fully functional cartilage is still in progress.21 Henceforth, using extrinsic biologic, chemical, structural, and mechanical cues, intensive research is now under way to fabricate new biologically inspired materials.19 If these fundamental parameters are met, tissue engineered scaffolds will be able to restore cartilage functions more efficiently and effectively for clinical applications.