Major biological obstacles for persistent cell-based regeneration of articular cartilage

Abstract

Hyaline articular cartilage, the load-bearing tissue of the joint, has very limited repair and regeneration capacities. The lack of efficient treatment modalities for large chondral defects has motivated attempts to engineer cartilage constructs in vitro by combining cells, scaffold materials and environmental factors, including growth factors, signaling molecules, and physical influences. Despite promising experimental approaches, however, none of the current cartilage repair strategies has generated long lasting hyaline cartilage replacement tissue that meets the functional demands placed upon this tissue in vivo. The reasons for this are diverse and can ultimately result in matrix degradation, differentiation or integration insufficiencies, or loss of the transplanted cells and tissues. This article aims to systematically review the different causes that lead to these impairments, including the lack of appropriate differentiation factors, hypertrophy, senescence, apoptosis, necrosis, inflammation, and mechanical stress. The current conceptual basis of the major biological obstacles for persistent cell-based regeneration of articular cartilage is discussed, as well as future trends to overcome these limitations. IntroductionStructure and function of articular cartilage Articular cartilage is a highly specialized tissue that protects the bones of diarthrodial joints from forces associated with load bearing and impact, and allows nearly frictionless motion between the articulating surfaces [1,2]. The extracellular matrix (ECM) of articular cartilage is distinct from that of other connective tissues, consisting of an intricate network containing predominantly fibrillar collagens and proteoglycans. The collagens, types II, IX and XI, form a fibrous framework that gives the tissue its shape, strength and tensile stiffness [3]. Collagen type VI is found pericellularly around chondrocytes [4], and collagen type X is found in calcifying cartilage [5]. Although collagen type I is the most prevalent collagen throughout the body, the primary constituent of the articular cartilage matrix is type II, comprising 80% to 90% of the collagen content [3]. The proteoglycans in articular cartilage in their most abundant form exist as large hydrophilic aggregates, which contain the fluid component and control its movement. The level of compaction of the proteoglycans within the collagen lattice will determine their level of hydration and, in turn, the stiffness of the articular cartilage. The synthesis, incorporation and degradation of ECM proteins are orchestrated by chondrocytes that populate the matrix at low density [3]. Because articular cartilage is avascular, nutrients for the chondrocytes are supplied from the capillaries of the synovium and must diffuse into the synovial fluid and then into the cartilage matrix. Coordinated synthesis and proteolytic breakdown of certain ECM components by chondrocytes enables certain components of the cartilage matrix to undergo turnover and maintenance [3]. Factors that impair cho...

Increased Chondrocyte Death after Steroid and Local Anesthetic Combination

“…Recent studies have proved local anesthetics and glucocorticoids have cytotoxic effects on various cell types [7,23,34,39]. The link between the articular degeneration in osteoarthritis and apoptosis has been investigated in previous studies [5,25,51,55]. This connection can be explained by the specific structure of articular cartilage as in the absence of macrophages, the apoptotic bodies release their content (proteases) into the extracellular space causing irreversible damage to extracellular matrix [5,18].…”

Regeneration Mechanism of Full Thickness Cartilage Defect Using Combination of Freeze Dried Bovine Cartilage Scaffold - Allogenic Bone Marrow Mesenchymal Stem Cells - Platelet Rich Plasma Composite (SMPC) Implantation

“…Mesenchymal stem cells (MSCs) implantation will bring new hope in treatment of articular cartilage damage since their ability to differentiate as chondrocyte shall produce extra cellular matrix to regenerate cartilage defect [5]. In this study we used allogenic BM-MSCs which known has immunosuppressive effect and no Graft Versus Host Disease (GVHD) [10,11]. BM-MSCs in combination with scaffold will regenerate full thickness cartilage defect by facilitate proliferation and produce matrix as progenitor cells source that is more accessible, easily manipulated, and renew themselves [12].…”

Controlled Delivery of Transforming Growth Factor β1 by Self-Assembling Peptide Hydrogels Induces Chondrogenesis of Bone Marrow Stromal Cells and Modulates Smad2/3 Signaling

“…4 To achieve all of these goals, a feature likely to be of critical importance will be to incorporate into scaffold design bioactive motifs that induce chondrogenesis and promote cartilage extracellular matrix (ECM) synthesis. 2 Transforming growth factor b1 (TGF-b1) has been widely used to promote chondrogenesis of BMSCs in a variety of in vitro culture systems by supplying it in the medium continuously for over four weeks. [5][6][7] Due to the short serum half-life of TGF-b isoforms in vivo 8 and their potent action on other cell types, including induction of inflammation leading to cartilage degradation in vivo, 9 various technologies have been engineered with the goal of local delivery and controlled release of an appropriate concentration of these growth factors in vivo.…”

“…Tissue engineering scaffolds seeded with bonemarrow-derived stromal cells (BMSCs) have been extensively studied with the goal of delivering and retaining cells in irregular defects, providing an appropriate environment for cell attachment, migration, proliferation, and differentiation, thereby stimulating production of cartilage neotissue that integrates with the surrounding native tissue. [1][2][3] Although BMSCs are multipotent, they require a strategy to direct them to a stable chondrocytic phenotype. 4 To achieve all of these goals, a feature likely to be of critical importance will be to incorporate into scaffold design bioactive motifs that induce chondrogenesis and promote cartilage extracellular matrix (ECM) synthesis.…”