Tissue engineering of functional articular cartilage: the current status

Abstract

Osteoarthritis is a degenerative joint disease characterized by pain and disability. It involves all ages and 70% of people aged >65 have some degree of osteoarthritis. Natural cartilage repair is limited because chondrocyte density and metabolism are low and cartilage has no blood supply. The results of joint-preserving treatment protocols such as debridement, mosaicplasty, perichondrium transplantation and autologous chondrocyte implantation vary largely and the average long-term result is unsatisfactory. One reason for limited clinical success is that most treatments require new cartilage to be formed at the site of a defect. However, the mechanical conditions at such sites are unfavorable for repair of the original damaged cartilage. Therefore, it is unlikely that healthy cartilage would form at these locations. The most promising method to circumvent this problem is to engineer mechanically stable cartilage ex vivo and to implant that into the damaged tissue area. This review outlines the issues related to the composition and functionality of tissue-engineered cartilage. In particular, the focus will be on the parameters cell source, signaling molecules, scaffolds and mechanical stimulation. In addition, the current status of tissue engineering of cartilage will be discussed, with the focus on extracellular matrix content, structure and its functionality.

Fig. 1

Sections of cultured periosteal explants, stained with Safranin-O (red, proteoglycans)/Fast Green (blue, collagen) (a–d, magnification ×40) and with antibodies for collagen types I and II (e–h, magnification ×40). Cartilage was produced by the explants between agarose layers, with and without addition of TGF-β1 (a, b) and collagen type II was synthesized in this cartilage (e–f). Only collagen type I was visible in explants that were cultured under tension by dynamic loading and no cartilage was formed (c, g). When dynamic loading was combined with TGF-β1 supplementation, cartilage formation was visible (d) and collagen type II could be seen in the chondrogenic area (h)

Fig. 2

Sliding with an indenter over an chondrocyte-seeded agarose construct (1). The sliding indentation protocol led to a depth-dependent strain field (maximal principal strains) (2), with highest strains in the superficial zone (SZ) and the middle zone (MZ) and lowest strains in the deep zone (DZ). The sliding indentation protocol induced depth-dependent ECM deposition (3), leading to the highest GAG content in the top half of the construct (SZ and MZ), which receives high strains according to numerical simulations. *p < 0.0017

Fig. 3

Outlook on the approaches for tissue engineering of cartilage with sufficient ECM amounts, ECM organization and mechanical properties. The traditional approach relies on experimentally exploring the effect of (a combination of) different input parameters (1, 2). These experiments are very time consuming, labor intensive and therefore expensive. We propose a computer-aided approach which includes theoretical and computational evaluation of the influence of different input parameters in a modeling approach (3). With such models, it is possible to discriminate promising protocols from those with poor potential via in silico experiments. In addition, the outcome of experiments could be used for optimization and validation of the theoretical and computational models (4). This approach is less based on trial and error, less time consuming and therefore cheaper

Fig. 4

Determining optimized mechanical loading regimes for engineering functional cartilage involves understanding how mechanical loading at the macroscopic levels perturbs cells at the microscopic level, how that perturbation stimulates the chondrocyte to adjust its pericellular matrix by matrix turnover, and how that microscopic tissue development modulates the functional properties at the macroscopic scale. Ultimately, modeling will need to cross these scales to predict how mechanical perturbation would modulate tissue properties with time of culture