Tissue engineering of the meniscus
Introduction
The menisci are unique wedge-shaped semi-lunar discs present in duplicate in each knee joint [1], [2]. The menisci are attached to the transverse ligaments, the joint capsule, the medial collateral ligament (medially) and the menisco-femoral ligament (laterally) [3]. Initially, the menisci were considered as functionless remains of leg muscles, but are now unquestionably thought to be very important in load bearing, load distribution, shock absorption, joint lubrication and stabilisation of the knee joint [4], [5].
The function of the meniscus is reflected in its anatomy as its cells and extracellular matrix are arranged in such a way that compressive forces, shear stresses, circumferentially directed forces and tensile hoop stresses can be endured and redirected optimally. During embryonic development non-differentiated mesenchymal fibroblast-like progenitor cells differentiate into the highly specialised meniscus tissue. Particularly in the highly loaded, avascular, inner region of the wedge-shaped meniscus, the phenotype of the tissue is fibro-cartilage-like. In the peripheral, vascularised region, however, where the meniscus connects to the internal knee joint capsule, the cells and matrix have a fibrous phenotype. In general, the matrix of the meniscus is mainly composed of type I collagen, but a number of minor collagens (for instance, types II–VI) and glycosaminoglycans (GAGs) are present in lower quantities, particularly associated with the fibro-cartilaginous phenotype. The numerous collagen type I bundles, which are strong in tensile stress, are oriented in a circumferential direction and are considered to be very important in preventing radial extrusion of the meniscus and maintaining the structural integrity of the meniscus during load bearing [1], [6]. The GAGs play an important role in the maintenance of optimal visco-elastic behaviour, compressive stiffness and tissue hydration (78% is water). Furthermore, GAGs and surface zones proteins are thought to facilitate a smooth frictionless movement of the menisci over the articular surfaces of the tibia and femur [1], [6].
Tears usually are located in the inner avascular part of the meniscus and as a consequence do not heal spontaneously. Particularly, the large, more complex tears have a very limited potential for repair, especially if there is knee instability due to additional ligamentous trauma. In the 1960s it was believed that menisci could be removed without any immediate consequences for the function of the knee joint. In fact, the short-term consequences were even very satisfactory. As osteoarthritis develops very slowly, it took several decades before it was broadly accepted that meniscectomy inevitably leads to severe joint degeneration [7], [8], [9], [10], [11]. Since then various techniques have been advocated in literature to preserve the meniscus tissue and to initiate repair of the lesion. Most procedures have had mixed results and a limited application only. Due to the increase in popularity of arthroscopic surgery, partial meniscectomy, in which the torn part of the meniscus is removed, has become one of the most commonly performed surgical procedures [12]. This treatment resolves the short-term clinical problems [12]. However, in the longer term, with the decreased amount of meniscus tissue remaining, the load bearing and load-distribution capacity is still compromised. Although the biomechanical changes are not as severe as after a total meniscectomy, this condition will still lead to cartilage degradation and increase in pain and loss of function of the joint [12], [13], [14], [15], [16].
Tissue engineering may offer new treatment modalities for the regeneration of meniscus lesions or for the complete replacement of a degenerated (part of the) meniscus by a tissue-engineered construct. Tissue engineering is based on a smart and unique combination of cells, growth factors and scaffolds, and this review focuses on specific aspects for the meniscus. In Section 2 the selection of an optimal cell source is discussed. In Section 3 we discussed the use of growth factors to stimulate non-differentiated cells into a fibro-cartilaginar phenotype. Optimal mechanical properties of a tissue-engineered construct or of a biomaterial used for tissue ingrowth in vitro or in vivo seem to be of utmost importance. In Section 4 we addressed the optimisation of scaffold properties for the facilitation of tissue ingrowth and tissue differentiation. The application of these scaffolds for lesion repair and for use in meniscus prosthesis is discussed in 5 Partial reconstruction of meniscus tears, 6 Production of meniscus prosthesis, respectively. In conclusion, the effect of these polymers on articular cartilage degradation is reviewed as well as opportunities for further research in this challenging field (Section 7).
Section snippets
Cell culture experiments in tissue engineering of the meniscus
Particularly, the group of Webber and co-workers has developed protocols for isolating meniscus cells [17], [18], [19], [20]. Practically, the procedures are similar to those used for articular chondrocytes, but a few extra isolation steps are needed to free the cells from the more complex extracellular matrix. After slicing of the meniscus, the isolation starts with a short digestion in 0.05% hyaluronidase for 5 min and a subsequent digestion in 0.2% trypsin for 30 min, followed by the regular
Growth factors for tissue engineering of the meniscus
So far, several growth factors have been demonstrated to have an effect on meniscus explants or on isolated meniscus cells in culture. In particular, growth factors that stimulate synthesis and inhibit degradation of extracellular matrix production could be very useful to direct the cells into an optimal phenotype [29]. TGF-β seems to be a very effective growth factor to stimulate the production of GAGs and biglycan by meniscus cells in culture [23].
It remains to be seen whether this will lead
Biomaterials used in meniscus repair
An ideal scaffold material should be biocompatible and biodegradable in the long term. Moreover, it should permit unrestricted cellular ingrowth, allow free diffusion of nutrients, may be used as a carrier for stimulatory and inhibitory growth factors and it should be strong enough to withstand the load in the joint and maintain its structural integrity under these loaded conditions. Furthermore, it should have a degradation profile that allow ingrowth of new tissue and thereafter allow
Partial reconstruction of meniscus tears
It has already been demonstrated that tears located in the avascular, inner one-third of the meniscus have little potential for healing [49], [50]. Nevertheless, a variety of techniques have been developed to restore the structural integrity of menisci afflicted by these tears [51]. These techniques are mainly based on classical techniques, such as suturing or fixation of the loose fragment with anchors and screws. However, the healing response of these tears is still disappointing. In order to
Production of meniscus prosthesis
In case of a severely damaged meniscus, a total meniscectomy is inevitable. It therefore would be ideal to have an implant that could be used to replace the patient's own meniscus. Again, a number of potential solutions are available. Several groups have tried to develop meniscus prosthesis, which will be briefly reviewed. The prosthesis can be based on autologous, allograft or synthetic materials or a combination of synthetic materials and autologous tissues.
With respect to autologous
Effects of various procedures on articular cartilage degradation and final considerations
Despite all the effort put into procedures for meniscus repair, the effects of these procedures on the prevention of articular cartilage degeneration have been disappointing so far. Both in reconstructed menisci as in prosthetic replacement with a variety of tissues, articular degeneration still occurs [46], [62], [67], [72]. In a series of experiments going on in our laboratory using a polyurethane-based reconstruction method and prosthesis (unpublished results) we have the strong impression
Conclusions
Progression has been made with respect to the development of biomaterials that can be used for tissue engineering of the meniscus, but many questions pertaining to tissue engineering of the meniscus still remain unanswered.
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