Elsevier

Biomaterials

Volume 25, Issue 9, April 2004, Pages 1523-1532
Biomaterials

Tissue engineering of the meniscus

https://doi.org/10.1016/S0142-9612(03)00499-XGet rights and content

Abstract

Meniscus lesions are among the most frequent injuries in orthopaedic practice and they will inevitably lead to degeneration of the knee articular cartilage. The fibro-cartilage-like tissue of the meniscus is notorious for its limited regenerative capacity. Tissue engineering could offer new treatment modalities for repair of meniscus tears and eventually will enable the replacement of a whole meniscus by a tissue-engineered construct.

Many questions remain to be answered before the final goal, a tissue-engineered meniscus is available for clinical implementation. These questions are related to the selection of an optimal cell type, the source of the cells, the need to use growth factor(s) and the type of scaffold that can be used for stimulation of differentiation of cells into tissues with optimal phenotypes. Particularly in a loaded, highly complex environment of the knee, optimal mechanical properties of such a scaffold seem to be of utmost importance.

With respect to cells, autologous meniscus cells seems the optimal cell source for tissue engineering of meniscus tissue, but their availability is limited. Therefore research should be stimulated to investigate the suitability of other cell sources for the creation of meniscus tissue. Bone marrow stroma cells could be useful since it is well known that they can differentiate into bone and cartilage cells. With respect to growth factors, TGF-β could be a suitable growth factor to stimulate cells into a fibroblastic phenotype but the problems of TGF-β introduced into a joint environment should then be solved. Polyurethane scaffolds with optimal mechanical properties and with optimal interconnective macro-porosity have been shown to facilitate ingrowth and differentiation of tissue into fibro-cartilage. However, even these materials cannot prevent cartilage degeneration in animal models. Surface modification and/or seeding of cells into the scaffolds before implantation may offer a solution for this problem in the future.

This review focuses on a number of specific questions; what is the status of the development of procedures for lesion healing and how far are we from replacing the entire meniscus by a (tissue-engineered) prosthesis. Subquestions related to the type of scaffold used are: is the degree of tissue ingrowth and differentiation related to the initial mechanical properties and if so, what is the influence of those properties on the subsequent remodelling of the tissue into fibro-cartilage; what is the ideal pore geometry and what is the optimal degradation period to allow biological remodelling of the tissue in the scaffold. Finally, we will finish with our latest results of the effect of tear reconstruction and the insertion of prostheses on articular cartilage degradation.

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.

References (82)

  • T.G. van Tienen et al.

    Presence and mechanism of knee articular cartilage degeneration after meniscal reconstruction in dogs

    Osteoarthritis Cartilage

    (2003)
  • J. Klompmaker et al.

    Meniscal replacement using a porous polymer prosthesisa preliminary study in the dog

    Biomaterials

    (1996)
  • G.M. Peretti et al.

    Meniscal repair using engineered tissue

    J Orthop Res

    (2001)
  • J. Klompmaker et al.

    Porous polymer implant for repair of meniscal lesionsa preliminary study in dogs

    Biomaterials

    (1991)
  • J. Klompmaker et al.

    Meniscal repair by fibrocartilage in the dogcharacterization of the repair tissue and the role of vascularity

    Biomaterials

    (1996)
  • J.F. Cummins et al.

    Meniscal transplantation and degenerative articular changean experimental study in the rabbit

    Arthroscopy

    (1997)
  • K.R. Stone

    Meniscus replacement

    Clin Sports Med

    (1996)
  • D.J. Wood et al.

    Replacement of the rabbit medial meniscus with a polyester–carbon fibre bioprosthesis

    Biomaterials

    (1990)
  • K. Messner

    The concept of a permanent synthetic meniscus prosthesisa critical discussion after 5 years of experimental investigations using Dacron and Teflon implants

    Biomaterials

    (1994)
  • K. Messner et al.

    Cartilage mechanics and morphology, synovitis and proteoglycan fragments in rabbit joint fluid after prosthetic meniscal substitution

    Biomaterials

    (1993)
  • K. Messner

    Meniscal substitution with a Teflon–periosteal composite grafta rabbit experiment

    Biomaterials

    (1994)
  • K. Kobayashi et al.

    The long-term effects of hyaluronan during development of osteoarthritis following partial meniscectomy in a rabbit model

    Osteoarthritis Cartilage

    (2000)
  • C. Shimizu et al.

    Long-term effects of hyaluronan on experimental osteoarthritis in the rabbit knee

    Osteoarthritis Cartilage

    (1998)
  • A.P. Marques et al.

    The biocompatibility of novel starch-based polymers and compositesin vitro studies

    Biomaterials

    (2002)
  • M.E. Gomes et al.

    Cytocompatibility and response of osteoblastic-like cells to starch-based polymerseffect of several additives and processing conditions

    Biomaterials

    (2001)
  • P. Ghosh et al.

    The knee joint meniscus. A fibrocartilage of some distinction

    Clin Orthop

    (1987)
  • C.A. McDevitt et al.

    The ultrastructure and biochemistry of meniscal cartilage

    Clin Orthop

    (1990)
  • M.A. Sweigart et al.

    Toward tissue engineering of the knee meniscus

    Tissue Eng

    (2001)
  • P.S. Walker et al.

    The role of the menisci in force transmission across the knee

    Clin Orthop

    (1975)
  • K.E. DeHaven

    The role of the meniscus

  • Setton LA, Guilak F, Hsu EW, Vail TP. Biomechanical factors in tissue engineered meniscal repair. Clin Orthop...
  • T.J. Fairbank

    Knee joint changes after meniscectomy

    J Bone Jt Surg Br

    (1948)
  • P.R. Allen et al.

    Late degenerative changes after meniscectomy. Factors affecting the knee after operation

    J Bone Jt Surg Br

    (1984)
  • E.M. Tapper et al.

    Late results after meniscectomy

    J Bone Jt Surg Am

    (1969)
  • H. Appel

    Late results after meniscectomy in the knee joint. A clinical and roentgenologic follow-up investigation

    Acta Orthop Scand Suppl

    (1970)
  • A. Hede et al.

    Articular cartilage changes following meniscal lesions. Repair and meniscectomy studied in the rabbit knee

    Acta Orthop Scand

    (1991)
  • Y. Hoshikawa et al.

    The prognosis of meniscectomy in athletes. The simple meniscus lesions without ligamentous instabilities

    Am J Sports Med

    (1983)
  • W. Maletius et al.

    Chondral damage and age depress the long-term prognosis after partial meniscectomy. A 12- to 15-year follow-up study

    Knee Surg Sports Traumatol Arthrosc

    (1996)
  • C.E. Henning et al.

    Use of the fascia sheath coverage and exogenous fibrin clot in the treatment of complex meniscal tears

    Am J Sports Med

    (1991)
  • R.J. Webber et al.

    In vitro cell proliferation and proteoglycan synthesis of rabbit meniscal fibrochondrocytes as a function of age and sex

    Arthritis Rheum

    (1986)
  • R.J. Webber et al.

    Serum-free culture of rabbit meniscal fibrochondrocytesproliferative response

    J Orthop Res

    (1988)
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