**Author details**

Articular cartilage damage is a persistent and increasing problem as the ageing population expands and treatments to achieve biological repair have been challenging [176]. Cartilage tissue engineering has been around for over 20 years. However, none of the approaches available so far have been able to achieve the consistency, effectiveness and reliability that are required for clinical applications. Tissue engineering of a mechanically resilient cartilage construct that meets the structural and functional criteria for effective functional integration into a defect site in the host is a difficult endeavour [177]. One of the fundamental weaknesses of all the models available to date is that none of them possess the normal zonal organization of chondrocytes that is seen *in vivo* (i.e. superficial, middle, deep and calcified zones) and the local composition of extracellular matrix in each zone. This structural organisation is a prerequisite for normal cartilage function and the success of any future clinical applications. The currently available 3-D models produce fairly homogeneous populations of cells without the ability to achieve any zonal organization *in vitro* [176]. The ability to produce a construct that recapitulates the zonal and structural architecture of the original tissue is currently lacking. Even the mechanically stable scaffolds that have been created so far do not allow regeneration of a sufficiently large mass of structurally and functionally competent cartilage construct especially if they were constructed and seeded with 2-D passaged (monolayer) chondrocytes in combination with a biomimetic carrier or scaffold [177]. This is one reason why future studies must begin with 3-D cultured chondrocytes maintained in a physiologically relevant microenvironment that replicates the ionic, osmotic and biomechanical milieu of cartilage. The 3-D and microenvironmental impact on cell phenotype is a significant factor creating cartilage

In summary, it may be difficult to imagine research being done without animal models but it is worth pointing out that *in vitro* models of joint and musculoskeletal tissues have been around for several decades and new researchers are increasingly adopting them for work on muscu‐ loskeletal diseases. Therefore, it is our optimistic view that in future many animal models could potentially be replaced with biomimetic and animal sparing alternatives in a variety of research

A. Mobasheri acknowledges the financial support of The Wellcome Trust, the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) (grant number: Mobasheri.A.28102007), the Biotechnology and Biological Sciences Research Council (BBSRC) (grants BBSRC/S/M/2006/ 13141 and BB/G018030/1), the Engineering and Physical Sciences Research Council (EPSRC), Arthritis Research UK (ARUK) and the European Commission Framework 7 (EU FP7). M. Lewis acknowledges the financial support of the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), the Engineering and Physical Sciences Research Council (EPSRC), Arthritis Research UK (ARUK), The Wellcome Trust, the National Centre for Sport and Exercise Medicine

constructs within biomimetic scaffold constructs [177].

disciplines and applications.

526 Regenerative Medicine and Tissue Engineering

**Acknowledgements**

(NCSEM).

Ali Mobasheri1 and Mark Lewis2

1 Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis, Arthritis Research UK Pain Centre, Medical Research Council and Arthritis Research UK Centre for Musculoskele‐ tal Ageing Research, The University of Nottingham, Musculoskeletal Research Group, Divi‐ sion of Veterinary Medicine, School of Veterinary Medicine and Science, Faculty of Medicine and Health Science, The University of Nottingham, Sutton Bonington Campus, Sutton Bo‐ nington, Leicestershire, UK

2 Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis, Musculoskeletal Biolo‐ gy Research Group, School of Sport, Exercise and Health Sciences, Loughborough Universi‐ ty, Loughborough, Leicestershire, UK
