Bioreactor Tissue Engineering for Cartilage Repair

Abstract

Already in utero developing articular cartilage is exposed to, and is as well dependent of, a certain degree of mechanical stimulation (Brommer et al., Equine Vet J 37(2):148–154, 2005). Likewise, adult hyaline cartilage is strongly regulated by a frequent input of dynamic load. It is now clear that articular chondrocytes and mesenchymal stem cells clearly benefit from physical stimuli in vitro (Grad et al., Clin Orthop Relat Res 469(10):2764–2772, 2011). The term preconditioning has evolved in the field of cartilage tissue engineering, roughly describing an enhanced in vitro chondrogenesis by application of different stimuli which aims to generate more functional constructs for implantation. Physical stimulation is one way to precondition cells and is commonly realized by the use of bioreactors. Bioreactor systems can closely reproduce the in vivo environment, and can provoke a highly efficient chondrogenesis. They offer the possibility to evaluate novel therapeutic approaches while avoiding ethically challenging animal models. Mechanical load can be applied by tension, hydrostatic pressure, compression, shear, and any combination of these stimuli. In particular, the combination of compression and shear very closely resembles a human joint situation (Grad et al., Tissue Eng 12(11):3171–3179, 2006). Physical stimulation of articular chondrocytes and mesenchymal stem cells can result in an upregulation of the classical chondrogenic markers such as collagen 2, proteoglycan-4 and aggrecan. Furthermore it has been shown that cell-matrix constructs that have been subjected to physical loading highlighted an organized cell-matrix alignment in the direction of the mechanical stimulation, when compared to free-swelling cell-matrix constructs (Salzmann et al., Tissue Eng Part A 15(9):2513–2524, 2009). Significantly increased mechanical properties have also been reported following mechanical stimulation in vitro. However, an effective chondrogenesis can only be generated when the stimulus is correctly applied in terms of modulus, frequency, duration and force. Furthermore, subjected cells have to be embedded within a 3-D environment which provides a sufficient mechanical backbone to withstand and transmit mechanical loads while in parallel still permitting effective chondrogenesis. Novel bioreactor tissue engineering approaches aiming for articular cartilage repair may focus on stem cell chondrogenesis combining physical with chemical stimuli, which have been shown to be very efficient in promoting in vitro chondrogenesis (Li et al., J Cell Physiol 227(5):2003–2012, 2011).