**6.1 Future prospects in cartilage regeneration**

MCS is becoming a more popular source of cells for cartilage regeneration due to in vitro expansion without running the risk of losing their phenotype. However, MSC tends to develop hypertrophic phenotype and further differentiation into the endochondral bone formation. It is becoming more crucial to carefully examine the detailed molecular and epigenetic events that lead the transformation of a chondrocyte to its terminally differentiated pathway. There is a growing need to develop strategies to control chondrocyte hypertrophy and be able to arrest the chondrocyte at one desirable phenotypic stage that helps to maintain the cartilage-specific ECM as described in **Figure 3**. With the current epigenetic knowledge, it is possible to identify a number of epigenetic factors as listed in **Table 1** that can make cartilage regeneration possible.

Other option in cartilage regeneration is the application of hydrogel through injection or through arthroscopy. These hydrogels are capable of controlled release of chondroinductive and chondroprotective drugs [60–62]. These cell-laden hydrogels can be combined with other types of solid scaffolds such as collagen sponge, decellularized cartilage as well as synthetic scaffolds of polyglycolic acid for cartilage repair and clinical applications.


#### **Table 1.**

*Major Epigenetic events remodelling the regeneration of Cartilage.* 

#### **Figure 3.**

*The role of epigenetics in cartilage degradation and regeneration. (a) Healthy articular cartilage with distinct stratifications. (b) As a result of high inflammatory markers such as IL-1β and TNFα, cartilage degradation takes place, with upregulation of a number of cartilage-degrading enzymes (e.g., HDAC, MMP3, MMP9, and ADAMTS4). (c) The onset of OA, which can be reversed with the help of MSC therapy and their initiations as shown in (d). The maintenance of healthy articular cartilage is achieved through a cascade of genes and their products, such as IGFII, SOX5, SOX6, SOX9, NFAT, FGFR3 and TGFβ1-β2. They are all controlled through epigenetics (***Table 1***). Future cartilage regeneration technique should involve the promotion of invasion and migration of MCSs to the lesion area and through various epigenetic signalling undergoing chondrogenesis and maintaining the cartilage.* 
