**4.1.3 Growth factor**

During the cartilage regeneration process growth factors play a crucial role in regulating cellular proliferation, differentiation, migration, and gene expression. Besides, they have large influences on the communication between cells and their microenvironment. A number of growth factors have been studied and include bone morphogenetic protein (BMP), transforming growth factor (TGF), insulin-like growth factor (IGF) and basic fibroblast growth factor (bFGF). Their main functions in cartilage regeneration are summarized in Table 2. For example, the BMP family can stimulate mitosis and matrix production by chondrocytes and induce chondrogenesis of mesenchymal cells, triggering them to differentiate and maintain a chondrogenic phenotype (Yuji et al., 2004). TGF-β not only enhances chondrocyte proliferation, but also increases the synthesis of proteoglycans (H. Park et al., 2005).

In-Situ Forming Biomimetic Hydrogels for Tissue Regeneration 49

Chitosan gels supported cartilage matrix accumulation by cells 48 days after

Neocartilage was produced and evenly distributed in the gels after 6 weeks. The P0 and P1 chondrocytes produced neocartilage tissue that resembled native auricular cartilage after 12 weeks.

Defects treated with chondroitin sulfate adhesive and hydrogel showed improved cartilage repair compared to an empty, untreated defect after 6 months.

Chitosan gel can reside at least 1 day in a full-thickness chondral defect and for at least 1 week in a mobile osteochondral

Defects were completely filled with elastic, firm, translucent cartilage at 12 weeks and showed superior integration of

the repair tissue with the cartilage.

hydrogels degraded rapidly.

Wound healing is a complicated process which requires coordination of complex cell and biomaterial interactions. Desirable properties of biomaterials involve formability in situ from aqueous solutions, good adhesion to tissues at one surface (tissue surface) and resistance to adhesion to the other (free surface), and degradability without induction of inflammation (Hubbell, 1996). In-situ forming hydrogels are attractive biomaterials in the application for would healing due to their ability of adjusting the moisture of the wound tissue (wetting the dehydrate tissue and absorb exudation) and conformability of the

Polysaccharides, e.g. chitosan, represent a class of hydrogels used as would healing materials. Native chitosan has low solubility above pH 6. Modifications on chitosan can improve its solubility and make it suitable as in-situ forming materials. Ono et al. reported potocrosslinked chitosan as a dressing for wound occlusion (Ono et al., 2000). The modified chitosan (Az-CH-LA) containing both lactose moieties and azide groups exhibited a good

ELP formed stable, well-integrated gels and supported cell infiltration and matrix synthesis 3 months after injection. These

(Hoemann et al., 2005)

(Chung et al., 2006; Ifkovits & Burdick, 2007)

(D.A. Wang et al., 2007)

(Hoemann et al., 2005)

(Liu et al., 2006)

(Nettles et al., 2008)

Hydrogel (+/-cell) Animal model Outcome Ref.

injection.

defect.

Subcutaneous injection in nude mice

Subcutaneous implantation in nude mice

Goat chondral defects

(osteo)chondral

osteochondral

Goat chondral defects

Table 3. In-situ forming hydrogels for *in vivo* cartilage regeneration

Rabbit

defects

Rabbit

defect

dressing on wounds (Jones & Vaughan, 2005).

**4.2.1 Chitosan-based hydrogels** 

Chitosan-GPglucosamine (+ primary calf chondrocytes)

Hyaluronic acid (+ swine auricular chondrocytes)

PEGDA with methacrylated chondroitin sulfate as adhesive

Chitosan-GPglucosamine

Hyaluronic acidgelatin-PEGDA (+ autologous

**4.2 Would healing** 

MSC)

Elastin-like polypeptide


Table 2. Delivery of growth factors using injectable hydrogels for cartilage regeneration
