Hydrolysable crosslinkers containing polyester segments Acrylate or methacrylate were often used to introduce polymerizable functions at each

extremities of hydrolysable polymer segments. Typical examples are diacrylates of PLA, PGA, PCL, PPF, saturated polyanhydride and their corresponding copolymers (Svaldi Muggli et al. 1998; He et al. 2001; Kweon et al. 2003; Chan-Park et al. 2004; Mespouille et al. 2008;

Paris and Quijada-Garrido 2009; Cai and Wang 2010). The general structure of the resulted crosslinkers is illustrated in the example given in Fig. 14.

Figure 14. PLA-PCL-PLA diacrylated crosslinkers (Chan-Park et al. 2004)

It can be noted in this example that the crosslinker molecule also included PEG in its chemical structure. Although PEG is not biodegradable by itself, it can be eliminated from the body via kidney filtration with a molecular weight fragments lower than 30 kDa, (Yamaoka et al. 1994). Its incorporation in the chemical structure of degradable crosslinkers has numerous advantages. During the synthesis, PEG can be used as a ROP initiator to include PLA and/or PCL segments in the hydrolysable crosslinker prior to the addition of the acrylate residues at both ends of the molecule. Another interest is to increase the capacity of the final material to absorb water. This ensures that the material will degrade according to a bulk degradation mechanism (Deng et al. 1990). Regarding the physico-chemical property of the final material, the incorporation of PEG segments in the hydrogel structure increases the elasticity of the obtained hydrogel. Finally, in general, the surface of PEG containing materials displays valuable antifouling properties against proteins, bacteria and cell adhesion (Desai and Hubbell 1991). All of these advantages are combined with the fact that numerous PEG containing hydrogels are approved by the US Food and Drug Administration (FDA) for various clinical uses (Peppas et al. 2006). It can be considered that introducing PEG in the composition of the crosslinker was an important milestone in the development of degradable hydrogels for biomedical application,which emerged in the pioneer work of Sawhney et al. (Sawhney et al.

1993) (Fig. 15).

The chemical structure of the crosslinker developed by Sawhney et al. (Sawhney et al.

1993) served as model to the development of many types of crosslinker. This model can be modulated to suit different properties and further, to meet the different requirements found in

biomedical applications. The hydrolysable segment included at each end of the PEG segment can be modified as needed (PLA, PGA, PCL or mixtures) to tune both the physical properties and the degradation rate. Sawhney et al. have mainly worked with homopolymers of PLA and PGA (Sawhney et al. 1993) while Chan-Park et al. have introduced PCL segments into the chemical structure of the crosslinker (Chan-Park et al. 2004). A versatile choice is offered among the different hydrolysable materials.

O

O H H

n O

O

O

O + m

Sn(Oct)₂

NEt₃ ^Cl

O

O O

n

O O

O

O O

O

m m

O O

n

O H O

O

O m m

H

Figure 15. Synthesis of the triblock PLA-PEG-PLA diacrylate (Sawhney et al. 1993).

In addition to this, the model used for the synthesis of these materials has the advantage to also tailor the length of each hydrolysable segment composing the crosslinker (hydrolyable oligomer, PEG segment and either the double bond extremities). Thus, physical properties of polymer networks obtained with these crosslinkers can be finely tuned by changing the molecular weight, the composition and the architecture of the crosslinkers (Burdick et al.

2001, Jiao et al. 2006). Although acrylate was widely used to introduce polymerizable bonds in the structure of the crosslinker, other chemicals can be included such as methacrylate,

urethane methacrylate (Bencherif et al. 2009a,b), glycidyl methacrylate (Wang et al. 2010) or fumarate (Grijpma et al. 2005).

Zhu et al. have suggested replacing the PEG segments of the crosslinker by Pluronic® which is a triblock copolymer of PEG-PEO-PEG (Fig. 16) (Zhu et al. 2005). A new value was introduced in the hydrolysable crosslinker which gave thermosensitive properties to the final materials. Indeed, at low temperature, the hydrogel obtained with this crosslinker swells when it is placed in an aqueous solution but it shrinks at human body temperature. Such crosslinkers were designed with PLA (Zhu et al. 2005) and PCL (Wang et al. 2010) as hydrolysable segments.

Figure 16. PLA-PEG-PPO-PEG-PLA diacrylate macromers (Zhu et al. 2005)

Replacing PEG by glycerol resulted in the synthesis of star shaped crosslinkers; as shown in Fig. 17 (Grijpma et al. 2005, Jiao et al. 2006). Indeed, the hydroxyl groups of glycerol can initiate the ROP with the different monomers which can be used to add the hydrolysable polymer segments to the crosslinker. By increasing the number of vinyl groups on the crosslinker structure, longer inhibition times for the mass loss was observed during degradation studies performed on corresponding hydrogels. It can be explained by the necessity to break more degradable units to release the crosslinking chain (Anseth et al.

2002).

n

Figure 17. Chemical structure of PLA-glycerol-PLA triacrylate.

In complement to the series of triblock PLA-PEG-PLA diacrylate macromers, macromers with a reverse sequence arrangement were proposed by Clapper et al. (Clapper et al. 2007) in which PLA is the central block as illustrated in Fig. 18. The synthesis of this copolymer is more complicated than that of PLA-PEG-PLA macromers requiring multiples chemical modifications (Fig. 18).

Figure 18. Chemical structure and scheme of the synthesis of PEG-PLA-PEG diacrylate crosslinker (Clapper et al. 2007).

In general, this crosslinking agent is formed with a block of PLA of low molecular weight (MW < 2000). It contains more PEG than the corresponding reverse sequence. It is well-known that the balance in the content of PLA and PEG in the crosslinking agent influences the swelling and degradation properties of hydrogels in which it is incorporated.Consequently, an increasing amount of PEG implies a faster degradation profil.

In the model of PEG-PLA-PEG crosslinker described previously, the polyester segments can be replaced by poly(malic acid) (PMA) to obtain a triblock PMA-PEG-PMA diacrylate crosslinker (Poon et al. 2009). However, this method required several synthesis steps to form the cyclic compound necessary for the ROP. A less complex method was developed via the addition of polymerizable double bonds on PMA obtained by polycondensation (Leboucher-Durand et al. 1996). In this case, chemical modifications are performed on the carboxylic pendant groups of the PMA chain. For example, this approach was used to graft HEMA residues on PMA chains to make possible the formation of crosslinked PMA (He et al. 2006).

3.2.2. Hydrolysable crosslinkers containing hydrolysable segments