Polymeric hydrogels are of special importance in polymeric biomaterials because of

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1 POLYMERIC HYDROGELS

2 Polymeric hydrogels are of special importance in polymeric biomaterials because of their favorable biocompatibility. Hydrogels are cross-linked macromolecular networks formed by hydrophilic polymers swollen in water or biological fluids. The cross-links can be formed by either covalent bonds or physical cohesion forces that exist between the polymer segments. Polymeric hydrogels are primarily classified into chemical and physical hydrogels (based on the bonding type of the cross-links), though they can also be classified in many other ways. Chemical hydrogels can be prepared by copolymerization of a monomer with cross-linker, or by cross-linking of water-soluble polymers. Physical hydrogels can be made of natural biopolymers, thermo-sensitive synthetic polymers, amphiphilic triblock copolymers or many other copolymers.

3 Introduction Of many polymeric biomaterials, hydrogels are of special interest because of their favorable biocompatibility and a host of unique advantages that accompany them. For example, hydrogels play an important role in controlled drug delivery: they are able to deliver delicate bioactive agents such as proteins and peptides. In addition, hydrogels have also been reported to promote tissue repair and regeneration. Definition of Hydrogels Hydrogels are cross-linked macromolecular networks formed by hydrophilic polymers swollen in water or biological fluids. Their three-dimensional networks can retain large volumes of water in the cross-linked structures. The extent of swelling and the content of water retained depend on two factors: the hydrophilicity of the polymer chains and the cross-linking density. The cross-links can be formed by covalent bonds. Alternatively, they can be formed by physical cohesion forces that exist between the polymer segments- such as ionic bonding, hydrogen bonding, van der Waals forces, or forces that arise due to hydrophobic interactions (Figure 7-1 ).

4 Hydrogels can also be described in a rheological way. Aqueous solutions of hydrophilic polymers without cross-linking at low concentration (where no significant chain entanglements occur) normally show Newtonian behavior. However, the cross-linked polymer networks- either chemically or physically - show visco-elastic and sometimes pure elastic behavior upon swelling in water. Figure 7-1 Schematic presentation of (a) chemically cross-linked hydrogel; and (b) physical hydrogel with multiple interaction zones

5 Classification of Hydrogels Polymeric hydrogels can be classified in two different ways as follows : Based on the bonding type of the cross-links, hydrogels are divided into chemical and physical hydrogels (Figure 7-2). Figure 7-2 Classification of polymeric hydrogels based on the bonding type of the cross-links

6 Based on the sources of the polymers, hydrogels are classified into natural hydrogels, synthetic hydrogels, and natural and synthetic combination hydrogels (Figure 7-3). In addition to the above classifications, Figures 7-4 to 7-6 show other forms of classification based on polymer structures, physical properties, and biodegradability. Figure 7-3.

7 Figures 7-4 Figures 7-5 Figure 7-6 Classification of polymeric hydrogels based on the biodegradability of the polymer

8 Chemical Hydrogels and Their Biomedical Applications Polymer networks of chemical hydrogels are formed by chemical cross-linking through covalent bonding. Chemical hydrogels are also called permanent hydrogels. They cannot be dissolved in water or other solvents unless the covalent cross-links are cleaved. Chemical hydrogels are mainly prepared using one of these approaches : Copolymerization of a monomer with cross-linker; Cross-linking of water-soluble polymers with cross-linker; Cross-linking of water-soluble polymers with irradiation.

9 Copolymerization of Monomer with Cross-linker Free radical polymerization of water-soluble monomers in the presence of cross-linker results in chemical cross-linked hydrogels Figure 7-7 Formation of chemical hydrogel by copolymerization of a monomer with cross-linker

10 Cross-Linking of Water-Soluble Polymers Cross-linking of water-soluble multifunctional polymers by reaction between the functional groups results in chemical hydrogels (Figure 7-10(a)). Besides this approach, cross-linking of water-soluble multifunctional polymers by addition of bifunctional or multifunctional reagents also results in chemical hydrogels (Figure 7-10(b)). Figure 7-10 Preparation of hydrogel by cross-linking of water soluble polymers (a) reaction between functional groups; (b) reaction with cross-linker

11 Physical Hydrogels and Their Biomedical Applications Physical hydrogels are continuous, disordered, and three-dimensional hydrophilic polymer networks formed by cohesion forces capable of constituting non-covalent cross-links [2]. The cohesion forces include ionic bonding, hydrogen bonding, van der Waals forces, as well as forces that arise due to hydrophobic interaction, stereocomplexation, crystallization, and other weak interactions. Since physical hydrogels are not covalently cross-linked, the formation of the physical cross-links is largely dependent on the thermodynamic parameters of the medium such as temperature, ph, salt type, and ionic strength. This also means that the formation is reversible upon change in any of these thermodynamic parameters - which renders a physical hydrogel as an in situ gelation system in water without any chemical reaction. This property thus makes it feasible to utilize physical hydrogels in macromolecular drug delivery and tissue engineering applications because of their simplicity and safety in in vivo situations.

12 1- Natural Biopolymer Hydrogels Typical natural biopolymers that form physical hydrogels include proteins such as collagen and gelatin, and polysaccharaides such as agarose, amylose, and cellulose derivatives [9]. Renaturation to the triple helical conformation in the proteins and double helical conformation in polysaccharides induces physical cross-linking during gel formation. As an example, type I collagen is predominant in higher order animals especially in the skin, tendon, and bone where extreme forces are transmitted. Figure shows the chemical, secondary, tertiary, and quaternary structures of type I collagen. Figure 7-13 Chemical structure of type I collagen: (a) primary amino acid sequence; (b) secondary left-handed helix and tertiary right-handed triple-helix structure; (c) staggered quaternary structure.

13 A helix formation followed by aggregation of the helices results in a junction point, which acts as physical cross-linking for the gelation of the biopolymer aqueous solution (Figure 7-14). The attractiveness of collagen and gelatin as biomaterials stems from the view that they are natural materials of low immunogenicity. Figure 7-14 Gelation mechanism of biopolymers in water: random coils become helices, which subsequently aggregate to form the junction zones of a gel.

14 2- Thermo-shrinking Hydrogels Aqueous solutions of some polymers, such as poly(n4sopropylacrylamide) (poly(nipaam) as shown in Figure 7-16), undergo precipitation upon temperature increase. The temperature at which a polymer solution undergoes precipitation is called low critical temperature (LCST). Below LCST, the enthalpy term - which is mostly contributed by the hydrogen bonding etween polymer polar groups and water molecules - leads to dissolution of the polymer. Hydrogels made of such polymers or their copolymers accordingly undergo shrinking upon temperature increase. Hence they are known as thermo-shrinking hydrogels. Figure 7-16 Chemical structure of poly(n-isopropyl acrylamide).

15 Thermo-shrinking hydrogels undergo thermally reversible swelling and deswelling. It was found that an aqueous solution of high-molecular-weight NiPAAM/acrylic acid copolymer (2-5 mol%) showed reversible gelation above a critical concentration (-4 wt%), without noticeable hysteresis at around 32 C. This resulted in an opaque, loose gel that was deformable under shear stress. It was proposed that such properties could be used for the design of a refillable macrocapsule-type biohybrid artificial pancreas. another significant advantage of the gel was its higher permeability (brought about by the gel's heterogeneous character), which then helped to facilitate insulin secretion from the entrapped islets.

16 3- Amphiphilic Triblock Copolymer Hydrogels Recently, physical hydrogels formed by synthetic amphiphilic triblock copolymers and their potential applications in drug delivery have attracted special attention. As an illustration, the temperature-induced sol-gel transition behavior of block copolymers of poly(ethy1ene glycol)-poly(propy1ene glycol)-poly(ethy1ene glycol) (PEG-PPG-PEG as shown in Figure 7-17) have been extensively studied and utilized to deliver drugs such as polypeptides and proteins. Figure 7-17 Chemical structure of PEG-PPG-PEG triblock copolymer

17 Another well-studied triblock copolymer that undergoes temperature induced gelation is poly(ethy1ene glycol)-poly(l-lactide)-poly(ethy1ene glycol) (PEG-PLLA-PEG as shown in Figure 7-18). However PEG-PLLA-PEG differs from PEG-PPG-PEG in that it is biodegradable - due to the PLLA block. Figure 7-18 Preparation of PEG-PLLA-PEG triblock copolymer

18 4- Other Novel Synthetic Copolymer Physical Hydrogels More novel physical hydrogel systems formed with temperature- or ph-sensitive copolymers or based on complexation of enantiomeric polymer or polypeptide segments have also been reported recently. Graft copolymers of poly(n-isopropyl acry1amide)-poly(acry1ic acid) were synthesized and found to undergo temperatureinduced sol-gel phase transitions over a wide ph range

19 5- Polyelectrolyte Complex Hydrogels Some water-soluble polyelectrolyte copolymers can form hydrogels with metal ions or with another counter-charged polyelectrolyte polymer. Recently, we reported hydrogel formation between positively charged modified collagen and negatively charged synthetic polyelectrolyte terpolymer containing poly(methacrylic acid) under certain ph, ionic strength, and concentration of the polymers (Figure 7-21). The novel hydrogel system has been applied in tissue engineering for microencapsulation of hepatocytes that are used in bioartificial liver assist device. Figure 7-21 (a) Gel formation between modified collagen and terpolymer containing poly(methacry1ic acid) by ionic complexation; (b) chemical structure of polyelectrolyte terpol ymer

20 6- Supramolecular Hydrogels Formed by Cyclodextrins and Poly mers In the past decade, there have been extensive studies into the macromolecular self-assembly between polymers and cyclodextrins - when cyclodextrins thread onto the polymer chains. Such supramolecular structures are called polyrotaxanes. A new class of polymer hydrogels with novel supramolecular systems, which is suitable for a wide range of biomedical applications, has been developed based on the formation of polyrotaxanes (Figure 7-23). Figure 7-23 Schematic representation of supramolecular hydrogel formed by cyclodextrin and poly(ethy1ene glycol)

21 The supramolecular hydrogels were found to be thixotropic and reversible. The viscosity of the hydrogel greatly diminished as it was agitated (Figure 7-24(a)). This property renders the hydrogel formula injectable even through a fine needle. Figure 7-24(a) Viscosity changes of Gel-20K-60 as function of agitation time at a shear rate of 120 s-'

22 The diminished viscosity of the hydrogel eventually restored towards its original value, in most cases within hours, when there were no more agitations (Figure 7-24(b)). These thixotropic and reversible properties of the gel afford us with a unique injectable hydrogel drug delivery system. Now bioactive agents (such as drugs, proteins, vaccines, or plasmid DNAs) can be incorporated in the gel - which is in a syringe at room temperature - without any contact with organic solvents. The drug-loaded hydrogel formula can then be injected into the tissue under pressure because of the thixotropic property. After gelling is restored in situ, the hydrogel serves as a depot for controlled release. Compared to implantable hydrogels, the injectable hydrogel is definitely more appealing. Figure 7-24(b) Restoration of gel viscosities after 20-min agitation at a shear rate of 120 s-'