Hydrogel Preparation The Term Gels And Hydrogels

Published Date: 02 Nov 2017

CHAPTER 2

Hydrogel Preparation

The term gels and hydrogels are very commonly used amongst the biomaterial scientists to describe the polymeric crosslinked network structures. Gels are dilute crosslinked system and are usually strong or weak depending on their flow behavior in a steady state at a temperature (Ferry, 1980). Gels that are edible are widely used in the food industry such as polysaccharides, gelatin and pectin (Philips., et al., 2000).

Gelatin is a link of macromolecular chains which together would lead to a large branched and soluble polymer which depends on the structure and the starting material used to produce it. This type of mixture is called a ‘sol’. The continuation of the linking process would definitely result in a widely branched polymer with decreased solubility. This is now termed as ‘gel’ and which has been permeated with micro molecules known as ‘sol-gel transition’ and the gel point forms. A gel point is the critical point where the gel first forms in the solution (Rubinstein et al., 2003). Another term used for sol-gel transition is gelation.

Hydrogels could be prepared using various ways but it all depends on the structure design and the application it will be used on. Gelation would happen either by physical crosslinking or chemical crosslinking. The few methods of preparation are,

Free Radical Polymerization

Irradiation Crosslinking of Polymers

Chemical Crosslinking of Polymers

Physical Crosslinking of Polymers

Ionic Interaction

Hydrogen Bonding

Hydrophobic Association

Free Radical Polymerization

This method is the most preferred method for the hydrogel preparation as it is mostly based on monomers such as acrylates, vinyl lactams and amides. This method could also be used for hydrogels prepared with natural polymers that have suitable functional groups. This method of preparation involves a typical four steps which are initiation, propagation, chain transfer and termination (Peppas et al., 2000).

Figure 2. Four steps of Free Radical Polymerization (Bajpai A.K. et al., 2008).

The free radical polymerization could be performed in solution or neat by itself. Since solution polymerization is highly favored during the synthesis of large batch of hydrogels, water is used as the common solvent. Nevertheless, other polar solvents could also be used if they could be exchanged by water by hydration. The neat polymerizations usually have a higher advantage than solution polymerization because it is very fast and there is no need for solvent to be removed. In order to remove the solvent, it takes a longer time to do it (Peppas et al., 2000).

Free radical emulsion and suspension polymerizations are also used to prepare hydrogels. Usually this free radical polymerization is the way to create hydrogels in the form of beads and microspheres. Therefore, this way is very good for creating hydrogels that could be used as matrices for drug delivery system. As in this method defines, a predetermined amount of suspension agent or an emulsifier is placed together with the monomer, the solvent and the initiator. The procedure is quite simple but it is only difficult dispose of the emulsifier or the suspension agent. Methylene bisacrylamide is one of the most used bi-functional crosslinking agents for hydrogels that are made based on acrylamide monomers (Peppas et al., 2000).

Figure 2. Synthesis of hydrogel by free radical polymerization (Bajpai A.K. et al., 2008).

Irradiation Crosslinking of Polymers

Simultaneous sterilization combined with ionizing techniques is convenient tools for synthesizing hydrogels. The ionizing radiations possess high energy that could ionize molecules both in the air and water. This irradiation includes both electron beam and γ-irradiation which when radiate a polymer solution, could form many reactive sites along the polymer backbone. The combination of these radicals forms many crosslinks. The hydrogels can be formed in bulk or in solution using this technique. This technique also uses less energy for macro radical formation. In the solution, the efficiency of the radical could also be higher due to the viscosity reduction of the reaction mixture (Masteikova et al., 2003).

There are many advantages to applying irradiation to hydrogel during the preparation compared to other conventional methods such as,

No catalysts or additives are added to initiate the irradiation process.

The method is very simple.

The degree of crosslinking can be controlled easily by differentiating the irradiation dosage.

Due to the said advantages, this technique of hydrogel production is greatly favored in the biomedical and pharmaceutical areas where the slightest contamination is undesirable. Nevertheless, the irradiation is not preferred for polymers that could degrade under the ionizing irradiation. Every polymer system is unique on its own way and therefore, every irradiation and external conditions are monitored to ensure minimal degradation and maximize the crosslinking occurrence (Haque et al., 2012).

Chemical Crosslinking of Polymers

This method is one of the very fundamental methods of hydrogel preparation. It basically combines the addition of a bi-functional crosslinking agent to dilute solutions of the hydrophilic polymers that have a suitable functionality which would be able react with the crosslink agent provided. The reaction with the gelatin is usually performed in the solution but it could also be performed in a suspension if required to form beads, spheres or micro particles. This method is very suitable for reactions with natural or synthetic polymers. In the naturally occurring hydrophilic polymers such as gelatin and albumin, they could be crosslinked with a functional dialdehyde or formaldehyde (Bajpai A.K. et al., 2008).

Chemical gelation involves the formation of covalent bonds and therefore produces strong hydrogels (Syed K.H. et al., 2011).

Figure 2. Polymerization of water soluble monomers in the presence of bi-or multifunctional crosslinking agent.

The gelatin is involved in the reaction between the aldehyde groups with an amino group along the albumin polymer backbone. By using an analogous approach, the diaminododecane catalyzed by dicyclohexycarbodiimide could be used to crosslink the chrondroitin sulfate. Transparent hydrogels are usually made by using this method (Peppas et al., 2000).

Figure 2. Diagram of chemical crosslinking using a chemical crosslinker (Syed K.H. et al., 2011).

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Figure 2. An example of hydrogel preparation by chemical crosslinking of an amino-bearing polymer using formaldehyde or a dialdehyde crosslinking agent (Bajpai A.K. et al., 2008).

Physical Crosslinking of Polymers

This method is one of the easiest methods ever to form a hydrogel. The physical crosslinking includes,

Ionic Interaction

Hydrogen Bonding

Hydrophobic Association

The hydrogels are usually prepared under milk and weak conditions. Physical hydrogels too can be categorized as strong physical gels and weak gels. Strong hydrogels have strong bonds between the polymer chains. Therefore, they are analogous to chemical hydrogels (Syed K.H. et al., 2011). The typical procedure usually involves solvent casting or precipitation techniques to cast the hydrogel films. Hydrophilic-hydrophobic polymers usually produce composite hydrogels that are phase separated. The blend of different polymers and still conserving their physical properties is a unique way to obtain a new structured material that is inexpensive (Bajpai A.K. et al,. 2008).

. The polymers would definitely show some synergistic properties. The advantages of these systems would include,

Easy fabrication of devices

Manipulation of device properties such as dehydration, degradation rate and the mechanical strength

Drug loading and utilizing it as micro reservoir

There are examples of strong physical gels with strong physical bonds such as lamellar microcrystals, glassy nodules or double and triple helices (Syed K.H. et al., 2011).

Figure 2. Hydrogel network formation due to low intermolecular H-bonding at low pH (Syed K.H. et al., 2011).

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Ionic Interaction

Another name for this method is called as the polyelectrolyte complexation. In this method, the hydrogels are easily formed because the links would form between the charged sites along the polymer backbone. The hydrogels formed using this method is usually insoluble in water and the electrolytic formation varies according to the pH stability of their system. Hydrogel complexes formed by the ionic interactions are usually divided either as strong acid-strong base, strong acid-weak base, weak acid-weak base, and weak acid-strong base (Bajpai A.K. et al,. 2008).

Hydrogen Bonding

The hydrogen bonding is also used in the fabrication of hydrogels. A hydrogen bond is typically formed between an electron deficient atom and a functional group with high electron density. The hydrogen bonded polymeric systems exists in many biological systems. There are a few factors that affect these hydrogels, such as,

Polymer concentration

Molar ratio of each polymer

Type of solvent used

Solution temperature

Polymer structure

Hydrophobic Interaction

Hydrogels could also be formed through hydrophobic interactions. Such polymer systems formed are,

Graft copolymers

Block copolymers

Polymers blends

These systems are usually form structures separated by hydrophobic micro domains. These domains act as an associated crosslinking sites in the whole polymeric structure and surrounded by hydrophilic water absorbing regions (Bajpai A.K. et al., 2008).

Figure 2. An example of hydrophobic interactions between polymers (Bajpai A.K. et al., 2008).

Usually the mechanical properties of these polymers are poor due to poor interfacial adhesion and macro phase polymer separation which causes the hydrogels are opaque when formed. In this method, the cost of hydrogel production is low. Therefore, hydrogels could be made commercially available and with high strength. These hydrogels are also soluble in organic solvents and flows at high temperature. These special characteristics help the hydrogel processing through a technique called the injection molding technique (Masteikova et al., 2003).

Block copolymers

Block copolymers traditionally contains chemically connected hydrophilic and hydrophobic segments that provide a varying morphology, both in solid state and in a few selective solvents. Polyampholytes which has two blocks of opposite charge that has synthetic analogs for proteins forms a block copolymer with unique properties (Bajpai A.K. et al., 2008).

Biodegradable aliphatic polyesters such as polylactic acid, polylactic acid-co-glycolic acid and poly (ε-caprolactone) are chemically modified to produce thermo sensitive block copolymers. These polymers are usually free flowing sols at room temperature and gels at body temperature, which makes them a perfect system to be used as injectable hydrogels for drug delivery system and cancel cell therapy (Bajpai A.K. et al., 2008).

The sol-gel transition of the thermosensitive block copolymers are not suitable for injecting into deep anatomical sites in the body because of the premature gelatin inside the catheter used to transfer the hydrogel. Nevertheless, this was overcome with the introduction of pH-sensitive sulfamethazine oligomer into the block copolymer which prevents the premature gelatin and degradation of the hydrogel. The sulfonamide modified block copolymer is also able to maintain its sol phase at body temperature and rapidly forms a gel when the physiological conditions are ideal for it (Bajpai A.K. et al., 2008).

Figure 2. Group transfer polymerization for the synthesis of acrylic block polymer.

Polymers Blends

Some natural polymers such as carbohydrates, gelatins, albumins, starches, agar, alginates and pectin can be used for films for packaging and agriculture, but their natural properties would not fit the specific application and thereby needs to blend with a synthetic polymer in order to fit the application. The natural polymers are usually combined with synthetic polymers such as polycaprolactone, polylactide and polyvinyl alcohol (Bajpai A.K. et al., 2008).

Binary polymeric blends of crosslinked starch and gelatin would undergo enzymatic degradation using the α-amylase. In this way, the hydrogels formed would be biodegradable. Hydrogel blends of polyvinyl alcohol and sodium sulfonate are flexible and transparent.

Figure 2. Diagram depicting a preparation of polymer blend.

Melt blending is another process that is done at high temperature at melt or near melt state by using the shearing force. This could be achieved by extrusion using blowing agents and compression molding. When two components in a common solvent are blend by adding a suitable precipitant, it is called solution blending. This is quite useful especially in casting films (Bajpai A.K. et al., 2008).