As elastic materials, hydrogels can exert forces against confining or attached structures. As will be described later, the degree of swelling and shrinking of hydrogels can be affected by physical and chemical stimuli. Thus, the hydrogels can act as “artificial muscles,” which direct the motion of such structures. This property has also been utilized in controlled-release applications.

This chapter serves as an introduction to hydrogels. More details can be found in the references listed at the end of the chapter. We first describe methods of synthesis. We then discuss factors that affect their swelling, elasticity, solute partitioning, and permeability properties. Finally, examples of present and future applications in the pharmaceutical arena are presented.

“Natural” hydrogels are produced from biological polymers. Because they are the result of biological synthesis, the structure of biopolymers comprising the hydrogels is often well controlled. Their building blocks, by nature, are often biocompatible, although care must be taken to purify the biopolymers and remove antigens and pyrogens. Examples of biopolymers used to form natural hydrogels include fibrous proteins such as collagen, gelatin (denatured collagen), and fibrin and polysaccharides such as calcium alginate, agarose, hyaluronic acid, cellulose and its derivatives, dextrans, chitosan, carrageenans, pectins, and pullulans.

Long-chain biopolymers often form physical cross-links by winding two or more chains to form helical domains. Such cross-links can be loosened by melting or by applying chemical denaturants. Calcium alginate hydrogels are produced when alginic acid chains form coordination complexes that are wrapped around calcium ions, leading to a so-called “egg case” structure. When calcium is replaced with sodium ions, these cross-linking structures are dissolved and the alginate becomes fluid. Physical cross-linking can also occur by formation of microcrystalline domains, usually driven by hydrogen-bonding interactions, as in cellulose, or by aggregation of hydrophobic domains as in pullulans.

Physical cross-links are advantageous since they can often be formed and reversed by mild processing techniques. On the other hand, physical cross-links may not be permanent, and with persistent stress, physically cross-linked hydrogels may deform permanently. Hydrogels formed from fibrous proteins can form more permanent, stress-resistant structures if they are chemically cross-linked. Here, a linker molecule such as glutaraldehyde forms covalent bonds between side chains on separate protein molecules. Companies specializing in biochemicals sell a variety of such cross-linkers, which are also used for protein conjugation. Chemical cross-linking of polysaccharides is often accomplished by chemistries that have been developed for synthetic polymers, as will be described in the following texts. Alternatively, biopolymers can be cross-linked by exposure to radiation, which works by forming free radicals along different polymer chains, which find each other and recombine, forming covalent cross-links.

Synthetic polymers and their hydrogels are usually formed from petroleum-based organic chemicals. Except for some unusual cases, these systems exhibit less intrinsic structural regularity than biopolymers. Also, only a limited set of synthetic hydrogels are biocompatible. Nevertheless, synthetic hydrogels can be produced cheaply, and their chemical compositions and network structures are easily studied and controlled. In recent decades, there have been major advances in the synthesis of organic polymers, resulting in improved quality of hydrogels. Here, we will describe several methods for preparing hydrogels, beginning with a brief review of polymer synthesis.

In step-growth polymerization, polymer-building blocks or monomer units contain end groups that react with each other to form larger molecules having the same end groups. Imagine a monomer with two end groups, say A and B, that react with each other. Two monomers of structure A–B will form a dimer of structure A–B′–A′–B. The prime symbols in the middle indicate that the joined A and B units might be modified as a result of the reaction. For example, if A is an acid group and B is a hydroxyl group, then B′–A′ will be an ester linkage. If A is an acid group and B is an amide group, then B′–A′ will be an amide linkage. In these two examples, a water molecule is liberated in a condensation reaction. However, the dimer still retains unmodified A and B end groups, which can enter into reaction with other A–B monomers. Similarly, already formed chains with A and B end groups can react with each other to form even longer chains. Thus, reactions such as

$A-{[B^{\prime }-A^{\prime }]}_x-B+A-{[B^{\prime }-A^{\prime }]}_{y}B\to A-{[B^{\prime }-A^{\prime }]}_{x+y}-B$

are possible, for any chain lengths x and y. If the reactions are condensations, then the step-growth polymerization can also be called a condensation polymerization. The two reactions mentioned earlier lead, respectively, to polyesters and polyamides. It should be noted that A and B need not be distinct, provided that an end group can react with an identical end group. For example, two organic acids, –COOH, can combine to form an anhydride linkage, with a water molecule liberated. It is also possible to perform step-growth polymerizations from the initial monomers, A–A and B–B, since these can react to form A–A′–B′–B, which can then go on to form longer polymer chains.

Since condensation reactions are reversible, water removal is usually required for sustained growth. Also, step-grown reactions are particularly sensitive to impurities containing only one reactive end, which will cap the polymer and prevent further growth.

In chain-growth or addition polymerization, individual chains form by initiation at one end, where a reaction center is formed. Monomers are then added, one by one, during propagation steps, with the reactive center shifting to the last monomer added. Propagation proceeds until a termination event occurs, in which the growing chain reacts with a species that permanently blocks further monomer addition.

Free radical polymerization, along with other addition polymerizations, possesses several advantages. It is relatively easy to carry out, and there exists a wide variety of vinylic monomers containing different side chains, which endow the polymer with desired properties. More than one monomer species can be included in a polymerization in order to fine-tune these properties or to confer two or more properties at once. Polymers containing more than one monomeric species are called copolymers. The structure of a copolymer depends on the rate that each monomer reacts with its own kind rather than with other types of monomers. When there are two types of monomers, chain propagation proceeds according to the following mechanism:

$\begin{array}{l}-{\text{M}}_1\cdot +{\text{M}}_1\stackrel{k_{11}}{\to }-{\text{M}}_1-{\text{M}}_1\cdot \\ -{\text{M}}_1\cdot +{\text{M}}_2\stackrel{k_{12}}{\to }-{\text{M}}_1-{\text{M}}_2\cdot \\ -{\text{M}}_2\cdot +{\text{M}}_1\stackrel{k_{21}}{\to }-{\text{M}}_2-{\text{M}}_1\cdot \\ -{\text{M}}_2\cdot +{\text{M}}_2\stackrel{k_{22}}{\to }-{\text{M}}_2-{\text{M}}_2\cdot \end{array}$

where k₁₁, k₁₂, k₂₁, and k₂₂ are the propagation rate constants. The reactivity ratios r₁ = k₁₁/k₁₂ and r₂ = k₂₂/k₂₁ provide information regarding the preference of monomers to react with their own kind and, hence, the tendency of monomers to be arranged (1) in blocks or (2) in alternating sequences. If r₁ and r₂ are much larger than unity, the likelihood of forming blocks of similar monomers increases, while if both are less than unity, the monomers tend to be arranged alternately. When the product r₁r₂ is close to unity, then the monomers are randomly incorporated in the copolymer chains, so long as the supply of both monomers remains adequate. It should be noted that unless special precautions are made, the monomer feed ratio will drift as the polymerization progresses, and there will be changes in monomer content.

Like step-growth polymerization, free radical polymerization produces chains whose lengths present a rather broad distribution. The reason for this is that the termination step can occur at any time, independent of the extent of propagation. Other kinds of addition polymerization can minimize such variability in chain length by suppressing the termination step. In anionic and cationic polymerizations, the growing chains have charged reaction centers at their growing ends, so termination by encounter between two chains does not occur. In ring-opening polymerization, the terminal monomer in a chain reacts with a cyclic-free monomer, which opens as it joins the polymer. Normally, there is no basis for interchain termination reactions.

In the past two decades, novel free radical polymerization schemes, including atom transfer radical polymerization (ATRP) and reversible addition-fragmentation chain transfer (RAFT) polymerization, have received much attention. In these schemes, most of the growing chain ends are “masked” by added reagents, slowing both the propagation and termination steps. Since termination is bimolecular, the likelihood of two unmasked chains finding each other and recombining or disproportionating is severely reduced. At the cost of slower polymerization, much more uniform polymer chain lengths are obtained.

We have already emphasized that the molecular weight of synthetic polymers is subject to random variation. Further structural variation can be introduced by copolymerization. Besides molecular weight and composition, another characteristic of a polymer is its tacticity. During an addition polymerization, the reactive center may be chiral with respect to the side chain, and sequential pairs of side chains may take on trans or cis configurations. Usually, this sequence of chiral additions is random, and the polymer is atactic. Chains in which all the side groups are added on the same side are called “isotactic,” whereas if the side groups alternate consistently, then the chain is considered syndiotactic. The latter two situations may require special polymerization conditions, e.g., catalysts, but there is a potential benefit insofar as the resulting polymers can form crystalline domains, or crystallites, by aligning with neighboring chains. Such crystalline domains form physical crosslinks, which may be stable even in the presence of solvent. For example, properly processed polyvinyl alcohol (PVA) can form stable hydrogels that absorb a substantial amount of water, even though there is no chemical cross-linking. Atactic polymers cannot crystallize. Similarly, copolymers must either consist of long homomonomeric blocks (blocks containing the same monomer) or long alternating sequences, in order to crystallize.

Since cross-links provide cohesiveness to the hydrogel, it follows that by incorporating biodegradable cross-linkers, the hydrogel can be programmed to lose its strength over time. This may be important for injectable and implantable systems, since it obviates the need to retrieve the hydrogel from the body after its purpose (e.g., for drug delivery or cell engraftment) has been served.