Hydrogels for biomedical applications

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Abstract

This article reviews the composition and synthesis of hydrogels, the character of their absorbed water, and permeation of solutes within their swollen matrices. The most important properties of hydrogels relevant to their biomedical applications are also identified, especially for use of hydrogels as drug and cell carriers, and as tissue engineering matrices.

Introduction

Since the pioneering work of Wichterle and Lim in 1960 on crosslinked HEMA hydrogels [1], and because of their hydrophilic character and potential to be biocompatible, hydrogels have been of great interest to biomaterial scientists for many years [2], [3], [4], [5], [6], [7], [8], [9]. The important and influential work of Lim and Sun in 1980 [10] demonstrated the successful application of calcium alginate microcapsules for cell encapsulation. Later in the 1980s, Yannas and coworkers [11] incorporated natural polymers such as collagen and shark cartilage into hydrogels for use as artificial burn dressings. Hydrogels based on both natural and synthetic polymers have continued to be of interest for encapsulation of cells [12], [13], [14], [15] and most recently such hydrogels have become especially attractive to the new field of ‘tissue engineering’ as matrices for repairing and regenerating a wide variety of tissues and organs [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41].

Hydrogels are hydrophilic polymer networks which may absorb from 10–20% (an arbitrary lower limit) up to thousands of times their dry weight in water. Hydrogels may be chemically stable or they may degrade and eventually disintegrate and dissolve. They are called ‘reversible’, or ‘physical’ gels when the networks are held together by molecular entanglements, and/or secondary forces including ionic, H-bonding or hydrophobic forces [42], [43]. Physical hydrogels are not homogeneous, since clusters of molecular entanglements, or hydrophobically- or ionically-associated domains, can create inhomogeneities. Free chain ends or chain loops also represent transient network defects in physical gels.

When a polyelectrolyte is combined with a multivalent ion of the opposite charge, it may form a physical hydrogel known as an ‘ionotropic’ hydrogel. Calcium alginate is an example of this type of hydrogel. Further, when polyelectrolytes of opposite charges are mixed, they may gel or precipitate depending on their concentrations, the ionic strength, and pH of the solution. The products of such ion-crosslinked systems are known as complex coacervates, polyion complexes, or polyelectrolyte complexes. For example, the calcium alginate capsules of Lim and Sun [10] were coated with a complex coacervate of alginate–poly(l-lysine) (PLL) in order to stabilize the capsule. Complex coacervates and polyion complex hydrogels have become attractive as tissue engineering matrices. Sometimes, physical gels can form from biospecific recognitions, such as Conconavalin A with a polymeric sugar [44], or avidin with a polymeric biotin [45]. All of these interactions are reversible, and can be disrupted by changes in physical conditions such as ionic strength, pH, temperature, application of stress, or addition of specific solutes that compete with the polymeric ligand for the affinity site on the protein.

Hydrogels are called ‘permanent’ or ‘chemical’ gels when they are covalently-crosslinked networks. The synthetic hydrogels of Wichterle and Lim [1] were based on copolymerization of HEMA with the crosslinker EGDMA (see Abbreviations for definitions of acronyms). Chemical hydrogels may also be generated by crosslinking of water-soluble polymers, or by conversion of hydrophobic polymers to hydrophilic polymers plus crosslinking to form a network. Sometimes in the latter case crosslinking is not necessary. For example, in the hydrolysis of PAN to form amide and acid groups from the nitrile groups, if the nitrile groups remain in sufficient concentration and association, they can stabilize the hydrogel by hydrophobic interactions, thus forming a physical hydrogel. In the crosslinked state, crosslinked hydrogels reach an equilibrium swelling level in aqueous solutions which depends mainly on the crosslink density (estimated by the MW between crosslinks, Mc). Like physical hydrogels, chemical hydrogels are not homogeneous. They usually contain regions of low water swelling and high crosslink density, called ‘clusters’, that are dispersed within regions of high swelling, and low crosslink density. This may be due to hydrophobic aggregation of crosslinking agents, leading to high crosslink density clusters [46]. In some cases, depending on the solvent composition, temperature and solids concentration during gel formation, phase separation can occur, and water-filled ‘voids’ or ‘macropores’ can form. In chemical gels, free chain ends represent gel network ‘defects’ which do not contribute to the elasticity of the network. Other network defects are chain ‘loops’ and entanglements, which also do not contribute to the permanent network elasticity.

There are many different macromolecular structures that are possible for physical and chemical hydrogels. They include the following: crosslinked or entangled networks of linear homopolymers, linear copolymers, and block or graft copolymers; polyion–multivalent ion, polyion–polyion or H-bonded complexes; hydrophilic networks stabilized by hydrophobic domains; and IPNs or physical blends. Hydrogels may also have many different physical forms, including (a) solid molded forms (e.g., soft contact lenses), (b) pressed powder matrices (e.g., pills or capsules for oral ingestion), (c) microparticles (e.g., as bioadhesive carriers or wound treatments), (d) coatings (e.g., on implants or catheters; on pills or capsules; or coatings on the inside capillary wall in capillary electrophoresis), (e) membranes or sheets (e.g., as a reservoir in a transdermal drug delivery patch; or for 2D electrophoresis gels), (f) encapsulated solids (e.g., in osmotic pumps), and (g) liquids (e.g., that form gels on heating or cooling).

A wide and diverse range of polymer compositions have been used to fabricate hydrogels, and Table 1 summarizes the many varied compositions. The compositions can be divided into natural polymer hydrogels, synthetic polymer hydrogels and combinations of the two classes. Many different routes have been used to synthesize hydrogels, and they are summarized in Table 2 and shown schematically in Fig. 1, Fig. 2, Fig. 3, Fig. 4.

Section snippets

Water in hydrogels

The character of the water in a hydrogel can determine the overall permeation of nutrients into and cellular products out of the gel. When a dry hydrogel begins to absorb water, the first water molecules entering the matrix will hydrate the most polar, hydrophilic groups, leading to ‘primary bound water’. As the polar groups are hydrated, the network swells, and exposes hydrophobic groups, which also interact with water molecules, leading to hydrophobically-bound water, or ‘secondary bound water

Pores and permeation in hydrogels

The amount of water in a hydrogel, i.e. the volume fraction of water, and its free vs. bound water ‘character’ will determine the absorption (or partitioning) and diffusion of solutes through the hydrogel. Pores may be formed in hydrogels by phase separation during synthesis, or they may exist as smaller pores within the network. The average pore size, the pore size distribution, and the pore interconnections are important factors of a hydrogel matrix that are often difficult to quantitate, and

Hydrogels as tissue engineering matrices

When parts or the whole of certain tissues or organs fail, there are several options for treatment, including repair, replacement with a synthetic or natural substitute, or regeneration. Fig. 5 shows how tissue or organ injury, disease or failure has evolved to reach the field of tissue engineering. Tissue repair or replacement with a synthetic substitute is limited to those situations where surgical methods and implants have achieved success. Although implants have been a reasonably successful

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