Hydrogels in Healthcare: From Static to Dynamic Material Microenvironments

Abstract

Advances in hydrogel design have revolutionized the way biomaterials are applied to address biomedical needs. Hydrogels were introduced in medicine over 50 years ago and have evolved from static, bioinert materials to dynamic, bioactive microenvironments, which can be used to direct specific biological responses such as cellular ingrowth in wound healing or on-demand delivery of therapeutics. Two general classes of mechanisms, those defined by the user and those dictated by the endogenous cells and tissues, can control dynamic hydrogel microenvironments. These highly tunable materials have provided bioengineers and biological scientists with new ways to not only treat patients in the clinic but to study the fundamental cellular responses to engineered microenvironments as well. Here, we provide a brief history of hydrogels in medicine and follow with a discussion of the synthesis and implementation of dynamic hydrogel microenvironments for healthcare-related applications.

Keywords: Hydrogels; biomaterials; cellular microenvironment; dynamic; tissue engineering.

Figure 1

Applications of hydrogels in healthcare. These examples cover a range of hydrogel microenvironments from static to dynamic that have been employed to address clinical needs. This list is not comprehensive but depicts some of the prominent hydrogels used in clinical applications.

Figure 2

The relationship between cross-linking density and hydrogel properties. Two network structures representative of low and high cross-linking densities are depicted to demonstrate the relationship between cross-linking density and basic hydrogel properties for highly swollen, nonionic gels: shear modulus (G), equilibrium swelling ratio (Q) and diffusivity (D). As cross-linking density increases mesh size (ζ), which is a measure of the space that is available between macromolecular chains for the diffusion decreases.

Figure 3

Dynamic hydrogel microenvironments. Hydrogel networks can be tailored to be responsive to a continuum of stimuli ranging from user-defined to cell and tissue-dictated. This schematic highlights a few specific examples of the mechanisms currently used to elicit dynamic responses in hydrogel materials that will be reviewed. The orange macromolecular chain segments represent photodegradable linkages that can be manipulated to degrade a hydrogel (far left) or release bioactive moieties (left middle). The green and purple chains depict a thermoresponsive hydrogel that assembles or disassembles in response to temperature (right middle). The pink macromolecular chain segments illustrate cell-responsive linkages that degrade the hydrogel upon enzyme secretion (right).

Figure 4

User-defined, photoresponsive dynamic hydrogels. a) Photocleavage of courmarin-caged-thiols enables spatial and temporal patterning of multiple growth factors in 3D. Reprinted by permission from Macmillan Publishers Ltd: Nature Materials [47], copyright 2011. b) Photodegradable hydrogel networks containing-nitrobenzyl ether moieties in the cross-linking molecules can be used to guide cellular outgrowth. Scale bar, 100 μm. Reprinted by permission from Macmillan Publishers Ltd: Nature Chemistry [50], copyright 2011. c) Photoisomerization of azobenzene cross-linkers facilitates delivery of small therapeutic molecules modeled by fluorescein release upon UV irradiation. Reproduced in part from [53] with permission of The Royal Society of Chemistry.

Figure 5

User-defined dynamic mechanisms in hydrogels that respond to temperature and electromagnetic fields. a) Poly(N-isopropylacrylamide) (PNIPAAm) swells or deswells in response to temperature changes near its lower critical solution temperature (LCST), which is near physiological temperature. b) Pluronic F127 is a triblock co-polymer that exhibits thermoreversible, physical gelation in response. c) A dually responsive system of drug-loaded polypyrrole nanoparticles in a thermoresponsive hydrogel matrix enable gelation upon injection and drug release triggered by an electric field.

Figure 6

Cell-dictated degradation of a hydrogel. Cells naturally produce and secrete enzymes called matrix metalloproteinases (MMP). Incorporation of MMP-cleavable sequences into a hydrogel allows cell migration throughout the construct such as fibroblast migration from a cell-loaded fibrin clot depicted here. Scale bar, 150 μm. Reprinted from [87], copyright (2003) with permission from National Academy of Sciences, U.S.A.