Hydrogels in Biology and Medicine: From Molecular Principles to Bionanotechnology

s, and 5 issued or pending patents on the use of microand nanoscale technologies and hydrogels in biomedical applications. His current research involves the synthesis and use of novel materials and technologies for regulating cellular behavior. He has received many awards including outstanding undergraduate research mentor at MIT (2004), outstanding graduate student award by the Biomedical Engineering Society (2005), and outstanding research in polymer science by OMNOVA/MIT (2005). He obtained his Ph.D. in Bioengineering from MIT (2005) and M.A.Sc. (2001) and B.A.Sc. (1999) degrees in Biomedical and Chemical Engineering from the University of Toronto. J. Zach Hilt is currently an Assistant Professor of Chemical Engineering in the Department of Chemical and Materials Engineering at the University of Kentucky. He completed undergraduate degrees in Chemistry and Physics at Miami University (OH). While completing his Masters degree in Chemical Engineering at Purdue University, his research focused on the application of hydrogels in MEMS devices for sensor applications. He then focused on the microand nanoscale integration of hydrogels for diagnostic and therapeutic applications in his doctoral research at the University of Texas at Austin. His current research interests include the design of novel intelligent polymer networks, the development of new methods for the micro-/nanoscale synthesis and characterization of polymer networks, and the application of these polymer networks as functional components of medical microand nanodevices. He has received numerous awards, including a graduate student silver award from the Materials Research Society (2003) and an outstanding graduate student award from the IEEE Engineering in Medicine and Biology Society (2002). mers, ceramics, and metals have been used for many years in medical applications. In addition to the over 40 000 pharmaceutical preparations in use, it is estimated that currently there are over 8000 medical devices and 2500 diagnostic products that employ biomaterials being used in various medical applications. Despite the widespread use of materials in medicine, many biomaterials lack the desired functional properties to interface with biological systems and have not been engineered for optimized performance. Therefore, there is an increasing need to develop new materials to address such problems in medicine and biology. Hydrophilic polymers, and especially their crosslinked forms, known as hydrogels, are a class of biomaterials that have demonstrated great potential for biological and medical applications. The ability to engineer traditional hydrophilic polymers with specific material properties is hampered by lack of control of molecular weight, chain configuration, and polymerization kinetics. Hybrid materials have been developed to preserve the bulk properties of traditional polymers while making their molecular chains look more like proteins. The elusive goal of molecular recognition in synthetic polymer systems has been reached in certain cases. For example, acrylic gels have been designed with recognition capabilities by incorporating non-covalently crosslinked antibodies. These proteins couple the reversible-swelling character of the networks with molecular recognition by only swelling in the presence of a specific antigen. The advantage of using synthetic polymeric materials based solely on proteins or peptides is that it offers a high degree of control over properties. Peptides and proteins can be coded for specific properties using a basic knowledge of interand intrachain interactions. While these interactions are understood in other polymer systems, there is much less of an ability to control them. The present and future of biomedical materials development requires this degree of control prediction in the design, synthesis, and function of next-generation materials. Recent work with this principle in mind has resulted in protein-based materials with properties analogous to more widely used polymers, as well as new properties. These new materials have been generated with a variable degree of efficiency and complexity. Many of these hydrophilic polymer networks have a high affinity for water but are prevented from dissolving due to their chemically or physically crosslinked network. Water can penetrate in between the polymer chains of the polymer network, subsequently causes swelling and the formation of a hydrogel. Hydrogels are appealing for biological applications because of their high water content and biocompatibility. In the last couple of decades, hydrogels have attracted a great deal of attention, and significant progress has been made in designing, synthesizing, and using these materials for many biological and biomedical applications. Recent developments include the design and synthesis of novel hydrogels and their use in tissue engineering, drug delivery, and bionanotechnology. 2. Hydrogel Design, Structure, and Characterization The suitability of hydrogels as biomedical materials and their performance in a particular application depend to a large extent on their bulk structure. The most important parameters used to characterize the network structure of hydrogels are the polymer volume fraction in the swollen state (t2,s), the molecular weight of the polymer chain between two neighboring crosslinking points (Mc), and the corresponding mesh size (n). The polymer volume fraction in the swollen state is a measure of the amount of fluid imbibed and retained by the hydrogel. The molecular weight between two consecutive crosslinks, which can be either chemical or physical in nature, is a measure of the degree of crosslinking of the polymer. It is important to note that due to the random nature of the polymerization process itself only average values of Mc can be calculated. The correlation length or distance between two adjacent crosslinks, n, provides a measure of the space available between the macromolecular chains (e.g., for drug diffusion); again, it can be reported only as an average value. These parameters, which are related to one another, can be determined theoretically or through the use of a variety of experimental techniques. Two methods that are prominent among the growing number of techniques utilized to elucidate the structure of hydrogels are equilibrium-swelling theory and rubber-elasticity theory. The structure of hydrogels that do not contain ionic moieties can be analyzed by the Flory–Rehner theory. This combination of thermodynamic and elasticity theories states that a crosslinked polymer gel that is immersed in a fluid and allowed to reach equilibrium with its surroundings is subject only to two opposing forces: the thermodynamic force of mixing and the retractive force of the polymer chains. At equilibrium these two forces are equal. This physical situation is defined in terms of the Gibbs free energy: DGtotal =DGelastic +DGmixing (1) Here, DGelastic is the contribution due to the elastic retractive forces developed inside the gel, and DGmixing is the result of the spontaneous mixing of the fluid molecules with the polymer chains. The term DGmixing is a measure of the compatibility of the polymer with the molecules of the surrounding fluid. This compatibility is usually expressed by the polymer–solvent interaction parameter, v1. Differentiation of Equation 1 with respect to the number of solvent molecules while keeping temperature and pressure constant results in l1 –l1,o =Dlelastic +Dlmixing (2) In Equation 2, l1 is the chemical potential of the solvent in the polymer gel and l1,o is the chemical potential of the pure R EV EW N. A. Peppas et al./Hydrogels in Biology and Medicine Adv. Mater. 2006, 18, 1345–1360 © 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advmat.de 1347 solvent. At equilibrium, the difference between the chemical potentials of the solvent outside and inside the gel must be zero. Therefore, changes in the chemical potential due to mixing and elastic forces must balance each other. The change of chemical potential due to mixing can be expressed using heat and the entropy of mixing. The change in chemical potential due to the elastic retractive forces of the polymer chains can be determined from the theory of rubber elasticity. Upon equaling these two contributions, an expression for determining the molecular weight between two adjacent crosslinks of a neutral hydrogel prepared in the absence of a solvent can be written as