of diffusion control,there are two main drug distribution ge of control of the drug or protein release/delivery rate.Podual ometries that are used a (200) In e rate This type of has trol,the polymer can b ither deg ded by water ora chem 1996).Another ove is for the rele under the condition ved by and release the d into place ing the em and Per PAA-be in ee is carch in different y pertain to The de of tems (graft,block or comb-like polymers)hav on hydr in s (Pe of 1997 and"dis olution ofiles "Fo r thr not fully rele have t studies(Peppas and Wr 6)shc light on xhibit an unus ppa ntrol of the c spe ms to b prom ng teell a the to the amorphous c tually lead Certain hydroges may (PE and d by non bio active agent release proce The stability of the as ations is dependent on h fa lly Resp everal factors affe of th nperature,type of d OH a They include dcgree of ionization in the net structure ting ide de tics of protein stability and Don na equilibrium the chemical ntial of the ic icid-ethen col hvdrogels (Bell and cppa a hibit A kkalanka c ium is est blished in the form of doub fixe the group of MAA and the ether ges on ependant groups a ge nthe gel cts th welling of th Work on environmentally re spac in veral ating pre the pH and mperature-sensi 199% clot ple,various types of olyN-i to further deve lop and char e the structure c f pre do nave drug very.Acry tions in the past 15 years.Work by the group of Kopecek and AIChE Journal December 2003 Vol.49.No.12 2993of diffusion control, there are two main drug distribution ge￾ometries that are usedeither a reservoir where the drug is surrounded by a polymer barrier or a matrix where the drug is generally uniformly distributed through the polymer. In ei￾ther case, diffusion through the polymer is the rate-limiting step Narasimhan et al., 1999 . In the case of chemical con- Ž . trol, the polymer can be either degraded by water or a chemi￾cal reaction to release the drug. Alternatively, the drug can be attached to the polymer by a covalent bond that can be cleaved by water or an enzyme and release the drug. A third mechanism is solvent activation. The drug can be released either by swelling of the polymer in which the drug was previ￾ously locked into place within the polymer matrix in a glassy state or by an osmotic effect, which can be accomplished by external water entering the drug delivery system because of an osmotic driving force and subsequently driving the drug out of the system Langer and Peppas, 1983 . We now discuss Ž . research in different hydrogel polymers as they pertain to controlled release as examples of ongoing research. No®el Hydrogels for Drug Deli®ery. The development of ‘‘conventional’’ controlled release devices based on hydrogels or hydrophilic carriers that can swell in the presence of a biological fluid has been described in several reviews Pep- Ž pas, 1997 . Swelling-controlled release systems have found . many applications for the solution of a wide range of medical problems. Recent developments concentrate on the novel use of the solute diffusional process to achieve desirable release rates and ‘‘dissolution profiles.’’ For example, new phase ero￾sion controlled release systems have been reported Mal- Ž lapragada and Peppas, 1997; Peppas and Colombo, 1997 that . exhibit an unusual molecular control of the drug or protein delivery by simple dissolution of the carrier. Hydrophilic car￾riers pass through a process of chain unfolding from the semicrystalline phase to the amorphous one, eventually lead￾ing to complete chain disentanglement. It has been shown that poly vinyl alcohol PVA and poly ethylene glycol Ž .Ž . Ž . Ž . PEG are useful systems for such release behavior, and that such devices have the potential to be used for a wide range of bioactive agent release processes. En®ironmentally Responsi®e Hydrogels. Several factors affect the swellingrdeswelling of environmentally responsive hydro￾gels. They include the degree of ionization in the network, the ionization equilibrium and the nature of the counterions. As the ionic content of a hydrogel is increased in response to an environmental stimulus, increased repulsive forces de￾velop and the network becomes more hydrophilic. Because of the Donnan equilibrium, the chemical potential of the ions inside the gel must be equal to the chemical potential of the ions in the solvent outside of the gel. An ionization equilib￾rium is established in the form of a double layer of fixed charges on the pendant groups and counterions in the gel. The nature of counterions in the dissolution medium also af￾fects the swelling of the gel. Work on environmentally re￾sponsive hydrogels has taken several directions over the past several years, concentrating predominantly on ingeniously designed systems that utilize the pH- and temperature-sensi￾tivity characteristics of certain hydrogel structures. For example, various types of poly N-isopropyl acrylamide Ž . Ž . Ž. PNIPAAm have been used both as expanding swelling and squeezing hydrogels Brazel and Peppas, 1996, 1999 . Such Ž . systems have been shown to exhibit an ‘‘onroff’’ mechanism of control of the drug or protein releaserdelivery rate. Podual et al. 2000a have shown how such systems can be employed Ž . for auto-feedback drug delivery, whereby the hydrogel will be connected to a biosensor and will respond to fast changes in the external biological conditions. This type of idea has been used to develop novel insulin delivery systems Doyle et al., Ž 1996 . Another novel use of these systems is for the release . of human calcitonin Serres et al., 1996 . The physicochemi- Ž . cal understanding of such hydrogels under the conditions of application is neither simple nor well developed. Considering that all these carriers are ionic hydrogels, and that several ionic and macromolecular components are involved, with as￾sociated thermodynamically non-ideal interactions, it is evi￾dent that analysis and prediction of the swelling and drug delivery behavior is rather complex. Recently, there has been significant interest in the synthe￾sis of PNIPAAm-based hydrogels that contain increased amounts domains of the temperature-sensitive component Ž . NIPAAm. Major new methods of preparation of such sys￾tems graft, block or comb-like copolymers have been re- Ž . ported. NIPAAm-rich hydrogels can be prepared by simple methods Vakkalanka and Peppas, 1996 . Such systems show Ž . promise for rapid and abrupt or oscillatory release of drugs, peptides, or proteins, because their swellingrsyneresis pro￾cess can occur relatively fast. Conjugates of PNIPAAm with various enzymes have also been reported Podual et al., Ž 2000a . The details of the molecular mechanism of solute . transport through ionic networks are not fully understood. Recent studies Peppas and Wright, 1996 shed light on the Ž . special interactions between an ionic drug and an ionic net￾work polymer carrier . ATR-FTIR spectroscopy seems to be Ž . a promising technique for the analysis of drug binding on hydrogels as well as for visualization of drug distribution amŽ Ende and Peppas, 1995 . Certain hydrogels may exhibit envi- . ronmental sensitivity due to the formation of interpolymer complexes. These complexes, which have been shown in homo- and copolymer networks, are formed by non-covalent association between two or more complimentary polymers. The stability of the associations is dependent on such factors as the nature of the swelling agent, temperature, type of dis￾solution medium, pH and ionic strength, network composi￾tion and structure, and length of the interacting polymer chains. The incorporation of poly ethylene glycol PEG in Ž .Ž . pH- or temperature-sensitive materials seems to provide de￾sirable characteristics of protein stability and biological stealth behavior. Hydrogen-bonded, complexation networks of poly methacrylic acid-g-ethylene glycol hydrogels Bell and Ž .Ž Peppas, 1996; Vakkalanka et al., 1996 exhibit abrupt expan- . sion and contraction which is based on hydrogen bonding be￾tween the carboxyl group of MAA and the etheric group of EG. There is a rather abrupt change in the gel swelling ratio q, and mesh size Žwhich is a linear measure of the diffu￾sional space available in a hydrogel due to pH changes. . Modulation of drug permeation is thus possible for delivery of a number of drugs, including streptokinase Vakkalanka et Ž al., 1996 for clot dissolution. . Neutral Hydrogels. Significant efforts have been undertaken to further develop and characterize the structure of predomi￾nantly neutral hydrogels used in drug delivery. Acrylamide￾based hydrogels have been used for a wide range of applica￾tions in the past 15 years. Work by the group of Kopecek and AIChE Journal December 2003 Vol. 49, No. 12 2993