thesized directly,so that desirable chain segments or fund classified as amorphous.semicrystalline.hvdrogen-bonded tional groups(Bures)rc bult nto the material. structures,supermolecular structures,and hydrocolloidal ag- nsive hydrogels (Pep tures that can be ratio due to chans swelling behavior cor tain either acidic or basic endan biomaterials(Ward and Peppas groups aqucous media of appropriate pppithoctined acid peptides and proteins from the pote uring t techniques ty of the release site appro ach would be extended. ed in the future for the oral delivery of proteins ma modf or as conjugates zed thatp csirable Hydrophobie carriers and Molecular Design Initial ing have d into polymer rs for potential use as uch as being reaso ably biocompatible,although the proper on.In the 1970s ethvlenc-vinl a oolymer that bccn ap- nee (Barrera et al..1993:Vacanti and L er1999) ppicaionseefmcOy objects such as hetic appro onic strength. temp Procedures such as et traction were developed for h th(Fo reasingly clear that polymer specific biomaterials is now discussed. me pu material Hydrogels Is in commodity ob the tures)comp hilic homopol ers or co exact medical app ey a e1 ter can be entangler which the po er matrix beco mes highly porous as time pr ghout the matrix,the drug d po erode de their high water content and rubbery nature hich is simila de by surfac erosion(Figure 2).To achieve this goal ue as well as eppas e (i)wha the type of charges of their pendent groups.They can be also AIChE Journal December 2003 Vol.49.No.12 2991thesized directly, so that desirable chain segments or func￾tional groups Bures et al., 2001 are built into the material, Ž . or indirectly, by chemical modification of existing structures to add desirable segments or functional groups. Polymeric biomaterials can be produced by copolymeriza￾tions of conventional monomers to achieve nearly monodis￾perse polymers. It is possible to produce polymers containing specific hydrophilic or hydrophobic entities, biodegradable repeating units, or multifunctional structures that can be￾come points for three-dimensional 3-D expansion of net- Ž . works Peppas, 2000 . Advanced computer techniques allow Ž . researchers to follow the kinetics of formation of 3-D struc￾tures of these biomaterials Ward and Peppas, 2000 . Ž . Another synthetic approach involves genetic engineering for the preparation of artificial proteins of uniform structure Ž . Tirrell et al., 1996, 1998 . This enables the synthesis of peri￾odic polypeptides that form well-defined lamellar crystals, polypeptides containing non-natural amino acids, and monodisperse helical rods. Important issues to be addressed include immunogenicity and purification from contaminants during large-scale production. If techniques were developed to produce polymers with the use of non-amide backbones, the versatility of this approach would be extended. Efforts have also been made toward chemical modification of polymer surface or bulk properties, by treatments such as plasma modification. One surface treatment of biomaterials involves grafting inert substances such as PEO segments onto or within existing polymers such as polyurethanes to enhance biocompatibility or reduce protein adsorption Peppas et al., Ž 1999; Morishita et al., 2002 . In addition, polymers have been . synthesized that promote a desirable interaction between themselves and surrounding cells. Thus, peptide sequences, such as Arg-Glu-Asp-Val, that promote endothelial cell seed￾ing have been synthesized into polymers for potential use as artificial blood vessels vascular grafts and copolymers of Ž . lactic acid and lysine have been synthesized, to which specific amino acid sequences that promote adhesion of hepatocytes or other cells can be attached for potential use in tissue engi￾neering Barrera et al., 1993; Vacanti and Langer 1999 . Ž . Other synthetic approaches have been used to develop en￾vironmentally responsive biomaterials to surrounding pH, Ž ionic strength, or temperature . For example, poly acrylic . Ž acid with ionizable side groups responds to changes in pH or . ionic strength Foss and Peppas, 2001 . Research in certain Ž . specific biomaterials is now discussed. Hydrogels Hydrogels are water-swollen networks crosslinked struc- Ž tures composed of hydrophilic homopolymers or copolymers . Ž . Lowman and Peppas, 1999 . They are rendered insoluble due to the presence of chemical covalent or ionic or physical Ž . crosslinks. The latter can be entanglements, crystallites, or hydrogen-bonded structures Peppas, 1987 . The crosslinks Ž . provide the network structure and physical integrity. Over the past 35 years, hydrogels have been extremely useful in biomedical and pharmaceutical applications mainly due to their high water content and rubbery nature which is similar to natural tissue, as well as their biocompatibility Peppas et Ž al., 2000 . They can be neutral or ionic hydrogels based on . the type of charges of their pendent groups. They can be also classified as amorphous, semicrystalline, hydrogen-bonded structures, supermolecular structures, and hydrocolloidal ag￾gregates. Hydrogels may exhibit swelling behavior dependent on the external environment. Thus, in the last thirty years there has been a major interest in the development and analysis of en￾vironmentally or physiologically responsive hydrogels Pep- Ž pas, 1993 . These hydrogels show drastic changes in their . swelling ratio due to changes in their external pH, tempera￾ture, ionic strength, nature of the swelling agent, and electro￾magnetic radiation. Hydrogels which exhibit pH-dependent swelling behavior contain either acidic or basic pendant groups. In aqueous media of appropriate pH and ionic strength, the pendent groups can ionize, developing fixed charges on the gel. Some advantages to using ionic materials, as they exhibit pH and ionic strength sensitivity, are relevant in drug delivery applications. An additional advantage of hydrogels, which is only now being realized, is that they may provide desirable protection of drugs, peptides, and especially proteins from the poten￾tially harsh environment in the vicinity of the release site Lee Ž et al., 1995; Peppas et al., 2000 . Thus, such carriers may be . used in the future for the oral delivery of proteins or pep￾tides. Finally, hydrogels may be excellent candidates as biorecognizable biomaterials Kopecek et al., 1996 . As such, Ž . they can be used as targetable carriers of bioactive agents, as bioadhesive systems, or as conjugates with desirable biologi￾cal properties. Hydrophobic carriers and Molecular Design Initial studies in our laboratories focused on materials that were commercially available and had some useful properties such as being reasonably biocompatible, although the proper￾ties may not have always been optimal for a particular appli￾cation. In the 1970s ethylene-vinyl acetate copolymer was a polymer that was particularly useful. It had already been ap￾proved in certain medical devices; even though it’s original applications were in commodity objects such as coatings. Nonetheless, to try to make it useful as a biomaterial, it was important that certain types of antioxidants be extracted from it. Procedures such as ethanol extraction were developed for this purpose Langer et al., 1985 . Ž . In the 1980s, it became increasingly clear that polymers should be more rationally designed for medical purposes. A particular example is polyanhydrides. We and others had sug￾gested that, rather than using materials in commodity ob￾jects, the biomaterial could be chemically synthesized from first principles to possess precisely the correct chemical, engi￾neering, and biological properties for the exact medical appli￾cation. In the case of synthetic degradable polymers for drug delivery, most polymers displayed bulk erosion Figure 1 , in Ž . which the polymer matrix becomes highly porous as time pro￾gresses and fell eventually apart. Thus, if a drug were origi￾nally distributed uniformly throughout the matrix, the drug could potentially ‘‘dump’’ out as the matrix erodes. From an engineering standpoint, it would be better if polymers de￾graded by surface erosion Figure 2 . To achieve this goal, Ž . the following engineering design questions were asked: Ž .i What should cause polymer degradation - enzymes or water? Water was chosen because enzyme levels differ be￾AIChE Journal December 2003 Vol. 49, No. 12 2991