北京化工大学：《材料导论》课程阅读材料（生物材料）Advances_in_Biomaterials,_Drug_Delivery,_and_Bionanotechnology

BIOENGINEERING,FOOD,AND NATURAL PRODUCTS Advances in Biomaterials,Drug Delivery,and Bionanotechnology Dept.of Chemical Engineering.Massa obert f .Cambridge,MA.02139 Nicholas A.Peppas maceutics,The University of Texas at Austin engineer al,materials and approaches used in drug and protein delivery systems,materials used Introduction the rapidly changing f onger is the treatment o engin (m gress in these fields over anre coupled coey th e coupled clos Polymeric Materials as Biomaterials The development of biomaterials has been an evolving p clinical us were no d clopment of ing wa the last 3 contained in therapeutic or diagnostic systems that are in sed for artificial heart y are use n man ral role in extra complications Dialys Dacron-b ed va grafts can only be used if their diam biomat found in about 8,000 dif it 6 mm.Otherw tions.Althougl inter ns (Peppas and Langer, physical. ng this artiele should he d to R.Lange properties to biomaterials.Materials have either been syn- 990 December 2003 Vol.49.No.12 AIChE Journal

BIOENGINEERING, FOOD, AND NATURAL PRODUCTS Advances in Biomaterials, Drug Delivery, and Bionanotechnology Robert Langer Dept. of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 Nicholas A. Peppas Depts. of Chemical and Biomedical Engineering, and Div. of Pharmaceutics, The University of Texas at Austin, Austin, TX, 78712 Biomaterials are widely used in numerous medical applications. Chemical engineer￾ing has played a central role in this research and de®elopment. Polymers as biomateri￾als, materials and approaches used in drug and protein deli®ery systems, materials used as scaffolds in tissue engineering, and nanotechnology and microfabrication techniques applied to biomaterials are re®iewed. Introduction In the rapidly changing scientific world, contributions of scientists and engineers are leading to major new solutions of significant medical problems. No longer is the treatment of diabetes, osteoporosis, asthma, cardiac problems, cancer, and other diseases based only on conventional pharmaceutical formulations. Biology and medicine are beginning to reduce the problems of disease to problems of molecular science, and are creating new opportunities for treating and curing disease. Such advances are coupled closely with advances in biomaterials and are leading to a variety of approaches for relieving suffering and prolonging life. Of particular interest is the central position that materials Ž . especially polymers, ceramics and metals have taken in the development of novel treatments over the last 30 years. Bio￾materials are generally substances other than food or drugs contained in therapeutic or diagnostic systems that are in contact with tissue or biological fluids. They are used in many biomedical and pharmaceutical preparations, they play a cen￾tral role in extracorporeal devices, from contact lenses to kid￾ney dialyzers, and are essential components of implants, from vascular grafts to cardiac pacemakers. There are many cur￾rent biomaterials applications, found in about 8,000 different kinds of medical devices, 2,500 separate diagnostic products, and 40,000 different pharmaceutical preparations. Although biomaterials already contribute greatly to the improvement of health, the need exists for better polymer, ceramic, and metal systems and improved methods of characterizing them Ž . Peppas and Langer, 1994 . Correspondence concerning this article should be addressed to R. Langer In this article we discuss recent advances in the fields of: Ž. Ž . i polymers as biomaterials; ii materials in drug and protein delivery; iii materials for tissue engineering; and iv materi- Ž . Ž. als used in nanotechnology and microfabrication of medical devices. We analyze scientific progress in these fields over the last ten years, and we stress the impact of chemical engi￾neering thinking on developments in this field. Polymeric Materials as Biomaterials The development of biomaterials has been an evolving pro￾cess. Many biomaterials in clinical use were not originally de￾signed as such, but were off-the-shelf materials that clinicians found useful in solving a problem. Thus, dialysis tubing was originally made of cellulose acetate, a commodity plastic. The polymers initially used in vascular grafts, such as Dacron, were derived from textiles. The materials used for artificial hearts were originally based on commercial-grade polyurethanes. These materials allowed serious medical problems to be ad￾dressed. Yet, they also introduced complications. Dialysis tubing may activate platelets and the complement system. Dacron-based vascular grafts can only be used if their diame￾ter exceeds about 6 mm. Otherwise, occlusion can occur be￾cause of biological reactions at the blood-material and tissue-material interfaces. Blood-materials interactions can also lead to clot formation in an artificial heart, with the sub￾sequent possibility of stroke and other complications Peppas Ž and Langer, 1994 .. In the last few years, novel synthetic techniques have been used to impart desirable chemical, physical, and biological properties to biomaterials. Materials have either been syn- 2990 December 2003 Vol. 49, No. 12 AIChE Journal

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 2991

thesized 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

Bulk Erosion (Leong et al, )Today,polyanhydrid it sis has beer 。 for s for f the Leads to b e of approach potent drugs The monome r icular,the diamine ing materials: Figure 1.Bulk eroding polymer matri (ii)Purification steps are generally not necessary because indiv and the celular produced during the polymerio ro rent enzymes) In one study L roaches wer th arti hydroph ugh this synthetic ap 、mc）What should the中oran that the68 nds be lydme ents currenth ere it i sed for DN trar c(Lynn et al, 2001)Most recently ()What shoud be the the er 2000 such ccng th was and stand point;several mond mers epeRoypopaneand Materials in Drug and Protein Delivery There are several different goals in drug delivery.One goal be placed inside then dthe drug to co i he dur t the ond is arget the drug to particular places or cells in the ellular barriers as may be important in applications such as gene therapy. Surface Erosion Controlled drug delivery 号 s a constant rates (La e1998.0 ccent area of great im which have shown restenosi have d loped ap 0202 Figure 2.Surface eroding polymer matrix 2992 December 2003 Vol.49.No.12 AIChE Journal

Figure 1. Bulk eroding polymer matrix. tween individuals and the cellular response cells contain dif- Ž ferent enzymes surrounding a material changes over time. . However, everyone has excess water. Ž . ii What should be the nature of the monomers? To achieve surface erosion, the monomers should be hydropho￾bic to keep water out of the polymer matrix interior. Ž . iii What should the chemical bonds connecting the monomers be? Here it is important that the bonds be hydro￾lytically labile. The anhydride bond was chosen. Ž . iv What should be the precise chemical structure of the monomers connecting the anhydride bonds? This was exam￾ined from both a toxicological and polymer chemistry stand￾point; several monomers such as carboxyphenoxypropane and sebacic acid were selected on this basis. The polymers were then synthesized, formed into micro￾spheres or discs, and drugs could be placed inside them Ž . Tamada and Langer, 1992 . One of the advantages of polyanhydrides is that they can be made by procedures such as bulk polycondensation Leong et al., 1985 that do not have Ž . Figure 2. Surface eroding polymer matrix. initiators or other types of impurities. As such, they ended up being relatively biocompatible Leong et al., 1986 . A variety Ž . of methods for polyanhydride synthesis were then developed Ž . Leong et al., 1987 . Today, polyanhydrides have been used in combination with drugs to treat thousands of patients with brain cancer through localized controlled release. Most recently, high throughput polymer synthesis has been employed to rapidly synthesize new polymers and screen them for different applications Brocchini et al., 1997, 1998; Belu Ž et al., 2000 . For example, recently in trying to design poly- . mers for gene therapy delivery, a parallel synthesis approach was developed for creating poly
amino esters. Some of the properties of these polymers that make them amenable to this type of approach are: Ž .i The monomers, in particular, the diamine and diacry￾late monomers, are inexpensive, commercially available start￾ing materials; Ž . ii The polymerization can be achieved in a single syn￾thetic step; Ž . iii Purification steps are generally not necessary because byproducts are not produced during the polymerization pro￾cedure. In one study, approaches were developed to synthesize these polymers Lynn and Langer, 2000 . A library of 140 Ž . such polymers were synthesized by starting with seven differ￾ent diacrylates and 20 diamines. Through this synthetic ap￾proach, two polymers showed higher transfection efficacies than existing polymers or other non-viral reagents currently used for DNA transfection Lynn et al., 2001 Most recently, Ž . methods were developed to automate these approaches and over 2000 such polymers in a single day were synthesized Ž . Anderson et al., 2003 . Materials in Drug and Protein Delivery There are several different goals in drug delivery. One goal controlled drug deliveryis to control the duration of ac￾tion of the drug and the drug’s level in the human body. A second is to target the drug to particular places or cells in the body. A third is to overcome certain tissue barriers such as the lung, skin, or intestine. A fourth is to overcome certain cellular barriers as may be important in applications such as gene therapy. Controlled drug deli©ery Numerous controlled release systems exist today ranging from implants that release contraceptive drugs for up to 5 years to novel osmotically driven pills that deliver drugs at constant rates Langer, 1998 . One recent area of great im- Ž . portance has been the development of polymer-coated stents, which have shown remarkable results in reducing restenosis following angioplasty. Various scientists have developed ap￾proaches where they can coat metal, stents using drugs such as paclitaxel Heldman et al., 2001 , sirolimus Oberhoff et Ž .Ž al., 2002 , and other drugs. Clinical trials have shown remark- . able results in keeping blood vessels open and enhancing pa￾tient survival Morice et al., 2002 . Ž . In controlled drug delivery, drug release generally occurs by one of three main mechanisms: i diffusion, ii chemical Ž. Ž . reaction; and iii solvent activation and transport. In the case Ž . 2992 December 2003 Vol. 49, No. 12 AIChE Journal

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 2993

of 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

associates have provided synthetic roots for improved appli- heir e in ph 1993).Griffit and I namic therapy diation of PEO star po of PEO th tec ast oiologicaldrug livery application rareports of the f olymers as templa nd thei mesh size in detail (St inge and Peppa 996).Micelles o may not be imm ause of the stealth nature of hom and c lyvinyl alc A)ha Peptide nd prote delivery app andom rates but graft on drug t th ally when山e PH-sensit promise ing applicatior of such sys been dis sed.Other hydr with alternative thod of targetn ery vehicle of PEC oas and Sahlin. 1996).Such tures (Kevs atal.199) th due to in pen Controlling drug phar macokineties and targeting PEG chains could be added t ntly 'sp (PEG)to 1997).Such systems,espe ly those 1994)that can no one week in humar ling application non-im which Research has also been ted by th corpo arge mo cule,the iodistrib of th is sitive hydr en used in cer chemotherapy.The con ent is that lo ta灯 gh cancer drug e the given int nd Peppas,19 St memb Thus the drug is istribute be om NIPAAmC-MAA hydro ith no Ho ed so th ange in lood the polymer-drug jugate for thods of deli hydrogels have been recent reported.For example various sugar-containing copolymer Be most nc tissues have intac eutic ae K ecek and s have or that has a bed (Dur an et for releas 99 last few yean there have be new methods of upled The conjugates an be cleav rs than in no blies for drug deliv (O free drug (Duncan et al,1996:Mur ami et al 1997) a large numb The injection of a styrene-maleic anhydride copolymer cou 2994 December 2003 Vol.49.No.12 AIChE Journal

associates have provided synthetic roots for improved appli￾cation of such systems. For example, hydroxypropyl methacrylamide-based copolymers and hydrogels have been developed for use in photodynamic crosslinking Shen et al., Ž 1996 . Such polymers could potentially be used in photody- . namic therapy of tumors. Hydrogels of PEO have received significant attention in the last few years, especially because of their associated stealth characteristics in certain biological drug delivery applications. Radiation-crosslinked PEO hydrogels have been prepared and their mesh size and drug diffusional behavior have been analyzed in detail Stringer and Peppas, 1996 . Micelles of Ž . PEO with various other comonomers are promising systems for release of drugs because of the stealth nature of particles prepared from these polymers. Poly vinyl alcohol PVA has Ž .Ž . also received significant attention in recent studies. For ex￾ample, PVA hydrogels Peppas and Mongia, 1997 have been Ž . well characterized and various studies have been performed on drug transport through these structures. Of particular promise are PVA hydrogels prepared by a freezingrthawing process that creates crystallites and forms a physically-cross￾linked 3-D network. Bioadhesi®e Hydrogels. An alternative method of targeting drugs to specific sites is by the use of bioadhesive and mu￾coadhesive hydrogels Peppas and Sahlin, 1996 . Such sys- Ž . tems usually consist of hydrogen-bonded structures such as poly acrylic acid PAA -based hydrogels which adhere to the Ž .Ž . mucosa due to hydrogen bonding andror polymer chain pen￾etration into the mucosa or tissue. In one study Sahlin and Peppas indicated that linear PEG chains could be added to PAA-based mucoadhesives either as free chains or as teth￾ered structures to serve as mucoadhesion promoters Sahlin Ž and Peppas, 1997 . Such systems, especially those prepared . from PVA, can be promising for wound healing applications Ž . Mongia et al., 1996 . Glucose-Sensiti®e Hydrogels. Research has also been con￾ducted in the utilization of environmentally responsive hydro￾gels as glucose-sensitive systems. Typically, this is achieved by incorporation of glucose oxidase Podual et al., 2000a during Ž . or after the polymerization for the production of pH- or tem￾perature-sensitive hydrogels. Other Hydrogels. Environmentally-sensitive hydrogels have been reported as excellent agents for the release of fibri￾nolytic enzymes or heparin Brazel and Peppas, 1996 . Strep- Ž . tokinase can be released from P NIPAAm-co-MAA hydro- Ž . gels by a simple change of temperature and pH in a narrow range. New methods of delivery of chemotherapeutic agents using hydrogels have been recently reported. For example, biorecognition of various sugar-containing copolymers Ž . Putnam et al., 1996 can be used for the release of chemotherapeutic agents. Kopecek and associates have used poly N-2-hydroxypropyl methacrylamide carriers for release Ž . of a wide range of such agents. In the last few years there have been new methods of preparation of hydrophilic polymers and hydrogels that may be used in the future in drug delivery applications. For exam￾ple, novel biodegradable polymers include polyrotaxanes, which are considered potentially useful for molecular assem￾blies for drug delivery Ooya and Yui, 1997 . Dendrimers and Ž . star polymers are new materials that enable a large number of functional groups to be available in a very small volume. Merrill has offered a useful review of PEO star polymers and their applications in the biomedical and pharmaceutical fields Ž . Ž. Merrill, 1993 . Griffith and Lopina 1995 prepared gels of controlled structure and large biological functionality by irra￾diation of PEO star polymers. Such gels may be promising materials as carriers for drug delivery if combined with tech￾niques of molecular imprinting. Indeed, there have been sev￾eral reports of the use of crosslinked polymers as templates for drug imprinting and subsequent release Cheong et al., Ž 1997 . Still, this field is relatively new and its applications . may not be immediately forthcoming. Thus, new synthetic methods have been used to prepare homo- and copolymeric hydrogels for a wide range of drug, peptide, and protein delivery applications. Random copoly￾mers with balanced hydrophobicityrhydrophilicity can offer desirable release rates and dissolution profiles, but graft, block, and comb-like copolymers offer additional advantages, especially when they contain temperature- or pH-sensitive pendent groups. Several interesting applications of such sys￾tems in the treatment of diabetes, osteoporosis, cancer or thrombosis have been discussed. Other hydrogels with promise as drug delivery vehicles include neutral gels of PEO or PVA, and gels of star molecules and other complex struc￾tures Keys at al., 1998 . Ž . Controlling drug pharmacokinetics and targeting One approach for altering the drug’s pharmacokinetics and duration of action is to covalently couple polymers such as polyethylene glycol PEG to it. This has been used to Ž . lengthen the lifetime of proteins such as interferon Burn- Ž ham, 1994 that can now last up to one week in humans. . For tissue targeting, water-soluble non-immunogenic bio￾compatible polymers, which will either degrade or be elimi￾nated by the body, are chemically linked to drugs, ideally through bonds that are cleaved once they reach their target Ž . for example, a tumor . By changing the drug from a small to a large molecule, the biodistribution of the drug is altered Ž . Duncan et al., 1996; Putnam et al., 1995 . This approach has been used in cancer chemotherapy. The concept is that low molecular weight anticancer drugs when given intravenously will penetrate most tissues because they pass rapidly through cell membranes. Thus, the drug is quickly distributed throughout the body, with no tumor selectivity. However, if the polymer-drug linkages are designed so that they are sta￾ble in blood, the polymer-drug conjugate circulates for a longer time than just the drug itself because the high molecu￾lar weight polymer-drug can generally only gain entry to cells by endocytosis. Because most normal tissues have intact non-leaky microvasculature, the polymer-drug accumulates more in the tumor that has a leaky vascular bed Duncan et Ž al., 1996; Putnam and Kopecek, 1995 . One approach in- . volves N- 2-hydroxypropyl methacrylamide HPMA copoly- Ž. Ž mer coupled to doxorubicin. The conjugates can be cleaved . by thiol-dependent proteases in lysosomes. Nearly seventy times more doxorubicin accumulates in mouse melanoma tu￾mors than in normal tissues. Furthermore, the maximum tol￾erated dose of the polymer-drug is 510 times greater than the free drug Duncan et al., 1996; Murakami et al., 1997 . Ž . The injection of a styrene-maleic anhydride copolymer cou- 2994 December 2003 Vol. 49, No. 12 AIChE Journal