Therefore,there isan optimum crosslinking to functional ferent lengt sca der ing on the physical molecular na ure of the crosslink 1993:Podual et al 2000ab.c Peppas and Colombo, 997 ink do chains and free mpete for binding po thin the pr the of a 1991).Ash eoC to put on within the bulk phase ork struct drug is underneath it can be released.In proof of principle bot ells in nd in tro (San Grayson et a of imprinted reco gnitio syst ms is not out on ns imprin the place of the prote within the al e-ment sc/ low One concept implant such systems in small interpe ing proc ase.small sensors are in)Zhan and Pepp 2000 When in of ana ompatibility will be important,and,as such,packaging is ccurs The releasable loading scheme involye an electrochem cal se ition (equilb 2:Kin wh coud monitor such substances.c developed to replace lost p Microfabrication and microeclectronic devices ion of different sense ine ple has been the n-id wel simulato cals or,alternativ ndreds of different dos of such sul Another intere involves the development of Figure 4) f approa an h of having unique prope ties.It is ausing signif ficant pain to the atible pH range. ap such as 1 volt)in the ount of electronel tio table micro nodules have been used to deliver vices su ch as neuromuscular stimulators to peo 3002 December 2003 Vol.49.No.12 AIChE Journal Therefore, there is an optimum crosslinking to functional monomer molecular weight ratio, which directly depends on the size of the template. For multifunctional crosslinking agents, the corresponding linear portions of the vinyl chains are expected to follow the same relationship, albeit on a dif￾ferent length scale depending on the physical molecular na￾ture of the crosslinker. Although it is important to consider that as the macromolecular chains increase in size, the flexi￾bility of the chains also increases. Analyte sensitive polymer networks have been designed in a number of ways Figure 12 . They include enzymes, which, Ž . as a result of reaction, invoke a local pH change, modulating the swelling of the network and thus release Albin et al., Ž 1985; Goldreich and Kost, 1993; Podual et al., 2000a,b,c; Peppas and Colombo, 1997 . They can include crosslink de- . pendent systems where pendent attached to the copolymer Ž . chains and free analyte compete for binding positions within protein sites. As analyte replaces pendent analyte groups within the protein, the network loses effective crosslinks, opens the network mesh size, and regulates release Lee and Ž Park, 1996; Obaidat and Park, 1996, 1997, Miyata et al., 1999; Nakamae et al., 1994: Kokufata et al., 1991 . As the analyte . decreases in concentration within the bulk phase, the protein binds again with the pendent analyte groups closing the net￾work structure. Similarly, systems have been designed that have a specific antigen and corresponding antibody grafted to a semi-interpenetrating network, which swells in response to binding of the antigen due to a loss of effective crosslinks Ž . Miyata et al., 1999 . The design and implementation of imprinted recognition release systems is not simple, but one envisions imprinted gel particles or particles with thin coatings of imprinted films taking the place of the proteins within the above-mentioned gels. In particular, low crosslinked gels have been formed consisting of a functionalized network with template not Ž bound and then an interpenetrating procedure where an- . other network is formed in the presence of template with Ž additional crosslinks imposed by pendant analyte group inter￾action Zhang and Peppas, 2000 . When in a solution of ana- .Ž . lyte, the gel loses effective imprints or complexation and Ž . release occurs. The releasable drug loading scheme involves imbibition equilibrium partitioning or entrapment during Ž . polymerization if the drug does not interfere with the net- Ž work formation and the template complex itself .. Microfabrication and microeclectronic de©ices There are a variety of microelectronic devices that are be￾ing studied for controlled drug delivery systems. One exam￾ple has been the creation of microchips with nano-sized wells that can house literally hundreds of different drugs or chemi￾cals or, alternatively, hundreds of different doses of such sub￾stances Figure 14 . The original types of systems were made Ž . out of silicon and coated with gold. Gold has the advantages of having unique electro-chemical properties. It is easily de￾posited and patterned, has a low reactivity compared to other substances, and resists spontaneous corrosion generally in aqueous based solutions over a wide pH range. It also ap￾pears to be highly biocompatible. By applying a small voltage Ž . such as 1 volt in the presence of a small amount of chloride ion, however, the gold can be made to corrode and whatever Figure 14. Photograph of top and bottom views of a drug delivery microchip and a U.S. coin. Although 34 wells are shown, it is possible to put in at least 400 wells in a similar sized chip drug is underneath it can be released. In proof of principle experiments, both single and multiple drugs have been re￾leased on demand from tiny microchips both in ®i®o and in ®itro Ž . Santini et al., 1999 . More recently, polymer based mi￾crochips have been designed as well Richards-Grayson et al., Ž 2003 .. Sensors represent another area where microfabrication can be important. For example, scientists are building capacitor￾based sensors which have been tested in ®itro in model blood vessels. One concept is to implant such systems in small ani￾mals to measure blood pressure during cardiovascular studies Ž . Ziaie and Najafi, 2001 . In another case, small sensors are being used to measure intraocular pressure for glaucoma pa￾tients Stangel et al., 2001 . For Ž . in ®i®o sensors, issues of bio￾compatibility will be important, and, as such, packaging is￾sues may become significant. To address such issues, in one case an electrochemical sensor array was developed to put inside a biocompatible tube which can be monitored by telemetry Madou, 2002; Kim et al., 1993 . This sensor was Ž . designed so that it could monitor such substances as pH, car￾bon dioxide and oxygen. Other sensors are being developed to replace lost percep￾tion of different senses. For example, scientists are studying approaches for retinal stimulation to compensate for pho￾toreceptor regeneration in the back of the eye. A silicon mi￾crosimulator has been developed which can be controlled by telemetry Schwarz et al., 2000 . Ž . Another interesting approach involves the development of microfabricated microneedles. This type of approach can have a remarkable effect in enhancing the delivery of drugs with￾out causing significant pain to the patient. Microneedles are able to do this without pain because they don’t penetrate deep enough into the skin layers that contain nerves, but are able to penetrate far enough into the skin for the therapeutic compounds to enter the circulation Kaushik et al., 2001 . In Ž . addition, injectable micromodules have been used to deliver electronic devices such as neuromuscular stimulators to peo- 3002 December 2003 Vol. 49, No. 12 AIChE Journal