tems is a significant focus of recent research.Configurationa The CBIP network structure depends upon the type of s the solvent (controls the overall polyme n the ture that ing high ratios of cr gnition el erage molecular weight aa20dartc chains be ome more imprinting ic 3-D bir lecular chain or inte nd and raction para using an ep oach and im ap s is rex hle and transie ntly affects the bind- repr famictl2noand ds to s with vary biomimetie(CBP)technique eonpre-polyme z: lons to mov 55. that nal 2000:Wiz ds on the r man and Kofinas. et al wth ent and the intende non-covalent inter. by covalent (Wulff, 199 ach and ra 199 and van der 997.d hitcombe o 9)the reaction rs in the pres all nition site phobicdo product is a h wn binding and lecule Several rev evolving field mimetic impr inted nety first used s carrier rug al,2002.0n- ppas an 一© Figure 10.Hydrogels may expand or contract due to pH or temperature changes. r impeded depending on the molecular radius of the drug r with respect to the mesh size of the AIChE Journal December 2003 Vol.49.No.12 2999tems is a significant focus of recent research. Configurational biomimetic imprinting of an important analyte on an intelli￾gent gel leads to preparation of new biomaterials that not only recognize the analyte, but also act therapeutically by lo￾cally or systemically releasing an appropriate drug. The design of a precise macromolecular chemical architec￾ture that can recognize target molecules from an ensemble of closely related molecules has a large number of potential ap￾plications. The main thrust of research in this field has in￾cluded separation processes chromatography, capillary elec- Ž trophoresis, solid-phase extraction, membrane separations ,. immunoassays and antibody mimics, biosensor recognition el￾ements, and catalysis and artificial enzymes Takeuchi et al., Ž 1999; Piletsky et al., 2001 . Configurational biomimesis and . nanoimprinting create stereo-specific 3-D binding cavities based on the template of interest. However, efforts for the imprinting of large molecules and proteins have focused upon 2-D surface imprinting Shi and Ratner, 2000 , a method of Ž . recognition at a surface rather than within a bulk polymer matrix. More recently, by using an epitope approach and im￾printing a short peptide chain representing an exposed frag￾ment of the total protein, 3-D imprinting of proteins within a bulk matrix has been successfully prepared Rachkov and Mi- Ž noura, 2001 .. Configurational biomimetic imprinting CBIP techniques Ž . involve forming a pre-polymerization complex Figure 9 be- Ž . tween the template molecule and functional monomers or functional oligomers or polymers Byrne et al., 2000; Wize- Ž .Ž man and Kofinas, 2001; Byrne et al., 2002 with specific . chemical structures designed to interact with the template ei￾ther by covalent Wulff, 1995; Mosbach and Ramstrom, 1996; Ž Sellergren, 1997 , or both Whitcombe et al., 1995 . Once the .Ž . pre-polymerization complex is formed Figure 9 , the poly- Ž . merization reaction occurs in the presence of a crosslinking monomer and an appropriate solvent, which controls the overall polymer morphology and macroporous structure. Once the template is removed, the product is a heteropolymer ma￾trix with specific recognition elements for the template molecule. Several reviews exist describing the evolving field of molecular imprinting and designed molecular recognition Ž . Ansell and Mosbach, 1996 . The CBIP network structure depends upon the type of monomer chemistry anionic, cationic, neutral, and am- Ž phiphilic , the association interactions between monomers . and pendent groups, the solvent controls the overall polymer Ž morphology , and the relative amounts of comonomers in the . feed from which the structure is formed Figure 10 . Since Ž . recognition requires 3-D orientation, most techniques limit the movement of the memory site via macromolecular chain relaxation, swelling phenomena, and other processes, by us￾ing high ratios of crosslinking agent to functional monomers. As an increase in crosslinking monomer content leads to a decrease of the average molecular weight between crosslinks Ž . see also Figure 11 , the macromolecular chains become more rigid. In less crosslinked systems, movement of the macro￾molecular chains or, more specifically, of the spacing of func￾tional groups will change as the network expands or contracts depending on the chosen rebinding solvent thermodynamic Ž interaction parameters characterizing the segment-solvent in￾teraction or application solution environment Figures 9e and . Ž 9f . This process is reversible and transiently affects the bind- . ing behavior Enoki et al., 2000 and leads to sites with vary- Ž . ing affinity and decreased selectivity Katz and Davis, 1999 . Ž . In biological applications, non-covalent techniques are the preferred synthesis routine since an easy binding non-binding template switching method is needed that is, no harsh condi- Ž tions to remove template . Imprinting success, that is, the . ability to correlate high binding affinity and specificity, de￾pends on the relative amount of cross interaction between the solvent and the intended non-covalent interactions hy- Ž drogen bonding, hydrophobic interactions, - orbital inter￾actions, ionic interactions, and van der Waals forces em- . ployed during template-monomer complex formation Ž . Mosbach and Haupt, 1998; Andersson et al., 1995 . Proper tuning of non-covalent interactions such as increasing macro￾molecular chain hydrophobicity Yu et al., 1997 , including Ž . strong ionic directed recognition sites with hydrophobic do￾mains Haupt, 1998 , has been shown to enhance binding and Ž . achieve selective recognition in aqueous solutions. Biomimetic imprinted networks were first used as carriers for drug delivery see also Figure 12 by Peppas and cowork- Ž . ers Byrne et al., 2002 . On the forefront of controlled drug Ž . Figure 10. Hydrogels may expand or contract due to pH or temperature changes. Drug diffusion may be facilitated or impeded depending on the molecular radius of the drug r with respect to the mesh size of the s polymeric gel carrier. AIChE Journal December 2003 Vol. 49, No. 12 2999