ABSTRACT:To control the release of insulin in response to the concentration of glucose, a glucose-responsive polymer membrane was designed by combining a glucose oxidase (GOD) immobilized membrane, a sensor for glucose, with a poly(amine) membrane which regulates the permeation rate of insulin. The permeability of insulin was increased by the addition of glucose. Gluconic acid produced by an enzymatic reaction between GOD and glucose induced a decrease in the pH value of the medium. This caused the protonation of tertiary amino groups in the membrane resulting in an increase in the water content of the poly( amine) membrane. The permeability of insulin through a complex membrane thus increases with glucose concentration.KEY WORDS Glucose I Insulin I Glucose Oxidase I Poly(amine) I Membrane I Permeation I Swelling I Recently, many investigations have been carried out on the controlled release systems of drugs utilizing polymeric materials and maintaining the concentration of drugs in plasma within a therapeutic range for extended periods of time. 1 Langer et al. demonstrated that ethylene-vinyl acetate copolymers impregnated with insulin maintained diabetic blood glucose levels near normal levels for one month. 2 In comparison with insulin infusion pumps, the advantage of these implantable polymer pellets is that large amounts of insulin can be concentrated in a small volume as opposed to a mechanized pumping which must be refilled daily. 3 However, the insulin release rate from these pellets dose not depend on variation in blood glucose levels and minor surgery is required for their implant and retrieval.For an ideal insulin delivery system, insulin release should be controlled directly by the amount of blood glucose present at any particular time. This requires a continual feedback between the blood glucose level and insulin release rate. Brownlee et al. proposed a self regulating insulin delivery system based on a combination of biological modulations and controlled release. 4 The design of this delivery system utilizes the concept of competitive and complementary binding behavior of concanavalin A with glucose and glycosilated insulin.We reported in a previous paper that the permeation rate of insulin through an amphiphilic polymer membrane can be controlled by the water fraction of the membrane. 5 We also reported a preparation method for a polymer membrane capable of regulating the permeation of insulin in response to change in the concentration of glucose. 6 The membrane

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ABA-type block copolymers composed of 2-hydroxyethyl methacrylate (HEMA), a hydrophilic monomer, and styrene (St), a hydrophobic monomer, were synthesized by the coupling reaction of telechelic oligomers used as prepolymers. These block copolymers may be represented as microphase-separated structures. It is therefore possible to change the balance between hydrophilicity and hydrophobicity in the level of an assembled order of macromolecules. In response to the relative composition of the copolymers, three typical morphological patterns were observed in electron microscopic photographs: dispersed domains of continuous St chains in the region of HEMA chains, alternate HEMA and St lamellae and finally, dispersed phases of continuous HEMA chains in the region of St chains. The effect of the hydrophilic and hydrophobic microdomains of the copolymers on the mode of interaction between polymers and platelets was studied by the microsphere column method. In the case of homopolymers and random copolymers, a significant degree of platelet adhesion and aggregation was observed. However, the degree of platelet adhesion and deformation was suppressed on the surfaces of the block copolymers containing 0.608 and 0.347 mole fractions of HEMA whose microdomains were hydrophilic-hydrophobic lamellae and isolated hydrophilic islands in hydrophobic areas, respectively. These results show that the microphase-separated structures were antithrombogenic and prevented platelet adhesion and deformation. On the basis of the results obtained, the interaction between platelets and polymer surfaces was described in terms of the effect of hydrophilic and hydrophobic microdomains.

The electrical conductivity of hybrid films consisting of polyacrylonitrile (PAN), ethylene carbonate (EC), and LiClO4 was investigated. In these films, EC and LiClO4 are found to be molecularly dispersed in PAN, forming solid solutions over a wide composition range. The ionic character of the electrical conductivity is demonstrated. The conductivity is not correlated with the content of LiClO4 or of PAN, but primarily with the mole ratio [EC]/[LiClO4] in the films. An increase in the [EC]/[LiClO4] ratio enhances the conductivity. When the ratio is about 2, the conductivity attains 10−4–10−5 S cm−1 at 25°C. This change in conductivity results from a change in carrier mobility. PAN makes the films solid without decreasing the carrier mobility. In the hybrid films, the carrier mobility and the macroscopic viscosity are not related by Walden's rule. The high conductivity is due to regions in the film characterized by a low microscopic viscosity. This is determined by the mole ratio [EC]/[LiClO4] and largely controls the carrier mobility.

Block copolymers were synthesized by a coupling reaction of hydrophilic chains of poly(2-hydroxyethyl methacrylate) (PHEMA) with hydrophobic chains of polystyrene (PSt), or poly(dimethyl siloxane) (PDMS). Microstructures of films of the block copolymers exhibited a hydrophilic-hydrophobic microphase separated structure. For evaluation of in vivo antithrombogenicity, small diameter tubes (1.5 mm I.D. and 20 cm length) coated by the copolymers on their internal surfaces were implanted in rabbits as arteriovenous shunts. Occlusion times of the tubes, measured by formation of thrombus, were three days for PHEMA, two days for PSt, and three days for PDMS. The block copolymers showed excellent antithrombogenic properties: occlusion times were 20 days for HEMA-St block copolymer and 12 days for HEMA-DMS block copolymers. In vitro examination of polymer-platelet interaction in terms of platelet adhesion and aggregation, which are important initial processes of blood coagulation, demonstrated suppressed adhesion and aggregation on microdomain surfaces constructed of hydrophilic and hydrophobic block copolymers. From both in vivo and in vitro examination, it was concluded that HEMA-St and HEMA-DMS block copolymers showed promising antithrombogenic activities by suppressing activation and aggregation of platelets.