Organo Hydrogel Hybrids. Formation of Reservoirs for Protein Delivery Fredrik Nederberg, † Junji Watanabe, ‡ Kazuhiko Ishihara,* ,‡ Jo ¨ ns Hilborn, † and Tim Bowden* ,† Department of Materials Chemistry, Polymer Chemistry, Box 538, Uppsala University, SE-751 21 Uppsala, Sweden, and Department of Materials Engineering, School of Engineering, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan Received June 17, 2005; Revised Manuscript Received August 2, 2005 A biodegradable organo hydrogel hybrid material is presented, which is formed through the water uptake of a phosphoryl choline zwitterionomer (PC ionomer). The water uptake and subsequent swelling is induced by the phosphoryl choline (PC) end group functionality. The nonfunctional poly(trimethylene carbonate) is hydrophobic and as such does not absorb any water. Disks of the PC ionomer showed significant water uptake, typically above 90 wt % when fully swollen. This high water uptake triggered us to utilize the material for drug and protein loading and subsequent release. Fluorescein and fluorescein-labeled proteins were used as simple models for the loading and release characteristics of the material which was studied by fluorescence spectroscopy. The rate of release of the loaded molecules was compared, and it was shown that the release rate was similar for FITC and insulin but slightly slower for albumin. These results suggest that the PC ionomer may be used as a biodegradable and low elastic modulus material with an additional drug and/or protein release capacity. Such materials are of particular interest for use in a variety of applications in ViVo, for example as drug eluting stents. 1. Introduction In this paper we present the water uptake properties of a biodegradable phosphoryl choline zwitterionomer (PC iono- mer) in combination with its ability to load and release drugs and proteins. We have in a series of recent articles described the synthesis and surface migration properties of various biomimetic phosphoryl choline (PC) functional biodegradable polymers. 1 This has led to the development of a novel biodegradable PC ionomer material that through a careful synthesis protocol provides additional bulk organization of PC groups, thus forming a macroscopic physically cross- linked network consisting of PC-enriched domains. 2 As further evidence of the presence of such domains we have recently found that the PC ionomer swells in water and phosphate-buffered saline (PBS, pH 7.4) solution. This discovery prompted us to use the material for drug and/or protein loading and subsequent release. The utilization of the polar PC domains is the foundation in this work and suggests that the PC ionomer could be used as an elastic, biodegradable, and hemocompatible material with an ad- ditional drug and/or protein delivery capacity. In general, hydrogels are cross-linked polymers which do not dissolve in water but swell significantly and retain a considerable amount of water within their structure. Numer- ous reviews have appeared in the literature which provide an excellent overview of this area. 3 Hydrogels are either chemically or physically cross-linked, and most are formed spontaneously as they capture water within their structure. The advantage of physical hydrogels over covalently linked hydrogels is that they form their cross-linked structure by ionic, coiled-coil, or hydrophobic interactions and do not require any cross-linking agents for their formation. 4 Hydrogels are frequently used in drug delivery systems due to the ease with which they can be loaded with drugs. 5 The release of the loaded substance occurs either through diffusion of the drug molecule or by the continuous degrada- tion or erosion of the gel. The degradation is dependent on the polymer and occurs either from the material bulk or from the surface. In the latter, the molecular weight is retained throughout the degradation process, whereas the former continuously decrease in molecular weight. 6 The PC ionomer described in this paper consists of a poly- (trimethylene carbonate) (PTMC) polymer backbone. PTMC is hydrolytically stable under in Vitro conditions but degrades in ViVo through probable enzymatic degradation. 7 The PC ionomer does not swell immediately but over a period of days. The water uptake, however, is significant, typically being over 90% after 48 h, and in this way an organo hydrogel hybrid is formed. Drugs and proteins were loaded during the water uptake of manufactured PC ionomer disks, and the subsequent release was studied by fluorescence spectroscopy following the drying of the material. No polymer loss was detected during its swelling, which is consistent with the reported hydrolytic stability in Vitro, 7 and as such the degradation was not measured in this model. The release was affected by diffusion of loaded drugs or proteins * Corresponding authors. E-mail: tim.bowden@polymer.uu.se (T.B.); ishihara@bmw.t.u-tokyo.ac.jp (K.I.). † Uppsala University. ‡ The University of Tokyo. 3088 Biomacromolecules 2005, 6, 3088-3094 10.1021/bm0504173 CCC: $30.25 © 2005 American Chemical Society Published on Web 10/05/2005