european journal of pharmaceutical sciences 36 ( 2 0 0 9 ) 310–319 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/ejps In vivo implantation of 2,2 ′ -bis(oxazoline)-linked poly--caprolactone: Proof for enzyme sensitive surface erosion and biocompatibility Mika Pulkkinen a,∗ , Minna Malin c , Jan Böhm d , Tommy Tarvainen a , Thomas Wirth b , Jukka Seppälä c , Kristiina Järvinen a a Department of Pharmaceutics, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland b Department of Molecular Medicine and Biotechnology, A.I. Virtanen Institute, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland c Department of Biotechnology and Chemical Technology, Helsinki University of Technology, P.O. Box 6100, FIN-02015, Finland d Department of Pathology and Forensic Medicine, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland article info Article history: Received 12 August 2008 Received in revised form 22 September 2008 Accepted 16 October 2008 Published on line 31 October 2008 Keywords: Biocompatibility Degradation Erosion Poly--caprolactone abstract Previously, we have demonstrated that 2,2-bis(2-oxazoline) linked poly--caprolactone (PCL- O) is degraded in vitro enzymatically by surface erosion which could enable the novel use of this material for drug delivery and other biomedical applications. In this study, degradation, erosion (weight loss) and toxicity of PCL-O poly(ester-amide)s were evaluated in vivo. PCL and three PCL-O polymers with different PCL block lengths (M n : 1500, 3900, 7500 g/mol) were melt-pressed in the form of discs and implanted subcutaneously in Wistar rats (dose ∼340mg/kg) for 1, 4 and 12 weeks. With implantation for 12 weeks, up to 16.5% weight loss of polymer discs was measured for the most extensively linked PCL-O polymer (block length 1500 g/mol) whereas practically no weight loss was observed with the other polymers. NMR, DSC and SEC studies as well as SEM micrographs before and after implantation and in vitro hydrolysis studies indicate that enzyme based surface erosion of PCL-O polymers occurred in vivo. The in vivo evaluation based on results from hematology, clinical chemistry and histology of the implantation area and main organs (i.e. heart, lung, liver, kidney, spleen and brain) demonstrated that PCL-O polymers are biocompatible and safe, enzyme sensitive biomaterials. © 2008 Elsevier B.V. All rights reserved. 1. Introduction Poly--caprolactone (PCL) is a widely used biodegradable polymer which has both pharmaceutical and biomedical applications (Perrin and English, 1997). In addition to deliv- ery of small drug molecules (Pitt, 1990), PCL has been recently evaluated for potential use in protein and antigen delivery (Jameela et al., 1997; Baras et al., 1999; Benoit et al., 1999; Youan ∗ Corresponding author. Tel.: +358 17 163556; fax: +358 17 163549. E-mail address: Mika.Pulkkinen@uku.fi (M. Pulkkinen). et al., 1999, 2001; Devineni et al., 2007), because it does not generate an acidic environment during degradation. However, slow hydrolytic bulk degradation of PCL (Pitt, 1990), hinders the development of controlled drug delivery systems. Thus, PCL has been extensively modified by using copolymerization or polymer blends in attempts to achieve controllable and faster degradation rate (Pitt et al., 1979, 1981; Malin et al., 1996; Perrin and English, 1997; Li et al., 2004). 0928-0987/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2008.10.011