Tissue response in the rat and the mouse to degradable dextran hydrogels Wim H. De Jong, 1 Jan A.M.A. Dormans, 1 Mies J. Van Steenbergen, 2 Henny W. Verharen, 1 Wim E. Hennink 2 1 Laboratory for Toxicology, Pathology and Genetics, National Institute for Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven, The Netherlands 2 Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), University Utrecht, P.O. Box 80.082, 3508 TB Utrecht, The Netherlands Received 12 September 2006; revised 4 December 2006; accepted 16 January 2007 Published online 25 May 2007 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jbm.a.31302 Abstract: Two types of hydroxyethyl-methacrylated dex- tran (dex-HEMA) hydrogels differing in crosslink density were compared for local tissue responses and degradation characteristics in mice and rats. Implants (1 mm thick, rat: 10 mm diameter, mouse: 6 mm diameter) varying in degree of HEMA substitution (DS5 and DS13, meaning 5 or 13 HEMA groups per 100 glucose units of dextran) were subcutaneously implanted and tissue responses were evaluated at week 2, 6, and 13 after implantation. In the rat after 2 weeks a slight fibrous capsule was formed com- posed of macrophages and fibroblasts sometimes accompa- nied by a minimal infiltrate. Small fragments, surrounded by macrophages and giant cells indicated hydrogel degra- dation. After 13 weeks DS5 implants were resorbed while parts of the DS13 implants were still present. In the mouse a moderate to strong capsule formation was present at 2 weeks accompanied by inflammatory cells (macrophages and polymorphonuclear granulocytes) and debris. Drain- ing lymph node activation was observed. Skin ulceration was present irrespective of the type of implant. Clear dif- ferences in the tissue responses between the rat and mouse were noted, as well as between implants of different degree of substitution. Mice showed a more pronounced early in- flammatory response compared with rats, whereas the degradation was more complete in rats than in mice. The differences in histology between the hydrogels disap- peared over time at 13 weeks after implantation and simi- lar responses were noted for both types of hydrogels. Both in mice and rats the DS5 hydrogels showed a faster degra- dation rate than the DS13 hydrogels. Ó 2007 Wiley Periodi- cals, Inc. J Biomed Mater Res 83A: 538–545, 2007 Key words: implant; histology; hydrogel; dextran; biocom- patibility INTRODUCTION Biodegradable polymers are currently investigated as biomaterials in surgical applications in osteosyn- thesis, 1,2 as controlled drug delivery systems, 3 or in tissue engineering. 4,5 Hydrogels are polymeric net- works of hydrophilic polymers and due to their water absorbing characteristics they are used for medical and pharmaceutical applications. 6–9 Biodegradable hydrogels can be obtained by polymerization of dex- tran to which methacrylate groups are grafted (dex- HEMA ¼ dextran-hydroxyethyl-methacrylate). By hy- drolytic scission of the carbonate ester bonds connect- ing the polymerized HEMA groups and dextran, the gels will swell and finally will dissolve. 10,11 The swel- ling and degradation time of these hydrogels is de- pendent on the crosslink density, which can be varied by changing the DS (degree of methacrylate substitu- tion: the number of methacryloyl groups per 100 glu- cose units of the polymer) and/or the initial water content of the hydrogel. 10,12,13 Further, the network properties of these gels can be tailored by the poly- merization conditions, giving possibilities to modu- late the release rate of entrapped compounds. 14 Previ- ous studies showed rapidly degrading dextran based hydrogels to be biocompatible when evaluated up to 21 days as hydrogel disks or evaluated up to 42 days as microspheres after implantation in rats. 15,16 The international standard EN/ISO 10993 part 6 ‘‘Tests for local effects after implantation’’ prescribes how the local in vivo reactivity of a biomaterial or product is examined within the framework of biologi- cal evaluation of medical devices and biomaterials. 17 After 13 weeks the local response to the implant is examined, assuming that a ‘‘steady state’’ has been achieved. In the case of biodegradable materials a steady state situation is not reached until after final Correspondence to: W.H. De Jong; e-mail: w.de.jong@ rivm.nl ' 2007 Wiley Periodicals, Inc.