Tissue reactions of in situ formed dextran hydrogels crosslinked by stereocomplex formation after subcutaneous implantation in rats.
In this study, the in vivo biocompatibility of physically crosslinked dextran hydrogels was investigated. These hydrogels were obtained by mixing aqueous solutions of dextran grafted with L-lactic acid oligomers and dextran grafted with D-lactic acid oligomers. Gelation occurs due to stereocomplex formation of the lactic acid oligomers of opposite chirality. Since gelation takes some time, in situ gel formation is possible with this system. A number of sterilization methods was evaluated for their effect on the chemical and physical properties of the hydrogel. It was shown that of the investigated options (filtration, gamma irradiation, dry-heat and autoclaving) dry-heat sterilization was the preferred method to prepare sterile gels suitable for in vivo evaluations. Two types of stereocomplex gels were prepared and implanted subcutaneously in rats. The tissue reaction was evaluated over a period of 30 days. A mild ongoing foreign body reaction was observed characterized by infiltration of macrophages. Giant cells were only scarcely formed and the low numbers of lymphocytes showed that priming of the immune system is hardly involved. Importantly, the gels fully degraded in vivo within 15 days, which is in good agreement with the in vitro degradation behaviour of these gels. In conclusion, stereocomplexed dextran-oligolactic gels showed good biocompatibility which makes them suitable candidates for the design of controlled release devices for pharmaceutically active proteins.
Bos
Gert W
GW
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O. Box 80 082, 3508 TB Utrecht, The Netherlands.
Hennink
Wim E
WE
Brouwer
Linda A
LA
den Otter
Wim
W
Veldhuis
Theo F J
TF
van Nostrum
Cornelus F
CF
van Luyn
Marja J A
MJ
D020341:Absorbable Implants / Q000009:adverse effects; D000818:Animals; D001672:Biocompatible Materials / Q000009:adverse effects* / Q000737:chemistry; D003432:Cross-Linking Reagents / Q000737:chemistry; D003911:Dextrans / Q000009:adverse effects* / Q000737:chemistry; D004343:Drug Implants / Q000009:adverse effects* / Q000737:chemistry; D005549:Foreign-Body Reaction / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology*; D020100:Hydrogels / Q000009:adverse effects* / Q000737:chemistry; D020007:Implants, Experimental / Q000009:adverse effects; D019344:Lactic Acid / Q000009:adverse effects / Q000737:chemistry; D008297:Male; D008422:Materials Testing; D051381:Rats; D013237:Stereoisomerism; D013242:Sterilization / Q000379:methods*
D001672:Biocompatible Materials; D003432:Cross-Linking Reagents; D003911:Dextrans; D004343:Drug Implants; D020100:Hydrogels; D019344:Lactic Acid