Dextran-based hydrogels were obtained by polymerization of aqueous solutions of methacrylated dextran (dex-MA) or lactate-hydroxyethyl methacrylate-derivatized dextran (dex-lactate-HEMA). Both nondegradable dex-MA and degradable dex-lactate-HEMA disk-shaped hydrogels, varying in initial water content and degree of substitution (DS, the number of methacrylate groups per 100 glucose units), were implanted subcutaneously in rats. The tissue reaction was evaluated over a period of 6 weeks. The initial foreign-body reaction to the dex-MA hydrogels was characterized by infiltration of granulocytes and macrophages and the formation of fibrin, and exudate, as well as new blood vessels. This reaction depended on the initial water content as well as on the DS of the hydrogel and decreased within 10 days. The mildest tissue response was observed for the gel with the highest water content and intermediate DS. At day 21 all dex-MA hydrogels were surrounded by a fibrous capsule and no toxic effects on the surrounding tissue were found. No signs of degradation were observed. The initial foreign-body reaction to the degradable dex-lactate-HEMA hydrogels was less severe compared with the dex-MA gels. In general, the size of the dex-lactate-HEMA hydrogels increased progressively with time and finally the gels completely dissolved. Degradation of the dex-lactate-HEMA hydrogels was associated with infiltration of macrophages and the formation of giant cells, both of which phagocytosed pieces of the hydrogel. A good correlation between the in vitro and the in vivo degradation time was found. This suggests that extra-cellular degradation is not caused by enzymes but depends only on hydrolysis of the ester and/or carbonate bonds present in the crosslinks of the hydrogels. After 21 days, the degradable hydrogels, as such, could not be retrieved, but accumulation of macrophages and giant cells was observed, both of which contained particles of the gels intracellularly. As for the dex-MA hydrogels, no toxic effects on the surrounding tissue were found. The results presented in this study demonstrate that dextran-based hydrogels can be considered as biocompatible materials, making these hydrogels attractive systems for drug delivery purposes.

In order to investigate the physiological role of the autonomic nervous system on insulin secretion, neonatal pancreases were implanted under the kidney capsule of alloxan diabetic rats, resulting in recovery from diabetes, with denervated insulin secreting tissue. Rats were also provided with permanent double cardiac catheters allowing simultaneous infusion and rapid blood sampling with free movement. Intracardiac glucose infusion caused, coincident with the rapid rise of blood glucose, an increase of plasma insulin in the first minute in both controls and transplanted rats. After ingestion of food plasma insulin in normal control rats increased in the first minute, and prior to the first rise of glucose, from 23 + 2 mU/1 to 66 + 4 mU/1 in the fed state, and from 9 _+ 3 mU/1 to 34 _+ 3 mU/1 after 24 h of fasting. In contrast, this response was absent in the transplanted animals. In the fed state maximum insulin responses were attained at 20 minutes and were 63 + 10 mU/1 for controls, 104 + 15 mU/l for transplants and 20 _ 3 mU/1 for rats which recovered from diabetes one week after alloxan. The concomittant glucose responses were 22 + 2, 34 + 3 and 45 + 4mg/ 100 ml respecitively. Ingestion of a meal after fasting showed a similar decreased insulin response and insulinogenic index at t = 20 in both the transplanted and control group. Histology and electronmicroscopy of the transplanted pancreas showed vascularized groups of well granulated B-cells. The data of these experiments suggest that 1) The early insulin response after food intake is under direct control of the autonomic nervous system, 2) Glucose homeostasis is disturbed after transplantation, 3) Mainly humoral factors are responsible for the decreased insulin response after fasting.

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