COADMINISTRATION OF INSULIN-LIKE GROWTH-FACTOR (IGF)-I AND IGF-BINDING PROTEIN-1 STIMULATES WOUND-HEALING IN ANIMAL-MODELS

The stimulatory effect of recombinant human insulin-like growth factor -I (rhIGF-I) and recombinant human insulin-like growth-factor-binding protein-1 (rhIGFBP-1) on wound healing was assessed using diabetic db/ db mice and normal rabbits. Full-thickness wounds of 6 mm diameter wer e prepared on the backs of diabetic C57BL/KsJ db/db mice and on the in ner sides of normal rabbit ears, Various concentrations of rhIGF-I and /or rhIGFBP-1 were applied locally to the open wounds of db/db mice on ce daily for 5 d and to the covered wounds of normal rabbits once afte r wounding, Sections of the wounds were evaluated histologically on th e seventh or eighth day by measuring re-epithelialization (%), area of granulation tissue (mm(2)), and capillary numbers, Wound repair was a ccelerated by each of the treatments in descending order of rhIGF-I pl us rhIGFBP-1, rhIGF-I, rhIGFBP-1, and vehicle alone, In db/db mice, th e combination of 50 mu g rhIGF-I and 165 mu g rhIGFBP-1 (equimolar rat io) significantly stimulated granulation tissue formation (p < 0.01) a nd capillary numbers (p < 0.05), Doses of rhIGFBP-1 greater than 16.5 mu g were required for significant acceleration of the healing stimula ted by 50 mu g of rhIGF-I. In normal rabbits, co-administration of 10 mu g rhIGF-I and 33 mu g rhIGFBP-1 (equimolar ratio) significantly sti mulated all three wound-healing parameters (p < 0.01), with such stimu lation being much greater than that induced by rhIGF-I alone, Interest ingly, rhIGFBP-1 alone showed a mild stimulatory activity on wound hea ling in both models despite its lack of mitogenic activity in vitro, T hese results demonstrate that rhIGFBP-1 enhances the stimulatory activ ity of rhIGF-I on wound healing and suggest the clinical utility of th e co-administration of rhIGF-1 and rhIGFBP-1 for wound repair.