Stimulation of steroid-suppressed cutaneous healing by repeated topical application of IGF-I: different mechanisms of action based upon the mode of IGF-I delivery.
BACKGROUND
Insulin-like growth factor-I (IGF-I) is accepted as a potent stimulus of wound healing when applied in combination with its binding proteins. However, there is only one study published that has investigated the effect of repeated topical application of unbound IGF-I on ischemic wound healing. The aim of this study was to show the effect of daily topical IGF-I therapy on cutaneous ulcer healing in a steroid-suppressed wound model.


METHODS
Full-thickness wounds were created on the back of 40 male Sprague-Dawley rats. Before surgery, animals received depot-steroids subcutaneously. Wounds were treated daily with either a standard hydrogel dressing (control), topical IGF-I dissolved in 0.2% methylcellulose gel (IGF-I gel), or a hydrogel dressing containing IGF-I (IGF-I dressing). After 7 days of treatment, wounds were excised and measured by photoplanimetry. SMA- and PCNA-expression as well as the formation of granulation tissue were assessed in tissue sections. Results are given as median(min-max). Differences between groups were calculated by the Mann-Whitney U test.


RESULTS
Subcutaneous injection of depot-steroids induced a significant delay in healing, as shown by an enlarged wound size [44(33-65) versus 25(20-35)] mm(2); P = 0.001). In steroid-treated rats, both IGF-I gel and IGF-I dressing enhanced excisional healing, as shown by a significant reduction in wound size (P = 0.0001), with IGF-I released from the dressing being even more effective than IGF-I gel (P = 0.03). However, in these animals only IGF-I released from the hydrogel dressing stimulated SMA- (P = 0.03) as well as PCNA-expression (P = 0.001) and increased granulation tissue formation (P = 0.018).


CONCLUSIONS
Our data indicate that a repeated application of topical IGF-I enhances cutaneous ulcer healing. In addition, only the controlled release of IGF-I from the hydrogel dressing is capable of reversing the steroid-induced delay of healing, suggesting different mechanisms of action with respect to the mode of IGF-I delivery.
Beckert
Stefan
S
Department of General and Transplant Surgery, University of Tübingen, Tübingen, Germany. stefan.beckert@med.uni-tuebingen.de
Haack
Sebastian
S
Hierlemann
Helmut
H
Farrahi
Farshid
F
Mayer
Petra
P
Königsrainer
Alfred
A
Coerper
Stephan
S
D000199:Actins / Q000378:metabolism; D000287:Administration, Topical; D000818:Animals; D001458:Bandages; D016503:Drug Delivery Systems; D004343:Drug Implants; D005782:Gels; D006097:Granulation Tissue / Q000473:pathology; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D008747:Methylcellulose; D009130:Muscle, Smooth / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019233:Retreatment; D012883:Skin Ulcer / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D013256:Steroids / Q000008:administration & dosage / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects*
D000199:Actins; D004343:Drug Implants; D005782:Gels; D018809:Proliferating Cell Nuclear Antigen; D013256:Steroids; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D007334:Insulin-Like Growth Factor I; D008747:Methylcellulose