Tissue repair processes in healing chronic pressure ulcers treated with recombinant platelet-derived growth factor BB.
Cellular and molecular mechanisms responsible for the observed vulnerary effects of recombinant human platelet-derived growth factor BB (rP-DGF-BB) in man have not been elucidated. In a double-blinded trial, patients having chronic pressure ulcers were treated topically with either rPDGF-BB or placebo for 28 days. To explore how rPDGF-BB may induce chronic wounds to heal, biopsies were taken from the ulcers of a cohort of 20 patients from the trial and evaluated in a blinded fashion by light microscopy for 1), fibroblast content, 2) neovessel formation, and 3), collagen deposition. Electron microscopy also was used to assess fibroblast activation and collagen deposition. Before initiation of therapy most wounds had few fibroblasts and most of those present were not activated. When mean scores for the total active treatment phase (days 8, 15, and 29) for rPDGF-BB-treated ulcers were compared with the scores for placebo-treated ulcers, fibroblast content was significantly higher for the rPDGF-BB-treated ulcers (P = 0.03, Kruskal-Wallis test). More significant differences in fibroblast and neovessel content were observed when six nonhealing wounds were eliminated from the analysis (three placebo, three treatment). Thus, in all healing wounds, rPDGF-BB therapy significantly increased fibroblast (P = 0.0007) and neovessel (P = 0.02) content. These results were correlated with increased collagen fibrillogenesis by fibroblasts from healing rPDGF-BB-treated wounds, as assessed by intracellular procollagen type I immunostaining, and by electron microscopy, and were concordant with clinical measurements (eg, area of ulcer opening and ulcer volume) which showed greater healing in rPDGF-BB-treated wounds. These results suggest induction of fibroblast proliferation and differentiation is one mechanism by which rPDGF-BB can accelerate wound healing and that rPDGF-BB can augment healing responses within a majority of, but not all, nonhealing chronic pressure ulcers in man.
Pierce
G F
GF
Department of Experimental Pathology, Amgen Inc., Thousand Oaks, California.
Tarpley
J E
JE
Allman
R M
RM
Goode
P S
PS
Serdar
C M
CM
Morris
B
B
Mustoe
T A
TA
Vande Berg
J
J
D000906:Antibodies / Q000276:immunology; D000077214:Becaplermin; D001706:Biopsy; D001808:Blood Vessels / Q000254:growth & development; D002908:Chronic Disease; D015331:Cohort Studies; D003094:Collagen / Q000378:metabolism; D004311:Double-Blind Method; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D010446:Peptide Fragments / Q000276:immunology; D010919:Placebos; D010982:Platelet-Derived Growth Factor / Q000627:therapeutic use*; D003668:Pressure Ulcer / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D011347:Procollagen / Q000737:chemistry; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; D014945:Wound Healing / Q000187:drug effects*
D000906:Antibodies; D010446:Peptide Fragments; D010919:Placebos; D010982:Platelet-Derived Growth Factor; D011347:Procollagen; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; D000077214:Becaplermin; D003094:Collagen