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					Use of a Growth Factor-Impregnated Drug Delivery
System To Promote Wound Healing in Radiation-
Impaired Rat Wounds
Chad Tattini MD, Victor Zaporojan, Gene Carderelli, Scott Schmidt MD, Jane Kim MD,
Anthony Spangenberger BS, Lawrence Bonassar PhD, Jeffrey Weinzweig MD

INTRODUCTION: Polypeptide growth factors have stimulated an enormous surge in
wound healing research over the last few decades. A more thorough understanding of
cellular, physiologic, and biochemical events that occur after tissue injury has provoked
researchers to continually strive for ways to enhance wound repair or retard abnormal
scarring1.
    Models of impaired wound healing that mimic clinical settings have been developed
to further investigate the role of specific growth factors2,3,4. One of the most clinically
important factors that impairs wound healing is radiotherapy. It is well known that
radiation predominantly affects fibroblast function and therefore, the collagen production
by fibroblasts do not meet the demands of the healing wound.
    Many techniques have been previously developed to incorporate peptide growth
factors into these impaired wounds5,6. Most of these techniques, however, are limited in
their dose of growth factor or their penetration into the wound or the short term effect of
a one-time application. Our study focused on a drug delivery system that would be able
to exert its effects for a longer duration during the most fragile part of the wound healing
phase. The present work demonstrates the role of a growth factor delivery system,
containing TGF-B and FGF, that can successfully reverse the impaired wound healing
seen in a radiated rat wound.

METHODS: Ninety-six Sprague-Dawley rats underwent dorsal skin surface irradiation
of 2,500 rads via a medical linear accelerator capable of producing energy of 6 MeV. Six
groups of sixteen rats were established; rats received no growth factor, one growth factor,
or both. Two days after radiation, full-thickness dorsal skin incisions were made and the
specific growth factor system was implanted. The drug delivery system was a
filamentous polyglycolic acid rod measuring 1cm in length. Impregnation with 2
micrograms of experimental growth factor per delivery system was performed
preoperatively and ultimately permited delivery of about 50ng of experimental growth
factor/day. On post-wounding days 4, 7, 14, and 28, euthanization of four rats in each
group was performed. Wounds were then harvested for histological and tensiometric
analysis. Statistical analysis was performed using two-way analysis of variance multiple
comparison procedures (Bonferroni t-test).

RESULTS: The radiated rats demonstrated an impaired model of healing when
compared to normal, non-radiated rats (p<0.001) as indicated by wound breaking
strength. On post-wounding days 4 and 7, growth factor treated wounds demonstrated
slightly greater wound breaking strengths than radiated controls. On post-wounding day
14, wounds that contained both growth factors demonstrated a statistically significant
increase in wound breaking strength when compared to radiated controls (p<0.05) (Fig.
1). Growth factor-treated wounds also revealed a general increase in cellularity and more
stable collagen architecture throughout the study as evident in the mallory trichrome stain
(Fig. 2).


                                     600


                                     500                                        BSA
   Ultimate Tensile Strength (kPa)




                                     400                                        CONTROL
                                                                                IRRADIATED
                                     300
                                                                                FGF
                                     200
                                                                                TGFb
                                     100                                        FGF+TGFb

                                       0
                                           0   4   8   12   16   20   24   28   32




Fig. 1: Ultimate tensile strength vs. post-wounding day time-points 4, 7, 14, and 28.
Growth factor treated wounds show improved UTS on days 4 and 7, and become
statistically significant on day 14.




Fig. 2: Mallory trichrome stain of all 6 groups. The control and growth factor-treated
wounds exhibit a stable, more organized collagen framework.


CONCLUSIONS: A significant improvement in wound breaking strength was
demonstrated by the radiated rat wounds treated with FGF and/or TGF-B on day 14.
Interestingly, this time point also correlated with the increased cellularity and mature
collagen framework seen histologically in the growth factor treated wounds. We attribute
these results to our time-released growth factor delivery system.
REFERENCES

  1. Cromak D, Pierce G, Mustoe T: TGF-B and PDGF mediated tissue repair:
     identifying mechanisms of action using impaired and normal models of wound
     healing: Clinical and Experimental Approaches to Dermal and Epidermal Repair:
     Normal and Chronic Wounds, Wiley-Liss Inc, 1991, 359-373.
  2. Cromak D, Beatriz P, Purdy J, et al : Acceleration of tissue repair by TGF-B:
     identification of in vivio mechanism of action with radiotherapy-induced specific
     healing defecits; Surgery; 113; 36-42; 1993.
  3. Vegesna V, McBride W, Taylor J, et al: The effect of Interleukin 1 or TGF-B on
     radiation-impaired murine skin wound healing; J Surg Research; 59; 699-704;
     1995.
  4. Ferguson, P, Boynton E, Wonder J, et al: Intradermal injection of autologous
     dermal fibroblasts improves wound healing in irradiated skin; J Surg Research;
     85; 331-338; 1999.
  5. Mustoe T, Purdey J, Devel T, et al : Reversal of impaired wound healing in
     irradiated rats by PDGF-BB; Am J Surgery; 158; 345-350; 1989.
  6. Bernstein E, Hariziadis L, Salomon G, et al : TGF-B improves healing of
     radiation-impaired wounds; J Invest Derm; 97; 430-434; 1991.

				
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