Relevance of Animal Models for Wound Healing

  • Thu, 9/4/08 - 11:52am
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Author(s): 
Roberto Perez, PhD and Stephen C. Davis, BS

Animal models and in-vitro assays have become indispensable tools for researchers in nearly every scientific discipline. In product development there is a need for translational research to obtain data that can lead to sound clinical trials and ultimately, improved wound care. This process is usually performed in a stepwise fashion starting with in-vitro testing, preclinical, and then clinical evaluations (Figure 1). In-vitro studies help determine which concentrations may be effective in-vivo and determine whether certain products are effective on various cell types (eg, fibroblasts and keratinocytes). The next step is to examine the effect of the product’s use in an animal model(s). This facilitates investigation of the product in the presence of wound fluid, blood, immune cells, proteases, etc., which can have an effect on the activity of the active agent. Many in-vivo animal studies initially investigate the safety and/or irritancy of the product. It is important to be sure that these agents do not have a toxic effect on tissues. Efficacy animal trials are conducted after the safety studies are completed. This eventually allows the product to be evaluated in human trials.

Although definitive studies conducted on human subjects are needed, such studies present several practical, ethical, and moral concerns. For example, in order to examine wounds histologically throughout the entire healing process one must biopsy a human subject at multiple time points, which is impractical. Furthermore, ethical considerations prevent the intentional infection of a wound on a human or the use of an untreated control subject. Some of the practical difficulties lie in obtaining enough subjects with similar or identical situations to conduct well controlled studies. Another complication to factor in with human trials is compliance (eg, subject’s level of cooperation, ability to understand and follow instructions). The above difficulties have led researchers to develop multiple in-vitro and in-vivo models that attempt to mimic or reproduce human conditions.

In-vitro assays. In-vitro assays are great for examining the effect of agents on particular cell types. They are relatively inexpensive, fast, and convenient for the researcher. In addition to providing useful results in a short time, they possess an obvious humane appeal since they usually do not involve the use of animals or humans.1 In-vitro assays are useful in wound healing research for determining the possible effectiveness of various treatments, particularly antimicrobial and healing enhancing agents. Another noteworthy attribute of in-vitro testing is the ability to screen multiple agents or samples simultaneously. Assays can aid in the early detection of antimicrobial resistance among pathogens and determination of minimal inhibitory concentrations (MIC), and allow for highly specific control over the experimental conditions. However, it is difficult to simulate a “real world” application. Although some variables such as pH, salinity, and temperature are easily controlled, in-vitro assays are incapable of completely reproducing biological conditions (eg, immune responses, healing) and diseases, such as diabetes.2

References: 

1. Cross SE, Naylor IL, Coleman RA, Teo TC. An experimental model to investigate the dynamics of wound contraction. Br J Plast Surg. 1995;48(4):189–197.
2. Davis SC, Bouzari N. Development of antimicrobials for wound care: in-vitro and in-vivo assessments. WOUNDS. 2004;16(11);344–347.
3. Calderon M, Lawrence WT, Banes AJ. Increased proliferation in keloid fibroblasts wounded in-vitro. J Surg Res. 1996;61(2):343–347.
4. Cha D, O’Brien P, O’Toole EA, Woodley DT, Hudson LG. Enhanced modulation of keratinocyte motility by transforming growth factor-alpha (TGF-alpha) relative to epidermal growth factor (EGF). J Invest Dermatol. 1996;106(4):590–597.
5. Eckes B, Krieg T, Nusgens BV, Lapiere CM. In-vitro reconstituted skin as a tool for biology, pharmacology and therapy: a review. Wound Repair Regen. 1995;3(3):248–257.
6. Grinnell F. Fibroblasts, myofibroblasts, and wound contraction. J Cell Biol. 1994;124(4):401–404.
7. Moll I, Houdek P, Schmidt H, Moll R. Characterization of epidermal wound healing in a human skin organ culture model: acceleration by transplanted keratinocytes. J Invest Dermatol. 1998;111(2):251–258.
8. Gottrup F, Agren MS, Karlsmark T. Models for use in wound healing research: a survey focusing on in-vitro and in-vivo adult soft tissue. Wound Repair Regen. 2000;8(2):83–96.
9. Sullivan TP, Eaglstein WH, Davis SC, Mertz P. The pig as a model for human wound healing. Wound Repair Regen. 2001;9(2):66–76.
10. Davidson JM. Animal models for wound repair. Arch Dermatol Res. 1998;290(Suppl):S1–S11.
11. Arfors KE, Jonsson JA, McKenzie FN. A titanium rabbit ear chamber: assembly, insertion and results. Microvasc Res. 1970;2(4):516–518.
12. Lebel L, Gerdin B. Sodium hyaluronate increases vascular ingrowth in the rabbit ear chamber. Int J Exp Pathol. 1991;72(2):111–118.
13. Algire GH. An adaptation of the transparent-chamber technique to the mouse. J Nat Cancer Inst. 1943;4:1–11.
14. Baker JH, Hammersen F, Bondar I, et al. The hairless mouse ear for in-vivo studies of skin microcirculation. Plast Reconstr Surg. 1989;83(6):948–959.
15. Ehrlich HP, Needle AL. Wound healing in tight-skin mice: delayed closure of excised wounds. Plast Reconstr Surg. 1983;72(2):190–198.
16. Dorsett-Martin WA. Rat models of skin wound healing: a review. Wound Repair Regen. 2004;12(6):591–599.
17. Grose R, Werner S. Wound-healing studies in transgenic and knockout mice. Mol Biotechnol. 2004;28(2):147–166.
18. Friedman HI, Fitzmaurice M, Lefaivre JF, Vecchiolla T, Clarke D. An evidence-based appraisal of the use of hyperbaric oxygen on flaps and grafts. Plast Reconstr Surg. 2006;117(7 Suppl):175S–192S.
19. Meyer W, Schwarz R, Neurand K. The skin of domestic mammals as a model for the human skin, with special reference to the domestic pig. Curr Probl Dermatol. 1978;7:39–52.
20. Heinrich W, Lange PM, Stirtz T, Iancu C, Heidermann E. Isolation and characterization of the large cyanogens bromide peptides from the alpha1- and alpha2-chains in the pig skin collagen. FEBS Lett. 1971;16(1):63–67.
21. Broughton G 2nd, Janis JE, Attinger CE. The basic science of wound healing. Plast Reconstr Surg. 2006;117(7 Suppl):12S–34S.
22. Gottrup F, Lorentzen H, Jørgensen LN. Human models. In: Mani R, Falanga V, Shearman CP, Sandeman D, eds. Chronic Wound Healing: Clinical Measurements and Basic Science. London, England: Saunders; 1999:156–169.
23. Eaglstein WH, Mertz PM. New method for assessing epidermal wound healing: The effect of triamcinolone acetonide and polyethylene film occlusion. J Invest Dermatol. 1978;71(6):382–384.
24. Serralta VW, Harrison-Balestra C, Cazzaniga AL, Davis SC, Mertz PM. Lifestyles of bacteria in wounds: presence of biofilms? WOUNDS. 2001;13(1):29–34.
25. Walters MC 3rd, Roe F, Bugnicourt A, Franklin MJ, Stewart PS. Contributions of antibiotic penetration, oxygen limitation, and low metabolic activity to tolerance of Pseudomonas aeruginosa biofilms to ciprofloxacin and tobramycin. Antimicrob Agents Chemother. 2003;47(1):317–323.
26. Cazzaniga AL, Serralta VW, Davis SC, Orr R, Eaglstein W, Mertz PM. The effect of an antimicrobial gauze dressing impregnated with .2-percent polyhexamethylene biguanide as a barrier to prevent Pseudomonas aeruginosa wound invasion. WOUNDS. 2002;14(5):169–176.

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