Comparison of Human, Porcine & Rodent Wound Healing with New Miniature Swine Study Data
Accidental wounds are one of the most common reasons for human visits to hospital emergency services. Healthy individuals normally heal accidental skin wounds in a rapid period if complications, such as infections, can be avoided. Aged individuals or diabetics frequently suffer delayed wound healing. Wound researchers require efficient animal models which are predictive of human responses.
Pig skin is anatomically, physiologically, biochemically and immunologically similar to human skin, and the skin is ‘fixed skin’ like humans and unlike rodents or rabbits. Loose skin allows accelerated closure of surgically induced rodent wounds by primary contraction unlike the normal primary response of re-epithelialization in swine and humans. Pig skin mirrors human skin in having a sparse haircoat, a relatively thick epidermis, similar epidermal turnover kinetics, lipid composition and carbohydrate biochemistry, lipid biophysical properties, and a similar arrangement of dermal collagen and elastic fibers. In our studies, healthy juvenile miniature swine wound re-epithelialization progressed relatively quickly (average 0.109 mm/hr at d19) while geriatrics progressed more slowly (average 0.048 mm/hr at d32). Untreated adult diabetic Yucatan miniature swine wound re-epithelialization rates were 88% of conventional non-diabetic (control) Yucatan models at d29 post wounding. Postulations for this minor difference will be offered. Control juvenile or young adult Sinclair or Yucatan miniature swine dermal wounds heal at faster rates (re-epithelialization rate) than those of geriatric or diabetic animals. The healing rate differential can be as high as 2:1 for juveniles over geriatrics. Porcine or miniature swine models offer significant advantages and have a record of predicting treatment modalities in human over models with loose skin. Miniature swine models can provide useful efficacy data for novel cutaneous therapy products.
Liu, J., Kim, D., Brown, L., Madsen, T., Bouchard, G.F
Overall Research Objectives
The purposes of these literature and in-life studies were to:
- Compare human, porcine and rodent wound healing looking for unique traits which could influence healing rates in an animal model system.
- Measure Yucatan and Sinclair miniature swine full-thickness dermal healing rates following surgical wounding.
- That apparent advantages and disadvantages or unique traits exists for various animal models used in wound healing studies.
- That diabetic miniature swine full-thickness dermal wound healing rates will be considerably less than non-diabetic and geriatric rates will be less than juvenile animals
- Perform literature search on wound healing in humans and animal models of interest.
- Perform wound healing studies on normal vs diabetic Yucatan and on juvenile vs geriatric Sinclair miniature swine. Assess re-epithelialization rates in each group.
- Literature references, papers and databases were screened for appropriate comparison parameters and a summary table constructed. Parameters of interest included: skin thickness, strateum corneum thickness, presence of fixed or loose skin, haircoat density, melanin content of epidermis, presence and distribution of eccrine or apocrine glands in skin, epidermal cellular turnover rate, dermal vascularization, skin blood flow, skin pH, presence of delayed healing for diabetic wounds, adult body mass, skin surface area/unit mass, primary wound healing pattern, and wound healing time-course.
- Full-thickness wound studies were performed in juvenile and geriatric Sinclair miniature swine and in diabetic and control adult Yucatan miniature swine and rates of re-epithelialization calculated and compared.
Literature Review on Models: In 2001, Sullivan et al. evaluated 25 wound treatments and showed that the porcine model results was predictive with human study results 78% of the time.3 The anatomy and physiology of the cutaneous blood supply and the wound healing characteristics have made the miniature pig a standard model for plastic surgical and wound healing studies.4,5 Besides the anatomic similarities, swine are equivalent to primates for percutaneous absorption studies and have similar lipid biophysical properties, epidermal turnover kinetics and carbohydrate metabolism in the skin. Pigs have fixed skin like humans and heal primarily by re-epithelialization while rodents close wounds by primarily contraction.12 For our research, Yucatan (Mini or Micro) or Sinclair miniature swine have found the greatest applications for wound healing. Fewer animals are required when miniature swine models are used for wound healing experiments because of the potential number of wound treatment sites per animal. Each animal can serve as its own internal control, as long as the drug effect is localized to dermis and not systemic. Many 1.5 cm square wounds (16-20, up to 24) can be placed on an adult MS dorsum without difficulty. Swine tolerate the wound modeling incredibly well with the use of central acting drugs (opioids) based on food intake, behavior, and tolerance of wound handling. The ability to perform paired wound healing measurements reduces the effect of inter-animal variability and permits more robust paired statistical tests.7 Unlike rodents, pigs possess sufficient body weight to tolerate prolonged topical administration of potent drugs.8 Bellinger et al. (2006) have stated “Pigs have great potential as a relevant animal; model of insulin-resistant type 2 DM to identify mechanisms that lead to the development of diabetic complications and to develop and test novel therapeutic compounds.”9 Pigs can serve as models of delayed wound healing associated with the diabetic state. Although dorsal pig skin does not contain eccrine sweat glands like human skin, the porcine model of partial-thickness skin wound healing has been validated and appears to predict effectively the effects of novel treatments in humans.7,10Hartwell (1955) determined that porcine skin is anatomically and physiologically more similar to human skin than is skin from small laboratory animals.11
Why So Little Difference Between SRC Diabetic and Control Re-epithelialization Rates?
- Insulin therapy level was not restricted leading to nearly normal (88% of normal) wound healing in diabetic miniature swine.
- Control conventional miniature swine rate of epithelial closure was delayed by low grade infections.
- The diabetic status of the pigs had not become chronic and/or the age of the pig was too young to fully model geriatric diabetic or chronic diabetic wounds.
- The miniature swine model is a predictive wound healing surrogate for human wound healing research. Putative treatment drugs or modalities can be screened in these models.
- Control juvenile or young adult Sinclair or Yucatan miniature swine dermal wounds heal at faster rates (re-epithelialization rate) than those of geriatric or diabetic animals. The healing rate differential can be as high as 2:1 for juveniles over geriatrics. The re-epithelialization rate of wounds on adult diabetic Yucatan miniature swine was 88% of that of wounds on normal Yucatans.
- Porcine or miniature swine models offer significant advantages and have a record of predicting treatment modalities in human over models with loose skin.
- Re-epithelialization is one of four major parts of wound healing and is a critical phase.
- MilosChvapil, Thomas A. Chvapil. Wound-Healing Models in the Miniature Yucatan Pig. Ch 17, In: M. Michael Swindel(Ed). Swine As Models in Biomedical Research,. Iowa State University Press, Ames1992, 265-289.
- et al. Impaired wound healing in an acute diabetic pig model and the effects of local hyperglycemia. Wound Repair and Regeneration 2008:(16),: p288-293.
- Sullivan TP, EaglsteinWH, Davis SC, Mertz P. The pig as a model for human wound healing. Wound Repair Regen2001;9:66-76.
- Kerrigan, CL, RG Zelt, JG Thomson & E Diano: The pig as an experimental animal in plastic surgery research for the study of skin flaps, myocutaneous flaps and fasciocutaneous flaps. Lab AnimSci, 36(4): 408-412, 1986.
- Mertz, PM, PA Hebda& WH Eaglstein: A porcine model for evaluation of epidermal wound healing. In: Tumbleson, ME (ed.), Swine in Biomedical Research, Vol. 1, pp. 291-302, 1986.
- Montiero-Riviere, NA & J Riviere: The pig as a model for cutaneous pharmacology and toxicology research. In: Tumbleson, ME and Schook, LB (eds.), Advances in Swine in Biomedical Research, Vol. 2,
- Paddock HN et al. Methods of Reepithelialization: A Porcine Model of Partial-Thickness Wounds. Ch 2 In Luisa A. Di Pietroand AimeL. Burns (Eds). Wound Healing Methods and Protocols. Humana Press, Totowa, NJ, 2003, p 17-36.
- et al. Use of Miniature Pig for Biomedical Research, with Reference to Toxicological Studies. J. Toxicol. Pathol. 2007;20:125-132.
- Bellinger DW et al. Swine Models of Type 2 Diabetes Mellitus: Insulin Resistance, Glucose Tolerance, and Cardiovascular Complications. ILAR Journal, Vol47, No. 3, 2006: 258-342.
- Montagna W, YunJS. The skin of the domestic pig. J. Invest Dermatol1964; 42:11-21.
- Hartwell SW. The Mechanism of Healing in Human Wounds, Charles C. Thomas, Springfield, IL, 1955.
- Dorsett-Martin WA, Wysocki AB. Rat Models of Skin Wound Healing. Ch 65 In: Conn MP, Sourcebook of Models for Biomedical Research, Humana Press, Jan 2008, p631.