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The Development of a Rat/Human Skin Flap Served by a Defined and Accessible Vasculature on a Congenitally Athymic (Nude) Rat
Abstract
The Development of a Rat/Human Skin Hap Served by a Denned and Accessible Vasculature on a Congenitally Athymic (Nude) Rat. Krueger, G. G., WOJCIECHOWSKJ, Z. J., BURTON, S. A., GILHAR, A., HUETHER, S. E., LEONARD, L. G., ROHR, U. D., PETELENZ, T. J., HlGUCHI, W. I., and PERSHING, L. K. (1985). Fundam. Appl. Toxicol. 5, S112–S121. Experience in microvascular surgery on rats and availability of athymic (nude) rats led us to believe that a long-term functional rat/human skin sandwich flap could be generated on a defined and experimentally accessible vasculature on nude rats. Such a system has been developed and validated. Microvasculature has been assessed. The volume of blood to the flap ranges from 1 to 2 ml/min, collateral circulation to the flap exists, but is negligible, and there is little change in the capillary blood flow as the flap ages. The flap can be utilized to study absorption of compounds from a half-cell diffusion chamber or from direct deposition on the skin, and can be utilized to study various parameters of percutaneous absorption, e.g., the effect of hydration on the stratum corneum. Transdermal flux can be determined. Altering the microcirculation directly affects the percutaneous absorption of compounds that are rapidly absorbed. The absorption of benzoic acid through an experimentally vasoconstricted area (iontophoresis of phenylephrine) significantly alters the time to peak absorption, with values being 14 times that of the control site. The system has been utilized to assess metabolic activity of skin in situ using [³H]adenine arabinoside and studying the appearance of its major metabolite, [³H]Ara-H, in flap blood, as well as the back diffusion of this compound into the donor chamber. Recently the human/rat skin sandwich flap component has been developed. With this system, it has been demonstrated that benzoic acid, when applied to the human skin component of the flap has an absorption profile which is quite different from that when benzoic acid is applied to rat skin, peak flux occurred 2 hr after application. This contrasts with 10 min to peak flux when the same experiment is carried out on the rat/rat skin sandwich flap. To our knowledge, the human/rat skin sandwich flap is the first example of a viable, functional human organ that is chronically maintained by a biologic support system which has the added distinction of being on an independent but accessible vasculature. The validation experiments strongly suggest that this system will be important in gaining insights into the more sophisticated in vivo components of skin, relative to toxicology and pharmacology.
Until now, ex vivo human skin explant utilization in tissue culture has consisted of limited short-term studies (less than a week). This short timeframe does not allow for the investigation of metabolic responses of complex tissues to specific molecules or compounds. Here, we aim to develop an improved mouse transplantation model that maintains the viability, structure and functionality of the human skin explants for prolonged periods of time.
Healthy human skin explants derived from biopsies were grafted onto nude mice and used to perform a toxicological study of the reactivity and functionality of grafted skin explants after one month. Histological observations suggest that the tissue properties and phenotype of the human skin graft are conserved as a result of re-vascularization upon tissue integration. The toxicological test performed shows that the human skin graft reacts to systemic exposure of a xenobiotic metabolic inducer when applied to this mouse model.
This mouse/human chimeric model can be effective for the long-term study of human skin reactivity to chemicals as well to study in vivo responses to complex co-exposures.
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