Current Status of Skin Substitutes

Symposium on Burns

Current Status of Skin Substitutes Michael J. Tavis, M.D.,* James Thornton,t Richard Danet,f. and Robert H. Bartlett, M.D.§

If a functional skin substitute and a reliable skin tissue culture technology became available tomorrow, the treatment of burn injuries would change overnight. Eschar would be excised in the early postburn period and the surface covered with a skin substitute. Within one or two weeks the patient would be discharged, while small pieces of autologous healthy skin were growing in the tissue culture laboratory. In a month the skin substitute could be replaced by confluent sheets of autogenous cultured skin. Within the next two decades this method of treatment may well become a reality. The purpose of this article is to review the current status of prosthetic skin substitutes.

SKIN SUBSTITUTES Material currently in use to cover burns or denuded surfaces may be divided into two categories: Dressings Covers that are designed to be removed and replaced at regular intervals. Skin substitutes Temporary-material designed to be placed on a fresh wound (partial thickness) and left until healed. Semipermanent-material remaining attached to the wound for months, and eventually replaced by autogenous skin grafts.

The term prosthesis refers to any temporary or semipermanent skin substitute; artificial skin refers to man-made materials that may be biological or synthetic in origin. "Director of Burn Laboratory Research, Burn Center, University of California at Irvine; Resident in Plastic Surgery, UCLA Medical Center, Westwood, California tSenior Medical Student, University of California at Irvine, Orange, California tBurn Technician, University of California at Irvine, Orange, California §Professor of Surgery, University of California at Irvine; Director of Burn Center, and Chief, Division of General Surgery, Medical Center, University of California at Irvine, Orange, California

Sllrgical Clinics of North America-Vol. 58, No.6, December 1978

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Applications Prosthetic skin is needed in two clinical settings: short-term (one to three weeks) skin replacement for covering donor sites, second degree burns, and small full-thickness excisions or abrasions prior to skin grafting; and semipermanent (one to four months) coverage on granulating surfaces or following excision of extensi ve full-thickness burns in association with staged autografting. Many materials have been evaluated as short-term prosthetics on donor site surfaces with promising results; however, none is ideal. Donor sites or small second degree burns will heal promptly if kept clean regardless of the type of coverage or dressing. The real test of short-term prosthetics comes in the management of large second degree burns and the coverage of moderate tissue loss in debrided electrical injuries or excised full-thickness burns. The only approach to semipermanent skin prosthesis which has been successful to date is viable allograft with immune suppression (skin transplantation). Less than 20 cases have been reported with only a few survivors (all children). The technique is extremely time-consuming, complex, and not appropriate for general clinical usage. Trials in adults have given uniformly dismal results. However, the few good results reported by BurkeS are extremely encouraging for the field of skin prosthetics. These cases suggest that removing all the eschar in extensive burns is a reasonable and rational approach to this devastating injury. The availability of an ideal skin prosthesis could make the technique of immediate excision and staged autografting applicable in adults and appropriate for general clinical use.

Ideal Properties The ideal properties of a skin substitute are listed below: Adherence Water vapor transport Elasticity Durability Intact bacterial barrier Nonantigenic and nontoxic Antiseptic Hemostatic Ease of application and removal Expense

The most important property of a biological or prosthetic material applied to a deepithelialized surface is adherence. 9,49.53 The importance of adherence is supported by our own observations 54, 56 and the demonstration that adherence of a skin substitute to split-thickness defects such as donor sites and partial thickness burns can reduce pain, limit infection, and consequently optimize the rate of healing. 10. 27. 29. 45. 49 It has also been shown that adherence of a dressing to a granulating or freshly excised surface can significantly reduce bacterial contamination 10• 17 with a subsequent increased graft "take."

r

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Adherence must occur rapidly and be strong enough to resist shear stresses. It must be uniform since small areas of nonadherence will lead to fluid-filled pockets where bacteria may proliferate. Most prostheses and grafts rely on the endogenous adhesive, fibrin. The adherence properties of a material, therefore, are determined by the strength of the bond that it forms with fibrin. Studies have demonstrated that fibrin bonds preferentially to collagen in normal skin. 56 A second mechanism of adherence is entrapment of the graft material in the coagulum that forms on the tissue surface. Using this principle, materials such as polyurethane, nylon, and Dacron which do not bind fibrin can be made adherent to tissue by formation ittto sponge, flocking, loose fabric, or similar configurations. The coagulum in the interstices of such material allows bacteria and fibroblasts to grow and dry with time, forming a crusty scab. This may be desirable in some applications, such as coverage of donor sites with scarlet red gauze, or achieving wound debridement by pulling off the dressing and associated coagulum, but this approach would not be successful for any semipermanent skin prosthesis. A third mechanism by which prosthetics adhere involves the use of an adhesive (such as methacylate) that binds to wet human tissue. Normal skin allows water vapor to pass through it at a rate of approximately 8.5 gm per m 2 per hr while retaining protein and electrolytes. A skin prosthesis should have similar water vapor transfer characteristicS. 28 If the substance is more permeable the tissue will dry, the capillaries will thrombose, and excess water will be lost. If the prosthesis is less permeable, blisters or bullae will form below the material preventing adherence. Skin prosthetics should have enough elasticity to stretch freely over joints without causing shear stresses that will break the adherence bond between the material and the surface. Nonelastic materials could be used over flat surfaces. The elasticity and mobility of normal skin are a function of the subcutaneous fat and dermis. A skin prosthesis must compensate for both. Ideally, a prosthetic skin should be durable enough to allow sitting, lying, rolling, bathing, and the wearing of clothes. It must be strong enough to remain intact for the duration required, and provide a bacterial barrier. Antigen icity, tissue reactivity, and toxicity are obviously important considerations. Some of these problems could be accepted if other characteristics are outstanding. One of the best skin substitutes currently available is living allograft combined with immune suppression. Elimination of antigenicity would be a more desirable approach. The material should be readily available, easily stored, and inexpensive. Expense is related to the alternative prolonged hospitalization. A material that saves one week of hospitalization at $500 per day would be a bargain at $3000. A material possessing hemostatic properties would be desirable and would minimize the time expenditure and tissue destruction inherent in electrocoagulation. 32 Although the antibacterial effect of adherent wound coverings is well documented,lO. 17. 46 improved bacterial control could be achieved by com-

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bining the prosthesis with topical antibiotics. Chemical incorporation of the antibiotic into the prosthesis or simple diffusion of topically applied creams has been found effective. 36 Ease of application and removal are properties directly related to adherence. Application as a liquid or powder is ideal. 2The material should be either biodegradable or not dependent upon tissue ingrowth for adherence. If the prosthesis becomes incorporated into the dermis, complete removal is difficult and may require re-debridement before grafting. 27, 39

CONTEMPORARY PROSTHETICS Materials used for skin substitution are listed below and compared with ideal properties in Table 1: Biologic Human Allograft (Homograft) Living donor Cadaver donor fresh Cadaver donor frozen Amniotic membrane Xenograft (Heterograft) Living donor fresh Frozen, radiated, or dried Tissue Derivatives Collagen sheet, fabric, or sponge Bioplast fibrin Synthetic Solid Silicone Polymer Membrane Other Plastics Microporous Materials Adherent Materials (Hydron) Composite Materials Surface Membrane (silicone, microporous, Hydron) Adherent Substrate Collagen, cotton gauze, synthetic, polymer, sponge, velour, flocking, or fabric

Biological Materials ALLOGRAFT (HOMOGRAFT). Closure of granulating and contaminated wounds has been accomplished with human allograft. Wound closure results in a decrease in fever and pain, restoration of function, increased appetite, and improved general well-being. Homograft (allograft) was found to decrease bacteria colonization and stimulate granulation tissue. 6, 17, 24 Allograft is an ideal prosthetic material with the exceptions of antigenicity, availability, and bacterial contamination. Contamination of homografts can cause serious and occasionally lethal infection.35 Harvesting cadaver skin is time-consuming and often difficult to procure. At 4° C viability is limited to approximately two weeks.24 Allograft banking is possible in both high and low temperature environments. Glycerintreated grafts stored at -160° C remain viable for up to 6 months. Banking at -20° C in glutaraldehyde produces nonviable grafts capable of prolonged storage. Viable grafts can be stored for several days in tissue culture media at 37° C.

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Table 1. Properties of Various Skin Prostheses

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EASE OF USE WATER ADHERENCE

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DURABILITY

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Figure 1. Cadaver allograft and immune suppression after primary excision in a 12 year old child. The skin is growing well 10 days after grafting.

Burke and colleagues 8 have advocated taking skin from living related donors when true transplantation is planned; the viability, "take," and quality of growth are probably as good from cadaver sources (Fig. 1). The duration of coverage is limited to prevent "take" and rejection which leaves the patients with large open wounds. 26 The first set of allografts will become vascularized. Grafts are removed and replaced at the first sign of rejection. Subsequent allografts are removed as soon as vascularization begins. 59 Prolonged retention of glutaraldehyde-treated grafts implies that viability is not necessary for adherence and that nonviable homograft might be considered to be a collagen-elastin prosthesis. 47 Other viable allografts that have been advocated for skin substitution are amnion 14.23.44.58 and omentum. 33 Omentum is too thick to be vascularized. Amnion has been evaluated by several investigators. It provides an adequate coverage with moderate adherence and elasticity, but is so thin that durability is the major problem. As living tissue, amnion will elicit a rejection response; therefore it seems to have no benefits over cadaver skin or nonviable biologic dressing. XENOGRAFT (HETEROGRAFT). The use of heterologous tissue as a temporary dressing for full-thickness skin defects was largely a result of the difficulty of obtaining and storing adequate amounts of homograft. The adherence of allograft and xenograft is similar,6. 10. 53 related to their respective collagen content53 and unrelated to their viabilityy· 53. 58 Nonviable heterograft could be considered to be a collagen-elastin prosthetic. Heterograft provides a readily available, easily stored, and sterilized dressing in contrast to homograft. The only xenograft in common use is pigskin. Viable xenograft "take" and vascularization with rejection require removal and replacement at regular intervals. 5. 22. 43 Although this material is widely used, controlled studies have failed to show any benefits from the use of heterograft when compared with gauze-antibiotic dressings. 19

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Figure 2. Porcine xenograft is used as a temporary prosthesis on granulation tissue when autograft supply is insufficient.

Variable results have been reported with porcine xenograft coverage of donor sites and partial thickness burns ranging from early reepithelialization l l • 43 to conversion to full-thickness skin 10ss.34 It has also been reported that incorporation of xenograft tissue on healing donor sites occurs in 35 per cent of cases. 45 There appears to be no significant difference in the effectiveness of fresh compared with fresh-frozen or frozenirradiated porcine skin. 22 The sterility, ease of handling, and shelf life properties of dead xenograft are better than those of living grafts. Therefore, the use of frozen, radiated, or lyophilized xenograft seems preferable to the use of fresh skin (Fig. 2). Xenograft has most ofthe properties of the ideal skin substitute (Table 1). Viable xenograft is antigenic, but dead tissue is not. The major problem is the propensity to digestion by wound collagenase and subsequent infection. BIOLOGIC TISSUE DERIVATIVES. Collagen has been used in many forms as a biological dressing and offers several unique advantages. It can be isolated and purified in large amounts. Structure and immunologic chemistry are well characterized. Antigenicity may be altered. It can be made into a variety of physical structures. It possesses a hemostatic effect. The rate of resorption is easily controlled. It has a hydrophilic surface for cell adhesion and mobility. Water vapor transport may be modified.

It has been used as a collagen-fabric composite film,20 reconstituted collagen fibrils,41 reconstituted extruded strips, 15 reconstituted sheets on Dacron mesh, 52 reconstituted pure sheets, 1 microcrystalline porous mats,30 microcrystalline sheets,31 dermal collagen allografts,39 microcrystalline powder,21 and collagen sponge grafts. 13 The adherence of modified bovine collagen membrane is equivalent to intact skin, 52, 53 and there is evidence to suggest that graft materials are bound by collagen-fibrin links. 56

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Figure 3. Collagen membrane prosthesis. A, Tangential debridement of full thickness burn. B, Collagen prosthesis after one week, ready for removal and autografting. C, Three months after grafting. Both collagen-treated (right) and conventional dressing-treated (left) legs were grafted by stamp technique. Greater scar formation on the right is the result of grafting on granulation tissue.

Collagen dressings have demonstrated a marked potential to stimulate the formation of a highly vascularized granulating bed (Fig. 3).52 Collagen membrane is relatively nonelastic and may dislodge with shear stress. This can be largely solved by structural modification to a tanned collagen sponge which provides for fibrous tissue ingrowth and proliferation. 13, 40 The greatest obstacle to the long-term use of collagen prosthetic materials lies in the control of infection. Collagen's permeability to most commonly used topical antibiotics may provide a partial solution. 52 Another biologically derived material is Bioplast fibrin which has not been evaluated in burn care. 51

Synthetic Materials The problems associated with biological materials provided an impetus to search for a synthetic material with ideal properties for a skin prosthesis. Beginning with the early work ofPickrell42 who made sulfonamide films in 1942, a vast array of materials has been studied. These early studies were to a large extent concerned with evaluating vertical composites with a semipermeable membrane on the exterior and a porous material against the wound. 3 • 12. 16, 20, 27 Many of these materials adhere by entrapment of coagulum in the interstices of the material. They are sometimes proposed as skin substitutes but are actually planned for regular removal to debride the surface and are more properly classified as dressings. 3 Silicone polymer membrane is the best material available because it is elastic, durable, and the water vapor transfer characteristics can be controlled by varying the thickness. Silicone polymer is inert and does not bind fibrin and therefore must be laminated to other fibrin binding materials for its adherence. We have used thin silicone membrane bonded to cotton gauze for temporary skin substitution. 27 , 55 This is the best synthetic material we have evaluated (Fig. 4). The cotton gauze backing lacks elasticity and creates a

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8 Figure 4.

Silicone polymer membrane ready for use (A) and on a donor site (B).

nonuniform pattern of adherence. Therefore, the material is useful only on relatively flat surfaces (Fig. 5). Iodine can be incorporated into silicone, providing an effective delivery system for molecular iodine 36 to the wound surface. It is permeable to a number of chemical substances potentially useful in surface care. Some manufacturers have modified polyvinyl chloride or similar plastics to provide more elasticity and water vapor transfer characteristics. 25 , 28, 57 These materials (Cling Film, Via-film, Opsite) are provided with an adhesive coating on one side. The adhesive is designed to adhere to normal skin adjacent to the injured area. The biggest disadvantage is the lack of adherence to the wound itself. These materials seem to have great promise as a temporary skin substitute for short-term applications.

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Figure 5. a donor site.

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Silicone polymer membrane (left) and collagen membrane (right) compared on

Plastics that are impermeable to water can be made microporous by expansion or fabrication techniques. This creates durable elastic materials that can be used to cover wound surfaces. These materials are nonadherent, and must be incorporated with an adhesive or laminated to some material that bonds to fibrin or provides a surface for coagulum entrapment. A unique concept in the treatment of burn wounds has evolved from the development of Hydron, 2.38 a synthetic dressing that is formed from a two component system (Fig. 6). The dressing binds to dry and wet tissue ifnot actively bleeding. Polyhydroxyethylmethacrylate monomer powder is sprayed onto the surface followed by a small amount of polyethylene glycol. The polyethylene glycol solubilizes the powder forming. a uniform homogenous sheet that conforms to a regular contour, is adherent to tissue, elastic, non antigenic , inert, and provides effective antimicrobial barrier. Water vapor transfer depends upon thickness, but in general the material is excessively permeable to water. The final polymer softens and comes off in water, so that the surface cannot be washed and moderate oozjng or bleeding will eliminate the covering entirely. The material therefore has a low degree of durability on wet or weeping wounds. If the initial application remains in good condition, drying of the material and the underlying tissues may occur over a period of several days leading to a loss of elasticity and cracking of the surface. Cracks can be repaired by applying more Hydron. Its use as a long-term prosthesis is precluded by its poor durability.

Composite Materials Most artificial skins have been made by combining two or more materials,3. 16,27,50 the outer layer designed for durability and elasticity. Microporous materials. silicone polymer, and modified plastic films are all suitable for this purpose. The inner layer is designed for maximum adherence and elasticity. Cotton gauze, Dacron flocking, and collagen sponge have all been proposed for this layer. However, these materials adhere largely by incorporation of coagulum which may lead to infection.

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Figure 6. Hydron prosthesis. A, Application by spraying powder and polyethylene glycol. B, Completed dressing.

Homogenous collagen film, collagen powder in an elastic material, or adherent polymers such as Hydron are more satisfactory. A middle layer may be included in composite materials to regulate water vapor transfer, provide a bacterial barrier, or to add strength.

DISCUSSION No satisfactory prosthesis exists for temporary or semipermanent application. A review of current practices may serve as a guide to future development.

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Autograft Homograft Collagen

67 106 63 54

Silicone

72 HOURS

ADHERENCE %ADHERENCE

84gm/em 2

TAVIS ET AL.

CUMULATiVE INDEX

5 HOURS MATERIAL

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76 B6 BI 74 9B

MATERIAL AutoQraft

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ADHERENCE %AOHERENCf

360gm/cm 2 491 521 473 34B

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Figure 7. Laboratory testing of skin substitutes. Adherence is measured in gm per cm' by pulling small grafts from test surfaces under controlled conditions. A. Durability and shear resistance are measured by the number remaining on the animal. B. These factors are combined into an index for comparison. (From Tavis, M. J., et al.: Graft adherence to deepithelialized surfaces: A comparative study. Ann. Surg., 184:594, 1976, with permission.)

Donor sites will heal well as long as infection is prevented. They provide an excellent test surface for skin prosthetics (Fig. 5). The usefulness of silicone and collagen membrane and Hydron has been demonstrated in this situation. 25 , 27, 57 Similarly, testing of xenograft on donor sites identified the potential problem of porcine collagen incorporation into the healing surface. 27 , 45 This is serious enough to preclude its general usage for donor sites or second degree burns. The common treatment of moderate size second degree burns, particularly those involving the hands, face, or other joints, is with topical dressings usually applied daily in association with washing the surface. Since the vast majority of burned patients fall into this category, the development of a temporary prosthesis for this application is an important consideration. After adherence, durability and elasticity are high priority characteristics. Allograft and xenograft are satisfactory in.this regard, but do not provide uniform coverage and are subject to infection. Elastic plastic films made adherent by adhesi ves 25 , 57 or incorporation of fibrin binding materials 5L 52 have the most promise in this area.

CURRENT STATUS OF SKIN SUBSTITUTES

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When small areas of full-thickness burns are excised, usually the defect is immediately covered with autogenous split thickness grafts. However, the freshly excised small surface provides an ideal testing grou~d for evaluation of semipermanent prostheses (see Fig. 3). We encounter this situation in electrical burns, in which it is our practice to excise all the nonviable tissue, cover the surface with a prosthesis, and remove the prosthesis in two or three days for further debridement (if necessary) and autografting. In this context, we have found collagen membrane ,52 allograft,59 and Hydron to be the most satisfactory materials. The most scientifically challenging area of bum surface management is the extensive full-thickness injury. Early excision and temporary coverage would be the most desirable way to deal with this problem if a satisfactory skin substitute were available. 32 The alternative is waiting for granulation tissue coverage after gradual removal of the eschar. The drawbacks to that approach are the increased metabolic rate prior to wound closure, the continuing possibility of infection before wound closure, and ultimate scarring secondary to fibroblasts in the granulation tissue. 4. 17. 18 For covering large excised areas, a skin substitute must have all the ideal properties listed in Table 1, particularly adherence, elasticity, and durability. Allograft is currently the only satisfactory skin substitute for this application (Fig. 1). The problems of that approach (with or without immune suppression) have been outlined previously. None of the biological or synthetic skin substitutes is adequate for this aplication. Hydron has not been evaluated in this setting, but probably would not be durable enough to be useful. The prosthetic material used for covering large areas of granulation tissue when there is insufficient autograft skin is currently allograft or xenograft (Fig. 2). These materials provide satisfactory coverage during the 10 to 14 days required for healing and reharvesting of autograft donor sites. The problem of digestion by collagenase and subsequent bacterial infection which always accompanies the use of biologic tissue is a greater hazard in covering granulation tissue than covering excised surfaces. Granulation tissue is rich in proteolytic enzymes and is normally colonized with bacteria. Hence any prosthesis faces its severest test in covering a large granulating surface. 10. 17.46 Water vapor permeability should be high for prostheses that cover granulation tissue, since the rich vascularity keeps the surface moist. The problem of drying and microvascular thrombosis is minor when a prosthesis covers granulation tissue as compared with partial thickness bums. An adherent, highly water-permeable composite synthetic prosthesis would be the most desirable for this application. 27. 29. 50 There is a need for a good skin prosthesis. Since the best material for most applications is currently human allograft, any new material must be shown to be as good or better than allograft. Almost all of the testing and demonstration can be done in the laboratory.7. 39. 46. 48. 49. 52 Adherence, water vapor permeability, elasticity, durability, hemostatic properties, and response to collagenase can all be measured in vitro. Figure 7 shows a typical laboratory preparation and data system. In this fashion only materials that are as good as, or better than, allograft in animal testing are brought to clinical protocols.

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SUMMARY In the current state ofthe art, viable human allograft is the best skin prosthesis available, but it leaves much to be desired. Characteristics of skin substitutes can be defined and measured, resulting in a rational approach to design and testing of synthetic skin substitutes. Thin silicone polymer and modified plastic membranes, collagen films, and adherent methacrylate polymer applied by a spray technique (Hydron) are the most promising materials at present.

REFERENCES 1. Abbenhaus, J. I., and Donald, P.: The use of collagen grafts for replacement of major skin loss. Laryngoscope, 81: 1650, 1971. 2. Nathan, P., Law, E. J., MacMillan, B. G., et al.: Anew biomaterial for the control ofinfection in the bum wound. Trans. Am. Soc. Artif. Intern. Organs, 22:30,1976. 3. Alexander, J. W., MacMillan, B. G., et al.: Clinical evaluation ofEpigard, a new synthetic substitute for homograft and heterograft skin. J. Trauma, 13:374, 1973. 4. Baur, P. S., Larson, D. L., and Stacey, T. R.: The observation ofmyofibroblastsin hypertrophic scars. Surg. Gynecol. Obstet., 141 :22, 1975. 5. Bromberg, B. E., Song, I. C., and Mohn, M. P.: The use of pig skin as a temporary biological dressing. Plastic Reconstr. Surg., 36:80, 1965. 6. Brown, J. B., Fryer, M. P., Landall, P., et al.: Postmortem homografts as "biological" dressings for extensive bums and denuded areas. Ann. Surg., 138:619, 1953. 7. Buldalian, J.: A comparative study ofsynthetic and biological materials for wound dressings. J. Trauma, 13:32,1973. 8. Burke, J. F., Quinby, W. C., Bondoc, C. C., etal.: Immunosuppression and temporary skin transplantation in the treatment of massive third degree bums. Ann. Surg., 182:183, 1975. 9. J;Jurleson, R., and Eiseman, B.: Nature of the bond between partial-thickness skin and wound granulations. Surgery, 72:315, 1972. 10. Burleson, R., and Eiseman, B.: Mechanisms of antibacterial effect of biologic dressings. Ann Surg., 177:181, 1973. 11. Burleson, R., and Eiseman, B.: Effect of skin dressings and topical antibiotics on healing of partial-thickness skin wounds in rats. Surg. GynecoI. Obstet., 136:958, 1973. 12. Chardack, W. M., Dewane, A. B., et a!.: Experimental studies on synthetic substitutes for skin and their use in the treatment of bums. Ann. Surg., 155:127,1962. 13. Chvapil, M.: Collagen sponge: Theory and practice of medical applications. J. Biomed. Mat. Res., 11 :721, 1977. 14. Colocho, G., Graham, W. P., Green, A. E., et aI.: Human amniotic membrane as aphysiologic wound dressing. Arch. Surg., 109:370, 1974. 15. Copenhagen, H.: A new collagen tape in reconstructive surgery. Brit. J. Surg., 52:897, 1965. 16. Dressler, D. P., Roxin, R. R., et al.: A new prosthetic skin for the control of experimental bum wound sepsis. Ann. N. Y. Acad. Sci., 150:980, 1962. 17. Eade, G. G.: The relationship between granulation tissue, bacteria and grafts in burned patients. Plast. Reconstr. Surg., 22:42, 1958. 18. Gabbiani, G:, Hirschel, B. J., Ryan, G. B., et al.: Granulation tissue as a contractile organ: A study of structure and function. J. Exp. Med., 135:719, 1972. 19. German, J. C., Bartlett, R. H., et aI.: Porcine xenograft bum dressings: A critical reappraisal. Arch. Surg., 104:806,1972. 20. Guldallian, J., Jelenko, C., et al.: A comparative study of synthetic and biological materials for wound dressings. J. Trauma, 13:32,1973. 21. Hait, M., Stark, R., Battista, O. A., et al.: Microcrystalline collagen as a biological dressing, vascular prosthesis, and hemostatic agent. Surg. Forum, 20:51, 1969. 22. Harris, N. S., Compton, J. B., Abston, S., et aI.: Comparison offresh, frozen, and lyophilized porcine skin and xenograft on burned patients. Bums, 2:71, 1977. 23. Hoover, H., Walters, P. T., and Scheflan, M.: Experience with human amnion as a biological dressing. Presented to the American Bum Association, 1978. 24. Jackson, D.: A clinical study of the use of skin homografts for bums. Brit. J. Plast. Surg., 7: 26,1954.

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25. James, J. H., and Watson, A. C.: The use of Opsite, a vapor permeable dressing on skin graft donor sites. Brit J. Plast. Surg., 28:107,1975. 26. Kim, F. W., Kron, S., et al.: The effect of homograft rejection on wound healing. Surg. Gynecol. Obstet., 131 :495, 1970. 27. Kornberg, j., Bums, N. E., Kafesjian, R., et al.: Ultra thin silicone polymer membrane: A new synthetic skin substitute. Trans. Am. Soc. Artif. Intern. Organs, 18:39, 1972. 28. Lamke, L. 0., Nilsson, G. E., and Reithner, H. L.: The evaporative water loss from bums and the water vapor permeability of grafts and artificial membranes used in the treatment of bums. Bums, 3:159,1977. 29. Lee, Y.: Early heterografting of partial-thickness bums. J. Trauma, 12:818,1972. 30. Lorenzetti, O. J.: Influence of microcrystalline collagen on wound healing. 1. Wound closure of normal excised and bum excised wounds of rats. Proc. Soc. Exp. BioI. Med., 140: 896,1972. 31. Lorenzetti, O. j.: Influence ofmirocrystalline collagen in wound healing. II. Comparison of several collagen dressings on excised wounds of pigs and rabbits. Res. Comm. Chern. Path. Phar., 5:431,1973. 32. MacMillan, B. G.: Indication for early excision. SURG. CLIN. NORTH AM., 50:1337, 1970. 33. McLean, D. H., and Buncke, H. J., Jr.: Autotransplant of omentum to a large scalp defect with microsurgical revascularization. Plast. Reconstr. Surg., 49:268, 1972. 34. Miller, T. A.: The deleterious effect of split skin homograft coverage on split-skin donor sites. Plast. Reconstr. Surg., 53:316, 1974. 35. Monafo, W. W., Tandon, S. N., Bradley, R. E., et al.: Bacterial contamination of skin used as a biological dressing. J.A.M.A., 235:1248,1976. 36. Morain, W.O., and Vistnes, L. R.: Iodinated silicone-An antibacterial alloplastic material. Pia st. Reconstr. Surg., 59:216, 1977. 37. Nathan, P., MacMillan, B. G., and Holder, I. A.: Effect ofa synthetic dressing formed on a bum wound in rats: A comparison of allografts, collagen sheets, and polyhydroxyethylmethacrylate in the control of wound infection. Appl. Microbiol., 28:465,1974. 38. Nathan, P., MacMillan, B. G., and Holder, 1. A.: In situ production of a synthetic barrier dressing for bum wounds in rats. Infect. Immun., 12:257, 1975. 39. Oliver, R. F., Grant, R. A., Hulona, M. J., et al.: Incorporation of stored cell-free dermal collagen allografts into skin wounds: A short term study. Brit. J. Plast. Surg., 30:88, 1977. 40. Oluwasanmi, 1., and Chvapil, M.: A comparative study offourmateriaIs in local bum care in the rabbit. J. Trauma, 16:348, 1976. 41. Peacock, E. E.: The effects of acid extract of collagen, cold neutral solutions of collagen, and reconstituted collagen fibrils on wound healing in normal protein-depleted rats. Surg. Gynecol. Obstet., 113:329, 1961. 42. Pickrell, K. L.: A sulfonamide film for use as a surgical dressing. Bull. Johns Hopkins Hosp., 71 :304, 1942. 43. Rappaport, I., Pepino, A. T., and Dietrick, W.: Early use ofxenografts as a biological dressing in bum trauma. Am. J. Surg., 120:144, 1970. 44. Robson, M. C., Krizek, T. J., Koss, N., et al.: Amniotic membranes as a temporary wound dressing. Surg. Gynecol. Obstet., 136:904, 1973. 45. Salisbury, R. E., Wilmore, D. W., Silverstein, P., et al.: Biological dressing for skin graft donor sites. Arch. Surg., 106:705, 1973. 46. Saymen, D. G., Nathan, P., Holder, 1. A., et al.: Control of surface wound infection: Skin versus synthetic grafts. Appl. Microbiol., 25:921, 1973. 47. Schechter, 1., Belldegrin, A., Ben-Basat, M., et al.: Prolonged retention of glutaraldehydetreated skin homografts in humans. Brit. J. Plast. Surg., 28:198, 1975. 48. Schwope, A. D., Wise, D. L., Sell, K. W., et al.: Evaluation of wound covering materials. J. Biomed. Mat. Res., 11 :489,1977. 49. Shornik, W. A., Dressler, A. P., and Richard, J. K.: Adherence ofprosthetic skin. J. Biomed. Mat. Res., 2:447, 1968. 50. Silverstein, P., and McDonough, R. J.: Laboratory evaluation of a new synthetic biIaminate physiologiC dressing. Surg. Forum, 28:538, 1977. 51. Tapaszto, 1., and Kerenyi, G.: Skin replacement with Bioplast fibrin in ophthalmology. J. Biomed. Mat. Res., 11 :799, 1977. 52. Tavis, M. J., Harney, J. H., Thornton, J. W., et al.: Modified collagen membrane as a skin substitute: Preliminary studies. J. Biomed. Mat. Res., 9:285, 1975. 53. Tavis, M. J., Thornton, J. W., Harney, J. H., etal.: Graft adherence to de-epithelialized surfaces: A comparative study. Ann. Surg., 184:594, 1976. 54. Tavis, M. J., Thornton, J. W., Harney, J. H., et al.: Mechanism of skin graft adherence: Collagen, elastin and fibrin interactions. Surg. Forum, 28:522, 1977. 55. Tavis, M. J., Danet, R. J., Thornton, J. W., et al.: Silicone polymer membrane as a donor site dressing: A five year clinical experience. Plast. Reconstr. Surg., in press.

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56. Thornton, J. W., Tavis, M. J., Harney, J. H., et aI.: Graft adherence to wound surfaces: collagen fibrin interactions, Bums, 3:23, 1977. 57. Townsend, P. L. G.: The quest for a cheap and painless donor-site dressing. Bums, 2:82, 1977. 58. Unger, M. G., and Roberts, M.: Lyophilized amniotic membranes on graft donor sites. Brit. J. Plast. Surg., 29: 102, 1976. 59. Zaroff, L. I., Mills, W., et aI.: Multiple uses of viable cutaneous homo grafts in the burned patient. Surgery, 59:368, 1966. Bum Center University of California, Irvine 101 City Drive South Orange, California 92668