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Skin Grafts and Skin Substitutes

Philip L Kelton Jr MD

HISTORY Ratner and Hauben, Baruchin, and Mahler give excellent overviews of the history of skin grafting. The following highlights are excerpted from these two sources. Grafting of skin originated among the tilemaker caste in India approximately 3000 years ago.1 A common practice then was to punish a thief or adulterer by amputating a nose, and surgeons of this day took free grafts from the gluteal area to repair the resulting deformities. From this modest beginning, skin grafting evolved into one of the basic clinical tools in plastic surgery. In 1804 an Italian surgeon named Boronio successfully autografted a full-thickness skin graft on a sheep. In 1817 Sir Astley Cooper grafted a fullthickness piece of skin from a mans amputated thumb onto the stump for coverage. Bunger in 1823 successfully reconstructed a nose with a skin graft. On the other side of the Atlantic, Jonathan Mason Warren in 1840 and Joseph Pancoast in 1844 grafted autogenous full-thickness skin from the arm to the nose and the earlobe, respectively.2 In 1869, 25 years later, Reverdin rekinkled worldwide interest in skin grafting with his report of successful pinch grafts. Ollier in 1872 pointed out the importance of the dermis in skin grafts, and in 1886 Thiersch used thin split-thickness skin to cover large wounds. To this day the names Ollier and Thiersch are synonymous with thin (0.0050.01") split-thickness grafts. Lawson, Le Fort, and Wolfe all used full-thickness grafts to successfully treat ectropion of the lower eyelid; nevertheless, it is Wolfe whose name is generally associated with the concept of fullthickness skin grafting. Krause popularized the use of full-thickness grafts in 1893, known today as Wolfe-Krause grafts. Brown and McDowell3 reported thick split-thickness grafts (0.010.022") for the treatment of burns in 1942. In 1964 Tanner, Vandeput, and Olley4 gave us the technology to expand skin grafts with a ma1 2

chine that would cut the graft into a lattice pattern, enlarging it up to 12X its original surface area. In 1975 epithelial skin culture technology was published by Rheinwald and Green,5 and in 1979 cultured human keratinocytes were grown to form an epithelial layer that was satisfactory for grafting wounds.6 ANATOMY The character of the skin varies greatly among individuals and within each subject it varies with age, sun exposure, and area of the body. For the first decade of life the skin is quite thin, but from age 10 to 35 or so it thickens progressively. At some time during the fourth decade the thickening stops and the skin once again begins to decrease in substance. From that time until the person dies there is gradual thinning of dermis, decreased skin elasticity, and progressive loss of sebaceous gland content. The skin also varies greatly from body site to body site. Skin from the eyelid, postauricular and supraclavicular areas, medial thigh, and upper extremity is thin, whereas skin from the back, buttocks, palms of the hands and soles of the feet is much thicker. Approximately 95% of the skin is dermis, while the other 5% is epidermis.7 The dermis contains sebaceous glands. Sweat glands and hair follicles are located in the subcutaneous fat just beneath the dermis. The skin vasculature is superficial to the superficial fascia and parallels the skin surface. The cutaneous vessels branch at right angles to penetrate subcutaneous tissue and arborize in the dermis. The final destination of these blood vessels is a capillary tuft that terminates between dermal papillae.

TERMINOLOGY An autograft is a graft taken from one part of an individuals body that is transferred to a different part of the body of that same individual. An isograft

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Rudolph and Klein9 review the biologic events that take place in a skin graft and its bed. An ungrafted wound bed is essentially a healing wound, which if left alone will undergo the typical processes of granulation, contraction, and reepithelialization to seal its surface.10 When a skin graft is placed on a wound bed, these processes are altered by the presence of the graft.11 Marckmann 12 studied biochemical changes in a skin graft after placement on a wound bed and noted similarities Fig 1. Split-thickness skin grafts include a variable amount of dermis. Fullwith normal skin in its response to physithickness grafts are taken with all the dermis. (Reprinted with permission from cal or chemical injury and aging. The Grabb WC: Basic Techniques of Plastic Surgery. In: Grabb WC and Smith JW: Plastic Surgery, 3rd Ed. Boston, Little Brown, 1979.) changes in wound healing brought about by the skin graft can also be described as a general adaptation of conis a graft from genetically identical donor and renective tissue to a diminished blood supply.12 cipient individuals, such as litter mates in inbred rats or identical twins in humans. An allograft (previously homograft) is taken from another individual EPIDERMIS of the same species. A xenograft (heterograft) is a graft taken from an individual of one species that In the mid-1940s Medawar studied the behavis grafted onto an individual of a different species. ior and fate of healing skin autografts.13-15 His findA split-thickness skin graft (STSG) contains epiings are summarized as follows. dermis and a variable amount of dermis. A fullthickness skin graft (FTSG) includes all of the derHistologic Aspects mis as well as the epidermis (Fig 1).8 The donor site of an FTSG must be closed either by direct During the first 4 days postgraft there is tremensuture approximation or skin graft. dous activity in the graft epithelium, which doubles in thickness, with crusting and scaling of the graft surface. Three cellular processes may explain this PROPERTIES OF SKIN GRAFTS thickening: 1) swelling of the nuclei and cytoSkin grafts have been used for over a century to plasm of epithelial cells; 2) epithelial cell migration resurface superficial defects of many kinds. toward the surface of the graft; and 3) accelerated Whether intended for temporary or permanent mitosis of follicular and glandular cells. By the cover, the transplanted skin does not only protect third day after grafting there is considerable mithe host bed from further trauma, but also prototic activity in the epidermis of a split-thickness vides an important barrier to infection. skin graft, whereas mitotic activity in full-thickness Thin split-thickness skin grafts have the best skin grafts is much less common and may be totake and can be used under unfavorable conditally absenta reflection of their less-efficient early tions that would spell failure for thicker split-skin circulation. grafts or full-thickness grafts. On the minus side, Between the fourth and eighth days after graftthin STSG tend to shrink considerably, pigment ing there is great proliferation and thickening of abnormally, and are very susceptible to trauma.9 the graft epithelium associated with obvious In contrast, full-thickness grafts, being thicker by desquamation. Epithelial thickness may increase nature than STSG, require a well-vascularized reup to sevenfold, with rapid cellular turnover. At cipient bed9 until graft perfusion has been reestabthe same time, the surface layer of epithelium exlished. On the plus side, full-thickness skin does foliates and is replaced by upwardly migrating cells not contract upon grafting, resists trauma better, of follicular epithelium at an accelerated rate. This and generally looks more natural after healing. heightened mitosis does not begin to regress until
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after the first week postgrafting. By the end of the fourth week postgraft, the epidermal thickness has returned to its normal, pregraft state. Histochemical Aspects The RNA content of graft epithelial cells changes little in the first few days postgraft.16 By the fourth day postgraft, RNA content increases greatly in the basal layers of the epithelium, paralleling the hyperactivity of epithelial cells. This hyperactivity reflects an acceleration of protein synthesis during a period of rapid cellular replication. By the 10th postgraft day, the RNA level returns to normal.16 Over the first 2 to 3 days, enzymatic activity progressively decreases in split-thickness skin grafts, but as new blood vessels enter the dermisepidermis junction, the enzyme levels rebound.

DERMIS Cellular Component The source of fibroblasts in a skin graft remains obscure.17 Early investigators believed that these cells came from large mononuclear cells in the blood, while Grillo18 theorized that they originated from local perivascular mesenchymal cells. Whatever their origin, most authors are convinced that active fibroblasts in a healing skin graft do not come from indigenous fibrocytes. Converse and Ballantyne19 studied cell viability in rat skin grafts by assaying levels of diphosphopyridine nucleotide diaphorase, an indicator of active electron transport. The authors noted falling fibrocyte numbers in the first 3 days after grafting. The remaining fibrocytes lay in two narrow layers, one beneath the dermisepidermis junction and the other just above the host bed. After day 3 fibroblast-like cells began to appear, first in the graft bed and later in the graft itself. By the seventh to eighth day postgraft, the fibroblast population and enzymatic activity were greater than in normal skin. After this early burst in fibroblastic activity, however, both fibroblast numbers and enzyme levels resumed their normal, pregraft states over the ensuing weeks. Fibrous Component Medawar13,14 stated that most of the collagen in an autograft persists through the 40th day after

grafting. Hinshaw, Miller, and Cramer,20,21 on the other hand, concluded that split-thickness and fullthickness skin autografts undergo considerable collagen turnover. In their experiments the dermal collagen became hyalinized by the third or fourth day postgraft, and by the seventh day all of the collagen was replaced by new small fibers. The replacement continued through the 21st postgraft day, and by the end of the sixth week postgraft all the old dermal collagen had been completely replaced. Interestingly, the rates of collagen turnover and epithelial hyperplasia peaked simultaneously in the first 23 weeks postgraft. Klein22,23 and Peacock24 used hydroxyproline assays to determine the collagen content of grafted wounds. Hydroxyproline is an amino acid found exclusively in collagen at a constant proportion of 14%. Changes in hydroxyproline and monosaccharide content of grafted beds paralleled those of other healing wounds.25 Independent studies by Hilgert26 and Marckmann27 confirmed these findings and documented plunging levels of hydroxyproline soon after grafting. The hydroxyproline (and therefore, collagen) level eventually rebounded and finally returned to the normal levels of unwounded skin. Although Hilgerts cycle lasted 10 days and Marckmanns lasted 1421 days, it is now well established that most of the collagen in a graft is ultimately replaced. On the basis of studies involving tritiated proline-labeled mature collagen, Udenfriend28 and Rudolph and Klein29 agreed that 85% of the original collagen in a graft is replaced within 5 months postgraft. The collagen turnover rate of grafts is 3 to 4X faster than that of unwounded skin.30 In addition, although equal amounts of collagen are lost from full- and split-thickness grafts, STSGs replace only half as much of their original collagen as do FTSGs of equal size. Elastin fibers in the dermis account for the resilience of skin. While the elastin content of the dermis is small, the elastin turnover rate in a healing graft is considerable, and most of the elastin in a graft is replaced within a short time. Elastin fiber integrity is maintained through the third postgraft day, but by postgraft day 7 the fibers are short, stubby, and have begun to fragment.20 Elastin degeneration continues through the third postgraft week until new fibers can be seen beginning to grow at 4 to 6 weeks postgraft. This replacement process is the same in full- and splitthickness skin grafts.
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Extracellular Matrix Far from simply supporting cells passively, the extracellular matrix (ECM) plays a vital role in cellto-cell communication.31 Through specific arrangements of protein sequences within, the ECM influences cellular behavior in adjacent tissues with regard to proliferation, differentiation, migration, and attachment. The extracellular matrix in the skin consists of large insoluble proteins of fibroblast origin and smaller soluble proteins produced either by fibroblasts or keratinocytes. Both kinds of proteins appear to be involved in directing the behavior of keratinocytes and in promoting appropriate communication between keratinocytes and fibroblasts. Epithelial Appendages The sweating capability of grafted skin is a function of the number of sweat glands transplanted during grafting and of the extent of sympathetic reinnervation to the graft. A skin graft will sweat much like its recipient site due to ingrowing sympathetic nerve fibers from the graft bed. Thus a graft that is placed on the abdomen will sweat in response to physical activity, whereas an identical graft placed on the palm will sweat in response to emotional stimuli. Although both full- and split-thickness skin grafts demonstrate sebaceous gland activity, thin splitthickness grafts do not contain functional sebaceous glands and typically appear dry and brittle after take. Hair follicles are subjected to the same hyperplastic stimuli as the rest of the graft. On the fourth day following grafting, the original hair sloughs off and the graft becomes hairless. Soon after the graft follicles begin to produce new hair, and by the 14th postgraft day very fine, baby-like hair is seen growing out of the graft.13 Full-thickness skin grafts produce hair while splitthickness skin grafts produce little or no hair. Fullthickness skin grafts that take well grow normal hair in terms of orientation, pigmentation, and follicular clustering.14 Suboptimal graft revascularization will damage the graft hair follicles and result in decreased hair density. Similarly, when graft take is interrupted for any reason, subsequent hair growth will be sparse, random, and lacking in pigment.15
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In summary, unlike STSGs, full-thickness grafts contain sweat glands, sebaceous glands, and hair follicles.8 Only full-thickness skin grafts, therefore, are capable of sweating, oil secretion, and hair growth.

GRAFT TAKE As mentioned above, the large array of physiologic events usually seen in a healing skin wound are altered and modified by placement of a graft. The graft becomes incorporated in the host bed through the process of graft take. The success of a graftits takedepends on the extent and speed at which vascular perfusion is restored to this parasitic, ischemic tissue. Given equal clinical and technical conditions, two qualities of a skin graft influence its fate. The first determinant is the blood supply of the skin from which the graft was harvested. A graft taken from a highly vascular donor site will predictably heal better than a graft taken from a poorly perfused area. The second factor in graft take is the metabolic activity of the skin graft at the time of application, which will dictate its tolerance to the inevitable period of ischemia. Skin graft take occurs in three phases. The first phase consists of serum imbibition and lasts 24 to 48 hours. This is followed by an inosculatory phase and a process of capillary ingrowth that occur essentially simultaneously, until generalized blood flow has been established by the fifth or sixth postop day. Plasmatic Imbibition The exact significance of plasmatic imbibition to the healing of a skin graft is not clear. Hinshaw and Miller20 and Pepper32 believed that plasmatic imbibition is nutritionally important. Others such as Clemmesen,33,34 Converse,35,36 and Peer37,38 were of the opinion that serum imbibition merely prevents the graft from drying out and keeps the graft vessels patent in the early postgraft period. Regardless of whose theory is correct, all authors concur in the following: The graft is ischemic for an undetermined period of time that varies according to the wound bed: 24 hours for a graft placed on a bed that is already proliferative; 48 hours for a graft covering a fresh wound.

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Grafts placed on poorly vascularized beds will be ischemic for a longer time than those placed on wounds with good blood supply. Exactly how long a graft will tolerate this ischemic interval is not clear, but thick full-thickness grafts seem to tolerate ischemia for up to 3 days while thin full-thickness grafts survive for up to 5 days.33,38 Split-thickness grafts take well even after 4 days of ischemia.38 Plasmatic imbibition allows a skin graft to survive this immediate postgraft ischemic period until such time as graft vasculature reestablishes itself.9 Grafts gain weight during the phase of plasmatic imbibition,34-36 adding as much as 40% to their pregraft weight through fluid movement from bed to graft.36 The origin of graft edema is believed to be the same as that of inflammatory edemaie, from disaggregation and depolymerization of proteoglycans, accumulation of osmotically active metabolites, and increased vascular permeability.39-42 Inosculation and Capillary Ingrowth At the end of 48 hours, a fine vascular network is established in the fibrin layer between the graft and its recipient bed. Capillary buds from the blood vessels in the recipient bed make contact with the graft vessels and open channels are formed. Blood flow is established and the skin graft becomes pink. Revascularization Three theories have been put forth to explain how a skin graft is revascularized. Connection of graft and host vessels. The first theory holds that after the inosculatory event, the definitive vasculature of the graft consists of the blood vessels originally present within the graft. According to this theory, circulation is restored in a graft via the original skin graft vessels by anastomoses formed between the recipient bed and the skin graft through inosculation. Peer and Walker,37 Clemmesen,33,34 Haller and Billingham,43 and Birch and Branemark,39,40 among others, support this line of thinking. Clemmesen,34 working on a pig model, injected India ink into the host vessels of the autograft. No

ink was seen within the graft in the first postgraft day, but on day 2 a number of graft vessels contained India ink, suggesting communication between the host and graft vessels. After the second day, many graft vessels contained India ink, indicating patent connections between vessels of the graft and its bed. Initially a fine fibrin mesh linked the graft to the bed, but over the first 4 days this meshwork became lined with endothelial cells and linked up with the vessels of the graft. Haller and Billingham43 reached a similar conclusion in a study using the hamster cheek pouch model. They too noted that the pattern of vessels in the healed graft was the same as the pattern before grafting. Formation of new vascular channels. The second theory of graft revascularization holds that the graft is perfused through new vessels going from the recipient bed into the transplanted graft. Converse,19,36,44-46 Zarem,47 Ljungvist and Almgard,48 and Wolff and Schellander49 espouse this theory. Converse and Rapaport44 studied skin grafts in humans and determined that after an early connection of graft and host vesselsthe inosculatory event, active invasion of the graft by host vessels gives rise to the definitive vasculature of the skin graft. On the basis of a later study involving diaphorase in a rat model,19 Converse concluded that definitive vasculature of the graft stemmed from ingrown vessels from the host bed. Degenerative changes in the original graft vasculature were apparent in the first 4 days postgraft, as evidenced by progressive loss of diaphorase activity during this time. With subsequent vessel ingrowth there was return of diaphorase activity. Wolff and Schellander49 measured cellular enzymes to evaluate return of circulation in porcine skin grafts. ATP activity correlated well with the pattern of new vessel ingrowth, leading the author to conclude that the new graft vasculature consisted entirely of ingrown vessels. Working with mice, Zarem et al47 theorized that preexisting graft vessels served only as nonviable conduits through which the endothelium of the ingrowing vessels progressed. The rate of vessel ingrowth was measured at approximately 5 microns per hour. According to the authors, the original graft vessels degenerated concomitantly and at the same rate, leaving those vessels grow5

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ing from the recipient bed as the definitive vasculature of the graft. Combined old and new vessels. Smahel11 and Tsukada50 proposed a third (and much less popular) hypothesis of final graft revascularization: a compromise between the two above theories. The authors feel that circulation in a graft is reestablished in various ways; that is, in any graft old vessels may be recycled and new ones may grow to variable degrees. These two pathways to restore circulation to ischemic tissue may occur simultaneously or as consecutive stages in the interaction between the graft and its bed. There are two methods of skin graft revascularization: primary and secondary. Primary revascularization. Under the scanning electron microscope, it can be seen that no real circulation to the graft exists for the first 6 to 7 days postgrafting. Whatever flow there is within the graft is sluggish, varying in direction, with attendant pooling and pendulum-like movement.51 Clinically this manifests as cyanotic discoloration and is particularly noticeable in full-thickness skin grafts.19,39,44 In the normal course of events, circulation in a skin graft is reestablished through vascular anastomoses between budding neovessels from the bed and those already present in the graft (inosculation). Blood enters the graft via these newly formed vascular connections and the graft turns pink. A pink color is generally considered a sign of probable graft survival, although the intensity of coloration does not allow any conclusions regarding the grafts circulatory status. Inside the graft, the hemodynamic situation is complex. The old vessels of the graft are dilated and denervated and some of the circulatory routes are severed during graft harvest. Blood vessels from the recipient bed attach to both arteries and veins of the graft, yet all these connections are afferent with respect to the graft. Blood and tissue fluids moving into the graft are trapped there and unable to return to the bed because of inadequate reverse circulation. Sometime between the fourth and seventh days after grafting, the newly formed vascular connections differentiate into afferent and efferent vessels and other vessels retain their capillary-like char6

acter or simply disappear.52 At this point the proper vascular system within the graft is reestablished and blood flow is restored. Secondary revascularization. When vascular connections between the bed and the graft are delayed, secondary revascularization occurs. Under normal graft conditions, the vasoactive agent directing the ingrowth of new blood vessels ceases to function and capillary proliferation stops as good blood flow is established via neovascularization. However, the longer a graft remains ischemic, the longer the vasoactive substance remains in the tissue. As a result, great numbers of new capillaries grow into the graft and granulation tissue accumulates under the graft. This phenomenon is known as secondary revascularization and its mechanism is as follows. Vascular connections between the graft bed and the graft with attendant blood flow into the newly formed vessels of the graft inhibit the formation of capillary buds. If the graft is not well applied to the bed and vascular connections are not established earlyeg, in the periphery of large grafts, the inhibiting effect of the vascular connection does not take place. Within the graft itself the vessels may be functionally deficient or the vascular ingrowth may not reach the required level of biologic activity for the inosculatory event. If these anastomoses fail to develop in time, the ischemic period is extended and capillary proliferation in the bed continues. Degenerative processes in the graft and exuberant granulation tissue in the host bed go hand in hand with prolonged ischemia. In summary, if blood vessels reach the graft in time, the graft will survive; if not, the graft will fail. In the host bed, insufficient vascular proliferation and wound contamination are the two common causes of delayed inosculation. Anastomoses may not form at the right time because of the increased distance between the graft and its bed resulting from interposed necrotic material, a thick fibrin layer, hematoma, seroma, or air bubbles. Grafts that heal by secondary intention are smooth, fibrotic, tight, and have a slick, silvery sheen on the surface, reflecting the large amount of cicatrix within the graft. Large grafts often heal both by primary and secondary revascularization, and certain areas show the typical appearance of desquamation where the secondary process occurs.

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Histologically, the epidermis and papillary dermis are destroyed by necrosis in the full-thickness graft that has healed by secondary revascularization. The papillary dermis is replaced by a thin layer of connective tissue which in turn is covered by a flattened epidermis. The reticular dermis is normal histologically, but beneath the graft there is a layer of newly formed connective tissue that infiltrates the dermis, resulting in graft fibrosis. Hinshaw and Miller20 noted accelerated collagen turnover in pig autografts that had healed by secondary revascularization. Adherence Adherence of the graft to its bed is the first requirement of skin graft take. A thin fibrin layer holds the graft to the bed and forms a barrier against potential infection.53 Two distinct phases of graft adherence occur. Phase 1 begins immediately after grafting and lasts about 72 hours.54 During this time the graft remains adherent to the bed through the bond formed by the fibrin layer. Phase 2 coincides with the onset of fibrovascular ingrowth and vascular anastomoses between the graft and the host. Successful fixation of STSG to tangentially excised wounds using fibrin glue is well documented.55,56 Fibrin glue is manufactured from autologous plasma, eliminating the risk of transmission of viral diseases. The material is strong, transparent, does not interfere with the healing process, does not promote wound infection, and is homeostatic. Proponents of fibrin glue say that it improves graft survival, reduces blood loss, speeds reconstruction by allowing large sheet graft coverage, and produces better esthetic results. Cederholm-Williams57 supports the use of fibrin glue, emphasizing its many applications and superiority to bovine proteins. Dean, Nicholls, and Wedderburn58 note the usefulness of fibrin glue in thrombocytopenic patients. Achauer and colleagues,59 however, found no advantage to topical fibrin glue in the healing of graft donor sites in burn patients. A number of recent articles address new methods of graft fixation. Himel et al,60,61 Sheridan and coworkers,62 and Best and colleagues63 describe the use of disposable graft staplers to hold freshly applied skin grafts in place with absorbable staples. The advantages of these devices over standard

metal staples or bolstered sutures are said to include speed of delivery, ease of use, reliable application, and no postoperative staple removal. Skin grafts to the penis and scrotum are particularly difficult to immobilize and dress. Netscher, Marchi, and Wigoda64 suggest wrapping the graft area with nonadherent gauze mesh over which Reston self-adhering foam is secured with staples or sutures. The foam maintains penile length and provides firm but gentle compression on the skin graft during the crucial first week. The authors cite ease of application and removal, sterility, and effectiveness in wound coverage as advantages of this method for grafted defects of the penis and scrotum. Saltz and Bowles65 and Caldwell and colleagues66 also advocate the use of Reston foam applied over Xeroform gauze for securing skin grafts in wounds of the shoulder and face, respectively. Balakrishnan67 prefers Lyofoam, a semipermeable, nonwoven polyurethane foam dressing for similar purposes. The foam is easy to apply directly on the graft and, because it is biologically inert, does not interact with the wound. Its hydrophobic outer surface is purported to retard bacterial colonization. Johnson, Fleming, and Avery68 opt for a simple, versatile, and rapid technique consisting of staples and latex foam dressing to secure skin grafts. Wolf and coworkers69 confirmed the effectiveness of rubber foam with staple fixation in various patterns for providing even pressure distribution on skin grafts. Smoot70 uses a Xeroform sandwich filled with molded cotton balls that is stapled into place, while Amir et al71 modify a cutoff disposable syringe to affix the silk threads of their graft dressings. Cheng and colleagues72 accomplish graft fixation with a disk cut from the bottom of an IV infusion bottle. Multiple radial slits are made along the perimeter for tying the sutures holding the graft in place. Other suggested fixation methods for grafts include silicone rubber dressings73 and silicone gel sheets,74 rubber band stents,75 transparent gasbag tie-over dressings,76 Coban self-adherent wrap,77 thin hydrocolloid dressings,78 and assorted Silastic and foam dressings for grafts to the neck or hand.79-81 Schneider, Morykwas, and Argenta82 report using a Vacuum-Assisted Closure (VAC) device to secure grafts in difficult recipient sites. The VAC pump prevents fluid collection beneath the graft
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and ensures contact and even pressure distribution between the graft and its bed, regardless of location or irregularity of surface. GRAFT HEALING Medawar13-15 described the clinical appearance of healing grafts. Immediately after removal from the donor area the skin graft is white, but once applied to the recipient area it becomes pink over the next few days. There is blanching on pressure with prompt capillary refill. At first the graft surface is depressed below the level of the surrounding skin, but by the 14th to 21st postgraft day it becomes level with the surrounding surface.20 Histologically, lymphatic drainage is present through connections between the graft and host lymphatics by the fifth or sixth postgraft day, and subsequently the graft loses weight until the pregraft weight level is attained by the ninth day.83 Collagen replacement in the graft begins by the seventh postgraft day and is complete in about 6 weeks. The healing graft exhibits an abundance of polymorphonuclear lymphocytes and monocytes that persist in the dermis for several weeks. Vascular remodeling in the graft may take many months.84 Host vessel ingrowth is perpendicular to the dermisepidermis junction, creating a characteristic vascular pattern in the graft. The newly formed vessels are more numerous and show greater arborization than those of normal skin. Other phenomena associated with healing of a skin graft are discussed in detail below. Contraction A skin graft begins to shrink immediately after being harvested from its donor site. Primary contraction is passive and probably due to recoil of the dermal elastic fibers. A full-thickness graft loses about 40% of its original area as a result of primary contraction; a medium-thickness split-skin graft about 20%; and a thin split-thickness graft only about 10%. True Thiersch grafts do not undergo primary contraction. After transfer to a recipient site, the skin graft will shrink as it heals in a process known as secondary contraction. Full-thickness grafts tend to remain the same size (after primary contraction) and do not show secondary contraction. Splitthickness grafts, on the other hand, contract whenever the circumstances allow. Unless split-thick8

ness skin grafts are fixed to underlying rigid structures and cannot move, they will contract secondarily. Once wound contraction ends, full-thickness grafts are able to grow whereas split-thickness grafts tend to remain in a fixed, contracted state and grow minimally, if at all.85,86 Wound contraction is a critical part of wound healing and clinically useful because it reduces wound size. On the other hand, a contracted wound is often tight and immobile and there is distortion of surrounding normal tissue. It is possible to exercise some control on the degree of contraction that a wound will undergo by manipulating the thickness and proportion of dermis in the graft used for repair. The inhibitory effect depends more on the percentage of dermis included in the graft than in the overall thickness of the graft: the greater the proportion of dermis included in the graft, the more the graft will inhibit contraction. Full-thickness grafts, therefore, prevent wound contraction better than split-thickness grafts.85-87 In fact, thin full-thickness grafts inhibit wound contraction better than split-thickness grafts of equal or greater thickness, and thick split-thickness grafts inhibit wound contraction better than thin ones.8,88,89 Various hypotheses have been proposed to explain the mechanism of this inhibition, including a mass effect, cellular interactions between graft cells and host bed, epidermal interaction, mechanical restriction, etc.90 Brown, Garner, and Young90 concluded that the capacity of a skin graft to inhibit wound contraction is directly proportional to the amount of structurally intact dermal collagen present in the skin graft. The rate of wound contraction is not affected by graft orientation, amount of epidermis, or noncollagenous protein. However, if the amount of intact dermal collagen is decreased or is structurally destroyed, then the grafts ability to inhibit wound contraction is reduced. Rudolph91,92 explains the interaction between a graft and its bed in terms of the lifecycle of a myofibroblast. Application of a skin graft appears to check the stimulus of a wound to myofibroblast formation, function, or both.93 Split-thickness grafts cause a rapid decline in the number of myofibroblasts, and wounds contract less than comparable nongrafted sites. Full-thickness grafts trigger an even faster decrease in myofibroblast population, and wounds show minimal contraction. In this hypothesis the lifecycle of myofibroblasts is accel-

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erated rather than retarded, thereby reducing wound contraction. Bertolami and Donoff88,89 studied the effect of dermis on the actinomycin content of granulating wounds and suggest that the mechanism of wound contraction is not simply the result of myofibroblast activity;93 the active role of collagen cannot be ignored. Substances that inhibit wound contraction also inhibit prolyl hydroxylase activity (an indicator of collagen synthesis). Lower levels of this enzyme beneath a full-thickness graft may reflect decreased collagen synthesis, which in turn may be involved in preventing wound contraction.88 Oliver and associates94,95 demonstrated the importance of an inactive collagen matrix in inhibiting wound contraction. The collagen matrix was prepared for grafting by adding azide to destroy the cells and trypsin to remove noncollagenous protein. These grafts, cell-free and noncollagenousprotein-free, resist wound contraction as well as full-thickness skin grafts, suggesting that dermal cells and noncollagenous proteins are not part of the inhibitory process. Grafts free of dermal cells but possessing a collagen matrix in fact behave much like full-thickness grafts. It may be possible, therefore, to store nonantigenic dermal substitutes produced from banked cadaver skin or xenogeneic sources by adding trypsin or azide to remove noncollagenous protein and cells respectively. This would increase dramatically the clinical availability of substitute dermis as a potential source of grafts. Reinnervation Nerves grow into skin grafts from the wound margins and the graft bed.96 The timing of neural invasion and the disposition of nerves within a skin graft vary with graft thickness and recipient site. Human skin grafts begin to show sensory recovery at 4 to 5 weeks postgrafting, but occasionally sensation is delayed for up to 5 months. The return of normal sensation is usually complete by 12 to 24 months. The extent of reinnervation depends on how accessible the neurilemmal sheaths are to the invading nerve fibersie, most accessible in full-thickness grafts and least accessible in thin split-thickness grafts. Skin grafts are initially hyperalgesic and then slowly regain normal sensation.8 If skin graft healing is uneventful, the results of two-point discrimination testing will be very close to those of normal skin. Other sensations do not recover so well.

Waris and associates measured the thermal sensitivity of 22 split skin grafts transplanted 1-4 years earlier. Cold sensitivity was present in 14, warmth in 6, and heat-pain in 8 grafts. If the warmth sensibility had recovered, the threhold was lower than for cold. Seven grafts showed no thermal sensibility at all. Haro and colleagues97 confirmed poor return of sensitivity in grafts using immunohistochemical methods. Grafts less than 7 months old showed no sensitivity whatsoever, and pain sensation had developed only in the 15-month-old grafts. Although deep and superficial nerve plexuses regenerated, no sensory corpuscles were detected in grafted skin at any time. Stella et al98 independently verified these findings and speculate that the failure of regeneration of sensory corpuscles may be related to the degeneration of periaxonal corpuscular elements. Ponten99 stated that grafts assume the sensory pattern of the host tissue, but Adeymo and Wyburn 100 and later Fitzgerald, Martin, and Paletta101 noted that nerves entering the graft follow the evacuated neurilemmal sheaths and reestablish the innervation pattern of the donor skin. Weis-Becker and coworkers102 note better reinnervation of split skin grafts placed on intact muscle fascia than if the fascia had been removed. Sensory functions on grafted skin were generally reduced. Pigmentation Immediately after harvesting, a skin graft blanches from circulatory interruption. The consequent loss of melanoblast content causes profound alteration in the ratio of pigment-producing to nonpigment-producing cells in the graft.103 After transplantation and graft revascularization, there is inflow of erythrocytes and the normal equilibrium of melanocyte population is restored. The graft resumes a pink coloration which over time fades to a basically normal skin tone. Mir y Mir104 reviews melanogenesis, its peripheral nervous system control, the hyperpigmentation state that follows cutaneous grafting, and the effects of ultraviolet radiation on the skin. Skin grafts change color during healing.11 Grafts harvested from the abdomen, buttocks, and thigh become darker as they heal, while grafts taken from the palm tend to lighten. Grafts taken from brunettes progressively darken, while those from
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blondes usually lighten. Full-thickness grafts from the eyelid, postauricular and supraclavicular areas are usually good color match for the face, although they may remain red for many months. In general, grafts taken from below the clavicle assume a yellowish-brown hue, while grafts taken from above the clavicle provide a better color match for facial skin. Thin split-thickness skin grafts from the same donor site are usually darker than thick ones.99 The best treatment for hyperpigmented grafts is dermabrasion. For dermabrasion to be effective, however, it must be done at the appropriate time. If it is performed too soon after skin graft, the blanching will not last and the dark pigment will reappear. Best results are seen when dermabrasion follows biologic reinnervation of the graft. Generally, the later the dermabrasion is done after grafting, the more effective it is in removing unwanted pigment. Skin depigmentation states and their treatment are reviewed by Taki et al.105 Vitiligo, senile leukoderma, dyschromatosis symmetrica hereditaria, and second- or third-degree burns can produce significant cosmetic deformity, particularly in darkskinned patients. Corticosteroids and oral psoralen may, with exposure to sunlight, be successful in the treatment of vitiligo provided that dopa-positive melanocytes are present in the skin.106 Burns that invade the dermis (second-degree and thirddegree) decrease the number of dopa-positive melanocytes, so that appropriate treatment necessitates removal of the depigmented skin and replacement by very thin split-thickness grafts of normal color. This protocol is also successful in treating leukoderma. A number of authors report successful repigmentation in leukoderma or vitiligo after treatment with ultra-thin, melanocyte-containing epidermal sheet grafts107-114 or in-vitro cultured melanocytes.115 Hosokawa and colleagues116 report a novel method of tattoo elimination in which the epidermis of the tattooed skin is replaced after chemically removing the dermis, which contained tattoo pigments. Wound healing time was much shorter than for typical skin grafts.

subcutaneous tissues, is a relatively simple procedure, and the tissue consequences of graft failure are minimal. Rees and Casson118 offer technical details of skin removal and bed preparation and list the best donor sites. Their indications for overgrafting are as follows: unstable, depressed, corrugated, or hypertrophic scars unstable or hyperpigmented skin grafts large pigmented nevi radiation damage tattoos Pigmented lesions should be excised deep enough to remove all the pigment before the graft is applied. A potential complication of the technique is the formation of cysts and granulomas from retained epithelial remnants.118

GRAFT EXPANSION Because a wound is reepithelialized from the edges toward the center, the perimeter of the graft is the only part that contributes to the epithelialization process. An expanded graft presents a larger cumulative diameter through which epithelial outgrowth can proceed. With graft expansion, larger areas can be covered with smaller sections of skin. Various ways to expand skin for grafting have been described. These include pinch grafts,119 relay transplantation,120 meshing,121-124 Meek island grafts,125 and microskin grafts.126-131 More unconventional is the Chinese technique of intermingling autografts and allografts.132,133 A pinch graft breaks up a whole graft of skin into tiny pieces to increase the edge area. Pinch grafts are reported to be effective in treating small to medium-sized venous leg ulcers,134,135 radiodermatitis, pressure sores, and small burns.119 Relay transplantation consists of cutting a graft into strips 36 mm wide and 510 mm apart. When the epithelial growth becomes clinically obvious (5 to 7 days later), the original strips are removed and transplanted, leaving the epithelial explants in place. This process may be repeated up to 4 times.120 Meshing is the term used for cutting slits into a sheet graft and stretching it open prior to transplantation. Meshed grafts have a number of advantages over sheet grafts: (1) meshed grafts will

OVERGRAFTING Dermal overgrafting consists of applying a splitthickness skin graft to a recipient bed of dermis or denuded scar tissue.117 Overgrafting preserves
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cover a larger area with less morbidity to the patient than nonmeshed grafts; (2) the contour of the meshed graft can be adapted to fit in a regular recipient bed; (3) blood and exudate can drain freely through the interstices of a meshed graft; (4) in the event of localized bacterial contamination, only a small area of meshed graft will be jeopardized; (5) a meshed graft offers multiple areas of potential reepithelialization.121-123 The foremost disadvantages of meshed grafts are the considerable surface area that must heal by secondary intention and the less-than-ideal cosmetic result. Davison et al122 solved these problems by using a small ratio of expansion1:1.5and pulling the graft lengthwise to narrow the skin perforations to slits before transplantation. Richard and colleagues124 compared the Tanner and Bioplasty skin graft meshing systems in terms of their respective expansion ratios and predicted versus actual expansion. Both systems delivered approximately 50% of the anticipated skin expansion, leading the authors to recommend harvesting skin grafts larger than needed to compensate for the eventual shortage. Kirsner and and associates136 analyzed their results with meshed grafts in the treatment of recalcitrant leg ulcers and concluded that meshed STSGs are safe and effective therapy. The Meek technique of graft expansion consists of using a special dermatome and prefolded gauzes to expand autograft surfaces from small pieces of split skin graft.125 The expansion ratio obtained with the Meek technique is almost 1:9. In contrast, the expansion ratio of allograft meshed with the Zimmer II dermatome set at 1:6 was measured as 1:4. The Meek technique is a useful alternative to meshed grafts when donor sites are limited. The resultant expanded island grafts are particularly suited for transplantation onto granulating wounds that present poor grafting conditions. The technique of microskin grafting in which sheet grafts are minced using a Tanner-Vandeput dermatome has been described by Zhang,126,127 Lai,128 Lin,129,130 and Vandeput and Tanner,131 all of whom report successful coverage of burn wounds. The expansion ratio achieved is 1:10 and graft take is said to be excellent even under poor grafting conditions. Intermingled transplantation of autograft with allograft has been practiced successfully in China since at least 1973,132,133 primarily in the treatment

of large burns. Yeh and colleagues137 compared this technique with the microskin method in a rat model and noted significantly less scar contracture associated with the Chinese method. Other healing parameters were similar between the two groups. GRAFT SURVIVAL/FAILURE A meticulous surgical technique contributes greatly to the survival of a skin graft. Particular attention should be paid to ensuring atraumatic graft handling a well-vascularized, scar-free bed careful hemostasis and removal of accumulated blood before dressing the wound postoperative immobilization of the graft recipient site use of a tourniquet during graft harvest and transfer no proximal constricting bandages Flowers138 reviews the usual complications associated with graft failure and recommends steps to avoid them. The graft bed should be as clean as possible, free of dead tissue, and have an appropriate substrate (eg, bone should have periosteum, tendon should have peritenon). A clean area with endothelium is all that is required in the bed of a successful skin graft. The most common cause of autologous skin graft failure is hematoma. The clot isolates the undersurface of the graft from the endothelial buds of the recipient site so that revascularization cannot take place.138 The second most common cause of graft loss is infection. Infection can be avoided by carefully preparing the wound bed, using quilting sutures, meshing or pie-crusting the graft surface to allow free egress of subjacent fluids, and applying wet saline dressings that are changed every 4 hours.138 Fluid beneath the graft can also cause graft necrosis. Areas rich in lymphatics such as supraclavicular, inguinal, and axillary regions are particularly prone to develop seromas. Atraumatic tissue handling, cauterization of lymphatic vessels, limited use of electrocautery in the graft bed, and a light pressure dressing minimize the risk of fluid accumulation under the graft.138 Excessive pressure on a fresh graft may also cause it to die. The applied pressure should never
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exceed 30 mmHg. Other causes of graft failure include gravitational dependency, movement of the area, arterial insufficiency, venous congestion, and lymphatic stasis. Teh139 studied 21 patients with stasis ulcers in an attempt to pinpoint the causes of graft failure. Wound exudates were assayed for fibrin degradation products, fibrinogen, available plasminogen, and active plasmin. All wounds showed granulation tissue and were classified as clean or dirty. Clean wounds had low bacterial counts and showed no detectable plasmin activity. Dirty wounds had high bacterial counts and increased levels of active plasmin. High plasmin and proteolytic enzyme activity was generally seen in wounds contaminated with beta-hemolytic streptococci and various species of Pseudomonas. The presence of fibrin under autografts was associated with success in 17 of 21 ulcers, and the absence of fibrin was associated with graft failure. This finding suggested to the author that dissolution of fibrin by plasmin and proteolytic enzymes is the probable mechanism in graft failure secondary to microorganisms. In conclusion, a grafted wound is rendered sterile through the blocking action of fibrin in the interface between the bed and the graft. Fibrin plays a central role in graft survival and is responsible for the antibacterial character of adherent dressings and autografts. This bacteriostatic effect of grafts has proved invaluable in the management of large burns.139 Hill140 recommends a number of measures to enhance the survival of full-thickness grafts. Because streptococci produce streptokinase and other enzymes that break down the fibrin clot and decrease adherence of the graft to its bed, he proposes the administration of low-dose erythromycin for the first 5 days after grafting to combat potential strep and staph colonization. Patients should also take vitamin C and zinc for a week to 10 days to promote healing and should abstain from using alcohol for at least 2 days before and 5 days after sugery.140 Ethanol in the bloodstream has been shown to decrease the initial phase of wound healing (the PMN clean-up phase) and can result in infection and decreased graft adherence. Wolfort and colleagues,141 working with rabbits, found that epinephrine added to local anesthetic solutions decreased inosculation in full-thickness grafts but had no effect on ultimate survival of split-thickness skin grafts. Subsequently Fazio and Zitelli142 assessed the clinical effects of epineph12

rine in local anesthesia of the donor site. The authors found only an increased risk of graft complications at 1 week and no effect on the 6-week cosmetic outcome. They do not recommend using plain lidocaine for harvesting full-thickness grafts unless the vascular supply of the donor area is compromised. Robson and Krizek143 predict skin graft survival on the basis of successful homograft take prior to autografting. Perry144 notes a direct correlation between skin graft survival and bacterial counts of <105 in the recipient bed.

DONOR SITE MANAGEMENT Open Wound The open-wound technique of donor-site management is associated with prolonged healing time, more pain, and higher risk of complications. Most authors recommend covering the donor area in skin grafting as protection against trauma and infection. Allen and associates145 obtained bacterial counts of wounds left open to granulate and of wounds covered by skin dressings. They found 12.5% of the open wounds were sterile but all the dressed wounds showed some microbial flora. Autografts and allografts gave similar results. When antibiotics were added, however, there was a dramatic decrease in bacterial colonization of the wounds, leading the authors to conclude that it was the antibiotic, not the dressing, that had a sterilizing influence. In other words, skin grafts have no intrinsic bactericidal properties.146

Biologic Dressings Autografts Feldman147 recommends returning unused skin to the donor site as an autologous biologic dressing. He feels this is an effective and logical procedure from the standpoint of wound healing, tissue conservation, and expense.

Allografts Traditionally, cadaver allografts have been the method of choice for resurfacing large denuded areas. They serve as temporary wound covers,

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reduce pain and fever, restore function, increase appetite, control fluid loss, and promote wound healing. As they revascularize, they form a barrier against bacterial invasion and prevent further loss of water, electrolytes, and protein from the wound. Allografts decrease bacterial counts of underlying tissues, facilitating future grafting by promoting a sterile wound bed.148 Allografts preserved in various ways have been used successfully for decades. Hoekstra, Kreis, and du Pont149 trace the history of preservation technologies at the Euro Skin Bank in Holland since its founding in 1976. Initially allografts were treated with 0.5% glutaraldehyde and stored at 4C, but this led to early deterioration characterized by epidermolysis. In 1983 the benefits of glycolization became evident150 and henceforth cadaver allografts have been treated with glycerol before freezing.149-151 Modern cryopreservation techniques use 30% glycerol or 5% DMSO as cryoprotective agents. The graft is gas sterilized, dried, frozen, and stored in plastic containers for use up to 4 years later. Reconstitution involves 15 to 20 minutes of agitated washout with normal saline solution at room temperature. Studies on the immunogenicity of glycerol-preserved donor skin and its virucidal effect are encouraging.152,153 Pirnay and colleagues154 reviewed the literature for evidence of the presence of HIV in human skin and the possible transmission of HIV by transplantation of human allograft skin. Reverse transcriptase polymerase chain reaction (RT-PCR) detection of viral RNA in plasma is the most sensitive HIV screening test, but is complex, expensive, and not very reliable. Even though avascular tissue processing can inactivate HIV,155,156 at the present time it is unknown whether allograft processing can inactivate HIV without affecting the functional integrity of the allograft.157,158 Glycerol-treated, cryopreserved allografts have a number of applications, including scald burns in children,159,160 for coverage of extensive burn wounds in children and adults,161 and, combined with allogeneic cultured epithelial grafts, for the treatment of deep burns down to muscle fascia or fat.162,163 The major drawback of glycerol-preserved allografts is their expenseapproximately $5 per square inch for the final product. As discussed above, Chinese investigators have successfully used combinations of allografts and autografts for coverage of open wounds.132-134 The autograft is cut into small pieces and placed in the

slits of meshed allografts or is laid down in alternating strips of auto- and allograft. As rejection unfolds, epidermal cells in the autograft gradually replace the allograft.164 The host-immune mechanism can also be manipulated to prolong the interval from allograft application to rejection. Immunosuppressive agents include alloantiserum,165-168 azothiaprine,148 antithymocyte globulin,148 and cyclosporine.148,169 Cyclosporine extends graft viability by suppressing T lymphocytes.169 First-set rejection is prevented by inhibiting donor-specific T cells, but second-set rejection proceeds in normal fashion, and future grafts from another donor are rejected.170 The techniques of intermingling grafts and immunosuppresion extend the period that allografts can be left in contact with open wounds, allowing more time for regeneration of autogenous donor sites and decreasing the amount of allograft required for cover. Kolenik and Leffell171 report using cryopreserved skin allografts following Mohss chemosurgery to provide continuous wound coverage until full-thickness grafting could be performed. Xenografts Xenografts (collagenelastin prostheses) adhere to a wound bed via fibrin bonding, which is a function of the collagen content of the dermis and is not related to viability. The advantages of xenografts are relatively low cost, ready availability, easy storage, and easy sterilization. Disadvantages are lack of antimicrobial activity, no proof that they promote reepithelialization, potential for absorption of toxic breakdown products, and poor performance with respect to healing time and pain when measured against other donor site dressings. Csnge and colleagues172 preserve cadaver allograft and xenograft skin at their Tissue Bank in Budapest using a combination of 1000 mg/L ceftazidime, 1000 mg/L ampicillin, and 80 mg/L amphotericin. To date there has not been a graftoriginated infection in many burned patients treated with this skin. Nevertheless, most authors today condemn the use of xenograft dressings in modern clinical practice. Amnion Amnion is composed of an inner membrane and an outer membrane. The inner membrane is the amnion proper and the outer membrane is the
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chorion. The extraembryonic fetal membranes have a mesenchymal surface in addition to their epithelial (amniotic) and decidual (chorionic) surfaces. These terms are used to describe how the membrane is placed on the wound. The amnion has been used successfully in the temporary dressings of leg ulcers, contaminated or infected raw surfaces such as burns, postvulvectomy defects, gastroschisis, and pilonidal cyst sinuses. Amniotic membranes are less expensive than and superior to pig skin as biologic dressings. Amnion is more effective than human skin in decreasing bacterial counts in burn wounds.173 Amnion can be sterilized and stored at room temperature for up to 9 months after delivery.174 The amniotic membranes effectively reduce pain, decrease fluid and protein loss, and protect raw surfaces until a permanent cover is available. Neovascularization of amnion does not occur, and the membrane can be removed in 7 to 10 days as the wound begins to close painlessly. However, amnion does not promote healing and appears to potentiate increased hyperemic reactions and scarring.175 In summary, amnion is inexpensive, convenient, ubiquitous, and biologically effective.176 Synthetic Materials Feldman147 reviewed methods for dressing the donor site of a skin graft (Table 1). Synthetic wound dressings can be semiopen, semiocclusive, or occlusive. Semiopen dressings include Xeroform, Biobrane, and fine mesh gauze impregnated with Scarlet Red or Vaseline. Semiocclusive dressings include Op-Site, Tegaderm, and DuoDERM. Because they are bacteria- and liquid impermeable, fluid tends to collect under these dressings and should be drained frequently. Feldman and colleagues177 evaluated the effectiveness of various donor site dressings in 30 patients with respect to healing, pain, infection, and expense. Xeroform was judged to be better than Biobrane, with an average healing time of 10.46 days, no infections, and an average cost per patient of $1.16. The healing time for Biobrane was 19 days and for DuoDERM was 15.3 days. Biobrane was more comfortable than Xeroform but had 29% more infections and cost $102.50 per patient. In another study,178 donor site wounds dressed with Op-Site and Tegaderm showed rapid, rela14

Table 1

Techniques for dressing skin graft donor sites Fine mesh gauze Scarlet Red Vaseline Gauze Xeroform Biobrane Duoderm Op-Site Tegaderm Autograft Excess skin graft Allograft Human cadaver skin Xenograft Pigskin Amniotic membrane Cultured keratinocyte grafts

Semiopen

Occlusive Semiocclusive

Biologic

(Annotated from Feldman DL: Which dressing for split-thickness skin graft donor sites? Ann Plast Surg 27:288, 1991. With permission.)

tively painless healing and low infection rates. These are expensive materials, however, particularly in dressing large donor areas, and must be changed frequently due to fluid collection. Brady179 compared Op-Site, Vaseline gauze, Jelonet, Scarlet Red, and exposure in terms of healing time, pain, infection, and cost. Pig skin was also included in the study initially but was soon eliminated because of the incidence of Pseudomonas infection and hypertrophic scarring. Wounds dressed with Jelonet healed quickly, followed closely by Vaseline gauze. The interval to healing was longest with the open method. Op-Site was the most comfortable dressing according to patients, but also the most expensive. Vaseline gauze was second only to exposure in low cost. Recommendations from the authors were Op-Site or Jelonet for dressing small donor areas and Vaseline gauze for large wounds. Barnett and coworkers180 compared synthetic adhesive, moisture-vapor-permeable and fine mesh gauze dressings for STSG donor sites with respect to pain, rate of healing, adherence, and infection. Op-Site and Tegaderm promoted fast healing with a mean of 6.8 days from graft to closure and were basically painless. Wounds covered with fine mesh gauze healed in 10.5 days but were 3X as painful. Zapata-Sirvent181 compared Biobrane and Scarlet Red and found Biobrane was better for controlling pain and exudate accumulation and had shorter

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healing times. Tavis et al agree that Biobrane reduces pain, limits infection and desiccation, and optimizes healing times, though it is considerably more expensive. Poulsen and colleagues183 found conventional impregnated gauze (Jelonet) superior to semipermeable polyurethane film (Op-Site) in the treatment of outpatient partial-thickness burns, both in terms of speed of healing (7 vs 10 d) and residual scars (8% vs 21%). Lawrence and Blake184 as well as Porter185 evaluated Kaltostat, a calcium alginate dressing, in the healing of split-thickness skin graft donor sites. The rate of epithelialization, pain, and convenience of use were measured and compared with those in patients treated with Scarlet Red and DuoDERM, respectively. The authors documented slower healing times with Kaltostat (15.5 d) than with either Scarlet Red (10 d) or hydrocolloid (10 d). On the other hand, the alginate was easier to use and seemed to lend itself well to outpatient treatment.185 Dressings that provide a moist environment for the wound speed the rate of healing. Nemeth et al186 noted faster healing by nearly 4 days and 6X less pain in shaved biopsy sites treated with DuoDERM than those managed with conventional therapy consisting of hydrogen peroxide cleansing, bacitracin ointment, and bandaids. Sawada et al187 reported prompt epithelialization (average 7 days), no infection, and little pain in donor site wounds treated with silicone gel sheet containing ofloxacin. Owen and Dye188 found that topical application of 2% lignocaine gel to the skin graft donor sites controlled discomfort during the first week of grafting and did not impair healing. Alvi and colleagues189 attest to the safety of topical anesthetic agents in gel form to provide relief at split skin donor sites.

182

impenetrability to microorganisms rapid and persistent adherence to a wound surface porosity for ingrowth of fibrovascular tissue from the wound bed malleability to conform to an irregular wound surface elasticity for motion of underlying tissues structural stability to resist linear and shear stresses a smooth surface to discourage bacterial proliferation sufficient tensile strength to resist fragmentation biodegradability low cost ease of storage indefinite shelf life Biological Autologous skin substitutes basically combine allogeneic fibroblasts with collagen to form a neodermal matrix to which is added a suspension of autologous epidermal cells.191 In early clinical trials these skin equivalents appeared to heal well and approximate the color of normal skin some 8 months after grafting. At 18 months postgraft there was no evidence of either fragility nor hypertrophic scar. Other successful reports by Harriger et al,192 Maruguchi et al,193 and Beumer and colleagues194 attest to the growing popularity of the technique. Although slightly different from each other, these skin equivalents are basically a composite of bovine type I collagen-containing sponge neodermis with a suspension of cultured keratinocytes as the neoepidermis. Ghosh and associates195 review various techniques for the preparation of human skin composites based on deepidermized acellular dermal matrix, epidermal keratinocytes, and dermal fibroblasts. In 1975 Rheinwald and Green5 pioneered a method for growing human epidermal cells in vitro. Four years later Green et al,6 seeking to make a product suitable for grafting, perfected the technique of cultured epithelial autografts. Subsequently OConnor and Green196 reported the clinical application of epithelial cell cultures in burn
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SKIN SUBSTITUTES Unlike temporary wound dressings, skin substitutes are designed to be left in place for long periods of time. Fifteen years ago Pruitt and Levine190 listed attributes of the ideal skin substitute, which are still current today: little or no antigenicity tissue compatibility lack of toxicity, either local or systemic permeability to water vapor just like normal skin

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patients, and since that time cultured epithelial autografts (CEA) have been used to solve a number of clinical problems. The tissue-culture technique is essentially simple.6 Skin biopsies are taken and the epithelial cells are separated from the dermis by means of trypsin. Lethally-irradiated mouse fibroblasts are used as a surface on which to place the keratinocytes for growth. The cells are incubated for 10 to 14 days in bovine fetal serum, at which time they are divided. A second generation of grafts is then grown in a similar medium for an additional 2 to 2.5 weeks, and by the end of 4 weeks a 1.5-cm skin biopsy has grown into enough skin to cover a wound 1.7 m2. Phillips et al197 serially biopsied the cultured epidermal grafts which were applied to leg ulcers to study their histologic appearance. Ten days postgraft there was compact hyperkeratosis, a normallooking epidermis, and a flat dermisepidermis junction. At 6 months postgraft the area looked very similar to hyperproliferative skin, with a basketweave appearance of the stratum corneum. The dermisepidermis junction continued to be flat. Teepe et al198 continued this line of work for a period of almost 5 years. The authors confirmed the results of previous studies, namely that the cultured epidermis remains in a hyperproliferative state for a long time after grafting. This unchecked proliferation could be the result of an absent modulating dermal factor. Keratinocyte maturation following cultured autografts does not return to normal for at least 4.5 years after healing of full-thickness burn wounds. Cultured keratinocyte grafts lack Langerhans cells and T lymphocytes, thus it is felt that allogeneic epidermal grafts were immunologically protected and could be used whenever the situation demanded early wound coverage and could not withstand the obligatory 3 to 4 week delay for cultured epithelial autograft. Phillips199 demonstrated that cultured allogeneic epithelial grafts do not take in the traditional sense, but are rapidly replaced by host epithelium. In about 6 months after grafting, all the keratinocytes in the allogeneic grafts have been replaced by keratinocytes of recipient origin, so that by this time the allograft for all intents and purposes has become an autograft. Other authors confirm these observations.200-204 Tomson and coworkers205 note improved in-vitro generation of epithelial cells harvested from the oral mucosa. Keratinocytes obtained from this
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source replicate at a much faster rate than keratinocytes from normal biopsied skin elsewhere. At the present time, cultured epidermal grafts are being used extensively in the treatment of burns, either alone,199-204,206-217 in combination with allogeneic skin transplants,218,219 or as composite grafts of CEA and bipolymer.192 Cultured epithelial cells to be used for grafting have an expansion capability of 10,000X the original surface area.206,220,221 When cultured cells and allografts are combined, they tend to be more stable than either of the components alone, yet many prefer to use CEA alone on large total body surface area burns.222,223 In addition to their usefulness in massive burns and chronic skin ulcers, cultured keratinocytes have been shown to be effective in treating keloids,224 vitiligo,208 epidermolysis bullosa,225 idiopathic pyoderma gangrenosum,226 bullous pemphigoid,227 after excision of giant hairy nevi,228 in postoperative otorrhea from failure of epithelialization of open mastoid cavities,208,229 to cover skin graft donor sites,230 and in a number of other conditions. One of the most popular applications of CEA preparations has been in the treatment of chronic leg ulcers.208,212,224,231-235 In terms of graft take, overall coverage, healing time, and cosmetic result, CEAs compare favorably with standard punch grafts. Green208 explains the effectiveness of CEAs in chronic ulcers as follows: Keratinocytes synthesize a large number of polypeptide growth factors, among them transforming growth factor alpha (TGF-), which promotes proliferation and migration of the keratinocytes in a biofeedback mechanism that stimulates growth of the cell which produces it. Many burn centers continue to use cultured epidermal autografts. The following conclusions regarding grafts of cultured keratinocytes derive from their combined reported experiences: Tissue cultured grafts are commercially available. CEAs are very expensive: a 2 x 2 inch graft cost approximately $550 in 1996. Sheets of cultured keratinocytes are very fragile and must be handled with extreme care. CEAs require well vascularized beds. Once the CEA takes, the cells will spread peripherally to join other grafts or surrounding skin.

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CEAs are extremely sensitive to infection, tolerating maximum bacterial counts of 102 to 103/cm3 (compared with 104105/cm3 for standard STSG).207 Synthetic Synthetic skin substitutes may be solid or microporous, slitted or smooth, adherent or nonadherent, and unilaminar or bilaminar. Unilaminar membranes are of one of three types: hydrogels, hydrocolloid dressings, or vapor-permeable membranes.236 These materials effectively debride the wound, absorb fluids, decrease bacterial counts, and stimulate granulation tissue growth.237,238 They seem to be the most effective in accelerating the healing of partial-thickness wounds239 and do not provide any mechanical protection. Bilaminar skin substitutes consist either of totally synthetic, biologically inert materials or collagensynthetic composites. Totally synthetic. In 1975 Levine et al240 devised a totally synthetic, biologically inert bilaminar membrane for use as a skin substitute. The material is made up of an inner layer or dermis which is nylon fabric, while the epidermis consists of polytetrafluoroethylene (PTFE). At its thinnest point the material is 0.635 mm thick. The PTFE is 1 mil thick and has a 0.1 mcm pores. The membrane attaches to the bed of an excised wound within 5 days, and in about 10 days fibrovascular tissue has invaded two-thirds into the dermis. The membrane allows passage of water vapor, protects the host from infection, and increases patient survival in burns greater than 60% total body surface area. Clinically the membrane was applied to patients with 30% to 75% TBSA burns and left in place for 2 to 3 days, at which time it was removed and the wounds autografted. (By definition, then, the material qualifies as a dressing rather than a true skin substitute.) Autograft take following application of the synthetic membrane was excellent. Levine notes the following advantages of this nylonPTFE skin: it conforms well to irregular wound surfaces

it does not fragment and is flexible enough to permit motion of the extremities is semitransparent so that the wound surface can be observed through the dressing Collagen-synthetic composites. In a landmark report in 1981, Burke and colleagues241 described the clinical treatment of extensive burns with an artificial skin consisting of a collagen dermis attached to a Silastic epidermis. The dermis was a porous sponge-like matrix of bovine type I collagen and glycosaminoglycans. The epidermis was a 0.1-mm thick Silastic layer to retain moisture. When placed on a granulating bed or excised fullthickness burn wound, the dermal component converts to a synthesized connective tissue matrix similar to human dermis within 23 weeks.241,242 At this point the Silastic epidermis can be replaced with a thin STSG or CEA-fibrin preparation.243,244 An alternative method was described by Hansbrough and colleagues245 and consists of human neonatal fibroblasts cultured in Biobrane. The Biobrane-HF grafts adhered well to full-thickness wounds, provided effective wound closure, and were long lasting (up to 40 d). There was rapid fibrovascular ingrowth and minimal inflammatory response associated with these cultured grafts. Making an Informed Choice In an editorial in Archives of Dermatology titled New Skin for Old and dated 1998, Phillips246 reviews developments in biological skin substitutes and addresses the following questions: (1) What skin substitutes are available and how does human skin equivalent (HSE) compare with them? (2) How do the results of this study compare with the standard of care for venous ulcers? (3) What are the risks and benefits of treatment with biological skin substitutes? (4) What are the possible mechanisms of action of these biological agents? and (5) How will these products be used in clinical practice? Readers are urged to read this article if contemplating the use of skin substitutes. Other recommended papers exploring various facets of skin equivalents are by Nangia and Hung,247,248 Yang,249 Grisolia et al,250 Prunieras,251 Bertolami and colleagues,252 Carver and Leigh,253 Matsuda and associates,254 Cooper and Spielvogel,255 and Nakazawa and coworkers.256

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BIBLIOGRAPHY
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26. Hilgert I: Changes in the hydroxyproline and hexosamine content of grafts after transplantation. Folia Biol (Praha) 91:136, 1963. 27. Marckmann A: Autologous skin grafts in the rat. Uptake of 3-5-S-sulfate. Proc Soc Exp Biol Med 119:557, 1965. 28. Udenfriend S: Formation of hydroxyproline in collagen. Science 152:1335, 1966. 29. Rudolph R, Klein L: Isotopic quantification of collagen turnover in skin grafts. Surg Forum 22:489, 1971. 30. Ohuchi K, Tsurufugi F: Degradation and turnover of collagen in the mouse skin and the effect of whole body x-irradiation. Biochem Biophysiol Acta 208:475, 1970. 31. Mac Neil S: What role does the extracellular matrix serve in skin grafting and wound healing? Burns 20:S67, 1994. 32. Pepper FJ: Studies on the viability of mammalian skin autografts after storage at different temperatures. Br J Plast Surg 6:250, 1954. 33. Clemmesen T: The early circulation in split skin grafts. Acta Chir Scand 124:11, 1962. 34. Clemmesen T: Experimental studies on the healing of free skin autografts. Danish Med Bull 14, Suppl 11, 1967. 35. Converse JM, Uhlschmid GK, Ballantyne DL Jr: Plasmatic circulation in skin grafts. Plast Reconstr Surg 43:495, 1969. 36. Converse JM et al: Inosculation of vessels of skin graft and host bed: A fortuitous encounter. Br J Plast Surg 28:274, 1975. 37. Peer LA, Walker JC: The behaviour of autogenous human tissue grafts, I. Plast Reconstr Surg 7:6, 1951. 38. Peer LA: Transplantation of Tissues, Vol 2. Baltimore, Williams & Wilkins, 1955. 39. Birch J, Branemark PI: The vascularization of a free fullthickness skin graft. I. A vital microscopic study. Scand J Plast Reconstr Surg 3:1, 1969. 40. Birch J, Branemark PI, Lundskog J: The vascularization of a free full-thickness skin graft. II. A microangiographic study. Scand J Plast Reconstr Surg 3:11, 1969. 41. Birch J, Branemark PI, Nilsson K: The vascularization of a free full-thickness skin graft. III. An infrared thermographic study. Scand J Plast Reconstr Surg 3:18, 1969. 42. Psillakis JM et al: Water and electrolyte changes in autogenous skin grafts. Discussion of the so-called plasmatic circulation. Plast Reconstr Surg 43:500, 1969. 43. Haller JA, Billingham RE: Studies of the origin of the vasculature in free skin grafts. Ann Surg 166:896, 1967. 44. Converse JM, Rapaport FT: The vascularization of skin autografts and homografts; an experimental study in man. Ann Surg 143:306, 1956. 45. Converse JM et al: A study of viable and non-viable skin grafts transplanted to the chorio-allantoic membrane of the chick embryo. Transplant Bull 5:108, 1958. 46. Converse JM, Filler M, Ballantyne DL: Vascularization of split-thickness skin autografts in the rat. Transplantation 3:22, 1965. 47. Zarem HA, Zweifach BW, McGehee JM: Development of microcirculation in full thickness autogenous skin grafts in mice. Am J Physiol 212:1081, 1967. 48. Ljungvist A, Almgard IE: The vascular reaction in the free skin allo- and autografts. Acta Path Microbiol Scand 68:553, 1966. 49. Wolff K, Schellander FG: Enzyme-histochemical studies on the healing process of split skin grafts. J Invest Dermatol 45:38, 1965. 50. Tsukada S: Transfer of free skin grafts with a preserved subcutaneous vascular network. Ann Plast Surg 4:500, 1980.

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51. Ericksson G et al: Electron microscopic studies on the epidermis in human split-skin autografts. Scand J Plast Reconstr Surg 2:83, 1968. 52. Zoltan J: Transplantationslehre. In: Gohrbandt-GabkaBerndorfer (eds), Handbuch der Plastischen Chirurgie, Band 1, Lieferung 3, Beitrag 12. Berlin, Walter de Gruyter, 1965, p 1-244. 53. Burleson R, Eiseman B: Nature of the bond between partial-thickness skin and wound granulations. Am Surg 177:181, 1973. 54. Tavis MJ et al: Graft adherence to de-epithelialized surfaces: A comparative study. Ann Surg 184:594, 1976. 55. Stuart JD, Morgan RF, Kenney JG: Single-donor fibrin glue for hand burns. Ann Plast Surg 24:524, 1990. 56. Saltz R et al: Experimental and clinical applications of fibrin glue. Plast Reconstr Surg 88:1005, 1991. 57. Cederholm-Williams SA: Benefits of adjuvant fibrin glue in skin grafting. Med J Aust 161(9):575, 7 Nov 1994. 58. Dean M, Nicholls M, Wedderburn C: Benefits of adjuvant fibrin glue in skin grafting. Med J Aust 160(8):526, 18 Apr 1994. 59. Achauer BM, Miller SR, Lee TE: The hemostatic effect of fibrin glue on graft donor sites. J Burn Care Rehabil 15:24, 1994. 60. Himel HN et al: A new device for securing meshed splitthickness skin grafts. Scand J Plast Reconstr Hand Surg 28:299, 1994. 61. Himel HN et al: Biomechanical performance of a disposable graft stapler with absorbable skin tacs. Burns 20:244, 1994. 62. Sheridan RL, Petras L, Basha G, Tompkins RG: Clinical experience with the use of biodegradable tacks in pediatric patients with burns. J Burn Care Rehabil 16:143, 1995. 63. Best T, Lobay G, Moysa G, Tredget E: A prospective randomized trial of absorbable staple fixation of skin grafts for burn wound coverage. J Trauma 38:915, 1995. 64. Netscher DT, Marchi M, Wigoda P: A method for optimizing skin graft healing and outcome of wounds of the penile shaft and scrotum. Ann Plast Surg 31:447, 1993. 65. Saltz R, Bowles BJ: Reston: an alternate method of skin graft fixation (letter). Plast Reconstr Surg 99:601, 1997. 66. Caldwell RK, Giles WC, Davis PT: Use of foam bolsters for securing facial skin grafts. Ear Nose Throat J 77(6):490, 1998. 67. Balakrishnan C: Dressing for skin grafts of the penis (letter). Plast Reconstr Surg 95:208, 1995. 68. Johnson PA, Fleming K, Avery CME: Latex foam and staple fixation of skin grafts. Br J Oral Maxillofac Surg 36:141, 1998. 69. Wolf Y, Kalish E, Badani E, et al: Rubber foam and staples: Do they secure skin grafts? A model analysis and proposal of pressure enhancement techniques. Ann Plast surg 40:149, 1998. 70. Smoot EC: A rapid method for splinting skin grafts and securing wound dressings (letter). Plast Reconstr Surg 100(6):1622, 1997. 71. Amir A, Sagi A, Fliss DM, Rosenberg L: A simple, rapid, reproducible tie-over dressing. Plast Reconstr Surg 98(6):1092, 1996. 72. Cheng LC, Lim TC, Tan WTL: A simple tie-over dressing (letter). Plast Reconstr Surg 101(1):246, 1998. 73. Vloemans AFPM, Kreis RW: Fixation of skin grafts with a new silicone rubber dressing (Mepitel). Scand J Plast Reconstr Hand Surg 28:75, 1994. 74. Sawada Y, Yotsuyanagi T, Ara M, Sone K: Experiences using silicone gel tie-over dressings following skin grafting. Burns 16(5):353, 1990. 75. Renz BM, Stout M, Sherman R: Rubberband stents for skin grafts: How I do it. Am Surg 60:707, 1994. 76. Ren J et al: Transparent gasbag tie-over for persistent pressure and inspection in free skin grafting. Plast Reconstr Surg 95:396, 1995. 77. Ward RS et al: Uses of Coban self-adherent wrap in management of postburn hand grafts: Case reports. J Burn Care Rehabil 15:364, 1994. 78. Grabski WJ, Giandoni MB, Anderson LL: Surgical pearl: Hydrocolloid dressings for full-thickness skin grafts. J Am Acad Dermatol 32:273, 1995. 79. Watson SB, Miller JG: Optimizing skin graft take in childrens hand burnsthe use of Silastic foam dressings. Burns 19:519, 1993. 80. Balakrishnan C: Simple method of applying pressure to skin grafts of neck with foam dressing and staples. J Burn Care Rehabil 15:432, 1994. 81. Wells MD, Kirn DS: A new method of skin-graft stabilization: the Reston technique. Ann Plast Surg 34:554, 1995. 82. Schneider AM, Morykwas MJ, Argenta LC: A new and reliable method of securing skin grafts to the difficult recipient bed. Plast Reconstr Surg 102(4):1195, 1998. 83. McGregor IA, Conway H: Development of lymph flow from autografts and homografts of skin. Transplant Bull 3:46, 1956. 84. Gloor M, Ludwig G: Revascularization of free full-thickness skin autografts. Arch Dermatol Forsch 246:211, 1973. 85. Corps BVM: The effect of graft thickness, donor site and graft bed on graft shrinkage in the hooded rat. Br J Plast Surg 22:125, 1969. 86. Padgett EC: Calibrated intermediate skin grafts. Plast Reconstr Surg 39:195, 1967. 87. Rudolph R: The effect of skin graft preparation on wound contraction. Surg Gynecol Obstet 142:49, 1976. 88. Bertolami C, Donoff RB: The effect of full-thickness skin grafts on the actomyosin content of contracting wounds. J Oral Surg 37:471, 1979. 89. Bertolami CN, Donoff RB: The effect of skin grafting upon prolyl hydroxylase and hyaluronidase activities in mammalian wound repair. J Surg Res 27:359, 1979. 90. Brown D, Garner W, Young VL: Skin grafting: Dermal components in inhibition of wound contraction. South Med J 83:789, 1990. 91. Rudolph R et al: Control of contractile fibroblasts by skin grafts. Surg Forum 28:524, 1977. 92. Rudolph R: Inhibition of myofibroblasts by skin grafts. Plast Reconstr Surg 63:473, 1979. 93. Montandon D et al: The contractile fibroblast: Its relevance in plastic surgery. Plast Reconstr Surg 52:286, 1973. 94. Oliver RF, Grant RA, Kent CM: The fate of cutaneously and subcutaneously implanted trypsin purified dermal collagen in the pig. Br J Exp Pathol 53:540, 1972. 95. Oliver RF et al: Incorporation of stored cell-free dermal collagen allografts into skin wounds: A short term study. Br J Plast Surg 30:88, 1977. 96. Waris T et al: Regeneration of cold, warmth and heat-pain sensibility in human skin grafts. Br J Plast Surg 42:576, 1989. 97. Haro JJ, Del Valle ME, Calzada B, et al: Human glabrous skin autografts partially reinnervated without sensory corpuscles. An immunohistochemical study. Scand J Plast Reconstr Hand Surg 28:25, 1994.

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98. Stella M, Calcagni M, Teich-Alasia S, et al: Sensory endings in skin grafts and scars after extensive burns. Burns 20(6):491, 1994. 99. Ponten B: Grafted skin. Observations on innervation and other qualities. Acta Chir Scand Suppl 257, 1960. 100. Adeymo O, Wyburn G: Innervation of skin grafts. Transplantation 4:152, 1957. 101. Fitzgerald MJT, Martin F, Paletta FX: Innervation of skin grafts. Surg Gynecol Obstet 124:808, 1967. 102. Weis-Becker C, Fruhstorfer H, Friederich H-C, Winter H: Reinnervation of split skin grafts in humans: comparison of two different methods of operation. Scand J Plast Reconstr Hand Surg 32:157, 1998. 103. Conway H, Sedar J: Report of the loss of pigment in full thickness autoplastic skin grafts in the mouse. Plast Reconstr Surg 18:30, 1956. 104. Mir y Mir L: The problem of pigmentation in the cutaneous graft. Br J Plast Surg 14:303, 1961. 105. Taki T et al: Surgical treatment of skin depigmentation caused by burn injuries. J Dermatol Surg Oncol 11:1218, 1985. 106. Jarrett A, Szabo G: The pathologic varieties of vitiligo and their response to treatment with mladinin. Br J Dermatol 68:313, 1956. 107. Falabella R: Repigmentation of leukoderma by autologous epidermal grafting. J Dermatol Surg Oncol 10:136, 1984. 108. Hatchome N, Kato T, Tagami H: Therapeutic success of epidermal grafting in generalized vitiligo is limited by the Koebner phenomenon. J Am Acad Dermatol 22:87, 1990. 109. Kahn AM, Cohen MJ: Vitiligo: treatment by dermabrasion and epithelial sheet graftinga preliminary report. J Am Acad Dermatol 28:773, 1993. 110. Behl PN: Vitiligo: treatment by dermabrasion and epithelial sheet grafting (letter). J Am Acad Dermatol 30:1044, 1994. 111. Achauer BM, Le Y, Vander Kam VM: Treatment of vitiligo with melanocytic grafting. Ann Plast Surg 33:644, 1994. 112. Olsson MJ, Juhlin L: Epidermal sheet grafts for repigmentation of vitiligo and piebaldism, with a review of surgical techniques. Acta Derm Venereol (Stockh) 77:463, 1997. 113. Yang JS, Kye YC: Treatment of vitiligo with autologous epidermal grafting by means of pulsed erbium:YAG laser. J Am Acad Dermatol 38(2 Pt 1):280, 1998. 114. Kahn AM, Cohen MJ: Repigmentation in vitiligo patients. Melanocyte transfer via ultra-thin grafts. Dermatol Surg 24:365, 1998. 115. Kaufmann R, Greiner D, Kippenberger S, Bernd A: Grafting of in vitro cultured melanocytes onto laser-ablated lesions in vitiligo. Acta Derm Venereol (Stockh) 78:136, 1998. 116. Hosokawa K, Hata Y, Yano K, et al: Treatment of tattoos with pure epidermal sheet grafting. Ann Plast Surg 24:53, 1990. 117. Webster GV: Annual Report to the American Society of Plastic and Reconstructive Surgeons. Hollywood, Florida, October 1954. 118. Rees TD, Casson PR: The indications for cutaneous dermal overgrafting. Plast Reconstr Surg 38:522, 1966. 119. Wheeland RG: The technique and current status of pinch grafting. J Dermatol Surg Oncol 13:873, 1987. 120. Smahel J, Ganzoni N: Relay transplantation: A new method of expanding a free skin graft. Br J Plast Surg 28:49, 1975. 121. Knight SL, Moorghen M: Configurational changes within the dermis of meshed split skin grafts: a histological study. Br J Plast Surg 40:420, 1987. 122. Davison PM, Batchelor AG, Lewis-Smith PA: The properties and uses of non-expanded machine-meshed skin grafts. Br J Plast Surg 39:462, 1986. 123. Glogau RG, Stegman SJ, Tromovitch TA: Refinements in split-thickness skin grafting technique. J Dermatol Surg Oncol 13:853, 1987. 124. Richard R, Miller SF, Steinlage R, Finley RK Jr: A comparison of the Tanner and Bioplasty skin mesher systems for maximal skin graft expansion. J Burn Care Rehabil 14:690, 1993. 125. Kreis RW, Mackie DP, Hermans RK, Vloemans AR: Expansion techniques for skin grafts: comparison between mesh and Meek island (sandwich-) grafts. Burns 20:S39, 1994. 126. Zhang ML et al: Microskin grafting. II. Clinical report. Burns 12:544, 1986. 127. Zhang ML et al: Microskin grafting in the treatment of extensive burns: A preliminary report. J Trauma 28:804, 1988. 128. Lai C-S et al: An easy way to prepare microskin grafts. Burns 20:151, 1994. 129. Lin T-W: The algebraic view-point in microskin grafting in burned patients. Burns 20:347, 1994. 130. Lin T-W, Horng S-Y: A new method of microskin mincing. Burns 20:526, 1994. 131. Vandeput J, Tanner J: Easy way to prepare microskin grafts. Burns 20:476, 1994. 132. Wang LN, Hsu JH, Lu KH: Experimental studies on combined use of homografts and autografts. Chin Med J 4:221, 1973. 133. Yang CC et al: The intermingled transplantation of autoand homografts in severe burns. Burns 6:141, 1980. 134. Hatchome N, Kato T, Tagami H: Therapeutic success of epidermal grafting in generalized vitiligo is limited by the Koebner phenomenon. J Am Acad Dermatol 22:87, 1990. 135. Christiansen J, Ek L, Tegner E: Pinch grafting of leg ulcers. A retrospective study of 412 treated ulcers in 146 patients. Acta Derm Venereol (Stockh) 77:471, 1997. 136. Kirsner RS, Mata SM, Falanga V, Kerdel FA: Splitthickness skin grafting of leg ulcers. The University of Miami Department of Dermatologys experience (19901993). Dermatol Surg 21:701, 1995. 137. Yeh FL, Yu GS, Fang CH, et al: Comparison of scar contracture with the use of microskin and Chinese-type intermingled skin grafts on rats. J Burn Care Rehabil 11:221, 1990. 138. Flowers R: Unexpected postoperative problems in skin grafting. Surg Clin North Am 50:439, 1970. 139. Teh BT: Why do skin grafts fail? Plast Reconstr Surg 63:323, 1979. 140. Hill TG: Enhancing the survival of full-thickness grafts. J Dermatol Surg Oncol 10:639, 1984. 141. Wolfort S, Rohrich RJ, Handren J, May JW Jr: The effect of epinephrine in local anesthesia on the survival of fulland split-thickness skin grafts: an experimental study. Plast Reconstr Surg 86(3):535, 1990. 142. Fazio MJ, Zitelli JA: Full-thickness skin grafts. Clinical observations on the impact of using epinephrine in local anesthesia of the donor site. Arch Dermatol 131:691, 1995. 143. Robson MC, Krizek TJ: Predicting skin graft survival. J Trauma 13:213, 1973.

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144. Perry AW et al: Skin graft survivalThe bacterial answer. Ann Plast Surg 22:479, 1989. 145. Allen HE et al: Skin dressings in the treatment of contaminated wounds. Am J Surg 126:45, 1973. 146. Szabo SE, Toomey JM, Linn BS: Does skin have antimicrobial properties? An in-vitro experiment and literature review. Am Surg 44:55, 1978. 147. Feldman DL: Which dressing for split-thickness skin graft donor sites? Ann Plast Surg 27:288, 1991. 148. Gallico GG III: Biologic skin substitutes. Clin Plast Surg 17:519, 1990. 149. Hoekstra MJ, Kreis RW, du Pont JS: History of the Euro Skin Bank: the innovation of preservation technologies. Burns 20:S43, 1994. 150. Basile ARD: A comparative study of glycerinized and lyophilized porcine skin dressings for third degree burns. Plast Reconstr Surg 69:969, 1982. 151. Backere ACJ: Euro Skin Bank: large scale skin-banking in Europe based on glycerol-preservation of donor skin. Burns 20:S4, 1994. 152. Hettich R, Ghofrani A, Hafemann B: The immunogenicity of glycerol-preserved donor skin. Burns 20:S71, 1994. 153. Baare J, Buitenwerf J, Hoekstra MJ, du Pont JS: Virucidal effect of glycerol as used in donor skin preservation. Burns 20:S77, 1994. 154. Pirnay JP, Vandenvelde C, Duinslaeger L, et al: HIV transmission by transplantation of allograft skin: a review of the literature. Burns 23:1, 1997. 155. Simonds RJ: HIV transmission by organ and tissue transplantation. AIDS 7:35, 1993. 156. Asselmeier MA, Caspari RB, Bottenfield S: A review of allograft processing and sterilization techniques and their role in transmission of the human immunodeficiency virus. Am J Sports Med 21:170, 1993. 157. Buck BE, Resnick I, Shah SM, Malinin TI: Human immunodeficiency virus cultured from bone: implications for transplantation. Clin Orthop 251:249, 1990. 158. Conway B, Tomford W, Mankin HJ, et al: Radiosensitivity of HIV-1: potential application to sterilisation of bone allografts. AIDS 5:608, 1991. 159. Brans TA, Hoekstra MJ, Vloemans AFPM, Kreis RW: Long-term results of treatment of scalds in children with glycerol-preserved allografts. Burns 20:S10, 1994. 160. Peeters R, De Caluwe D, Neetens C, Hubens A: Use of glycerolized cadaver skin for the treatment of scalds in children. Burns 20:S32, 1994. 161. Hussmann J et al: Use of glycerolized human allografts as temporary (and permanent) cover in adults and children. Burns 20:S61, 1994. 162. Schiozer WA et al: Composite grafts of autogenic cultured epidermis and glycerol-preserved allogeneic dermis for definitive coverage of full thickness burn wounds: case reports. Burns 20:503, 1994. 163. McKay I et al: Reconstruction of human skin from glycerol-preserved allodermis and cultured keratinocyte sheets. Burns 20:S19, 1994. 164. Phipps AR, Clarke JA: The use of intermingled autograft and parental allograft skin in the treatment of major burns in children. Br J Plast Surg 44:608, 1991. 165. Dohi K et al: Studies of alloantibody effect on skin graft survival in mice. Hiroshima J Med Sci 33:271, 1984. 166. Dohi K et al: Studies of immunosuppressive effect of anti-recipient alloantiserum. I. Effect on skin graft survival in mice. Hiroshima J Med Sci 33:507, 1984. 167. Steines NA, Gug K, Davies DAL: Passive enhancement of mouse skin allografts; specificity of the antiserum for major histocompatibility complex antigens. Transplantation 18:192, 1974. 168. McCullough CS, Sugarbaker PH, Matthews W: Effects of passive enhancement on graft and host. Transplantation 37:91, 1984. 169. Towpik E et al: Cyclosporine and experimental skin allografts: Long-term survival in rats treated with low maintenance doses. Plast Reconstr Surg 77:268, 1986. 170. Towpik E: Meshed allograft skin and cyclosporin immunosuppression (letter). Br J Plast Surg 42:618, 1989. 171. Kolenik SA III, Leffell DJ: The use of cryopreserved human skin allografts in wound healing following Mohs surgery. Dermatol Surg 21:615, 1995. 172. Csnge L, Pellet S, Szenes A, Istvn J: Antibiotics in the preservation of allograft and xenograft skin. Burns 21(2):102, 1995. 173. Robson MC, Krizek TJ: The effect of human amniotic membranes on the bacterial population of infected rat burns. Ann Surg 177:144, 1973. 174. Rao TV, Chandrasekharam V: Use of dry human and bovine amnion as a biological dressing. Arch Surg 116:891, 1981. 175. Waikakul S et al: Application of freeze-dried amniotic membrane: A control trial at the donor site of splitthickness skin grafting. Bull Hosp Jt Dis Orthop Inst 50:27, 1990. 176. (Anonymous): Anyone for amnion? (editorial). Lancet 1:719, Mar 31, 1984. 177. Feldman DL, Karpinski RHS: A prospective trial comparing Biobrane, Duoderm, and xeroform for skin graft donor sites. Surg Gynecol Obstet 173:1, 1991. 178. Morris WT, Lamb AM: Painless split skin donor sites: A controlled double-blind trial of Op-Site, scarlet red, and bupivacaine. Aust NZ J Surg 60:617, 1990. 179. Brady SC, Snelling CFT, Chow G: Comparison of donor site dressings. Ann Plast Surg 5:238, 1980. 180. Barnett A et al: Comparison of synthetic adhesive moisture vapor permeable and fine mesh gauze dressings for split-thickness skin graft donor sites. Am J Surg 145:379, 1983. 181. Zapata-Sirvent R et al: Comparison of Biobrane and Scarlet Red dressings for treatment of donor site wounds. Arch Surg 120:743, 1985. 182. Tavis MJ et al: A new composite skin prosthesis. Burns 7:123, 1981. 183. Poulsen TD, Freund KG, Arendrup K, et al: Polyurethane film (Opsite*) vs. impregnated gauze (Jelonet*) in the treatment of outpatient burns: a prospective, randomized study. Burns 17:59, 1991. 184. Lawrence JE, Blake GB: A comparison of calcium alginate and scarlet red dressings in the healing of split thickness skin graft donor sites. Br J Plast Surg 44:247, 1991. 185. Porter JM: A comparative investigation of reepithelialisation of split skin graft donor areas after application of hydrocolloid and alginate dressings. Br J Plast Surg 44:333, 1991. 186. Nemeth AJ et al: Faster healing and less pain in skin biopsy sites treated with an occlusive dressing. Arch Dermatol 127:1679, 1991. 187. Sawada Y, Yotsuyanagi T, Sone K: A silicone gel sheet dressing containing an antimicrobial agent for split thickness donor site wounds. Br J Plast Surg 43:88, 1990.

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188. Owen TD, Dye D: The value of topical lignocaine gel in pain relief on skin graft donor sites. Br J Plast Surg 43:480, 1990. 189. Alvi R, Jones S, Burrows D, et al: The safety of topical anaesthetic and analgesic agents in a gel when used to provide pain relief at split skin donor sites. Burns 24:54, 1998. 190. Pruitt BA Jr, Levine NS: Characteristics and uses of biologic dressings and skin substitutes. Arch Surg 119:312, 1984. 191. Hull BE, Finley RK, Miller SF: Coverage of full-thickness burns with bilayered skin equivalents: A preliminary clinical trial. Surgery 107:496, 1990. 192. Harriger MD et al: Pigmentation and microanatomy of skin regenerated from composite grafts of cultured cells and biopolymers applied to full-thickness burn wounds. Transplantation 59:702, 1995. 193. Maruguchi T et al: A new skin equivalent: keratinocytes proliferated and differentiated on collagen sponge containing fibroblasts. Plast Reconstr Surg 93:537, 1994. 194. 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Plast Reconstr Surg 82:99, 1988. 208. Green H: Cultured cells for the treatment of disease. Sci Am 265:96, 1991. 209. Herndon DN, Rutan RL: Comparison of cultured epidermal autograft and massive excision with serial autografting plus homograft overlay. J Burn Care Rehabil 13:154, 1992. 210. Desai MH et al: Lack of long-term durability of cultured keratinocyte burn-wound coverage: A case report. J Burn Care Rehabil 12:540, 1991. 211. Blight A et al: The treatment of donor sites with cultured epithelial grafts. Br J Plast Surg 44:12, 1991. 212. Blight A et al: Treatment of full skin thickness burn injury using cultured epithelial grafts. Burns 17:495, 1991. 213. Munster AM, Weiner SH, Spence RJ: Cultured epidermis for the coverage of massive burn wounds. A single center experience. Ann Surg 211:676, 1990. 214. Petersen MJ, Lessane B, Woodley DT: Characterization of cellular elements in healed cultured keratinocyte autografts used to cover burn wounds. Arch Dermatol 126:175, 1990. 215. Clugston PA et al: Cultured epithelial autografts: Three years of clinical experience with eighteen patients. J Burn Care Rehabil 12:533, 1991. 216. Ronfard V et al: Use of human keratinocytes cultured on fibrin glue in the treatment of burn wounds. Burns 17:181, 1991. 217. Nanchahal J, Davies D: Cultured composite skin grafts for burns. Br Med J 301:1342, 1990. 218. Krupp S et al: Mid-term results with cultured epidermal autografts, allogenic skin transplants and cyclosporin A medication. Burns 20:15, 1994. 219. Hickerson WL, Compton C, Fletchall S, Smith LR: Cultured epidermal autografts and allodermis combination for permanent burn wound coverage. Burns 20:S52, 1994. 220. Latarjet J et al: The grafting of burns with cultured epidermis as autografts in man. Scand J Plast Reconstr Surg 21:241, 1987. 221. Thivolet J et al: Long-term survival and immunological tolerance of human epidermal allografts produced in culture. Transplantation 42:274, 1986. 222. 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lents and full-thickness skin punch grafts. J Am Acad Dermatol 24:77, 1991. Brysk MM et al: Grafting of leg ulcers with undifferentiated keratinocytes. J Am Acad Dermatol 25:238, 1991. Phillips TJ, Bigby M, Bercovitch L: Cultured allografts as an adjunct to the medical treatment of problematic leg ulcers. Arch Dermatol 127:799, 1991. De Luca M et al: Treatment of leg ulcers with cryopreserved allogeneic cultured epithelium. A multicenter study. Arch Dermatol 128:633, 1992. Roenigk RK et al: Dermatologic Surgery: Principles and Practice. New York, BC Decker, 1989. Brown AS, Barot LR: Biologic dressings and skin substitutes. Clin Plast Surg 13:69, 1986. Kickhofen B, Wokalek H, Scheel D, Ruh H: Chemical and physical properties of a hydrogel wound dressing. Biomaterials 7:67, 1986. Eloy R et al: Physical and biological properties of a new synthetic amino acid copolymer used as a wound dressing. J Biomed Mater Res 26:695, 1992. Levine NS, Peterson HD, Mason AD Jr: Use of synthetic dressing on denuded wounds in burn patients. Ann Res Prog Rep, Ft Sam Houston, TX, US Army Inst Surg Res, Brooke Army Med Ctr, June 1975, pp 343-363. Burke JF et al: Successful use of a physiologically acceptable artificial skin in the treatment of extensive burn injury. Ann Surg 194:413, 1981. Suzuki S et al: Further applications of bilayer artificial skin. Br J Plast Surg 48:222, 1995. Suzuki S et al: Clinical evaluation of a new bilayer artificial skin composed of collagen sponge and silicone layer. Br J Plast Surg 43:47, 1990. 244. Suzuki S et al: Experimental study of a newly developed bilayer artificial skin. Biomaterials 11:356, 1990. 245. Hansbrough JF, Morgan J, Greenleaf G, Underwood J: Development of a temporary living skin replacement composed of human neonatal fibroblasts cultured in Biobrane, a synthetic dressing material. Surgery 115:633, 1994. 246. Phillips TJ: New skin for old. Developments in biological skin substitutes (editorial). Arch Dermatol 134:344, 1998. 247. Nangia A, Hung CT: Preclinical evaluation of skin substitutes. Burns 16(5):358, 1990. 248. Nangia A, Hung CT: Laboratory evaluation of a new hydrogel-type skin substitute. Burns 16(5):368, 1990. 249. Yang J-Y: Clinical application of collagen sheet, YCWM, as a burn wound dressing. Burns 16(6):457, 1990. 250. Grisolia GA, Pelli P, Pinzauti E, et al: Skin substitutes in the treatment of deep partial skin thickness burns in children: clinical experience and long-term results. Burns 17(1):52, 1991. 251. Prunieras M: To reconstitute skin: theme and variations. Matrix 11:302, 1991. 252. Bertolami CN, Shetty V, Milavec JE, et al: Preparation and evaluation of a nonproprietary bilayer skin substitute. Plast Reconstr Surg 87(6):1089, 1991. 253. Carver N, Leigh IM: Synthetic dressings. Int J Dermatol 31(1):10, 1992. 254. Matsuda K, Suzuki S, Isshiki N, Ikada Y: Re-freeze dried bilayer artificial skin. Biomaterials 14(13):1030, 1993. 255. Cooper ML, Spielvogel RL: Artificial skin for wound healing. Clin Dermatol 12:183, 1994. 256. Nakazawa K, Nakazawa H, Sahuc F, et al: Pigmented human skin equivalent: new method of reconstitution by grafting an epithelial sheet onto a non-contractile dermal equivalent. Pigment Cell Res 10:382, 1997.

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SUGGESTED READING:
Hauben DJ, Baruchin A, Mahler D: On the history of the free skin graft. Ann Plast Surg 9:242, 1982. Stuart JD, Morgan RF, Kenney JG: Single-donor fibrin glue for hand burns. Ann Plast Surg 24:524, 1990. Sawada Y, Yotsuyanagi T, Ara M, Sone K: Experiences using silicone gel tie-over dressings following skin grafting. Burns 16(5):353, 1990. Haro JJ, Del Valle ME, Calzada B, et al: Human glabrous skin autografts partially reinnervated without sensory corpuscles. An immunohistochemical study. Scand J Plast Reconstr Hand Surg 28:25, 1994. Hatchome N, Kato T, Tagami H: Therapeutic success of epidermal grafting in generalized vitiligo is limited by the Koebner phenomenon. J Am Acad Dermatol 22:87, 1990. Kirsner RS, Mata SM, Falanga V, Kerdel FA: Split-thickness skin grafting of leg ulcers. The University of Miami Department of Dermatologys experience (1990-1993). Dermatol Surg 21:701, 1995. Yeh FL, Yu GS, Fang CH, et al: Comparison of scar contracture with the use of microskin and Chinesetype intermingled skin grafts on rats. J Burn Care Rehabil 11:221, 1990. Fazio MJ, Zitelli JA: Full-thickness skin grafts. Clinical observations on the impact of using epinephrine in local anesthesia of the donor site. Arch Dermatol 131:691, 1995. Feldman DL, Karpinski RHS: A prospective trial comparing Biobrane, Duoderm, and xeroform for skin graft donor sites. Surg Gynecol Obstet 173:1, 1991. Ghosh MM, Boyce S, Layton C, et al: A comparison of methodologies for the preparation of human epidermal-dermal composites. Ann Plast Surg 39:390, 1997. Blight A, Fatah MF, Datubo-Brown DD, et al: The treatment of donor sites with cultured epithelial grafts. Br J Plast Surg 44:12, 1991. Beele H, Naeyaert JM, Goeteyn M, et al: Repeated cultured epidermal allografts in the treatment of chronic leg ulcers of various origins. Dermatologica 183:31, 1991. Phillips TJ: New skin for old. Developments in biological skin substitutes (editorial). Arch Dermatol 134:344, 1998. Nangia A, Hung CT: Preclinical evaluation of skin substitutes. Burns 16(5):358, 1990. Bertolami CN, Shetty V, Milavec JE, et al: Preparation and evaluation of a nonproprietary bilayer skin substitute. Plast Reconstr Surg 87(6):1089, 1991. Carver N, Leigh IM: Synthetic dressings. Int J Dermatol 31(1):10, 1992. Matsuda K, Suzuki S, Isshiki N, Ikada Y: Re-freeze dried bilayer artificial skin. Biomaterials 14(13):1030, 1993. Cooper ML, Spielvogel RL: Artificial skin for wound healing. Clin Dermatol 12:183, 1994.

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