Introduction

Although medical science is increasingly able to elucidate the biochemical basis of many diseases, certain basic wound healing problems remain essentially unchanged. Plantar foot wounds and venous stasis ulceration continue, for example, to affect millions of people annually.

Tissue Engineering - What's the Point ?

Very large wounds, whether from venous ulceration, burns or trauma, represent significant problems because of the relatively slow nature of epithelial migration. Wound closure via autografting, the use of the patient's own skin for coverage, usually by split thickness skin grafting, while highly effective in properly prepared wounds, usually requires hospitalization or immobilization, anesthesia and the surgical creation of another, often very painful wound (the donor site). Some areas of the body, moreover, are not amenable to grafting, such as the plantar foot. As a result of all these factors, a cost-effective alternative to autografting would be highly desirable.

The creation of human-like skin in the laboratory is a logical evolution of grafting technology. Xenografts (from a nonhuman donor, e.g., pigskin) can provide useful temporary coverage but are always rejected. Allografts (the use of donor skin from another person) have had the obvious disadvantage of immunological rejection unless there is a genetic match.

Acellular preparations act as a "scaffold" to promote cell migration and act as a temporary covering but, unfortunately, can not provide the same biochemical stimulus or mechanical coverage as skin, while cellular preparations, in contrast, can actually synthesize growth factors and other materials that aid the healing process. Cells cultured from the patient's own skin, however, take weeks to grow and do not provide actual mechanical coverage.

The ideal coverage material would illicit no immunologic response, would not require the creation of another wound, would be easily transportable and readily available, would be simple to store and apply, would compare favorably with the cost of surgical wound closure, would structurally resemble skin and would be at least as effective as allografting. Apligraf (Novartis) is an entirely new category of product, the first bi-layer skin substitute developed in the laboratory to simulate the structure of human skin. It is the only FDA approved semi-synthetic human skin currently available. While semi-synthetic skin does not satisfy all of the above criteria, it does represent the next step in tissue engineering technology.

Brief overview of the Healing Process

Normal wounds heal in a predictable period of time. Complete epithelialization can not occur in the absence of adequate granulation tissue. All the aspects of the healing process, including angiogenesis, collagen deposition and epithelialization, are controlled by the interaction of numerous growth factors (cytokines). In addition to mechanical coverage, skin grafts achieve wound closure by contributings cytokines which promote the synthesis of matrix and angiogenesis.

Healing at any stage can be inhibited by many factors, including ischemia, infection or heavy bacterial colonization, nutritional deficiency, bleeding, edema, a dry wound environment or toxic topical preparations.

What is the Apligraf Skin ?

The unique feature of Apligraf human skin is that, like human skin, it has two primary layers. In fact, microscopic cross sections of human skin, when compared to Apligraf human skin, look strikingly similar. The dermis is created using bovine collagen seeded with human fibroblasts. The epidermal layer has a stratum corneum formed of living human keratinocytes, isolated originally from neonatal foreskins. Upon manufacture, the Apligraf human skin is supplied as a circular disc of translucent skin.

Clinical Data

In a randomized venous stasis ulcer trial, Apligraf with compression was compared to compression and standardized wound care (n=120). Apligraf was three times more effective than compression therapy alone in achieving closure of ulcers of greater than a year in duration (p=.048). A particularly well designed FDA trial in diabetic neuropathic plantar foot wounds compared the healing rate of patients off-loaded by an excellent custom-made walking sandal to those utilizing the sandal and receiving Apligraf human skin. Preliminary reports describe a statistically significant improvement in the rate of closure with semi-synthetic human skin for these chronic neuropathic wounds compared to off-loading alone.

The Logistics of Obtaining and Using Semi-synhetic skin

A potentially significant disadvantage to the clinician is that the shelf life of Apligraf human skin is only five days from the day of packaging. By the time the Apligraf skin arrives in the office, the physician must apply it within 72 hours. Otherwise, it must be disposed of. This poses logistical and economic challenges, since semi-synthetic human skin must be purchased directly by the facility and the cost of wasted tissue must be borne by the clinic.

The importance of adequate wound preparation can not be over emphasized. The likelihood that the semi-synthetic human skin will actually be integrated into the wound increases as the quantitative bacterial load decreases (see clinical hints below). Semi-synthetic skin is not a substitute for good standard wound protocols. Infection has occurred in patients receiving Apligraf human skin but this has not been directly attributed to the semi-synthetic skin. There has been no evidence of rejection or other type of immune reaction to date.

Practical Clinical Guidelines

The following suggestions are based on our clinical experience:

1) Apligraf human skin is for clean, well-vascularized, well-granulated wounds. Although not specifically FDA approved for other types of wounds, any well-vascularized wound that has failed to epithelialize after appropriate management could be considered for semi-synthetic skin.
2) Wounds must be adequately debrided.
3) Do not use on infected wounds. Treat infection with adequate doses of antibiotics directed at specific pathogens.
4) Minimized bacterial colonization before applying. Small tissue biopsies for quantitative bacterial counts and the use of non-cyto-toxic topical agents for a week before applying semi-synthetic human skin may significantly improve results by lowering bacterial colony counts.
5) Apply to the wound immediately after removing from packaging, with the same orientation (it is packaged "epidermis up"). Position over the wound bed, trim with sterile scissors to match the contour of the wound and remove air pockets by rolling a sterile cotton swab along the surface.
6) Immobilize the semi-synthetic human skin with a non-adherent primary dressing, then a bolster of some sort of absorbent dressing. Overlay of the semi-synthetic skin margins with the intact skin at the wound periphery may also be helpful.
7) After application, wounds should not be traumatized. Resist the temptation to aggressively "clean" the wound bed as the semi-synthetic skin changes its appearance.
8) Edema must be controlled both before and after the application with mild to moderate compression. Some decrease in activity for the week following application is highly advisable.
9) Fenestrating the Apligraf may significantly improve results, as it allows fluid to be absorbed by the secondary dressings.
10) The semi-synthetic human skin should be left alone for at least four days after application, although the absorptive dressings over the graft can be changed.

The Question of Cost Effectiveness

Patient charges for application of this semi-synthetic skin exceed the cost of the semi-synthetic skin alone and if the clinical situation necessitates application in the operating room rather than the clinic, charges for semi-synthetic human skin can equal the cost of traditional split thickness skin grafting. However, the likelihood of a primary "take" with Apligraf skin is less than that of a STSG. Continued wound care beyond what would be required for the immediate post operative management of an autograft will be necessary for several days or weeks after semi-synthetic human skin is used.

For wounds in which the usual conservative modalities have failed to effect epithelialization, semi-synthetic human skin would seem to represent substantial cost savings over autografting, if performed in the clinic setting. In such cases, proper wound preparation is essential in order to increase the likelihood of benefit.

In wounds which are amenable to split thickness skin grafting, the cost-effectiveness of substituting semi-synthetic human skin would seem to be reduced if multiple discs are required for coverage of a large surface area or multiple applications are required over the same area. However, in cases where autografting is not possible or is unlikely to be successful (extensive burns, primary skin disorders, etc.), even the cost of multiple discs or multiple applications may be easily justifiable.

We suggest the following questions are considered before semi-synthetic human skin is applied:

1) Is the wound well granulated (i.e., would it be considered favorably for traditional autografting)?
2) Has the wound failed to respond to a reasonable trial of appropriate conservative management (e.g., adequate compression or adequate off-loading, preferably over at least four- weeks duration)?
3) Is there a clinical reason why an autograft is NOT a good option at this time (concurrent medical problems, skin disorder, etc.)?
4) Can the number of semi-synthetic human skin discs needed for wound coverage be justified in comparison to an autograft?

Until further data are available, if the above questions can be answered in the affirmative, then the cost of Apligraf human skin is probably justifiable.

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