*3.1. Acellular Dermal Substitutes*

The most used commercially available acellular dermal substitutes (Table 1) are composed of natural extracellular matrix components and can be divided in two categories: decellularized extracellular matrices and reconstructed extracellular matrices. The first category is formed by natural connective tissues (dermis, mesothelium, intestine) deprived of any cellular components and allergenic/immunogenic agents.

The most used commercially available decellularized matrices (Table 1) for the treatment of deep wounds after burns and trauma, or for reconstruction and treatment of diabetic/venous/pressure ulcers are (but not limited to): Alloderm®, Dermacell®, Dermamatrix®, SureDerm®, OASIS®, Permacoll® and EZ-DERM®. Alloderm®, Dermacell®, Dermamatrix® and SureDerm®, are decellularized cadaveric dermis, non-cross-linked, that can be incorporated into the wound bed [4,6–9,40,42,103,104]. In general, such systems retain the basement membrane after the decellularization process but lack an epidermal layer. The acellular matrix provides a good natural 3D environment for fibroblasts and endothelial cells influx in order to promote the formation of a new extracellular matrix and vascular network. OASIS®, Permacoll® and EZ-DERM® are decellularized matrices of porcine origins. OASIS® is obtained using similar processing methods to those of human derived matrices but start from porcine small intestine submucosa. Permacoll® and EZ-DERM® are decellularized porcine dermis that are further cross-linked. Alloderm® was approved and considered as banked human tissue by the FDA; it has been used to treat burns since 1992 and has also been used to treat severe soft tissue defects [105]. This product has been shown to have good graft take rates and to reduce subsequent scarring of full-thickness wounds, even though the graft take of split-skin grafts in a one-step procedure is low. Alloderm® is considered medically necessary in post-mastectomy breast reconstructive surgery

for at least one of the following indications: there is insufficient tissue expander or implant coverage by the pectoralis major muscle and additional coverage is required; there are thin post-mastectomy skin flaps that are at risk of dehiscence or necrosis; or the infra-mammary fold and lateral mammary folds have been undermined during mastectomy and re-establishment of these landmarks is needed [39]. By retrieving information form the websites of Dermacell® and Dermamatrix®, it is possible to note that they are intended for soft tissue reconstruction (face defects, nasal reconstruction, abdomen, etc.) and for breast reconstruction. Moreover, different clinical trials involving Dermacell® and Dermamatrix® can be retrieved by consulting the database of clinicaltrials.gov. SureDerm® is indicated by the manufacturer as suitable for gingival and root reconstruction. EZ-DERM® is a porcine-derived xenograft in which the collagen has been chemically cross-linked with aldehyde in order to provide strength and durability [106]; it has FDA 510(k) approval for the treatment of partial-thickness burns and venous, diabetic, and pressure ulcers. In a randomized study involving 157 patients affected by partial-thickness burns, it was found to have satisfactory results: non-correct positioning = 1.5%, infection = 3.0%, incomplete epithelialization at time of separation = 2.2%, need for additional excision and grafting = 4.5%, and hypertrophic scaring = 3.3% [106]. OASIS® Wound Matrix and OASIS® Ultra Tri-Layer Matrix are considered medically necessary for treatment of chronic, noninfected, partialor full-thickness lower-extremity vascular ulcers, which have not adequately responded following a one-month period of conventional ulcer therapy. They are regulated by the FDA as a Class II (moderate risk) device and received FDA 510(k) approval (K061711), on 19 July, 2006 [39]. OASIS® Wound Matrix was subjected to a randomized controlled study in 120 patients with chronic venous leg ulcers. Significantly more wounds (55% vs. 34%) were observed to be healed in comparison with conventional therapy [67].

Using other routes, the production of acellular dermis is obtained in vitro using the main constituents of the connective tissues (collagen, elastin, glycosaminoglycan, etc.) which are extracted from animals and then reconstructed. Once extracted and purified, the extracellular matrix components can be eventually combined together and processed to form 3D porous structures according to the techniques discussed in Section 2.1 (e.g., cross-linking, lyophilization and electrospinning). In the class of reconstructed extracellular matrices (Table 1), we find: Integra®, Biobrane®, Matriderm® and Hyalomatrix®. Integra® Dermal Regeneration Template consists of a bi-layered extracellular matrix of fibers of cross-linked bovine collagen and chondroitin-6-sulfate (a component of cartilage) with a silicone membrane as transient epithelium. Once the neodermis is formed, the disposable silicone sheet is removed, and an ultrathin autograft is placed over the neodermis [9,20,26]. Integra® Dermal Regeneration Template is considered medically necessary in the post-excisional treatment of severe burns when autografting is not feasible. It has an FDA PMA for treatment of life-threatening, full-thickness or deep partial-thickness thermal injuries where sufficient autograft is not available at the time of excision or not desirable due to the physiologic condition of the individual [39]. This product also has an FDA PMA for repair scar contractures. An issue affecting this kind of skin substitute is the time required for neovascularization. Indeed, when the dermis bed is not well vascularized, or it takes a long time to achieve vascularization, the take of the STSG is compromised. Matriderm® becomes vascularized faster than Integra®, supporting the take of a split-skin graft in a one-step procedure. This is due to the presence of elastin in the Matriderm® model, which is able to attract more vascular cells than the chondroitin-6-sulphate present in Integra®. Biobrane® is an acellular dermal matrix composed of bovine type 1 collagen, silicone and nylon, and mechanically bonded to a flexible knitted nylon fabric. The semipermeable membrane is comparable to human epidermis and controls the loss of water vapor, allows for drainage of exudates, and provides permeability to topical antibiotics. The nylon/silicone membrane provides a flexible adherent covering for the wound surface [2,6,9,10,31,39,41,57,61,67,76,99,107,108]. Biobrane® holds an FDA 510(k) approval for the treatment of clean partial-thickness burn wounds and donor site wounds. It is considered medically necessary [39] for the treatment of burn wounds when all of the following criteria are met: the treatment is specific to non-infected partial-thickness burn wounds and donor site wounds;

excision of the burn wound is complete (e.g., nonviable tissue are removed) and homeostasis achieved; sufficient autograft tissue is not available at the time of excision; and autograft is not desirable due to the individual's physiologic condition (e.g., individual has multisystem injuries such that creating new wounds may cause undue stress). It has been shown to be as effective as frozen human allografts. Furthermore, when used on excised full-thickness burns, it reduces hospitalization time in the case of pediatric patients with second-degree burn injuries. Nylon present in Biobrane® is not incorporated, making such an acellular matrix a wound dressing rather than a skin substitute. Hyalomatrix® [2,6,9,42,107,109–111] is a bilayer, esterified hyaluronic acid (HYAFF®) matrix with an outer silicone membrane. The connective-mimicking layer HYAFF® is a long-acting derivative of hyaluronic acid providing a microenvironment suitable for optimal tissue repair and accelerated wound healing. Specifically intended for the treatment of deep burns and full-thickness wounds, it also provides a wound preparation support for the implantation of autologous skin grafts.
