The dermal equivalent, also known as dermal replacement or neodermis, is an in vitro model of the dermal layer of skin. There is no specific way of forming a dermal equivalent, however the first dermal equivalent was constructed by seeding dermal fibroblasts into a collagen gel. This gel may then be allowed to contract as a model of wound contraction. This collagen gel contraction assay may be used to screen for treatments which promote or inhibit contraction and thus affect the development of a scar. Other cell types may be incorporated into the dermal equivalent to increase the complexity of the model. For example, keratinocytes may be seeded on the surface to create a skin equivalent, or macrophages may be incorporated to model the inflammatory phase of wound healing. [1]
A number of commercial dermal equivalents with different compositions and development methods are available. These include Integra, AlloDerm, and Dermagraft, among others.
Autotransplantation has been common practice for treating individuals who have a need for skin transplants. However, there is the issue of needing repeated grafts or transplants for patients with serious injuries such as burn victims, leading to numerous problems including lack of supply of the skin, preservation, and the possibility if disease transmission. [2] Thus, this prompted for the development of various techniques to create artificial skin, including dermal equivalents.
Now, the use of dermal equivalents has expanded from burn wounds to other areas such as various reconstructive surgeries and treatment of chronic wounds.
There are potential risks when it comes to the application of any dermal equivalent, as there is with any skin grafting or skin substitution technique. These concerns include but are not limited to a negative immune response, possible infection, slow healing, pain, and scarring. [3]
The development of artificial skin and dermis began in the 20th century. [4] It was prompted by the discovery of the ability to isolate and culture cells in vitro , which was in 1907 by American embryologist Ross Granville Harrison when he was able to isolate and grow embryonic tissues from frogs in his laboratory. [4] In 1975, keratinocytes, which are cells that account for the majority epidermal skin cells, [5] were first isolated and successfully cultured in vitro by James G. Rheinwald and Howard Green. [6] Afterwards, in 1981, bilayer artificial skin or dermal graft was developed by John F. Burke, Ioannis Yannas, and other researchers, which was successful in covering “physiologically close to 60% of the body surface.” [7]
Burke’s dermal graft was one of the earliest developments of the dermal equivalent, or “neodermis”. [7] Years later, Integra artificial skin, which is now called Integra Dermal Regeneration Template (IDRT) by Integra LifeSciences, was developed from Burke et al.'s innovation. [8] It became the first commercial product approved by the FDA for dermal replacements and listed as one of the "Significant Medical Device Breakthroughs" in 1996. [9]
There are a variety of dermal equivalents from how they are developed and what they are used for. The following three are some of the most commonly reviewed and assessed dermal equivalents. [10] [11]
The initial research of dermal equivalent leading to the Integra product resulted in a bilayer structure consisting of a dermal portion and epidermal portion. The dermal portion is composed of bovine hide collagen and chondroitin 6-sulfate that is crosslinked with glutaraldehyde. [7] The epidermal portion is composed of Silastic covering the dermis. [7] For application, the bilayer structure is placed on the wound after removal of the eschar and left for several days. [7] Then, the epidermal layer is removed and replaced with artificial epidermis. [7] The dermal equivalent, or neodermis layer, is not removed as it is suitable for growth of cells and vessels. [7] The two layer process, however, may potentially lead to an infection due to any unwanted accumulation between the layers. [3] The main and primary use of Integra was for burn victims who required skin grafts. [2] [7]
Formerly known as Integra artificial skin, Integra Dermal Regeneration Template, or IDRT, was the first FDA approved product for dermal replacements. The Integra Dermal Regeneration Template’s bilayer structure is composed of bovine tendon collagen and chondroitin-6-sulfate for the dermal layer, and polysiloxane for the epidermal layer. [12] The polysiloxane epidermal layer is semipermeable, allowing for the controlled water vapor loss, flexible anti-bacterial support of the wound, and mechanical strength for the dermal equivalent. [11] The dermal layer scaffold promotes vascularization and generation of a neodermis. [11] Similar to its predecessor, the method of application is the same. IDRT has low risks of immunogenic response, as well as low disease transmission. [11]
AlloDerm is the first type of acellular dermal matrix (ADM) derived from the skin of cadavers from the collagen fiber network after the removal of the epidermal layer of the cadaveric skin. [13] [14] It is widely used in dental surgeries for gingival grafting, [15] abdominal hernia repair, [13] oculoplastic and orbital surgeries, [14] and breast surgeries. [16] Due to its acellular structure, there is no immunogenic response caused from the application of AlloDerm. [11]
Dermagraft is a human fibroblast–derived dermal replacement. [17] It is derived from neonatal dermal fibroblasts implanted into a bioabsorbable polyglactin mesh scaffold along with extracellular matrix proteins that are secreted by the fibroblasts. [17] It can promote re-epithelization, however, there is a potential for antigenic response. [11] Dermagraft is mainly used for the treatment of chronic wounds such as various ulcers including diabetic foot ulcers and venous foot ulcers. [17] It received premarket approval from the FDA in 2001 for the treatment of diabetic foot ulcers. [18] [19]
The integumentary system is the set of organs forming the outermost layer of an animal's body. It comprises the skin and its appendages, which act as a physical barrier between the external environment and the internal environment that it serves to protect and maintain the body of the animal. Mainly it is the body's outer skin.
A scar is an area of fibrous tissue that replaces normal skin after an injury. Scars result from the biological process of wound repair in the skin, as well as in other organs, and tissues of the body. Thus, scarring is a natural part of the healing process. With the exception of very minor lesions, every wound results in some degree of scarring. An exception to this are animals with complete regeneration, which regrow tissue without scar formation.
The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water released from the body into the atmosphere through transepidermal water loss.
Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue.
Skin grafting, a type of graft surgery, involves the transplantation of skin. The transplanted tissue is called a skin graft.
The dermis or corium is a layer of skin between the epidermis and subcutaneous tissues, that primarily consists of dense irregular connective tissue and cushions the body from stress and strain. It is divided into two layers, the superficial area adjacent to the epidermis called the papillary region and a deep thicker area known as the reticular dermis. The dermis is tightly connected to the epidermis through a basement membrane. Structural components of the dermis are collagen, elastic fibers, and extrafibrillar matrix. It also contains mechanoreceptors that provide the sense of touch and thermoreceptors that provide the sense of heat. In addition, hair follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic vessels, nerves and blood vessels are present in the dermis. Those blood vessels provide nourishment and waste removal for both dermal and epidermal cells.
A skin condition, also known as cutaneous condition, is any medical condition that affects the integumentary system—the organ system that encloses the body and includes skin, nails, and related muscle and glands. The major function of this system is as a barrier against the external environment.
Hyaluronic acid, also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglycans as it is non-sulfated, forms in the plasma membrane instead of the Golgi apparatus, and can be very large: human synovial HA averages about 7 million Da per molecule, or about 20,000 disaccharide monomers, while other sources mention 3–4 million Da.
A chronic wound is a wound that does not heal in an orderly set of stages and in a predictable amount of time the way most wounds do; wounds that do not heal within three months are often considered chronic. Chronic wounds seem to be detained in one or more of the phases of wound healing. For example, chronic wounds often remain in the inflammatory stage for too long. To overcome that stage and jump-start the healing process, a number of factors need to be addressed such as bacterial burden, necrotic tissue, and moisture balance of the whole wound. In acute wounds, there is a precise balance between production and degradation of molecules such as collagen; in chronic wounds this balance is lost and degradation plays too large a role.
The human skin is the outer covering of the body and is the largest organ of the integumentary system. The skin has up to seven layers of ectodermal tissue guarding muscles, bones, ligaments and internal organs. Human skin is similar to most of the other mammals' skin, and it is very similar to pig skin. Though nearly all human skin is covered with hair follicles, it can appear hairless. There are two general types of skin, hairy and glabrous skin (hairless). The adjective cutaneous literally means "of the skin".
Dermatopontin also known as tyrosine-rich acidic matrix protein (TRAMP) is a protein that in humans is encoded by the DPT gene. Dermatopontin is a 22-kDa protein of the noncollagenous extracellular matrix (ECM) estimated to comprise 12 mg/kg of wet dermis weight. To date, homologues have been identified in five different mammals and 12 different invertebrates with multiple functions. In vertebrates, the primary function of dermatopontin is a structural component of the ECM, cell adhesion, modulation of TGF-β activity and cellular quiescence). It also has pathological involvement in heart attacks and decreased expression in leiomyoma and fibrosis. In invertebrate, dermatopontin homologue plays a role in hemagglutination, cell-cell aggregation, and expression during parasite infection.
Artificial skin is a collagen scaffold that induces regeneration of skin in mammals such as humans. The term was used in the late 1970s and early 1980s to describe a new treatment for massive burns. It was later discovered that treatment of deep skin wounds in adult animals and humans with this scaffold induces regeneration of the dermis. It has been developed commercially under the name Integra and is used in massively burned patients, during plastic surgery of the skin, and in treatment of chronic skin wounds.
Photoaging or photoageing is a term used for the characteristic changes to skin induced by chronic UVA and UVB exposure. Tretinoin is the best studied retinoid in the treatment of photoaging.
Acellular dermis is a type of biomaterial derived from processing human or animal tissues to remove cells and retain portions of the extracellular matrix (ECM). These materials are typically cell-free, distinguishing them from classical allografts and xenografts, can be integrated or incorporated into the body, and have been FDA approved for human use for more than 10 years in a wide range of clinical indications.
Dermal fibroblasts are cells within the dermis layer of skin which are responsible for generating connective tissue and allowing the skin to recover from injury. Using organelles, dermal fibroblasts generate and maintain the connective tissue which unites separate cell layers. Furthermore, these dermal fibroblasts produce the protein molecules including laminin and fibronectin which comprise the extracellular matrix. By creating the extracellular matrix between the dermis and epidermis, fibroblasts allow the epithelial cells of the epidermis to affix the matrix, thereby allowing the epidermal cells to effectively join together to form the top layer of the skin.
Tissue engineering of oral mucosa combines cells, materials and engineering to produce a three-dimensional reconstruction of oral mucosa. It is meant to simulate the real anatomical structure and function of oral mucosa. Tissue engineered oral mucosa shows promise for clinical use, such as the replacement of soft tissue defects in the oral cavity. These defects can be divided into two major categories: the gingival recessions which are tooth-related defects, and the non tooth-related defects. Non tooth-related defects can be the result of trauma, chronic infection or defects caused by tumor resection or ablation. Common approaches for replacing damaged oral mucosa are the use of autologous grafts and cultured epithelial sheets.
The dermoepidermal junction or dermal-epidermal junction (DEJ) is the interface between the epidermal and the dermal layers of the skin. The basal cells of the epidermis connect to the basement membrane by the anchoring filaments of hemidesmosomes; the cells of the papillary layer of the dermis are attached to the basement membrane by anchoring fibrils, which consist of type VII collagen.
Diabetic foot ulcer is a major complication of diabetes mellitus, and probably the major component of the diabetic foot.
Scar free healing is the process by which significant injuries can heal without permanent damage to the tissue the injury has affected. In most healing, scars form due to the fibrosis and wound contraction, however in scar free healing, tissue is completely regenerated. During the 1990s, published research on the subject increased; it is a relatively recent term in the literature. Scar free healing occurs in foetal life but the ability progressively diminishes into adulthood. In other animals such as amphibians, however, tissue regeneration occurs, for example as skin regeneration in the adult axolotl.
Integra LifeSciences is a global medical device manufacturing company headquartered in Princeton, New Jersey. Founded in 1989, the company manufactures products for skin regeneration, neurosurgery, reconstructive and general surgery. Integra artificial skin became the first commercially reproducible skin tissue used to treat severe burns and other skin wounds.