Review of the Latest Methods of Epidermolysis Bullosa and Other Chronic Wounds Treatment Including BIOOPA Dressing

Dressings

Recently developed innovative dressing materials include bioelectric dressings, double-layered silk gelatine and dressings with new ointments such as Triterpine. An “ideal” burn wound dressing was described as having non-adhesive, absorbent properties and antimicrobial activity. Goertz et al. [13] described a solidifying gel that dissolves in a specific temperature range, providing an interface that is better accepted by patients with superficial wounds. Their new gel is liquid at room temperature and hardens to a gel consistency at normal body temperature or above, which causes less pain and leads to better results regarding staining, leakage, and odour compared to silver sulfadiazine gauze. Another promising dressing recently described in non-human studies involves a gelling dendrite dressing based on hydrogel, with three-stage bonds that can dissolve on demand. The possibility of applying the gel, which solidifies in a few minutes, greatly simplifies the process of applying the dressing. In vivo studies have shown that these gels ensure effective haemostasis and prevent infection while providing a moist wound-healing environment. An important feature of this dressing is the ability of clinicians to dissolve the dressing on demand for atraumatic removal [7]. Antibacterial gel dressings based on chitosan (Opticell Ag+) have recently been introduced, which provide a moist, adaptable, highly absorbable antimicrobial dressing to reduce dressing changes and alleviate pain. Catrix powder (bovine cartilage powder; Cranage Healthcare International) is a medically recommended alternative, and early studies suggest faster healing of blisters after Catrix application [14]. Honey, in the form of impregnated dressings and ointments, is effective in both the treatment of chronic wounds and reducing the biological load [15]. Cutimed Sorbact dressings remove bacteria through hydrophobic interactions. They are coated with a fatty acid derivative that attracts bacteria to the dressing, where they are bound [16]. Preliminary studies have shown that this dressing is effective for wound healing in people with chronic EB-related wounds. Dressings containing polyhexanide, such as Suprasorb X1 PHMB (Activa Healthcare, Lohmann & Rauscher, UK), provide antimicrobial treatment for critically colonised and infected wounds, and they are recommended for long-term application [13]. The polymer membrane dressing (PolyMem, Ferris, OH, USA) contains a cleaning agent (surfactant), which reduces the biological load and allows the healing of resistant wounds. Polymeric membrane dressings have the advantage of being “self-contained” without the need for a non-adherent primary or secondary dressing to protect or manage exudation. The frequency of dressing changes depends on personal choice, available time, and level of exudation [17]. Infected or critically colonised wounds require more frequent dressing changes. The use of honey products and polymeric dressings on the membrane initially increases the amount of exudate, so before starting, the patient must commit to daily dressing changes.

Ibuprofen-soaked (Biatain-Ibu) dressings have proven to be helpful for some wounds; however, they are not licensed for children aged under 12–15 years [18].

Autogenic Skin Transplantation

Skin transplantation is an old technique that was rediscovered during World War I and II, becoming the main way to heal wounds. Padget and Hood invented the dermatome, an indispensable device still used to this day to collect large portions of skin. In 1929, Brown developed a split-thickness skin transplantation technique, distinguishing between full-thickness, medium-thickness, and epidermal transplants [19].

Skin grafts can be categorised by graft thickness, geometry, and source. Depending on the thickness of the graft, a distinction is made between split-thickness skin grafts (SSG) and full-thickness skin grafts (FTSG) [20].

Split-thickness skin grafts consist of epidermis and some layers of dermis. Different types of SSGs can be identified: thin SSG (0.15–0.3 mm), medium SSG (0.3–0.45 mm), and thick SSG (0.45–0.6 mm) [21].

FTSG consist of epidermis, dermis, and various layers of subcutaneous tissue. The amount of dermis plays a key role in determining the mechanical, functional, aesthetic, and transplant trophic properties. In fact, a thicker transplant has better mechanical, functional, and aesthetic properties, but neovascularisation and revascularisation occur with some difficulties and last for at least 5 days [21, 22].

Split-thickness skin grafts are characterised by a poor cosmetic outcome. In addition, SSGs contain fewer tissues requiring revascularisation after implantation; therefore, thin grafts can be used to treat wounds with reduced blood supply [21].

The method employed for supplying and covering skin defects (FTSG or SSG) varies depending on the centre and the experience of the surgeon. However, there is little evidence in the literature of the superiority of one method over the other, and long-term results may vary slightly. There are several factors to consider: availability of donor sites and their potential to heal, delaying the onset of contraction, the likelihood of a successful transplant, and patient selection [21].

It has been suggested that FTSG may delay contract recurrences better than SSG. However, the use of FTSG is often less successful than applying SSG, leading to potential scar formation. In addition, the site of skin collection shows much poorer healing in patients with EB, limiting the skin surface that can act as a source and increasing the likelihood of scar contracture at the site of collection [23].

Problems can be minimised by only collecting the epithelium as a “split” graft. With this technique, healing is faster, and the epithelium can be collected from any place where there are no damaged skin and blisters with purulent substance. Recurrent contracture is more common within the first 6 months, but healing at the donor site is more predictable and usually occurs within 2 weeks. The authors have used this technique several times [22].

Gene Engineering

Until recently, EB treatment only consisted of symptomatic treatment. With advances in the field of genetics, new and exciting therapies are being proposed to address the cause of skin fragility in these patients, including replacement of the abnormal protein (e.g., collagen VII in RDEB) and bone marrow transplantation.

Recent studies have suggested that the delivery of allogeneic fibroblasts to the skin of patients with RDEB may be beneficial for improving skin adhesion and increasing the deposition of type VII collagen at the dermoepidermal junction. There is promising data in patients with RDEB treated with immune myeloablative chemotherapy and allogeneic stem cell transplantation, which resulted in better wound healing, reduced blistering, and increased collagen VII deposition at the dermoepidermal junction. Viral vectors are the most common form of gene therapy for the treatment of genetic disorders. Retroviral, lentiviral, and adenoviral vectors have been developed for RDEB gene therapy. One study used a retroviral vector for the transduction of fibroblasts, which were then evaluated and injected into a mouse model of RDEB. Transduced fibroblasts have been shown to express functional C7, embed it as mature anchor fibrils, and ensure improvement based on both in vitro and in vivo evaluation. The first application of gene therapy in RDEB patients was a retroviral vector used for the transduction of keratinocytes containing full-length human COL7A1. Transduced keratinocytes were then cultured in a good manufacturing practice device to generate corrected epidermal sheets for autologous therapy. These external autologous transplants were tolerated for 12 months with positive results. Adenoviral vectors have been similarly used to correct RDEB cells with both fibroblasts and keratinocytes and then to determine the induced pluripotent stem cell (iPSC) line for future therapeutic applications. These improved iPSCs were then differentiated into keratinocytes that were able to express C7 and transform into layers both in vitro and in vivo. Lentiviral vectors have also been developed for C7 gene therapy. Recently, a lentiviral vector containing the codon-optimised COL7A1 gene was developed and used to correct RDEB fibroblasts. Corrected fibroblasts have been shown to express full-length functional C7 in vitro and embed C7 in DEJ in skin grafts in immunodeficient mice. These approaches may be useful to develop the combinatorial therapies needed to address the systemic problems of this disease [2428].

Although encouraging, more research is needed to determine the long-term safety and effectiveness of this modality. Until then, the goals of treatment are to optimise wound healing and minimise disability caused by blisters [29, 30].

Tissue Engineered Skin Substitutes

Tissue engineering is rapidly progressing from basic research to commercial applications. Many skin substitutes have been produced by in vitro methods. They are available in various forms, mainly classified into epidermal, dermal, and dermoepidermal or composite skin analogues, which may consist of cell-based or cell-free scaffolds [31].

Biocompatibility, biodegradability, non-carcinogenic cross-linking, cost-effectiveness, risk of infectious diseases, and prevention of immune system stimulation are all factors that need to be considered to create safe and high-quality engineering requirements for the skin. The main approach in the engineering of skin substitutes is the culture of primary skin cells, such as stem cells, fibroblasts, keratinocytes, melanocytes, and Langerhans cells, in a natural or biosynthetic scaffold mimicking the three-dimensional (3D) structure of normal cells [32].

Although there is a wide range of tissue engineering products available on the market, almost none of them meet all the requirements for real skin, including deep skin processes, appropriate vascularisation, and normal pigmentation [32].

The first product to apply tissue engineering to EB is the autologous cultured epidermal substitute (CES). Pioneering work by Green [33] demonstrated that it is possible to grow epidermal keratinocytes as layered sheets from a single cell suspension, and multilayer sheets obtained in this way are very effective for healing burns and wounds in patients with EB.

Along with the acceptable demand for skin components, several types of two-layer skin substitutes consisting of both epidermal and dermal components have been developed. Bell et al. [34] developed a cultured skin substitute (CSS), the equivalent of live skin, which consists of a collagen gel with fibroblasts covered with keratinocytes. Boyce [35] developed a CSS consisting of collagen/glycosaminoglycan with fibroblasts deposited by keratinocytes. Kuroyanagi et al. [36] also developed a cultured skin substitute consisting of a spongy collagen matrix with fibroblasts applied over keratinocytes. These two-layer skin substitutes are designed to be a permanent cover for FTSGs [31, 37, 38]. Recent tissue engineered skin substitutes are included in Table 1.

Table 1 Recent tissue engineered skin substitutesFig. 1figure1

Day 0, procedure: wound covered with the prepared graft (allogenic human skin equivalent)

Fig. 2figure2

BIOOPA dressing: an acellular human skin allograft seeded with multipotent stem cells

Fig. 3figure3

Result at 30-day follow-up. All examination techniques revealed host-cell infiltration and neovascularisation of the biological dressing. It was characterised by low immunogenicity, as confirmed by histopathology and in vitro T-cell proliferation assays

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