Microfluidic Skin-on-a-Chip Models: Toward Biomimetic Artificial Skin.

The role of skin in the human body is indispensable, serving as a barrier, moderating homeostatic balance, and representing a pronounced endpoint for cosmetics and pharmaceuticals. Despite the extensive achievements of in vitro skin models, they do not recapitulate the complexity of human skin; thus, there remains a dependence on animal models during preclinical drug trials, resulting in expensive drug development with high failure rates. By imparting a fine control over the microenvironment and inducing relevant mechanical cues, skin-on-a-chip (SoC) models have circumvented the limitations of conventional cell studies. Enhanced barrier properties, vascularization, and improved phenotypic differentiation have been achieved by SoC models; however, the successful inclusion of appendages such as hair follicles and sweat glands and pigmentation relevance have yet to be realized. The present Review collates the progress of SoC platforms with a focus on their fabrication and the incorporation of mechanical cues, sensors, and blood vessels.

A Comparative Study of Engineered Dermal Templates for Skin Wound Repair in a Mouse Model.

Engineered dermal templates have revolutionised the repair and reconstruction of skin defects. Their interaction with the wound microenvironment and linked molecular mediators of wound repair is still not clear. This study investigated the wound bed and acellular "off the shelf" dermal template interaction in a mouse model. Full-thickness wounds in nude mice were grafted with allogenic skin, and either collagen-based or fully synthetic dermal templates. Changes in the wound bed showed significantly higher vascularisation and fibroblast infiltration in synthetic grafts when compared to collagen-based grafts (P ≤ 0.05). Greater tissue growth was associated with higher prostaglandin-endoperoxide synthase 2 (Ptgs2) RNA and cyclooxygenase-2 (COX-2) protein levels in fully synthetic grafts. Collagen-based grafts had higher levels of collagen III and matrix metallopeptidase 2. To compare the capacity to form a double layer skin substitute, both templates were seeded with human fibroblasts and keratinocytes (so-called human skin equivalent or HSE). Mice were grafted with HSEs to test permanent wound closure with no further treatment required. We found the synthetic dermal template to have a significantly greater capacity to support human epidermal cells. In conclusion, the synthetic template showed advantages over the collagen-based template in a short-term mouse model of wound repair.

Current Status and Future of Skin Substitutes for Chronic Wound Healing.

Chronic wounds, including diabetic ulcers, pressure ulcers, venous ulcers, and arterial insufficiency ulcers, are both difficult and expensive to treat. Conventional wound care may sometimes lead to suboptimal wound healing and significant morbidity and mortality for patients. The use of skin substitutes provides an alternative therapy showing superior efficacy and, in some cases, similar cost-effectiveness compared to traditional treatments. This review discusses the different types of currently available commercial skin substitutes for use in chronic wounds as well as the paucity of strong evidence supporting their use. It then delves into the limitations of these skin substitutes and examines the most recent research targeting these limitations.

The use of dermal substitutes in burn surgery: acute phase.

Major burns represent a challenge in autologous skin coverage and may lead to severe functional and cosmetic sequelae. Dermal substitutes are increasingly becoming an essential part of burn care during the acute phase of treatment. In the long term dermal substitutes improve functional and cosmetic results and thus enhance quality of life. In the chronic wound setting, dermal substitutes are used to reconstruct and improve burn scars and defects. Despite the potential of dermal substitutes, further research is required to strengthen scientific evidence regarding their effects and also to develop new technologies and products. Furthermore, dermal substitutes have a pivotal role in future research strategies as they have the potential to provide adequate scaffold for stem cells, tissue engineering, and regenerative medicine with conceivable application of obtaining long-lasting and scarless artificial skin. This review discusses the status quo of dermal substitutes and novel strategies in the use of dermal substitutes with a focus on burn care.

The role of skin substitutes in the management of chronic cutaneous wounds.

Chronic wounds, including diabetic and venous ulcers, represent disruption of normal healing processes resulting in a pathological state of nonhealing cutaneous inflammation. They place an increasingly significant economic burden on healthcare providers as their prevalence is rising in keeping with an aging population. Current treatment modalities are slow acting and resource intensive. Bioengineered skin substitutes from autogenic, allogenic, or xenogenic sources have emerged as a new and alternative therapeutic option. A range of such products is licensed for clinical use, which differ in terms of structure and cellular content. Placed directly onto a prepared wound bed, skin substitutes may stimulate or accelerate healing by promoting revascularization, cellular migration, and repopulation of wound fields through provision of an appropriate scaffold material to facilitate these processes. Products containing fetal or autologous cells also benefit from early release of bioactive molecules including growth factors and cytokines. To date, limited numbers of randomized controlled trials studying skin substitutes have been published but evidence from case series and case-control studies is encouraging. This review discusses chronic wound biology, the influence that skin substitutes can exert on this environment, the products currently available, and examines the evidence for their use in chronic wound management.

Bioengineered skin substitutes: key elements and novel design for biomedical applications.

Significant progress has been made in the development of in vitro-engineered skin substitutes that mimic human skin, either to be used for the replacement of lost skin or for the establishment of in vitro skin research models. However, at the present time, there are no models of bioengineered skin that completely replicate the nature of uninjured skin. Obviously, there is still much room for improvement of the components of bioengineered skin and their interplay. This review summarises the important new discoveries in key elements of engineering of tissue-engineered skin including cell sources, biomaterials and growth factors, etc. Furthermore, basic and clinical applications for engineered skin substitutes in cell therapy, tissue engineering, and biomedical research continue to drive design improvements premised on these structure and function-based engineering paradigms.

[Skin substitutes--the present and the future]. / Materialy zastepcze skóry--terazniejszosc i przyszlosc.

Full-thickness skin deficits are indications to autologic skin graft. In extensive skin injuries an employment of skin substitutes is sometimes necessary. In this study we presented the classification of skin substitutes (permanent, temporary, biological, synthetic). The different kinds of skin substitutes approved to commercial production were described (epidermal substitutes, dermal substitutes, composite dermo-epidermal substitutes). The possibilities of clinical applications of skin equivalents and results obtained by many authors after employment of artificial skin were also presented. Still existing limitations in possibilities of recovery of all skin functions were emphasized and the directions of future development of the studies were presented.

New dermal substitutes.

The quality of skin wound healing can be improved by the application of scaffolds as skin replacement materials. Although the clinical requirements for the function of such materials are defined, the translation of these requirements into physical and mechanobiological properties of scaffolds is difficult. Natural as well as constructed biological materials and synthetic substitutes are discussed. Furthermore, new techniques such as electrospinning and solid freeform fabrication as well as new types of materials such as self-assembling peptides are reviewed with regard to their potential role in the production of skin substitute materials.

Mortality in paediatric burns at the Women's and Children's Hospital (WCH), Adelaide, South Australia: 1960-2017.

BACKGROUND: Burn injuries are the third leading cause of preventable death in children worldwide, resulting in over 100 000 annual hospitalisations. In the paediatric population, scalds are the commonest mechanism and burn injuries of greater than 40% total burn surface area (TBSA) are associated with a high mortality and morbidity rate. AIMS: The aim of this study was to review mortality in paediatric burns in a tertiary burns centre over a 60-year period, providing an understanding of local causes of mortality and directing future clinical research. METHODS: We reviewed data collected prospectively from patients treated for burn injuries at the WCH from 1960 to 2017. Data of age, gender, mechanism of injury and TBSA were collected. TBSA of 40% and greater were included in the study. RESULTS: All patients with total burn surface area (TBSA) less than 40% survived. There were a total of 75 patients who sustained burns of or greater than 40% TBSA. Overall mortality was 34% (26 of 75) of which 24 occurred in the 1960s. Of the 21 patients who died of flame burn injuries, 12 of them were described as clothes catching alight from being in close proximity to the source of flame. Average length of stay for patients who did not survive was 7 days (1-26). CONCLUSION: Mortality has since declined and the prognosis for survival good, even in TBSA of greater than 90%. The investigations in fabric flammability led by Dr Thomas Pressley and Mr Murray Clarke prompted the rewriting of Australian standards for production of children's clothing. This, in combination with advances in paediatric resuscitation, surgical techniques as well as wound care has improved survival rates and outcomes in extensive burn injuries. Future studies focus to see not only better survival rates, but also better aesthetic and functional outcomes in burn survivors.

Artificial skin through super-sensing method and electrical impedance data from conductive fabric with aid of deep learning.

Sense of touch is a major part of man's communication with their environment. Artificial skins can help robots to have the same sense of touch, especially for their social interactions. This paper presents a pressure mapping sensing using piezo-resistive fabric to represent aspects of the sense of touch. In past few years' electrical impedance tomography (EIT) is considered to be able offer a good alternative for artificial skin in particular for its ease of adaptation for large area skin compared to individual matrix based sensors. The EIT has also very good temporal performance in data collection allowing for monitoring of fast responses to touch stimulation, enabling a truly real time touch sensing. Electromechanical responses of a conductive fabric can be exploited using EIT to create a low cost and large area touch sensing. Such electromechanical properties are often very complex, so to improve the imaging resolution and touch visibility an artificial intelligent (AI) was used in addition to the state of the art spatio-temporal imaging algorithm. This work demonstrates a step towards an integrated seamless skin with large area sensing in dynamical settings, closer to natural human skin's behaviour. For the first time a dynamical touch sensing are studies by means of a spatio-temporal based electrical impedance tomography (EIT) imaging on a conductive fabric. The experimental results demonstrated the successful results by a combined AI with dynamical EIT imaging results in single and multiple points of touch.

Tissue Engineered Skin and Wound Healing: Current Strategies and Future Directions.

The global volume of skin damage or injuries has major healthcare implications and, accounts for about half of the world's annual expenditure in the healthcare sector. In the last two decades, tissue-engineered skin constructs have shown great promise in the treatment of various skin-related disorders such as deep burns and wounds. The treatment methods for skin replacement and repair have evolved from utilization of autologous epidermal sheets to more complex bilayered cutaneous tissue engineered skin substitutes. However, inadequate vascularization, lack of flexibility in drug/growth factors loading and inability to reconstitute skin appendages such as hair follicles limits their utilization for restoration of normal skin anatomy on a routine basis. Recent advancements in cutting-edge technology from stem cell biology, nanotechnology, and various vascularization strategies have provided a tremendous springboard for researchers in developing and manipulating tissue engineered skin substitutes for improved skin regeneration and wound healing. This review summarizes the overview of skin tissue engineering and wound healing. Herein, developments and challenges of various available biomaterials, cell sources and in vitro skin models (full thickness and wound healing models) in tissue-engineered skin research are discussed. Furthermore, central to the discussion is the inclusion of various innovative strategies starting from stem cells, nanotechnology, vascularization strategies, microfluidics to three dimensional (3D) bioprinting based strategies for generation of complex skin mimics. The review then moves on to highlight the future prospects of advanced construction strategies of these bioengineered skin constructs and their contribution to wound healing and skin regeneration on current practice.

Update on tissue-engineered biological dressings.

Tissue-engineered biological dressings offer promise in the treatment of burns, chronic ulcers, donor site and other surgical wounds, and a variety of blistering and desquamating dermatologic conditions. For example, the prevalence of diabetic foot ulcers ranges from 4.4% to 10.5% of diabetics, resulting in 82,000 lower extremity amputations annually; venous leg ulcers affect 0.18% to 1.35% of the population; and pressure ulcers are found in 5.0% to 8.8% of institutionalized patients and 14.8% of patients in acute care facilities. Despite the large number of potential beneficiaries, cellular tissue-engineered products have suffered setbacks in recent years and have garnered considerably lower market share than commercial promoters anticipated. The mechanism of action of these products is not universally agreed upon, but delivery of growth factors and extracellular matrix components to the wound is thought to be important; graft "take" is not usually considered to occur. These "engineered" products do not specifically match a treatment modality to an underlying pathology. Clinical effect is often modest, and sometimes not justi- fiable from a cost-benefit perspective. Nevertheless, clinical reports in the literature of uses of tissueengineered biological dressings continue to mount, indicating that these products are finding niche applications where clinical utility is high and the cost can be defended. Despite commercial setbacks, the first-approved products, Dermagraft, Apligraf, and Cultured Epidermal Autograft (Epicel) are still being marketed, and new ones, such as OrCel, continue to be developed. The major indications for these products are summarized and a brief review of the available clinical literature is offered.

Emerging drugs for diabetic foot ulcers.

Diabetic foot ulceration results from factors extrinsic to the foot such as repeated trauma, ischaemia and infection, as well as intrinsic factors that lead to impairment of wound healing. Intrinsic factors are less well understood, but include deficiency of growth factors, changes in extracellular matrix components with excess proteases, reduced fibroblast activity, cellular abnormalities, deficiencies of angiogenesis, nitric oxide abnormalities and hyperglycaemia. The scientific rationale of therapy is to correct both the external factors that cause diabetic foot ulcers and the internal factors that lead to impairment of wound healing. Current research is leading to new therapies that can be divided into the following classes: growth factors, skin substitutes, extracellular matrix proteins, stem cell therapy, gene therapy, protease inhibitors, angiogenesis stimulants, nitric oxide-releasing agents, adenosine agonists, immunostimulants, vasoactive compounds and granulating agents. These therapies should be considered when existing treatments to correct extrinsic factors have failed to heal ulceration in the diabetic foot.

Biological skin substitutes for wound cover and closure.

In the past 30 years, the development and use of artificial skin in the treatment of acute and chronic wounds has advanced from an experimental concept to a working reality. However, while there have been an increasing number of artificial skin substitutes licensed for clinical use, they have yet to supplant the current gold standard of an autologous tissue graft for most applications. This article reviews the advantages and disadvantages of the currently available, biologically based substitutes, with special emphasis on their relative efficacy and suitability for treatment of particular wound types. Economic considerations, desirable improvements of currently available materials and the potential impact of future advances in the field will also be discussed.

A prospective, multicenter, randomized, controlled clinical trial comparing a bioengineered skin substitute to a human skin allograft.

An estimated 25% of all people with diabetes may experience a foot ulcer in their lifetime, which may lead to serious complications including infection and amputation. A prospective, multicenter, randomized, controlled clinical trial was conducted to compare an in vitro-engineered, human fibroblast-derived dermal skin (HFDS) substitute and a biologically active cryopreserved human skin allograft (HSA) to determine the relative number of diabetic foot ulcers (DFUs) healed (100% epithelialization without any drainage) and the number of grafts required by week 12. Secondary variables included the proportion of healed patients at weeks 16 and 20, time to healing during the study, and wound size progression. The 23 eligible participants (11 randomized to the HSA, 12 to the HFDS group) were recruited from two hospital-based outpatient wound care centers. Baseline patient (body mass index, age, gender, race, type and duration of diabetes, presence of neuropathy and/or peripheral arterial disease, tobacco use) and wound characteristics (size and duration) were recorded, and follow-up visits occurred every week for up to 20 weeks. Descriptive and multivariate regression analyses were used to compare wound outcomes. At baseline, no statistically significant differences between patients and wounds were observed. At week 12, seven (63.6%) patients in the HSA and four (33.3%) in the HFDS group were healed (P = 0.0498). At the end of the 20-week evaluation period, 90.91% of HSA versus 66.67% of HFDS were healed (P = 0.4282). Among the subset of wounds that healed during the first 12 weeks of treatment, an average of 4.36 (range 2-7) HSA grafts were applied versus 8.92 (range 6-12) in the HFDS subset (P <0.0001, SE 0.77584). Time to healing in the HSA group was significantly shorter (8.9 weeks) than in the HFDS group (12.5 weeks) (log-rank test, P = 0.0323). The results of this study are similar to previous outcomes reported using these treatment modalities and suggest that, after 12 weeks of care, DFUs managed with HSA are approximately twice as likely to heal as DFUs managed with HFDS with approximately half the number of grafts required. Research confirming these results with a larger sample size and inpatients with different types of wounds is warranted.

Wound coverage technologies in burn care: novel techniques.

Improvements in burn wound care have vastly decreased morbidity and mortality in severely burned patients. Development of new therapeutic approaches to increase wound repair has the potential to reduce infection, graft rejection, and hypertrophic scarring. The incorporation of tissue-engineering techniques, along with the use of exogenous proteins, genes, or stem cells to enhance wound healing, heralds new treatment regimens based on the modification of already existing biological activity. Refinements to surgical techniques have enabled the creation of protocols for full facial transplantation. With new technologies and advances such as these, care of the severely burned will undergo massive changes over the next decade. This review centers on new developments that have recently shown great promise in the investigational arena.

Advances in the topical treatment of diabetic foot ulcers.

The diabetic foot remains a major cause of morbidity worldwide. Even though considerable progress has been achieved over the past years, there is still an urgent need for improvement. While established therapeutic modalities (revascularization, casting and debridement) remain the mainstay of management, there is, therefore, continuous development of new treatment options. This review provides an outlook of advances in topical treatment, including bioengineered skin substitutes (such as Dermagraft, Apligraf, HYAFF, OASIS and Graftjacket), extracellular matrix proteins (such as Hyalofill and E-matrix), as well as miscellaneous further therapeutic adjuncts. Although promising, new therapies should not, for the time being, constitute the basis of management, since clinical experience has not yet confirmed their effectiveness in hard-to-heal diabetic foot ulcers. Furthermore, their cost-effectiveness merits further investigation. Instead, they should only be considered in combination with established treatments or be attempted when these have not been successful. Moreover, we should not be oblivious to the fact that established and emerging treatments need to be practised in the setting of multidisciplinary foot clinics to reduce the number of amputations.