In Situ Structural Densification of Hydrogel Network and Its Interface with Electrodes for High-Performance Multimodal Artificial Skin.

The multisensory responsiveness of hydrogels positions them as promising candidates for artificial skin, whereas the mismatch of modulus between soft hydrogels and hard electrodes as well as the poor adhesion and conductance at the interface greatly impairs the stability of electronics devices. Herein, we propose an in situ postprocessing approach utilizing electrochemical reactions between metals (Zn, etc.) and hydrogels to synergistically achieve strong adhesion of the hydrogel-electrode interface, low interfacial impedance, and local strain isolation due to the structural densification of the hydrogel network. The mechanism is that Zn electrochemically oxidizes to Zn2+ and injects into the hydrogel, gradually forming a mechanically interlocked structure, Zn2+-polymer dual-helix structural nodes, and a high-modulus ZnO from the surface to the interior. Compared to untreated samples, the treated sample displays 8.7 times increased interfacial adhesion energy between the hydrogel and electrode (87 J/m2), 95% decreased interfacial impedance (218.8 Ω), and a high-strain isolation efficiency (εtotal/εisolation > 400). Akin to human skin, the prepared sensor demonstrates multimodal sensing capabilities, encompassing highly sensitive strain perception and simultaneous perception of temperature, humidity, and oxygen content unaffected by strain interference. This easy on-chip preparation of hydrogel-based multimodal sensor array shows great potential for health and environment monitoring as artificial skin.

Evaluating micronized adipose tissue niche and artificial dermis grafts following nonmelanoma skin cancer excision: a pilot study.

BACKGROUND: Recently, micronized adipose tissue (MAT) grafts have shown promising results in wound healing, including diabetic ulcers. OBJECTIVE: To assess the possibility of using 3D printed MAT niche grafts in the management of skin and soft tissue defects resulting from non-melanoma skin cancer (NMSC) resections. MATERIALS AND METHODS: A retrospective feasibility study was conducted on patients with skin and soft tissue defects resulting from NMSC resections. Twenty-one patients were treated using either artificial dermis (n = 11) or MAT niche (n = 10) grafting. Healing time and POSAS scores were compared. The Mann-Whitney U test and the Pearson chi-square test were used in statistical analysis to compare between and within groups based on preoperative and postoperative measurements. RESULTS: Wounds in the MAT niche group reepithelialized significantly faster than those in the artificial dermis group (mean [SD] 39.2 [11.4] days vs 63.7 [34.8] days; P = .04). In the 21 scar parameters evaluated, the MAT niche group demonstrated significantly superior outcomes in only 2 parameters based on operator assessment scores: relief (mean [SD] 1.6 [0.7] vs 2.2 [0.6]; P = .047) and scar contracture (mean [SD] 1.3 [0.5] vs 2.5 [1.0]; P = .011). CONCLUSION: This study proves the feasibility of exploring the effects of MAT niche grafting following NMSC excision on healing time and specific parameters of scarring, including scar relief and scar contracture.

A three-dimensionally architected electronic skin mimicking human mechanosensation.

Human skin sensing of mechanical stimuli originates from transduction of mechanoreceptors that converts external forces into electrical signals. Although imitating the spatial distribution of those mechanoreceptors can enable developments of electronic skins capable of decoupled sensing of normal/shear forces and strains, it remains elusive. We report a three-dimensionally (3D) architected electronic skin (denoted as 3DAE-Skin) with force and strain sensing components arranged in a 3D layout that mimics that of Merkel cells and Ruffini endings in human skin. This 3DAE-Skin shows excellent decoupled sensing performances of normal force, shear force, and strain and enables development of a tactile system for simultaneous modulus/curvature measurements of an object through touch. Demonstrations include rapid modulus measurements of fruits, bread, and cake with various shapes and degrees of freshness.

Artificial keloid skin models: understanding the pathophysiological mechanisms and application in therapeutic studies.

Keloid is a type of scar formed by the overexpression of extracellular matrix substances from fibroblasts following inflammation after trauma. The existing keloid treatment methods include drug injection, surgical intervention, light exposure, cryotherapy, etc. However, these methods have limitations such as recurrence, low treatment efficacy, and side effects. Consequently, studies are being conducted on the treatment of keloids from the perspective of inflammatory mechanisms. In this study, keloid models are created to understand inflammatory mechanisms and explore treatment methods to address them. While previous studies have used animal models with gene mutations, chemical treatments, and keloid tissue transplantation, there are limitations in fully reproducing the characteristics of keloids unique to humans, and ethical issues related to animal welfare pose additional challenges. Consequently, studies are underway to create in vitro artificial skin models to simulate keloid disease and apply them to the development of treatments for skin diseases. In particular, herein, scaffold technologies that implement three-dimensional (3D) full-thickness keloid models are introduced to enhance mechanical properties as well as biological properties of tissues, such as cell proliferation, differentiation, and cellular interactions. It is anticipated that applying these technologies to the production of artificial skin for keloid simulation could contribute to the development of inflammatory keloid treatment techniques in the future.

Living Artificial Skin: Photosensitizer and Cell Sandwiched Bacterial Cellulose for Chronic Wound Healing.

Chronic wounds pose a significant global public health challenge due to their suboptimal treatment efficacy caused by bacterial infections and microcirculatory disturbances. Inspired by the biofunctionality of natural skin, an artificial skin (HV@BC@TBG) is bioengineered with bacterial cellulose (BC) sandwiched between photosensitizers (PS) and functionalized living cells. Glucose-modified PS (TBG) and vascular endothelial growth factor (VEGF)-functionalized living cells (HV) are successively modified on each side of BC through biological metabolism and bio-orthogonal reaction. As the outermost layer, the TBG layer can generate reactive oxygen species (ROS) upon light illumination to efficiently combat bacterial infections. The HV layer is the inner layer near the diabetic wound, which servs as a living factory to continuously secrete VEGF to accelerate wound repair by promoting fibroblast proliferation and angiogenesis. The sandwiched structural artificial skin HV@BC@TBG is nontoxic, biocompatible, and demonstrated its ability to significantly accelerate the healing process of infected diabetic wounds, rendering it a promising next-generation medical therapy for chronic wound management.

Skin graft with dermis and appendages generated in vivo by cell competition.

Autologous skin grafting is a standard treatment for skin defects such as burns. No artificial skin substitutes are functionally equivalent to autologous skin grafts. The cultured epidermis lacks the dermis and does not engraft deep wounds. Although reconstituted skin, which consists of cultured epidermal cells on a synthetic dermal substitute, can engraft deep wounds, it requires the wound bed to be well-vascularized and lacks skin appendages. In this study, we successfully generate complete skin grafts with pluripotent stem cell-derived epidermis with appendages on p63 knockout embryos' dermis. Donor pluripotent stem cell-derived keratinocytes encroach the embryos' dermis by eliminating p63 knockout keratinocytes based on cell-extracellular matrix adhesion mediated cell competition. Although the chimeric skin contains allogenic dermis, it is engraftable as long as autologous grafts. Furthermore, we could generate semi-humanized skin segments by human keratinocytes injection into the amnionic cavity of p63 knockout mice embryos. Niche encroachment opens the possibility of human skin graft production in livestock animals.

Use of Integra® on avascular tissue.

Integra® (Integra LifeSciences) is a well-known dermal regeneration template used in partial and full-thickness wound reconstruction. It can be applied directly on to vascular tissue to create a bed for a skin graft, which is often placed in a second surgery. We present our experience of its novel use in oral and maxillofacial surgery patients, using it directly on bone and cartilage (avascular tissue) without further skin grafting. Patients who required full-thickness excision of lesions down to bone or cartilage and who were treated using Integra® were included. After scalp or ear lesion resection, the collagenous dermal layer of Integra® was placed directly on to bone or cartilage and, along with its outer silicone epidermal layer, secured to the defect with absorbable sutures and a bolster dressing. The wounds were kept dry for 14 days, at which point the dressing and silicone were removed and patients continued regular wound care. Seventeen patients were included, 15 of whom had squamous cell carcinoma. One was lost to follow up. The rest achieved complete healing of the defect. Histology showed epidermis developing on the Integra® surface and at one year, the appearance of normal scarred skin. This novel approach could redefine the uses of Integra®, avoiding the need for free-flap surgery or skin grafting when reconstructing large defects. Further resection of close margins or recurrence is easier after reconstruction using dermal regeneration material than after reconstruction with a local or free flap.

Three-dimensional bioprinting of tissue-engineered skin: Biomaterials, fabrication techniques, challenging difficulties, and future directions: A review.

As an emerging new manufacturing technology, Three-dimensional (3D) bioprinting provides the potential for the biomimetic construction of multifaceted and intricate architectures of functional integument, particularly functional biomimetic dermal structures inclusive of cutaneous appendages. Although the tissue-engineered skin with complete biological activity and physiological functions is still cannot be manufactured, it is believed that with the advances in matrix materials, molding process, and biotechnology, a new generation of physiologically active skin will be born in the future. In pursuit of furnishing readers and researchers involved in relevant research to have a systematic and comprehensive understanding of 3D printed tissue-engineered skin, this paper furnishes an exegesis on the prevailing research landscape, formidable obstacles, and forthcoming trajectories within the sphere of tissue-engineered skin, including: (1) the prevalent biomaterials (collagen, chitosan, agarose, alginate, etc.) routinely employed in tissue-engineered skin, and a discerning analysis and comparison of their respective merits, demerits, and inherent characteristics; (2) the underlying principles and distinguishing attributes of various current printing methodologies utilized in tissue-engineered skin fabrication; (3) the present research status and progression in the realm of tissue-engineered biomimetic skin; (4) meticulous scrutiny and summation of the extant research underpinning tissue-engineered skin inform the identification of prevailing challenges and issues.

Bioengineering Skin Substitutes for Wound Management-Perspectives and Challenges.

Non-healing wounds and skin losses constitute significant challenges for modern medicine and pharmacology. Conventional methods of wound treatment are effective in basic healthcare; however, they are insufficient in managing chronic wound and large skin defects, so novel, alternative methods of therapy are sought. Among the potentially innovative procedures, the use of skin substitutes may be a promising therapeutic method. Skin substitutes are a heterogeneous group of materials that are used to heal and close wounds and temporarily or permanently fulfill the functions of the skin. Classification can be based on the structure or type (biological and synthetic). Simple constructs (class I) have been widely researched over the years, and can be used in burns and ulcers. More complex substitutes (class II and III) are still studied, but these may be utilized in patients with deep skin defects. In addition, 3D bioprinting is a rapidly developing method used to create advanced skin constructs and their appendages. The aforementioned therapies represent an opportunity for treating patients with diabetic foot ulcers or deep skin burns. Despite these significant developments, further clinical trials are needed to allow the use skin substitutes in the personalized treatment of chronic wounds.

Evaluation of viscoelastic parameters and photo-based assessment of newly developed dermal substitutes modified with thermostabilized fibroblast growth factor 2.

BACKGROUND: The purpose of dermal substitutes is to mimic the basic properties of the extracellular matrix of human skin. The application of dermal substitutes to the defect reduces the formation of hypertrophic scars and improves the scar quality. This study aims to develop an original dermal substitute enriched with stable fibroblast growth factor 2 (FGF2-STAB®) and test it in an animal model. METHODS: Dermal substitutes based on collagen/chitosan scaffolds or collagen/chitosan scaffolds with nanofibrous layer were prepared and enriched with FGF2-STAB® at concentrations of 0, 0.1, 1.0, and 10.0 µg ‧ cm-2. The performance of these dermal substitutes was tested in vivo on artificially formed skin defects in female swine. The outcomes were evaluated using cutometry at 3 and 6 months. In addition, visual appearance was assessed based on photos of the scars at 1-month, 3-month and 6-month follow-ups using Yeong scale and Visual Analog Scale. RESULTS: The dermal substitute was fully integrated into all defects and all wounds healed successfully. FGF2-STAB®-enriched matrices yielded better results in cutometry compared to scaffolds without FGF2. Visual evaluation at 1, 3, and 6 months follow-ups detected no significant differences among groups. The FGF2-STAB® effectiveness in improving the elasticity of scar tissues was confirmed in the swine model. This effect was independently observed in the scaffolds with nanofibres as well as in the scaffolds without nanofibres. CONCLUSION: The formation of scars with the best elasticity was exhibited by addition 1.0 µg ‧ cm-2of FGF2-STAB® into the scaffolds, although it had no significant effect on visual appearance at longer follow-ups. This study creates the basis for further translational studies of the developed product and its progression into the clinical phase of the research.

Development of a novel human stratum corneum mimetic phospholipid -vesicle-based permeation assay models for in vitro permeation studies.

OBJECTIVES: To develop and evaluate a novel human stratum corneum (SC) mimetic phospholipid vesicle-based permeation assay (PVPASC) model for in vitro permeation studies. SIGNIFICANCE: Due to the increasing restrictions on the use of human and animal skins, artificial skin models have attracted substantial interest in pharmaceuticals and cosmetic industries. In this study, a modified PVPASC model containing both SC lipids and proteins was developed. METHODS: The PVPASC model was optimized by altering the lipid composition and adding keratin in the formulation of large liposomes. The barrier properties were monitored by measuring the electrical resistance (ER) and permeability of Rhodamine B (RB). The modified PVPASC model was characterized in terms of the surface topography, solvent influence and storage stability. The permeation studies of the active components in Compound Nanxing Zhitong Plaster (CNZP) were performed to examine the capability of PVPASC in the application of skin penetration. RESULTS: The ER and Papp values of RB obtained from the optimized PVPASC model indicated a similar barrier property to porcine ear skin. Scanning electron microscope analysis demonstrated a mimic 'brick-and-mortar' structure. The PVPASC model can be stored for three weeks at -20 °C, and withstand the presence of different receptor medium for 24 h. The permeation studies of the active components demonstrated a good correlation (r2 = 0.9136) of Papp values between the drugs' permeation through the PVPASC model and porcine ear skin. CONCLUSION: Keratin contained composite phospholipid vesicle-based permeation assay models have been proven to be potential skin tools in topical/transdermal permeation studies.

Biomimetic tri-layered artificial skin comprising silica gel-collagen membrane-collagen porous scaffold for enhanced full-thickness wound healing.

Full-thickness wounds are severe cutaneous damages with destroyed self-healing function, which need efficient clinical interventions. Inspired by the hierarchical structure of natural skin, we have for the first time developed a biomimetic tri-layered artificial skin (TLAS) comprising silica gel-collagen membrane-collagen porous scaffold for enhanced full-thickness wound healing. The TLAS with the thickness of 3-7 mm displays a hierarchical nanostructure consisting of the top homogeneous silica gel film, the middle compact collagen membrane, and the bottom porous collagen scaffold, exquisitely mimicking the epidermis, basement membrane and dermis of natural skin, respectively. The 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide/N-Hydroxysuccinimide-dehydrothermal (EDC/NHS-DHT) dual-crosslinked collagen composite bilayer, with a crosslinking degree of 79.5 %, displays remarkable biocompatibility, bioactivity, and biosafety with no risk of hemolysis and pyrogen reactions. Notably, the extra collagen membrane layer provides a robust barrier to block the penetration of silica gel into the collagen porous scaffold, leading to the TLAS with enhanced biocompatibility and bioactivity. The full-thickness wound rat model studies have indicated the TLAS significantly facilitates the regeneration of full-thickness defects by accelerating re-epithelization, collagen deposition and migration of skin appendages. The highly biocompatible and bioactive tri-layered artificial skin provides an improved treatment for full-thickness wounds, which has great potential in tissue engineering.

NovoSorb® Biodegradable Temporising Matrix (BTM): What we learned from the first 300 consecutive cases.

INTRODUCTION: Extensive full-thickness soft-tissue defects remain a challenge in reconstructive surgery. NovoSorb® Biodegradable Temporising Matrix (BTM) represents a novel dermal substitute and was evaluated in wounds deriving from different aetiologies and to highlight risk factors for poor take rates. METHODS: All patients treated with BTM at our department between March 2020 and October 2022 were included. Differences in univariate and linear regression models identified predictors and risk factors for take rates of BTM and split-thickness skin grafts (STSG). RESULTS: Three hundred patients (mean age 54.2 ± 20.1 years, 66.3% male, 59.7% burns, 19.7% trauma and 20.6% others) were evaluated. Mean take rates of BTM and STSG after BTM delamination were 82.7 ± 25.2% and 86.0 ± 22.6%, respectively. Multiple regression analyses showed that higher body mass index (BMI, OR 0.43, 95% CI 0.86, -0.01, p = 0.44), prior allograft transplantation (OR 15.12, 95% CI 26.98, -3.31, p = 0.041), longer trauma-to-BTM-application intervals (OR 0.01, 95% CI 0.001, -0.001, p = 0.038), positive wound swabs before BTM (OR 7.15, 95% CI 13.50, -0.80, p = 0.028) and peripheral artery disease (OR 10.80, 95% CI 18.63, -2.96, p = 0.007) were associated with poorer BTM take. Higher BMI (OR 0.40, 95% CI 0.76, -0.08, p = 0.026), increasing BTM graft surface areas (OR 0.58, 95% CI -1.00, -0.17, p = 0.005), prior allograft (OR 12.20, 95% CI -21.99, -2.41, p = 0.015) or autograft transplantations (OR 22.42, 95% CI 38.69, -6.14, p = 0.001), tumour as the aetiology of the wound (OR 37.42, 95% CI 57.41, -17.83, p = 0.001), diabetes (OR 6.64, 95% CI 12.80, -0.48, p = 0.035) and impaired kidney function (OR 5.90, 95% CI 10.94, -0.86, p = 0.021) were associated with poorer STSG take after delamination of BTM, whereas higher BTM take rates were associated with better STSG take (OR 0.40, 95% CI 0.31,0.50, p < 0.001). CONCLUSION: Extensive complex wounds of different aetiologies unsuitable for immediate STSG can be successfully reconstructed by means of two-staged BTM application and subsequent skin grafting. Importantly, presence of wound contamination or infection and prior allograft coverage appear to jeopardise good BTM and STSG take.

Improving stability of human three dimensional skin equivalents using plasma surface treatment.

In developing three-dimensional (3D) human skin equivalents (HSEs), preventing dermis and epidermis layer distortion due to the contraction of hydrogels by fibroblasts is a challenging issue. Previously, a fabrication method of HSEs was tested using a modified solid scaffold or a hydrogel matrix in combination with the natural polymer coated onto the tissue culture surface, but the obtained HSEs exhibited skin layer contraction and loss of the skin integrity and barrier functions. In this study, we investigated the method of HSE fabrication that enhances the stability of the skin model by using surface plasma treatment. The results showed that plasma treatment of the tissue culture surface prevented dermal layer shrinkage of HSEs, in contrast to the HSE fabrication using fibronectin coating. The HSEs from plasma-treated surface showed significantly higher transepithelial electrical resistance compared to the fibronectin-coated model. They also expressed markers of epidermal differentiation (keratin 10, keratin 14 and loricrin), epidermal tight junctions (claudin 1 and zonula occludens-1), and extracellular matrix proteins (collagen IV), and exhibited morphological characteristics of the primary human skins. Taken together, the use of plasma surface treatment significantly improves the stability of 3D HSEs with well-defined dermis and epidermis layers and enhanced skin integrity and the barrier functions.

Duragen: A dermal substitute for the management of suboptimal wounds.

Using a flap in a large wound with a very small area of exposed vital structures may be an excessive intrusion and cause unnecessary donor site morbidity. Dermal matrix (DuraGen) was applied onto critical areas where bone or tendons were exposed and a split skin graft was placed thereon. All patients had satisfactory wound closure without the need for a flap. DuraGen appears to be a safe, single-stage alternative, to a flap for the healing of complex wounds.

La matriz extracelular en la curación de las heridas cutáneas. Aspectos físicos, químicos y biológicos / Extracellular matrix in healing of cutaneous wounds. Physical, chemical and biological aspects

Se revisan los nuevos conocimientos sobre la matriz extracelular (MEC), que han permitido descubrir su importante rol en la cicatrización de las heridas cutáneas. Se describen sus características morfofisiológicas y cómo interviene en la curación de las heridas cutáneas. Se presentan cuatro casos clínicos en los que se aplicó este enfoque terapéutico: los sustitutos de piel y la "cura húmeda"

We review the new knowledge about the extracellular ma-trix (ECM) that has allowed us to discover its important role in the healing of cutaneous wounds. The morpho-physiological characteristics of ECM and its role in the healing of cutaneous wounds are described. Four clinical cases are presented where this therapeutic approach was applied: the skin substitutes and the "moist wound healing".

Burns in the Elderly.

Burns in the elderly are a significant cause of morbidity and mortality. Frailty is an important indicator of patient health and physiologic reserve. Comorbidities and typical age-related changes significantly impact the outcomes of elderly burn patients and decisions made during their burn care. It is essential to have early and thorough discussions about the goals of care and rehabilitation plans. Physiologic changes that occur from aging cause slower wound healing and may make operative treatment more challenging, although techniques such as autographing, skin substitutes, and flaps may all play a role in treating this patient population.

Skin Substitutes and Autograft Techniques: Temporary and Permanent Coverage Solutions.

Coverage of burn wounds is crucial to prevent sequalae including dehydration, wound infection, sepsis, shock, scarring, and contracture. To this end, numerous temporary and permanent options for coverage of burn wounds have been described. Temporary options for burn coverage include synthetic dressings, allografts, and xenografts. Permanent burn coverage can be achieved through skin substitutes, cultured epithelial autograft, ReCell, amnion, and autografting. Here, we aim to summarize the available options for burn coverage, as well as important considerations that must be made when choosing the best reconstructive option for a particular patient.

Challenges in the Management of Large Burns.

Large burns provoke profound pathophysiological changes. Survival rates of patients with large burns have improved significantly with the advancement of critical care and adaptation of early excision protocols. Nevertheless, care of large burn wounds remains challenging secondary to limited donor sites, prolonged time to wound closure, and immunosuppression. The development of skin substitutes and new grafting techniques decreased time to wound closure. Individually, these methods have limited success, but a combination of them may yield more successful outcomes. Early identification of patients with likely poor prognosis should prompt goals of care discussion and involvement of a palliative care team when possible.