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.

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.

Determination of potential dermal exposure rates of phosphorus flame retardants via the direct contact with a car seat using artificial skin.

Dermal exposure to phosphorus flame retardants (PFRs) has received much attention as a major alternative exposure route in recent years. However, the information regarding dermal exposure via direct contact with a product is limited. In addition, in the commonly used dermal permeability test, the target substance is dissolved in a solvent, which is unrealistic. In this study, a dermal permeability test of PFRs in three car seats was performed using artificial skin. The PFR concentrations in the car seats are 0.12 wt% tris(2-chloroethyl) phosphate (TCEP), 0.030-0.25 wt% tris(2-chloroisopropyl) phosphate (TCPP), 0.15 wt% triphenyl phosphate (TPhP), 0.89 wt% cresyl diphenyl phosphate (CsDPhP), 0.074 wt% tricresyl phosphate (TCsP), and 0.46-4.7 wt% diethylene glycol bis [di (2-chloroisopropyl) phosphate (DEG-BDCIPP). The mean skin permeation rates for a contact time of 24 h are 14 (TCEP), 5.4-160 (TCPP), 0.67 (CsDPhP), 0.38 (TPhP), and 3.3-58 ng cm-2 h-1 (DEG-BDCIPP). The concentrations of TCsP in receptor liquid were lower than the limit of quantification at the contact time of 24 h. The skin permeation rates were significantly affected by the type of car seat (e.g., fabric or non-fabric). The potential dermal TCPP exposure rate for an adult via direct contact with the car seat during the average daily contact time (1.3 h), which was the highest value assessed in this study, was estimated to be 16,000 ng kg-1 day-1, which is higher than that related to inhalation and dust ingestion reported as significant exposure route of PFRs in previous studies. These facts reveal that dermal exposure associated with direct contact with the product might be an important exposure pathway for PFRs.

Real-world data analysis of bilayered living cellular construct and fetal bovine collagen dressing treatment for pressure injuries: a comparative effectiveness study.

Aim: To determine the effectiveness of bilayered living cellular construct (BLCC) versus a fetal bovine collagen dressing (FBCD) in pressure injuries (PRIs). Methods: A real-world data study was conducted on 1352 PRIs analyzed digitally. 1046 and 306 PRIs were treated with BLCC and FBCD, respectively. Results: Cox healing for BLCC (n = 1046) was significantly greater (p < 0.0001) at week 4 (13 vs 7%), 8 (29 vs 17%), 12 (42 vs 27%), 24 (64 vs 45%), and 36 (73 vs 56%). The probability of healing increased by 66%, (hazard ratio = 1.66 [95% CI (1.38, 2.00)]; p < 0.0001. Time to healing was 162 days for FBCD and 103 days for BLCC showing a 36% reduction in time to healing with BLCC; (p < 0.0001). Conclusion: BLCC significantly improved healing of PRIs versus FBCD.

Cancer Spheroids Embedded in Tissue-Engineered Skin Substitutes: A New Method to Study Tumorigenicity In Vivo.

Tumorigenic assays are used during a clinical translation to detect the transformation potential of cell-based therapies. One of these in vivo assays is based on the separate injection of each cell type to be used in the clinical trial. However, the injection method requires many animals and several months to obtain useful results. In previous studies, we showed the potential of tissue-engineered skin substitutes (TESs) as a model for normal skin in which cancer cells can be included in vitro. Herein, we showed a new method to study tumorigenicity, using cancer spheroids that were embedded in TESs (cTES) and grafted onto athymic mice, and compared it with the commonly used cell injection assay. Tumors developed in both models, cancer cell injection and cTES grafting, but metastases were not detected at the time of sacrifice. Interestingly, the rate of tumor development was faster in cTESs than with the injection method. In conclusion, grafting TESs is a sensitive method to detect tumor cell growth with and could be developed as an alternative test for tumorigenicity.

Bionic artificial skin with a fully implantable wireless tactile sensory system for wound healing and restoring skin tactile function.

Tactile function is essential for human life as it enables us to recognize texture and respond to external stimuli, including potential threats with sharp objects that may result in punctures or lacerations. Severe skin damage caused by severe burns, skin cancer, chemical accidents, and industrial accidents damage the structure of the skin tissue as well as the nerve system, resulting in permanent tactile sensory dysfunction, which significantly impacts an individual's daily life. Here, we introduce a fully-implantable wireless powered tactile sensory system embedded artificial skin (WTSA), with stable operation, to restore permanently damaged tactile function and promote wound healing for regenerating severely damaged skin. The fabricated WTSA facilitates (i) replacement of severely damaged tactile sensory with broad biocompatibility, (ii) promoting of skin wound healing and regeneration through collagen and fibrin-based artificial skin (CFAS), and (iii) minimization of foreign body reaction via hydrogel coating on neural interface electrodes. Furthermore, the WTSA shows a stable operation as a sensory system as evidenced by the quantitative analysis of leg movement angle and electromyogram (EMG) signals in response to varying intensities of applied pressures.

Connective tissue inspired elastomer-based hydrogel for artificial skin via radiation-indued penetrating polymerization.

Robust hydrogels offer a candidate for artificial skin of bionic robots, yet few hydrogels have a comprehensive performance comparable to real human skin. Here, we present a general method to convert traditional elastomers into tough hydrogels via a unique radiation-induced penetrating polymerization method. The hydrogel is composed of the original hydrophobic crosslinking network from elastomers and grafted hydrophilic chains, which act as elastic collagen fibers and water-rich substances. Therefore, it successfully combines the advantages of both elastomers and hydrogels and provides similar Young's modulus and friction coefficients to human skin, as well as better compression and puncture load capacities than double network and polyampholyte hydrogels. Additionally, responsive abilities can be introduced during the preparation process, granting the hybrid hydrogels shape adaptability. With these unique properties, the hybrid hydrogel can be a candidate for artificial skin, fluid flow controller, wound dressing layer and many other bionic application scenarios.

[Skin substitutes : a step forward in skin regeneration using tissue engineering]. / Les substituts cutanés :un progrès dans la régénération de la peau à l'aide de l'ingénierie tissulaire.

The use of skin substitutes in burn surgery and in the treatment of acute or chronic wounds is constantly evolving. For years, scientists have been researching skin substitutes that can be used in place of autologous skin. New products are regularly developed and approved for clinical use. In this article, we take a look at the skin substitutes most commonly used in Europe and briefly summarize the current clinical experience of our centre.

L'utilisation des substituts cutanés dans la chirurgie des grands brûlés et dans le traitement des plaies aiguës ou chroniques est en constante évolution. Depuis des années, les scientifiques recherchent des substituts cutanés qui peuvent être utilisés à la place de la peau autologue. De nouveaux produits sont régulièrement développés et approuvés pour l'utilisation clinique. Dans cet article, nous examinons les substituts cutanés les plus utilisés en Europe et résumons brièvement l'expérience pratique de notre centre.

A multimodal magnetoelastic artificial skin for underwater haptic sensing.

Future exploitation of marine resources in a sustainable and eco-friendly way requires autonomous underwater robotics with human-like perception. However, the development of such intelligent robots is now impeded by the lack of adequate underwater haptic sensing technology. Inspired by the populational coding strategy of the human tactile system, we harness the giant magnetoelasticity in soft polymer systems as an innovative platform technology to construct a multimodal underwater robotic skin for marine object recognition with intrinsic waterproofness and a simple configuration. The bioinspired magnetoelastic artificial skin enables multiplexed tactile modality in each single taxel and obtains an impressive classification rate of 95% in identifying seven types of marine creatures and marine litter. By introducing another degree of freedom in underwater haptic sensing, this work represents a milestone toward sustainable marine resource exploitation.

Patterns of use of advanced wound matrices in the Veterans Administration clinics.

Chronic wounds are a common and costly health issue affecting millions of individuals in the United States, particularly those with underlying conditions such as diabetes, venous insufficiency, and peripheral artery disease. When standard treatments fail, advanced wound care therapies, such as skin substitutes, are often applied. However, the clinical effectiveness, indications, and comparative benefits of these therapies have not been well established. In this study, we report on the usage of both acellular and cellular, single and bilayer, natural and synthetic, dermal, and epidermal skin substitutes in a VA hospital system. We performed a retrospective chart review to understand the ordering and usage patterns of advanced wound therapies for patients with chronic wounds at the VA Northern California Health Care System. We examined types of products being recommended, categories of users recommending the products, indications for orders, and rate of repeated orders. Neuropathic, venous, or pressure ulcers were the main indications for using advanced wound matrices. Only 15.6% of patients for whom the matrices were ordered had supporting laboratory tests. Exactly 34.3% of the ordered matrices were not applied. And the use of wound matrices resulted in increased costs per patient visit of $1018-$3450. Our study sheds light on the usage patterns of these therapies in a VA healthcare facility and highlights the need for more robust evidence-based studies to determine the true benefits, efficacy, and cost-effectiveness of these innovative treatment options.

A potential bilayer skin substitute based on electrospun silk-elastin-like protein nanofiber membrane covered with bacterial cellulose.

Skin substitutes are designed to promote wound healing by replacing extracellular matrix. Silk-elastin-like protein is a renewable extracellular matrix-like material that integrated the advantages of silk and elastin-like protein. In this study, electrospun silk-elastin-like protein (SELP) nanofiber membrane covered with bacterial cellulose (BC) was created as a potential skin substitute to mimic gradient structure of epidermis and dermis of skin. The two layers were glued together using adhesive SELP containing 3,4-dihydroxyphenylalanine (DOPA) converted from tyrosine by tyrosinase. Skin topical drugs commonly used in clinical practice can penetrate through the SELP/BC barrier, and the rate of penetration is proportional to drug concentration. BC with dense fibrous structure can act as a barrier to preserve the inner SELP layer and prevent bacterial invasion, with a blocking permeation efficiency over 99% against four species of bacteria. Cell experiments demonstrated that the reticular fibers of SELP could provide an appropriate growth environment for skin cells proliferation and adhesion, which is considered to promote tissue repair and regeneration. The promising results support this strategy to fabricate a silk-elastin-like protein-based biomaterial for skin substitutes in the clinical treatment of full skin injuries and ulcers.

Piezoionic High Performance Hydrogel Generator and Active Protein Absorber via Microscopic Porosity and Phase Blending.

Generating electricity in hydrogel is very important but remains difficult. Hydrogel with electricity generation capability is more capable in bio-relevant tasks such as tissue engineering, artificial skin, or medical treatment, because electricity is indispensable in regulating physiological activities. Here, a porous and phase blending hydrogel structure for effective piezoionic electricity generation is developed. Dynamic electric field is generated taking advantage of the difference in streaming speeds of sodium and chloride in the material. Microscopic porosity and hydrophilic-hydrophobic phase blending are the two key factors for prominent piezoionic performance. Voltages as high as 600 mV are first realized in hydrogels in response to medical ultrasound stimulation. The hydrogel structure is also subjective to effective substance exchange and can actively enrich proteins from surroundings under mechanical stimuli. Preliminary applications in neural stimulation, constructing complex spatial-temporal chemical and electric field distribution patterns, mimetic tactile sensor, sample pretreatment in fast detection, and enzyme immobilization are demonstrated.

Thirty Years of Tissue Engineering.

From a literary perspective, the concept of tissue engineering and regenerative medicine dates back several thousand years. However, from a scientific aspect, the current state of the field owns its initial origin to the discovery of cell culture methods and the ability to maintain cells outside the body in the early 1900s, to later discoveries surrounding stem cells. The science of biomaterials evolved more recently, from the use of degradable natural biomaterials in the 1970's to artificial biomaterials in the 1980s, and bioprinting hydrogels this century. Tissue engineering, originally involving the combination of cells and biomaterials, owes its roots to the early attempts in the 1960s to create artificial skin grafts as temporary wound covers for burn patients. Much has transpired since, with an increasing number of technologies reaching patients. Academia, industry, government agencies, societies, and nonprofit organizations have all played a role in advancing the field to where it is today. This overview, presented at the Rice Short Course on Advances in Tissue Engineering, highlights some of the historical aspects, as well as past and future challenges and opportunities. At the current pace of discovery, the field is poised to continue its exponential growth.

Immediate Results of the Use of Split-Thickness Skin Autografts With and Without Acellular Dermal Matrix in Patients with Burns: A Comparative Study in a Colombian Population.

Dermal substitutes have become fundamental tools for covering skin defects, most recently with biological subtypes such as glycerolized acellular dermal matrix (GADM). However, literature regarding this matter is scarce in Latin America and Colombia. In this descriptive observational study, we compared the use of partial skin autografts (PSA) combined with GADM and autografts without GADM. Patients were selected from the burn unit of a hospital in northeastern Colombia between 2021 and 2022. Two study groups were defined: one receiving GADM plus PSA and the other control receiving only a partial split-thickness autograft. A total of 29 patients with 68 body areas were included, with an average age of 20 years. Most cases involved third-degree burns caused by flame. Hospitalization time was the same for both groups (41 days). The percentage of grafts taken was similar in both groups; in the GADM with autografts group, it was 94.7% compared with 96% in the control group. The presence of complications was similar in both groups. GADM produced in local tissue banks is a cost-effective alternative. It can be used in a single surgical procedure without increasing complications, providing a postsurgical course similar to autografts alone. Granting the potential long-term benefits that dermal matrices give for healing in these patients, which should be evaluated in subsequent studies.

The expression pattern of cytokeratin 6a in epithelial cells of different origin in dermo-epidermal skin substitutes in vivo.

Keratinocytes are the predominant cell type of skin epidermis. Through the programmed process of differentiation, they form a cornified envelope that provides a physical protective barrier against harmful external environment. Keratins are major structural proteins of keratinocytes that together with actin filaments and microtubules form the cytoskeleton of these cells. In this study, we examined the expression pattern and distribution of cytokeratin 6a (CK6a) in healthy human skin samples of different body locations, in fetal and scar skin samples, as well as in dermo-epidermal skin substitutes (DESSs). We observed that CK6a expression is significantly upregulated in fetal skin and scar tissue as well as in skin grafts after short-term transplantation. Importantly, the abundance of CK6a corresponds directly to the expression pattern of wound healing marker CK16. We postulate that CK6a is a useful marker to accurately evaluate the homeostatic state of DESSs.

A simple and rapid assay of lysosomal-targeting CDy6 for long-term real-time viability assessments in 2D and 3D in vitro culture models.

CDy6, a BODIPY-derived compound, is used to label lysosomes and visualize proliferating cells. However, its effectiveness in long-term, real-time cell viability assays using 2D or 3D cell culture models is unclear. We evaluated the suitability of CDy6 by assessing cell health using human keratinocyte and fibroblast cell lines in both models. Cells were stained with CDy6 or other dyes and fluorescent images were obtained with confocal microscopy. CLV extracts derived from CDy6-stained HaCaT cells were also dissolved with DMSO and analyzed using a spectrometer. Furthermore, we added CDy6-stained collagen hydrogels to CCD-986sk cells, loaded them into a frame construction to establish a 3D dermal layer for long-term culture, and analyzed the status of the CLVs. The CLV method, also measured using a spectrometer, yielded results similar to MTT assay for validating viability. In contrast to calcein AM staining, the CLV method allows for both absorbance measurement and imaging under short-term and long-term culture conditions with less cytotoxicity. In conclusion, the CLV method provides a simple and sensitive tool for assessing the status of live cells in 2D and 3D in vitro cell culture models and can be used as an alternative to animal testing, such as with 3D artificial skin models.