Tissue engineering of skin and regenerative medicine for wound care

Abstract ᅟ Engineering of biologic skin substitutes has progressed over time from individual applications of skin cells, or biopolymer scaffolds, to combinations of cells and scaffolds for treatment, healing, and closure of acute and chronic skin wounds. Skin substitutes may be categorized into three groups: acellular scaffolds, temporary substitutes containing allogeneic skin cells, and permanent substitutes containing autologous skin cells. Combined use of acellular dermal substitutes with permanent skin substitutes containing autologous cells has been shown to provide definitive wound closure in burns involving greater than 90% of the total body surface area. These advances have contributed to reduced morbidity and mortality from both acute and chronic wounds but, to date, have failed to replace all of the structures and functions of the skin. Among the remaining deficiencies in cellular or biologic skin substitutes are hypopigmentation, absence of stable vascular and lymphatic networks, absence of hair follicles, sebaceous and sweat glands, and incomplete innervation. Correction of these deficiencies depends on regulation of biologic pathways of embryonic and fetal development to restore the full anatomy and physiology of uninjured skin. Elucidation and integration of developmental biology into future models of biologic skin substitutes promises to restore complete anatomy and physiology, and further reduce morbidity from skin wounds and scar. This article offers a review of recent advances in skin cell thrapies and discusses the future prospects in cutaneous regeneration.

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Bioengineered Skin Substitutes: The Role of Extracellular Matrix and Vascularization in the Healing of Deep Wounds

Journal of Clinical Medicine ◽

10.3390/jcm8122083 ◽

2019 ◽

Vol 8 (12) ◽

pp. 2083 ◽

Cited By ~ 8

Author(s):

Francesco Urciuolo ◽

Costantino Casale ◽

Giorgia Imparato ◽

Paolo A. Netti

Keyword(s):

Extracellular Matrix ◽

Hair Follicles ◽

Sweat Glands ◽

Skin Wounds ◽

Skin Substitutes ◽

Skin Tissue Engineering ◽

Skin Cells ◽

Bioengineered Skin ◽

A Current

The formation of severe scars still represents the result of the closure process of extended and deep skin wounds. To address this issue, different bioengineered skin substitutes have been developed but a general consensus regarding their effectiveness has not been achieved yet. It will be shown that bioengineered skin substitutes, although representing a valid alternative to autografting, induce skin cells in repairing the wound rather than guiding a regeneration process. Repaired skin differs from regenerated skin, showing high contracture, loss of sensitivity, impaired pigmentation and absence of cutaneous adnexa (i.e., hair follicles and sweat glands). This leads to significant mobility and aesthetic concerns, making the development of more effective bioengineered skin models a current need. The objective of this review is to determine the limitations of either commercially available or investigational bioengineered skin substitutes and how advanced skin tissue engineering strategies can be improved in order to completely restore skin functions after severe wounds.

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Scratch-induced partial skin wounds re-epithelialize by sheets of independently migrating keratinocytes

Life Science Alliance ◽

10.26508/lsa.202000765 ◽

2020 ◽

Vol 4 (1) ◽

pp. e202000765

Author(s):

Laura Bornes ◽

Reinhard Windoffer ◽

Rudolf E Leube ◽

Jessica Morgner ◽

Jacco van Rheenen

Keyword(s):

Intravital Microscopy ◽

Skin Barrier ◽

Cell Loss ◽

Hair Follicles ◽

Migration Pattern ◽

Sweat Glands ◽

Skin Wounds ◽

Wound Model ◽

Scratch Wound ◽

Suprabasal Keratinocytes

Re-epithelialization is a crucial process to reestablish the protective barrier upon wounding of the skin. Although this process is well described for wounds where the complete epidermis and dermis is damaged, little is known about the re-epithelialization strategy in more frequently occurring smaller scratch wounds in which structures such as the hair follicles and sweat glands stay intact. To study this, we established a scratch wound model to follow individual keratinocytes in all epidermal layers in the back skin of mice by intravital microscopy. We discover that keratinocytes adopt a re-epithelialization strategy that enables them to bypass immobile obstacles such as hair follicles. Wound-induced cell loss is replenished by proliferation in a distinct zone away from the wound and this proliferation does not affect overall migration pattern. Whereas suprabasal keratinocytes are rather passive, basal keratinocytes move as a sheet of independently migrating cells into the wound, thereby constantly changing their direct neighboring cells enabling them to bypass intact obstacles. This re-epithelialization strategy results in a fast re-establishment of the protective skin barrier upon wounding.

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A pulsed current electric field alters protein expression creating a wound healing phenotype in human skin cells

Regenerative Medicine ◽

10.2217/rme-2019-0087 ◽

2020 ◽

Vol 15 (5) ◽

pp. 1611-1623

Author(s):

Luciana E Bostan ◽

Sofia Almqvist ◽

Christine E Pullar

Keyword(s):

Electric Field ◽

Protein Expression ◽

Chronic Wounds ◽

Expression Profiles ◽

Dermal Fibroblasts ◽

Pulsed Current ◽

Skin Cells ◽

Skin Cell ◽

Skin Keratinocytes ◽

Protein Expression Profiles

Aim: Pulsed current (PC) electric field (EF) devices promote healing in chronic wounds but the underpinning mechanisms are largely unknown. The gap between clinical evidence and mechanistic understanding limits device uptake in clinics. Materials & methods: Migration, proliferation and gene/protein expression profiles were investigated in the presence/absence of PCEF, in skin: keratinocytes (NHK); dermal fibroblasts (HDF); dermal microvascular endothelial cells (HDMEC) and macrophages (THP-1). Results: While PCEF had little effect on migration or proliferation, it significantly altered the expression of 31 genes and the secretion of 7 pro-angiogenic and pro-regenerative growth factors using ELISAs. Conclusion: PCEF significantly altered skin cell genomes/proteomes which provides some evidence of how PCEF devices promote healing of chronic wounds.

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On skin substitutes for wound healing: Current products, limitations, and future perspectives

TECHNOLOGY ◽

10.1142/s2339547820300024 ◽

2021 ◽

pp. 1-7

Author(s):

Sarah Susan Kelangi ◽

Georgios Theocharidis ◽

Aristidis Veves ◽

William G. Austen ◽

Robert Sheridan ◽

...

Keyword(s):

Wound Healing ◽

Chronic Wounds ◽

Cost Effective ◽

Cell Types ◽

Skin Substitute ◽

Future Research ◽

Skin Substitutes ◽

High Quality ◽

Skin Cell ◽

Skin Replacement

Cutaneous wound healing is a highly coordinated process involving numerous molecular pathways that regulate the function of specific skin cell types. One of the key decisions in acute and/or chronic wound healing management is to choose the skin substitute that, based on its composition and/or properties, may act as permanent skin replacement or temporary wound cover. The current products however are limited in their action, especially in the context of large chronic wounds or extensive second-/third-degree burns, due to the risk of developing infection, the limited vascularization, the inability to integrate to host tissue, and the lack in the healed area of skin apparatus responsible for temperature control, pigmentation, immune regulation, and nerve supply. In addition, the high cost of skin substitutes precludes their use in small- and moderate-size burns because they are economically impractical and protract the time to definitive wound closure. Thus, the need to develop cost-effective substitutes of high quality is imperative. The purpose of this review is to discuss current available products, their limitations and to provide some perspectives on future research toward generation of cost-effective, high-quality substitutes.

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Generation of Skin Organoids: Potential Opportunities and Challenges

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.709824 ◽

2021 ◽

Vol 9 ◽

Author(s):

Hui Sun ◽

Yi-Xuan Zhang ◽

Yu-Mei Li

Keyword(s):

Human Skin ◽

Skin Diseases ◽

Hair Follicles ◽

Sweat Glands ◽

Generation Model ◽

Skin Substitutes ◽

Local Skin ◽

Cell Microenvironment ◽

And Function

Although several types of human skin substitutes are currently available, they usually do not include important skin appendages such as hair follicles and sweat glands, or various skin-related cells, such as dermal adipocytes and sensory neurons. This highlights the need to improve the in vitro human skin generation model for use as a tool for investigating skin diseases and as a source of cells or tissues for skin regeneration. Skin organoids are generated from stem cells and are expected to possess the complexity and function of natural skin. Here, we summarize the current literatures relating to the “niches” of the local skin stem cell microenvironment and the formation of skin organoids, and then discuss the opportunities and challenges associated with multifunctional skin organoids.

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535 Intermediate Skin Substitutes Are Unnecessary in Small (< 10% TBSA) Burns

Journal of Burn Care & Research ◽

10.1093/jbcr/iraa024.164 ◽

2020 ◽

Vol 41 (Supplement_1) ◽

pp. S105-S106

Author(s):

Alexandra M Lacey ◽

Justin Gillenwater ◽

Ellen Maniago ◽

Haig A Yenikomshian ◽

Warren L Garner

Keyword(s):

Graft Failure ◽

Wound Care ◽

Graft Loss ◽

Total Body Surface Area ◽

Complete Healing ◽

Single Stage ◽

Skin Substitute ◽

Split Thickness Skin Graft ◽

Skin Substitutes ◽

Time From Injury

Abstract Introduction The use of intermediate skin substitutes between debridement and final autografting is routine for many practitioners. Materials such as xenografts and allografts have been promoted to help with wound coverage before autografting. However there is limited data for their use in relatively small burn wounds (< 10% total body surface area, TBSA). In this study, we analyzed the outcomes of one hundred consecutive patients who underwent autografting for burns < 10% TBSA at our ABA verified burn unit in the absence of intermediate skin substitute use. Methods We retrospectively analyzed one hundred patients who underwent split thickness skin graft autografting for burns < 10% TBSA between November 2017 and June 2019. No patients were treated with intermediate skin substitutes. Analysis included basic demographics, comorbidities, TBSA burned, mechanism of burn, time to grafting, if grafting was performed in a single procedure or staged, graft loss (>50% graft failure), and time to complete healing (no further wound care required). Results Twelve patients (12%) had unpredictable graft beds and their procedure was staged. These patients underwent surgical debridement and were dressed in antimicrobial dressing for an average of 5 days before autografting. No patients had intermediate skin substitutes between procedures. Eighty-eight patients (88%) were debrided and grafted in a single stage. In the staged group, there was a 0% rate of graft failure compared to 9.1% rate of graft failure in the primarily grafted group (p=0.004). There was a similar length of stay and time to complete healing in the staged group and primarily grafted group (p=0.496 and p=0.571). There was a significantly shorter time from injury to first procedure between the staged group and the primarily grafted group (8.7 days and 13.5 days, p=0.014). Many of the patients with these small burns were first managed outpatient and then brought in for autografting leading to a longer time from injury to surgery; while the staged group often presented with wounds that appeared infected and required urgent debridement. In the eight instances of graft failure, infection or inadequate debridement was the cause. Seven of these eight cases required further surgical intervention. Conclusions Intermediate skin substitutes are an unnecessary step in grafting small burns. These add only complexity and cost to patient care. Many patients can be debrided and grafted in a single stage. Debridement alone with delayed grafting is a highly effective surgical method when the wound bed is not suitable for immediate grafting. Applicability of Research to Practice The use of intermediate skin substitutes in small burns requires further investigation as this study finds low benefit for this product.

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Current Status and Future of Skin Substitutes for Chronic Wound Healing

Journal of Cutaneous Medicine and Surgery ◽

10.1177/1203475416664037 ◽

2016 ◽

Vol 21 (1) ◽

pp. 23-30 ◽

Cited By ~ 31

Author(s):

Mathew N. Nicholas ◽

Jensen Yeung

Keyword(s):

Wound Healing ◽

Chronic Wounds ◽

Wound Care ◽

Alternative Therapy ◽

Current Status ◽

Skin Substitutes ◽

Venous Ulcers ◽

Different Types ◽

Arterial Insufficiency ◽

Similar Cost

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.

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Systematic Review: Adipose-Derived Mesenchymal Stem Cells, Platelet-Rich Plasma and Biomaterials as New Regenerative Strategies in Chronic Skin Wounds and Soft Tissue Defects

International Journal of Molecular Sciences ◽

10.3390/ijms22041538 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1538 ◽

Cited By ~ 2

Author(s):

Pietro Gentile ◽

Simone Garcovich

Keyword(s):

Systematic Review ◽

Stem Cells ◽

Wound Healing ◽

Soft Tissue ◽

Chronic Wounds ◽

Platelet Rich Plasma ◽

Skin Wounds ◽

Soft Tissue Defects ◽

Chronic Skin ◽

Tissue Defects

The number of clinical trials evaluating adipose-derived mesenchymal stem cells (AD-MSCs), platelet-rich plasma (PRP), and biomaterials efficacy in regenerative plastic surgery has exponentially increased during the last ten years. AD-MSCs are easily accessible from various fat depots and show intrinsic plasticity in giving rise to cell types involved in wound healing and angiogenesis. AD-MSCs have been used in the treatment of soft tissue defects and chronic wounds, employed in conjunction with a fat grafting technique or with dermal substitute scaffolds and platelet-rich plasma. In this systematic review, an overview of the current knowledge on this topic has been provided, based on existing studies and the authors’ experience. A multistep search of the PubMed, MEDLINE, Embase, PreMEDLINE, Ebase, CINAHL, PsycINFO, Clinicaltrials.gov, Scopus database, and Cochrane databases has been performed to identify papers on AD-MSCs, PRP, and biomaterials used in soft tissue defects and chronic wounds. Of the 2136 articles initially identified, 422 articles focusing on regenerative strategies in wound healing were selected and, consequently, only 278 articles apparently related to AD-MSC, PRP, and biomaterials were initially assessed for eligibility. Of these, 85 articles were excluded as pre-clinical, experimental, and in vitro studies. For the above-mentioned reasons, 193 articles were selected; of this amount, 121 letters, expert opinions, commentary, and editorials were removed. The remaining 72 articles, strictly regarding the use of AD-MSCs, PRP, and biomaterials in chronic skin wounds and soft tissue defects, were analyzed. The studies included had to match predetermined criteria according to the patients, intervention, comparator, outcomes, and study design (PICOS) approach. The information analyzed highlights the safety and efficacy of AD-MSCs, PRP, and biomaterials on soft tissue defects and chronic wounds, without major side effects.

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Cosmetic and Dermatological Properties of Selected Ayurvedic Plant Extracts

Molecules ◽

10.3390/molecules26030614 ◽

2021 ◽

Vol 26 (3) ◽

pp. 614

Author(s):

Martyna Zagórska-Dziok ◽

Aleksandra Ziemlewska ◽

Tomasz Bujak ◽

Zofia Nizioł-Łukaszewska ◽

Zofia Hordyjewicz-Baran

Keyword(s):

Skin Diseases ◽

Multiple Reaction Monitoring ◽

Antioxidant Properties ◽

Radical Scavenging ◽

Biologically Active ◽

Cell Protection ◽

Skin Cells ◽

Skin Cell ◽

Aging Properties ◽

Enzyme Superoxide Dismutase

Due to the constantly growing interest in ingredients of natural origin, this study attempts to evaluate the possibility of using extracts from three Ayurvedic plants in preparations for the care and treatment of skin diseases. Therefore, studies of antioxidant properties were carried out using DPPH and ABTS radicals, obtaining 76% and 88% of these radical scavenging, respectively. A significant decrease in the intracellular level of free radicals and an increase in the activity of the antioxidant enzyme-superoxide dismutase by almost 60% were also observed. In addition, the extracts were assessed for anti-inflammatory and anti-aging properties, obtaining over 70% inhibition of lipoxygenase activity and almost 40% of collagenase. Additionally, the cytoprotective properties of the obtained extracts on skin cells, keratinocytes and fibroblasts, were demonstrated. To assess the content of biologically active compounds, HPLC-electrospray ionization (ESI)-MS/MS multiple reaction monitoring (MRM) analyses were performed. The obtained results show that all three analyzed plants are a valuable source of biologically active substances with desired properties in the context of skin cell protection. Particularly noteworthy is the extract of Epilobium angustifolium L., for which the most promising results were obtained.

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