Ellen K. White and Elizabeth A. Grice

Department of Dermatology, University of Pennsylvania, Perelman School of Medicine, Philadelphia,

Pennsylvania 19104, USA

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      Breach of the skin barrier and subsequent wound healing occur in the context of microbial communities of bacteria, fungi, and viruses. These polymicrobial communities are dynamic and important components of the wound environment and are associated with differential healing outcomes. Here, we highlight both culture-dependent and -independent methods that have furthered our understanding of the wound microbiome. We discuss common themes that have developed from such studies about the microbial inhabitants of diverse wound types.We additionally explore the wide range of microbial mechanisms that influence healing, from invading pathogens to beneficial commensals. These insights can be leveraged to better predict healing outcomes and derive novel microbial-based therapies for chronic wounds.

Editors: Xing Dai, Sabine Werner, Cheng-Ming Chuong, and Maksim Plikus Additional Perspectives on Wound Healing: From Bench to Bedside available at www.cshperspectives.org Copyright © 2022 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a041218

Qinghan Tang a,1 , Nannan Xue a,b,1 , Xiaofeng Ding c,d , Kevin H.-Y. Tsai e , Jonathan J. Hew f , Ruihan Jiang a ,

Rizhong Huang a , Xuxi Cheng a , Xiaotong Ding a , Yuen Yee Cheng g , Jun Chen a,b,⇑ , Yiwei Wang a,b,e,⇑

a Jiangsu Provincial Engineering Research Center of TCM External Medication Development and Application, Nanjing University of Chinese Medicine, Nanjing 210023, PR China

b Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, PR China

c Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, PR China

d Department of Plastic Surgery, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai 200434, PR China

e Burns and Reconstructive Surgery Group, ANZAC Research Institute, Concord Hospital, The University of Sydney, Concord West, NSW 2137, Australia

f General Surgery, Lesimore Hospital, NSW 2480, Australia

g Institute for Biomedical Materials and Devices, School of Mathematical and Physical Sciences, University of Technology Sydney, NSW 2007 Australia

abstract

      Delayed wound healing is one of the most global public health threats affecting nearly 100 million people each year, particularly the chronic wounds. Many confounding factors such as aging, diabetic disease, medication, peripheral neuropathy, immunocompromises or arterial and venous insuffificiency hyperglycaemia are considered to inhibit wound healing. Therapeutic approaches for slow wound healing include anti-infection, debridement and the use of various wound dressings. However, the current clinical outcomes are still unsatisfified. In this review, we discuss the role of skin and wound commensal microbiota in the different healing stages, including inflflammation, cell proliferation, re-epithelialization and remodelling phase, followed by multiple immune cell responses to commensal microbiota. Current clinical management in treating surgical wounds and chronic wounds was also reviewed together with potential controlled delivery systems which may be utilized in the future for the topical administration of probiotics and microbiomes. This review aims to introduce advances, novel strategies, and pioneer ideas in regulating the wound microbiome and the design of controlled delivery systems.

article info

Article history:

Received 27 September 2022 Revised 23 November 2022 Accepted 14 December 2022 Available online 17 December 2022

Keywords:

Wound healing，Skin microbiome，Inflammation，Clinical wound care，Cell response to microbiome，Probiotic delivery

Abbreviations: 16S-rDNA, 16S ribosomal DNA identifification; b2-AR, b2-adrenergic receptor; ADAM10, A disintegrin and metalloprotease 10; AHR, aryl hydrocarbon receptor; AMP, adenosine monophosphate; B. subtilis, Bacillus subtilis; C. albicans, Candida albicans; CSF, colony-stimulating factor; CXCL2, chemokine (C-X-C motif) ligand 2; CXCL10, chemokine (C-X-C motif) ligand 10; CXCL12, chemokine (C-X-C motif) ligand 12; DFU, diabetic foot ulcer; ECM, extracellular matrix; E. coli, Escherichia coli; EPB, epidermal permeability barrier; EVs, extracellular vesicles; FDA, Food and Drug Administration; hBD, human b-defensin; HF, Hair follicle; HMP, Human Microbiome Project; IL-1, interleukin-1; IL-1R, interleukin-1R; IL-1b, interleukin-1b; IL-6, interleukin-6; IL-23, interleukin-23; K. pneumoniae, Klebsiella pneumoniae; L. acidophilus, Lactobacillus acidophilus; L. lactis, Lactococcus lactis; L. plantarum, Lactobacillus plantarum; L. reuteri, Lactobacillus reuteri; L. rhamnosus, Lactobacillus rhamnosus; M
CSF, macrophage colonystimulating factor; MHCII, major histocompatibility complex II; MMP-9, matrix metalloproteinase-9; MRSA, methicillin-resistant Staphylococcus aureus; MYD88, myeloid differentiation factor 88; NETs, neutrophil extracellular traps; NIH, National Institutes of Health; NPWT, negative pressure wound therapy; P. aeruginosa, Pseudomonas aeruginosa; pDCs, plasmacytoid dendritic cells; PEO, polyethylene oxide; PLA, polylactic acid; ROS, reactive oxygen species; PRP, Plat-rich plasma; PVA, polyvinyl alcohol; PVP, polyvinyl pyrrolidone; SadA, serum adenosine deaminase; S. aureus, Staphylococcus aureus; Sbi, staphylococcal immunoglobulin-binding protein; SCMC, sodium carboxymethylcellulose; S. epidermidis, Staphylococcus epidermidis; SLO, streptolysin O; SpA, Staphylococcal protein A; SPF, specifific pathogen-free; SSWI, surgical site wound infection; TAs, trace amines; Tc17, cytotoxic T cells 17; TGF-b1, transforming growth factor-b1; TNF-a, tumor necrosis factor-a; VEGF, vascular endothelial growth factor; WHO, World Health Organisation. ⇑ Corresponding authors at: Jiangsu Provincial Engineering Research Center of TCM External Medication Development and Application, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing 210023, PR China. E-mail addresses: 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。, 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (J. Chen), 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 (Y. Wang). 1 These authors contributed equally to these work.

https://doi.org/10.1016/j.addr.2022.114671 0169-409X/
2022 Published by Elsevier B.V.

Lihong Chen MD1 | Shiyi Sun MD1 | Yunyi Gao MD2 | Xingwu Ran MD1

1 Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China

2 Department of Medical Affairs, West China Hospital, Sichuan University, Chengdu, China

Correspondence

Xingwu Ran, MD, Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, 37 Guo Xue Lane, Chengdu 610041, China.

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Funding information

This study was partially supported by the Science and Technology Bureau of Sichuan Province (grant no. 2021JDKP004), West China Nursing Discipline Development Special Fund Project, Sichuan University (grant no. HXHL20005) and the 1.3.5 Project for disciplines of excellence, West China Hospital, Sichuan University (grant no. ZYGD18025).

Abstract

Aim: To estimate the long-term mortality and risk factors in patients with diabetic foot ulcer (DFU).

Methods: We systematically searched Medline (PubMed), Embase, Scopus, Web of Science, Cochrane Library, China Science and Technology Journal Database (CQVIP), China National Knowledge Infrastructure, the Chinese Biomedical Literature Database (SinoMed) and Wanfang Data from 1 January 2011 to 31 July 2022. All observational studies that reported long-term mortality of patients with DFU were included. Random effect models were used to pool the reconstructed participant data from Kaplan–Meier curves. The primary outcome was the long-term survival of patients with DFU. An aggregate data meta-analysis was also performed.

Results: We identified 34 studies, with 124 376 participants representing 16 countries, among whom there were 51 386 deaths. Of these, 27 studies with 21 171 patients were included in the Kaplan–Meier-based meta-analysis. The estimated Kaplan–Meier-based survival rates were 86.9% (95% confidence interval [CI] 82.6%- 91.5%) at 1 year, 66.9% (95% CI 59.3%-75.6%) at 3 years, 50.9% (95% CI 42.0%- 61.7%) at 5 years and 23.1% (95% CI 15.2%-34.9%) at 10 years. The results of the aggregate data-based meta-analysis were similar. Cardiovascular disease and infection were the most common causes of death, accounting for 46.6% (95% CI 33.5%-59.7%) and 24.8% (95% CI 16.0%-33.5%), respectively. Patients with older age (per1 year, hazard ratio [HR] 1.054, 95% CI 1.045-1.063), peripheral artery disease (HR 1.882, 95% CI 1.592-2.225), chronic kidney disease (HR 1.535, 95% CI 1.227-1.919), end-stage renal disease (HR 3.586, 95% CI 1.333-9.643), amputation (HR 2.415, 95% CI 1.323-4.408) and history of cardiovascular disease (HR 1.449, 95% CI 1.276-1.645) had higher mortality risk.

Conclusions: This meta-analysis found that the overall mortality of DFU was high, with nearly 50% mortality within 5 years. Cardiovascular disease and infection were the two leading causes of death.

KEYWORDS

cardiovascular disease, diabetic foot, mortality

Mandy Li Ling Tan, Jiah Shin Chin, Leigh Madden & David L. Becker

To cite this article: Mandy Li Ling Tan, Jiah Shin Chin, Leigh Madden & David L. Becker (2022): Challenges faced in developing an ideal chronic wound model, Expert Opinion on Drug Discovery,

DOI: 10.1080/17460441.2023.2158809

To link to this article: https://doi.org/10.1080/17460441.2023.2158809

© 2022 The Author(s). Published by Informa

UK Limited, trading as Taylor & Francis

Published online: 26 Dec 2022.

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Mandy Li Ling Tana,b# , Jiah Shin Chinb# , Leigh Maddenb and David L. Beckerb,c,d a Nanyang Institute of Health Technologies, Interdisciplinary Graduate School, Nanyang Technological University, 639798, Singapore; b Lee Kong Chian School of Medicine, Nanyang Technological University, 308232, Singapore; c Skin Research Institute Singapore, Clinical Sciences Building, 11 Mandalay Road, 308232, Singapore; d National Skin Centre, Mandalay Road, Singapore

ABSTRACT

Introduction: Chronic wounds are a major drain on healthcare resources and can lead to substantial reductions in quality of life for those affected. Moreover, they often precede serious events such as limb amputations and premature death. In the long run, this burden is likely to escalate with an ageing population and lifestyle diseases such as obesity. Thus far, the identification of beneficial therapeutics against chronic wounds have been hindered by the lack of an ideal chronic wound animal model. Although animal models of delayed healing have been developed, none of these models fully recapitulate the complexity of the human chronic wound condition. Furthermore, most animals do not develop chronic wounds. Only the thoroughbred racehorse develops chronic ulcers.

Areas covered: In this review, the different characteristics of chronic wounds that highlight its complexity are described. In addition, currently available models reflecting different aspects of chronic wound pathology and their relevance to human chronic wounds are discussed. This article concludes by listing relevant features representative of an ideal chronic wound model. Additionally, alternative approaches for the development of chronic wound models are discussed.

Expert opinion: Delayed models of healing, including the streptozotocin diabetic model, skin flap model and magnet-induced IR models have emerged. While these models have been widely adopted for preclinical therapeutic testing, their relevance towards human chronic wounds remains debatable. In particular, current delayed healing models often fail to fully incorporate the key characteristics of chronic ulcers. Ultimately, more representative models are required to expedite the advancement of novel therapeutics to the clinic.

ARTICLE HISTORY

Received 5 October 2021 Accepted 12 December 2022

KEYWORDS

Animal models; biofilm infection; chronic wounds; delayed healing models; delayed wound closure; excessive extracellular matrix degradation; hyper thickened epidermis; increased senescent cells population; persistent inflammation