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Research hotspot and trend of chronic wounds: A bibliometric analysis from 2013 to 2022

August 2023
Wound Repair and Regeneration 31(7)

August 2023
31(7)

DOI:10.1111/wrr.13117

Authors:

Haitao Xiao

Sichuan University

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Chronic wounds have been confirmed as a vital health problem facing people in the global population aging process. While significant progress has been achieved in the study of chronic wounds, the treatment effect should be further improved. The number of publications regarding chronic wounds has been rising rapidly. In this study, bibliometric analysis was conducted to explore the hotspots and trends in the research on chronic wounds. All relevant studies on chronic wounds between 2013 and 2022 were collected from the PubMed database of the Web of Science (WOS) and the National Center for Biotechnology Information (NCBI). The data were processed and visualized using a series of software. On that basis, more insights can be gained into hotspots and trends of this research field. Wound Repair and Regeneration has the highest academic achievement in the field of chronic wound research. The United States has been confirmed as the most productive country, and the University of California System ranks high among other institutions. Augustin, M. is the author of the most published study, and Frykberg, RG et al. published the most cited study. Furthermore, the hotspots of wound research over the last decade were identified (e.g., bandages, infection and biofilms, pathophysiology and therapy). This study will help researchers gain insights into chronic wound research's hotspots and trends accurately and quickly. Moreover, the exploration of bacterial biofilm and the pathophysiological mechanism of the chronic wound will lay a solid foundation and clear direction for treating chronic wounds. This article is protected by copyright. All rights reserved.

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Chen Xinghan (Orcid ID: 0000-0002-9189-0437)

Research hotspot and trend of chronic wounds: a bibliometric

analysis from 2013 to 2022

Xinghan Chen1,2#, Xiujun Shi2 #, Haitao Xiao1, Dongqin Xiao2*, Xuewen Xu1 *

1 Department of Burns and Plastic Surgery, West China Hospital, Sichuan University,

Chengdu, Sichuan, China.

2 Research Institute of Tissue Engineering and Stem Cells, Nanchong Central

Hospital, the Second Clinical College of North Sichuan Medical College, Nanchong,

Sichuan, China.

# Xinghan Chen and Xiujun Shi contributed equally to this work

* Correspondence should be addressed to:

Dongqin Xiao. No.97, South Renmin Road, Nanchong, Sichuan, 637000, China.

Email address: xiaodongqin@nsmc.edu.cn

Xuewen Xu. #37 Guoxue Alley, Wuhou District, Chengdu, Sichuan, 610041, China.

Email: xuxuewen@scu.edu.cn

This article has been accepted for publication and undergone full peer review but has

not been through the copyediting, typesetting, pagination and proofreading process

which may lead to differences between this version and the Version of Record. Please

cite this article as doi: 10.1111/wrr.13117

Abstract

Chronic wounds have been confirmed as a vital health problem facing people in the global population

aging process. While significant progress has been achieved in the study of chronic wounds, the treatment

effect should be further improved. The number of publications regarding chronic wounds has been rising

rapidly. In this study, bibliometric analysis was conducted to explore the hotspots and trends in the

research on chronic wounds. All relevant studies on chronic wounds between 2013 and 2022 were

collected from the PubMed database of the Web of Science (WOS) and the National Center for

Biotechnology Information (NCBI). The data were processed and visualized using a series of software.

On that basis, more insights can be gained into hotspots and trends of this research field. Wound Repair

and Regeneration has the highest academic achievement in the field of chronic wound research. The

United States has been confirmed as the most productive country, and the University of California System

ranks high among other institutions. Augustin, M. is the author of the most published study, and Frykberg,

RG et al. published the most cited study. Furthermore, the hotspots of wound research over the last decade

were identified (e.g., bandages, infection and biofilms, pathophysiology and therapy). This study will

help researchers gain insights into chronic wound research's hotspots and trends accurately and quickly.

Moreover, the exploration of bacterial biofilm and the pathophysiological mechanism of the chronic

wound will lay a solid foundation and clear direction for treating chronic wounds.

KEYWORDS

Chronic wound; Hotspot; Bibliometric analysis; Biclustering analysis; Visualization

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1. Introduction

Chronic wounds have been confirmed as a serious health issue, specifically among geriatric populations

afflicted by chronic illnesses (e.g., diabetes, vascular disease, and cancer)(1). For example, within the

United States, chronic wounds affected approximately 6.5 million patients, resulting in annual healthcare

expenditures exceeding $25 billion(2). Similarly, in Germany, the prevalence of chronic wounds among

residents in nursing homes exceeded 7%(3). Wound healing that shifts from a histopathological state to

a natural one requires delicate coordination of a wide variety of molecules and cells(4-7). And a wound

that fails to recover in three months can be diagnosed as a chronic wound(8). Chronic wounds can be

roughly classified into three broad types, including diabetic foot ulcers (DFU), vascular ulcers (veins and

arteries), as well as pressure ulcers(9). In addition, there are other types of chronic wounds, such as

radiation ulcers(10) and chronic ulcers resulting from scars(11); however, the incidence of these ulcers

is relatively lower compared to the aforementioned three types. Despite differences in etiology, chronic

wounds' pathophysiological features are similar. The above features comprise long-term wound

stagnation at the inflammatory stage, repeated infection, tissue necrosis, inhibition of angiogenesis,

microenvironment disorders, as well as delayed healing(12-15). The immune system directly plays a

certain role in tissue regeneration throughout wound healing(16). However, the formation of bacterial

biofilms can weaken the host immune system's resistance to local infections and activate excessive

inflammatory cells and factors(17, 18). Besides, the dysfunctional immune system can facilitate biofilm

growth and the persistence of inflammation(19-25).

However, the causal relationship between biofilm, immune dysregulation, and persistent inflammation

for chronic wounds should be clarified(26, 27). Researchers have been developing different strategies to

treat chronic wounds for years. The above methods (e.g., cleaning the wound, destroying the biofilm,

regulating the immune system, and stimulating angiogenesis and epithelial regeneration) have been

designed to improve the local wound environment and facilitate regeneration(28-32). The above

strategies have been often proposed based on biomaterials, biologics, and cellular and molecular

biotechnology developments(18, 33-37). Although research on chronic wounds has made significant

progress, clinicians still have to face considerable challenges in practical treatment due to several

limitations (e.g., an inadequate understanding of chronic wound pathophysiology and biofilm

complexity). Moreover, the incidence of chronic wounds continues to increase as the global population

ages(38-40). Accordingly, more effective treatment methods should be urgently developed to address the

health hazards arising from chronic wounds(41, 42).

Bibliometrics analysis refers to a quantitative statistical method for literature in a certain field, and it is

capable of presenting research hotspots and trend through visualization(43, 44). Moreover, biclustering

analysis can be conducted to strengthen the function of bibliometric analysis and more effectively show

the characteristics of studies in a certain field. For instance, we previously analyzed microneedles’

research hotspots and general trend(45). Moreover, another recent bibliometrics analysis researched the

current state of biofilm(46). Thus, bibliometrics is capable of objectively revealing research hotspots and

guiding future research directions.

There has been increasing research on chronic wounds, whereas rare bibliometric analysis of this topic

has been conducted. Existing studies of chronic wounds were investigated through bibliometric analysis,

and then chronic wound studies were comprehensively evaluated using co-word biclustering analysis.

This study is expected to help researchers gain insights into chronic wound research more quickly and

accurately.

2. Methods

2.1. Data source and search approaches

First, WOS's Science Citation Index Extension (SCI-E) was used according to the following search

strategies: TI = (Chronic wound) and language = English, with a limited time from January 1, 2013, to

December 31, 2022. A total of 2,090 studies were collected, and then some literature was excluded (Fig.

1). Non-study or review publications were filtered out. Furthermore, non-English literature also was

excluded. After that, the co-word clustering analysis will be completed through the Medical Subject

Words (MeSH) terms retrieval function of the National Center for Biotechnology Information (NCBI).

The time was set as 2013 to 2022, and "Chronic wound" was searched as the MeSH word. All the

publications were retrieved on October 21, 2022, to avoid biases due to database updates.

2.2. Data collection

The search results (title, date of publication, country and region, author, sum of citations, and H-index)

were independently evaluated by two reviewers (XJ Shi and HT Xiao), and the overall agreement ratio

was calculated as 0.90. The third reviewer (XH Chen) evaluated the data with conflicting and determined

whether to include them.

The imported data format of the online analysis platform of Bibliometrics (http://bibliometric.com/) and

VOSviewer V1.6.17 (Leiden University, Leiden, the Netherlands) was "Tab Delimited File". The

imported data format of CiteSpace V 6.1.R4 (Drexel University, Philadelphia, PA, United States) was

"Plain Text File". MeSH terms retrieved from NCBI were input into BICOMB V2.02 in "PubMed"

format for analysis. The co-word matrix file obtained from the analysis was input into gCLUTO V1.0

(Graphical Clustering Toolkit) to complete the biclustering visualization.

3. Data investigation

3.1. Bibliometric analysis and geographical distribution

International collaborations and national/regional contributions were visualized using the online analysis

platform of Bibliometrics (http://bibliometric.com/). The colorful clustering visualization was generated

by VOSviewer based on the inter-agency cooperation degree between institutions. The H-index is a

metric used to assess the scholarly achievements of researchers or journals, so it can be employed as a

principal indicator of a journal's scientific impact. Moreover, the density clustering visualization was

based on the number of journals published. When using VOSviewer, we selected "Create a map based

on bibliographic data" as the data format, set "Co-authorship" for the type of analysis, and then created

the "Density Visualization" graphic. Moreover, CiteSpace was adopted to obtain the burst words that

change over time to visualize the research trends and predict the future research direction. After the data

was imported into CiteSpace, the "Remove duplicates" function should be completed before setting the

"keyword" as node types and setting "The number of states" as 2. The journal impact factors (IF) were

determined by the Journal Citation Report (JCR) published in 2022.

3.2. Co-word biclustering analysis

BICOMB and gCLUTO were used for biclustering analysis of major MeSH terms/MeSH subheadings

to find out the research hotspots. Create the "PubMed-2" format file in BICOMB, then import the

corresponding data of MeSH terms and set "main topic + sub-topic" in the "Extract" function.

Subsequently, the major MeSH terms were matrixed using software, and the co-word matrix of high-

frequency MeSH words was established. Next, the co-word matrix was imported into gCLUTO and set

the value of "Number of Clusters" and chose "Repeated Bisection" in the "Cluster Method" function.

Lastly, the matrix and mountain visualization were established for rendering biclustering analysis. Based

on this biclustering analysis, insights into the hotspots of chronic wound research can be gained.

4. Results

4.1. Investigation of publications output

Overall, 1162 studies and 281 reviews of chronic wound studies met the inclusion criteria (Fig. 1). From

2013 to 2022, the number of its publications showed an upward trend, especially the explosive growth

in 2020 (Fig. 2). 215 studies have been published in 2022 thus far, nearly triple the 79 published in 2011.

Nevertheless, the number of publications throughout the year should be higher (215 is not the total

number of publications in 2022).

4.2. The contributions of nations and institutions to global publications

All the studies on chronic wounds came from 88 different countries or regions. According to the thermal

world map after data import (Fig. 3), the above studies are primarily distributed in North America,

Southeast Asia, and Western Europe. The US (n=399) is the critical contributor, followed by China

(n=248) and the UK (n=129) (Table 1). The growth trend of major countries' published literature in this

field is shown in Fig. 4. A national/regional cooperation survey showed that the United States and the

United Kingdom cooperate most frequently (Fig. 5). Centrality is an important indicator for participating

countries in international cooperation. The higher the centrality, the greater the influence on others. The

results show that the United States with the most prominent centrality (center =0.35), followed by

England (0.30) and Germany (0.14) (Table 1). For research institutions, the top five were the University

of California System (n=38), Shanghai Jiao Tong University (n=29), Harvard University (n=24),

University of Miami (n=22), and University of Hamburg (n=22) (Table 1). Based on the co-authors, we

used VOSviewer to cluster the inter-agency collaborations and presented them as density visualizations

(Fig. 6). In this analysis of inter-agency partnerships, agencies in different clusters were divided into nine

clusters with different colors.

4.3. Journals publishing research on chronic wound

Five hundred journals have published studies on chronic wound, and the journals that have made

outstanding contributions to this field are shown in Fig. 7. Of all 1443 studies of chronic wounds, 385

(26.68%) were published in the top 10 journals (Table 2). The top three journals include Wound Repair

and Regeneration (H-index=23), International Wound Journal (H-index=19), and Advances in Wound

Care (H-index=16), accounting for 13.10% of all the included studies. The Journal with the highest IF

among the journals that published over 10 studies was Chemical Engineering Journal (16.744), it was

followed by Advanced Healthcare Materials (11.092) and ACS Applied Materials & Interfaces (10.383).

All three journals are classified as Q1 in accordance with the JCR 2022 standard.

4.4. Authors' contributions to chronic wound research

Table 3 lists the top 10 productive researchers of the 6,870 authors in this study. Augustin Matthias from

Health Care Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf,

Hamburg, Germany. Wang Yunbing from Engineering Research Center for Biomaterials, Sichuan

University, Chengdu, Sichuan, China. Serena Thomas E from Serena Group Research Foundation,

Cambridge, Massachusetts, USA. The studies with high citation frequency were investigated, and the top

10 studies on chronic wounds were listed. The most frequently cited study was "Challenges in the

Treatment of Chronic Wounds" published by Robert et al. in ADVANCES IN WOUND CARE in 2015

(n=863) (Table 4).

4.5. Research hotspots of chronic wound

CiteSpace was used to extract keywords from 1443 literature and obtain the top 25 burst words from

2013 to 2022, which revealed the changing trend of research hotspots (Fig. 8). Based on the retrieval

results, there were 2,513 major MeSH terms /MeSH subheadings with a cumulative frequency of 6,123

times. In accordance with the G-index standard, MeSH terms that occur over 10 times can be defined as

high-frequency terms (Table 5). BICOMB and gCLUTO were employed for biclustering analysis and

visualization of hotspots. BICOMB was adopted to establish the co-word matrix, and the matrix data was

imported into gCLUTO to obtain the matrix visualization (Fig. 9). The matrix on the left corresponds to

the main MeSH terms /MeSH subheading terms on the right. The shade of the blocks in the matrix

indicated the frequency with which the terms were. Next, gCLUTO generated a mountain graph, with

three mountains revealing that the research field could be divided into three clusters (Fig. 10). The

distance between mountains represents the correlation degree between clusters. The height of the

mountains represents the similarity within the cluster. The volume of a mountain is proportional to the

number of terms covered. The peak color reveals the internal standard deviation: the color from red to

green indicates the deviation from low to high. Three clusters were obtained through the biclustering

analysis of publications: (�) Bandages of chronic wound; (�) Infection and biofilms of chronic wound;

(�) Pathophysiology and therapy of chronic wounds.

5. Discussion

As revealed by the result of bibliometric analysis, with the rapid increase of existing research on chronic

wounds from 2013 to 2022, it is hard to keep up with the research hotspots. Bibliometric analysis and

biclustering analysis can be beneficial to find research hotspots and predict future trends. In this study,

existing studies of chronic wounds were extracted from WOS and NCBI, and the research status of

chronic wounds in the past decade was systematically analyzed.

5.1 Overview of chronic wound research

National academic contributions and quality in the field were evaluated by analyzing the number of

studies, total number of citations, centrality, and average number of citations produced by the

country/region. At present, the United States has most significantly affected the studies regarding chronic

wounds (Study counts=399, Total number of citations =11,117), followed by China (Study counts= 248,

Total number of citations =4,138), the UK (Study counts =129, Total number of citations =3,705).

However, the number of studies in the United States reached a high in 2020 (69) and then declined. The

number of publications in China continued to increase, nearly matching the US in 2021 and surpassing

2022 (when data was collected). However, the impact of China's published studies is insufficient

(Centrality=0.04), ranking 7th among the Top 10 countries. Moreover, the overall quality of publications

should be improved further (average number of citations=16.69), ranking 8th among the top 10 countries.

The thermal world map indicates which regions have invested more in research efforts. Furthermore,

Africa, the Middle East, and Eastern Europe have less research in this field, and more international

cooperation and help may be required.

More than half of the top 10 institutions belong to the United States (n=4) and China (n=3), demonstrating

their significant contributions. The colorful density visualization presents the clusters of

different institutions, and the cooperative relationship between them can be intuitively determined.

Institutions that collaborate closely wound be the same color cloud. The larger of cluster area, the more

contributions the group made in the field will be. The bigger of institution’s name, the closer the

cooperation with others. Universities (e.g., Shanghai Jiao Tong University, Harvard University, the

University of Copenhagen, and the University System of Ohio) made outstanding contributions.

The Top 3 journals, Wound Repair and Regeneration, International Wound Journal, and Advances in

Wound Care are highly respected and influential academic publications in the field of chronic wound

management. In addition, the number of research articles published in these journals was comparable to

the combined output of the following seven journals. The Wound Repair and Regeneration is recognized

as the premier publication in the field and holds the top position for total number of citations. Additionally,

its average number of citations is more than twice that of the second-ranked journal, further reinforcing

its status as a highly influential academic journal.

This study reveals that the keywords in the research hotspot have changed roughly between 2016 and

2017 through the time graph of burst words. Before this time, hot topics included bacterial biofilms,

negative pressure wound therapy, and gene expression. Subsequently, hot words in this study focus on

silver nanoparticles, hydrogel, and antibacterial. It is worth noting that this does not mean that the burst

words of the previous period have lost research interest.

5.2 Three clustering hotspots of chronic wound research.

5.2.1. Bandages of chronic wounds

Cluster 0 presents a correlation with bandages of chronic wounds. Polymer materials exhibit excellent

characteristics (e.g., biocompatibility, biodegradability, low toxicity, the balance of strength and

toughness, a simple manufacturing process, and low cost)(47-50). Accordingly, the existing research on

polymer dressing for chronic wounds has been increasing. The necrotic tissue of chronic wound may

cause local or even systemic infection and exert a physical space-occupying effect, thus hindering wound

healing(51). Thus, polymer dressings with the autolytic debridement effect were invented. Thus, polymer

dressings with the autolytic debridement effect were invented(52). Numerous polymer dressings have

been designed with antimicrobial activity to prevent chronic wound infection. For instance,

Arenbergerova et al. prepared electrospun nanofiber dressings that are capable of generating cytotoxic

singlet oxygen(53). Moreover, Ding et al. added cationic groups to the polyurethane dressing to endow

the synthetic material with antibacterial activity(54). However, adding metal ions to the dressing matrix

to enhance the antibacterial ability is still mainstream since metal ions exhibit strong antibacterial ability

and high stability(55-57). Currently, silver nanoparticles are added in most antibacterial dressings since

these nanoparticles exhibit a strong antibacterial ability, thus destroying disulfide bonds in protein

structures(58, 59). However, silver ions are capable of penetrating and destroying cell membranes,

inducing oxidative stress, affecting DNA replication and transcription, and interfering with energy

metabolism in cells(60). Furthermore, copper ions exhibit a strong nonspecific bactericidal ability, and

they can stimulate angiogenesis to promote wound healing(61-64). For instance, Qiao et al. used the

photothermal effects of nano-copper sulfate to increase the bactericidal power of copper ions(65).

Hydrogels have often served as antibacterial carriers for treating wounds. Existing research has suggested

that phage-loaded hydrogel dressings are promising in treating wounds infected with multidrug-resistant

bacteria (MDR)(66, 67). Aerogel has been applied to the research on chronic wound healing(68, 69).

Aerogel exhibits good air permeability, water absorption, biocompatibility, and high drug loading

compared with numerous conventional dressing materials(70, 71). Lopez-Iglesias et al. treated chronic

infectious wounds with vancomycin-loaded chitosan aerogel(72). However, the topical use of antibiotics

for the prevention and treatment of infected wounds is not recommended, which may facilitate the

production of resistant bacteria(73, 74). Excessive ROS can hinder the healing process of chronic

wounds(75). Dressings with antioxidant properties can facilitate the healing of chronic wounds. For

instance, Poly (polyethylene glycol citrate-co-N-isopropyl acrylamide) hydrogel dressings, which have

antioxidant capabilities, are capable of expediting the growth of granulation tissue and facilitating the

maturation of wound epithelial cells(76).

Immune regulation is of vital importance in controlling wound inflammation and facilitating wound

healing. Wang et al. developed a glycopeptide hybrid hydrogel that can facilitate macrophage

polarization to M2 phenotype, mitigate inflammation, and facilitate angiogenesis for chronic wound

healing(77). The establishment of local vascular network takes on a critical significance in chronic wound

healing. Researchers have added adipose-derived mesenchymal stem cell exosomes to hyaluronic acid

dressings. The synergies can more significantly promote neovasculature and endothelial cell proliferation

in chronic wounds, compared with hyaluronic acid hydrogel dressings or exosomes alone(78). Medical-

grade larvae's excretion/secretion was found to have antibacterial, antifungal, and angiogenic effects(79,

80). Biological dressing that indirectly contacts larvae provided a new idea for treating chronic

wounds(81). Wound care management would have a profound effect on the therapeutic effect. Smart

bandage was used for monitoring and Treatment of Chronic Wounds. By monitoring the wound data,

doctors can adjust the treatment plan in time to achieve individualized treatment(82, 83). Over the past

decade, a wide variety of bandages have been developed to facilitate the healing of chronic wounds, thus

profoundly affecting future chronic wound research.

5.2.2. Infection and biofilms of chronic wounds

Cluster 1 presents the correlations with infection and biofilms of chronic wounds. The human body

is home to more than 1,000 species of bacteria that selectively colonize different parts(36, 84). The above

microorganisms play an overall positive role in healthy individuals(85-87). However, when the internal

environment of the human body changes (e.g., diabetes, venous ulcers of the lower extremities, pressure

ulcers, aging, and immunosuppression), the wound bed's colonized bacteria and biofilm can induce

chronic infections and non-healing wounds(87, 88). The formation of bacterial biofilm in chronic

wounds can significantly improve the tolerance of internal bacteria to the immune system(89). Besides,

it may cause the dysfunction of the host's innate immune activation and the cessation of wound

healing at the inflammatory stage(19, 24, 25). Moser et al. have suggested that Pseudomonas

aeruginosa biofilm induced polymorphonuclear leucocytes to stationary phase by inhibiting local

neutrophilic markers (S100A8/A9), keratin-derived chemokines (KC), and granulocyte colony-

stimulating factor (G-CSF). Subsequently, the host is insensitive to the infection of the wound, such

that the tissue around the wound is continuously damaged(17). In addition, biofilm, a public domain

for bacteria to live, provides a medium for information exchange between bacteria. This form of

bacterial communication is termed quorum sensing(90). Bacteria in biofilms communicate with each

other by secreting signaling molecules called autoinducers, thus helping bacteria regulate gene

expression in accordance with environmental conditions and evade host immune responses(91-93).

Accordingly, quorum sensing has become a new strategy for treating chronic wound infections.

Geng et al. employed luteolin as a quorum-sensing inhibitor. The result indicated that the quorum-

sensing gene expression of P. aeruginosa was significantly down-regulated, and the accumulation

of signal molecules was weakened, thus inhibiting the formation of biofilms(94).

Although the harmful effects of biofilm on wound healing have been well recognized, the diagnosis

of biofilm remains challenging at present, and it is largely dependent on experienced physicians to

determine the macro manifestations of wounds(95). Thus, objective and reliable methods for biofilm

detection are worth developing. Biofilm detection methods have been primarily divided into

morphology, microbiology, and molecular detection(18). To be specific, scanning electron

microscopy and confocal laser scanning microscopy based on morphological analysis are

considered the most accurate and reliable tools for biofilm diagnosis(96). However, the above

methods have disadvantages such as high cost, long time, and limited application scenarios, so they

cannot be widely used in the diagnosis of wound biofilm(97, 98). Wu et al. developed a stain detection

method for extracellular polymeric substances, which is capable of quickly and easily achieving

bedside diagnosis of biofilms in chronic wound beds(99).

The prevention or treatment of biofilm refers to the prerequisite for the wound to cross the

inflammatory stage. Since biofilms significantly enhance the tolerance of bacteria to external

pressure, conventional antibiotic treatment usually achieves poor results and easily trigger the

development of drug-resistant bacteria(90, 100). Many researchers have recently focused on

developing safe and effective ways to better destroy biofilms to treat chronic wound infections. For

instance, negative pressure wound therapy (NPWT), ultrasound, antibacterial nanoparticles, phage

therapy, quorum sensing inhibitor antimicrobial peptides (AMP), and maggot debridement therapy(101-

110). Most chronic wound biofilms (Over 90%) are composed of various microorganisms(111). However,

many studies have used a single bacterial biofilm. Although the therapeutic strategies of the above

studies show their innovation and advantages, they are still limited compared with the complex multi-

microbial biofilm in chronic human wounds(112). Accordingly, it is necessary to explore further the

formation mechanism and biological characteristics of biofilm. This will facilitate the construction of

multi-microbial biofilm models more similar to realistic chronic wounds and promote the development

of new treatment strategies.

5.2.3. Pathophysiology and therapy of chronic wounds

Cluster 2 presents a correlation with the pathophysiology and therapy of chronic wounds. The immune

system takes on a crucial significance on wound healing(16). However, chronic wounds are characterized

by ongoing immune dysregulation and inflammation, which interfere with the wound microenvironment

and impede wound healing(113). Biofilms refer to major exogenous factors that interact with the host

immune system. Endogenous factors should be discussed from the pathophysiology of the immune

system. The pathophysiology of chronic wounds involves various immune cells (e.g., basophils, mast

cells, dermal dendritic cells, and T and B lymphocytes)(114-117). However, neutrophils and

macrophages take on a critical significance(118). Proinflammatory M1 macrophages and prolonged

survival of neutrophils may lead to delayed wound healing. Neutrophils recruit more neutrophils and

macrophages by releasing cytokines and chemokines (e.g., TNF-α, IL-1, IL-6, CXCL8, CXCL2, and

MCP-1)(119). In addition, excessive aggregation of neutrophils in chronic wounds can cause excessive

ROS production and disrupt the balance between proteases and protease inhibitors, such that anti-

inflammatory cytokines are excessively degraded(120). Failure of macrophage M1 to M2 phenotype

polarization is also an important cause of immune dysregulation(121-123). Liechty et al. have noted that

M1 macrophages in the hyperglycemic microenvironment overexpressed microRNA-21, such that the

proinflammatory markers were up-regulated, and the M1 phenotype of macrophages were

maintained(124). Pathologic factors (e.g., hypoxia, hyperglycemia, and related advanced glycation end

products (AGEs)) can reduce the ability of macrophages to endocytosis of neutrophils, thus preventing

the polarization of macrophages towards the M2 phenotype(125). Due to failure to endocytose excessive

neutrophils, more proinflammatory M1 macrophages may be recruited.

Immunomodulatory approaches using inflammatory factor antagonists for tissue repair had been

attempted. TNF-α plays a certain role in the regulation of neutrophils and macrophages at the early

inflammatory stage of wound repair. Huang et al. used TNF-α antagonist to increase the wound healing

rate in diabetic rats(126). IL-1 refers to another critical therapeutic target for immune regulation. Perrault

et al. employed an IL-1 receptor antagonist to facilitate chronic wound healing by reducing the infiltration

of macrophages and neutrophils(127). Toita et al. successfully induced macrophage polarization towards

the M2 phenotype using phosphatidylserine-containing liposomes(128). MiRNA is also a vital

immunomodulator, which can control the response of immune cells by regulating gene expression(129).

Zgheib et al. used cerium oxide nanoparticles in combination with miR-146a to facilitate diabetic wound

healing(130). Immunomodulatory-based therapy has been confirmed as a promising and attractive

strategy for treating chronic wounds. However, animal models cannot fully simulate the

immunohistochemical and healing processes because of the complexity of chronic human wounds(131,

132). Thus, the pathophysiology of chronic wounds should be studied in depth.

5.3. Limitation

It should be acknowledged that bibliometric evaluation has some unavoidable limitations. First, some

high-quality studies may not be included in the data due to insufficient citations. As an essential function

of bibliometrics is to analyze the citation number of publications(133), it is difficult for recently

published studies to be widely cited in a short time. Secondly, we used biclustering analysis to classify

and discuss the hot words, but covering all the expected topics was difficult. Third, the data was collected

from WOS, where some recent publications may not have been collected due to delays in updating the

WOS database. Nevertheless, bibliometric analysis can still help us better and faster understand the

research status of a particular field.

6. Conclusions

Since the number of chronic wound studies has been growing increasingly over the past decade, the

research trends in this field should be accurately analyzed. The basic information regarding publications

on chronic wound research (e.g., number, country, institution, and journal) was summarized. The United

States has made the most significant contribution. Although the number of publications published in

China has achieved remarkable progress, the studies' overall quality should be improved. The research

on dressing to facilitate chronic wound healing has made great progress as polymer material technology

has been leaping forward. However, due to the complexity of different bacterial biofilms and the limited

understanding of the pathophysiology of chronic wounds, the treatment of chronic wounds is still facing

challenges. Accordingly, insights into biofilms and the pathophysiological mechanisms of chronic

wounds should be gained, which will lay a solid foundation for chronic wound research. Hopefully, this

study can provide guidance for global researchers.

Acknowledgments

Funding: We are grateful to the funds for supporting this study, including the National Natural Science

Foundation of China (82002289), Natural Science Foundation of Sichuan Province (2022NSFSC0685),

Medical Research Project Plan of Sichuan Province (S20012) and College-City Cooperation Project of

Nanchong City (22SXJCQN0002, 20SXQT0335, 20SXQT0162 and 20SXQT0106).

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the

authors.

Conflict of interest

The authors declared that they have no conflicts of interest to this work.

Informed consent

No human is involved.

Data availability statement

Supporting data can be obtained from the corresponding author.

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with inflammation-suppressing, ROS-scavenging, oxygen and nitric oxide-generating

properties.

Biomaterials

2022;286:121597.

121. Snyder RJ, Lantis J, Kirsner RS, Shah V, Molyneaux M, Carter MJ. Macrophages: A

review of their role in wound healing and their therapeutic use.

Wound repair and

regeneration : official publication of the Wound Healing Society [and] the European

Tissue Repair Society

2016;24(4):613-29.

122. Krzyszczyk P, Schloss R, Palmer A, Berthiaume F. The Role of Macrophages in

Acute and Chronic Wound Healing and Interventions to Promote Pro-wound Healing

Phenotypes.

Frontiers in physiology

2018;9:419.

123. Wilkinson HN, Hardman MJ. Wound healing: cellular mechanisms and pathological

outcomes.

Open biology

2020;10(9):200223.

124. Liechty C, Hu J, Zhang L, Liechty KW, Xu J. Role of microRNA-21 and Its Underlying

Mechanisms in Inflammatory Responses in Diabetic Wounds.

International journal of

molecular sciences

2020;21(9).

125. Guo Y, Lin C, Xu P, Wu S, Fu X, Xia W, et al. AGEs Induced Autophagy Impairs

Cutaneous Wound Healing via Stimulating Macrophage Polarization to M1 in Diabetes.

Scientific reports

2016;6:36416.

126. Huang SM, Wu CS, Chiu MH, Wu CH, Chang YT, Chen GS, et al. High glucose

environment induces M1 macrophage polarization that impairs keratinocyte migration

via TNF-α: An important mechanism to delay the diabetic wound healing.

Journal of

dermatological science

2019;96(3):159-67.

127. Perrault DP, Bramos A, Xu X, Shi S, Wong AK. Local Administration of Interleukin-

1 Receptor Antagonist Improves Diabetic Wound Healing.

Annals of plastic surgery

2018;80(5S Suppl 5):S317-s21.

128. Toita R, Shimizu E, Murata M, Kang JH. Protective and healing effects of apoptotic

mimic-induced M2-like macrophage polarization on pressure ulcers in young and middle-

aged mice.

Journal of controlled release : official journal of the Controlled Release

Society

2021;330:705-14.

129. Jia Y, Wei Y. Modulators of MicroRNA Function in the Immune System.

International

journal of molecular sciences

2020;21(7).

130. Zgheib C, Hilton SA, Dewberry LC, Hodges MM, Ghatak S, Xu J, et al. Use of Cerium

Oxide Nanoparticles Conjugated with MicroRNA-146a to Correct the Diabetic Wound

Healing Impairment.

Journal of the American College of Surgeons

2019;228(1):107-15.

131. Grada A, Mervis J, Falanga V. Research Techniques Made Simple: Animal

Models of Wound Healing.

The Journal of investigative dermatology

2018;138(10):2095-105.e1.

132. Zindle JK, Wolinsky E, Bogie KM. A review of animal models from 2015 to 2020 for

preclinical chronic wounds relevant to human health.

Journal of tissue viability

2021;30(3):291-300.

133. Wallin JA. Bibliometric methods: pitfalls and possibilities.

Basic & clinical

pharmacology & toxicology

2005;97(5):261-75.

Figure legends

Fig. 1. Flow chart of inclusion and exclusion.

Fig. 2. Growth of publications on chronic wounds (2013–2022).

Fig. 3. Geographical distribution of retrieved articles in chronic wounds (2013–2022).

Fig. 4. The growth trends of the top 10 nations/regions in chronic wounds (2013–2022).

Fig. 5. The network map of country/region' cooperation.

Fig. 6. Cluster density visualization map of institutions on chronic wounds (2013–2022).

Fig. 7. Density visualization map of journals on chronic wounds (2013–2022).

Fig. 8. The top 25 burst words from 2013 to 2022.

Fig. 9. Matrix visualization of major MeSH terms/MeSH subheading terms of articles on chronic

wounds.

Fig. 10. Mountain visualization of major MeSH terms/MeSH subheading terms of articles on chronic

wounds.

Fig.1.tif

Fig.2.tif

Fig.3.tif

Fig.4.tif

Fig.5.tif

Fig.6.tif

Fig.7.tif

Fig.8.tif

Fig.9.tif

Fig.10.tif

Table 1. Top ten productive Country/region and institutions on chronic wounds (2013–2022).

Rank Country/region

Article

counts

Centrality

Total number of

citations

Average number of

citations

Institutions

Article

counts

Total number of

citations

1 USA 399 0.35 11, 117 27.86 University of California Syste m 38 723

2 China 248 0.04 4,138 16.69 Shanghai Jiao Tong University 29 590

3 England 129 0.30 3,705 28.72 Harvard University 24 635

4 Germany 107 0.14 2,276 21.27 University of Miami 22 847

5 Ita ly 81 0.07 1,403 17.32 University of Hamburg 22 600

6 India 81 0.02 964 11.9 Sichuan Unive rsity 22 557

7 Aus tralia 69 0.06 2,393 34.68 University of Copenhagen 20 827

8 Canada 52 0.01 1,087 20.9 University of London 20 268

9 Spain 51 0.12 1,242 24.35 University System of Ohio 19 1186

10 Poland 38 0.02 502 13.21 Chinese Academy of Sciences 19 613

Table 2. Top ten journals in the publication on chronic wounds (2013–2022).

Rank Journal H-index IF (2022) Article counts Percentage (N=1,443) Total number of

citations

Average number

of citations

1 Wound Repair and

Regeneration

23 3.401 53 3.673% 1,724 32.53

2 International Wound

Journal 19 3.099 97 6.722% 1,242 12.8

3 Advances in Wound Care 16 4.947 39 2.703% 1,654 42.41

4 Journal of Wound Care 15 2.066 54 3.742% 959 17.76

5 Plos One 10 3.752 17 1.178% 307 18.06

6 Advances in Skin Wound

Care 9 2.373 27 1.871% 4.89 8.7

7 International Journal of

Molecular Sciences 9 6.208 22 1.525% 917 41.68

8 Journal of Materials

Chemistry B 9 7.571 14 0.970% 354 25.29

Wounds a Compend ium of

Clinical Research and

8 1.441 36 2.495% 176 4.89

10 International Journal of

Lower Extremity Wounds 7 1.922 26 1.802% 160 6.15

Table 3. The top ten most productive authors contributed to publications in chronic wounds research

(2013–2022).

Rank Author Article counts H-index Total number of citations

Average number of

citations

1 Augustin M 14 8 423 30.21

2 Wang YB 13 6 2 27 17.46

3 Serena TE 12 4 76 6.33

4 Kirsne r RS 11 5 2 51 22.82

5 Kumar A 10 6 100 10

6 Li Y 10 4 81 8.1

7 Romanelli M 10 6 102 10.2

8 Dissemond J 9 6 246 27.33

9 Guo Y 9 6 148 16.44

10 Lantis JC 9 4 97 10.78

Table 4. Top ten cited articles on chronic wounds (2013–2022).

Rank Title Journal

Corresponding

author

Publication

year

Total

citations

1 Challenges in the Treatment of Chronic Wounds

ADVANCES IN WOUND

CARE

Frykberg, RG 2015 863

Chronic Wound Healing: A Review of Current Management and

Treatments

ADVANCES IN THERAPY Han, G 2017 717

The Role of Macrophages in Acute and Chronic Wound Healing

and Interventions to Promote Pro-wound Healing Phenotypes

FRONTIERS IN

PHYSIOLOGY

Berthiaume, F 2018 464

An Economic Evaluation of the Impact, Cost, and Medicare

Policy Implications of Chronic Nonhealing Wounds.

VALUE IN HEALTH Nusgart, M 2018 451

Mesenchymal Stem Cell Exosomes Induce Proliferation and

Migration of Normal and Chronic Wound Fibroblasts, and

Enhance Angiogenesis In Vitro

STEM CELLS AND

DEVELOPMENT

Van Badiavas, E 2015 374

Cellular and molecular mechanisms of repair in acute and

chronic wound healing

BRITISH JOURNAL OF

DERMATOLOGY

Martin, P 2015 365

7 Inflammation in Chronic Wounds

INTERNATIONAL

JOURNAL OF

MOLECULAR SCIENCES

Xue, ML 2016 364

Electrospun Nanofibers as Dressings for Chronic Wound Care:

Advances, Challenges, and Future Prospects

MACROMOLECULAR

BIOSCIENCE

Kingshott, P 2014 344

Engineering Bioactive Self-Healing Antibacterial Exosomes

Hydrogel for Promoting Chronic Diabetic Wound Healing and

Complete Skin Regeneration

THERANOSTICS Mao, C 2019 320

Macrophage Phenotypes Regulate Scar Formation

and Chronic Wound Healing

INTERNATIONAL

JOURNAL OF

MOLECULAR SCIENCES

Murray, RZ 2017 317

Table 5. Major MeSH terms/MeSH subheadings from the included publications on chronic wounds

(n=1,443).

Rank Major MeSH terms/MeSH subheadings Frequency

Proportion of

frequency (%)

Cumulative

percentage (%)

1 Wound Hea ling 52 3.6036 3.60 36

2 Wound Healing/pathophysiology 42 2.9106 6.5142

3 Wound H ealing/drug effects 40 2.7720 9 .2862

4 Wounds and Injuries/therapy 35 2.4255 11.7117

5 Wound Infection/microbiology 19 1.3167 13.0284

6 Biofilms/drug effects 14 0.9702 13.9986

7 Bandag es 14 0.9702 14.9688

8 Wound Inf ection/therapy 14 0.9702 15.939

9 Skin Ulcer/therapy 11 0.7623 16.7013

10 Anti-Bacterial Agents/pharmacology 10 0.6930 17.3943

11 Hydrogels/chemistry 10 0.6930 18.0873

Bibliometric analysis and visualization of quorum sensing research over the last two decade

Article

Full-text available

Apr 2024

Background Quorum sensing (QS) research stands as a pivotal and multifaceted domain within microbiology, holding profound implications across various scientific disciplines. This bibliometric analysis seeks to offer an extensive overview of QS research, covering the period from 2004 to 2023. It aims to elucidate the hotspots, trends, and the evolving dynamics within this research domain. Methods We conducted an exhaustive review of the literature, employing meticulous data curation from the Science Citation Index Extension (SCI-E) within the Web of Science (WOS) database. Subsequently, our survey delves into evolving publication trends, the constellation of influential authors and institutions, key journals shaping the discourse, global collaborative networks, and thematic hotspots that define the QS research field. Results The findings demonstrate a consistent and growing interest in QS research throughout the years, encompassing a substantial dataset of 4,849 analyzed articles. Journals such as Frontiers in Microbiology have emerged as significant contributor to the QS literature, highlighting the increasing recognition of QS's importance across various research fields. Influential research in the realm of QS often centers on microbial communication, biofilm formation, and the development of QS inhibitors. Notably, leading countries engaged in QS research include the United States, China, and India. Moreover, the analysis identifies research focal points spanning diverse domains, including pharmacological properties, genetics and metabolic pathways, as well as physiological and signal transduction mechanisms, reaffirming the multidisciplinary character of QS research. Conclusion This bibliometric exploration provides a panoramic overview of the current state of QS research. The data portrays a consistent trend of expansion and advancement within this domain, signaling numerous prospects for forthcoming research and development. Scholars and stakeholders engaged in the QS field can harness these findings to navigate the evolving terrain with precision and speed, thereby enhancing our comprehension and utilization of QS in various scientific and clinical domains.

The effect of VEGF stimulation in diabetic foot ulcers: A systematic review

Article

Full-text available

Mar 2024
WOUND REPAIR REGEN

Diabetic foot ulcers are a common and severe complication of diabetes mellitus, and a risk factor for amputation. Because of the vessel insufficiency in diabetic foot ulcers (DFU), vascular endothelial growth factor (VEGF) that simulates angiogenesis is of interest to promote wound healing. This systematic review evaluates the last 16 years of in‐vivo studies with VEGF stimulation as a treatment for DFU, developed based on the last published systematic article. A total of 961 articles were identified through databases in two phases. 947 articles were excluded by exclusion criteria, and four articles met our inclusion criteria and were included. The effects of VEGF on wound healing were analysed in all four studies. In three studies, the VEGF‐treated wounds showed statistically faster healing than those not treated with VEGF. In one study, the VEGF‐treated wounds revealed a positive trend toward faster healing. Furthermore, all four studies were in favor of using VEGF, but concluded that further research is needed. These studies showed a positive trend towards faster healing and was safe when using VEGF topically on humans. Furthermore, viral particles of VEGF seem to have a systematic effect when a dose exceeding 5.0 × 10 ⁹ vp pr wound. Future research in using VEGF on DFU should focus on VEGF's relevant dosage, release rate, and specific mechanism. This review inspires further research, and a consistent study design is prerequisite such that results are more homogenic and comparable. Much effort is needed to translate the results into our clinical practice.

Bibliometric analysis and visualization of endocrine therapy for breast cancer research in the last two decade

Article

Full-text available

Dec 2023

Background Breast cancer endocrine therapy research has become a crucial domain in oncology since hormone receptor-positive breast cancers have been increasingly recognized, and targeted therapeutic interventions have been advancing over the past few years. This bibliometric analysis attempts to shed light on the trends, dynamics, and knowledge hotspots that have shaped the landscape of breast cancer endocrine therapy research between 2003 and 2022. Methods In this study, we comprehensively reviewed the scientific literature spanning the above-mentioned period, which included publications accessible through the database of the Web of Science (WOS) and the National Center for Biotechnology Information (NCBI). Next, a systematic and data-driven analysis supported by sophisticated software tools was conducted, such that the core themes, prolific authors, influential journals, prominent countries, and critical citation patterns in the relevant research field can be clarified. Results A continuous and substantial expansion of breast cancer endocrine therapy research was revealed over the evaluated period. A total of 1,317 scholarly articles were examined. The results of the analysis suggested that research on endocrine therapy for breast cancer has laid a solid basis for the treatment of hormone receptor-positive breast cancer. From a geographical perspective, the US, the UK, and China emerged as the most active contributors, illustrating the global impact of this study. Furthermore, our analysis delineated prominent research topics that have dominated the discourse in the past two decades, including drug therapy, therapeutic efficacy, molecular biomarkers, and hormonal receptor interactions. Conclusion This comprehensive bibliometric analysis provides a panoramic view of the ever-evolving landscape of breast cancer endocrine therapy research. The findings highlight the trajectory of past developments while signifying an avenue of vast opportunities for future investigations and therapeutic advancements. As the field continues to burgeon, this analysis will provide valuable guidance for to researchers toward pertinent knowledge hotspots and emerging trends, which can expedite the discoveries in the realm of breast cancer endocrine therapy.

Human Wound and Its Burden: Updated 2022 Compendium of Estimates

Article

Sep 2023

Chandan K. Sen

Significance: Chronic wounds affect 10.5 million (up 2.3 million from the 2014 update) of U.S. Medicare beneficiaries. Chronic wounds impact the quality of life of nearly 2.5% of the total population of the United States. This fraction is larger in the elderly. These wounds can lead to a range of complications and health care costs. Given the aging population, the continued threat of diabetes and obesity worldwide, and the persistent problem of infection, it is expected that chronic wounds will continue to be a substantial clinical, social, and economic challenge. Disparities in the prevalence and management of chronic wounds exist, with underserved communities and marginalized populations often facing greater challenges in accessing quality wound care. These disparities exacerbate the public health burden. Recent Advances: U.S. Centers for Medicare and Medicaid Services had proposed revision of its local coverage determination limiting the use of skin substitute grafts/cellular and/or tissue-based products for the treatment of diabetic foot ulcers and venous leg ulcers in the U.S. Medicare population. In response to the comment phase, this proposal has been put on hold. The U.S. Food and Drug Administration (FDA) has renewed its focus on addressing nonhealing chronic wounds and has outlined efforts to address identified barriers to product development for nonhealing chronic wounds. The new approach places emphasis on engaging key wound healing stakeholders, including academia, professional associations, patient groups, reimbursement organizations, and industry. Finally, recent advances demonstrating that wounds closed by current FDA definition of wound closure may remain functionally open because of deficiencies in restoration of barrier function warrant revisiting the wound closure endpoint. Such "closed" wounds that are functionally open, also known as invisible wounds, are likely to be associated with high wound recurrence. Future Directions: Addressing the public health problem of chronic wounds will require a multifaceted approach that includes prevention, improved wound care management, and addressing the underlying risk factors.

On‐Demand Removable Self‐Healing and pH‐Responsive Europium‐Releasing Adhesive Dressing Enables Inflammatory Microenvironment Modulation and Angiogenesis for Diabetic Wound Healing

Article

Full-text available

Nov 2022
SMALL

Current diabetic wound treatments remain unsatisfactory due to the lack of a comprehensive strategy that can integrate strong applicability (tissue adhesiveness, shape adaptability, fast self‐healability, and facile dressing change) with the initiation and smooth connection of the cascade wound healing processes. Herein, benefiting from the multifaceted bonding ability of tannic acid to metal ions and various polymers, a family of tannin–europium coordination complex crosslinked citrate‐based mussel‐inspired bioadhesives (TE‐CMBAs) are specially developed for diabetic wound healing. TE‐CMBAs can gel instantly (< 60 s), possess favorable shape‐adaptability, considerable mechanical strengths, high elasticity, considerable wet tissue adhesiveness (≈40 kPa), favorable photothermal antimicrobial activity, excellent anti‐oxidant activity, biocompatibility, and angiogenetic property. The reversible hydrogen bond crosslinking and sensitive metal–phenolic coordination also confers TE‐CMBAs with self‐healability, pH‐responsive europium ion and TA releasing properties and on‐demand removability upon mixing with borax solution, enabling convenient painless dressing change and the smooth connection of inflammatory microenvironment modulation, angiogenesis promotion, and effective extracellular matrix production leveraging the acidic pH condition of diabetic wounds. This adhesive dressing provides a comprehensive regenerative strategy for diabetic wound management and can be extended to other complicated tissue healing scenarios.

Global research status of pathological scar reported over the period 2001–2021: A 20‐year bibliometric analysis

Article

Full-text available

Oct 2022
Int Wound J

Pathological scar is a classic problem in plastic and reconstructive surgery. Although the researches on pathological scar have been conducted for decades, the way to go to address this thorny problem still remains challenging. To the best of our knowledge, few bibliometric analysis concerning pathological scar have been reported. In this study, we set out to employ bibliometric and visual analysis to offer research status and trends of pathological scar over the period 2001-2021. All publications covering pathological scar during 2001-2021 were retrieved and extracted from the Web of Science database. We applied VOSviewer software to evaluate the keywords and research hotpots, and the online tool (http://bibliometric.com/) was used to carried out the publication trends analysis. A total of 2221 pathological scar-related articles were identified over the period 2001-2021. China is the country which had the largest volume of publications (819, 36.87%), followed by the United States (416, 18.73%), Japan (144, 6.48%), Korea (142, 6.39%), and England (118, 5.31%). Among the institutions and journals, Shanghai Jiao Tong University (167) and Wound Repair and Regeneration (85) accounted for the most papers related to pathological scar, respectively. Professor Bayat A, who had the most citation frequency (2303), made great contribution in pathological scar field. "Fibroblast", "expression", and "proliferation" were identified as the pathological scar research hotspot through analysis of the keywords. In terms of publication, China ranked first all over the world, but the numbers of publication are inconsistent with the citation frequency, ranking first and second, respectively. Shanghai Jiao Tong University and journal Wound Repair and Regeneration stand for the highest level of research in this field to a certain extent. In the early stage, the research focus was mainly on the prevention, treatment, and risk factors for recurrence of pathological scar from cases. In the later stage, the research focus was on the comprehensive management, in which the mechanism research was in-depth to the molecular and gene level.

Synergistic Chemo-/Photothermal-therapy Based on Supercritical Technology-assisted Chitosan-Indocyanine Green/Luteolin Nanocomposites for Wound Healing

Article

Full-text available

Sep 2022

Despite the success, it is highly challenging to battle against pathogenic biofilms-based chronic bacterial infections by conventional antibiotic therapy. Herein, we report a near-infrared (NIR)/acid-induced nanoplatform based on chitosan (CS)-coated indocyanine green (ICG, photosensitizer)/luteolin (LUT, a natural quorum sensing inhibitor) nanocomposites (ICG/LUT-CS) as antibacterial and antibiofilm agents for skin wound healing. Initially, the ICG/LUT nanoplatforms are prepared by the supercritical antisolvent technology (SAS) and coated with the CS layer. The obtained ICG/LUT-CS with ultra-high encapsulation efficiency exhibited more favorable photothermal conversion effects and improved NIR laser/acid dual-induced drug release behavior than individual modalities, achieving exceptional bacteria-killing and biofilm elimination effects. Moreover, the ICG/LUT-CS realized the synergetic effects of chemotherapy and photothermal therapy (PTT) outcomes for wound healing. Together, our findings provided an appealing strategy for the rapid preparation and future translational application of ICG/LUT-CS as an ideal agent for fighting against biofilm infections.

Bactericidal and anti-biofilm effects of uncharged and cationic ultrasound-responsive nitric oxide microbubbles on Pseudomonas aeruginosa biofilms

Article

Full-text available

Aug 2022

Bacterial biofilms are a major and ongoing concern for public health, featuring both inherited genetic resistance traits and a conferred innate tolerance to traditional antibiotic therapies. Consequently, there is a growing need for novel methods of drug delivery, to increase the efficacy of antimicrobial agents. This research evaluated the anti-biofilm and bactericidal effects of ultrasound responsive gas-microbubbles (MBs) of either air or nitric oxide, using an in vitro Pseudomonas aeruginosa biofilm model grown in artificial wound medium. The four lipid-based MB formulations evaluated were room-air MBs (RAMBs) and nitric oxide MBs (NOMBs) with no electrical charge, as well as cationic (+) RAMBs⁺ and NOMBs⁺. Two principal treatment conditions were used: i) ultrasound stimulated MBs only, and ii) ultrasound stimulated MBs with a sub-inhibitory concentration (4 µg/mL) of the antibiotic gentamicin. The total treatment time was divided into a 60 second passive MB interaction period prior to 40 second ultrasound exposure; each MB formulation was tested in triplicate. Ultrasound stimulated RAMBs and NOMBs without antibiotic achieved reductions in biofilm biomass of 93.3% and 94.0%, respectively. Their bactericidal efficacy however was limited, with a reduction in culturable cells of 26.9% and 65.3%, respectively. NOMBs with sub-inhibitory antibiotic produced the most significant reduction in biofilm biomass, corresponding to a 99.9% (SD ± 5.21%); and a 99.9% (SD ± 0.07%) (3-log) reduction in culturable bacterial cells. Cationic MBs were initially manufactured to promote binding of MBs to negatively charged biofilms, but these formulations also demonstrated intrinsic bactericidal properties. In the absence of antibiotic, the bactericidal efficacy of RAMB⁺ and NOMB⁺ was greater that of uncharged counterparts, reducing culturable cells by 84.7% and 86.1% respectively; increasing to 99.8% when combined with antibiotic. This study thus demonstrates the anti-biofilm and bactericidal utility of ultrasound stimulated MBs, and specifically is the first to demonstrate the efficacy of a NOMB for the dispersal and potentiation of antibiotics against bacterial biofilms in vitro. Importantly the biofilm system and complex growth-medium were selected to recapitulate key morphological features of in vivo biofilms. The results us offer new insight for the development of new clinical treatments, for example, in chronic wounds.

ECM-mimetic immunomodulatory hydrogel for methicillin-resistant Staphylococcus aureus –infected chronic skin wound healing

Article

Full-text available

Jul 2022

The treatment of difficult-to-heal wounds remains a substantial clinical challenge due to deteriorative tissue microenvironment including the loss of extracellular matrix (ECM), excessive inflammation, impaired angiogenesis, and bacterial infection. Inspired by the chemical components, fibrous structure, and biological function of natural ECM, antibacterial and tissue environment–responsive glycopeptide hybrid hydrogel was developed for chronic wound healing. The hydrogel can facilitate the cell proliferation and macrophage polarization to M2 phenotype, and show potent antibacterial efficacy against both Gram-negative and Gram-positive bacteria. Significantly, the glycopeptide hydrogel accelerated the reconstruction of methicillin-resistant Staphylococcus aureus (MRSA)–infected full-thickness diabetic and scalding skin by orchestrating a pro-regenerative response indicated by abundant M2-type macrophages, attenuated inflammation, and promoted angiogenesis. Collectively, ECM-mimetic and immunomodulatory glycopeptide hydrogel is a promising multifunctional dressing to reshape the damaged tissue environment without additional drugs, exogenous cytokines, or cells, providing an effective strategy for the repair and regeneration of chronic cutaneous wounds.

Biofilms in wound healing: A bibliometric and visualised study

Article

Full-text available

Jun 2022
Int Wound J

Bibliometric analyses are often used as a means of visualising the knowledge base and associated trends and patterns in a target scientific field based on a quantitative review of the corresponding literature. In this study, we explore the current status of research pertaining to biofilms in wound healing and elucidate trends in this research space. Through this process, we gain insight into findings from papers indexed in the Web of Science Core Collection. These references were then analysed and plotted using Microsoft Excel 2019, VOSviewer, and CiteSpace V. The results provide a fresh perspective regarding global trends and hotspots in biofilm‐related wound healing research. These findings also offer a foundation that researchers can use to identify active hotspots of scientific interest to guide further research endeavours.

Point-of-Care Wound Blotting with Alcian Blue Grading versus Fluorescence Imaging for Biofilm Detection and Predicting 90-Day Healing Outcomes

Article

Full-text available

May 2022

Biofilm infection has been identified as a crucial factor of the pathogenesis of chronic wound, but wound biofilm diagnosis remains as an unmet clinical need. We previously proposed a modified wound blotting technique using Alcian blue staining for biofilm detection that was characterized as being non-invasive, time-saving, non-expansive, and informative for biofilm distribution. In this study, we adapted a novel Alcian blue grading method as the severity of biofilm infection for the wound blotting technique and compared its biofilm detection efficacy with MolecuLight i:X- a point-of-care florescence imaging device to detect bacteria and biofilm in wounds. Moreover, their predictive value of complete wound healing at 90 days was analyzed. When validated with wound culture results in the 53 enrolled subjects with chronic wounds, the modified wound blotting method showed a strong association with wound culture, while MolecuLight i:X only exhibited a weak association. In predicting 90-day wound outcomes, the modified wound blotting method showed a strong association (Kendall’s tau value = 0.563, p < 0.001), and the wound culture showed a moderate association (Spearman’s rho = 0.535, p < 0.001), but MolecuLight i:X exhibited no significant association (p = 0.184). In this study, modified wound blotting with the Alcian blue grading method showed superior value to MolecuLight i:X both in biofilm detection and predictive validity in 90-day wound-healing outcomes.

Antibiotics-Free Compounds for Chronic Wound Healing

Article

Full-text available

May 2022

The rapid rise in the health burden associated with chronic wounds is of great concern to policymakers, academia, and industry. This could be attributed to the devastating implications of this condition, and specifically, chronic wounds which have been linked to invasive microbial infections affecting patients’ quality of life. Unfortunately, antibiotics are not always helpful due to their poor penetration of bacterial biofilms and the emergence of antimicrobial resistance. Hence, there is an urgent need to explore antibiotics-free compounds/formulations with proven or potential antimicrobial, anti-inflammatory, antioxidant, and wound healing efficacy. The mechanism of antibiotics-free compounds is thought to include the disruption of the bacteria cell structure, preventing cell division, membrane porins, motility, and the formation of a biofilm. Furthermore, some of these compounds foster tissue regeneration by modulating growth factor expression. In this review article, the focus is placed on a number of non-antibiotic compounds possessing some of the aforementioned pharmacological and physiological activities. Specific interest is given to Aloe vera, curcumin, cinnamaldehyde, polyhexanide, retinoids, ascorbate, tocochromanols, and chitosan. These compounds (when alone or in formulation with other biologically active molecules) could be a dependable alternative in the management or prevention of chronic wounds.

Therapeutic applications of electrospun nanofibers impregnated with various biological macromolecules for effective wound healing strategy – A review

Article

Jan 2023
BIOMED PHARMACOTHER

A Non-healing infected wound is an ever-growing global epidemic, with increasing burden of mortality rates and management costs. The problems of chronic wound infections and their outcomes will continue as long as their underlying causes like diabetic wounds grow and spread. Commercial wound therapies employed have limited potential that inhibits pivotal functions and tissue re-epithelialization properties resulting in wound infections. Nanomaterial based drug delivery formulations involving biological macromolecules are developing areas of interest in wound healing applications which are utilized in the re-epithelialization of skin with cost-effective preparations. Research conducted on nanofibers has shown enhanced skin establishment with improved cell proliferation and growth and delivery of bioactive organic molecules at the wound site. However, drug targeted delivery with anti-scarring properties and tissue regeneration aspects have not been updated and discussed in the case of macromolecule impregnated nanofibrous mats. Hence, this review focuses on the brief concepts of wound healing and wound management, therapeutic commercialized wound dressings currently available in the field of wound care, effective electrospun nanofibers impregnated with different biological macromolecules and advancement of nanomaterials for tissue engineering have been discussed. These new findings will pave the way for producing anti-scarring high effective wound scaffolds for drug delivery.

Promoting the healing of infected diabetic wound by an anti-bacterial and nano-enzyme-containing hydrogel with inflammation-suppressing, ROS-scavenging, oxygen and nitric oxide-generating properties

Article

May 2022
BIOMATERIALS

The diabetic wound is easily to develop into a chronic wound because of the extremely serious and complex inflammatory microenvironment including biofilm formation, over-expressed reactive oxygen species (ROS), hypoxia and insufficiency of nitric oxide (NO) synthesis. In this work, a multifunctional hydrogel was designed and prepared by crosslinking hydrophilic poly (PEGMA-co-GMA-co-AAm) (PPGA) polymers with hyperbranched poly-L-lysine (HBPL)-modified manganese dioxide (MnO2) nanozymes. Pravastatin sodium, which is supposed to participate in the synthesis of nitric oxide (NO), was further loaded to obtain the HMP hydrogel. The capabilities of this hydrogel in scavenging different types of ROS, generating O2, killing broad spectrum bacteria, and protecting cells against oxidative stress were confirmed in vitro. The transcriptome analysis revealed that HBPL inhibited bacterial quorum sensing (QS) system, downregulated virulent genes, and interfered bacterial metabolism. The HBPL-crosslinked hydrogels killed up to 94.1%–99.5% of methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli (E. coli), Pseudomonas aeruginosa (PAO1) even at 10⁹ CFU/mL. HBPL modification greatly increased the stability of MnO2 nanosheets in physiological environment. The MRSA-caused infection was effectively treated by the HBPL-crosslinked HMP hydrogel in vivo, and thereby the wound closure at inflammatory phase was promoted significantly. The treatment of HMP hydrogel reduced significantly the ROS degree and relieved the inflammatory level, accompanied by the decreased neutrophil infiltration and M2-type macrophage polarization in vivo. Significantly lower levels of inflammatory factors such as interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α) and chemokines-1 (CXCL-1), and higher levels of anti-inflammatory cytokines such as IL-4 and IL-10 were also confirmed. Moreover, the HMP hydrogel could promote the secretion of TGF-β and stimulate neovascularization, and deposition of collagen with a thicker skin and epithelium structure.

Research hotspot and trend of chronic wounds: A bibliometric analysis from 2013 to 2022

Abstract

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