The Web of Science (WOS) is the greatest global database for collecting and retrieving publications from multiple academic disciplines. Searches were performed based on the WOS Core Collection (WOSCC) database to obtain literature in the Science Citation Index Expanded (SCI-EXPANDED) on April 27^th, 2022. The literature retrieval strategy was as follows. literature type=article, year=2000-2022. (((TS=diabetic foot ulcer) OR (TS= diabetic foot)) AND ((TS= fibroblast) OR (TS=fibroblasts))). After excluding literature that did not meet the language and article type requirements, we selected the rest of the literature by assessing the title and abstract of articles to determine whether they should be included or excluded. The raw data can be found in Supplementary Material ( Supplemental File 1 ). To avoid frequent database update bias, all literature searches and data extractions were performed on April 27^th, and all results were imported into Bibliometrics analysis tools for further analysis.

VOSviewer (24) and Citespace (25) are tools commonly used in knowledge mapping and visualization analysis of scientific literature. Bibliometrix is an open-source tool for performing bibliometric analysis, comprehensive visualization, and knowledge mapping analysis (23). The original data retrieved from WOSCC were analyzed using the bibliometrix package in R version 4.2.0 (Institute for Statistics and Mathematics, Vienna, Austria; www.r-project.org). Biblioshiny software was primarily performed to visualize all retrieved literature and generate visual maps. A visual analysis of annual scientific output and average citation counts provides access to trends in the field. The impact of countries, institutions, authors, and journals is estimated through visual analysis of various bibliometric indicators such as production, citation counts, and H-index. H-index is commonly utilized to evaluate a scholar’s scientific influence and outputs concisely and usefully. Inter-country and inter-author collaboration analyses were also performed, and country collaboration network and author collaboration network maps were generated. Subsequently, high-frequency keywords and highly cited literature analyses were performed. A keyword clustering network map and a historical direct citation network map were constructed to summarize the research hotspots in the field. Based on the analysis of the thematic map, trend topics map, and historical direct citation network map, we outlined the research frontiers and development of fibroblast-related DFUs. CiteSpace software version 6.1.2R was also performed to validate the analysis results (25).

The total number of publications (NP) over a given period could quantitatively and objectively reflect the general development trend of a specific field. A total of 479 articles on fibroblast-related DFUs were published in the WOSCC from January 1^st, 2000 to April 27^th, 2022. The annual publications and the average number of annual citations are presented in Figures S1A , S1B . The overall trend in the number of documents related to fibroblast-related DFUs has gradually increased since 2000, despite some fluctuations during this period. The growth has been rapid since 2011 and maintained a high level after 2016. Additionally, the number of annual citations is increasing rapidly. These findings generally indicated that the research on fibroblast-related DFUs has gradually stabilized. It also meant that fibroblast-related DFUs are arousing growing concern and have significant clinical significance and potential for essential experimental development.

The country scientific production map showed the distribution and numbers of publications by countries/regions worldwide ( Figure S2A ). The USA had the most publications (n=441), and its total citation is 4260 ( Figure 1A ), followed by China (321 records cited 2081 times) and Japan (116 records cited 1070 times). This indicated that the USA had the highest publication production and citations and is the leading prolific and impactful country for fibroblast-related DFUs research. According to the visualization country cooperation map ( Figure 1B ), the USA had the most significant central connection point, which indicated that the USA had the most collaborations with other publishing countries. While the line between the USA and China was the widest, it was noted that these two countries collaborated closely on fibroblast-related DFUs research. In contrast, the strength of research and inter-country partnerships in other countries can be further developed. Besides, Table 1 and Figure 1C illustrate the number of single-country and multi-country publications for the top 20 most productive countries/regions.

All institutions involved in the fibroblast-related DFUs were ranked based on the number of publications. Figure S2B shows the top 20 institutions with 326 relevant publications. The Chinese University of Hong Kong published the maximum number of publications (n=39), followed by Harvard University (n=59) and Shahid Beheshti University Medical Sciences (n=52). These three institutions are from China, the USA, and Iran. In summary, we hypothesized that the USA and China were the two most influential and contributing countries in fibroblast-related DFUs research.

Since 2000, 243 sources have published articles on fibroblast-related DFUs research. Based on Bradford’s Law, 19 high-production journals were classified as core sources based on the number of publications ( Figure 2A ) (26). The total number of articles published in the top 20 academic journals is 168 ( Figure 2B ), with 326 total citations ( Figure S2C ). The academic journal Wound Repair and Regeneration published the maximum number of articles (n=36), and its full citation is 664. Followed by the Journal of Wound Care (11 records cited 119 times), Wounds A Compendium of Clinical Research & Practice (11 records), International Wound Journal (10 records cited 156 times), and Acta Biomaterialia (9 records cited 139 times). These productive journals are essential sources of knowledge in this field. Wound Repair and Regeneration has the most publications and total citations, indicating its significant impact on fibroblast-related DFUs. Following this journal enables more rapid access to the research frontiers and crucial information in this field. Moreover, Figure 2C showed the growth in productivity with time for the top six most productive journals, which indicated that the number of publications per period of these journals increased rapidly.

The H index is predominantly used to evaluate the total influential power of a specific author (27). Since 2000, over 2650 authors have participated in publications on fibroblast-related DFUs research, and 15 authors had more than 25 publications. We identified the top 20 most productive authors, with 168 articles accounting for 35.07% of all articles. The top 20 most productive authors, the top 20 most locally cited authors, and the top 20 most locally influential authors measured by the H-index are presented in Figures S3A–C . Seung-Kyu Han had the most publications (n=18), total citations (n=74), and H-index (n=12). Woo Kyung Kim and Jonathan A. Garlick were relative leaders in each indicator. These authors contributed significantly and notably impacted fibroblast-related DFUs research. Seung-Kyu Han developed a fresh human fibroblast allograft approach and achieved positive results in clinical studies, laying a solid foundation for subsequent research (28). Additionally, according to the author’s collaboration network map ( Figure S4A ), Jonathan A. Garlick seemed to be the author with the most significant collaborative network. Figure S4 shows that Lin Yan has been a relatively active author recently.

Keywords are highly condensed versions of the critical content of the article and can efficiently identify research hotspots and other significant points (29). Figure 3A showed the growth in frequency with time for the top 10 most frequent keywords. It indicated that the keyword “expression” frequency had risen rapidly since 2014, especially after 2019, when it jumped to the number one position. Subsequently, we identified the top 50 high-frequency keywords for fibroblast-related DFUs research with a word cloud ( Figure 3B ) and a tree map ( Figure S5 ). Specifically, “expression” had the most frequency of occurrence (n=83), followed by “foot ulcers” (n=76), “diabetic foot ulcers” (n=72), “fibroblasts” (n=72), angiogenesis” (n=63), “proliferation” (n=47), “cells” (n=45), “skin” (n=44), “in-vitro” (n=42), and “foot” (n=39). More importantly, Biblioshiny software was performed for keyword co-occurrence analysis and categorized relevant keywords into 4 clusters, thus forming a keyword clustering network map ( Figure 3C ). These clusters reflected the preliminary study content and core research regions to which the keywords referred (30). Within the keyword co-occurrence network graph, each node represents a keyword, and the node size represents the popularity; the line between the nodes indicates the intimacy between the keywords.

Clusters1 (red): Mechanisms of fibroblasts in DFUs pathophysiological process and application of fibroblast-derived related materials. The crucial keywords in this group include “diabetic foot ulcers” (avg. pub. per year as of 2022. 72, 3.27 occurrences), “fibroblasts” (avg. pub. per year as of 2022. 72, 3.27 occurrences), “efficacy” (avg. pub. per year as of 2022. 26, 1.18 occurrences) and “management” (avg. pub. per year as of 2022. 26, 1.18 occurrences).

Cluster2 (blue): The molecular mechanisms and therapeutic targets associated with DFUs angiogenesis. The most recent four hot topics in this cluster include “expression” (avg. pub. per year as of 2022. 83, 3.77 occurrences), “foot ulcers” (avg. pub. per year as of 2022. 76, 3.45 occurrences), “angiogenesis” (avg. pub. per year as of 2022. 63, 2.86 occurrences) and “cells” (avg. pub. per year as of 2022. 45, 2.05 occurrences).

Cluster 3 (green): Bioengineered scaffolds for cutaneous wound healing. The most recent four hot topics in this cluster include “proliferation” (avg. pub. per year as of 2022. 47, 2.14 occurrences), “skin” (avg. pub. per year as of 2022. 44, 2 occurrences), and “foot” (avg. pub. per year as of 2022. 39, 1.77 occurrences), “migration” (avg. pub. per year as of 2022. 32, 1.45 occurrences).

Cluster 4 (purple): Validation of fibroblast differentiation-related mechanisms in DFUs in an in vitro model. The most recent four hot topics in this cluster include “in-vitro” (avg. pub. per year as of 2022. 42, 2.1 occurrences), “model” (avg. pub. per year as of 2022. 28, 1.27 occurrences), “tissue” (avg. pub. per year as of 2022. 28, 1.27 occurrences) and “differentiation” (avg. pub. per year as of 2022. 27, 1.23 occurrences).

Research on the molecular mechanisms involved in the pathophysiological process of DFUs, the potential therapeutic targets, and the value of bioengineered scaffolds in wound healing in translational medicine have been highly investigated and were the primary research directions.

Overall, global citations reflect the impact of an article on the whole database, while local citations reflect the influence of a particular article in our retrieval collection. The top 20 most locally cited documents among the 479 publications were summarized in Table 2 , along with their journals, authors, and years of publication. Figure 4A and Table 3 showed the top 20 most global cited documents, and 16 documents had more than 130 citations. The article of William A Marston (31) with the title “The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers,” which was published in 2003 in Diabetes Care, was the most local cited article (49 citations). Followed by the article with the title “Cellular dysfunction in the diabetic fibroblast: impairment in migration, vascular endothelial growth factor production, and response to hypoxia” by Oren Z. Lerman in 2003 from The American Journal of Pathology with 27 local citations. Then the article “Clinical application of fresh fibroblast allografts for the treatment of diabetic foot ulcers: a pilot study” by Seung-Kyu Han in 2004 from Plastic and Reconstructive Surgery. More importantly, these articles revealed the mechanisms underlying the role of fibroblast dysfunction in non-healing DFUs wounds. The safety and efficacy of human fibroblast-derived dermal substitutes in promoting DFUs healing were demonstrated. A solid foundation has been laid to guide the clinical treatment of complex refractory DFUs.

Subsequently, to acquire the interrelationships between this literature and the historical evolution and hotspots of the field, the software performed the historical direct citation network analysis, and a visual map was generated ( Figure 4B ). Each node represents a piece of literature, and the lines between the nodes indicate the citation relationships between publications. Articles with similar subjects and keywords would be integrated into the same cluster. Moreover, articles with a high normalized local citation score were considered vital documents. Based on these connections, papers were grouped into five clusters representing the four research themes of fibroblast-related DFUs since the 21st century. The first cluster (red) can be traced back to 2002 (32), when scholars, represented by Loots, worked on mechanisms related to DFUs generation and healing in the diabetic microenvironment (32). Including increased expression of Cx43 in DFUs dermal fibroblasts retarded fibroblasts migration (33). Increased inflammatory response, expression of inflammatory factors, and abnormal growth factor levels are the primary factors associated with DFUs failure to heal. Targeting these factors may assist in the management of DFUs (34). The second group (purple) focused on several potential therapeutic measures to promote DFUs wound healing (31, 35–39). Clinical study results demonstrated that human fibroblast cell-derived dermal substitutes and autologous in vitro expanded fibroblasts are a safe and effective treatment for DFU (31). Besides, the basic fibroblast growth factor (bFGF) also promotes wound healing in patients with DFU (37).

The third cluster (green) is centralized on the mechanisms of dysfunction of fibroblast migration and release of associated growth factors in DFU and associated therapeutic measures (40–42). Reduced expression of leukocyte chemokines and growth factors at the margins of DFU wounds, resultant angiogenesis in DFU wounds, and impaired fibroblast chemotaxis may explain the poor granulation tissue formation and chronic epithelialization of ulcers (41). Neurotensin-loaded collagen dressings significantly stimulate fibroblast migration and collagen deposition by inhibiting the expression of inflammatory factors, thus promoting DFU wound healing (40, 42). The fourth cluster (blue) is centralized on the potential mechanism of Chinese herbal formula made from the herbs Radix Rehmanniae and Radix Astragali in promoting wound healing in DFU. Chinese herbal formula made from the herbs Radix Rehmanniae and Radix Astragali promotes human fibroblast proliferation and angiogenic and anti-inflammatory effects by increasing fibroblast activity in DFU patients, thereby facilitating the healing of DFU wounds (43, 44). Accordingly, we hypothesized that these research themes might indicate the evolution of research hotspots in the research field of fibroblast-related DFUs.

Biblioshiny software was performed to construct a two-dimensional thematic map with density as the y-axis and centrality as the x-axis ( Figure 5A ). Density represents the development degree of a single theme, and higher density values mean higher maturity of the theme. Centrality indicates the degree of intimacy with different themes, and high centrality means the heart of the research field.

Motor themes represent the core themes with high centrality and maturity. The crucial keywords in this group include “diabetic foot ulcers”, “fibroblasts”, and “model”. Consistent with clustering 1 in the keyword co-occurrence network, the efficacy of human fibroblast-derived skin substitutes on DFU healing was revealed. Clinical studies have shown that human fibroblast-derived skin substitutes can safely and effectively promote wound healing (45–47). This subject has long been of interest to scholars, and concrete results have been achieved. However, substantial breakthrough research is still urgently needed to drive further developments. Niche themes represent isolated themes with high maturity. The critical keywords in this group include “in-vitro”, “skin” and “tissue”. These themes are dedicated to the in vitro validation of measures to promote diabetic foot wound healing and related mechanisms. In 1999, the International Diabetic Foot Working Group published an international consensus and guidelines on the management and prevention of diabetic foot, bringing milestones in the management of diabetic foot (48). With the tireless efforts of researchers over the past decades, the physiological knowledge of wound healing and tissue repair, as well as the mechanisms of nonhealing diabetic foot wounds, has become increasingly sophisticated (49–52), which includes an imbalance between the accumulation of ECM components and their remodeling by tissue degrading matrix metalloproteinase(MMPs) (53), reduced or impaired production of growth factors (54, 55), impaired proliferation and migration of keratinocytes and fibroblasts (56). Further, tissue engineering of skin has been developed and extensively studied (57–59). Nevertheless, most of the studies are still in the in vitro stage, and high-quality clinical RCT studies may be needed to achieve translation from basic to clinical.

Emerging or declining themes indicate low centrality and maturity themes. The crucial keywords in this group include “double-blind”, “factor-bb”, and “mechanism”. These themes are recommended in the clinical study of human platelet-derived growth factor-BB (becaplermin) in treating patients with DFU. Platelet-derived growth factor-BB (becaplermin) is the most studied growth factor, and its local application in DFU has shown some success. Back in 1998, researchers conducted a phase III randomized, placebo-controlled, double-blind study. It investigated the efficacy and safety of a topical gel formulation of recombinant human platelet-derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers (60). Basic themes represent hot themes with low maturity. The empath keywords in this group include “expression”, “foot ulcers”, and “angiogenesis”. Consistent with clustering 2 in the keyword co-occurrence network, these themes are recommended as the molecular mechanisms and therapeutic targets associated with DFU angiogenesis. With the widespread availability of high-throughput sequencing technology in 2010 and the development of single-cell sequencing technology since 2013, extensive multi-omics and phenotypic correlation studies have been carried out. Consequently, researchers extensively investigated the molecular mechanisms associated with angiogenesis in diabetic foot ulcer wounds and their upstream and downstream potential therapeutic targets. This was a sacred step from basic research to translation to clinical application.

The trend topics analysis contributes to exploring research hotspots evolution, historical development trajectory, and future research directions in fibroblast-related DFUs. Biblioshiny software was performed to construct the trend topics map ( Figure 5B ). According to Figure 5B , it was observed that the evolution of topics related to the research of fibroblast-related DFUs is closely associated with the development of bioinformatics. In patients with diabetic foot, diabetic foot ulcers can be caused by pathogenic factors such as chronic inflammation, peripheral arterial disease, and peripheral neuropathy. However, chronic wound development caused by untreated DFU can often lead to amputation. Hence, Prior to 2010, key topics included “trials”, “venous leg ulcer” and “amputation”, etc. This was probably attributed to the fact that technologies such as high-throughput sequencing were not widespread then, and clinically relevant studies could only be conducted for complications related to diabetic foot ulcers to resolve the patient’s suffering as soon as possible. During this time, researchers have explored multiple pathophysiological mechanisms of DFU trauma and associated therapeutic targets. These include inhibition of fibroblast proliferation migration (61), decreased growth factor release, impaired angiogenesis, disrupted collagen accumulation, and increased levels of MMPs (62). Based on this, various therapeutic measures have been developed and applied to contribute significantly to the clinical management of patients with DFU. These included the use of platelet-derived growth factors, epidermal growth factors (63), inhibition of MMP release (62), and skin substitutes containing components such as collagen and fibroblasts to promote the healing of DFU wounds effectively (53). In contrast, after 2010, the explosion and popularity of second-generation sequencing (64) and single-cell sequencing technologies (64). Scientists turned to study the molecular mechanisms involved in the pathophysiological process of DFU and the potential therapeutic targets. Accordingly, the topic has gradually shifted to “expression”, “angiogenesis”, and “inflammation”, and peaked around 2016, which coincides with the peak in annual publications production.

Additionally, critical topics in recent years were focused on “chitosan”, “nanoparticles”, and “matrix-metalloproteinase-9”. Recent studies have shown that squilla chitosan nanosilver-metal complex and chitosan-hyaluronic acid/nano-silver antimicrobial sponges can be used as potential dressings for wounds infected with DFU-resistant bacteria and effectively inhibit infections with drug-resistant bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa (65, 66). The newly developed chitosan nanoparticle drug delivery system loaded with growth factors and metal oxides effectively promotes the healing of DFU wounds. This includes the removal of pathogens in biofilm structure, a reduced inflammatory response, thorough re-epithelization, and advanced collagen deposition and maturation (67, 68). Therefore, we speculated that applying chitosan-based nanoparticles in DFUs might be a trending topic in the future.

DFU is one of the most popular and severe complications of diabetes. The development of DFUs typically occurs in response to neuropathy, peripheral vascular disease, and decreased resistance to infection (2). The persistent non-healing of DFUs wounds may eventually evolve into serious complications such as amputation, causing significant physical and psychological damage to the patient. Thus, an adequate understanding of the mechanisms of functional alterations of DFUs is essential for finding relevant therapeutic targets to promote the healing of diabetic foot ulcers. Cutaneous wound healing is a complex time-dependent multicellular process separated into three overlapping phases: inflammation, proliferation, and remodeling. During this process, multiple cells in the skin, including fibroblasts, keratocytes, and macrophages play essential roles. However, in the diabetic foot wound microenvironment, the normal progression of these phases is impeded, and cellular functions are altered, contributing to a persistent inflammatory state and dysfunctional epithelialization of the wound, ultimately leading to chronic wounds Figures 6 , 7 .

In the current study, research on molecular mechanisms and therapeutic targets related to DFUs angiogenesis can be found in the keyword co-occurrence clustering network map, thematic map, and trend topics map. Combining the analysis of highly cited literature and the extensive related literature, we speculate that the study of molecular mechanisms and therapeutic targets related to DFUs angiogenesis is a focus of academic attention and potentially a research trend for the coming period significant for promoting diabetic wound healing. Angiogenesis refers to expanding its vascular branches by sprouting and forming vascular networks, which are essential for embryonic growth, tissue development, and wound healing (121). Inadequate arterial perfusion associated with peripheral arterial disease, along with macrovascular and microvascular disease, has been reported to be responsible for the chronicity of diabetic foot ulcers (6). Moreover, decreased nutrient supply due to poor granulation tissue angiogenesis is closely associated with impaired healing of diabetic ulcers (122). Inadequate blood perfusion combined with impaired angiogenesis complicates tissue repair in diabetes. Consequently, a thorough understanding of this topic can better reveal the molecular events that delay diabetic wound healing and potential molecular targets that promote healing. Thus, the current dilemma of non-healing DFUs and avoiding serious complications such as amputation can be avoided.

We have identified an explosion of studies related to DFUs angiogenesis starting in 2016. This may be attributed to single-cell sequencing being named “Technology of the Year” by Nature Methods in 2013 (123). It opens new perspectives on exploring molecular mechanisms and therapeutic targets related to DFUs angiogenesis. One of the most researched factors is recombinant human PDGF-BB (Becaprine gel), which has become the only growth factor authorized by the FDA for wound treatment (124). Dopamine is a primary central catecholamine neurotransmitter that controls cognition, mood, and movement and regulates cardiovascular, endocrine, renal, gastrointestinal, and immune functions (125–129). It was shown that activation of dopamine D1 receptors in dermal fibroblasts restores their production of vascular endothelial growth factor A via the protein kinase A pathway and consequently restores angiogenesis in subsequent diabetic skin wound tissue (130). Fibrocytes are bone marrow-derived hematopoietic stem cells integral to wound healing (131). Fibrocytes have been found to promote wound healing by facilitating cell proliferation, re-epithelialization, and angiogenesis compared to dermal fibroblasts and diabetic mice treated with PBS (132). Furthermore, Xing et al. identified that Netrin-1 levels were lowest in DFUs patients compared to healthy controls and DM patients. In in vitro experiments, overexpression of Netrin-1 restored the high glucose-induced impairment of the PI3K/Akt-eNOS pathway via restoring NO production that was significantly inhibited by high glucose, thereby improving DFUs angiogenesis (133).

Importantly, with the development of bioinformatics technologies such as high-throughput sequencing in recent years, extensive identification of Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) by scholars has opened new doors to studying the regulation of gene expression. lncRNAs have been demonstrated to be involved in the abnormal regulation of angiogenic genes by regulating the stability and translation of mRNAs (134). A recent study suggested that lncRNA Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), which is poorly expressed in DFUs patients and consistent with the expression of angiogenic factors such as nuclear factor erythroid 2-related factor 2 (NRF2), Hypoxia-inducible factor-1α (HIF-1α) and VEGF (135). Indeed, Nrf2 can positively regulate the MALAT1/HIF-1α loop and thus regulate angiogenesis, which may become a new target for treating diabetic wounds in the future (135). miRNAs are non-coding RNAs of approximately 22 nucleotides implicated in various roles in critical phases of inflammation, angiogenesis, epithelialization, and remodeling in diabetic wound healing (136, 137). Increasingly, miRNAs have been found to be associated with diabetic wound angiogenesis. In the latest study, Wang et al. (138) have discovered that, unlike non-DFUs wounds, the circulating exosome miR-181b-5p in the plasma of DFUs patients facilitates cellular senescence and inhibits angiogenesis via the NRF2/HO-1 pathway to impede DFUs healing. In further studies, the team used the miR-181b5p inhibitor in vivo experiments and found that angiogenesis was promoted, with the consequent restoration of wound healing capacity. Furthermore, other studies have shown that miR-217 (139) and miR23c (140) are overexpressed in DFUs patients and restrain angiogenesis by inhibiting the HIF-1α/VEGF pathway and targeting stromal-cell-derived factor-1 (SDF-1α). More importantly, inhibition of miR-217 and miR23c could facilitate DFUs angiogenesis by upregulating the above-mentioned corresponding pathways, thereby favoring wound healing. Another exciting study used maggot excreta/secretions to stimulate miR18a/19a overexpression. The results revealed that diabetic wound angiogenesis could be promoted by downregulating thrombochondroitin-1 (TSP-1) expression. This protein inhibits angiogenesis, which could be a new target for DFU therapy (141).

Back in the mid-19th century, the problem of diabetic foot ulcers was first described (142). In 1852, Marchal de Calvi discovered the phenomenon that there was an association between diabetes mellitus and foot gangrene. Subsequently, in 1854, Thomas Hodgkin was similarly aware of the problem. At that time, given the limited development of science and technology, the most popular method of treating ulcers was prolonged bed rest (142). Not until the late 19th century, the genius surgeon Treves provided a landmark contribution to the treatment of the diabetic foot. He established three essential principles for treating foot ulcers: rapid debridement, offloading pressure, and foot care (143). Afterward, these principles led to today’s standard of care for DFUs: surgical debridement, wound off-loading, dressing coverage, and infection control (144), as shown in Figure S6 . Along with a wide range of adjunctive therapies, such as growth factors, hyperbaric oxygen (HBOT), and negative pressure wound therapy (NPWT) (145). Furthermore, in addition to these measures, multidisciplinary diabetic foot care is becoming a focal point of treatment (146).

The goal of diabetic foot treatment is to achieve tissue healing while maintaining adequate function and weight bearing to bed (145). Debridement is a gold standard in treating DFUs, including removing necrotic and inactivated tissue, surrounding callus, and foreign debris from the wound. This process contributes to the formation and re-epithelialization of granulation tissue, and reduces the pressure in the plantar region of the foot (147). Meanwhile, removing necrotic tissue destroyed the breeding ground and physical barrier for bacterial colonization, which could be instrumental in controlling traumatic infections (148). A 10-year retrospective study of standardized wound care protocols revealed that amputation rates in diabetic foot patients decreased through timely and effective debridement (149). Current debridement modalities consist of surgical (sharp debridement), biological (maggot therapy), enzymatic (clostridial collagenase), autolytic (hydrogel), mechanical (hydro surgery), and ultrasound (150–152). Of note, according to the recommendations of the Wound Healing Society (WHS), sharp debridement is the preferred approach to debridement (153). High plantar pressure has been recognized as a primary factor in the development and poor healing of DFUs. Offloading not only destresses the ulcer site, but also ensures the redistribution of shear forces which is currently an effective strategy for treating DFUs (148). Off-loading can be accomplished through various mechanisms, including shoe modifications, boots, and orthopedic walkers (148). Guidelines published by the International Working Group on the Diabetic Foot (IWGDF) suggest that in the absence of infection or ischemia, non-removable and knee-high devices (total-contact casts or non-removable walkers) are the preferred treatment for neuropathic forefoot or midfoot plantar ulcers (154). Infection is a fundamental cause of DFUs morbidity, hospitalization, impaired healing, and amputation. Compared to uninfected DFUs, infection increases the risk of lower extremity amputation by 50% (155). In DFUs wounds, factors such as stress and pressure, decreased function of immune cells (e.g., macrophages and neutrophils), and ischemia makes them more susceptible to infection. More importantly, in diabetic ulcers, the infection can spread rapidly and induce cellulitis, abscesses and osteomyelitis. It can also lead to life-threatening infectious infections when treatment is delayed (156). Effective control of traumatic infections can be achieved through surgical and pharmacological approaches, which are essential for managing DFUs. Antibiotics are considered the most effective drugs available to fight infections in clinical practice. Nevertheless, the consequent problem of drug-resistant microorganisms is increasing. Fortunately, a variety of new anti-infective measures have been developed and proven to be effective. Fortunately, a variety of new anti-infective measures have been developed and proven to be effective. These include new vehicles for drug delivery systems (e.g., multifunctional nanomaterials) (157) and Bioactive Antimicrobial Peptides (5, 158), which bring hope for the control of DFUs infections.

The dressing provides a protective barrier to the wound, not only preventing bacterial contamination and maintaining a moist environment on the wound surface; it also promotes granulation, angiogenesis, autolysis processes, and rapid migration of epidermal cells at the base of the wound to promote wound healing (159). Recently, an RCT study including 160 patients presented a shred of critical evidence. That is, the combination of recombinant epidermal growth factor and nanosilver dressings can effectively promote DFUs’ wound healing and prevent infection (160). In addition, with the development of bioengineering science and technology, wound dressings can also be used as drug delivery systems to deliver various therapeutic substances (drugs, growth factors, peptides, stem cells, and other bioactive substances) to the wound surface (161), thus promoting wound healing and performing an instrumental role in the treatment of DFUs. Notably, several studies have shown the beneficial effects of hyperbaric oxygen therapy in promoting wound healing in DFUs (162–164). A recent multicenter RCT of 73 patients with chronic DFUs revealed superior efficacy of multimodality cyclical pressure Topical Wound Oxygen compared to standard care alone at 12 weeks and 12 months (164). In the end, the education of patients on meticulous foot care and appropriate foot products through a multidisciplinary approach must be considered (145).

Nevertheless, there are still some limitations to our study. First, we only retrieved publications from the WoSCC database, which may contribute to an imperfect collection of relevant publications. Second, we only accessed publications from January 1^st, 2000 to April 27^th, 2022, which would cause the exclusion of some of the most recent findings as this data is continuously updated. Third, some recent critical publications may have yet to receive sufficient attention and thus may not have been explored in depth. Despite these limitations, this study comprehensively reviews the global status and research trends on fibroblast-related DFUs.