Neutrophils and the repair of hard-to-heal wounds

Abstract

BACKGROUND: Dysfunction of neutrophils in the microenvironment of refractory wounds and their abnormal interactions with other immune cells and repair cells have become a central research focus for understanding the pathophysiology of chronic wounds and developing novel intervention strategies. OBJECTIVE: To investigate the current research status, hotspots, frontiers, and development trends regarding neutrophils in the field of hard-to-heal wound repair. METHODS: Relevant literature regarding neutrophils in the repair of hard-to-heal wounds published between 2004 and 2024 was retrieved from the Web of Science Core Collection database. Bibliometric visualization analysis methods were employed for analysis and visualization, revealing the research landscape, major hotspots, and frontier trends from dimensions including publication volume, countries/regions, institutions, authors, journals, references, and keywords. RESULTS AND CONCLUSION: A total of 1 062 relevant articles concerning neutrophils in hard-to-heal wound repair were included. The annual publication output in this field showed a significant growth trend, especially after 2014, with the number of publications exceeding 100 in 2023, indicating increasing academic attention. The United States led globally with 378 publications and extensive international collaboration networks; China ranked second with 189 publications, showing strong research vitality, though international collaboration and citations per paper still have room for improvement. Shanghai Jiao Tong University in China was the institution with the most publications, while the University of Illinois and Harvard University in the United States were centers of citation frequency. Journal analysis showed that Wound Repair and Regeneration was the core journal with the highest publication and citation counts. Research hotspots focused on inflammation, angiogenesis, diabetic foot ulcers, etc. Keyword clustering timeline and burst analysis revealed that neutrophil extracellular trap formation and neutrophil-macrophage interactions are frontier research trends. The results indicate that the field has formed a clear development path from clinical problems to molecular mechanisms and then to immune intervention strategies, and future precise regulation of neutrophil function is expected to open new avenues for the treatment of hard-to-heal wounds.

1. Introduction

Hard-to-heal wounds are complex wounds that fail to achieve structural and functional recovery after more than 4 weeks of standard treatment [1]. These wounds are prone to prolonged healing, persistent infection risk, and even severe consequences such as amputation [2], significantly impacting patients' quality of life and imposing a heavy socioeconomic burden. Wound healing is a precisely regulated biological process involving sequential phases of inflammation, proliferation, and remodeling [3]. Neutrophils are the first immune cells recruited to the wound site, where they clear pathogens, foreign bodies, and necrotic tissue through chemotaxis, phagocytosis, and bactericidal functions, creating a favorable environment for repair [4]. However, in hard-to-heal wounds, persistent excessive infiltration or functional abnormalities of neutrophils, especially excessive formation of neutrophil extracellular traps (NETs) [5], are closely associated with sustained chronic inflammation and impaired tissue repair [6].

Despite active clinical interventions such as debridement, anti-infection, and growth-promoting therapies, many hard-to-heal wounds remain unhealed [7], prompting researchers to delve into the regulatory mechanisms of immune cells in the wound microenvironment. Currently, dysfunction of neutrophils in the microenvironment of refractory wounds and their abnormal interactions with other immune cells and repair cells have become a central research focus for understanding the pathophysiology of chronic wounds and developing novel intervention strategies [8-11]. However, therapeutic strategies targeting neutrophil regulation are still in the exploratory stage, and their clinical translation faces multiple challenges.

Bibliometrics is an interdisciplinary field integrating principles of library science, mathematics, statistics, and information science. It uses quantitative analysis methods to study the distribution structure, quantitative relationships, and evolutionary patterns of literature, analyze collaboration networks, evaluate academic influence, reveal disciplinary development trends, and identify emerging hotspots and frontier trends, providing objective quantitative evidence for research management and decision-making [12]. Given the lack of systematic bibliometric analysis in this field, this study employed bibliometric methods to systematically review the research context and development trends of neutrophils in hard-to-heal wound repair. Using scientific knowledge mapping as a visualization tool, we applied VOSviewer (developed by Van Eck et al., Leiden University) and CiteSpace (developed by Professor Chen Chaomei's team at Drexel University) to construct visual bibliometric network maps [13-14]. Based on the Web of Science Core Collection database, we conducted an in-depth analysis of relevant literature over the past 20 years, focusing on countries, institutions, authors, journals, references, and keywords.