Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors present an exhaustive review of the role of chemokines in wound healing. The review is complete and has many good points. The main problem is that the paper is so long that it will be hard for the reviewer to complete the review. There are many redundancies that could be removed to streamline the paper. For instance, the authors provide descriptions of the types of chemokines in both the introduction, and then again in section 2. Right now, the paper reads like a thesis. I would suggest that the authors make the first part of the paper that reviews the different chemokines and their receptors much shorter. They should focus on the role of chemokines on wound healing (and make it more focused). The paper could be reduced by one third to one half. 

The references in text are also provided differently. For instance, on line 672 you provide author names and a date, and then a reference number. On line 679, you provide a DOI number. 

The tables and figures are well-done and should remain. 

Author Response

Response to comments from reviewer #1

The authors present an exhaustive review of the role of chemokines in wound healing. The review is complete and has many good points. The main problem is that the paper is so long that it will be hard for the reviewer to complete the review. There are many redundancies that could be removed to streamline the paper. For instance, the authors provide descriptions of the types of chemokines in both the introduction, and then again in section 2. Right now, the paper reads like a thesis. I would suggest that the authors make the first part of the paper that reviews the different chemokines and their receptors much shorter. They should focus on the role of chemokines on wound healing (and make it more focused). The paper could be reduced by one third to one half.

 

Response: We thank the reviewer for his valuable suggestions. As per the reviewer's comment, we have reduced the length of the introduction comprising the chemokines and its types without altering the important subject matter.

Comment: The references in text are also provided differently. For instance, on line 672 you provide author names and a date, and then a reference number. On line 679, you provide a DOI number.

Response: We regret that one reference was not cited. We have revised and updated the references in the revised manuscript.

Comment: The tables and figures are well-done and should remain.

Response: We thank the reviewer for his time and positive report of our manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

 

Based on the Abstract:

“This review synthesizes current knowledge on chemokine biology in wound repair, with a focus on their spatiotemporal regulation across hemostasis, inflammation, proliferation, and remodeling phases. We detail chemokine classification . . . evaluate emerging therapeutic strategies . . . designed to restore chemokine gradient integrity and promote healing. . . advances in structural biology and protein engineering are highlighted . . . to overcome chemokine redundancy. The review concludes that precision modulation of chemokine networks “offers a promising translational framework to redirect chronic inflammation toward regenerative healing, thereby addressing a significant unmet clinical need in chronic wound management.”

 

The review does a good job of describing current knowledge of the use of chemokines to improve chronic wound management, including specific strategies for specific dysregulations in each phase of healing. However “offers a promising translational framework to redirect chronic inflammation toward regenerative healing, thereby addressing a significant unmet clinical need in chronic wound management” requires more than provided. To suggest solving a clinical problem as well as providing a translational path requires more than just proving that chemokines can statistically significantly improve healing in chronic wounds.

 

First, there has to be a clinical problem that is currently unsolved as well as what an acceptable solution would be able to do. The review has to have this problem-solving bent and state where we are in terms of solving specific clinical problems including the translational issues. At least what are the next steps to show proof of concept for a particular clinical problem. It is complicated by the fact that different chronic wounds have different needs as well as different acceptable outcomes.

 

Although many of the biomechanisms needed to be improved to heal chronic wounds are similar, there is not a one size fits all. What is needed is a design hierarchy for each specific chronic wound. The review has to explain where we are in determining what the chemokine strategies can quantitatively do to improve each biomechanism as well as how it can be used to move up the design hierarchy for a particular application.

 

For example the design hierarchy for diabetic foot ulcers (DFU), a chronic wound is:

 

The actual problem is a clinical one (Level 1):

Level 1: Complications due to DFUs is too high (e.g. amputations and the resultant functional loss). Both how bad the problem is for current treatment and what an acceptable amount of functional loss would be (based on amputation rate).

 

Level 2: What causes Level 1 problem(s)? Complications due to slow or incomplete healing are too high (again could be the amputation rate). Again, both how bad the problem is for current treatment and what an acceptable complication rate would be to solve the Level 1 problem(s).

 

Level 3:  What causes the Level 2 problem(s). The healing is too slow or incomplete (potentially leading to infection). Again, both how bad the problem is for current treatment and what an acceptable healing rate to complete healing would be to solve the Level 2 problem(s).

 

Level 4:  What causes the Level 3 problem(s). In most cases, it is the rate of angiogenesis is too low. Again, both how bad the problem is for current treatment and what an acceptable angiogenesis rate would be to solve the Level 3 problem(s).

 

Level 5 and below: What causes the Level 4 problem(s); cell recruitment and activity are mentioned in the review. Again, both how bad the problem is for current treatment and what an acceptable bioprocess rate(s) would be to solve the Level 4 problem(s).

 

Although the review as claimed:

“provides an updated synthesis with a dedicated focus on biased signaling mechanisms. . . emphasize(s) advanced biomaterial-based delivery systems engineered to spatially and temporally control chemokine gradients. . . By integrating molecular insights with translational advances in antibody design, receptor antagonism, and engineered chemokines, this work aims to establish a precision medicine framework for targeting chemokine networks in chronic wounds. . . It highlights how specific chemokines influence cell recruitment, angiogenesis, and tissue remodeling, and discusses the consequences of chemokine dysregulation in chronic wounds.”

 

giving more comprehensive strategies than before including ways to better orchestrate the different phases of healing as well as tailor the treatment to the individual patient and their particular wound; this approach is far from clinical translation as claimed:

 

“By outlining these mechanisms, the article aims to provide a framework for future research and therapeutic development focused on modulating chemokine pathways to improve healing outcomes”.

 

To figure out the spatial-temporal delivery of all the chemokines to orchestrate the healing (essentially filling out the design hierarchy) is a complicated time-consuming task, which would require many iterations. Most likely the solution is to fix the dysregulation of some of these pathways to get the wound back on track and then let the recruited cells (and blood vessels) handle the biofeedback control of the different phases along with the scaffold. Meaning just fix part of the design hierarchy to get it back on track and let it regulate itself meeting the design constraints at each Level above it until it allows solving the Level 1 problem(s).

 

Therefore, the actual benefit of the review, however, is to give possible strategies to tackle various dysregulations (including specific ones during each phase); there however, is much development work to determine what to use for a given clinical problem (i.e. what has the potential to make a big enough change to allow solving a problem). The review just needs to be more realistic in terms of what we know and where we go from here. Although in some cases the biofeedback control strategies may be necessary vs. trying to figure out what is needed for each clinical presentation, it may only be necessary to fix a few biomechanisms to jump start the healing process.

 

This is similar to a debate I heard on whether it is better to try to regenerate in vitro or in vivo—or essentially make a graft substitute or use a degradable/regenerative scaffold. The debate misses the point on a few levels, first it is about recovery of function not structure and if you do not get 100% of structure back you probably will not get close to 100% of function. Second, in vitro regeneration usually requires adding in all the correct cues in the correct spatial-temporal fashion. In vivo (with a scaffold) many of cues are already there, but some of the dysregulation must be fixed to jump-start the wound.

 

Sections 2-10 do a good job of explaining current knowledge and strategies for specific dysfunctions during each phase of healing. This is very useful, but would require significant development work to determine, how the strategy can cause enough of a change in the dysregulation to get the wound back to meeting the design constraints at each Level above it to solve the clinical problem(s). The comments above are about changing what is stated in the Introduction. Below will highlight parts of the Future Directions and Conclusions. Again, the purpose of the review has to be more realistic as well as where we are and what it will take to solve Level 1 problems.

11.Future Directions              

It is true that:

“substantial knowledge gaps remain in translating these mechanistic insights into effective therapeutic strategies”.

Some specific areas are listed.

“One key area for future investigation is the development of multi-target approaches capable of overcoming chemokine network redundancy. Many inflammatory and infectious diseases are regulated by overlapping chemokine–receptor axes, and targeting only one pathway often produces incomplete modulation. Engineering bispecific chemokine variants, multivalent inhibitors, or multi-epitope neutralizing antibodies could offer improved efficacy and durability in conditions marked by compensatory signaling”.

 

“Advances in structural biology and computational protein engineering. . . will enable design of structure-guided modified chemokines that exhibit tunable bias, receptor-specific activation, or enhanced stability. . . capable of modulating disease-relevant signaling without impairing homeostatic immune function”.

 

“understanding the temporal dynamics of chemokine signaling during disease progression. . . will help identify areas in which chemokine-targeted interventions are most effective.”

 

“improved delivery platforms are essential for clinical translation. . . to deliver engineered chemokines or chemokine inhibitors may enhance therapeutic precision while minimizing systemic toxicity”.

 

Although all this is true it needs to be more problem-solving oriented versus just enhancing our abilities. Not all of these may be necessary for each clinical problem.

 

12.Conclusion

“Dysregulation of these pathways underpins chronic non-healing wounds. . . impaired chemokine gradients disrupt angiogenesis, immune coordination, and matrix remodeling”.

 

Then it summarizes the issues in the future directions:

 

“First, the redundancy and context-dependency of chemokine signaling necessitate multi-target approaches, such as bispecific inhibitors or combination therapies, to overcome compensatory pathway activation.

 

Second, temporal precision in intervention is critical; therapies must align with the dynamic phases of wound healing to avoid disrupting beneficial inflammation or delaying repair.

 

Third, patient-specific factors—including comorbidities, microbiome influences, and genetic variations in chemokine receptors—may dictate therapeutic responsiveness and require personalized treatment strategies”.

 

Then it gives future research:

“should prioritize the development of smart biomaterials capable of real-time chemokine sensing and release, the clinical validation of biased ligands that selectively promote regenerative over inflammatory signaling, and the integration of multiomics profiling to identify predictive biomarkers of healing. Additionally, long-term safety and immunogenicity of engineered chemokines and antibodies must be thoroughly evaluated in preclinical and early-phase trials”.  

 

Again, it needs to be problem-solving oriented vs. just how to expand our toolbox.

 

“In conclusion, modulating chemokine networks represents a promising frontier in precision wound care. By coupling molecular insight with innovative delivery systems and patient-stratified approaches, next-generation therapies can transform chronic wound management—shifting the paradigm from symptomatic treatment to biologically driven regeneration”.

 

Again, better techniques won’t transform wound management without a lot of development—it still needs to be more problem-solving vs. just a paradigm shift and better techniques.

 

Author Response

Based on the Abstract:

“This review synthesizes current knowledge on chemokine biology in wound repair, with a focus on their spatiotemporal regulation across hemostasis, inflammation, proliferation, and remodeling phases. We detail chemokine classification . . . evaluate emerging therapeutic strategies . . . designed to restore chemokine gradient integrity and promote healing. . . advances in structural biology and protein engineering are highlighted . . . to overcome chemokine redundancy. The review concludes that precision modulation of chemokine networks “offers a promising translational framework to redirect chronic inflammation toward regenerative healing, thereby addressing a significant unmet clinical need in chronic wound management.”

Comment: 

The review does a good job of describing current knowledge of the use of chemokines to improve chronic wound management, including specific strategies for specific dysregulations in each phase of healing. However “offers a promising translational framework to redirect chronic inflammation toward regenerative healing, thereby addressing a significant unmet clinical need in chronic wound management” requires more than provided. To suggest solving a clinical problem as well as providing a translational path requires more than just proving that chemokines can statistically significantly improve healing in chronic wounds.

First, there has to be a clinical problem that is currently unsolved as well as what an acceptable solution would be able to do. The review has to have this problem-solving bent and state where we are in terms of solving specific clinical problems including the translational issues. At least what are the next steps to show proof of concept for a particular clinical problem. It is complicated by the fact that different chronic wounds have different needs as well as different acceptable outcomes.

Although many of the biomechanisms needed to be improved to heal chronic wounds are similar, there is not a one size fits all. What is needed is a design hierarchy for each specific chronic wound. The review has to explain where we are in determining what the chemokine strategies can quantitatively do to improve each biomechanism as well as how it can be used to move up the design hierarchy for a particular application.

 For example the design hierarchy for diabetic foot ulcers (DFU), a chronic wound is:`

The actual problem is a clinical one (Level 1):

Level 1: Complications due to DFUs is too high (e.g. amputations and the resultant functional loss). Both how bad the problem is for current treatment and what an acceptable amount of functional loss would be (based on amputation rate).

 Level 2: What causes Level 1 problem(s)? Complications due to slow or incomplete healing are too high (again could be the amputation rate). Again, both how bad the problem is for current treatment and what an acceptable complication rate would be to solve the Level 1 problem(s).

 Level 3:  What causes the Level 2 problem(s). The healing is too slow or incomplete (potentially leading to infection). Again, both how bad the problem is for current treatment and what an acceptable healing rate to complete healing would be to solve the Level 2 problem(s).

 Level 4:  What causes the Level 3 problem(s). In most cases, it is the rate of angiogenesis is too low. Again, both how bad the problem is for current treatment and what an acceptable angiogenesis rate would be to solve the Level 3 problem(s).

 Level 5 and below: What causes the Level 4 problem(s); cell recruitment and activity are mentioned in the review. Again, both how bad the problem is for current treatment and what an acceptable bioprocess rate(s) would be to solve the Level 4 problem(s).

Although the review as claimed:

“provides an updated synthesis with a dedicated focus on biased signaling mechanisms. . . emphasize(s) advanced biomaterial-based delivery systems engineered to spatially and temporally control chemokine gradients. . . By integrating molecular insights with translational advances in antibody design, receptor antagonism, and engineered chemokines, this work aims to establish a precision medicine framework for targeting chemokine networks in chronic wounds. . . It highlights how specific chemokines influence cell recruitment, angiogenesis, and tissue remodeling, and discusses the consequences of chemokine dysregulation in chronic wounds.” 

giving more comprehensive strategies than before including ways to better orchestrate the different phases of healing as well as tailor the treatment to the individual patient and their particular wound; this approach is far from clinical translation as claimed:

“By outlining these mechanisms, the article aims to provide a framework for future research and therapeutic development focused on modulating chemokine pathways to improve healing outcomes”.

To figure out the spatial-temporal delivery of all the chemokines to orchestrate the healing (essentially filling out the design hierarchy) is a complicated time-consuming task, which would require many iterations. Most likely the solution is to fix the dysregulation of some of these pathways to get the wound back on track and then let the recruited cells (and blood vessels) handle the biofeedback control of the different phases along with the scaffold. Meaning just fix part of the design hierarchy to get it back on track and let it regulate itself meeting the design constraints at each Level above it until it allows solving the Level 1 problem(s).

 

Therefore, the actual benefit of the review, however, is to give possible strategies to tackle various dysregulations (including specific ones during each phase); there however, is much development work to determine what to use for a given clinical problem (i.e. what has the potential to make a big enough change to allow solving a problem). The review just needs to be more realistic in terms of what we know and where we go from here. Although in some cases the biofeedback control strategies may be necessary vs. trying to figure out what is needed for each clinical presentation, it may only be necessary to fix a few biomechanisms to jump start the healing process.

This is similar to a debate I heard on whether it is better to try to regenerate in vitro or in vivo—or essentially make a graft substitute or use a degradable/regenerative scaffold. The debate misses the point on a few levels, first it is about recovery of function not structure and if you do not get 100% of structure back you probably will not get close to 100% of function. Second, in vitro regeneration usually requires adding in all the correct cues in the correct spatial-temporal fashion. In vivo (with a scaffold) many of cues are already there, but some of the dysregulation must be fixed to jump-start the wound.

Sections 2-10 do a good job of explaining current knowledge and strategies for specific dysfunctions during each phase of healing. This is very useful, but would require significant development work to determine, how the strategy can cause enough of a change in the dysregulation to get the wound back to meeting the design constraints at each Level above it to solve the clinical problem(s). The comments above are about changing what is stated in the Introduction. Below will highlight parts of the Future Directions and Conclusions. Again, the purpose of the review has to be more realistic as well as where we are and what it will take to solve Level 1 problems.

Response:

We agree with the reviewer that discussing clinical applicability is important. Accordingly, we have included the currently available clinical evidence and highlighted translational perspectives in the revised manuscript. Nevertheless, most studies in this area are still confined to experimental or preclinical models, reflecting the early stage of development of chemokine-based therapeutic strategies, and this limitation has been clearly acknowledged in the discussion section.

11.Future Directions              

It is true that:

“substantial knowledge gaps remain in translating these mechanistic insights into effective therapeutic strategies”.

Some specific areas are listed.

“One key area for future investigation is the development of multi-target approaches capable of overcoming chemokine network redundancy. Many inflammatory and infectious diseases are regulated by overlapping chemokine–receptor axes, and targeting only one pathway often produces incomplete modulation. Engineering bispecific chemokine variants, multivalent inhibitors, or multi-epitope neutralizing antibodies could offer improved efficacy and durability in conditions marked by compensatory signaling”.

 “Advances in structural biology and computational protein engineering. . . will enable design of structure-guided modified chemokines that exhibit tunable bias, receptor-specific activation, or enhanced stability. . . capable of modulating disease-relevant signaling without impairing homeostatic immune function”.

 “understanding the temporal dynamics of chemokine signaling during disease progression. . . will help identify areas in which chemokine-targeted interventions are most effective.”

 “improved delivery platforms are essential for clinical translation. . . to deliver engineered chemokines or chemokine inhibitors may enhance therapeutic precision while minimizing systemic toxicity”.

 Although all this is true it needs to be more problem-solving oriented versus just enhancing our abilities. Not all of these may be necessary for each clinical problem.

Response:

We thank the reviewer for this valuable suggestion. In response, we have briefly highlighted the potential future research directions in the revised manuscript, emphasizing the need for further mechanistic studies and clinical validation to establish chemokines as therapeutic targets in chronic wound management.

12.Conclusion

“Dysregulation of these pathways underpins chronic non-healing wounds. . . impaired chemokine gradients disrupt angiogenesis, immune coordination, and matrix remodeling”.

 

Then it summarizes the issues in the future directions:

 “First, the redundancy and context-dependency of chemokine signaling necessitate multi-target approaches, such as bispecific inhibitors or combination therapies, to overcome compensatory pathway activation.

 Second, temporal precision in intervention is critical; therapies must align with the dynamic phases of wound healing to avoid disrupting beneficial inflammation or delaying repair.

Third, patient-specific factors—including comorbidities, microbiome influences, and genetic variations in chemokine receptors—may dictate therapeutic responsiveness and require personalized treatment strategies”.

Then it gives future research:

“should prioritize the development of smart biomaterials capable of real-time chemokine sensing and release, the clinical validation of biased ligands that selectively promote regenerative over inflammatory signaling, and the integration of multiomics profiling to identify predictive biomarkers of healing. Additionally, long-term safety and immunogenicity of engineered chemokines and antibodies must be thoroughly evaluated in preclinical and early-phase trials”.  

Again, it needs to be problem-solving oriented vs. just how to expand our toolbox.

“In conclusion, modulating chemokine networks represents a promising frontier in precision wound care. By coupling molecular insight with innovative delivery systems and patient-stratified approaches, next-generation therapies can transform chronic wound management—shifting the paradigm from symptomatic treatment to biologically driven regeneration”. 

Again, better techniques won’t transform wound management without a lot of development—it still needs to be more problem-solving vs. just a paradigm shift and better techniques.

Response:

We thank the reviewer for this comment. The conclusion section has already been revised in the manuscript to better summarize the key findings and highlight the clinical relevance and future perspectives of chemokine-targeted strategies in chronic wound management.

Reviewer 3 Report

Comments and Suggestions for Authors

The work is devoted to an important and interesting problem - modulation of chemokine activity for enhanced angiogenesis and tissue regeneration in chronic wounds.

• This review summarizes the current understanding of chemokine involvement in the different stages of wound healing. It highlights how specific chemokines influence cell recruitment, angiogenesis, and tissue remodeling, and discusses the consequences of chemokine dysregulation in chronic wounds. By outlining these mechanisms, the article aims to provide a framework for future research and therapeutic development focused on modulating chemokine pathways to improve healing outcomes.
• I consider the topic is original and relevant in the field of tissue regeneration research during the healing of chronic wounds, in particular, the disclosure of the molecular regulatory mechanisms of these processes with the participation of chemokines.
• This review synthesizes current knowledge on chemokine biology in wound repair, with a focus on their spatiotemporal regulation across hemostasis, inflammation, proliferation, and remodeling phases. The authors detail chemokine classification, receptor interactions, and downstream signalling pathways - including G protein-dependent and arrestin-biased mechanisms. Recent advances in structural biology and protein engineering are highlighting for enabling the design of biased ligands and multi-target inhibitors to overcome chemokine redundancy.
• Regarding the methodology of the study, a qualitative and quantitative meta-analysis would be useful, which would allow to summarize the published research results on the problem under study.
• The conclusions are consistent with the evidence and arguments presented and related to the main questions posed. The review concludes that precision modulation of chemokine networks offers a promising translation framework to redirect chronic inflammation toward regenerative healing, thereby addressing a significant unmet clinical need in chronic wound management.
• The references used in the work are appropriate, but a very large number of old sources (1978-2000 years) are noteworthy. Maybe they can be reduced?
• Figures and tables are informative and visual, do not require edits.

Author Response

Response to comments from reviewer #3

The work is devoted to an important and interesting problem - modulation of chemokine activity for enhanced angiogenesis and tissue regeneration in chronic wounds

This review summarizes the current understanding of chemokine involvement in the different stages of wound healing. It highlights how specific chemokines influence cell recruitment, angiogenesis, and tissue remodeling, and discusses the consequences of chemokine dysregulation in chronic wounds. By outlining these mechanisms, the article aims to provide a framework for future research and therapeutic development focused on modulating chemokine pathways to improve healing outcomes.

I consider the topic is original and relevant in the field of tissue regeneration research during the healing of chronic wounds, in particular, the disclosure of the molecular regulatory mechanisms of these processes with the participation of chemokines.

This review synthesizes current knowledge on chemokine biology in wound repair, with a focus on their spatiotemporal regulation across hemostasis, inflammation, proliferation, and remodeling phases. The authors detail chemokine classification, receptor interactions, and downstream signalling pathways - including G protein-dependent and arrestin-biased mechanisms. Recent advances in structural biology and protein engineering are highlighting for enabling the design of biased ligands and multi-target inhibitors to overcome chemokine redundancy.

Response: We appreciate and thank the reviewer for his time and positive note on our review manuscript.

Comment: Regarding the methodology of the study, a qualitative and quantitative meta-analysis would be useful, which would allow to summarize the published research results on the problem under study.

 

Response: We thank the reviewer for this valuable suggestion. The present article was designed as a narrative mechanistic review focusing on the molecular roles of chemokines in wound healing and the emerging therapeutic strategies targeting chemokine signaling pathways. The objective of this review was to synthesize mechanistic insights, signaling pathways, and translational approaches, including biomaterial-based delivery systems, receptor antagonists, and engineered chemokines, rather than to quantitatively compare outcomes across clinical or experimental studies.

A formal meta-analysis requires a homogeneous set of studies with comparable experimental designs, endpoints, and quantitative outcome measures. However, the literature on chemokines in wound healing is highly heterogeneous, encompassing in vitro studies, animal models, biomaterial-based delivery systems, mechanistic signaling studies, and limited clinical investigations, which makes a quantitative meta-analysis difficult to perform without introducing substantial methodological bias. Therefore, we adopted a comprehensive narrative synthesis approach to integrate findings across diverse experimental systems and highlight emerging therapeutic strategies.

 

Comment: The conclusions are consistent with the evidence and arguments presented and related to the main questions posed. The review concludes that precision modulation of chemokine networks offers a promising translation framework to redirect chronic inflammation toward regenerative healing, thereby addressing a significant unmet clinical need in chronic wound management.

 

Response: We thank the reviewer for his time and positive report of our manuscript.

 

Comment: The references used in the work are appropriate, but a very large number of old sources (1978-2000 years) are noteworthy. Maybe they can be reduced?

 

Response:  As per the reviewer’s comment, we have reduced the large number of old references between 1978-2000.

 

Comment: Figures and tables are informative and visual, do not require edits.

 

Response: We thank the reviewer for his time and positive report of our manuscript.

Reviewer 4 Report

Comments and Suggestions for Authors

Comments attached in pdf form

Comments for author File: Comments.pdf

Author Response

Response to comments from reviewer #4

The review titled ‘Modulation of Chemokine Activity for Enhanced Angiogenesis and Tissue Regeneration in Chronic Wounds’ by Adit et al highlights the modular regulation of chemokines and how it impacts various facets of wound healing, thereby influencing chronic wound biology, prominently observed in diabetic and vascular disease. Briefly, the authors have described chemokines as key regulators of leukocyte recruitment, extracellular matrix remodeling, and neovascularization across all phases of wound healing. The authors conclude that chemokine signaling pathways are ideal targets for developing strategies to improve the physiological wound-healing mechanism. However, the manuscript lacks novelty and lacks sufficient information on recent literature to confidently serve as an updated review of chemokine research in wound healing. The authors are requested to consider the following suggestions to improve the impact of the manuscript.

Comment: The authors have provided extensive information about chemokine engineering, not only wound healing, but also inflammatory response and overall immunity. Although the authors establish the relationship between inflammation and wound healing, their deeper dive into the enhancement of the immune response through modulation of chemokine signaling shifts the focus away from the manuscript's main goal: wound healing. The authors are advised to either shorten the sections detailing the broader immune effects of chemokines or better bridge the significance of wound healing to the broader immune response.

 

Response: As per the reviewer’s comments, we have shortened the section detailing the effect of chemokines in immune repose in the revised manuscript.

Comment: The authors have cited numerous references to research studies and reviews performed over the last decade. However, the number of references from the last 5 years is only 55 out of the 200+ references cited in the manuscript. This raises concerns whether the information presented in the manuscript accurately reflects the current state of chemokine research in chronic wound healing.

Response:  We thank the reviewer for highlighting the importance of incorporating recent literature. In response, we have revised the paper to incorporate several current research published in the last five years that examine advancements in chemokine signaling, angiogenesis, and treatment approaches for chronic wound healing. These enhancements guarantee that the review more precisely represents the present condition of research in this domain.

Comment: The topic of the review lacks novelty as a similar review was accepted for publication in Frontiers in Cell and Developmental Biology.Link: https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2026.1791888/abstract

 

Response: We appreciate the reviewer for emphasising the recently published review in Frontiers in Cell and Developmental Biology. Although both studies address chemokines in wound healing, our manuscript's focus is unique.

First, the cited review primarily focuses on the general role of chemokines in the wound healing cascade, whereas our manuscript specifically examines the modulation of chemokine activity as a therapeutic strategy to enhance angiogenesis and tissue regeneration in chronic wounds. Our study focuses on the molecular mechanisms via which chemokines govern vascular remodelling, endothelial cell recruitment, and neovascularisation, all of which are essential events in chronic wound repair.

Our review specifically focuses on the modulation of chemokine activity to promote angiogenesis and tissue regeneration in chronic wounds, highlighting mechanistic pathways and novel therapeutic approaches. Consequently, our work offers a targeted and supplementary viewpoint instead of reiterating the already published review.

Comment: 1.Table 2, Page 7: remove apostrophe after the word ‘recruits’.

 

Response:  As per the reviewer’s comment we have removed the apostrophe and highlighted the same in the revised manuscript.

Round 2

Reviewer 4 Report

Comments and Suggestions for Authors

Thank you to all authors for incorporating the necessary edits to the manuscript.

Regarding the minor edit suggested for the word 'recruits', there is no need for an apostrophe for this term. This mistake is repeated further in the table for CCL3 under Inflammation

One other minor point the authors should consider revising is the multiple spelling errors in the terms in Figures 1 and 2. It seems these figures were made using the Google Gemini AI tool, as the observed errors are very typical of AI image generation. The authors are suggested to rectify these before final submission. Additionally, please acknowledge the use of AI tools used for image generation.

Author Response

File attached

Author Response File: Author Response.pdf