Extracellular Matrix in Human Disease and Therapy: From Pathogenic Remodeling to Biomaterial Platforms and Precision Diagnostics

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The author summarized the characteristics of the extracellular matrix (ECM) in disease contexts such as fibrosis and tumors, as well as the cutting-edge progress regarding its applications as a disease diagnostic biomarker and in the field of biomedical materials. The illustrations and text are clear; however, there are still some concerns that require modification.

1. It is recommended to incorporate more clinical research related to ECM, such as its applications as therapeutic targets and in biomedical materials. What are the clinical research aspects in these fields?
2. Aging is currently a highly focused area of research. It is recommended that the author include more information on the characteristics of ECM in the aging microenvironment. Are there any studies targeting ECM to alleviate aging?
3. The author has briefly described some medical imaging probes for ECM, but the description is very simple. It is suggested to elaborate on how these probes can precisely target ECM and what is their mechanism.
4. Were the images in the article drawn by the author themselves? If not, citations and copyright permission applications need to be added.
5. With the rapid development of artificial intelligence (AI) technology, what kinds of tasks can AI perform in the field of ECM? It is recommended that the author expand the discussion on this aspect.

Author Response

Comment 1. Incorporate more clinical research related to ECM (therapeutic targets; biomedical materials). What are the clinical research aspects?

Response: We added a new subsection describing representative clinical-stage ECM-modulating strategies (crosslinking inhibition, stromal decompression/normalization, mechanotransduction inhibition) and added a new table summarizing clinical translational rationale and readouts.

Revised sentence now reads:
“Although many ECM-targeting strategies remain preclinical, several have advanced to clinical evaluation… simtuzumab… phase 2… [48]. … pegvorhyaluronidase alfa (PEGPH20)… phase 3 HALO 109-301… [49]. … defactinib… randomized phase 2… [50]. Table 2 summarizes representative clinical-stage ECM-modulating approaches…”

Comment 2. Add more about ECM in the aging microenvironment. Any studies targeting ECM to alleviate aging?

Response: We expanded Section 2.3 with a dedicated paragraph on aging-associated ECM changes (AGE crosslinks, elastin fragmentation, matrisome drift, senescence/SASP) and added examples of ECM-relevant interventional studies.

Revised sentence now reads:
“Beyond fibrosis, aging itself is accompanied by progressive ECM ‘hardening’… Emerging interventional studies suggest that targeting the aging ECM may be feasible… senolytic therapy… [46], and AGE crosslink–modifying approaches (e.g., alagebrium/ALT-711)… [47].”

Comment 3. Expand the mechanism of ECM imaging probes (how they precisely target ECM).

Response: We expanded Section 7.2 to explain direct ECM binding (collagen probes), receptor-based targeting (integrins/RGD), and how these function as quantitative, spatial readouts (also adding a new table of probe examples). We also ensured Figure 5B is cited in-text.

Revised sentence now reads:
“Mechanistically, ECM probes achieve specificity either by binding matrix macromolecules directly… or by targeting cell-surface receptors… … collagen-targeted PET… ⁶⁸Ga-CBP8… [51,54]. … collagen-specific molecular MRI… EP-3533… [52]. … ¹⁸F-galacto-RGD… [53]. … enabling precise… phenotyping (Figure 5B)…”

Comment 4. Are images drawn by the author? If not, add citations/permissions.

Response: We added an explicit disclosure in the Acknowledgments stating that the figures are original schematic figures were Gemini (v3.0) and edited by the author, with no third-party copyrighted content reproduced.

Revised sentence now reads:
“All schematic figures were generated with Gemini (v3.0) and edited by the author; no third-party copyrighted material was used.”

Comment 5. Expand discussion on AI tasks in ECM.

Response: We added a new bullet in the Conclusions describing AI-enabled ECM analytics (collagen architecture quantification, ECM signature extraction, biomarker discovery) and AI-assisted biomaterial/bioink optimization.

Revised sentence now reads:
“AI-enabled ECM analytics and design. Rapid advances… enable automated quantification of collagen architecture… integration of matrisome-scale proteomics… and data-driven optimization of ECM-mimicking hydrogels and bioinks… [55,56].”

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript reviewed recent progress concerning extracellular matrix in human disease and therapy. Overall, it is a comprehensive review. Here are the questions and suggestions about the manuscript.

1. You’d better add a scheme such as TOC in the introduction section to summarize your review.
2. Why just present only one table in Section 3. You’d better add a comprehensive table like table 1 for each section. Therefore, the readers can find useful information conveniently.
3. The figures from the manuscript is drawn by your own not from other related publications?
4. The authors should better highlight its advantages compared with other related reviews.
5. Could the author provide perspective on the application prospects of ECM based biomaterials in biomedical fields and their limitations?
6. The references style should be double checked before published. It would be better to cite more related references in a review article because only 45 publications were cited.

Author Response

Comment 1. Add a scheme/TOC in the Introduction.
Response: We added Scheme 1 (graphical overview) directly after the Introduction to summarize the logic and flow of the review.

Comment 2. Add a comprehensive table like Table 1 for each section.
Response: In addition to the existing Table 1, we added Table 2 (clinical-stage ECM-modulating approaches) and Table 3 (ECM-targeted imaging probes and readouts) so readers can retrieve key information more easily across sections.

Comment 3. Are the figures drawn by the author and not from other publications?
Response: Addressed via the added Acknowledgments disclosure (Gemini-generated, author-edited; no third-party reuse).

Revised sentence now reads:
“All schematic figures were generated with Gemini (v3.0) and edited by the author; no third-party copyrighted material was used.”

Comment 4. Highlight advantages compared with other related reviews.

Response: We added an explicit statement in the Introduction clarifying the manuscript’s differentiator: ECM remodeling as a shared, quantifiable mechanobiological axis across diseases and “ECM normalization” as a unifying translational principle.

Revised sentence now reads:
“Compared with prior reviews… we frame ECM remodeling as a shared, quantifiable mechanobiological axis… and highlight ‘ECM normalization’ as a unifying translational principle…”

Comment 5. Provide perspective on prospects and limitations of ECM-based biomaterials.

Response: We added a short “Perspective and limitations” paragraph in Section 5.2 discussing variability, decellularization residues, sterilization effects, mechanics, scalability, and regulatory considerations.

Revised sentence now reads:
“Perspective and limitations. Clinically, ECM-based biomaterials are attractive… but translation is constrained by batch-to-batch variability… incomplete decellularization… sterilization-induced loss of bioactivity… and regulatory requirements… [16–20,40].”

Comment 6. References style/check; cite more references (only 45).

Response: We added 11 additional references (now 56 total), focusing on clinical trials, imaging probes, and AI/quantitative ECM analytics, and formatted them consistently with DOI information.

Reviewer 3 Report

Comments and Suggestions for Authors

Overall, this review presents a broad and well-organized overview of extracellular matrix (ECM) biology across multiple disease contexts and translational applications, including fibrosis, cancer, metabolic disorders, biomaterials, and precision diagnostics. The manuscript successfully summarizes a large volume of literature and may serve as a useful reference for readers seeking an overview of the field. However, in its current form, the review reads primarily as a comprehensive synthesis of existing knowledge rather than as a work that clearly advances a new conceptual perspective. While the authors emphasize ECM as an active driver of disease, this idea has already been well established in prior reviews, and the manuscript would benefit from more explicitly articulating what new integrative insight or framework is being proposed. For instance, the authors could clarify whether the central contribution lies in positioning ECM remodeling as a shared, quantifiable mechanobiological axis across diseases, or in redefining ECM normalization as a unifying therapeutic principle, and state this explicitly in the Introduction and Conclusions.

 

The overall structure of the manuscript is logical and easy to follow, progressing from fundamental ECM organization to disease relevance and translational strategies. That said, the narrative is largely descriptive, with different disease sections presented in parallel rather than being conceptually integrated. Reader engagement could be improved by more frequent cross-sectional synthesis that highlights common mechanisms and contrasts between disease contexts. For example, instead of describing fibrosis, cancer, and metabolic disorders independently, the authors could explicitly draw connections, such as noting that ECM stiffening and integrin–FAK/YAP–TAZ signaling recur across these conditions and may represent shared therapeutic vulnerabilities. Short synthesis paragraphs at the end of major sections would help reinforce these connections and strengthen the coherence of the overall narrative.

 

From a scientific standpoint, the review is generally accurate and reflects the cited literature appropriately. Nevertheless, many sections summarize reported findings without sufficiently discussing the strength of evidence, potential limitations, or inconsistencies across studies. Introducing a more critical perspective would enhance the manuscript’s rigor. For example, when discussing ECM-degrading or ECM-normalizing strategies, it would be valuable to distinguish between robust preclinical evidence and areas where clinical translation remains uncertain, or to acknowledge situations in which ECM degradation may have context-dependent or even adverse effects. Such discussion would help avoid overgeneralization and provide readers with a more nuanced understanding of the field.

 

In addition, the manuscript places strong emphasis on consensus views but pays relatively little attention to unresolved questions or ongoing debates. Explicitly highlighting these areas could make the review more forward-looking and intellectually engaging. For instance, the authors might address whether ECM remodeling is primarily an initiating driver of disease or a self-reinforcing consequence of chronic pathology, noting that evidence across organ systems is not entirely consistent. Framing these uncertainties as open questions would help guide future research directions.

 

Regarding the references, the citation list appears appropriate in scope and coverage and does not raise concerns in terms of quantity. However, the impact of the review could be further strengthened by more clearly highlighting key advances from the past three years and signaling to readers which recent studies or reviews are particularly influential in shaping current directions in ECM research. This would help guide readers toward the most relevant and timely literature.

Author Response

Comment 1. The review is comprehensive but does not clearly state a new conceptual contribution; clarify what integrative insight/framework is being proposed (e.g., mechanobiological axis; ECM normalization).

Response: We agreed and explicitly stated the manuscript’s central contribution in both the Introduction and Conclusions: (i) positioning ECM remodeling as a shared, quantifiable mechanobiological axis across diseases; and (ii) framing ECM normalization as a unifying translational principle linking therapeutics, biomaterials, and diagnostics.

Revised sentence now reads (Introduction):
“In this review, we frame ECM remodeling as a shared, quantifiable mechanobiological axis across major chronic diseases and highlight ECM normalization as a unifying translational principle that connects mechanism-based therapeutics, ECM-informed biomaterials, and precision diagnostics.”

Revised sentence now reads (Conclusions):
“Viewed as a cross-disease mechanobiological axis, ECM remodeling provides measurable targets for intervention and a rationale for ECM normalization strategies that can be paired with biomaterials and diagnostic readouts to enable precision medicine.”

Comment 2. The narrative is largely descriptive; improve cross-sectional synthesis by drawing connections across disease contexts and adding short synthesis paragraphs at the end of major sections.

Response: We added brief synthesis paragraphs that explicitly connect recurring mechanisms (ECM stiffening, crosslinking, protease activity, and integrin–FAK/YAP–TAZ mechanotransduction) across fibrosis, cancer, and metabolic disease, highlighting shared therapeutic vulnerabilities and context-specific differences.

Revised sentence now reads (end of Section 3):
“Across fibrosis, cancer, and metabolic disease, ECM stiffening and remodeling converge on shared mechanotransduction programs (integrin–FAK and YAP/TAZ) and protease/crosslinking pathways, suggesting common vulnerabilities that can be targeted while accounting for organ- and context-specific matrix composition and immune constraints.”

Comment 3. Add a more critical perspective: discuss strength of evidence, limitations, and inconsistencies; distinguish preclinical vs clinical translation; acknowledge potential adverse/context-dependent effects of ECM degradation.

 

Response: We strengthened the critical tone in Section 4 by explicitly distinguishing robust preclinical evidence from uncertain clinical translation, and by emphasizing that indiscriminate matrix degradation may worsen invasion/metastasis or impair physiological repair. We also added guidance that ECM-targeting approaches should be paired with quantitative biomarkers and imaging readouts.

 

Revised sentence now reads (Section 4.2):

“Importantly, while stromal decompression and controlled ECM normalization show strong preclinical rationale, clinical translation remains context-dependent, and indiscriminate ECM degradation can exacerbate invasion or compromise essential repair processes; therefore, dose, timing, and patient selection should be guided by quantitative ECM readouts (turnover biomarkers and ECM-targeted imaging).”

 

Comment 4. Highlight unresolved questions and debates (e.g., ECM as initiating driver vs self-reinforcing consequence) and frame them as open questions to guide future research.

 

Response: We added a short “open questions” component in Future Directions, explicitly noting uncertainty about whether ECM remodeling is initiating versus self-reinforcing and emphasizing priorities such as causal mapping, spatial multi-omics, and standardized clinical-grade metrics.

 

Revised sentence now reads (Section 8):

“Key open questions remain, including whether ECM remodeling is primarily an initiating driver or a self-reinforcing consequence of chronic pathology in different organs; resolving this will require causal, longitudinal studies integrating spatial multi-omics with quantitative mechanics and validated clinical biomarkers.”

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

accept.

Author Response

thanks