Hydrogel-Based Strategies for the Prevention and Treatment of Radiation-Induced Skin Injury: Progress and Mechanistic Insights

Comments 1: What are the keys for the RISI treatment in clinic? And why hydrogel strategies are important, unique and useful compared to the clinical methods? Hydrogels have been widely used in clinical practice as wound dressings, so does RISI has any hydrogel products? Are there any requirements for the material's degradability, mechanical properties, etc.?

Response 1:

I will explain this in four main points:

(i) Major Clinical Challenges in RISI Treatment

Clinical management of radiation-induced skin injury (RISI) requires simultaneous regulation of inflammation, oxidative stress, and tissue remodeling. Conventional interventions—including topical corticosteroids, emollients, pentoxifylline, and growth factors—provide only temporary symptom relief and suffer from short drug retention, systemic side effects, and limited control over the local microenvironment. These limitations underscore the need for multifunctional, localized strategies that can protect, repair, and regenerate irradiated skin.

(ii) Distinct Advantages of Hydrogel-Based Approaches

With an increasing understanding of RISI’s molecular mechanisms, therapeutic research is shifting from nonspecific symptomatic management toward mechanism-driven radioprotective development. Hydrogels, characterized by high water content, soft viscoelasticity, and tunable physicochemical properties, provide a versatile therapeutic platform. They can prolong skin adherence, enable sustained drug release, modulate the wound microenvironment (through pH, ROS, or enzymatic responsiveness), and mimic the extracellular matrix (ECM).

Accordingly, hydrogels serve not only as radioprotective barriers but also as therapeutic carriers, integrating protective and regenerative functions within a single system. These combined attributes position hydrogels as promising candidates for next-generation radioprotective biomaterials.

(iii) Clinical Translation and Current Applications

Although no hydrogel formulation has yet been approved specifically for RISI, several clinically available wound dressings—including sodium hyaluronate gels, chitosan–gelatin hydrogels, and EGF- or DFO-loaded composites—have been repurposed for radiation-injury management with encouraging preclinical and early clinical results.

Ongoing investigations are also exploring radioprotective hydrogel patches for prophylactic use during radiotherapy, aiming to mitigate acute skin reactions and accelerate post-irradiation healing.

(iv) Material Design Considerations

An ideal hydrogel for RISI therapy should exhibit the following essential characteristics:

Degradability: It should degrade progressively in synchrony with the staged wound-healing process (hemostasis → inflammation → proliferation → remodeling), avoiding premature collapse or long-term persistence at the wound site. Degradation byproducts must be non-toxic and pH-neutral. Rapidly degradable systems are suitable for acute lesions requiring short-term drug delivery, whereas slower degradation benefits chronic RISI, ensuring sustained antioxidant and anti-inflammatory effects.

Mechanical properties: The hydrogel should be soft, flexible, and conformable, adhering closely to skin contours and movement without impeding reepithelialization. It must also possess adequate toughness to withstand dressing changes and patient motion, while maintaining structural integrity in moist or exudative conditions.

Porosity, mesh size, and swelling behavior: The network architecture should enable oxygen and nutrient diffusion while regulating drug-release kinetics, determined by crosslinking density and average molecular weight between crosslinks. These parameters can be tuned to achieve the desired release profile. A high water content helps maintain a moist healing microenvironment and promotes exudate absorption, though excessive swelling should be avoided to prevent skin maceration. Swelling behavior can be precisely adjusted by controlling the hydrophilic/hydrophobic ratio and crosslinking density.

Biocompatibility and safety: The material must exhibit low immunogenicity, minimal endotoxin contamination, and allow for sterilization without compromising physicochemical integrity. A clean degradation profile is critical to avoid acidic or reactive byproducts that could aggravate inflammation in irradiated tissue. Potential allergenicity associated with certain natural polymers should also be carefully evaluated during material selection.

Comments 2: A schematic diagram should be added to simply describe the progress and mechanism after the injuries are treated with hydrogel materials. In addition, for the cited literatures, it’s recommended to incorporate some diagrams from the referenced studies.

Response 2:  Thank you for your constructive suggestions. To enhance visual clarity, we have added two new diagrams—a Graphical Abstract (page 1) and Figure 3 (page 6)—that summarize the types and underlying mechanisms of hydrogel-based treatments for radiation-induced skin injury (RISI).

In addition, several illustrations adapted from referenced studies have been incorporated, with appropriate source attributions and citations provided (see Figures 1–2, 4–7; pages 3–4, 8, 11, 15, and 22). All newly added or modified figures are highlighted in red in the revised manuscript. .

Comments 3: Basically, the hydrogels can provide a moist environment and physical barriers, as well incorporated with some additional therapeutic agents, which are easily to understand. For the composite hydrogel or hybrid hydrogel, most studies emphasized the effects of certain “components” such as bioactive factors, nanoparticles, etc. Therefore, the “other composite hydrogels” and “hybrid hydrogels” are essentially no different. The author may consider combine these 2 sections together.

Response 3: We appreciate the reviewer’s insightful observation. After careful consideration, we have merged the sections on “Other Composite Hydrogels” and “Hybrid Hydrogels” into a unified section entitled “Hybrid Hydrogels” (see Section 2.3, pp. 16–19).

This integration eliminates redundancy and better reflects the multicomponent design concept, where nanoparticles, bioactive factors, exosomes, and signaling molecules synergistically contribute to multiscale protection and tissue regeneration. The corresponding tables and references have been updated accordingly. (pp. 18–19).

Comments 4: In order to provide clearer mentoring for researchers, authors can summarize the specific functions of each material. For example, the different polysaccharides itself can form highly hydration environment with grate biocompatibility, and different charges materials can be chosen for different purpose. Therefore, for Table 1, it is suggested to summarize the materials’ molecular structure, characteristics (including advantages and disadvantages), and key functions for RISI. The current table is quite disorganized, almost a list of cited references while losing citation numbers, and it’s hard to read.

Response 4: Thank you for your valuable suggestions. Table 1 has been completely reorganized and divided into Tables 2–4 to improve readability and provide clearer guidance for researchers. The revised tables now summarize, for each material, its molecular or structural properties, key advantages and disadvantages, and principal mechanisms/functions in RISI repair, with complete and updated reference numbers.

This structural reorganization facilitates direct comparison among different polysaccharide-based hydrogels and clarifies the relationship between specific molecular features (e.g., charge, hydration capacity, and functional groups) and their corresponding biological functions. The updated tables (pages 8-9, 11-13) are highlighted in red in the revised manuscript.

Comments 5: Protein-based materials can have special hemostatic function, the mechanism (structure-function) should be illustrated.

Response 5: Thank you for this valuable suggestion, reviewer. The hemostatic properties of protein-based materials are indeed an advantage of protein-based hydrogels. We have added a new table (Table 3, pages 11-12) highlighting these hemostatic advantages. We have also provided a supplementary description of their hemostatic mechanisms (structure-function) in the text.

Comments 6: For external composition, what are the disadvantages or challenges for them? For example, the incorporated nanoparticles, are there requirements for the size, concentration, toxicity, or release properties?

Response 6: Thank you for raising this important point. We have added a new table (Table 6) in Section 2.3 (pp. 18-19) discussing the application characteristics of hydrogels containing external functional components.

Nanoparticle size, dosage, and surface chemistry have a crucial impact on biodistribution, biocompatibility, and release kinetics. Concentration-dependent cytotoxicity and potential long-term metabolic risks must be carefully assessed. Furthermore, the reproducibility and stability of multicomponent hybrid systems remain major challenges in translational research.

In addition, the Conclusion section has been expanded to emphasize the need for precise interface control, dynamic component balance, and long-term safety validation to ensure clinical applicability. These revisions are highlighted in red in the revised manuscript.

Comments 7: The author should carefully check the writing, for example “2.1. Natural-Origin and their omposite Hydrogels”, 2.1.2 and 2.1.3 have the same title.

Response 7: We sincerely thank the reviewer for this careful observation. The typographical error in “2.1. Natural-Origin and their omposite Hydrogels” has been corrected to “2.1. Natural-Origin and Composite Hydrogels.” In addition, the duplicate section titles for 2.1.2 and 2.1.3 have been revised to clearly distinguish their contents:

2.1.2 Protein-Based Materials, and

2.1.3 Decellularized Tissue–Based Materials.

All corresponding section titles and references have been updated accordingly in the revised manuscript.