Injectable Scaffolds for Adipose Tissue Reconstruction

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

attached 

Comments for author File: Comments.pdf

Author Response

Review of the manuscript ID gels-4073612 by Pruzzo et al.

Reply to the comments of reviewer 1

We appreciate the fair and constructive comments of the reviewer. In the following, please find our point-by-point reply.

Overall comments:

1. Reviewer comment: The manuscript reviews current injectable scaffold strategies for restoring soft tissue volume defects, with a strong emphasis on their translational potential and future directions. It systematically elucidates the roles of natural, synthetic, and adipose ECM–derived injectable scaffolds in adipose tissue engineering. In addition, the manuscript provides an overview of natural-derived and commercially available fillers used for soft tissue augmentation. Future research directions are highlighted, particularly the need to optimize large-volume, long-lasting, and immunologically safe injectable adipose substitutes. Overall, the manuscript is well structured, supported by appropriate figures and tables, and is suitable for publication after addressing the following minor comment.

Reply: We thank the reviewer for this favorable comment.

Minor concerns:

1. Reviewer comment: The authors are encouraged to provide two or more figures that present graphical data and support their interpretation of the results.

Reply: According to this comment and additional comments from the other reviewers, we have included two novel figures and one novel table in our revised manuscript version, which provide more details about the discussed scaffold types (see Fig. 2 and 4; Table 3; see lines 259, 325-329, 412-417; marked in yellow).  

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript entitled «Injectable scaffolds for soft tissue reconstruction» presents an overview of current developments in hydrogel-based injectable scaffolds, with a particular focus on adipose extracellular matrix (ECM)-derived systems. The authors effectively establish the clinical context by outlining the significant limitations of autologous fat grafting—namely unpredictable resorption, donor-site morbidity, and the logistical challenges of tissue banking—which justify the pursuit of alternatives. The review is logically structured, progressing from the clinical problem to a detailed comparison of natural, synthetic, and adipose-derived extracellular matrix (ECM) injectable scaffolds, culminating in a forward-looking conclusion on translational potential. A particular strength is the clear and balanced analysis of the advantages and drawbacks of each scaffold category, highlighting the trade-off between the biocompatibility of natural materials and the tunability of synthetic ones. The authors convincingly argue for the superior translational promise of adipose ECM-derived hydrogels, emphasizing their inherent bioactivity and ability to promote host-driven regeneration.  Notably, the reference list demonstrates a strong command of recent literature, with 36 out of 73 cited articles published between 2020 and 2025, ensuring the review's relevance and contemporaneity.

Remarks

1. Soft tissues include not only adipose tissue but also skin, skeletal muscle, and other types (see: Mtetwa L, Marimuthu T, Mndlovu H, Sithole MN, Makatini MM, Choonara YE. Harnessing Cross-Linked Cysteine Scaffolds for Soft Tissue Engineering Applications. Polymers (Basel). 2025 Dec 4;17(23):3231. doi:10.3390/polym17233231). As the manuscript focuses exclusively on adipose tissue-related hydrogels, the scope in the title should be narrowed accordingly.
2. In lines 107–109, the statement that “adipose ECM-derived hydrogels preserve biochemical properties and ultrastructural features of the native ECM without additional manipulation” requires clarification. Specifically, the authors should explain how the hydrogel retains not only biochemical composition but also ultrastructure after decellularization, pregel solubilization, and gelation via physical–chemical polymerization processes.
3. ECM-derived hydrogels can be obtained from various tissues (see: Saldin LT, Cramer MC, Velankar SS, White LJ, Badylak SF. Extracellular matrix hydrogels from decellularized tissues: Structure and function. Acta Biomater. 2017 Feb;49:1–15. doi:10.1016/j.actbio.2016.11.068). Many contain similar components such as type I collagen, fibronectin, and laminin. The manuscript should clarify the specific differences between adipose ECM-derived hydrogels and those derived from other soft tissues.
4. A table should be included that describes specific examples of adipose ECM-derived hydrogel production, including detailed preparation protocols and verified in vitro and in vivo properties.

Author Response

Review of the manuscript ID gels-4073612 by Pruzzo et al.

Reply to the comments of reviewer 2

We appreciate the fair and constructive comments of the reviewer. In the following, please find our point-by-point reply.

1. Reviewer comment: Soft tissues include not only adipose tissue but also skin, skeletal muscle, and other types (see: Mtetwa L, Marimuthu T, Mndlovu H, Sithole MN, Makatini MM, Choonara YE. Harnessing Cross-Linked Cysteine Scaffolds for Soft Tissue Engineering Applications. Polymers (Basel). 2025 Dec 4;17(23):3231. doi:10.3390/polym17233231). As the manuscript focuses exclusively on adipose tissue-related hydrogels, the scope in the title should be narrowed accordingly.

Reply: According to the comment of the reviewer, we have changed the title of our revised manuscript to ‘Injectable scaffolds for adipose tissue reconstruction’ (see line 2; marked in yellow).

2. Reviewer comment: In lines 107–109, the statement that “adipose ECM-derived hydrogels preserve biochemical properties and ultrastructural features of the native ECM without additional manipulation” requires clarification. Specifically, the authors should explain how the hydrogel retains not only biochemical composition but also ultrastructure after decellularization, pregel solubilization, and gelation via physical–chemical polymerization processes.

Reply: According to the comment of the reviewer, we have included the following paragraph in the revised version of our manuscript:

‘For instance, Young et al. [22] reported that decellularized human lipoaspirates retain a complex, adipose tissue-specific composition of collagen isoforms, laminin, fibronectin and sulfated glycosaminoglycans. Although decellularization reduced the concentration of these components compared to native tissue, this assortment of biochemical cues still mimicked the microenvironment of adipose tissue. Uriel et al. [23] generated hydrogels from decellularized subcutaneous fat of donor rats, which polymerized into fibrous networks with a scale and architecture similar to native tissue.’

(See lines 111-118 and 487-490; marked in yellow)

References:

22. Young, D.A.; Ibrahim, D.O.; Hu, D.; Christman, K.L. Injectable hydrogel scaffold from decellularized human lipoaspirate. Acta Biomater. 2011, 7(3), 1040-1049.
23. Uriel, S.; Labay, E.; Francis-Sedlak, M.; Moya, M.L.; Weichselbaum, R.R.; Ervin, N.; Cankova, Z.; Brey, E.M. Extraction and assembly of tissue-derived gels for cell culture and tissue engineering. Tissue Eng Part C Methods. 2009, 15(3), 309-321.

3. Reviewer comment: ECM-derived hydrogels can be obtained from various tissues (see: Saldin LT, Cramer MC, Velankar SS, White LJ, Badylak SF. Extracellular matrix hydrogels from decellularized tissues: Structure and function. Acta Biomater. 2017 Feb;49:1–15. doi:10.1016/j.actbio.2016.11.068). Many contain similar components such as type I collagen, fibronectin, and laminin. The manuscript should clarify the specific differences between adipose ECM-derived hydrogels and those derived from other soft tissues.

Reply: According to the comment of the reviewer, we have included the following paragraph in the revised version of our manuscript:

‘In principle, ECM-derived hydrogels can also be obtained from many other soft tissues [60]. However, depending on the tissue source, they exhibit specific differences. In this context, it should be noted that adipose ECM-derived injectable scaffolds contain significant levels of the α4 chain of laminin 411, which may be explained by the dense microvascular networks in fat tissue [23]. Moreover, they are characterized by high levels of FGF-1 and FGF-2, which are, for instance, much greater than those of tumor-derived Matrigel™ [61].’

(See lines 310-316, 489-490 and 574-577; marked in yellow)  

References:

23. Uriel, S.; Labay, E.; Francis-Sedlak, M.; Moya, M.L.; Weichselbaum, R.R.; Ervin, N.; Cankova, Z.; Brey, E.M. Extraction and assembly of tissue-derived gels for cell culture and tissue engineering. Tissue Eng Part C Methods. 2009, 15(3), 309-321.

60. Saldin, L.T.; Cramer, M.C.; Velankar, S.S.; White, L.J.; Badylak, S.F. Extracellular matrix hydrogels from decellularized tissues: Structure and function. Acta Biomater. 2017, 49, 1-15.

61. Uriel, S; Huang, J.J.; Moya, M.L.; Francis, M.E.; Wang, R.; Chang, S.Y.; Cheng, M.H.; Brey, E.M. The role of adipose protein derived hydrogels in adipogenesis. Biomaterials. 2008, 29(27), 3712-3719.

4. Reviewer comment: A table should be included that describes specific examples of adipose ECM-derived hydrogel production, including detailed preparation protocols and verified in vitro and in vivo properties.

Reply: According to the comment of the reviewer, with have included a novel table in our revised manuscript version, which shows specific examples of adipose ECM-derived hydrogel production, including detailed preparation protocols and verified in vitro and in vivo properties (see Table 3; lines 325-329; marked in yellow).  

Reviewer 3 Report

Comments and Suggestions for Authors

The review, authored by Pruzzo et al., deals with the important subject of injectable scaffolds for broadly understood regenerative medicine, especially in the context of soft tissue regeneration. The manuscript is well-written and tracks modern approaches towards the preparation of scaffolds with special emphasis on those that utilize adipose ECM-derived injectable scaffolds. This is a critical review that clearly shows the benefits and drawbacks of the current state of the art. Additionally, the most relevant commercially available products are discussed, highlighting the translational relevance of the review. As a small suggestion, I would recommend constructing an infromative table or figure that will link specific scaffold types to clinical usage i.e. large volume reconstruction versus those restricted to the small area action etc. 

Author Response

Review of the manuscript ID gels-4073612 by Pruzzo et al.

Reply to the comments of reviewer 3

We appreciate the fair and constructive comments of the reviewer. In the following, please find our point-by-point reply.

1. Reviewer comment: The review, authored by Pruzzo et al., deals with the important subject of injectable scaffolds for broadly understood regenerative medicine, especially in the context of soft tissue regeneration. The manuscript is well-written and tracks modern approaches towards the preparation of scaffolds with special emphasis on those that utilize adipose ECM-derived injectable scaffolds. This is a critical review that clearly shows the benefits and drawbacks of the current state of the art. Additionally, the most relevant commercially available products are discussed, highlighting the translational relevance of the review. As a small suggestion, I would recommend constructing an informative table or figure that will link specific scaffold types to clinical usage i.e. large volume reconstruction versus those restricted to the small area action etc.

Reply: According to the comment of the reviewer, we have included a novel figure in the revised manuscript, which links specific scaffold types and their properties with special emphasis on adipose ECM-derived scaffolds (see Fig. 4; lines 412-417; marked in yellow).