Poly-L-lactic Acid (Sculptra^®): A Regenerative Aesthetic Treatment

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript does a good job explaining how regenerative treatments like PLLA-SCA work by helping the skin rebuild itself instead of just filling or covering up problems.
It’s clear and detailed, but it’s also pretty heavy with scientific jargon, which makes it tough for non-specialists to follow. The focus on collagen is strong, but other important skin components get less attention.

Also, the claim that results last long-term feels a bit promotional since no actual studies or data are mentioned. Cleaning up the language, balancing the science, and adding real-world evidence would make the explanation much more convincing and easier to read.

Comments on the Quality of English Language

the text suffers from stylistic density and redundancy, with repeated use of “regenerative” terminology that dilutes precision. 

Author Response

Reviewer #1:

Comment: This manuscript does a good job explaining how regenerative treatments like PLLA-SCA work by helping the skin rebuild itself instead of just filling or covering up problems.
It’s clear and detailed, but it’s also pretty heavy with scientific jargon, which makes it tough for non-specialists to follow. The focus on collagen is strong, but other important skin components get less attention.

Response: Many thanks for the feedback. The article is primarily focused towards specialists, hence the language reflects this. Hopefully the balance of information reflects that which is currently available in the published literature; that said, additional information has been provided on adipogenesis and dermal white adipose tissue (see lines 276–278).

 

Comment: Also, the claim that results last long-term feels a bit promotional since no actual studies or data are mentioned. Cleaning up the language, balancing the science, and adding real-world evidence would make the explanation much more convincing and easier to read.

Response: Text has been altered to reduce emphasis on long-term when citing clinical data (see lines 142-143; 166-167; 355).

 

Comments on the Quality of English Language

The text suffers from stylistic density and redundancy, with repeated use of “regenerative” terminology that dilutes precision.

Response: “Regenerative” was been removed from the text were appropriate to avoid overuse (see lines 44, 67, 121, 171, 338).

Reviewer 2 Report

Comments and Suggestions for Authors

In my opinion, this paper is complete and good, so it can be published as it is.

Author Response

Reviewer #2:

Comment: In my opinion, this paper is complete and good, so it can be published as it is.

Response: Many thanks for the positive feedback; no revision necessary.

Reviewer 3 Report

Comments and Suggestions for Authors

The article provides a comprehensive and well-structured review of the physicochemical properties and biological mechanisms of action of poly-L-lactic acid (PLLA-SCA; Sculptra®). The authors appropriately frame the topic within the concept of regenerative aesthetics, defined as the restoration of tissue function and structure through the activation of endogenous repair mechanisms, rather than merely replacing volume deficits. This approach is timely and aligns well with current trends in aesthetic medicine.

Particular recognition should be given to the clear presentation of the mechanistic foundations of PLLA-SCA. The authors convincingly describe the dual mechanism involving mechanotransduction and a controlled foreign body response, leading to extracellular matrix (ECM) remodeling. It is also worth emphasizing the multi-layered perspective on regenerative processes, from fibroblast stimulation in the dermis (type I and III neocollagenesis, elastogenesis) to effects on subcutaneous tissue, including adipogenesis. This holistic perspective significantly enhances the value of the work.

An important strength of the article is the inclusion of molecular data, including gene expression analyses (e.g., ELN, HGF, MMP), which goes beyond standard clinical descriptions and provides a solid scientific foundation. The authors’ conclusions are consistent with the presented data and convincingly demonstrate the long-lasting clinical effects of PLLA-SCA (up to 25 months), resulting from sustained activation of endogenous regenerative pathways.

Despite its high scientific quality, the article could be further strengthened by addressing the following key points:

• expansion of the discussion of common adverse events (e.g., nodules, swelling) and strategies for their prevention (e.g., dilution protocols, injection techniques),
• deepening of the comparison with other biostimulators, particularly calcium hydroxylapatite (CaHA), with a focus on differences in mechanisms (inflammatory vs. regenerative pathways),
• inclusion of practical guidance for body applications (e.g., buttocks, knees, cellulite), ideally in a concise table with concentrations, volumes, and techniques,
• stronger emphasis on the role of dermal white adipose tissue in immune and antimicrobial functions, along with clarification of the broader impact of PLLA-induced adipogenesis on skin health.

The manuscript is evaluated very positively in terms of both scientific merit and practical relevance. The suggested comments are complementary and do not affect the overall value of the work. Therefore, I recommend acceptance of the article after minor revision.

Author Response

Reviewer #3:

The article provides a comprehensive and well-structured review of the physicochemical properties and biological mechanisms of action of poly-L-lactic acid (PLLA-SCA; Sculptra®). The authors appropriately frame the topic within the concept of regenerative aesthetics, defined as the restoration of tissue function and structure through the activation of endogenous repair mechanisms, rather than merely replacing volume deficits. This approach is timely and aligns well with current trends in aesthetic medicine.

Particular recognition should be given to the clear presentation of the mechanistic foundations of PLLA-SCA. The authors convincingly describe the dual mechanism involving mechanotransduction and a controlled foreign body response, leading to extracellular matrix (ECM) remodeling. It is also worth emphasizing the multi-layered perspective on regenerative processes, from fibroblast stimulation in the dermis (type I and III neocollagenesis, elastogenesis) to effects on subcutaneous tissue, including adipogenesis. This holistic perspective significantly enhances the value of the work.

An important strength of the article is the inclusion of molecular data, including gene expression analyses (e.g., ELN, HGF, MMP), which goes beyond standard clinical descriptions and provides a solid scientific foundation. The authors’ conclusions are consistent with the presented data and convincingly demonstrate the long-lasting clinical effects of PLLA-SCA (up to 25 months), resulting from sustained activation of endogenous regenerative pathways.

Comments: Despite its high scientific quality, the article could be further strengthened by addressing the following key points:

• expansion of the discussion of common adverse events (e.g., nodules, swelling) and strategies for their prevention (e.g., dilution protocols, injection techniques),

Response: Many thanks for the feedback. The reviewer raises an important point regards adverse events; however, as this is a practical consideration (together with the point below regards guidance on the use of PLLA in different regions of the body), this is only touched upon here as it is mentioned in detail in cited guidance articles (e.g. Refs 27–29, lines 109–111) should the reader require further information. We hope this response is acceptable.

• deepening of the comparison with other biostimulators, particularly calcium hydroxylapatite (CaHA), with a focus on differences in mechanisms (inflammatory vs. regenerative pathways),

Response: Many thanks for the suggestion. While a comparison between PLLA and CaHA would be interesting to conduct, the purpose of this article is to focus on the regenerative potential of PLLA rather than try to compare various aspects of PLLA and CaHA, which might actually form a separate publication in its own right. Indeed, cited Refs 15 and 16 do compare the different mechanisms should the reader look for information on this.

• inclusion of practical guidance for body applications (e.g., buttocks, knees, cellulite), ideally in a concise table with concentrations, volumes, and techniques,

Response: Again, the reviewer raises an important point; practical guidance is already available on PLLA (Sculptra) in the medical literature and this is mentioned in the text (e.g. Refs 27–29, lines 109–111) should the reader require further information. We hope this response is acceptable.

• stronger emphasis on the role of dermal white adipose tissue in immune and antimicrobial functions, along with clarification of the broader impact of PLLA-induced adipogenesis on skin health.

Response: As requested, text has been added regards the broader impact of PLLA-induced adipogenesis on skin health (lines 271–272) and to emphasize the immune and antimicrobial function of dermal white adipose tissue (lines 276–278).

The manuscript is evaluated very positively in terms of both scientific merit and practical relevance. The suggested comments are complementary and do not affect the overall value of the work. Therefore, I recommend acceptance of the article after minor revision.

Response: Many thanks for the positive feedback. Hopefully with the revisions made the article is suitable for acceptance.

 

Journal comment: The reviewers indicate that the English requires improvement. Based on this, the journal provides several options: Rapid English Editing; Figure and Table Editing; Layout Editing; Graphical Abstract; Video Production.

Response: Many thanks for the feedback. It is anticipated that this is based on one comment from Reviewer 1 (note: not Reviewers 2 and 3) regards text redundancy; having addressed this it is assumed that this comment is also addressed.