Review Reports - Botulinum Toxin Type A Injections in the Bladder Wall—An Effective Treatment for Urinary Incontinence with Low Long-Term Adherence

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for the opportunity to review this manuscript.

This review offers a broad, generally well-organized overview of botulinum toxin type A (BoNT/A) for refractory urinary incontinence in neurogenic detrusor overactivity and idiopathic overactive bladder, with the manuscript’s “through-line” being a clinically important (and often under-discussed) issue: long-term adherence is poor in real-world practice despite strong efficacy in pivotal trials. To explain this gap, the authors emphasize practical burdens (repeated cystoscopy, procedure-related discomfort) and treatment-limiting adverse effects (notably UTIs and post-treatment voiding dysfunction/self-catheterization), then pivot to what the field is doing about it—namely, refining injection technique and developing less-invasive delivery strategies. The strongest value of the paper is this integrated framing of adherence as the main clinical driver for innovation, followed by a wide scan of emerging modalities (transporters/facilitators such as EMDA, low-energy shock waves, and multiple nanocarrier approaches), and an additional “alternative access” pathway (ultrasound-guided transabdominal injection). Overall, the topic is relevant, and the synthesis is useful, but the manuscript would be substantially stronger with more critical appraisal of the maturity, limitations, feasibility, and implementation pathway for each “emerging” approach, plus clearer stratification by patient population and a better evidence-summary architecture.

Comments/suggestions:

The review sometimes catalogs innovations rather than critiquing them; several delivery concepts discussed (especially nanoformulations/novel carriers) are still early-stage, and readers will benefit from a clearer “what would have to be true for this to work in practice?” analysis—e.g., durability of effect, repeatability, urothelial penetration vs systemic exposure, device or formulation standardization, and realistic safety monitoring horizons. Adding a short “readiness” appraisal for each technology (preclinical vs pilot vs comparative trial) would make the review more decision-useful and less descriptive.

Some modalities presented as “emerging” have been explored for many years (EMDA is a good example), and the paper should explicitly address why adoption has remained limited (equipment availability, workflow burden, variable efficacy, training requirements, reimbursement/regulatory friction). For EMDA, it would help to position the current state using clinical pilot data (e.g., in neuropathic detrusor overactivity) rather than implying a recent breakthrough (e.g., Koh C, et al. J Pediatr Urol. 2019;15(5):552.e1–552.e8. https://doi.org/10.1016/j.jpurol.2019.05.028).
Your central claim (poor adherence) needs a stronger evidence “spine” in the form of a comparative table; a dedicated table summarizing (1) continuation/discontinuation rates by timepoint, (2) primary reasons for discontinuation (primary failure, tolerability, “resolved symptoms,” logistics), and (3) population type (idiopathic OAB vs neurogenic DO) would materially strengthen the argument. The table can anchor key studies, such as:

Mohee A, Khan A, Harris N, Eardley I. BJU Int. 2013;111(1):106–113. https://doi.org/10.1111/j.1464-410X.2012.11282.x (reports high long-term discontinuation in “real-life” cohorts).
Baron M, et al. Progrès en Urologie. 2020;30(12):684–691. https://doi.org/10.1016/j.purol.2020.07.242 (provides long-term persistence/discontinuation-free survival and reasons).
Veeratterapillay R, et al. Int J Urol. 2014;21:175–178. https://doi.org/10.1111/iju.12205 (medium-term discontinuation and injection intervals).

NDO vs idiopathic OAB are discussed together too often without enough stratification. These populations differ meaningfully in baseline pathophysiology, tolerance of adverse events, willingness/ability to self-catheterize, and perceived benefit thresholds. The review would be stronger if each “delivery solution” were briefly scored or discussed for NDO-specific fit vs OAB-specific fit (e.g., acceptability of repeat procedures, safety priorities, expected retreatment interval, and consequences of urinary retention).
The manuscript focuses mainly on procedural burdens and biological adverse events; however, long-term continuation is also shaped by patient expectations, quality of education, fear/anxiety around procedures, stigma, daily-life disruption, caregiver support (especially in neurogenic cohorts), and decision fatigue in chronic disease management. Even a concise “psychosocial and system factors” subsection would make the adherence argument more complete and clinically realistic.
For drug–device combinations and novel formulations, the paper should address the translation requirements (regulatory pathway, manufacturing/scalability, clinic-level equipment/training, and post-market surveillance). This is especially relevant for approaches that move beyond standard cystoscopic injection into combination technologies.
Consider adding a short “Future Directions” section that (a) prioritizes the most plausible near-term approaches, (b) specifies what evidence would be required to change the standard of care (comparative effectiveness, durability, safety, patient-reported outcomes, and cost), and (c) highlights “high-yield” trial designs.
Duplicate reference needs correction. Your list indicates a duplication involving the Chuang et al. liposome-delivery paper; if the duplicated entry is indeed: Chuang YC, et al. “Urodynamic and immunohistochemical evaluation of intravesical botulinum toxin A delivery using liposomes.” J Urol. 2009 (ScienceDirect listing). Remove the duplicate and renumber consistently.
A one-sentence clarification in the Introduction would help (i.e., observational cohorts/registries and routine-practice discontinuation patterns vs tightly controlled RCT follow-up). This also aligns the reader with why Mohee et al. and other long-term cohorts are central to your premise (Mohee A, et al. BJU Int. 2013;111(1):106–113. https://doi.org/10.1111/j.1464-410X.2012.11282.x).
Even a short, balanced discussion (procedure costs, repeat visits, equipment needs for EMDA/ultrasound, scalability of manufacturing for carriers) will help readers judge which alternatives are realistically adoptable.
A dedicated section titled “Barriers to Long-Term Adherence” (procedural + adverse events + psychosocial/system factors) placed before “solutions” would improve narrative clarity and reduce repetition.
Add at least one visual aid. A simple schematic comparing: (1) cystoscopic injection, (2) intravesical instillation with carriers/facilitators, and (3) transabdominal ultrasound-guided injection, plus a short flowchart of “why patients discontinue,” would materially improve readability for a text-heavy review.
Overall readability is strong, but tightening terminology would help: pick one style and apply consistently (e.g., BoNT/A vs BoNT-A; NDO vs NDOi; idiopathic OAB vs OABi), and ensure each abbreviation is defined once, early, then used consistently.
Consider replacing informal phrasing like “real-life” with “real-world/routine practice” (unless quoting a study’s wording), and keep patient-centered language when discussing discontinuation (e.g., “stopped due to tolerability/retention burden” rather than implying noncompliance).
Two incomplete citations should be fixed or removed, and they may be patents rather than journal articles:

If “Botulinum nanoemulsions (2012)” refers to the patent record, cite it fully (e.g., Botulinum nanoemulsions. US patent US8318181B2; published 2012. https://patents.google.com/patent/US8318181B2).
If “Moeller (2017) Botulinum toxin and colloidal silver particles” refers to the patent application, cite it explicitly as such (e.g., Moeller KW, Willoughby AJM. Botulinum toxin and colloidal silver particles. US patent application US20170196946A1; published 2017. https://patents.google.com/patent/US20170196946A1).

If these sources are not directly relevant to intravesical/urologic delivery—or if the manuscript treats them as clinical evidence—either justify their inclusion clearly (as conceptual/engineering background) or remove them.

Comments on the Quality of English Language

see above

Author Response

Thank you for the opportunity to review this manuscript.

Comments/suggestions:

The review sometimes catalogs innovations rather than critiquing them; several delivery concepts discussed (especially nanoformulations/novel carriers) are still early-stage, and readers will benefit from a clearer “what would have to be true for this to work in practice?” analysis—e.g., durability of effect, repeatability, urothelial penetration vs systemic exposure, device or formulation standardization, and realistic safety monitoring horizons. Adding a short “readiness” appraisal for each technology (preclinical vs pilot vs comparative trial) would make the review more decision-useful and less descriptive.

Reply: Thank you for the suggestion. All the novelties under investigation for BoNT/A administration now have a comment in the lines 268-372. Namely, for EMDA, a negative trial was added (Koh et al). For new formulations, only those already in clinical trials were considered. However, an overarching comment on these innovations is made in lines 387 to 421, namely, the necessity of large clinical trials in the bladder and the need for regulatory approval. The costs are also mentioned.

We left it clear that a decrease in the number of injection points does not eliminate the need for cystoscopy, and none of the reports address potential advantages regarding adherence.

Some modalities presented as “emerging” have been explored for many years (EMDA is a good example), and the paper should explicitly address why adoption has remained limited (equipment availability, workflow burden, variable efficacy, training requirements, reimbursement/regulatory friction). For EMDA, it would help to position the current state using clinical pilot data (e.g., in neuropathic detrusor overactivity) rather than implying a recent breakthrough (e.g., Koh C, et al. J Pediatr Urol. 2019;15(5):552.e1–552.e8. https://doi.org/10.1016/j.jpurol.2019.05.028).

Reply: EMDA is a method of drug delivery that was applied to Botulinum toxin administration to the bladder wall by the group of Dr. Kajbafzadeh and co-workers. Multiple papers have been published by this group, but we decided to limit the quotation to a recent paper that summarizes the long-term experience (ref. 48). The group's experimental study is also quoted, as it demonstrates the toxin's transport in rabbit tissues. However, the data by Koh and co-workers are now also well explained, as no improvement was observed in the patients who received BoNT/A EMDA administration by these authors. In particular, we highlight that the non-EMDA responders achieved good outcomes with a post-administration of BoNT/A via bladder wall injections (see lines 283-300). The lack of robust evidence for the use of EMDA in the field is also clear in the manuscript

Your central claim (poor adherence) needs a stronger evidence “spine” in the form of a comparative table; a dedicated table summarizing (1) continuation/discontinuation rates by timepoint, (2) primary reasons for discontinuation (primary failure, tolerability, “resolved symptoms,” logistics), and (3) population type (idiopathic OAB vs neurogenic DO) would materially strengthen the argument. The table can anchor key studies, such as:

Mohee A, Khan A, Harris N, Eardley I. BJU Int. 2013;111(1):106–113. https://doi.org/10.1111/j.1464-410X.2012.11282.x (reports high long-term discontinuation in “real-life” cohorts).
Baron M, et al. Progrès en Urologie. 2020;30(12):684–691. https://doi.org/10.1016/j.purol.2020.07.242 (provides long-term persistence/discontinuation-free survival and reasons).
Veeratterapillay R, et al. Int J Urol. 2014;21:175–178. https://doi.org/10.1111/iju.12205 (medium-term discontinuation and injection intervals).

Reply: We thank the reviewer for this constructive suggestion. In response, we have added a new table summarizing (1) discontinuation rates by time point and (2) the primary reasons for treatment discontinuation. The table includes the three references suggested by the reviewer. This new table is now presented as Table 1, and the original Table 1 has been renumbered as Table 2. Also, additional papers were added beyond those suggested by the reviewer. A separation was also made in the text between the cohorts with high discontinuation rates (lines 167-187) and those with low discontinuation rates, which appear in the following paragraph (lines 188-195).

We now include in the text the discontinuation rates reported by the phase 3 trials and their long-term extensions to call attention to the fact that, in real-world conditions, adherence is much lower.

The barriers patients with NDOi and OABi might encounter are now discussed in more detail in section 2

NDO vs idiopathic OAB are discussed together too often without enough stratification. These populations differ meaningfully in baseline pathophysiology, tolerance of adverse events, willingness/ability to self-catheterize, and perceived benefit thresholds. The review would be stronger if each “delivery solution” were briefly scored or discussed for NDO-specific fit vs OAB-specific fit (e.g., acceptability of repeat procedures, safety priorities, expected retreatment interval, and consequences of urinary retention).

Reply: As none of the innovative approaches to BoNT/A delivery has yielded robust data until now, it remains speculative which of these will merit entering clinical practice. At this time, it is unknown whether they will enter clinical practice or be used in NDOi, OABi, or both.

We did our best to separate the NDO and OAB studies. This is clear from the discontinuation rates in section 2. The reasons for different rates among NDO and OAB patients are also discussed (lines 102-106 and 125-136 for NDO, lines 160-170 for OABi)

The manuscript focuses mainly on procedural burdens and biological adverse events; however, long-term continuation is also shaped by patient expectations, quality of education, fear/anxiety around procedures, stigma, daily-life disruption, caregiver support (especially in neurogenic cohorts), and decision fatigue in chronic disease management. Even a concise “psychosocial and system factors” subsection would make the adherence argument more complete and clinically realistic.

Reply: We agree with the reviewer and have added several comments on the importance of informing and supporting patients, particularly those with MS and OAB. In particular, this is addressed in lines 190-203. However, we also state that individual barriers to BoNT/A administration for the treatment of NDOi and OABi were never the subject of a careful investigation. That is, reasons for discontinuation were never the primary outcome in any BoNT/A study, whether NDO or OAB.

For drug–device combinations and novel formulations, the paper should address the translation requirements (regulatory pathway, manufacturing/scalability, clinic-level equipment/training, and post-market surveillance). This is especially relevant for approaches that move beyond standard cystoscopic injection into combination technologies.

Reply: Regulatory pathways for drug-device combinations vary across jurisdictions. We have added a paragraph to the future directions section describing this based on a 2024 review comparing regulators in the US, EU, and Korea (Kim 2024).

Consider adding a short “Future Directions” section that (a) prioritizes the most plausible near-term approaches, (b) specifies what evidence would be required to change the standard of care (comparative effectiveness, durability, safety, patient-reported outcomes, and cost), and (c) highlights “high-yield” trial designs.

Reply: A short section about this topic has been added to section 6. However, as we also highlight in that section, this is largely speculative. Importantly, given the investment required to address regulatory requirements (your comment #3), this will most likely require involvement of a company. It is in the nature of a for-profit organization that its decisions are determined by financial considerations and not driven by academic curiosity or medical need.

Duplicate reference needs correction. Your list indicates a duplication involving the Chuang et al. liposome-delivery paper; if the duplicated entry is indeed: Chuang YC, et al. “Urodynamic and immunohistochemical evaluation of intravesical botulinum toxin A delivery using liposomes.” J Urol. 2009 (ScienceDirect listing). Remove the duplicate and renumber consistently.

Reply: Duplicated references resulted from confusion between Chuang 2009 and Chuang et al 2016. The correction is made

A one-sentence clarification in the Introduction would help (i.e., observational cohorts/registries and routine-practice discontinuation patterns vs tightly controlled RCT follow-up). This also aligns the reader with why Mohee et al. and other long-term cohorts are central to your premise (Mohee A, et al. BJU Int. 2013;111(1):106–113. https://doi.org/10.1111/j.1464-410X.2012.11282.x).

Reply: As already stated, we included the discontinuation rates observed in phase 3 trials and in their long-term extensions to highlight the difference between clinical trials and real-world data

Even a short, balanced discussion (procedure costs, repeat visits, equipment needs for EMDA/ultrasound, scalability of manufacturing for carriers) will help readers judge which alternatives are realistically adoptable.

Reply: We have addressed this in the final paragraph of section 6. However, we feel that the net benefit to patients relative to costs etc. can only be determined once more robust data on the novel delivery approaches are available. Therefore, we have not discussed this as we see it as too speculative at the moment. Rather the added paragraph highlights the complexity of the issue.

A dedicated section titled “Barriers to Long-Term Adherence” (procedural + adverse events + psychosocial/system factors) placed before “solutions” would improve narrative clarity and reduce repetition.

Reply: We respectfully disagree with the reviewer on this point. As highlighted during sessions at the SUFU meeting last month, data on barriers to long-term adherence are not fully clear. To avoid overspeculation based on findings that are not yet conclusive, we have added corresponding language at the end of section 2. See also reply to query 5

Add at least one visual aid. A simple schematic comparing: (1) cystoscopic injection, (2) intravesical instillation with carriers/facilitators, and (3) transabdominal ultrasound-guided injection, plus a short flowchart of “why patients discontinue,” would materially improve readability for a text-heavy review.

Reply: Although the reviewer´s idea is interesting, we do not yet have firm data to establish a pathway for patients who stop BoNT/A treatment. Studies on new forms of bladder administration, such as reduced injection points, did not report on patients’ adherence. So, the figure would be speculative. We think that the new Table 1 will help the reader to understand the reasons for discontinuation. But there are no data to define a follow-up.

Overall readability is strong, but tightening terminology would help: pick one style and apply consistently (e.g., BoNT/A vs BoNT-A; NDO vs NDOi; idiopathic OAB vs OABi), and ensure each abbreviation is defined once, early, then used consistently.

Reply: We thank the reviewer for this helpful suggestion.
The manuscript has been carefully revised to ensure consistent terminology throughout. Abbreviations such as BoNT/A, NDOi, and OABi are now defined at first occurrence and used consistently thereafter.

Consider replacing informal phrasing like “real-life” with “real-world/routine practice” (unless quoting a study’s wording), and keep patient-centered language when discussing discontinuation (e.g., “stopped due to tolerability/retention burden” rather than implying noncompliance).

Reply: Informal expressions such as “real-life” have been replaced with “real-world clinical practice,” and patient-centered wording has been adopted when referring to treatment discontinuation.

Two incomplete citations should be fixed or removed, and they may be patents rather than journal articles:

If “Botulinum nanoemulsions (2012)” refers to the patent record, cite it fully (e.g., Botulinum nanoemulsions. US patent US8318181B2; published 2012. https://patents.google.com/patent/US8318181B2).
If “Moeller (2017) Botulinum toxin and colloidal silver particles” refers to the patent application, cite it explicitly as such (e.g., Moeller KW, Willoughby AJM. Botulinum toxin and colloidal silver particles. US patent application US20170196946A1; published 2017. https://patents.google.com/patent/US20170196946A1).

Reply: Although the references are not directly related to the application of BoNT/A in the bladder, they represent a significant advance that may lead in the future to new forms of bladder application of the toxin. They contain important information for the readers. We prefer to maintain the reference Willoughby AJM. Botulinum toxin and colloidal silver particles. US patent application US20170196946A1; published 2017. https://patents.google.com/patent/US20170196946A1). The citation was corrected

Reviewer 2 Report

Comments and Suggestions for Authors

This article examines the long-term therapeutic efficacy and safety of intravesical botulinum toxin type A (BoNT/A) injections for the management of urinary incontinence, providing a systematic evaluation of current injection protocols—including their documented limitations—and critically appraising emerging alternative administration strategies. The review holds substantial clinical relevance, presents a comprehensive synthesis of evidence, incorporates robust and appropriately selected literature support, and maintains a logically structured narrative. Nevertheless, several refinements are recommended to enhance methodological rigor and scholarly precision:
1. Terminological consistency: “BONT/A” has been standardized to “BoNT/A”, and “anobutilinumtoxinA” corrected to “onabotulinumtoxinA”, in accordance with established nomenclature guidelines (e.g., International Nonproprietary Names and peer-reviewed pharmacologic literature).
2. Citation integrity: In-text citations have been harmonized to a uniform sequential numeric format; duplicate references (e.g., Chuang et al., 2009, previously cited as both #49 and #51) have been consolidated, and the reference list has been verified for completeness and accuracy—resolving omissions (e.g., missing entries corresponding to original citations #55 and #57).
3. Analytical depth: Where multiple studies are cited within a single paragraph, the discussion now explicitly addresses key sources of heterogeneity—including variations in patient demographics, BoNT/A dosing regimens, and follow-up durations—and evaluates the implications of such variability for cross-study comparability and clinical generalizability.

Author Response

Terminological consistency: “BONT/A” has been standardized to “BoNT/A”, and “anobutilinumtoxinA” corrected to “onabotulinumtoxinA”, in accordance with established nomenclature guidelines (e.g., International Nonproprietary Names and peer-reviewed pharmacologic literature).

Reply: Terminology was verified and used consistently throughout the text.

Citation integrity: In-text citations have been harmonized to a uniform sequential numeric format; duplicate references (e.g., Chuang et al., 2009, previously cited as both #49 and #51) have been consolidated, and the reference list has been verified for completeness and accuracy—resolving omissions (e.g., missing entries corresponding to original citations #55 and #57).

Reply: Citation integrity: In-text citations have been harmonized to a uniform sequential numeric format; duplicate references (e.g., Chuang et al., 2009, previously cited as both #49 and #51) have been consolidated, and the reference list has been verified for completeness and accuracy—resolving omissions (e.g., missing entries corresponding to original citations #55 and #57).

Analytical depth:

Reply: Where multiple studies are cited within a single paragraph, the discussion now explicitly addresses key sources of heterogeneity—including variations in patient demographics, BoNT/A dosing regimens, and follow-up durations—and evaluates the implications of such variability for cross-study comparability and clinical generalizability. Also, for easy reading, the new Table 1 helps clarify this point.

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript “Botulinum Toxin Type A Injections in the Bladder Wall. An Effective Treatment for Urinary Incontinence with Low Long-Term Adherence” submitted to the journal Toxins (MDPI), is a narrative literature review on the use of botulinum toxin type A (BoNTA) for urinary incontinence, focusing on low long-term adherence due to the need for repeated cystoscopic injections. It discusses alternative administration methods, such as EMDA, shockwave therapy, and nanoformulations, and concludes with the need for cystoscopy-free approaches.

In general, and contextualized terms, the review is well-structured, with a clear introduction on the efficacy of BoNTA in NDOi and OABi, analysis of actual adherence (high discontinuation rates in OABi, ~60-70%), protocol variations (fewer injection points), and experimental alternatives. As a non-systematic review, it prioritizes interpretive synthesis over meta-analysis.

I can make the following suggestions:

Absence of selection criteria: It does not explain searches (databases, terms) or reasons for inclusion/exclusion, common in narratives but weakens rigor; I suggest adding justification for delimitation.
Lack of figures: It would benefit from a flowchart of alternatives vs. standard method or adherence timeline; Table 1 could be expanded with columns of evidence (GRADE levels).
Bibliographic update: References up to 2025; check studies up to 2026 on nanoformulations (e.g., thermal stability).

- Generic conclusion: Strengthen with specific gaps, such as RCTs for ultrasound-guided studies. It can be highlighted that the original content, without apparent plagiarism, with a critical synthesis of ~80 references; relevant to therapeutic toxins, aligned with the scope of Toxins. Low adherence is a real problem in urology, and alternatives such as EMDA/nano are innovative.

Author Response

In general, and in the context of the review, the review is well-structured, with a clear introduction to the efficacy of BoNTA in NDOi and OABi, an analysis of actual adherence (high discontinuation rates in OABi, ~60-70%), protocol variations (fewer injection points), and experimental alternatives. As a non-systematic review, it prioritizes interpretive synthesis over meta-analysis.

I can make the following suggestions:

Absence of selection criteria: It does not explain searches (databases, terms) or reasons for inclusion/exclusion, common in narratives but weakens rigor; I suggest adding justification for delimitation.

Reply: There are no comparative data on adherence between BoNT/A administration by cystoscopy and other investigative methods. The number of studies is small and discontinuation was analyzed at different time points. No systematic questionnaire was ever used to investigate the causes of treatment interruption. Thus, a systematic review would add very little, if any, additional information. This is now written at the end of the introduction.

Lack of figures: It would benefit from a flowchart of alternatives vs. standard method or adherence timeline; Table 1 could be expanded with columns of evidence (GRADE levels).

Reply: There are no firm data yet to establish a pathway for patients who stop BoNT/A treatment. Moreover, the only approved route of BoNT/S administration remains cystoscopy, with 20 to 30 injection points. Studies on new forms of bladder administration, such as reduced injection points, did not report on patients’ adherence. So, the figure would be speculative. We think that the new Table 1 will help the reader to understand the reasons for discontinuation

Bibliographic update: References up to 2025; check studies up to 2026 on nanoformulations (e.g., thermal stability).

Reply: In 2026, no relevant publications concerning the bladder application of Botulinum toxin encapsulated in nanoformulations were found, in addition to the already quoted one from 2025.

Reply: Thank you for the comments

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The following issues remain partially or completely unaddressed:

I requested a brief “readiness” appraisal for each technology (e.g., preclinical, pilot, or comparative trial) to make the review more decision-useful. While the authors added comments on the necessity of large clinical trials and regulatory approval (lines 387-421), there is no systematic classification or labeling of the maturity level for each specific technology discussed in Section 4 or Table 2.
I asked the authors to explicitly address why EMDA adoption has remained limited, citing factors such as equipment availability, workflow burden, variable efficacy, training requirements, and reimbursement/regulatory friction. The authors’ response focused on adding the negative trial by Koh et al. (lines 312-316), but the manuscript does not address the specific practical, logistical, or systemic barriers to EMDA adoption that were requested.
I suggested adding a concise “psychosocial and system factors” subsection to address patient expectations, fear/anxiety, stigma, and decision fatigue. While the authors added brief comments on the importance of informing and supporting patients (lines 107-113, 146-153, 200-203), they did not create a dedicated subsection, nor did they explicitly discuss factors such as fear/anxiety, stigma, or decision fatigue as requested.
I asked the authors to address the translation requirements for drug-device combinations, specifically mentioning regulatory pathways, manufacturing/scalability, clinic-level equipment/training, and post-market surveillance. The authors added a paragraph on regulatory pathways (lines 417-429) and briefly mentioned manufacturing scalability (lines 448-451). However, the requirements for clinic-level equipment and training, as well as post-market surveillance, remain unaddressed.
I requested a “Future Directions” section that prioritizes the most plausible near-term approaches, specifies the evidence required to change the standard of care, and highlights “high-yield” trial designs. The authors added a short section (Section 6, lines 417-451) but explicitly stated in their response that prioritizing approaches is largely speculative. The revised section does not rank the plausibility of near-term approaches, detail specific evidence types (e.g., patient-reported outcomes), or discuss trial designs.
Table 2 still uses “BoNT-A” in several entries instead of the preferred “BoNT/A”.
Multiple typographical errors were introduced in the newly added Table 1, including “Dicontinuation” (column header), “insuficient”, “MS severite”, “reasions”, and “ideopathic”.

Comments on the Quality of English Language

Author Response

Comments and Suggestions for Authors

The following issues remain partially or completely unaddressed:

I requested a brief “readiness” appraisal for each technology (e.g., preclinical, pilot, or comparative trial) to make the review more decision-useful. While the authors added comments on the necessity of large clinical trials and regulatory approval (lines 387-421), there is no systematic classification or labeling of the maturity level for each specific technology discussed in Section 4 or Table 2.

Reply: This is now well developed in Table 2 and in the end of section 5, lines 385-389.

I asked the authors to explicitly address why EMDA adoption has remained limited, citing factors such as equipment availability, workflow burden, variable efficacy, training requirements, and reimbursement/regulatory friction. The authors’ response focused on adding the negative trial by Koh et al. (lines 312-316), but the manuscript does not address the specific practical, logistical, or systemic barriers to EMDA adoption that were requested.

Reply: The section about EMDA is nor expanded and information about the generators presented more in depth (see lines 271-318)

I suggested adding a concise “psychosocial and system factors” subsection to address patient expectations, fear/anxiety, stigma, and decision fatigue. While the authors added brief comments on the importance of informing and supporting patients (lines 107-113, 146-153, 200-203), they did not create a dedicated subsection, nor did they explicitly discuss factors such as fear/anxiety, stigma, or decision fatigue as requested.

Reply: This is now developed in the new section 5, lines 405-442

I asked the authors to address the translation requirements for drug-device combinations, specifically mentioning regulatory pathways, manufacturing/scalability, clinic-level equipment/training, and post-market surveillance. The authors added a paragraph on regulatory pathways (lines 417-429) and briefly mentioned manufacturing scalability (lines 448-451). However, the requirements for clinic-level equipment and training, as well as post-market surveillance, remain unaddressed.

Reply: combination therapy (BoNT/A with oral medications I s now discussed in the end of the new section 6

I requested a “Future Directions” section that prioritizes the most plausible near-term approaches, specifies the evidence required to change the standard of care, and highlights “high-yield” trial designs. The authors added a short section (Section 6, lines 417-451) but explicitly stated in their response that prioritizing approaches is largely speculative. The revised section does not rank the plausibility of near-term approaches, detail specific evidence types (e.g., patient-reported outcomes), or discuss trial designs.

Reply: This is now stated in the end of section 4, lines 385-391. Although speculative we believe that EMDA and ESWL are closer to clinical trials if investors are found

Table 2 still uses “BoNT-A” in several entries instead of the preferred “BoNT/A”.

Reply: Corrected the terminology in Table 2

Multiple typographical errors were introduced in the newly added Table 1, including “Dicontinuation” (column header), “insuficient”, “MS severite”, “reasions”, and “ideopathic”.

Reply: Thank you for the suggestions. Typographical errors　in Table 1 have been corrected: “Discontinuation” (column header), “insufficient”, “MS severity”, “reasons”, and “idiopathic”.