Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript addresses an interesting and potentially clinically relevant topic by proposing a computational model of the protective biomechanical role of amniotic fluid and cerebrospinal fluid during maternal traumatic or convulsive events. The study is technically sophisticated and presents a promising modeling framework. However, several important issues should be addressed before the manuscript can be considered for publication:

1. The conclusions appear overstated relative to the presented data.
   The manuscript makes strong clinical inferences regarding fetal safety during maternal seizures/trauma, whereas the study is based solely on computational simulations without experimental or clinical validation. The discussion and conclusion should be revised to moderate these claims and clearly distinguish model predictions from clinically established evidence.  
2. The computational model requires stronger validation.
   Although the modeling approach is technically detailed, the manuscript lacks sufficient validation against experimental, phantom, animal, or previously published biomechanical data. Additional benchmarking or expanded discussion of this limitation is necessary to support confidence in the quantitative findings.
3. Material property assumptions require further justification.
   The mechanical parameters used for fetal tissues, skull, and fluid compartments should be more thoroughly justified, ideally with a dedicated table summarizing literature sources and assumptions. Given the likely sensitivity of the model to these parameters, discussion of uncertainty is warranted.
4. Comparison with neural injury thresholds should be interpreted more cautiously.
   The manuscript compares predicted stress values to published injury thresholds, but these thresholds may not be directly applicable to fetal neural tissue. This limitation should be explicitly acknowledged, and the corresponding conclusions should be tempered.

Author Response

We thank the reviewer for their thorough and constructive evaluation of our manuscript. The feedback has been very valuable in improving the manuscript. We have carefully addressed each concern, and all revisions are highlighted in red in the revised manuscript. Point-by-point responses to each comment are as follows:

Comment 1: The conclusions appear overstated relative to the presented data.

Response: We agree with this assessment and have revised the manuscript accordingly. Throughout the abstract, discussion, and conclusion sections, we have replaced definitive statements with qualifying language such as "computational modeling suggests," "model predictions indicate," and "these findings represent simulation outputs that have not been validated against experimental or clinical data." Additionally, we have reframed the central contribution of the study to emphasize the demonstration of hierarchical force attenuation through comparative analysis of separation dynamics at different anatomical levels, rather than absolute claims regarding fetal safety.

Location of changes: Please see red-highlighted text in the Abstract, Clinical Implications for Maternal Trauma Management subsection, and Conclusion section of the revised manuscript.

Comment 2: The computational model requires stronger validation.

Response: We acknowledge that the absence of direct validation represents a significant limitation of this investigation. We have expanded the Methodological Contributions and Validation Considerations subsection to explicitly address this concern. The new text acknowledges that the model has not been benchmarked against physical measurements, phantom studies, animal model data, or previously published biomechanical studies examining analogous nested fluid-structure systems. We have also identified specific validation approaches that could strengthen confidence in the findings, including phantom studies with embedded pressure sensors, comparison with animal model data, and systematic sensitivity analyses. The revised text clearly states that the quantitative predictions should be considered preliminary estimates requiring experimental confirmation.

Location of changes: Please see red-highlighted text in the Methodological Contributions and Validation Considerations subsection of the revised manuscript.

Comment 3: Material property assumptions require further justification.

Response: We have addressed this concern by adding a dedicated table (Table 1) that summarizes the material properties assigned to each model component along with literature sources and key assumptions. Additionally, we have included new text discussing parameter uncertainty, particularly for fetal brain tissue properties, which were extrapolated from adult tissue data using developmental scaling relationships. The revised manuscript explicitly acknowledges that direct measurements of human fetal neural tissue are ethically constrained and rarely reported, and that this scaling approach introduces uncertainty in predicted stress magnitudes.

Location of changes: Please see the new Table 1 and accompanying red-highlighted discussion in the Material Properties and Initial Conditions subsection of the revised manuscript.

Comment 4: Comparison with neural injury thresholds should be interpreted more cautiously.

Response: We agree that injury thresholds derived from adult neural tissue may not be directly applicable to fetal tissue. We have added explicit acknowledgment of this limitation wherever threshold comparisons are made. The revised text notes that fetal brain tissue differs substantially from adult tissue in cellular composition, extracellular matrix organization, water content, and mechanical properties, and that the injury susceptibility of fetal neurons may differ from mature cells. We have also added cautionary language in the Study Limitations subsection specifically addressing this issue. Furthermore, we have reframed the primary conclusion to emphasize the demonstration of relative force attenuation across hierarchical layers rather than absolute safety margins, as this comparative finding is more robust to uncertainties in injury threshold applicability.

Location of changes: Please see red-highlighted text in the Effective Stress Attenuation subsection, Study Limitations subsection, and Conclusion section of the revised manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

Mayer et al. describe an interesting and novel nested fluid-structure interaction predictive modeling to investigate fetal brain stress under maternal traumatic conditions, such as epilepsy. As my background is primarily in biomedical field, the suggestion will mainly focus on the biological rigor and translational value. Overall, the manuscript is well structured. However, I have some concerns regarding safety interpretations and considerations for input parameters.

Major points

1. The boundary conditions, serving as the primary input to the model, are derived from a training manikin. The authors do not clearly define the magnitude, severity, or clinical relevance of these inputs. The authors could provide a supplementary table describing specific input parameter value.
2. Maternal epilepsy is not purely a mechanical event, but also involves neurobiological and inflammatory processes that may contribute to fetal brain injury and stress.In the work, the authors only mimic the process by maternal body motion. However, biological factors such as inflammation and neurochemical changes are not considered. These factors may also influence fetal brain stress and development.

The authors could consider adding this discussion in the Manuscript and clarify that the model focuses on mechanical changes rather than the full biological effects of epilepsy. Future research could consider modeling based on parameters measured from animal models.

3. These interpretations from a medical training model may be model-dependent and so the conclusion should be written with caution.

For example, in the discussion, the sentence that “clinicians can be reassured the natural protective mechanisms” appears to overinterpret the model results, as the study is based on a simplified mechanical simulation without direct clinical validation. This safety description may mislead the reader.

4. Have the input parameters used in the author's model been compared against those in other similar articles?

 

Minor points

1. Boundary conditions are derived from a clinical training manikin, instead of clinical or animal data, the authorsshould avoid this kind of description like  “realistic boundary conditions”, which showed several times in the Method.
2. Whenever statements regarding fetal brain safety are presented, it should be explicitly noted that they are derived from a single medical trainingmodel, in order to prevent reader misunderstanding.
3. The statement in the discussionpart, such as “loading conditions ensure physiological relevance and clinical representativeness” is a little overstated. A more cautious sentence such as “may partially reflect simplified physiological motion patterns” would be more appropriate.
4. It is recommended that the authorscarefully review the phrasing throughout the manuscript to avoid overstating claims regarding biomedical safety.

Author Response

We thank the reviewer for the thorough and constructive evaluation of our manuscript. The comments regarding biological rigor, translational value, and the interpretation of safety-related findings have been particularly valuable in strengthening the scientific accuracy and clinical appropriateness of the work. The manuscript has been revised to address each point raised by the reviewer. All modifications to the manuscript text are highlighted in red to facilitate identification of changes during re-review. The following point-by-point responses detail the specific revisions made in response to each comment.

MAJOR POINT 1: Boundary Conditions Table and Clinical Relevance

Response: We thank the reviewer for this important suggestion. We have added Table 1, which summarizes the key kinematic parameters recorded during the mannequin seizure simulation experiments, including peak angular velocity, peak angular acceleration, angular displacement range, and dominant frequency. We have also expanded the Methods section to explicitly describe the mannequin instrumentation, the nature of the recorded kinematic data, and the limitations of deriving boundary conditions from a single mannequin configuration rather than clinical or animal data. We acknowledge that this represents a single case study utilizing patient-specific geometry with a single configuration of boundary and initial conditions, and we have clarified that the aim of this work is to demonstrate the computational framework rather than establish conclusions generalizable to the clinical population.

MAJOR POINT 2: Biological Factors (Inflammation, Neurochemical Changes)

Response: We appreciate the reviewer's insightful observation that maternal epilepsy involves not only mechanical but also neurobiological and inflammatory processes that may contribute to fetal brain injury. We have added a dedicated paragraph in the Limits section explicitly acknowledging that our model captures only the mechanical component of maternal seizures and does not account for biological factors such as inflammation, neurochemical changes, transient hypoxia, or metabolic disturbances. We clarify that the stress predictions should be interpreted solely as reflecting mechanical loading and not as a complete assessment of fetal risk. We also suggest that future research could integrate mechanical modeling with physiological parameters from animal models to provide a more comprehensive understanding.

MAJOR POINT 3: Cautious Conclusions and Model-Dependent Interpretations

Response: We agree with the reviewer that model-based conclusions should be stated with appropriate caution. We have revised statements throughout the manuscript to clearly indicate that findings represent computational predictions derived from a simplified mechanical simulation without direct clinical validation. Specifically, we have modified language that could be interpreted as providing clinical safety assurance, replacing definitive statements with appropriately hedged phrasing that acknowledges the need for experimental and clinical validation before any translation to clinical practice.

MAJOR POINT 4: Comparison of Input Parameters Against Other Articles

Response: We appreciate the reviewer's suggestion to compare our input parameters against those in similar articles. Computational modeling of fetal brain response during maternal seizure events represents a largely neglected area of investigation. To our knowledge, no prior computational studies have reported kinematic boundary conditions specifically derived from maternal seizure events. We have added a paragraph in the Limits section acknowledging this gap in the literature and emphasizing that the absence of comparable datasets precludes direct parameter validation while also highlighting the exploratory and framework-demonstrating nature of the present work. We suggest that future research establishing standardized kinematic databases for various maternal trauma scenarios would substantially benefit the field.

MINOR POINT 1: Avoid "Realistic Boundary Conditions"

Response: We appreciate the reviewer's attention to precise terminology. We have removed instances of "realistic boundary conditions" from the Methods section and replaced this phrasing with more accurate descriptions acknowledging that boundary conditions were derived from instrumented mannequin measurements designed to simulate clinically representative seizure patterns. We have been careful to distinguish between the mannequin's ability to reproduce typical seizure kinematics and the inherent limitations of using a training model rather than clinical or animal data.

MINOR POINT 2: Note Derivation from Single Medical Training Model

Response: We have added explicit statements noting that safety-related findings are derived from a single medical training model configuration, and we have clarified throughout the manuscript that the results represent a single case study rather than population-generalizable conclusions. Wherever statements regarding fetal brain safety are presented, we now note the computational and model-specific nature of these predictions.

MINOR POINT 3: "Loading Conditions Ensure Physiological Relevance"

Response: We agree with the reviewer that our original phrasing was overstated. We have revised the statement "loading conditions ensure physiological relevance and clinical representativeness" to more cautious language indicating that the boundary conditions may partially reflect simplified physiological motion patterns, while acknowledging that the extent to which mannequin kinematics capture clinical seizure complexity remains to be validated.

MINOR POINT 4: General Review of Overstated Safety Claims

Response: We have carefully reviewed the manuscript to identify and revise phrasing that could overstate claims regarding biomedical safety. Throughout the Abstract, Results, and Discussion sections, we have added qualifying language emphasizing that findings represent computational model predictions, that injury thresholds derived from adult tissue may not directly apply to fetal tissue, and that experimental and clinical validation are required before any translation to practice. We have replaced definitive safety statements with appropriately cautious phrasing acknowledging the limitations inherent to computational modeling based on simplified mechanical assumptions.

We believe that the revisions outlined above have improved the manuscript by providing clearer characterization of the boundary conditions, more appropriate framing of the model's scope and limitations, and more cautious interpretation of the computational findings. We are grateful for the reviewer's expertise and the opportunity to refine this work. Should any aspects of the revision require further clarification or additional modification, we are eager to address any outstanding concerns.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I thank the authors for improving the article. In current form, I recommend it for publication.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have carefully addressed the previous comments, and the manuscript has been significantly improved. My concerns have been adequately resolved, and I have no further major comments.