MRI Visibility and MR–DSA Concordance of the Nuvascular Harbor Intrasaccular Occlusion Device: A Preclinical Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Very interesting topic concerning a potential new device for endovascular therapy of brain aneurysms (Harbor Device). Its investigational clinical use is not the focus of this publication, but MRI visibility of the product. This work is relevant in the bride context of establishing a new device for neurovascular embolization, i.e. brain aneurysms. The study concept is easily undestandable and I did not notice any formal or linguistic errors. I support the publication of this article.

Author Response

Comment:

Very interesting topic concerning a potential new device for endovascular therapy of brain aneurysms (Harbor Device). Its investigational clinical use is not the focus of this publication, but MRI visibility of the product. This work is relevant in the bride context of establishing a new device for neurovascular embolization, i.e. brain aneurysms. The study concept is easily undestandable and I did not notice any formal or linguistic errors. I support the publication of this article.

Response:

We thank the reviewer for the positive and encouraging evaluation of our work. We appreciate the recognition of the relevance of MRI visibility for emerging intrasaccular devices and are grateful for the reviewer’s support for the publication of this manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

The current study “Preclinical Evaluation of MRI Visibility of a Nuvascular Harbor Occlusion Device in a Rabbit Model of Simulated Aneurysms” covers an interesting subject. However, the novelty of the work is debatable, and the text requires a minor revision.

* The title is a bit long. A more concise version could be written.

* The numerical results are not strong enough.

* The conclusion should be clearer: Is the device safe? Is it advantageous in terms of imaging? Does it have clinical potential?

Introduction:

Please clearly highlight the positive and negative aspects of the Harbor app.

The references are frequently duplicated; please include new and different sources.

Including MRI imaging parameters and explaining the technical reasons for the three cases where artifacts were observed would enhance the value of the study.

"Very good MR visibility" is a qualitative statement; a quantitative measure to support this could have been added to the abstract.

Instead of simply stating "does not contain ferromagnetic material," the reason why this system produces fewer artifacts compared to electrolytic systems should have been supported by a physical statement.

The literature review is weak; please make it stronger.

The working hypothesis is unclear.

Material and Metod:

Animal ethics approval must include an ethics committee number and an animal welfare protocol.

Sample size justification, the following information may be missing: Was a power analysis performed?

You should share a visual guide showing how the experiment was conducted.

Statistical Power Analysis: A power analysis of how the number 27 animals was determined is not included in the text.

Imaging Parameters: It is stated that 3T MRI was used, but detailed parameters of the sequences (TR, TE, slice thickness, etc.) are not provided. This is a deficiency in terms of the reproducibility of the study.

Discussion:

 Topics such as Thrombus characterization and 4D flow MRI could have been addressed, and a stronger preliminary data or theoretical basis could have been established regarding the compatibility of the Harbor instrument with these advanced techniques

Referans:

References to some classic rabbit model articles (e.g., early elastase models) could have been distributed more evenly.

Author Response

Comment 1:
The current study “Preclinical Evaluation of MRI Visibility of a Nuvascular Harbor Occlusion Device in a Rabbit Model of Simulated Aneurysms” covers an interesting subject. However, the novelty of the work is debatable, and the text requires a minor revision.

Response 1:
We thank the reviewer for the thoughtful evaluation and constructive comments. We have revised the manuscript to more clearly articulate the novelty of the study, which lies in the systematic and quantitative MR–DSA correlation for aneurysm occlusion assessment using an MRI-optimized intrasaccular device in a controlled preclinical setting.

Comment 2:
The title is a bit long. A more concise version could be written.

Response 2:
We thank the reviewer for this suggestion. The title has been revised to improve conciseness and better reflect the primary focus of the study on MRI visibility and MR–DSA concordance.

The revised title reads: MR–DSA Concordance and MRI Visibility of the Nuvascular Harbor Intrasaccular Device: A Preclinical Study

Comment 3:
The numerical results are not strong enough.

Response 3:
We thank the reviewer for this important comment. We would like to emphasize that the primary aim of this study was to assess intermodality agreement between MR imaging and DSA rather than treatment efficacy. To better reflect this, the Results section has been revised to more clearly highlight agreement metrics, including exact and clinically relevant concordance, Cohen’s κ, and Pearson correlation. As presented in the revised Results, a high level of concordance between MRA and DSA was observed in this experimental model, supporting the robustness of the findings within the scope of the study.

The Abstract section was revised accordingly and highlighted yellow: MR-based occlusion assessment demonstrated strong agreement with DSA, with exact Raymond–Roy class concordance in 80.6% of cases and clinically relevant agreement (adequate vs. incomplete occlusion) in 96.8%. Agreement analysis showed substantial concordance (Cohen’s κ = 0.65) and a strong positive correlation (r = 0.79). Adequate occlusion rates were comparable between modalities (87.1% on MRA vs. 83.9% on DSA), supporting the reliability of MR imaging for non-invasive occlusion assessment, reflecting consistent device visibility on MR imaging.

Results section was revised accordingly and highlighted yellow: 

Intermodality comparison demonstrated a high level of concordance between MRA and DSA for aneurysm occlusion assessment in this experimental aneurysm model. Using DSA as the reference standard, adequate occlusion (RROC I–II) was achieved in 83.9% of aneurysms compared with 87.1% on MRA. Exact Raymond–Roy class agreement was observed in 80.6% of cases, while clinically relevant concordance (RROC I–II vs. III) reached 96.8%, with only a single discordant case.

Agreement analysis demonstrated substantial agreement (Cohen’s κ = 0.65) and a strong positive correlation (r = 0.79), indicating that discrepancies were largely confined to adjacent occlusion classes rather than clinically meaningful misclassification. These findings highlight the strong agreement between modalities and support the reliability of MR imaging for non-invasive follow-up assessment of aneurysm occlusion in this experimental setting.

Comment 4:
The conclusion should be clearer: Is the device safe? Is it advantageous in terms of imaging? Does it have clinical potential?

Response 4:
We thank the reviewer for this important comment. We agree that the key message of the study should be more clearly articulated. The Conclusion has been revised to better reflect the primary focus of the present work, namely MRI visibility and MR–DSA concordance for aneurysm occlusion assessment.

The revised Conclusion emphasizes the imaging advantages of the device and the high level of agreement between MRA and DSA, supporting the role of MRI as a reliable, non-invasive modality for follow-up. At the same time, statements regarding broader clinical performance have been moderated, and the clinical relevance is framed within the context of this experimental model.

A more detailed evaluation of device safety is being conducted and will be reported separately.

Conclusion was revised as following and highlighted yellow in the manuscript: From a translational perspective, this preclinical study demonstrates that the Nuvascular Harbor device confers meaningful advantages in terms of MRI visibility and compatibility. The design features of the Harbor appear to mitigate susceptibility-related limitations encountered with conventional intrasaccular constructs, contributing to improved MR visualization in this experimental setting. The observed concordance between MR- and DSA-based assessments supports the notion that MRI could assume a more prominent role in routine post-procedural surveillance, particularly in patients for whom repeated radiation exposure or invasive angiography is less desirable.

Importantly, the use of a well-established experimental aneurysm model enhances the clinical relevance of these findings and supports further clinical evaluation of the Harbor device. More broadly, these data highlight an evolving paradigm in endovascular device development: performance can no longer be judged solely by deliverability and occlusion durability, but must also encompass reliable, high-quality longitudinal imaging. In this regard, devices designed with intrinsic MR compatibility may facilitate more efficient and patient-centered long-term follow-up strategies in contemporary neurovascular practice.

Comment 5:
Please clearly highlight the positive and negative aspects of the Harbor app.

Response 5:
We thank the reviewer for this helpful suggestion. The Introduction has been revised to more clearly outline both the advantages of the Harbor device, particularly its enhanced MRI visibility and compatibility, as well as its current limitations within the context of preclinical evaluation. To improve the flow and clarity, these aspects have been integrated more directly into the study rationale and linked to the experimental design.

Revised part is as following and highlighted yelow in the introduction: 

The Harbor device has been specifically designed to enhance MRI visibility, addressing a key limitation of many currently available intrasaccular devices, which often exhibit susceptibility-related artifacts that may impair reliable non-invasive follow-up. At the same time, its performance must be interpreted within the context of preclinical evaluation, and further studies are required to establish its broader clinical applicability. In this context, we implanted the Harbor device in a GLP-compliant experimental aneurysm model comprising 27 New Zealand White rabbits with 33 surgically created aneurysms.

Our objective was to evaluate whether the device’s MRI-optimized design enables consistent and reliable non-invasive assessment of aneurysm occlusion. Accordingly, we hypothesized that the Harbor device would allow robust and reliable MRI-based assessment of aneurysm occlusion, demonstrating a high level of concordance with DSA.To address this, MR-based occlusion grading was directly compared with DSA findings. Demonstrating high concordance between modalities would suggest that the Harbor device facilitates accurate, radiation- and contrast-free monitoring, thereby addressing a significant unmet need in the long-term follow-up of patients treated with intrasaccular devices.

Comment 6:

The references are frequently duplicated; please include new and different sources.

Response 6: 

We thank the reviewer for this important observation. The reference list has been revised to reduce redundancy and to incorporate additional complementary sources from a broader range of groups, improving the balance and contextualization of the study.

Comment 7:

Including MRI imaging parameters and explaining the technical reasons for the three cases where artifacts were observed would enhance the value of the study

Response 7: 

We thank the reviewer for this important suggestion. Detailed MRI acquisition parameters, including sequence-specific settings for TOF, DWI, and SWI, have been added to the Materials and Methods section to improve reproducibility.

Materials and Methods section was revised accordingly and highlighted yellow: 

MRI was performed on a 3T system using a standardized protocol including FLAIR, diffusion-weighted imaging (DWI), susceptibility-weighted imaging (SWI), and time-of-flight (TOF) MR angiography.

TOF-MRA was acquired with a repetition time (TR) of 24 ms, echo time (TE) of 4.37 ms, and a flip angle of 18°, using a slice thickness of approximately 0.55 mm and a high-resolution matrix (676), optimized for small-animal vascular imaging.

DWI was performed with a TR of approximately 3440 ms and TE of 54 ms using standard diffusion-weighting parameters for ischemia detection. SWI was acquired with a TR of 28 ms and TE of 20 ms, with a slice thickness of approximately 0.7 mm, allowing sensitive detection of susceptibility-related signal changes. FLAIR imaging was included to assess potential parenchymal abnormalities.

In addition, the Results section has been revised to more clearly describe the observed artifacts. Specifically, minor signal alterations were noted in three cases on DWI by the blinded neuroradiologist, without evidence of diffusion restriction. These findings have been interpreted as susceptibility-related effects at the device–tissue interface rather than true pathological changes.

The Results section was revised accordingly and highlighted yellow: In three cases, minor DWI signal alterations were noted by the blinded neuroradiologist without evidence of diffusion restriction, consistent with susceptibility-related artifacts rather than true pathological findings.

Comment 8:
"Very good MR visibility" is a qualitative statement; a quantitative measure to support this could have been added to the abstract.

Response 8:

We thank the reviewer for this thoughtful comment. We agree that the original phrasing was overly descriptive. The Abstract has been revised to replace qualitative wording with quantitative measures, including concordance rates, Cohen’s κ, and Pearson correlation, which more accurately reflect the level of agreement between MRA and DSA.

The Abstract section was revised accordingly and highlighted yellow: MR-based occlusion assessment demonstrated strong agreement with DSA, with exact Raymond–Roy class concordance in 80.6% of cases and clinically relevant agreement (adequate vs. incomplete occlusion) in 96.8%. Agreement analysis showed substantial concordance (Cohen’s κ = 0.65) and a strong positive correlation (r = 0.79). Adequate occlusion rates were comparable between modalities (87.1% on MRA vs. 83.9% on DSA), supporting the reliability of MR imaging for non-invasive occlusion assessment, reflecting consistent device visibility on MR imaging.

Comment 9:
Instead of simply stating "does not contain ferromagnetic material," the reason why this system produces fewer artifacts compared to electrolytic systems should have been supported by a physical statement.

Response 9:

We thank the reviewer for this insightful comment. We agree that the statement required a clearer physical basis. The manuscript has been revised accordingly to specify that MRI artifacts in this setting primarily arise from susceptibility-induced local magnetic field distortions at the metal–tissue interface. These effects are strongly influenced by

Accordingly the paragraph in Discussion was edited and highlighted yellow: The Harbor device, on the other hand, is a self-expanding, single-layer braided nitinol implant with a cylindrical configuration, incorporating a mechanical detachment system and a short (0.5 mm) proximal platinum marker band. Susceptibility-related artifacts in MRI are driven by local magnetic field distortions at the metal–tissue interface and depend on factors such as metal distribution, structural homogeneity, and device geometry. In this context, the Harbor device showed lower artifact burden and improved lumen definition—particularly on SWI and TOF sequences.

Comment 10:
The literature review is weak; please make it stronger.

Response 10:

We thank the reviewer for this helpful comment. The manuscript has been revised to strengthen the literature background by incorporating additional and more diverse references. These revisions aim to provide a broader context for the study and to better position our findings within the existing body of literature. The revised parts and newly added references were highlighted yellow.

Comment 11:
The working hypothesis is unclear.

Response 11:

We thank the reviewer for this helpful comment. The working hypothesis has been clarified in the Introduction. Specifically, we now state that the Harbor device is hypothesized to enable reliable MRI-based assessment of aneurysm occlusion, with a high level of concordance compared with DSA.

The following sentence was added to the manuscript: Our objective was to evaluate whether the device’s MRI-optimized design enables consistent and reliable non-invasive assessment of aneurysm occlusion. Accordingly, we hypothesized that the Harbor device would allow robust and reliable MRI-based assessment of aneurysm occlusion, demonstrating a high level of concordance with DSA.

Comment 12:
Animal ethics approval must include an ethics committee number and an animal welfare protocol.

Response 12:

We thank the reviewer for this important comment. The Materials and Methods section has been revised to include a statement confirming that all animal procedures were approved by the competent animal ethics authority and conducted in accordance with institutional and national animal welfare regulations.

The following section was added to the Materials and Methods section: The GLP24108_NV numbered study was performed in compliance with the GLP regulations at a federally registered test institution with Certificate Reference Number: INS-200015-0005-010. All animal procedures were approved by the competent animal ethics authority (Land Salzburg; approval number: 20901-TGV/128/21-2024) and conducted in accordance with institutional and national animal welfare regulations (animal welfare statement provided at the end of the manuscript).

Comment 13:
Sample size justification, the following information may be missing: Was a power analysis performed?

Response 13:

We thank the reviewer for this important comment. A formal power analysis was not performed, as the present study was designed as a GLP-compliant preclinical feasibility study. The sample size was determined based on established experimental aneurysm models and aligned with prior preclinical investigations in this field, providing adequate representation for imaging assessment and intermodality comparison.

Comment 14:
You should share a visual guide showing how the experiment was conducted.

Response 14:

We thank the reviewer for this valuable suggestion. The following schematic diagram illustrating the experimental workflow has been added to the manuscript. This figure outlines aneurysm creation, Harbor device implantation, follow-up imaging time points, group allocation, and cohort refinement to improve clarity and transparency.

Comment 15:
Statistical Power Analysis: A power analysis of how the number 27 animals was determined is not included in the text.

Response 15:

We thank the reviewer for this helpful comment. As noted in our previous response, a formal power analysis was not performed, as the study was designed as a GLP-compliant preclinical feasibility investigation. The number of animals (n = 27) was determined in line with established experimental models and informed by the existing preclinical literature.

Comment 16:
Imaging Parameters: It is stated that 3T MRI was used, but detailed parameters of the sequences (TR, TE, slice thickness, etc.) are not provided. This is a deficiency in terms of the reproducibility of the study.

Response 16:

We thank the reviewer for this important comment. Detailed MRI acquisition parameters (including TR, TE, and slice thickness) are included in the Materials and Methods section, improving methodological transparency and reproducibility.

Materials and Methods section was revised accordingly and highlighted yellow: 

MRI was performed on a 3T system using a standardized protocol including FLAIR, diffusion-weighted imaging (DWI), susceptibility-weighted imaging (SWI), and time-of-flight (TOF) MR angiography.

TOF-MRA was acquired with a repetition time (TR) of 24 ms, echo time (TE) of 4.37 ms, and a flip angle of 18°, using a slice thickness of approximately 0.55 mm and a high-resolution matrix (676), optimized for small-animal vascular imaging.

DWI was performed with a TR of approximately 3440 ms and TE of 54 ms using standard diffusion-weighting parameters for ischemia detection. SWI was acquired with a TR of 28 ms and TE of 20 ms, with a slice thickness of approximately 0.7 mm, allowing sensitive detection of susceptibility-related signal changes. FLAIR imaging was included to assess potential parenchymal abnormalities.

Comment 17:
Topics such as Thrombus characterization and 4D flow MRI could have been addressed, and a stronger preliminary data or theoretical basis could have been established regarding the compatibility of the Harbor instrument with these advanced techniques

Response 17:

We thank the reviewer for this insightful comment. We agree that advanced imaging approaches such as thrombus characterization and 4D flow MRI are of considerable interest in the evaluation of intrasaccular devices. However, these techniques were not part of the predefined scope of the present study, which was designed to assess MR–DSA concordance in a controlled preclinical setting.

Comment 18:
References to some classic rabbit model articles (e.g., early elastase models) could have been distributed more evenly.

Response 18:

We thank the reviewer for this valuable suggestion. The reference list has been revised to provide a more balanced representation of the literature. While the present study is based on a venous pouch aneurysm model, we have incorporated key foundational studies on rabbit aneurysm models to offer a broader contextual framework.

Reviewer 3 Report

Comments and Suggestions for Authors

The presented laboratory practice study evaluates the MRI compatibility and occlusion performance of Nuvascular Harbor intrasaccular devices for bifurcation aneurysms in rabbit aneurysm models. 31 treated aneurysms are analyzed. The MR-based occlusion grading was compared with digital subtraction angiography (DSA) findings. The results indicated a high level of concordance between MR and DSA, supporting the reliability of MR imaging as a non-invasive modality for follow-up of aneurysm occlusion. The conclusion of the paper is critical for promoting radiation-free and non-invasive post-procedural surveillance. In the paper, the methods and results are properly defined and presented. I recommend the minor revisions below:

• Can you provide the procedure or references for creating the clinical aneurysms in this study?
• The text in Figure 1 can be enlarged with higher resolution.
• Spaces should be added in the caption of Figure 2 between (a), (b), (c), (d).

Author Response

Comment 1:
The presented laboratory practice study evaluates the MRI compatibility and occlusion performance of Nuvascular Harbor intrasaccular devices for bifurcation aneurysms in rabbit aneurysm models. 31 treated aneurysms are analyzed. The MR-based occlusion grading was compared with digital subtraction angiography (DSA) findings. The results indicated a high level of concordance between MR and DSA, supporting the reliability of MR imaging as a non-invasive modality for follow-up of aneurysm occlusion. The conclusion of the paper is critical for promoting radiation-free and non-invasive post-procedural surveillance. In the paper, the methods and results are properly defined and presented. I recommend the minor revisions below.

Response 1:
We sincerely thank the reviewer for the positive evaluation of our work and for the constructive suggestions, which helped us further improve the clarity of the manuscript. The manuscript has been revised accordingly.

Comment 2:
Can you provide the procedure or references for creating the clinical aneurysms in this study?

Response 2:
Thank you for this helpful suggestion. A concise description of the aneurysm creation procedure, together with the relevant references, has now been added to the Materials and Methods section. Moreover new references were added.

Following part was added and highlighted yellow: 

To summarize, experimental aneurysms were created using a previously described microsurgical rabbit aneurysm model. Under sterile conditions and operating microscope visualization, the external jugular vein was exposed and harvested as a venous pouch graft. The common carotid arteries were then exposed bilaterally through a midline cervical incision.

For bifurcation aneurysms, the left common carotid artery was ligated proximally, transected, and transposed across the trachea beneath the pretracheal muscles. An end-to-side anastomosis between the left carotid stump and the right common carotid artery was constructed using 10-0 Prolene sutures, creating a bifurcation configuration. The prepared venous pouch graft was then sutured into the bifurcation apex to form a blind sac aneurysm.

For sidewall aneurysms, a longitudinal arteriotomy was created on the carotid artery, and the venous pouch graft was sutured directly to the arterial wall using 10-0 Prolene. The distal end of the venous pouch was ligated with 7-0 Prolene to form the aneurysm dome. Aneurysm neck width and height were adjusted by the length of the arteriotomy and the position of the ligature. The primary objective was to compare MRI and DSA in assessing the performance of the Nuvascular Harbor occlusion device.

Comment 3:
The text in Figure 1 can be enlarged with higher resolution.

Response 3:
We appreciate this comment. Figure 1 has been replaced with a higher-resolution version and the labels have been enlarged to improve readability.

Comment 4:
Spaces should be added in the caption of Figure 2 between (a), (b), (c), (d).

Response 4:
Thank you for pointing this out. The caption of Figure 2 has been revised accordingly.