Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The paper addresses an important clinical need. Please find below my comments:

1- The authors do not address clinical benefit or behavioral outcomes. Although the main supposed innovation is laser‑assisted sampling, the authors do not evaluate this component: there is no comparator arm using conventional sampling, no objective assessment of pain or local tissue effects, and no measurement of adherence or testing frequency over time. Therefore, the authors' suggestions regarding reduced pain and improved acceptance are not supported by the presented data.

2- The authors use capillary blood for both the HandyRay‑Glu and the reference measurements on the cobas c111 analyzer. However, the cobas c111 is a plasma‑calibrated laboratory system that is typically validated and using venous serum or plasma, not capillary whole blood. The manuscript does not explain whether the use of capillary samples on this platform has been validated locally, whether any whole‑blood to plasma‑equivalent conversion is applied, or how pre‑analytical handling of small capillary samples was standardized.

3- The handling of errors is insufficiently described. The methods state that, when a measurement error occurred, repeat measurement was allowed and the erroneous measurement was excluded from analysis, with up to three such exclusions per participant, but the authors didn't define what constitutes an error.

4- The user-accuracy analysis uses a single measurement per participant, but it is not clarified how many of those measurements fall into the hypoglycemic range, which is clinically crucial given tighter risk-benefit trade-offs in hypoglycemia. The authors admit limited data in extreme glucose ranges, but the actual numbers are not reported.

Author Response

Comments 1: The authors do not address clinical benefit or behavioral outcomes. Although the main supposed innovation is laser-assisted sampling, the authors do not evaluate this component: there is no comparator arm using conventional sampling, no objective assessment of pain or local tissue effects, and no measurement of adherence or testing frequency over time. Therefore, the authors' suggestions regarding reduced pain and improved acceptance are not supported by the presented data.

Response 1: We appreciate the reviewer's careful attention to this important issue. We fully agree that our study was not specifically designed to directly evaluate the clinical benefit of laser-assisted sampling, behavioral changes in patients, or the extent of pain reduction. The primary objective of the present study was to assess the analytical performance, clinical accuracy, and usability of the HandyRay-Glu system in accordance with the ISO 15197:2013 standard. As such, a direct comparison with conventional lancet-based sampling, as well as patient-centered outcomes such as pain perception, adherence, and testing frequency, were beyond the scope of the current investigation.

We would, however, like to respectfully note that comparative clinical data on laser-assisted blood sampling versus conventional lancet-based sampling have been previously reported by some of our authors (Kim JA, et al. Diabetes Metab J 2022;46:936-940). In that study, 150 patients with diabetes underwent paired capillary blood sampling using the LMT-1000 laser lancing device — which constitutes the laser sampling component subsequently integrated into the HandyRay-Glu system evaluated in the present study — and a conventional lancet, demonstrating strong agreement in glucose values together with significant reductions in puncture pain and improvements in patient satisfaction with the laser device. Importantly, those data were generated in that earlier independent study, which evaluated the laser sampling device in isolation, whereas the present study was prospectively designed to evaluate the integrated HandyRay-Glu system — combining laser-assisted sampling with electrochemical glucose measurement — under the ISO 15197:2013 framework. The 2022 comparative data were therefore not incorporated into the design or analysis of the present investigation. In the revised manuscript, we have added a brief citation to this earlier study in the Discussion as supporting background literature, while softening the relevant claims and explicitly acknowledging the absence of a comparator arm, objective pain measurement, and longitudinal adherence data within this study, as detailed in our point-by-point revisions below.

In response to the reviewer's comment, we have revised the manuscript at four locations to more clearly define the scope of the study and to soften previous statements that may have implied benefits not directly substantiated by our data. First, in the Abstract, the previous expression "improve patient acceptance of regular monitoring" has been softened to indicate that this possible role warrants further investigation. Second, in the Discussion, we have rephrased a previously declarative statement on reduced mechanical trauma into a literature-based suggestion, added a brief citation to a prior comparative study using the laser sampling component of this platform as supporting background literature, and have explicitly added that the present study did not directly assess pain, local tissue effects, or longitudinal adherence. Third, in the Limitations section, we have expanded the third limitation to explicitly state the absence of a comparator arm and objective assessment of pain or local tissue effects, and we have added to the fourth limitation that longitudinal data on adherence and testing frequency were not collected. Fourth, the future research statement in the Discussion has been revised to specifically include head-to-head comparisons with conventional sampling, the use of validated objective pain assessment tools, and longitudinal evaluations of adherence and testing frequency.

The revised sentences in the manuscript are as follows:

[line 39-41] "Laser-assisted blood sampling combined with electrochemical glucose measurement may offer a potential alternative to conventional SMBG systems, and its possible role in improving patient acceptance of regular monitoring warrants further investigation."

[line 338-348] "The use of an Er:YAG laser enables controlled micro-perforation of the skin, which has been suggested to potentially reduce mechanical trauma compared with conventional lancet-based sampling. In a previous comparative study using the laser sampling component of this platform, capillary blood sampling with the laser device showed strong agreement with conventional lancet-based sampling in glucose values and was associated with significant reductions in puncture pain and improvements in patient satisfaction in patients with diabetes. Although the favorable usability results observed in this study are consistent with the hypothesis that reducing sampling burden may improve user acceptance and adherence to regular glucose monitoring, it should be emphasized that the present study did not directly assess pain, local tissue effects, or longitudinal adherence; therefore, these potential benefits remain to be confirmed in dedicated comparative studies."

[line 370-374] "Third, the study did not include a comparator arm using conventional lancet-based sampling, and objective assessment of pain or local tissue effects was not performed; therefore, the potential advantages of laser-assisted sampling in terms of reduced pain and improved patient acceptance could not be directly substantiated by the present data."

[line 374-377] "Fourth, although usability was assessed using a structured questionnaire, more detailed evaluation of user errors and device handling would further strengthen the analysis, and longitudinal data on adherence and testing frequency over time were not collected."

[line 386-392] "Further studies are warranted, including multi-center investigations across more diverse patient populations, head-to-head comparisons with conventional lancet-based sampling, the use of validated objective pain assessment tools, longitudinal evaluations of usability, patient compliance, adherence, and testing frequency, and dedicated investigations targeting patients at higher risk of hypoglycemia, to substantiate the suggested patient-centered benefits of laser-assisted sampling and to confirm device performance in clinically critical glucose ranges."

Comments 2: The authors use capillary blood for both the HandyRay-Glu and the reference measurements on the cobas c111 analyzer. However, the cobas c111 is a plasma-calibrated laboratory system that is typically validated and using venous serum or plasma, not capillary whole blood. The manuscript does not explain whether the use of capillary samples on this platform has been validated locally, whether any whole-blood to plasma-equivalent conversion is applied, or how pre-analytical handling of small capillary samples was standardized.

Response 2: The reviewer raises an important methodological point, and we are grateful for the opportunity to clarify and strengthen the manuscript accordingly.

In the revised Section 2.3, we have provided a more detailed description of the sample-handling procedure and the concept of plasma-equivalent measurement. We now specify that capillary blood samples were analyzed promptly after collection, and that measurements obtained from the cobas c111 analyzer were treated as plasma-equivalent glucose values in accordance with standard glucose monitoring system evaluation practices, consistent with a point-of-care comparison protocol under the ISO 15197:2013 framework. This approach follows the standard methodology widely adopted in the evaluation of self-monitoring blood glucose devices, namely, comparing capillary whole blood measurements with plasma-equivalent reference values. The following sentence has been added to the Methods section:

[line 130-133] "Capillary blood samples were analyzed promptly, and measurements obtained from the cobas c111 analyzer were considered plasma-equivalent values in accordance with standard glucose monitoring system evaluation practices, consistent with a point-of-care comparison protocol under the ISO 15197:2013 framework."

In addition, we have transparently acknowledged the related limitation of our study in the Limitations section. We recognize that an independent local validation of the cobas c111 analyzer for capillary whole blood samples was not performed; at the same time, we have noted that this approach is commonly employed within the ISO 15197-based framework for evaluating blood glucose monitoring systems. The following sentence has been added to the Limitations section:

[line 377-380] "Fifth, an independent local validation of the cobas c111 analyzer for capillary whole blood samples was not performed in the present study; however, this approach is commonly employed within the ISO 15197-based framework for evaluating blood glucose monitoring systems."

These clarifications have, we believe, improved the methodological transparency of the revised manuscript.

Comments 3: The handling of errors is insufficiently described. The methods state that, when a measurement error occurred, repeat measurement was allowed and the erroneous measurement was excluded from analysis, with up to three such exclusions per participant, but the authors didn't define what constitutes an error.

Response 3: We thank the reviewer for highlighting the need for a clearer definition of what constitutes a measurement error, and we have accordingly revised the Methods section to address this point.

In the revised Section 2.3, we have replaced the previous brief statement on error handling with a more explicit definition of what constitutes a measurement error, the conditions under which repeat measurement was allowed, and our position on outlier handling. Specifically, measurement errors are defined as device-generated error messages or instances in which a valid numerical glucose result could not be obtained, and we have clarified that no selective removal of outliers was performed. We recognize that this approach is consistent with real-world self-monitoring blood glucose use and aligns with the ISO 15197 evaluation framework. The previous sentence ("If a measurement error occurred, repeat measurement was permitted; however, erroneous measurements were excluded from the final analysis, with up to three such exclusions allowed per participant.") has been replaced with the following:

[line 148-154] "Measurement errors were predefined as device-generated error messages (e.g., insufficient sample volume, improper strip insertion, or device malfunction) or failure to obtain a valid numerical glucose result. Only such technically invalid measurements were excluded from analysis, and repeat measurement was allowed in these cases, with up to three exclusions permitted per participant. No selective removal of outliers was performed, and this approach is consistent with real-world SMBG use and the ISO 15197 evaluation framework."

Comments 4: The user-accuracy analysis uses a single measurement per participant, but it is not clarified how many of those measurements fall into the hypoglycemic range, which is clinically crucial given tighter risk-benefit trade-offs in hypoglycemia. The authors admit limited data in extreme glucose ranges, but the actual numbers are not reported.

Response 4: We greatly appreciate the reviewer's thoughtful comment on this clinically important issue.

In response, we have revised the manuscript at four locations. First, in Section 3.2.1, we have added a sentence that explicitly reports the number of measurements falling within the hypoglycemic range (<70 mg/dL), along with the distribution across the hypoglycemic, euglycemic, and hyperglycemic categories, as well as the proportion meeting the ISO 15197:2013 accuracy criteria within the hypoglycemic range. Second, this distribution has been newly summarized in Table 2. Third, in the Limitations section, the second limitation has been expanded to state that the relatively small number of samples within the hypoglycemic range may constrain the reliability of accuracy assessment in this clinically critical region, and to indicate that results within this range should be interpreted with caution. Fourth, the future research statement in the Discussion has been revised to include dedicated investigations targeting patients at higher risk of hypoglycemia.

The revised sentences in the manuscript are as follows:

[line 249-253] "Among the total measurements, 12 (12.0%) were within the hypoglycemic range (<70 mg/dL), 38 (38.0%) were between 70–100 mg/dL, and 50 (50.0%) were ≥100 mg/dL. In the hypoglycemic range, 11 of the 12 measurements (91.7%) met the ISO 15197:2013 accuracy criteria. The distribution of glucose values across clinically relevant ranges is summarized in Table 3."

[line 254] Table 2 (newly added) Title: "Distribution of Glucose Concentrations and Accuracy by Range." The table presents glucose ranges (<70, 70–100, ≥100 mg/dL), number of samples (12, 38, 50), percentage (12.0%, 38.0%, 50.0%), and ISO criteria met (11 [91.7%], 37 [97.4%], 49 [98.0%]), with an overall accuracy of 97.8%.

[line 366-370] "Second, the relatively small number of samples within the hypoglycemic range (<70 mg/dL) and very high glucose levels may constrain the reliability of accuracy assessment in these clinically critical regions; accordingly, results within these ranges should be interpreted with caution and not over-interpreted."

[line 386-392] "Further studies are warranted, including multi-center investigations across more diverse patient populations, head-to-head comparisons with conventional lancet-based sampling, the use of validated objective pain assessment tools, longitudinal evaluations of usability, patient compliance, adherence, and testing frequency, and dedicated investigations targeting patients at higher risk of hypoglycemia, to substantiate the suggested patient-centered benefits of laser-assisted sampling and to confirm device performance in clinically critical glucose ranges."

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript explores the relation between self monitoring blood glucose and laser assisted glucose monitoring using a Handy ray glu system,with the aim of comparing the capillary blood glucose measurement with lancet and a new device which is not invasive. The aim research is quite new as there are no formal studies published in literature to compare those systems of measuring blood glucose. The manuscript is well written and well-structured with clear background information, methods explanation, analytical reports of results and discussion. The statistical analysis is appropriate and well structured for clinical research. The conclusion matches the original hypothesis, highlighting that the new laser device has a potential to be used as glucose monitoring, with the advantages of being less traumatic for patient; this could represent a great tool in particular in pt with needle-phobia, and it may worth exploring as a multi-centre study. The references are appropriate to the context.

Author Response

Comments 1: This manuscript explores the relation between self monitoring blood glucose and laser assisted glucose monitoring using a Handy ray glu system, with the aim of comparing the capillary blood glucose measurement with lancet and a new device which is not invasive. The aim research is quite new as there are no formal studies published in literature to compare those systems of measuring blood glucose. The manuscript is well written and well-structured with clear background information, methods explanation, analytical reports of results and discussion. The statistical analysis is appropriate and well structured for clinical research. The conclusion matches the original hypothesis, highlighting that the new laser device has a potential to be used as glucose monitoring, with the advantages of being less traumatic for patient; this could represent a great tool in particular in pt with needle-phobia, and it may worth exploring as a multi-centre study. The references are appropriate to the context.

Response 1: We are sincerely grateful to the reviewer for the encouraging evaluation of our manuscript and for recognizing the novelty of the laser-based sampling technology, the robustness of our statistical analysis, the clarity of the manuscript's structure, and the potential clinical utility of the device for patients with needle phobia.

Although no major concerns were raised, we have taken this opportunity to refine our conclusions and the future research statement so that our findings are presented as demonstrating the potential of the device rather than establishing definitive clinical superiority.

The revised sentences in the manuscript are as follows:

[line 39-41] "Laser-assisted blood sampling combined with electrochemical glucose measurement may offer a potential alternative to conventional SMBG systems, and its possible role in improving patient acceptance of regular monitoring warrants further investigation."

[line 384-392] "These findings suggest that the integration of laser-assisted sampling with electrochemical glucose measurement may represent a potential alternative to conventional SMBG systems, although definitive clinical superiority over conventional methods has not been established by the present data. Further studies are warranted, including multi-center investigations across more diverse patient populations, head-to-head comparisons with conventional lancet-based sampling, the use of validated objective pain assessment tools, longitudinal evaluations of usability, patient compliance, adherence, and testing frequency, and dedicated investigations targeting patients at higher risk of hypoglycemia, to substantiate the suggested patient-centered benefits of laser-assisted sampling and to confirm device performance in clinically critical glucose ranges."

We hope these revisions further strengthen the manuscript.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have adequately addressed all my concerns. I have no further comments.