MXene-Based Terahertz Metamaterial Biosensors: From Laboratory Simulation to Clinical Application

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The present review article needs some minor revision as below. 

1. The manuscript is well-structured and clearly highlights the significance of MXene-based THz biosensors. However, the importance of the present review compared to existing review article in the same field should be discussed in the introduction.
2. The research gap and clinical challenges should be highlighted. 
3. There were some prio publication on MXene should be discussed. ACS Appl. Nano Mater. 2022, 5, 3, 3252–3264; TrAC Trends in Analytical Chemistry, Volume 164, July 2023, 117096.
4. The discussion of MXene properties should be eloborated to allow a strong justification for their use in biosensing applications.
5. The typo, gramatical and formulae in the manuscript should be carefully checked. 
6. The challenges in the Field should be summarised.
7. The discussion on machine learning-assisted optimization adds a modern and interdisciplinary perspective. However, the discussion should be and some sentences could be shortened slightly to improve readability and flow.

Author Response

Response to Reviewer #1

 

We sincerely thank the reviewers for their insightful comments and constructive suggestions on our manuscript. These comments have significantly helped us improve the quality and clarity of our review. We have carefully addressed all the points raised and revised the manuscript accordingly. Below is our point-by-point response. All revisions in the manuscript are highlighted in blue.

 

Responses to Reviewer #1

Comment 1: The manuscript is well-structured and clearly highlights the significance of MXene-based THz biosensors. However, the importance of the present review compared to existing review article in the same field should be discussed in the introduction.

Response: We thank the reviewer for these valuable comments. To explicitly compares our review with existing literature for establishing its unique importance, we have added some discussion in Line 124-129 and Line 135-139, Page 3 in the Introduction as follows:

“While several excellent reviews have separately summarized the progress of MXene-based biosensors or THz metamaterial biosensors, none have systematically bridged these two fields with a specific focus on the translational pathway from laboratory simulation to clinical application. Previous reviews have primarily concentrated on material synthesis, general biosensing mechanisms, or THz metamaterial design principles, largely overlooking the fundamental disconnection between simulation-driven optimization and real-world clinical validation.……In contrast to existing overviews that remain either materials- or simulation-focused, this review provides a systematic side-by-side comparison of conventional gold-based and MXene-based platforms, a critical analysis of clinical translation bottlenecks, a clear distinction between simulation-oriented and application-oriented performance metrics, and a full-chain roadmap from material design to preclinical validation, thereby establishing its unique importance in the field.”

Comment 2: The research gap and clinical challenges should be highlighted.

Response: We thank the reviewer for these valuable comments. We have added a new paragraph in Line 129-135, Page 3 in the Introduction to highlights the critical research gap and three unresolved clinical challenges facing the field as follows:

“More critically, the field still faces three unresolved clinical challenges that pure simulation studies cannot address: the lack of quantitative correlation between simulation metrics and clinical di-agnostic outcomes, the complete neglect of physiological variables in ideal models, and a fragmented research chain that rarely extends beyond in vitro validation. The landmark in vivo work by Yang et al. has fundamentally shifted the field toward preclinical validation, calling for a timely re-evaluation from a clinical perspective.”

Comment 3: There were some prior publication on MXene should be discussed. ACS Appl. Nano Mater. 2022, 5, 3, 3252–3264; TrAC Trends in Analytical Chemistry, Volume 164, July 2023, 117096.

Response: We appreciate the reviewer pointing out these important references. In response, we have incorporated both into the manuscript. Specifically, we have added a new paragraph in Line 840-849, Page 22 in the Revised Manuscript to discuss the broader utility of MXenes in analytical and biomedical sensing as follows:

"Beyond these specific platforms, the broader utility of MXenes in analytical and biomedical sensing has been well recognized in the literature. For instance, systematic investigations into the tunable work function and layer-dependent electronic structures of MXenes have established a physicochemical basis for their integration into high-performance optical devices [114], while comprehensive reviews have highlighted the versatility of MXene-based optical sensors in detecting a wide range of analytes from environmental contaminants to early-stage disease biomarkers [115]. Collectively, these studies reinforce that MXene is not merely a passive conductive scaffold but an active functional material capable of addressing multiple challenges across different sensing modalities, thereby positioning it as an ideal candidate for next-generation THz metamaterial biosensors."

Within this paragraph, we cite Ref. [114] (ACS Appl. Nano Mater. 2022) to support the statement that systematic investigations into MXene's tunable work function and layer-dependent electronic structures have laid a physicochemical foundation for high-performance optical devices, and Ref. [115] (TrAC Trends Anal. Chem. 2023) to highlight the versatility of MXene-based optical sensors in detecting a wide range of analytes from environmental contaminants to early-stage disease biomarkers.

Comment 4: The discussion of MXene properties should be elaborated to allow a strong justification for their use in biosensing applications.

Response: We have elaborated on MXene properties in the Introduction. After listing the four core advantages, we added a detailed paragraph in Line 92-103, Page 2-3 in the Revised Manuscript to explain the origin of MXenes metallic-like conductivity (layered structure, high carrier concentration, low-dispersion THz response), the functional benefits of surface terminations (hydrophilicity, covalent immobilization, anti-fouling), and the systematic validation of biocompatibility (in vitro and in vivo data):

"To elaborate, the metallic-like conductivity of MXenes arises from their unique layered structure and high carrier concentration (~10²¹ cm⁻³), enabling low-dispersion electromagnetic response across the entire 0.5–10 THz spectrum—a crucial feature for achieving broadband impedance matching in metamaterial designs [73]. The abundant surface terminations not only facilitate covalent immobilization of antibodies and aptamers but also render the MXene surface hydrophilic, which effectively suppresses non-specific adsorption of high-abundance proteins in complex biological fluids such as whole blood and serum—a long-standing challenge for conventional gold surfaces [30,46]. Moreover, MXenes are widely recognized for their excellent biocompatibility and biosafety, which are essential prerequisites for biomedical and clinical ap-plications. These intrinsic properties collectively position MXene as a transformative material platform that not only matches but, in many aspects, surpasses conventional noble metals for THz biosensing applications."

Comment 5: The typo, grammatical and formulae in the manuscript should be carefully checked.

Response: We have carefully proofread the entire manuscript. Corrections include: (i) adding missing spaces (e.g., "the THz-TDS s-SNOM"), (ii) correcting figure reference errors (e.g., changing "Figure 3 (c)" to "Figure 2 (c)"), (iii) fixing punctuation around citations (e.g., moving periods outside brackets), (iv) correcting equation formatting (added missing period in Section 2.2.2), and (v) removing duplicate citation tags. These changes are minor and have been made throughout the text.

Comment 6: The challenges in the Field should be summarized.

Response: As requested, we have added a dedicated paragraph in Line 140-151, Page 3-4 in the Revised Manuscript to summarize the key challenges facing the field as follows:

" The field of MXene-based THz metamaterial biosensors still faces several critical challenges that must be addressed to enable clinical translation. First, the vast majority of studies remain at the pure simulation stage, with optimized sensitivity and Q-factor achieved in ideal electromagnetic models that bear little resemblance to real-world physiological environments. Second, the performance of these sensors in complex biological matrices such as whole blood, serum, and tissue fluid remains largely unverified, leaving critical issues including non-specific protein adsorption, material stability at 37 °C, and dynamic flow interference unresolved. Third, the lack of standardized evaluation frameworks that bridge simulation-oriented metrics and clinical diagnostic outcomes makes it difficult to compare different studies or assess their true translational potential. Fourth, scalable fabrication of high-precision MXene metamaterial arrays at low cost remains a significant manufacturing hurdle. Without systematic efforts to overcome these challenges, the remarkable performance demonstrated in simulations will likely never reach clinical practice."

This paragraph outlines four specific challenges: (i) over-reliance on pure simulations, (ii) unverified performance in complex biological matrices, (iii) lack of standardized evaluation frameworks, and (iv) manufacturing hurdles for scalable production. Location: Introduction, final paragraph before the review scope statement.

Comment 7: The discussion on machine learning-assisted optimization adds a modern and interdisciplinary perspective. However, the discussion should be and some sentences could be shortened slightly to improve readability and flow.

Response: We have significantly condensed and reorganized Section 2.2.2. The original three-category list has been rewritten into a more concise paragraph format. Redundant phrases and overly complex sentence structures have been simplified. The final paragraph on the limitations of ML models has also been shortened while retaining its critical message. The revised paragraphs appear in Line 343-354, Page 9 as follows:

"The growing complexity of THz metamaterial structures and parameter space has rendered traditional trial-and-error design inefficient. Machine learning (ML) offers a powerful alternative by learning complex relationships between structural parameters and sensing performance. ML has thus become a valuable tool for THz metamaterial optimization.

Current ML applications fall into three categories. Regression algorithms, such as WKNN and polynomial regression, work well with small datasets and offer strong interpretability. Neural networks, particularly 1D-CNN, excel at processing sequential THz spectra and can automatically extract local features, achieving prediction accuracy with R² up to 1.00. Ensemble learning methods, including Random Forest, XGBoost, and Stacking Ensemble, combine multiple base learners to improve prediction stability and are widely used for multi-objective optimization [50]. Figure 3 outlines the architecture of a convolutional neural network (CNN) used for feature extraction from THz spectra."

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

In this work, authors have prepared a very detailed up-to-date review on the development of MXene-Based Terahertz Metamaterial Biosensors: From Laboratory Simulation to Clinical Application. It is well written but quite long I have to say. The authors discuss the design of these biosensors, their structures, the materials used (in synergy as well), their surface modification, their properties, their performance, their types etc. They focus also on the progress made over the years, their disadvantages and their applications. The authors also give a critical view on all these topics and aspects, something which is necessary and very critical for a review. I have a few minor comments for the authors to furthermore improve the quality of their review.

1. In the introduction the authors mention other traditional laboratory methods that exist for accurate sensing and in lines 38-41 (page 1) they mention many disadvantages of these methods. However, the MXene-Based Terahertz Metamaterial Biosensors also suffer from many of these disadvantages and the authors need to rephrase that section in order to show that although these sensors suffer from some of the disadvantages mentioned, they manage to overcome many of them.
2. In section 4.2.1, the authors discuss bout the MXene based electrochemical biosensors. They make a comparison with other electrochemical sensors that have been developed over the years, but there is no mention about the cost of these MXene electrochemical sensors that should be much higher that other existing electrochemical biosensors.
3. Finally, it would be useful for the authors to show in a table the performance of the MXene biosensors compared with another type of biosensors (electrochemical, optical, immunosensors, magnetic etc.) for the same specific application (for a biomarker, virus, toxin, etc.).

Author Response

Response to Reviewer #2

 

We sincerely thank the reviewers for their insightful comments and constructive suggestions on our manuscript. These comments have significantly helped us improve the quality and clarity of our review. We have carefully addressed all the points raised and revised the manuscript accordingly. Below is our point-by-point response. All revisions in the manuscript are highlighted in blue.

 

Responses to Reviewer #2

Comment 1: In the introduction the authors mention other traditional laboratory methods that exist for accurate sensing and in lines 38-41 (page 1) they mention many disadvantages of these methods. However, the MXene-Based Terahertz Metamaterial Biosensors also suffer from many of these disadvantages and the authors need to rephrase that section in order to show that although these sensors suffer from some of the disadvantages mentioned, they manage to overcome many of them.

Response: We thank the reviewer for this important clarification. To present a more balanced view, we have revised the first paragraph of the Introduction in Line 34-46, Page 1-2 as follows:

"While traditional laboratory methods, such as polymerase chain reaction and enzyme-linked immunosorbent assay, guarantee accuracy, they suffer from several limitations including com-plex operational procedures, reliance on bulky equipment, and rigid structural designs. MXene-based THz metamaterial biosensors, the focus of this review, address some of these limitations—specifically, they offer label-free detection, eliminate the need for complex sample processing, and enable miniaturization potential through chip-scale integration. However, it must be acknowledged that MXene-THz sensors still face certain challenges, such as limited sensitivity in complex biological matrices, susceptibility to environmental interference, and long-term stability concerns under physiological conditions. Nevertheless, these obstacles are by no means fatal; through rational material engineering, optimized metamaterial designs, sur-face functionalization, and encapsulation strategies, the field has successfully overcome many of these issues, demonstrating the strong potential of MXene-based platforms for practical bio-sensing applications."

The modified text now acknowledges that while traditional methods have multiple limitations, MXene-based THz metamaterial biosensors address some of these (label-free detection, elimination of complex sample processing, miniaturization potential). However, we now clearly state that they still face certain challenges (limited sensitivity in complex biological matrices, susceptibility to environmental interference, long-term stability concerns). Importantly, we emphasize that these obstacles are by no means fatal and that the field has successfully overcome many of them through rational material engineering, optimized designs, surface functionalization, and encapsulation strategies.

Comment 2: In section 4.2.1, the authors discuss about the MXene based electrochemical biosensors. They make a comparison with other electrochemical sensors that have been developed over the years, but there is no mention about the cost of these MXene electrochemical sensors that should be much higher than other existing electrochemical biosensors.

Response: We thank the reviewer for raising this important practical limitation. To address the cost issue, we have added a new paragraph in Line 761-771, Page 20 as follows:

"However, it is important to acknowledge a major practical limitation: the cost of MXene-based electrochemical sensors remains substantially higher than that of conventional disposable electrodes such as screen-printed carbon or graphene oxide electrodes. The synthesis of high-quality MXene nanosheets involves expensive precursors like MAX phases, hazardous etching agents such as HF, and multi-step delamination processes... Without significant advances in low-cost, green synthesis routes and scalable, robust electrode fabrication methods, the translation of these high-performance MXene electrochemical sensors... will remain challenging."

The added text acknowledges that the synthesis of high-quality MXene nanosheets involves expensive precursors (e.g., MAX phases), hazardous etching agents (e.g., HF), and multi-step delamination processes, which are difficult to scale up cost-effectively. The suboptimal long-term storage stability of MXene-modified electrodes adds to operational costs. Without advances in low-cost, green synthesis, translation to resource-limited or point-of-care settings will remain challenging.

Comment 3: Finally, it would be useful for the authors to show in a table the performance of the MXene biosensors compared with another type of biosensors (electrochemical, optical, immunosensors, magnetic etc.) for the same specific application (for a biomarker, virus, toxin, etc.).

Response: We appreciate this constructive suggestion. In response, we have added a new subsection (4.2.4 Comparative Superiority of MXene-Based Biosensors Over Conventional Methods) and a new Table 2 to Section 4.2. This table compares the performance of MXene-based biosensors against electrochemical, optical (liquid crystal and fiber-optic), magnetic, and conventional ELISA methods, using HER2 breast cancer biomarker as a unified target. The table highlights that the MXene-based electrochemical immunosensor achieves an ultra-low LOD of 0.26 fg/mL in just 20 minutes, significantly outperforming other methods. The synergistic origin of this superior performance (high conductivity and abundant surface functional groups) is also explained. The relevant references [116-120] have been added. The added paragraph and Table appear in Line 850-871, Page 22-23 in the Revised Manuscript as follows:

"4.2.4. Comparative Superiority of MXene-Based Biosensors Over Conventional Methods

To quantitatively demonstrate the advantages of MXene-based biosensors, we compare their performance against electrochemical, optical, immunoassay, and magnetic methods using HER2 breast cancer biomarker as a unified target. As shown in Table 2, the MXene-based electrochemical immunosensor achieves a limit of detection as low as 0.26 fg/mL for HER2 with an assay time of only 20 minutes. This sensitivity is 50 to 100 times better than non-MXene electrochemical sensors, which typically achieve 13 to 33 fg/mL within 60 minutes, and nearly one million times better than conventional ELISA, which detects HER2 at 0.1 to 1 ng/mL and re-quires 4 to 6 hours. When compared with optical methods, the MXene sensor at 0.26 fg/mL surpasses the liquid crystal sensor at 1 fg/mL and the fiber-optic immunosensor at 0.001 nM, approximately 0.138 pg/mL. Although these optical methods approach similar sensitivity, they rely on costly spectrometers and laser sources, whereas the MXene platform operates with a simple low-cost potentiostat, making it far more suitable for point-of-care testing. The magnetic exosome method detects HER2 at 28 to 1232 particles per microliter, but its particle-based unit prevents direct comparison with protein-level sensors. The superior performance of the MXene-based sensor originates from two intrinsic material properties: its metal-like electrical conductivity reaching approximately 10⁴ S/cm facilitates efficient electron transfer at the electrode interface, and its abundant surface functional groups including fluorine, hydroxyl, and oxygen terminations enable high-density covalent immobilization of antibodies without requiring additional crosslinkers. These synergistic advantages position MXene as an ideal platform material bridging laboratory sensor design and clinical diagnostic requirements. [116-120]"

Table 1. Performance Comparison of MXene-Based and Conventional Methods for HER2 Detection

Ref   Method Type                         Target             LOD                  Assay Time
116	MXene-based electrochemical immunosensor	HER2	0.26 fg/mL	20 min
117	Optical (liquid crystal)	HER2	1 fg/mL	Real-time
118	Optical (fiber-optic immuno)	HER2	0.001 nM (~0.138 pg/mL)	Real-time
119	Magnetic (exosome)	Exosomal HER2	28–1232 particles/μL	—
120	Non-MXene electrochemical	HER2 (four targets)	13–33 fg/mL	60 min
	Conventional ELISA	HER2	0.1–1 ng/mL	4–6 h

 

Author Response File: Author Response.docx