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Novel Two-Dimensional MXene for Biomedical Applications

Huifeng Xu , Yongqiang Dong , Xi Zhu , Lishuang Yu

Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (5) : 752 -766.

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Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (5) : 752-766 DOI: 10.7536/PC200653
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Novel Two-Dimensional MXene for Biomedical Applications
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Abstract

As a novel kind of two dimensional material, MXene refers to the family of two-dimensional transition metal carbides, nitrides or carbonitrides. The general formula of this material is Mn+1XnTx(n=1~3) where M is transitional metal, X is carbon or nitrogen and T is active functional groups such as fluorine, hydroxyl or oxygen-containing group. The ultra-thin structure and fascinating physical and chemical(electronic, optical, magnetic, etc.) properties of this material has attracted wide interest in mechanical engineering, optics, energy, and electronics areas. Currently, MXenes are broadening their applications in the biomedical field. This is mainly originated from their large surface area and strong absorbance in near-infrared region, combining with their facile surface modifications with various molecular or nanoparticles. This review introduces the very recent progress and novel paradigms of MXenes for state-of-the-art biomedical applications. Firstly, the preparation methods and surface modifications of MXenes designed for biomedical applications is introduced. Then their applications in the biomedical areas are emphasized, including structural- and dose-dependent antimicrobial activity, bioimaging, photothermal cancer therapy, precise biosensors and so on. Finally, the current challenges and future opportunities of applying MXene-based nanomaterials and nanocomposites in biomedical field are summarized and discussed. It is highly expected that the ultrathin MXenes and their elaborately designed nanocomposites will become one of the most attractive biocompatible inorganic nano-platforms for multiple and extensive biomedical applications.

Contents

1 Introduction

2 Preparation methods

2.1 Synthesis of MXene

2.2 Surface modifications

3 Biomedical applications

3.1 Antibacterial activity

3.2 Bioimaging

3.3 Tumor therapy

3.4 Biosensing

3.5 Others

4 Conclusion and outlook

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Keywords

MXene / antibacterial / bioimaging / tumor diagnosis and therapy / biosensing

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Huifeng Xu, Yongqiang Dong, Xi Zhu, Lishuang Yu. Novel Two-Dimensional MXene for Biomedical Applications. Progress in Chemistry, 2021, 33(5): 752-766 DOI:10.7536/PC200653

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1 Introduction

MXene is a new class of two-dimensional (2D) nanomaterials composed of transition metal carbides, nitrides or carbonitrides with a thickness of several atomic layers, which was discovered and first reported by Gogotsi and Barsoum of Drexel University in 2011[1]. The chemical general formula of the material is Mn+1XnTx, and the meaning of the representation is shown in fig. 1A, specifically, n + 1 (n = 1 to 3) layers of front transition metals (M, green elements in the figure) and n layers of carbon or nitrogen atoms (X, gray elements in fig. 1A) are alternately arranged to form a two-dimensional nanosheet, and the Tx represents a surface terminal group (T, blue elements in fig. 1A) bonded to the outer M layer. The corresponding MXene sheet material can be obtained by selectively etching the A element (red element in Fig. 1A) in the MAX phase by chemical liquid phase method. As can be seen from that elemental analysis in the figure, the M-X bond has a covalent/metallic/ionic character, while the M-a bond has a purely metallic character, so that the MAX can be selectively etch using a suitable etchant to remove the a element lay without damaging the MX layer[2]. As a result, highly stable and tightly packed MXene nanosheets can be formed[1,3]. As shown in fig. 1B, after the MAX is etched in hydrofluoric acid (HF), the atomic layer of A is removed and replaced with groups of O, OH, and/or F (also known as surface end groups, i.e., Tx) to form a multilayer MXene. The multilayer MXene can be further exfoliated into a single ultra-thin 2D MXene nanosheet by ion/organic molecule intercalation into the multilayer structure and ultrasonic treatment.
The thickness of MXene materials is generally less than 1 nm, while the lateral dimensions vary from nanometers to micrometers, depending on the preparation method of the corresponding materials. Due to the conditions of the preparation process, a large number of functional groups such as hydrogen, oxygen, fluorine or hydroxyl are usually attached to the surface of the material. This new two-dimensional material, which has both a complete metal atomic layer and a large number of surface functional groups, uniquely combines the metallic conductivity of transition metal carbides/nitrides with the hydrophilicity of its hydroxyl/oxygen/fluorine terminated surface, and has attractive electronic, optical and magnetic properties. Thanks to this, MXenes has rapidly become one of the most attractive new materials in the fields of materials, energy, electronics and other research fields, and many research groups at home and abroad have systematically reviewed and summarized it from different perspectives[5⇓~7].
Although the application of this material in the field of biomedicine is only three years, it has become one of the most popular research materials in the fields of biosensors, cancer photothermal therapy, disease diagnostics and nerve electrodes. Huang Peng of Shenzhen University and others published a review article in Chemical Society Reviews in 2018. In this paper, we will introduce the preparation methods of MXenes based on medical applications and the latest progress in biomedical applications based on the latest research progress. Finally, we will look forward to the challenges and opportunities faced by MXenes in the field of biomedical applications[8].

2 Preparation method

2.1 Synthesis of MXene

Up to now, the methods of preparing MXene have been reported and reviewed in many literatures, and the classification of methods is also diversified (see Table 1)[4,7,9,10]. From the point of view of biomedical applications, it can be classified according to whether the etchant contains fluorine or not, that is, it is mainly divided into fluorine-containing etching method and fluorine-free etching method[11]. The fluorine-containing etching method mainly uses an aqueous hydrofluoric acid (HF) solution or a method in which HF is generated in situ by the reaction of an acid with a fluoride (usually HCl and LiF/NaF) to selectively etch an A-element layer (Al or Ga), thereby producing MXene[3,12⇓⇓⇓ ~16]. It has also been reported that MXene can be prepared using molten fluorides with the aid of high temperature heating[17]. Although HF etching is the earliest and currently the most widely used method, the resulting MXene is not very suitable for biomedical applications for two reasons: (1) fluorine-containing etchants are seriously harmful to biological organisms, and trace amounts of residual HF may cause cell apoptosis; (2) that method introduce a large number of F- group on the surface of the material. Although F- also endows MXene with hydrophilicity, biomolecules are difficult to couple through F-, resulting in the need for surface group modification before application.
In the past two years, significant progress has been made in the preparation of MXene without fluorine. Xuan et al. reported an intercalation method using tetramethylammonium hydroxide (TMAOH) as an etchant[18]; Similarly, in the presence of tetrabutylammonium hydroxide (TBAOH) intercalator, Yu et al. Successfully prepared fluorine-free Ti3C2Tx quantum dots by ultrasonic treatment[19]. In addition, inspired by the Bayer process widely used in bauxite extraction, Li et al. Proposed an alkali-assisted hydrothermal method to prepare Ti3C2Tx(T=OH,—O), a typical MXene material. However, the experimental conditions of this alkali-based method are usually harsh (27.5 M NaOH in autoclave, 270 ℃), and it is difficult to achieve mass production[20]. Another route is electrochemical synthesis in HCl or ammonium chloride/tetramethylammonium hydroxide (TMAOH) electrolytes at room temperature, however, scaling up the selective electrochemical etching process to mass production may also be a challenge[21][22].
In 2019, Huang et al. Successfully synthesized Ti3C2T and Ti2CTx with only chlorine termination using Lewis acid melts composed of ZnCl2, which paved the way for the discovery of MXene components with new terminal groups[23]. In 2020, they continued to construct the redox potential/Gibbs free energy mapping map of cation and element A in high temperature molten salt environment, and proposed a general strategy for synthesizing 2D MXene by etching MAX phase with Lewis acid molten salt[24]. This strategy is expected to excavate some MXene materials that are difficult to prepare by previous methods. With the deepening of research, it is believed that MXene preparation methods with milder experimental conditions, more suitable for mass production and more suitable for biomedical applications will be developed in the future.

2.2 Surface Modification of MXenes

At present, most synthetic methods endow the surface of MXene with a large number of hydrophilic functional groups such as hydrogen, oxygen, fluorine or hydroxyl, so MXene has excellent hydrophilicity, and appropriate surface modification/functionalization can enhance its biomedical properties such as biocompatibility, cyclicity, targeting ability and loading ability, which makes it have great potential in biomedical applications.
Due to the large number of negative charges on the surface of MXene, positively charged molecules can easily attach to the surface of the material through electrostatic forces. Some biocompatible polymers are preferred for surface modification of MXene due to their large surface area and biodegradability. Xuan et al. Modified the surface of Ti3C2Tx with polyethylene glycol (PEG), which can significantly improve the water dispersibility of the material by electrostatic adsorption on the surface of the Ti3C2Tx[18]. poly (vinyl pyrrolidone) (PVP) has also been used to modify the surface of MXene[25]. As an economical modifier, soybean phospholipid (SP), a natural polymer, can effectively improve the cycling stability and enhance the permeability of MXene (Fig. 2A), so it is also widely used in the surface modification of MXene[26,27]. In addition, some drug delivery systems based on MXene also load positively charged drugs, such as doxorubicin (DOX), through electrostatic binding, and combine with other negatively charged polymers (Fig. 2B) to improve the protection of drugs during circulatory therapy through layer-by-layer self-assembly[28].
However, the non-covalent adsorption force is relatively weak, which makes the stability of the material can not meet the needs of some specific biomedical applications, so it is still necessary to actively seek more stable surface modification methods. Recently, Han et al. Proposed a new strategy for covalently bonding PEGs to the surface of Nb2CTx by using (3-amino-propyl) triethoxysilane (APTES) as a bridge to link PEGs to Nb2CTx (Fig. 2C)[29]. On the one hand, APTES can bond with hydroxyl groups on the surface of Nb2CTx, on the other hand, the amino groups on the surface of APTES can react with PEGs to form PEGylated Nb2CTx composites.
The coupling reaction based on aryl diazonium salt and self-initiated photografting and photopolymerization (SIPGP) are also of great significance[30,31]. Aryl diazonium salts can form covalent bonds on the surface of various substrates including carbon materials, semiconductors, metal oxides, and metal nanoparticles[32]. Zhang et al. Functionalized two-dimensional Ti3C2Tx nanosheets by in-situ generation of benzenesulfonic acid groups derived from diazonium ions, and found that aryl diazonium salts could be covalently attached to the surface of the MXene material in the form of strong Ti-O-C bonds[33]. It is worth mentioning that the introduction of aryl diazonium salts can increase the interlayer spacing of the Ti3C2Tx, and the supercapacitor performance of the Ti3C2Tx is also significantly enhanced with the insertion of diazonium ions and the introduction of electroactive groups.
As a simple and easy polymerization method, SIPGP does not need anchoring layer, self-assembled monolayer and initiator, and can be directly grafted on the surface of the material through a one-step reaction under UV irradiation. Chen et al. explored a new strategy for MXene surface modification based on SIPGP, grafting 2- (dimethylamino) ethyl methacrylate brushes onto the surface of V2CTx materials (Fig. 2D)[34]. The research of these two modification methods is still in the initial stage of exploration, and it is hoped that more surface modification strategies of MXene with controlled polymerization can be developed in the future to improve the effective application of MXene in biomedicine.
After surface modification and functionalization, MXene will have more excellent physical and chemical properties, and will be widely explored and studied in the field of biomedical applications. The applications of 2D MXenes in antimicrobial agents, biological imaging, tumor diagnosis and therapy, and biosensing are summarized in this paper.

3 Biomedical application

3.1 Antibacterial material

In the past decade, the emergence of many 2D nanomaterials has brought good opportunities for the manufacture of highly effective antibacterial agents. The antibacterial mechanisms of new 2D nanomaterials are mainly as follows: increasing transmembrane permeability, causing cell membrane rupture, reducing metabolic activity, damaging DNA and physical damage of cell membrane induced by sharp edges of materials. MXene is considered as a high potential antibacterial agent with high stability and long life cycle because of its large specific surface area, easy chemical manipulation and functionalization, and the potential to load different antibacterial functional groups. Gogotsi et al. Studied the antibacterial ability of Ti3C2Tx against Escherichia coli and Bacillus subtilis cells[35]. The study confirmed that the MXene material had significant bacteriostatic ability by incubating the Ti3C2Tx with bacterial cells for 4 H and monitoring the number of colonies on the Petri dish after treatment with different concentrations of Ti3C2Tx (Fig. 3A). The study further used graphene oxide, a widely used 2D antibacterial agent, as a comparison, and found that Ti3C2Tx had stronger antibacterial activity against both Escherichia coli and Bacillus subtilis. They further verified and discussed the mechanism of its antibacterial effect, pointing out that the reasons may be as follows: First, Ti3C2Tx form conductive bridges on the lipid bilayer of cells, thus promoting the transfer of electrons from intracellular components to the external environment, eventually leading to cell apoptosis; Secondly, the high hydrophilicity of Ti3C2Tx can also promote the effective contact between bacteria and the surface of membrane materials, thus causing bacteria to adhere to the surface of materials and inactivate. In addition, the hydrogen bonding between the oxygen-containing groups of the Ti3C2Tx and the lipopolysaccharides on the cell membrane can also hinder the intake of nutrients by bacteria, thereby inhibiting the growth of bacteria, which is similar to that of graphene nanosheets, but due to the better conductivity of the Ti3C2Tx, the bacteriostatic efficiency will be higher. Their follow-up studies found that the antibacterial effect of aging micron-sized Ti3C2Tx basement membrane on Escherichia coli and Bacillus subtilis was significantly better than that of freshly prepared same material[36]. In fact, the antibacterial effect of different MXene materials is very different, and not all MXene materials have good antibacterial effect, which may depend on the stoichiometry of MXene[37].
In addition to the search for efficient antibacterial MXene matrix materials, the "strong combination" of MXene and other antibacterial agents is also one of the research ways to prepare high-performance antibacterial materials. Pandey et al. synthesized a MXene composite film modified by silver nanoparticles (AgNPs) by self-reducing AgNO3 on the surface of Ti3C2Tx nanosheets[38]. Interestingly, in this composite membrane, AgNPs were located between the layers of the Ti3C2Tx, increasing the interlayer gaps to 1-4 nm, which effectively served as water transport channels (Fig. 3B). Therefore, the composite membrane not only has a stronger bactericidal ability, but also improves the water permeability at the same time, showing a highly efficient and ultra-fast water purification ability.
MXenes not only has efficient bactericidal and bacteriostatic functions, but also has good film-forming properties, which also inspires researchers to use this material to prepare antibacterial films for sewage treatment[39][36,38]. At present, that variety of MXene and its complexes synthesize by experiments are various and increasing, among which there are many MXene materials worthy of further exploration, which are expect to become good antibacterial alternative products in the near future.

3.2 Biological Imaging

In addition to antibacterial activity, MXenes can also be used as a biological imaging contrast agent, and the most studied aspects include fluorescence luminescence imaging and photoacoustic imaging (PAI).
In the field of luminescence imaging, most of the research has focused on the ultra-small nano-sized MXene quantum dots (MQDs). Similar to carbon quantum dots and graphene quantum dots, MQDs also have fluorescence emission characteristics[40]. MQDs obtained by hydrothermal treatment of MXene sheets can emit light due to quantum confinement and surface defects induced by size effect, and can be used for cell imaging after appropriate surface modification[41⇓⇓~44]. Xue et al. First used a simple hydrothermal method to prepare water-soluble monolayer Ti3C2TxMQDs[41]. This study shows that the average size of the MQD can be adjusted by selecting the reaction temperature and exhibits an excitation-dependent fluorescence spectrum. The imaging results for RAW264.7 cells demonstrate the potential of MQD for biomedical and optical applications. Xu et al. Prepared nitrogen-doped Ti3C2TxQDs by hydrothermal treatment using Ti3C2Tx as precursor and ethylenediamine as nitrogen source[43]. The QDs emit blue fluorescence at 450 nm with a fluorescence quantum yield of 18. 7%. They went on to prepare nitrogen-and phosphorus-doped Ti3C2TxMQDs by hydrothermal reaction of diammonium hydrogen phosphate with Ti3C2Tx[44]. The particle size of the N, P-MQD is about 3 nm, the maximum emission wavelength is about 560 nm, the fluorescence quantum yield is 20.1%, and the N, P-MQD has good light stability and pH resistance, and can be effectively used as a fluorescent probe for macrophage labeling (fig. 4A). In addition, Yang et al. ultrasonically stripped the Nb2CTxQDs with oxygen-rich groups on the surface in tetrapropylammonium hydroxide solution, which not only has stable and excellent fluorescence and high biocompatibility, but also has the characteristics of biodegradation under the action of myeloperoxidase, and is expected to be used for in vivo biomedical diagnosis[45].
As a new non-invasive and non-ionizing biomedical imaging method, PAI combines the advantages of high contrast of optical imaging and deep penetration of ultrasound imaging, and has great potential in the field of medical imaging. The performance of contrast agent has a great influence on the imaging effect of PAI. In general, an effective PAI contrast agent should have a good photothermal conversion ability to show a significantly enhanced photoacoustic signal compared to the surrounding tissue. MXene material itself has excellent photothermal conversion ability, which is mainly attributed to the localized Surface Plasmon Resonance (LSPR) effect of its semi-metallic characteristics[28]. More interestingly, MXenes generally exhibit a strong absorption spectrum extending into the Near Infrared Ray (NIR) range, thus being more conducive to achieving PAI in deep tissues. The concept of MXene based PAI is shown in Figure 4B (a)[46]. After exposure to NIR laser light, tissue components absorb the light, undergo thermoelastic expansion, and subsequently generate an ultrasonic signal (photoacoustic effect) that can be detected by an ultrasonic sensor. Yu et al. screened PA images of the Ti3C2TxMQD at different excitation wavelengths and found that the best PA signal appeared at 680 nm (Fig. 4B (B))[19]. In addition, the PA signal increased with increasing Ti3C2TxMQD concentration (fig. 4B (C)), demonstrating the suitability of MQD for PAI applications. MXene materials currently proven for PAI include Ti3C2 T x ,Nb2C T x , Ta4C3 T x , etc.With the improvement of synthesis and preparation methods, more MXene species with high PAI potential will be excavated[19⇓⇓⇓⇓⇓⇓⇓⇓~28][25⇓⇓⇓~29][47]. Since the PA imaging of MXenes is basically used to guide tumor therapy, the application examples in this respect will be described in detail in the following aspects of imaging combined with tumor therapy.
In addition, conductivity changes using MXene can also be used for biological imaging. Xu et al. Prepared ultrathin MXene micropatterns by microcontact printing and used them to culture neuronal cells. Because the conductivity of MXene is sensitive to the surrounding environment, the neural activity of cells can be detected by the change of MXene field effect[48].

3.3 Tumor therapy

The application of nanomaterials in tumor therapy has always been the frontier of biomedical research. Since researchers began to focus on the application of MXene in biomedicine in 2017, many studies have explored the application potential of MXene in cancer therapy, as shown in Table 2. To sum up, these studies mainly include the following three types: (1) killing cells by photothermal effect; (2) photodynamic therapy produces reactive oxygen species (ROS) to kill cells; (3) drug carry synergistic therapy.
As mentioned above, MXene with metalloid properties generally has high photothermal conversion efficiency, so most of the current research focuses on the application of MXene in photothermal therapy (PTT) of tumors. PTT is a therapeutic method that uses photothermal materials to convert light energy into local superheat to kill cancer cells. Because of its non-invasive, controllable and good therapeutic effect, PTT has attracted wide attention of clinical medical researchers. The efficiency of PTT in vivo mainly depends on the location and depth of the tumor tissue, as well as the accumulation of photothermal materials in the cancer tissue, the ability of photothermal conversion and the light dose (that is, light excitation time and light power density). Ti3C2 T x 、Nb2C T x 、MXene materials such as Ta4C3 T x and Ti2C T x have been reported to have strong optical absorption characteristics and good photothermal conversion efficiency in a wide spectral range from ultraviolet to visible light to NIR.Therefore, it is expected to be used for the treatment of deep tissues[18,28,49][25,29][47,50][51]. Xuan et al. studied the light absorption capacity of aluminoxide-functionalized Ti3C2Tx nanosheets in the NIR spectral region and found that the mass extinction coefficient of the material could reach 29.1 L·g-1·cm-1 at 808 nm[18]. Lin et al. Used soybean phospholipid (SP) to functionalize Ti3C2Tx for photothermal therapy of tumors[26]. The results show that the introduction of SP enhances the stability of Ti3C2Tx nanosheets in the dispersion and improves their applicability in tumor diagnosis and treatment. Han et al. Synthesized a uniform silica coating based on sol-gel chemistry, which is called "therapeutic mesoporous"[29]. The photothermal conversion rate of the Nb2CTx composite in the NIR-II biological window is 28.6%, and the composite is proved to be used for reinforcing PTT. This study not only broadens the application of Nb2CTx as a MXene material in the field of cancer, but also provides an effective strategy for the surface engineering of MXene.
Shi Jianlin et al. Developed a biodegradable Nb2CTx-PVP nanosheet for the treatment of tumors[25]. This single-atom-thick nanosheet of Nb2CTx with a lateral size of approximately 150 nm has exceptional photothermal properties in the broad NIR spectrum and extremely high photothermal conversion efficiency (Fig. 5A, B), allowing efficient in vivo photothermal ablation of mouse tumor xenografts in the NIR-I and NIR-II windows (Fig. 5C). The in vitro toxicity of Nb2CTx-PVP to cells showed that as the laser energy increased, more cells were killed in the NIR-I and NIR-II biological windows (fig. 5D). Both in vitro cell experiments and in vivo mouse experiments showed that the Nb2CTx-PVP had no significant toxicity and could effectively kill tumor cells in the NIR-I and NIR-II windows (Fig. 5 E, F). Interestingly, the PTT of this material in the NIR-II window is more attractive (Fig. 5G), and its photothermal conversion efficiency can even reach 46.65% under 1064 nm laser irradiation. This work greatly broadens the application prospects of MXene in cancer therapy by reasonably designing its composition and exploring its related physical and chemical properties.
In addition, because imaging can show some important tumor information and real-time treatment progress, it is usually necessary to carry out tumor treatment under the guidance of imaging in clinic, which requires targeted materials to have imaging function at the same time. In the current research, there are mainly two ways to make MXene composites easily integrate with multi-modality Imaging methods including PAI, MRI (Magnetic Resonance Imaging) and CT (Computerized Tomography): one is to find and prepare MXene materials with this property[52]; The second is to compound with materials such as nano-metal or magnetic metal oxide particles[27,49,53,54]. Zhang and Dong et al. reported a green layering method based on algae extracts to produce high yields (90%) of V2CTx nanosheets[52]. The V2CTx obtained by this method showed good structural integrity and very high photothermal conversion (up to 48%) under 808 nm laser irradiation. A series of experiments in vivo and in vitro show that the material can be used for cancer therapy under the guidance of PAI and MRI. In addition to ultra-thin nanosheets, the performance of ultra-small MQDs on PTT is also eye-catching. The fluorine-free MQDs prepared by ultrasound in TBAOH solution were modified with a large number of aluminoxyl anions, which made them have strong and broad light absorption in the NIR region[19]. The results show that the MQDs exhibit an extinction coefficient as high as 52.8 L·g-1·cm-1 at 808 nm, and the photothermal conversion efficiency is as high as 52. 2%, which can realize PAI and PTT at the same time. Recently, the Ti2NTxMQDs prepared by Huang et al. Using hydrothermal method showed extremely high photothermal conversion efficiency (NIR-I, 808 nm, 48.62%; NIR-II, 1064 nm, 45.51%) under laser irradiation of NIR-I and NIR-II biological windows[55]. In vitro and in vivo evaluation showed that the Ti2NTxMQDs had excellent biocompatibility, PA effect and PTT efficiency. Moreover, the MQDs showed significant accumulation in the tumor at 4 H after injection, enabling PA imaging guided PTT in both NIR-I/II biological windows. It is encouraging to see that the MQDs not only have no obvious toxicity, but also can be smoothly excreted from animals, have certain biodegradability, and have great potential in precise cancer therapy.
Nanometer metal or magnetic metal oxide particles composite MXene materials are more reported. Hussein et al. synthesized MXene based composite nanomaterials containing both Au and Fe3O4 nanoparticles (Au/MXene and Au/Fe3O4/MXene, respectively), and studied the potential of the composite as a combination of PTT reagents[53]. Chen et al. loaded MnOx nanoparticles on a Ta4C3Tx for multimodality imaging (PA/CT/MR) guided tumor ablation[37]. The prepared Ta4C3Tx contains Ta element with high atomic number (Z = 73), thereby having excellent X-ray/CT contrast performance. Benefiting from the high photothermal conversion efficiency of the Ta4C3Tx and the MRI characteristics brought by the MnOx, the composite unconventionally performs MR/CT/PA triple-peak imaging guided PTT in the NIR-I window. Not long ago, Liu et al. Also reported Ta4C3Tx-Fe3O4 MXene composite materials, which were modified with soybean phospholipid SP for MRI/CT dual-modality imaging-guided photothermotherapy of breast cancer[47].
In addition, some MXenes with semiconductor properties can produce oxygen free radicals (ROS) under the excitation of light, which may be suitable for cell killing in photodynamic therapy (PDT)[26]. At present, the mechanism is still unclear, and more and more in-depth studies are needed.
In addition to directly killing cells by PDT or PTT, MXene with high specific surface area can also act as a carrier for chemotherapeutic drugs[28,56,57]. Liu et al. Loaded the positively charged chemotherapeutic drug DOX hydrochloride on the surface of negatively charged Ti3C2Tx by electrostatic adsorption, and attached the negatively charged hyaluronic acid (HA) to the top of DOX by layer-by-layer assembly, thus realizing the synergistic treatment of DOX-induced chemotherapy and the inherent PDT/PTT of MXene[28]. Xing et al. synthesized a composite hydrogel based on cellulose and Ti3C2Tx[56]. Exposure to 808 nm light triggers the enlargement of the pores in the cellulose network, which accelerates the release of DOX. The research shows that the cellulose /Ti3C2Tx composite hydrogel has outstanding photoinduced swelling and double-peak photothermal/chemotherapeutic anti-cancer activity.
Taken together, MXene is an effective vector with great application potential in integrated imaging and combined diagnosis and treatment of tumors.

3.4 Biosensing

Due to the combination of surface hydrophilicity, metal conductivity and two-dimensional layered atomic structure, MXene has also attracted great interest in chemical and biological sensing applications[58].
Firstly, the modification of terminal groups on the surface of MXene can significantly affect the physical and chemical properties of the material, which is widely used in the construction of gas sensors to detect NH3, ethanol, methanol, acetone and volatile organic compounds (Fig. 6a)[59⇓~61][62]. In addition, H2O2 can effectively oxidize the end of the surface of MXene and increase the oxygen density on the surface of the material, thus promoting charge transfer. Therefore, H2O2 sensors based on MXene have also been widely studied[63⇓~65].
Secondly, MXene has become an excellent material for electrochemical sensing due to its high conductivity and good ion insertion properties. At present, MXene has been reported as an electrode material to construct electrochemical sensors for the detection of NADH (fig. 6B), ascorbic acid, folic acid, deoxyadrenaline and other electroactive biomolecules[63][64][66][67]. The large surface area and unique biocompatibility of MXene enable some biological macromolecules such as enzymes and antibodies to be immobilized on its surface with high loading and maintain good biological activity. Wang et al. Immobilized hemoglobin (Hb) on a MXene(TiO2-Ti3C2Tx) nanocomposite modified by TiO2 nanoparticles to construct a media-free electrochemical biosensor for H2O2[68]. Similar strategies have also been used in some enzyme-based sensing interfaces for the detection of substances such as H2 O 2 , glucose, β-hydroxybutyric acid, and organophosphorus (fig. 6C), as well as in the construction of immunoreaction-based and aptamer-based biosensors[69,70][71][72][73][74][75]. In addition, Ma et al. fabricated a porous composite film by layer-by-layer self-assembly of negatively charged Ti3C2Tx nanosheets and positively charged NH2-CNT, and constructed a highly selective and sensitive electrochemical sensor for the detection of fisetin on the film by molecular imprinting technology[76]. In the composite membrane, the use of conductive NH2-CNTs as interlayer spacers can effectively inhibit the aggregation of MXene sheets and form a more regular porous structure, thereby enhancing the specific surface area and electrocatalytic activity of the material. Min and Lee et al. achieved simultaneous quantification of multiple OncomiRs on a single total plasma platform using a synergistic amplification strategy combining MXene based electrochemical signal amplification with a Duplex-Specific Nuclease (DSN) based amplification system[77]. This synergistic strategy reduces the analysis time of the DSN-based biosensor to 80 min and provides multiplicity, antifouling activity, and good sensitivity and specificity (single mutation recognition).
In addition to electrochemical sensors, MXene also performs well in optical sensors. In the aspect of electro-chemiluminescence (ECL), Fang et al. Formed a composite film of Nafion and Ti3C2Tx, and immobilized Ru (bpy) ) 3 2 + on the surface of the composite film through electrostatic adsorption to construct a solid-state ECL sensor for single base mismatch recognition[78]. The ECL electrode has excellent reproducibility (relative standard deviation of 0.69% for 107 consecutive cycles) and long-term stability (about 90% of its initial ECL intensity can be retained after intermittent use over a period of 90 days). In recent years, due to the important role of exosomes in life activities, the detection of exosomes has also attracted much attention. Zhang et al. modified the aptamer of exosomes on the Ti3C2Tx nanosheet as a nanoprobe to enhance the luminol ECL system to detect exosomes MCF-7, and developed an ultrasensitive ECL biosensor by reducing gold nanoparticles (AuNPs) on the surface of the Ti3C2Tx in situ to enhance the signal of the luminol ECL system (Fig. 6d)[79][80]. Dai et al. Constructed an ECL biosensor for exosome detection by using black phosphorous quantum dots (BPQD) as an ECL co-reactant of Ru (bpy) black phosphorous quantum dots and Ti3C2Tx as a signal amplifier. Ingeniously, due to the excellent photothermal effect of BPQD and Ti3C2Tx, the detection interface can also be used to construct a photothermal biosensor[81].
As mentioned above, some MQDs have intrinsic fluorescence characteristics, so it is easy to establish some sensitive and simple fluorescence biosensing methods based on this characteristic, such as rapid recognition of metal ions Fe3+, monitoring of intracellular pH, and the establishment of fluorescence and visual sensing methods for uric acid based on fluorescence resonance energy transfer, etc[45][82][83]. In addition, MXene can also serve as a signal quenching interface for other fluorophores due to its strong light absorption capacity (fig. 6 E)[84]. Pumera et al. elucidated the interaction of Ti3C2Tx with fluorophore-labeled DNA by fluorescence measurements and molecular dynamics simulations[85]. The results show that the system can detect DNA sequences at the picomolar level and has the ability of single base recognition, and the Ti3C2Tx has a unique kinetic behavior of nucleic acid encapsulation/release. Therefore, MXene has great potential as a biosensing platform for binding nucleic acids.
It is also interesting that several reports have revealed the potential application of MXene in surface-enhanced Raman sensing strategies. The enhancement of MXene to Raman signal is mainly due to two reasons: (1) MXene with partial metallic properties has LSPR characteristics[86⇓⇓⇓⇓⇓⇓~93]; (2) The hydrophilic and flexible surface of MXene enhances its interaction with Raman tag molecules. Yoshimura et al. First reported that Ag, Au and Pd @ MXene hybrids synthesized in situ on the surface of Ti3C2Tx were used as SERS substrates[88]. George et al. explored the possibility of using the Ti2NTx with filter paper as the fixed material as the SERS substrate, and found that compared with the SERS effect of silicon-based and glass-based loaded Ti2NTx, the SERS response signal of rhodamine 6G can be amplified by the filter paper-loaded Ti2NTx to 1012[89]. At present, this research direction is in the exploratory stage of improving the performance of SERS substrates, but we are still confident that MXene-based SERS substrates will be widely used in the biological field in the near future.
The application research of wearable sensing devices is the most eye-catching part of MXene series research[94⇓⇓⇓~98]. Lei et al. Prepared a wearable MXene biochemical sensor based on oxidase modification for the detection of glucose and lactate in sweat[94]. This wearable sensor uses enzymes to detect pH to monitor glucose and lactate levels. The disadvantage of this work is that the monitoring range of pH is relatively narrow due to the problem of enzyme activity. Guo et al. Made a highly sensitive, flexible and degradable pressure sensor by sandwiching MXene impregnated porous tissue paper between a polylactic acid (PLA) sheet and a PLA sheet coated with a comb electrode[95]. The sensor can be used as an electronic skin (E-skin) for mapping tactile stimuli to predict the potential health status of patients, which has great potential for personal health care monitoring, clinical diagnosis and next-generation artificial skin. Cai et al. designed a percolating mesh material based on a Ti3C2Tx/CNT composite and made it into a multifunctional strain sensor (Fig. 6 F)[96]. This braided structure with excellent electrical properties cross-connects sensitive MXene nanopatches with conductive and stretchable CNTs, resulting in a strain sensor that can be used to detect tensions as small as 0.1%.It offers high ductility (up to 130%), high sensitivity (strain factor up to 772.6), adjustable sensing range (30% to 130%), ultra-thin device size (< 2 μm) and excellent reliability and stability (> 5000 cycles). The wearable device has the comprehensive ability to track health and exercise physiological signals in real time and in situ, which provides a promising way for future wearable artificial intelligence.

3.5 Other biological applications

In addition to the wide range of applications mentioned above, the researchers also reported new applications of MXene in cell culture and tissue engineering. Huang et al. Prepared Ti3C2Tx composite MXene nanofibers by electrospinning, and introduced a large number of functional hydrophilic groups on the surface of the material, which made it have excellent hydrophilicity[99]. Experiments show that the nano-surface and functional groups provide a good microenvironment for the growth of bone mesenchymal stem cells (BMSCs) and enhance the differentiation of BMSCs into osteoblasts. Therefore, MXene also has unique advantages as an intelligent biomaterial for cell culture and tissue engineering. Yang et al. integrated a mesoporous silica coated Nb2C MXene loaded with S-nitrosothiol (nitric oxide donor) into the macropores of a 3D-printed bioactive glass (BG) scaffold, and used MXene-triggered photon hyperthermia and precisely controlled nitric oxide (NO) release in the NIR-II biological window to coordinate multi-target ablation of bone tumors to enhance the treatment of local osteosarcoma[100]. The formation of phosphorus and calcium components in situ during the degradation of BG scaffolds promotes bone regeneration, while regulated NO production plays an important role in adjuvant tumor ablation, combined promotion of angiogenesis and bone regeneration. The design of the multifunctional scaffold has the special functions of controllable NO release, efficient photothermal conversion and stimulating bone regeneration, and provides an interesting biomaterial platform for the diversified treatment of bone tumors.

4 Conclusion and prospect

The reason why Mxenes is favored by researchers in the field of biomedicine is that it has several characteristics: first, unlike inorganic quantum dots and upconversion nanoparticles, Mxenes has good hydrophilicity, which provides convenient conditions for biomedical applications; Secondly, carbon and nitrogen, the main elements of MXenes, are essential elements in the structure of biological organisms, and early transition metals such as Ti, Nb and Ta are relatively inert to biological organisms, so MXene has relatively low toxicity to living organisms and good biocompatibility. Again, MXenes has a strong absorptive capacity in the NIR region, providing an opportunity for in vivo PAI and PTT in either the first or second biological window. In addition, the abundant charged groups on the surface of MXene make it easy to achieve material interface functionalization through different modification methods, thus paving the way for new biomedical applications.
Although MXene-based materials have achieved a lot of brilliant research results in biomedical applications in just three years, most of the research is still in the initial stage of laboratory exploration, and there are still research gaps in many aspects. Before entering clinical and practical applications, there are still the following challenging problems to be solved:
(1) Developing a more green and easily-controlled preparation method of MXenes. At present, most of MXene is prepared by stripping its precursor through the top-down method which lacks controllability, and there is no successful study on obtaining single-layer MXene through the bottom-up synthesis method. Therefore, it is still necessary to devote more efforts to the study of more controllable synthesis methods to explore the preparation of MXene with controllable morphology, structure and surface termination groups. In addition, among a large number of MXenes predicted by theoretical calculations, only more than 20 MXenes have been successfully obtained by experiments. Therefore, it is also one of the directions of future efforts to devote to the synthesis of MXene, which has unique performance in theoretical prediction. Moreover, other different forms of MXene, such as MXene quantum dots, MXene nanotubes and nanocages with controllable size and morphology, are also worth exploring and studying.
(2) To find a more stable surface modification method. In most biomedical applications, MXene-based materials are typically modified with hydrophilic polymers in both electrostatic and physisorption modes. However, this non-covalent and physisorption interaction is not stable enough in some extreme cases to achieve controlled release in drug delivery systems. Therefore, more surface modification strategies based on covalent methods and dynamic bond formation need to be developed in the future to meet the requirements of biomedical applications such as drug delivery.
(3) Strengthen the performance prediction and mechanism calculation of theoretical calculation in the biomedical application of MXenes. At present, the theoretical calculation of MXenes focuses on the energy conversion and electronic properties, while the optical properties, which are essential for biomedical applications, are less studied. Theoretical calculation should pay more attention to the analysis of the light absorption ability of MXene in different surface States, predict the changes of optical properties of materials with different morphologies or doped with different atoms, so as to help find the type of MXene with better optical properties, and help to explore the relevant mechanism of action, so as to guide the better application of MXenes in biomedicine.
(4) The biological safety of MXenes was systematically investigated. Systematic studies on the biological safety of MXene are essential for further biomedical applications, and many factors such as cellular uptake behavior, cytotoxicity mechanism, in vivo distribution and in vivo toxicity need to be systematically examined before practical biomedical applications of MXene can be realized. Currently reported MXenes based on biomedical applications are generally biocompatible and some of them are even biodegradable in vivo[19]. Some researchers have also examined the cytotoxicity of Ti3C2Tx to normal cells and cancer cells[101]. It was observed that the cytotoxicity of Ti3C2Tx on cancer cells was higher than that on normal cells, suggesting that the cytotoxicity of MXenes may be related to the production of ROS. However, most of these studies are based on cell experiments or short-term hematological measurements, and the long-term biological safety of MXXenes has not been systematically evaluated, and the long-term toxicity, immunogenicity, pharmacokinetics and biodistribution of MXXenes in animal models still need a lot of efforts.
(5) Continue to explore new applications of MXenes in biomedical applications. For example, we actively explore the application of MXenes in PA imaging in NIR-II window, as well as in CT and MRI. Try to apply the SERS substrate interface based on MXene in medical detection, and introduce the catalytic properties of MXene into biological systems to catalyze specific biological reactions. In addition, MXenes, which has been proved to be sensitive to neurotransmitters, can also be used as devices such as field effect transistors and conductive microelectrodes, providing interesting opportunities for exploring neural activity in the brain and cancer therapy.
In the past three years, we have witnessed the rapid development of MXenes in biomedicine. It is believed that in the future, with the close and efficient cooperation among interdisciplinary researchers such as materials, chemistry, photophysics and biology, the technological breakthroughs and innovative applications of MXene nanomaterials in biomedicine will make more remarkable progress.

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Funding

NSFC(81773894)

Natural Science Funds of Fujian Province for Distinguished Young Scholar(2019J06021)

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