Engineering Safer MXenes for Biomedical Applications: Effects of Etching and Delamination on Biocompatibility of Ti-Based MXenes

MXenes, a class of two-dimensional transition metal carbides and nitrides, have emerged as promising candidates for biomedical applications due to their electrical conductivity, photothermal response, and rich surface chemistry. However, their biocompatibility is highly sensitive to synthesis conditions, particularly etching and delamination strategies. In this study, we systematically investigated the influence of different synthesis routes─using acidic (concentrated or diluted HF/HCl) etching and Li+ versus Na+ intercalation─on the surface chemistry, structural integrity, and biological behavior of Ti3C2Tx and its carbonitride analog Ti3C1.5N0.5Tx.

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Detailed physicochemical characterization revealed that water-assisted etching and Na+ intercalation enhanced hydroxylation and reduced fluorine terminations. Biological assays using human keratinocytes (HaCaT) demonstrated that Ti3C1.5N0.5Tx exhibited superior biocompatibility compared to Ti3C2Tx, with lower cytotoxicity, diminished ROS generation, minimal inflammatory signaling (IL-6 and IL-8 interleukins), and preserved wound healing capacity. Among Ti3C2Tx variants, the combination of diluted etchant and Na+ intercalation significantly improved biological tolerance, minimizing apoptosis and oxidative stress. These findings underscore the critical role of surface chemistry in MXene-cell interactions and offer a practical guide to engineering safer MXenes for biomedical use.

This study shows that the biocompatibility of Ti₃C₂Tₓ and Ti₃C₁.₅N₀.₅Tₓ MXenes can be finely tuned by adjusting synthesis parameters, particularly etching conditions and intercalant selection. The resulting surface terminations—determined by etchant chemistry and delamination route—play a central role in shaping cytotoxicity, oxidative stress, inflammatory signaling, wound healing, and skin tolerance. Notably, Ti₃C₁.₅N₀.₅Tₓ consistently outperformed Ti₃C₂Tₓ in terms of biological compatibility, while dilute etchants combined with Na⁺ intercalation produced MXenes with fewer −F terminations, greater hydroxylation, and improved cellular responses.

At subcytotoxic concentrations (≤25 μg/mL), these optimized formulations maintained keratinocyte viability, promoted wound closure, and elicited minimal oxidative and inflammatory reactions in vitro. Complementary in vivo histological analyses confirmed the absence of acute skin toxicity across all tested MXenes, with no evidence of tissue damage, immune cell infiltration, or mast cell activation—even in regions containing dermal MXene aggregates. Together, these findings highlight the decisive influence of surface terminations (−F vs. −OH), intercalant residues, particle size, and colloidal stability on MXene–cell interactions. By carefully tuning these parameters, it is possible to engineer MXenes that preserve their functional properties while minimizing cytotoxicity and inflammation. Such tailored MXenes hold strong promise for safe translation into biomedical applications, as demonstrated by the negligible cytotoxicity and lack of acute inflammatory response observed in our most refined samples.

This research was supported by Horizon Europe MSCA-2021-SE-01 projects MX-MAP (#101086184) and ESCULAPE (#101131147).

Read more about this study: Kateryna Diedkova, Iryna Roslyk, Nikola Kanas, Lita Grine, Volodymyr Deineka, Agata Blacha-Grzechnik, Martins Boroduskis, Igor Iatsunskyi, Błażej Anastaziak, Anastasia Konieva, Pavlo Shubin, Wojciech Simka, Marks Truhins, Oksana Sulaieva, Ilya Yanko, Veronika Zahorodna, Goran Stojanovic, Oleksiy Gogotsi, Yury Gogotsi, and Maksym Pogorielov. Effects of Etching and Delamination on Biocompatibility of Ti-Based MXenes. ACS Applied Materials & Interfaces. DOI: 10.1021/acsami.5c08807