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Dental enamels of different species exhibit a wide variety of microstructural patterns that are attractive to mimic in bioinspired composites to simultaneously achieve high stiffness and superior toughness. Non-human enamel types, however, have not yet received the deserved attention and their mechanical behaviour is largely unknown. Using nanoindentation tests and finite element modelling, we investigate the mechanical behaviour of Macropus rufogriseus enamel, revealing a dominating influence of the microstructure on the effective mechanical behaviour and allowing insight into structural dependencies. We find a shallow gradient in stiffness and low degree of anisotropy over the enamel thickness that is attributed to the orientation and size of microstructural features. Most notably, M. rufogriseus's modified radial enamel has a far simpler structural pattern than other species', but achieves great property amplification. It is therefore a very promising template for biomimetic design. STATEMENT OF SIGNIFICANCE: The diversity of dental enamel structures in different species is well documented, but the mechanical behaviour of non-human enamel types is largely unknown. In this work, we investigate the microstructure and structure-dependent mechanical properties of marsupial enamel by nanoindentation and finite element simulations. Combining these methods gives valuable insights into the performance of modified radial enamel structures. Their stiffness and toughness stems from a unique structural design that is far less complex than well-studied human enamel types, which makes it a uniquely suitable template for biomimetic design., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The limpet tooth is widely recognized as nature's strongest material, with reported strength values up to 6.5 GPa. Recently, microscale auxeticity has been discovered in the leading part of the tooth, providing a possible explanation for this extreme strength. Utilizing micromechanical experiments, we find hardness values in nanoindentation that are lower than the respective strength observed in micropillar compression tests. Using micromechanical modeling, we show that this unique behavior is a result of local tensile strains during indentation, originating from the microscale auxeticity. As the limpet tooth lacks ductility, these tensile strains lead to microdamage in the auxetic regions of the microstructure. Consequently, indentation with a sharp indenter always probes a damaged version of the material, explaining the lower hardness and modulus values gained from nanoindentation. Micropillar tests were found to be mostly insensitive to such microdamage due to the lower applied strain and are therefore the suggested method for characterizing auxetic nanocomposites. STATEMENT OF SIGNIFICANCE: This work explores the micromechanical properties of limpet teeth, nature's strongest biomaterial, using micropillar compression testing and nanoindentation. The limpet tooth microstructure consists of ceramic nanorods embedded in a matrix of amorphous SiO 2 and arranged in a pattern that leads to local auxetic behavior. We report lower values for nanoindentation hardness than for compressive strength, a unique behavior usually not achievable in conventional materials. Utilizing micromechanical finite element simulations, we identify the reason for this behavior to be microdamage formation resultant of the auxetic behavior, sharp indenter tip and lack of ductility of the limpet tooth microstructure. This formation of microdamage is not expected in micropillar compression tests due to lower locally imposed strain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Materials displaying negative Poisson's ratio, referred to as auxeticity, have been found in nature and created in engineering through various structural mechanisms. However, uniting auxeticity with high strength and high stiffness has been challenging. Here, combining in situ nanomechanical testing with microstructure-based modeling, we show that the leading part of limpet teeth successfully achieves this combination of properties through a unique microstructure consisting of an amorphous hydrated silica matrix embedded with bundles of single-crystal iron oxide hydroxide nanorods arranged in a pseudo-cholesteric pattern. During deformation, this microstructure allows local coordinated displacement and rotation of the nanorods, enabling auxetic behavior while maintaining one of the highest strengths among natural materials. These findings lay a foundation for designing biomimetic auxetic materials with extreme strength and high stiffness.

Nacre's superior mechanical properties and failure behavior are strongly orientation-dependent due to its brick-and-mortar microstructure. In this work, the anisotropic microscopic deformation and the resulting macroscopic mechanical properties are evaluated under different loading conditions. Our in situ transmission electron microscopy deformation experiments and finite element simulations reveal that nacre possesses enhanced indentation resistance along the direction normal to the tablets through delocalization of indentation-induced deformation by taking advantage of its layered structure. In addition, nacre's ability to recover from large deformations is observed. We study the strong loading direction dependence of nacre's macroscopic mechanical properties and elucidate the underlying microscopic deformation patterns in the tablets and the soft matrix. Particularly, its performance along the transverse direction is optimized to withstand the loading conditions in nature. We show the importance of the vertical matrix for the initial stiffness and fracture toughness of the composite. These findings provide guidelines for designing nacre-inspired artificial composites with enhanced mechanical properties. STATEMENT OF SIGNIFICANCE: Nacre is widely recognized as an excellent structural model for designing bio-inspired tough and strong artificial composites. Due to its brick-and-mortar microstructure, it exhibits loading direction-dependent mechanical behavior. In this contribution, we investigate the macroscopic mechanical properties and microscopic deformation behavior of nacre under different loading conditions by means of in situ TEM deformation tests and FE simulations. It is found that effective elastic moduli and microscopic deformation strongly depend on the loading direction. The organic matrix is highly deformable. The indentation resistance along the direction normal to tablets is enhanced via deformation delocalization. Our quantitative and qualitative results provide guidelines on optimizing the mechanical properties of nacre-inspired novel composites., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Tumor hypoxia is a major biological factor that drives resistance to chemotherapy and radiotherapy. We previously demonstrated that the pro-oxidative drug dihydroartemisinin (DHA) efficiently targeted normoxic and hypoxic cancer cells. Although well studied in normoxia, the mechanism behind DHA-mediated cytotoxicity in hypoxia is insufficiently explored. Here, we analyzed the effect of DHA in HCT116 wild type (wt) cells and in HCT116 Bax -/- Bak sh cells with a defective intrinsic apoptosis pathway. Normoxic HCT116 wt cells underwent apoptosis shortly after treatment with DHA. Autophagy-associated cell death contributes to short-term cytotoxicity of DHA in normoxia. These cells switched to an apoptosis- and autophagy-independent cell death after treatment with DHA in hypoxia and displayed similar long-term survival in response to DHA in normoxia and hypoxia. In HCT116 Bax -/- Bak sh cells, DHA induced cell cycle arrest shortly after treatment irrespective of oxygen levels. Later, HCT116 Bax -/- Bak sh cells induced a delayed cell death after treatment with DHA in hypoxia followed by return to normoxia, while treatment with DHA in normoxia was hardly toxic. We identified lower glutathione levels in hypoxic HCT116 cells which correlated with higher lipid peroxidation after treatment with DHA. Moreover, insufficient expression of Bax/Bak counteracted hypoxia-mediated downregulation of mitochondrial function, thereby adding to DHA-induced ROS production and lipid peroxidation in hypoxia. In summary, DHA-mediated cytotoxicity in normoxia depended on Bax/Bak expression, while cytotoxicity after treatment with DHA in hypoxia was regulated independently of Bax/Bak in HCT116 colorectal cancer cells., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The efficacy of radiotherapy depends not only on DNA damage but also on ROS production, both induced by ionizing radiation. Massive ROS production can induce cell death or activate protective pathways such as Keap1/Nrf2 pathway, which regulates intracellular cysteine availability through upregulation of SLC7A11, a subunit of xCT transporter, and subsequently glutathione synthesis, thus improving antioxidative defense. The anti-malaria drug dihydroartemisinin (DHA) shows anti-neoplastic potential. Previous publications suggested that DHA increased ROS production. We intended to enhance oxidative stress with DHA to improve the efficacy of radiotherapy. Therefore, we first analyzed the oxidative response to DHA in HCT116 colorectal and NCI-H460 lung adenocarcinoma cells. In response to DHA, we detected lipid peroxidation and protein oxidation, which resulted in mitochondrial damage and eventually in iron-dependent cell death. Concurrently, DHA activated Keap1/Nrf2 pathway in HCT116 cells, leading to increased SLC7A11 expression and glutathione level. In Keap1-mutant NCI-H460 cells, Nrf2 was constantly activated and responsible for high SLC7A11 and glutathione levels. Pancancer analysis revealed that lung cancer is the tumor entity with the most frequent Keap1 alterations. Although NCI-H460 cells reacted more refractory to DHA-induced cell death than HCT116 cells, eradication of clonogenic cells by DHA was more efficient in both cell lines when Keap1/Nrf2 pathway was inhibited. When applied simultaneously, radiotherapy and DHA more efficiently eradicated clonogenic cells than either therapy alone, but treatment schedule can mitigate the combinatory effect in HCT116 cells. In summary, DHA improved efficacy of radiotherapy, but treatment schedule must be considered with care especially in Keap1-wildtype cells., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Shark tooth enameloid is a hard tissue made up of nanoscale fluorapatite crystallites arranged in a unique hierarchical pattern. This microstructural design results in a macroscopic material that is stiff, strong, and tough, despite consisting almost completely of brittle mineral. In this contribution, we characterize and compare the enameloid microstructure of two modern lamniform sharks, Isurus oxyrinchus (shortfin mako shark) and Carcharias taurus (spotted ragged-tooth shark), based on scanning electron microscopy images. The hierarchical microstructure of shark enameloid is discussed in comparison with amniote enamel. Striking similarities in the microstructures of the two hard tissues are found. Identical structural motifs have developed on different levels of the hierarchy in response to similar biomechanical requirements in enameloid and enamel. Analyzing these structural patterns allows the identification of general microstructural design principles and their biomechanical function, thus paving the way for the design of bioinspired composite materials with superior properties such as high strength combined with high fracture resistance.

The most important demand of today's high-performance materials is to unite high strength with extreme fracture toughness. The combination of withstanding large forces (strength) and resistance to fracture (toughness), especially preventing catastrophic material failure by cracking, is of utmost importance when it comes to structural applications of these materials. However, these two properties are commonly found to be mutually exclusive: strong materials are brittle and tough materials are soft. In dental enamel, nature has combined both properties with outstanding success - despite a limited number of available constituents. Made up of brittle mineral crystals arranged in a sophisticated hierarchical microstructure, enamel exhibits high stiffness and excellent toughness. Different species exhibit a variety of structural adaptations on varying scales in their dental enamel which optimise not only fracture toughness, but also hardness and abrasion behaviour. Nature's materials still outperform their synthetic counterparts due to these complex structure-property relationships that are not yet fully understood. By analysing structure variations and the underlying mechanical mechanisms systematically, design principles which are the key for the development of advanced synthetic materials uniting high strength and toughness can be formulated. STATEMENT OF SIGNIFICANCE: Dental enamel is a hard protective tissue that combines high strength with an exceptional resistance to catastrophic fracture, properties that in classical materials are commonly found to be mutually exclusive. The biological material is able to outperform its synthetic counterparts due to a sophisticated hierarchical microstructure. Between different species, microstructural adaptations can vary significantly. In this contribution, the different types of dental enamel present in different species are reviewed and connections between microstructure and (mechanical) properties are drawn. By consolidating available information for various species and reviewing it from a materials science point of view, design principles for the development of advanced biomimetic materials uniting high strength and toughness can be formulated., Competing Interests: Declaration of Competing Interest The authors declare that they do not have any financial or nonfinancial conflict of interests., (Copyright © 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)