Nanoparticles and alloys for therapeutical and structural biomedical applications.

This thesis addresses 2 challenges in biomaterials research: 1) diffusion phenomena in Ti-Al-Nb alloys as materials for structural applications; and 2) the development of magnetic hyperthermia therapies against cancer more efficient and less invasive. Both challenges share a characteristic physical ground, which is the guideline of this work: they are based on transfer phenomena, mass transfer in the first case, and heat transfer in the second.Biomaterials research has been in an ascendant trend over the last decades. In biomedical applications, the first thing to be taken into consideration is biocompatibility. This property together with high specific strength, and good corrosion resistance has made titanium and its alloys the preferred materials for structural applications in the human body. Moreover, they have also been widely used in other fields like aerospace and marine industries. The composition of alloys is the most basic parameter that determines their properties. For instance, compared with the conventional Ti-6Al-4V alloy, some vanadium free titanium alloys like Ti-Al-Nb alloys, have higher fatigue strength, lower modulus of elasticity, and improved biocompatibility. All these properties are closely related to their microstructures that can be engineered by recovery, recrystallization, grain growth, transformation and precipitation. Furthermore, microstructural features can also be controlled to some extent by diffusion phenomena.Bibliometric studies show that in the uprising of Biomaterials research "Nanoparticles" has become the hottest topic after the turn of millennium. Indeed, nanotechnology, having been at the forefront of research for many years, has brought new genuine technical solutions in many different fields like biology, materials, electronics and medicine etc. One of the most exciting among them is that of therapeutical applications of nanoparticles (NPs), in which toxicity is also the main concern. For instance, in NP mediated magnetic hyperthermia for cancer therapy, only iron oxide nanoparticles (IONP), and particularly maghemite (-Fe2O3), are clinically accepted, in spite of existence of other materials like Co ferrite (CoFe2O4) that present clear advantages in terms of heating performance but show toxicity issues. Therefore, research efforts in this area have been mostly devoted to improve the performance of maghemite NPs by optimizing their structural parameters such as size, size distribution, shape, crystallinity, etc. There is however another polymorph of iron oxide, -Fe2O3, that has exceptional magnetic properties, but nevertheless has never been explored as a potential candidate for magnetic hyperthermia therapy.The idea of hyperthermia is to elevate the temperature of the tumor tissue over 42 ℃, in a selective way, to cause the apoptotic death of cancer cells. In order to heat selectively the tumor, it is peremptory to precisely monitor and control the temperature of the surrounding healthy tissue. Moreover, actual clinical magnetic hyperthermia technology uses massive direct injection of nanoparticles, which carries out some degree of invasiveness and toxicity issues. In order to avoid these problems and to expand the use of this technology in clinics, a new strategy has emerged that requires a reduced heat production. It is based on applying small amounts of heat but concentrated at certain intracellular regions that may lead to cancer cell apoptosis. To proof this hypothesis, it is first necessary to determine whether the heat produced by the MNPs is enough to generate large temperature gradients in small intracellular regions in the competition with heat dissipation process across the cell cytoplasm and then to the extracellular matrix. For this purpose, a non-invasive thermometric technique is required capable to determine local temperatures inside the cells with ultra-high spatial resolution. In this matter the use of lanthanide-based luminescent molecular thermometers can be a good option, as it will be shown in this thesis.This thesis is about: the diffusion phenomenon in the Ti-Al-Nb alloys, the hyperthermia performance of epsilon iron oxide nanoparticles, the fine-tuning of a ultra-high spatial and time resolution 2D temperature imaging system, the performance of Ln3+-bearing nanoparticles as nano-thermometry probes, obtaining intracellular temperature images, and the determination of temperature gradients in magnetic nanoparticles inside cancer cells under an ac magnetic field irradiation, and finally to investigate the validity of the local hyperthermia hypothesis.Chapter 1 will give a general introduction to the application of Titanium alloys and magnetic nanoparticles. The focus concerning titanium alloys will be put on diffusion phenomena, while in the case of magnetic nanoparticles, it will be mainly directed to magnetic hyperthermia and molecular nanothermometry.Chapter 2 contains the experimental section including methods, preparation and characterization of Titanium alloys, and magnetic and thermometric nanoparticle suspensions, and a description of the temperature imaging system.Chapter 3 is focused on diffusion phenomenon study of body centered cubic Ti-Al-Nb alloys by both experimental and computational methods, and the construction of a diffusion kinetic database. The experiments were conducted by the diffusion couple technique, and the computational work thereafter was accomplished by the DICTRA software.Chapter 4 and 5 demonstrates the hyperthermia performance of pure and Ga-doped epsilon iron oxide nanoparticles, in comparison with that of gamma iron oxide nanoparticles.Chapter 6 is dedicated to intracellular 2D temperature imaging and local magnetic hyperthermia by using Ln3+-bearing polymeric micelles.Chapter 7 is dedicated to the study of local hyperthermia by means of intracellular 2D temperature imaging of Ln3+-bearing iron oxide nanoparticles ac magnetic field application to cell cultures.<br /

Diffusion Research in BCC Ti-Al-Zr Ternary Alloys

Diffusion behavior in the BCC Ti-Al-Zr ternary alloys was experimentally investigated at 1273 K (1000 °C) and 1473 K (1200 °C) by means of the diffusion-couple technique. Upon the Whittle-Green and generalized Hall methods, the inter- and impurity diffusion coefficients were respectively extracted from the composition profiles acquired by the electron microprobe analysis (EPMA) and subsequently represented by the error function expansion. The extracted main interdiffusion coefficient D~AlAlTi increases with increasing the content of either Al or Zr, and the increase is appearing more considerably at the higher temperature. However, D~ZrZrTi was noticed to decrease with the increase of Al and Zr contents at 1273 K (1000 °C) while there is an upward trend at 1473 K (1200 °C). The impurity diffusion coefficients of Al in Ti-Zr binary alloys, DAl(Ti - Zr)*, and of Zr in Ti-Al binary alloys, DZr(Ti - Al)*, increase with increasing the Zr and Al contents respectively. A comparison of average main interdiffusion coefficient D~XXTi¯ made among ten Ti-Al-X ternary systems suggests that the Zr diffusion is most comparable to Cr and could operate via a vacancy-controlled mechanism

Real-time intracellular temperature imaging using lanthanide-bearing polymeric micelles

Measurement of thermogenesis in individual cells is a remarkable challenge due to the complexity of the biochemical environment (such as pH and ionic strength) and to the rapid and yet not well-understood heat transfer mechanisms throughout the cell. Here, we present a unique system for intracellular temperature mapping in a fluorescence microscope (uncertainty of 0.2 K) using rationally designed luminescent Ln3+-bearing polymeric micellar probes (Ln = Sm, Eu) incubated in breast cancer MDA-MB468 cells. Two-dimensional (2D) thermal images recorded increasing the temperature of the cells culture medium between 296 and 304 K shows inhomogeneous intracellular temperature progressions up to ∼20 degrees and subcellular gradients of ∼5 degrees between the nucleolus and the rest of the cell, illustrating the thermogenic activity of the different organelles and highlighting the potential of this tool to study intracellular processes.publishe

Luminescent temperature probes for real-time intracellular thermometry and magnetic hypertermia

Resumen del trabajo presentado a la XXXVIII Reunión Bienal de la Real Sociedad Española de Química, celebrada en el Palacio de Congresos de Granada, del 27 de junio al 30 de junio de 2022.This work was supported by the Spanish Ministry of Science Innovation and Universities [Grant No: PGC2018_095795_B_I00] and Diputación General de Aragón [E11/17R]. The support of the European Union's Horizon 2020 FET Open program under grant agreements No. 801305 (NanoTBTech) and 829162 (Hotzymes) is also acknowledged.Peer reviewe

Reply to the Comment on “Local Temperature Increments and Induced Cell Death in Intracellular Magnetic Hyperthermia"

Comentario.Peer reviewe

Whither Magnetic Hyperthermia? A Tentative Roadmap

The scientific community has made great efforts in advancing magnetic hyperthermia for the last two decades after going through a sizeable research lapse from its establishment. All the progress made in various topics ranging from nanoparticle synthesis to biocompatibilization and in vivo testing have been seeking to push the forefront towards some new clinical trials. As many, they did not go at the expected pace. Today, fruitful international cooperation and the wisdom gain after a careful analysis of the lessons learned from seminal clinical trials allow us to have a future with better guarantees for a more definitive takeoff of this genuine nanotherapy against cancer. Deliberately giving prominence to a number of critical aspects, this opinion review offers a blend of state-of-the-art hints and glimpses into the future of the therapy, considering the expected evolution of science and technology behind magnetic hyperthermia.This work was supported by the NoCanTher project, which has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 685795. The authors acknowledge support from the COST Association through the COST actions "RADIOMAG" (TD1402) and "MyWAVE" (CA17115). D.O., A.S.-O. and I.R.-R. acknowledge financial support from the Community of Madrid under Contracts No. PEJD-2017-PRE/IND-3663 and PEJ-2018-AI/IND-11069, from the Spanish Ministry of Science through the Ramon y Cajal grant RYC2018-025253-I and Research Networks RED2018-102626-T, as well as the Ministry of Economy and Competitiveness through the grants MAT2017-85617-R, MAT2017-88148R and the "Severo Ochoa" Program for Centers of Excellence in R&D (SEV-2016-0686). M.B. and N.T.K.T. would like to thank EPSRC for funding (grant EP/K038656/1 and EP/M015157/1) and AOARD (FA2386-171-4042) award. This work was additionally supported by the EMPIR program co-financed by the Participating States and from the European Union's Horizon 2020 research and innovation program, grant no. 16NRM04 "MagNaStand". The work was further supported by the DFG grant CRC "Matrix in Vision" (SFB 1340/1 2018, no 372486779, project A02)

Magnetic hyperthermia with ε-Fe2O3 nanoparticles

Biocompatibility restrictions have limited the use of magnetic nanoparticles for magnetic hyperthermia therapy to iron oxides, namely magnetite (Fe3O4) and maghemite (γ-Fe2O3). However, there is yet another magnetic iron oxide phase that has not been considered so far, in spite of its unique magnetic properties: ε-Fe2O3. Indeed, whereas Fe3O4 and γ-Fe2O3 have a relatively low magnetic coercivity, ε-Fe2O3 exhibits a giant coercivity. In this report, the heating power of ε-Fe2O3 nanoparticles in comparison with γ-Fe2O3 nanoparticles of similar size (∼20 nm) was measured in a wide range of field frequencies and amplitudes, in uncoated and polymer-coated samples. It was found that ε-Fe2O3 nanoparticles primarily heat in the low-frequency regime (20–100 kHz) in media whose viscosity is similar to that of cell cytoplasm. In contrast, γ-Fe2O3 nanoparticles heat more effectively in the high frequency range (400–900 kHz). Cell culture experiments exhibited no toxicity in a wide range of nanoparticle concentrations and a high internalization rate. In conclusion, the performance of ε-Fe2O3 nanoparticles is slightly inferior to that of γ-Fe2O3 nanoparticles in human magnetic hyperthermia applications. However, these ε-Fe2O3 nanoparticles open the way for switchable magnetic heating owing to their distinct response to frequency.This work was supported by European Union's Horizon 2020 FET Open program [Grants no: 801305 and 829162] Spanish Ministry of Science Innovation and Universities [Grant no: PGC2018_095795_B_I00] and Diputación General de Aragón [E11/17R]. Authors would like to acknowledge the use of Servicio General de Apoyo a la Investigación-SAI, Universidad de Zaragoza. This work was developed within the scope of the projects CoolPoint P2020-PTDC-CTMNAN-4511-2014 and CICECO-Aveiro Institute of Materials, UIDB/50011/2020 & UIDP/50011/2020, financed by national funds through the FCT/MEC and co-financed by FEDER under the PT2020 Partnership Agreement.We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).Peer reviewe

Nanoparticles and alloys for therapeutical and structural biomedical applications

This thesis addresses 2 challenges in biomaterials research: 1) diffusion phenomena in Ti-Al-Nb alloys as materials for structural applications; and 2) the development of magnetic hyperthermia therapies against cancer more efficient and less invasive. Both challenges share a characteristic physical ground, which is the guideline of this work: they are based on transfer phenomena, mass transfer in the first case, and heat transfer in the second. Biomaterials research has been in an ascendant trend over the last decades. In biomedical applications, the first thing to be taken into consideration is biocompatibility. This property together with high specific strength, and good corrosion resistance has made titanium and its alloys the preferred materials for structural applications in the human body. Moreover, they have also been widely used in other fields like aerospace and marine industries. The composition of alloys is the most basic parameter that determines their properties. For instance, compared with the conventional Ti-6Al-4V alloy, some vanadium free titanium alloys like Ti-Al-Nb alloys, have higher fatigue strength, lower modulus of elasticity, and improved biocompatibility. All these properties are closely related to their microstructures that can be engineered by recovery, recrystallization, grain growth, transformation and precipitation. Furthermore, microstructural features can also be controlled to some extent by diffusion phenomena. Bibliometric studies show that in the uprising of Biomaterials research "Nanoparticles" has become the hottest topic after the turn of millennium. Indeed, nanotechnology, having been at the forefront of research for many years, has brought new genuine technical solutions in many different fields like biology, materials, electronics and medicine etc. One of the most exciting among them is that of therapeutical applications of nanoparticles (NPs), in which toxicity is also the main concern. For instance, in NP mediated magnetic hyperthermia for cancer therapy, only iron oxide nanoparticles (IONP), and particularly maghemite (-Fe2O3), are clinically accepted, in spite of existence of other materials like Co ferrite (CoFe2O4) that present clear advantages in terms of heating performance but show toxicity issues. Therefore, research efforts in this area have been mostly devoted to improve the performance of maghemite NPs by optimizing their structural parameters such as size, size distribution, shape, crystallinity, etc. There is however another polymorph of iron oxide, -Fe2O3, that has exceptional magnetic properties, but nevertheless has never been explored as a potential candidate II for magnetic hyperthermia therapy. The idea of hyperthermia is to elevate the temperature of the tumor tissue over 42 ℃, in a selective way, to cause the apoptotic death of cancer cells. In order to heat selectively the tumor, it is peremptory to precisely monitor and control the temperature of the surrounding healthy tissue. Moreover, actual clinical magnetic hyperthermia technology uses massive direct injection of nanoparticles, which carries out some degree of invasiveness and toxicity issues. In order to avoid these problems and to expand the use of this technology in clinics, a new strategy has emerged that requires a reduced heat production. It is based on applying small amounts of heat but concentrated at certain intracellular regions that may lead to cancer cell apoptosis. To proof this hypothesis, it is first necessary to determine whether the heat produced by the MNPs is enough to generate large temperature gradients in small intracellular regions in the competition with heat dissipation process across the cell cytoplasm and then to the extracellular matrix. For this purpose, a non-invasive thermometric technique is required capable to determine local temperatures inside the cells with ultra-high spatial resolution. In this matter the use of lanthanide-based luminescent molecular thermometers can be a good option, as it will be shown in this thesis. This thesis is about: the diffusion phenomenon in the Ti-Al-Nb alloys, the hyperthermia performance of epsilon iron oxide nanoparticles, the fine-tuning of a ultra-high spatial and time resolution 2D temperature imaging system, the performance of Ln3+-bearing nanoparticles as nano-thermometry probes, obtaining intracellular temperature images, and the determination of temperature gradients in magnetic nanoparticles inside cancer cells under an ac magnetic field irradiation, and finally to investigate the validity of the local hyperthermia hypothesis.Peer reviewe

Diffusion research in HCP Mg–Al–Sn ternary alloys

Diffusion behavior in the HCP Mg–Al–Sn ternary alloys was experimentally investigated at 673 K and 723 K by analyzing solid-state diffusion couples. From the composition profiles analytically represented by error function expansion, the inter- and impurity diffusion coefficients were extracted by the Whittle-Green and generalized Hall methods respectively, which enable to establish the diffusion properties of the HCP Mg–Al–Sn alloys. The present results, together with the binary diffusion data of Mg–Al and Mg–Sn binaries, reveal that the average value of the main interdiffusion coefficient ~DMgSnSn over the investigated compositions is 1.39 times larger than ~DMgAlAl at 673 K and 1.36 times at 723 K, respectively, implying Sn diffuses comparably faster than Al in the HCP Mg–Al–Sn alloys. The main interdiffusion coefficients ~DMgAlAl and ​~DMgSnSn and the impurity diffusion coefficient D*Sn(Mg-Al) increases with increasing the content of diffusing element, either Al or Sn, however, D*Al(Mg-Sn) increases first and then decreases as the Sn composition increases. The cross interdiffusion coefficients are scattering, their composition dependences are not very conclusive, however, a trend that ~DMgAlSn and ~DMgSnA become negligibly small or even negative was evidenced as the content of Al or Sn approaches 0.The authors would like to acknowledge National Natural Science Foundation of China (Grant No. 51571113), Jiangsu Collaborative Innovation Center for Advanced Inorganic Function Composites, and Priority Academic Program Development of Jiangsu Higher Education Institution (PAPD).Peer reviewe

Ordered Mesoporous Ni-Fe-Al Catalysts for CO Methanation with Enhanced Activity and Resistance to Deactivation

A series of ordered mesoporous Ni-Fe-Al ternary oxide composites were prepared via a one-pot evaporation-induced self-assembly (EISA) method and applied in a CO methanation reaction to produce synthetic natural gas. The results showed that the ordered mesoporous Ni-Fe-Al catalyst with proper amount of Fe species (10N1FOMA) had better both CO conversion and CH4 selectivity than the impregnation-derived 10N1FA catalyst with unordered mesopores and identical component, owing to the higher Ni dispersion and larger H-2 uptake. In a 120 h atmospheric-pressure lifetime test, the ordered mesoporous 10N1FOMA catalyst showed significant enhancement in both antisintering and anticoking properties in comparison with the unordered mesoporous 10N1FA, mainly because of the confinement effect of the mesopore channels, the weak acidity of ordered mesoporous alumina support, and the smaller Ni particle size (&lt;5.0 nm).</p