Caracterización de micro y nanopartículas magnéticas para aplicaciones biomédicas

El uso de Partículas Magnéticas (PMs), ya sea a escala micro o nano, como elementos auxiliares en el diagnóstico y tratamiento de enfermedades ha despertado un gran interés tanto en la comunidad científica como médica. Sin embargo, actualmente se le dá mayor énfasis a la fabricación de PMs sin considerar la futura aplicación médica. Bajo esta premisa, esta revisión pretende enfatizar la relevancia de un cambio en el sentido evolutivo del empleo de PMs en la biomedicina, esto es, que dependiendo de la aplicación médica se diseñe, fabrique y pruebe la mejor solución en función de la caracterización de propiedades magnéticas de los materiales y respuestas mecánicas, dinámicas, térmicas y temporales de las PMs. En consecuencia, se optimizará el avance en las aplicaciones médicas potenciales. Palabras Clave: Partículas Magnéticas, AGFM, Guiado, Focalización, Relajometría, Hipertermia

A method to obtain the thermal parameters and the photothermal transduction efficiency in an optical hyperthermia device based on laser irradiation of gold nanoparticles

Optical hyperthermia systems based on the laser irradiation of gold nanorods seem to be a promising tool in the development of therapies against cancer. After a proof of concept in which the authors demonstrated the efficiency of this kind of systems, a modeling process based on an equivalent thermal-electric circuit has been carried out to determine the thermal parameters of the system and an energy balance obtained from the time-dependent heating and cooling temperature curves of the irradiated samples in order to obtain the photothermal transduction efficiency. By knowing this parameter, it is possible to increase the effectiveness of the treatments, thanks to the possibility of predicting the response of the device depending on the working configuration. As an example, the thermal behavior of two different kinds of nanoparticles is compared. The results show that, under identical conditions, the use of PEGylated gold nanorods allows for a more efficient heating compared with bare nanorods, and therefore, it results in a more effective therapy

Generación de hipertermia magnética empleando campos magnéticos alternos aplicados en ferrofluídos, para aplicaciones biomédicas

Este trabajo es resultado del diseño, desarrollo e implementación de la sección de caracterización en hipertermia magnética que surge como parte de la propuesta al interior del Centro de Tecnología Biomédica (CTB (UPM)) de la Universidad Politécnica de Madrid para habilitar la plataforma de caracterización de micro y nanopartículas. El objetivo se orienta a estudiar los fenómenos físicos que se presentan al exponer un ferrofluído magnético, enfocándose a posibles aplicaciones como el tratamiento para la eliminación de tejido canceroso, liberación de fármacos, etc., todo ello con la intención de proponer una nueva técnica de estudio que dependa de la configuraciones de excitación. La actualidad en el área de hipertermia magnética indica que una línea de investigación con oportunidad es la generación de señales con variación de frecuencia y forma; para ello se diseñaron y pusieron en marcha los elementos necesarios para generar hipertermia basada en el magnetismo, esto se realizó en el Laboratorio de Bioinstrumentación y Nanotecnología del CTB. Se propone la utilización de un dispositivo capaz de aplicar un rango de frecuencias que van de 100KHz hasta 2MHz (inexistente en el mercado), situación que permite versatilidad y a su vez aplicar distintas configuraciones en la señal de excitación encargada de producir el campo magnético alterno. Conociendo las virtudes que el equipo ofrece se ha realizado un estudio detallado aplicando 5 frecuencias: 200KHz, 400KHz, 600KHz, 800 KHz y 1MHz; aplicando distinta configuración de señales de excitación, para buscar diferencias en los fenómenos físicos presentes al compararlas con la sinusoidal, la cual es comúnmente utilizada en los equipos existentes en el mercado. El estudio se ha realizado detalladamente, estudiando tanto la configuración inicial de la señal, llevando un estricto control entre los parámetros que ofrece el equipo con respecto a la corriente, magnitud de campo, y otros; analizando la respuesta térmica del ferrofluído y desarrollando un análisis matemático. Los cambios de temperatura en la hipertermia magnética son explicados por dos fenómenos que se definen con el tiempo de Brown y de Néel; sin embargo este estudio se ha enfocado en observar si la trayectoria de las líneas de campo producidas por una señal de excitación distinta a la sinusoidal producen una respuesta magnética distinta en las nanopartículas con características superparamagnéticas. El estudio se llevó a cabo empleando nanopartículas de magnetita (Fe3O4) suspendidas en agua en una densidad de 100 mg/ml. La intensidad de campo magnético empleado varía de 0,1 ± 0,015 KA / m a 0,6 ± 0,015 KA / m. Los resultados dieron pauta para comprender que la pérdida de potencia depende de la frecuencia aplicada, así como que la normalización de la pérdida de potencia con respecto a la amplitud del campo magnético es mucho más alta para corrientes bajas que para corrientes altas. Lo anterior permite vislumbrar un nuevo camino para el uso de la técnica propuesta de cara a su uso en la medicina. ----------ABSTRACT---------- This work is the result of the design, development and implementation of the characterization in magnetic hyperthermia section that emerges as part of the proposal within the Center for Biomedical Technology (CTB), which is part of the Polytechnic University of Madrid (UPM) to enable the characterization platform of micro and nanoparticles. The goal is to study the physical phenomena that occur when a ferrofluid is exposed to an alternating magnetic field, focusing on possible applications such as the treatment for the removal of cancerous tissue, drug release, etc., all with the intention of proposing a new study technique that depends on the excitation configurations. The current situation in the area of magnetic hyperthermia indicates that a research line is the generation of signals with frequency and shape variation; for this purpose, the basic elements to generate hyperthermia based on magnetism were designed and implemented, this was done in the Laboratory of Bioinstrumentation and Nanotechnology of the CTB. It proposes the use of a device capable of applying a range of frequencies from 100KHz to 2MHz (non-existent in the market), a situation that allows versatility and in turn applies different configurations in the excitation signal, which is responsible for producing the alternating magnetic field. Knowing the virtues that the device offers, a detailed study has been carried out applying 5 frequencies: 200KHz, 400KHz, 600KHz, 800 KHz and 1MHz; applying different configurations of excitation signals, to look for differences in the physical phenomena when comparing them with the sinusoidal, which is commonly used in the existing equipment in the market. The study has been done in detail, studying the initial configuration of the signal, taking a strict control between the parameters that the equipment offers with respect to current, field magnitude, and others; analyzing the thermal response of ferrofluid and developing a mathematical analysis. The changes of the temperature in magnetic hyperthermia are explained by two phenomena defined by Brown and Neel; however this study has focused on observing if the trajectory of the field lines produced by a signal of excitation other than the sinusoidal produces a different magnetic response in the nanoparticles with superparamagnetic characteristics. The study was carried out using nanoparticles of magnetite (Fe3O4) suspended in water at a density of 100 mg / ml. The magnetic field strength employed ranges from 0.1 ± 0.015 KA / m to 0.6 ± 0.015 KA / m. The results gave a guideline to understand that the power loss depends on the frequency applied, as well as the normalization of power loss with respect to the amplitude of the magnetic field is much higher for low currents than high currents. This allows us to glimpse a new path for the use of the technique proposed for its use in medicine

Research lines in Hyperthermia at the Bioinstrumentation Laboratory of the Centre for Biomedical Technology

The Bioinstrumentation Laboratory belongs to the Centre for Biomedical Technology (CTB) of the Technical University of Madrid and its main objective is to provide the scientific community with devices and techniques for the characterization of micro and nanostructures and consequently finding their best biomedical applications. Hyperthermia (greek word for “overheating”) is defined as the phenomenon that occurs when a body is exposed to an energy generating source that can produce a rise in temperature (42-45ºC) for a given time [1]. Specifically, the aim of the hyperthermia methods used in The Bioinstrumentation Laboratory is the development of thermal therapies, some of these using different kinds of nanoparticles, to kill cancer cells and reduce the damage on healthy tissues. The optical hyperthermia is based on noble metal nanoparticles and laser irradiation. This kind of nanoparticles has an immense potential associated to the development of therapies for cancer on account of their Surface Plasmon Resonance (SPR) enhanced light scattering and absorption. In a short period of time, the absorbed light is converted into localized heat, so we can take advantage of these characteristics to heat up tumor cells in order to obtain the cellular death [2]. In this case, the laboratory has an optical hyperthermia device based on a continuous wave laser used to kill glioblastoma cell lines (1321N1) in the presence of gold nanorods (Figure 1a). The wavelength of the laser light is 808 nm because the penetration of the light in the tissue is deeper in the Near Infrared Region. The first optical hyperthermia results show that the laser irradiation produces cellular death in the experimental samples of glioblastoma cell lines using gold nanorods but is not able to decrease the cellular viability of cancer cells in samples without the suitable nanorods (Figure 1b) [3]. The generation of magnetic hyperthermia is performed through changes of the magnetic induction in magnetic nanoparticles (MNPs) that are embedded in viscous medium. The Figure 2 shows a schematic design of the AC induction hyperthermia device in magnetic fluids. The equipment has been manufactured at The Bioinstrumentation Laboratory. The first block implies two steps: the signal selection with frequency manipulation option from 9 KHz to 2MHz, and a linear output up to 1500W. The second block is where magnetic field is generated ( 5mm, 10 turns). Finally, the third block is a software control where the user can establish initial parameters, and also shows the temperature response of MNPs due to the magnetic field applied [4-8]. The Bioinstrumentation Laboratory in collaboration with the Mexican company MRI-DT have recently implemented a new research line on Nuclear Magnetic Resonance Hyperthermia, which is sustained on the patent US 7,423,429B2 owned by this company. This investigation is based on the use of clinical MRI equipment not only for diagnosis but for therapy [9]. This idea consists of two main facts: Magnetic Resonance Imaging can cause focal heating [10], and the differentiation in resonant frequency between healthy and cancer cells [11]. To produce only heating in cancer cells when the whole body is irradiated, it is necessary to determine the specific resonant frequency of the target, using the information contained in the spectra of the area of interest. Then, special RF pulse sequence is applied to produce fast excitation and relaxation mechanism that generates temperature increase of the tumor, causing cellular death or metabolism malfunction that stops cellular divisio

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research