Electric Field Bridging-Effect in Electrified Microfibrils’ Scaffolds

Introduction: The use of biocompatible scaffolds combined with the implantation of neural stem cells, is increasingly being investigated to promote the regeneration of damaged neural tissue, for instance, after a Spinal Cord Injury (SCI). In particular, aligned Polylactic Acid (PLA) microfibrils’ scaffolds are capable of supporting cells, promoting their survival and guiding their differentiation in neural lineage to repair the lesion. Despite its biocompatible nature, PLA is an electrically insulating material and thus it could be detrimental for increasingly common scaffolds’ electric functionalization, aimed at accelerating the cellular processes. In this context, the European RISEUP project aims to combine high intense microseconds pulses and DC stimulation with neurogenesis, supported by a PLA microfibrils’ scaffold. Methods: In this paper a numerical study on the effect of microfibrils’ scaffolds on the E-field distribution, in planar interdigitated electrodes, is presented. Realistic microfibrils’ 3D CAD models have been built to carry out a numerical dosimetry study, through Comsol Multiphysics software. Results: Under a voltage of 10 V, microfibrils redistribute the E-field values focalizing the field streamlines in the spaces between the fibers, allowing the field to pass and reach maximum values up to 100 kV/m and values comparable with the bare electrodes’ device (without fibers). Discussion: Globally the median E-field inside the scaffolded electrodes is the 90% of the nominal field, allowing an adequate cells’ exposure

Partitioning and Microdosimetry of Plutonium-239 and 55-Iron in Environmental Bacteria Grown in Liquid Cultures

The work presented herein provides quantitative data related to bacteria exposed in situ to two radionuclides relevant to nuclear sensing: plutonium-239 (239Pu) and iron-55 (55Fe). Originally motivated by the fundamental science underlying biosensing, liquid cultures of Pseudomonas putida and Escherichia coli were exposed to radionuclides over the course of 15-day experimental periods with the intent of gaining insight into the response of these bacteria. An essential component of characterizing or utilizing this response in a meaningful way is an understanding of the dose leading to that response. This dissertation narrows the knowledge gap associated with dose-response of microorganisms at environmentally relevant radionuclide concentrations through consideration of factors that influence the local dose, i.e., microdosimetry, experienced by the bacteria. These studies found that 239Pu accumulation in P. putida cells increased initially but plateaued after about 5 days, whether or not complexed with citrate. Moreover, 239Pu concentration in E. coli cells was greater than that in P. putida cells which may be the result of a stronger complexing agent made by E. coli for the purpose of Fe uptake. In cultures grown with 55Fe, over 75% of 55Fe was located in cell samples because of internal and external accumulation. When P. putida cultures were grown with 239Pu and 55Fe in combination, as well as 239Pu in combination with stable Fe, results indicate that 239Pu inhibited the uptake of 55Fe, and that the presence of Fe in cultures may promote pathways for Fe accumulation that are used by 239Pu. Finally, consideration of RNA extractions specifically suggested that 239Pu and 55Fe detected in RNA extraction samples is the result of binding to RNA prior to the time of extraction, as opposed to flow through or binding after cell lysis, and it highlights the practical importance of nucleic acid sample characterization to radiation protection, more generally. The work presented in this dissertation supports a more robust understanding of the behavior of 239Pu and 55Fe in bacteria systems and provides the groundwork necessary for the development of appropriate microdosimetric models for bacteria as well as more informed interpretation of transcriptomic analysis

Development and evaluation of low-dose rate radioactive gold nanoparticles for application in nanobrachytherapy

Depuis les dix dernières années, l’innovation des traitements d’oncologie a fait une utilisation croissante de la nanotechnologie. De nouveaux traitements à base de nanoparticules (NPs) sont notamment rendus au stade de l’essai clinique. Possédant des caractéristiques physico-chimiques particulières, les NPs peuvent être utilisées afin de bonifier l’effet thérapeutique des traitements actuels. Par exemple, l’amélioration de la curiethérapie (c.-à-d. radiothérapie interne) nécessite le développement de nouvelles procédures permettant de diminuer la taille des implants, et ce, tout en augmentant l’homogénéité de la dose déposée dans les tumeurs. Des études théoriques et expérimentales ont démontré que l’injection de NPs d’or à proximité des implants traditionnels de curiethérapie de faible débit de dose (par ex. 125I, 103Pd) permettrait d’augmenter significativement leur efficacité thérapeutique. L'interaction entre l’or et les photons émis par les implants de curiethérapie (c.-à-d. l’effet de radiosensibilisation) génère des rayonnements divers (photoélectrons, électrons Auger, rayons X caractéristiques) qui augmentent significativement la dose administrée. Dans le cadre de cette thèse, l’approche proposée était de développer des NPs d’or radioactives comme nouveau traitement de curiethérapie contre le cancer de la prostate. L’aspect novateur et unique était de synthétiser une particule coeurcoquille (Pd@Au) en utilisant l’isotope actuellement employé en curiethérapie de la prostate: le palladium-103 (103Pd, 20 keV). Dans ce cas-ci, la présence d’atomes d’or permet de produire l’effet de radiosensibilisation et d’augmenter la dose déposée. La preuve de concept a été démontrée par la synthèse et la caractérisation des NPs 103Pd@Au-PEG NPs. Ensuite, une étude longitudinale in vivo impliquant l’injection des NPs dans un modèle xénogreffe de tumeurs de la prostate chez la souris a été effectuée. L’efficacité thérapeutique induite par les NPs a été démontrée par le retard de la croissance tumorale des souris injectées par rapport aux souris non injectées (contrôles). Enfin, une étude de cartographie de la dose générée par les NPs à l’échelle cellulaire et tumorale a permis de comprendre davantage les mécanismes thérapeutiques liés aux NPs radioactives. En résumé, l’ensemble des travaux présentés dans cette thèse font office de précurseurs relativement au domaine de la nanocuriethérapie, et pourraient ouvrir la voie à une nouvelle génération de NPs pour la radiothérapie.The last decade saw the emergence of new innovative oncology treatments based on nanotechnology. New treatments using nanoparticles (NPs) are now translated to clinical trials. NPs possess unique physical and chemical properties that can be advantageously used to improve the therapeutic effect of current treatments. For instance, therapeutic efficiency enhancement related to internal radiotherapy (i.e., brachytherapy), requires the development of new procedures leading to a decrease of the implant size, while increasing the dose homogeneity and distribution in tumors. Several theoretical and experimental studies based on low-dose brachytherapy seeds (e.g., 125I and 103Pd) combined with gold nanoparticles (Au NPs) showed very promising results in terms of dose enhancement. Gold is a radiosensitizer that enhances the efficiency of radiotherapy by increasing the energy deposition in the surrounding tissues. Dose enhancement is caused by the photoelectric products (photoelectrons, Auger electrons, characteristic X-rays) that are generated after the irradiation of Au NPs. In this thesis, the proposed approach was to develop radioactive Au NPs as a new brachytherapy treatment for prostate cancer. The unique and innovative aspect of this strategy was to synthesize core-shell NPs based on the radioisotope palladium-103 (103Pd, 20 keV), which is currently used in low-dose rate prostate cancer brachytherapy. In this concept, the administrated dose is increased via the radiosensitization effect that is generated through the interactions of low-energy photons with the gold atoms. The proof-ofconcept of this approach was first demonstrated by the synthesis and characterization of the core-shell NPs (103Pd@Au-PEG NPs). Then, a longitudinal in vivo study following the injection of NPs in a prostate cancer xenograft murine model was performed. The therapeutic efficiency was confirmed by the tumor growth delay of the treated group as compared to the control group (untreated). Finally, a mapping study of the dose distribution generated by the NPs at the cellular and tumor levels provided new insights about the therapeutic mechanisms related to radioactive NPs. In summary, the studies presented in this thesis are precursors works in the field of nanobrachytherapy, and could pave the way for a new generation of NPs for radiotherapy

Nanomedicine applications mediated by electromagnetic fields

Recently, the introduction of nanotechnologies into medical applications has become more frequent due to the growing of several diseases originating from alteration of biological processes at molecular and nanoscale level (e.g. mutated genes, cell malfunction due to viruses or bacteria). The nanomedicine combines the innovation of the nanotechnology materials (shape and size of nm scale) to health care, providing new promising techniques for the diagnosis, the prevention, the tissue regeneration and therapeutic fields. Disorders like cancer, Alzheimer’s, Parkinson’s disease, cardiovascular problems or inflammatory diseases are serious challenges to be dealt with. For this reason researches are focusing their attention to the nanomaterials unique properties [Murty et al., 2013, Xia et al., 2009]. The progress in nanomedicine ranges from nanoparticles for molecular diagnostics, imaging and therapy to integrated medical nanosystems [Nune et al., 2009, Shi, 2009] to act at the cellular level inside the body. For a recent review on challenges, opportunities, and clinical applications in nanomedicine an interesting review is the one of Wicki et al. [Wicki et al., 2015]. Despite the concerns raised by the authors in their review, the expert opinion on clinical opportunities finds a generalized consensus on stimuli-responsive systems for targeting the compound (drug, gene, biomolecule) at the site of interest and on the use of lipid based nanosystems for the biocompatible platform to be used in clinical trials. In this scenario is placed the main activity of this Ph.D. thesis whose aim is to provide a multiscale and multidisciplinary approach to demonstrate the capability to activate lipid-based nanosystems by means of electromagnetic fields (EMFs). Specifically, the attention will be focused, on a first part, on the liposome-based systems mediated by EMF to provide a proof-of-concept of EMF stimuli-response systems for applications of drug delivery. This aspect will be approached both form a theoretic, technological and experimental point of view. Moreover, because proteins are considered a fundamental pattern as bio-sensors for signaling cell processes, a molecular dynamics simulation approach will be provided to study the interaction mechanisms between EMFs and proteins structures for potential protein activation

A New Model for Dose-Response Relations in Hadron Therapy: a Statistical Analysis of Hadron Therapy Data

In recent years, hadron therapy has become an increasingly popular cancer treatment alternative to conventional photon-based radiation. The distinct advantage of using proton or heavy ion radiation over other treatment modalities (x-rays) is the depositing of the desired dose directly onto a targeted tumour. This treatment avoids delivering lethal doses of radiation to the surrounding healthy and potentially radiation-sensitive tissues. The tissue sparing e ect of hadron therapy signi cantly improves the quality of life and minimises long-term health side-e ects in cancer patients from excessive radiation exposure. Understanding the response of a eukaryotic cell to ionising radiation is of vital importance in the eld. Many models have been developed to explain the response of a cell to ionising radiation, all of which are based on the Poisson count process. The most widely used model in the literature, the Linear-Quadratic model, is no exception. However, despite its wide use, the Linear-Quadratic model presents serious problems under statistical analysis and explaining the mid to high linear-energytransfer (LET) region of experimental data. In this study, we rst make use of rigorous statistical analyses of experimental world hadron therapy dose-response data to test the validity range of the Linear- Quadratic model under di erent radiation exposure and biological conditions. Our statistical analysis showed that it has a limited range of applicability and is restricted to the low to mid-LET region. Moreover, we demonstrated that it exhibits discrepancies under the considered regression analysis. To understand and explain these discrepancies, we make use of the TOPAS and Geant4 software toolkits to carry out a series of numerical simulations to study the dose-response relations by radiating V79 Chinese Hamster cells with a proton beam for a range of LET. Our analysis of the simulated data shows that the distribution of lethal damages per cell is overdispersed in the mid to high-LET range, violating the equidispersion condition of the Poisson process. However as the LET decreases, an overdispersed distribution of lethal damages approach to an equidispersed distribution, satisfying the Poisson condition. To explain the experimental and simulated data better, we proposed a new stochastic model based on a fractional Poisson count process which converges to the Poisson count process in the low-LET region. We rigorously tested our newly proposed model against the experimental and our simulated dose-response data and found that they are in excellent agreement. We showed that the distribution of lethal damages can be explained by a fractional Poisson process signi cantly better than the Poisson count process. The cell survival dose-response results exhibit a superior agreement with the Mittag-Le er distribution which corresponds to zero count events of the fractional Poisson process in all LET ranges for di erent cell lines and radiation types. The Mittag-Le er distribution predicts the DNA damage yield and therefore the relative biological e ectiveness extremely accurately. Compared with the Linear-Quadratic model, we demonstrated that our proposed model is superior.Thesis (MPhil) -- University of Adelaide, School of Physical Sciences, 202

Radiobiology Textbook:Space Radiobiology

The study of the biologic effects of space radiation is considered a “hot topic,” with increased interest in the past years. In this chapter, the unique characteristics of the space radiation environment will be covered, from their history, characterization, and biological effects to the research that has been and is being conducted in the field. After a short introduction, you will learn the origin and characterization of the different types of space radiation and the use of mathematical models for the prediction of the radiation doses during different mission scenarios and estimate the biological risks due to this exposure. Following this, the acute, chronic, and late effects of radiation exposure in the human body are discussed before going into the detailed biomolecular changes affecting cells and tissues, and in which ways they differ from other types of radiation exposure. The next sections of this chapter are dedicated to the vast research that has been developed through the years concerning space radiation biology, from small animals to plant models and 3D cell cultures, the use of extremophiles in the study of radiation resistance mechanisms to the importance of ground-based irradiation facilities to simulate and study the space environment