Medical research

Summary

Medical research (or biomedical research), also known as experimental medicine, encompasses a wide array of research, extending from "basic research" (also called bench science or bench research), – involving fundamental scientific principles that may apply to a preclinical understanding – to clinical research, which involves studies of people who may be subjects in clinical trials. Within this spectrum is applied research, or translational research, conducted to expand knowledge in the field of medicine. Both clinical and preclinical research phases exist in the pharmaceutical industry's drug development pipelines, where the clinical phase is denoted by the term clinical trial. However, only part of the clinical or preclinical research is oriented towards a specific pharmaceutical purpose. The need for fundamental and mechanism-based understanding, diagnostics, medical devices, and non-pharmaceutical therapies means that pharmaceutical research is only a small part of medical rese

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Analysis of photosensor frontends for biomedical applications: a focus on noise

Paul Stanislas Gosselin

Photosensing has proven to be highly useful in biomedical research and medical care. Being able to detect and quantify the light emitted by fluorescent or bioluminescent reporters has significantly participated in the development of new cancer treatments and made possible the development of cost-effective diagnosis techniques. While these advances relied on the large CCD devices or on laboratory-on-chips, the design of a bioluminescence-based implant for the continuous monitoring of biological data can be considered and would allow for the acquisition of insightful information in both research and care. To exist, such an implant requires a suited photosensing circuit, the design of which can be challenging due to the weakness of the target bioluminescent signal. This thesis addresses the design and evaluation of an appropriate analog-to-digital converter (ADC), with a focus on its expected accuracy. In particular, three integration-base current-to-frequency converters are considered: the current-controlled oscillator, the first-order Sigma-Delta converter with instantaneous feedback, the first-order Sigma-Delta converter with continuous feedback. Theoretical formulas are established to assess how the input-referred noise would impact the results from such ADCs, depending on the integration time as well as the time passed since last calibration. In addition to the general case, specific formulas are provided for white noise, flicker noise, and Lorentzian-shaped noise. Moreover, in practical cases that are conceivable with target application, these formulas cannot be used as they are due to the finite resolution of computing softwares. Consequently, the related implementation issues are addressed and solved. To guide the design of the current-to-frequency converters, how each of their imperfections affects their accuracy is analyzed in depth. This analysis and the obtained formulas serve a top-level-focused design strategy that is argued for in this thesis. It relies on maintaining a detailed top-level description of the system under study to help focus the designing efforts on the most impactful areas as well as guide the design choices at the transistor level. Applying such a strategy is made possible by the development of a MATLAB tool providing a flexible graphic user interface to explore the impact of each parameter of the design. In addition, to further assist the design of the ADC and/or of the photodetector, a Python tool is presented to explore configurations for successive simulations and data analyses, even when using multiple softwares. As an opening chapter, emphasizing the importance of considering the top-level in design, the case of heart rate monitoring through photoplethysmography is addressed. In this case, the highest level of the system includes the data processing, and only the latter can actually allow for drastic improvements of the power consumption by alleviating the requirements on the data acquisition. In fact, it is demonstrated that in many situations, the sampling frequency for the acquisition of the plethysmograph could be brought down to 10 to 25 Hz, while still ensuring a satisfying accuracy for the heart rate and heart rate variation monitoring.

EPFL2019

Hydrophilic Nanogels

Catherine Ann Schütz

Hydrophilic nanocarriers, formed by electrostatic interaction between their oppositely charged components, are recognized as nanomaterials with an enormous potential as vectors in biomedical and pharmaceutical applications. However, comprehensive information about their fate in various biological environments is still lacking. In general, due to their size, nanoparticles are able to enter and transport molecules into cells via pathways forbidden for bigger structures of even identical chemical nature. Research under defined conditions aiming at a better understanding of nanoparticle-cell interactions is crucial for the development of safe and successful nanocarriers for biomedical and pharmaceutical applications. Nanogels produced by electrostatic interaction of two types of the polysaccharide chitosan and pentasodium triphosphate were the subject of the research of this thesis. Additional surface coating with sodium alginate conferred to the nanogels a negatively charged surface enabling sufficient stability under physiological and in vivo relevant conditions. Of particular interest was the comparison of the two chitosan types, the first one obtained from usual animal sources while the second one became newly available from fungal sources. Prerequisite for the comparison in terms of nanogel formation, stability, interaction with cells and potential applications was the detailed analysis and characterization of the chitosan samples. The identification of almost identical degree of deacetylation, very similar molar mass distribution and solution behavior, but a somewhat higher molar mass of the animal chitosan as the only difference, allowed for a direct comparison. The animal and fungal derived chitosan samples yielded similar nanogels in relation to formation, size distributions and zeta potential. The nanogels were spherical with a hydrodynamic diameter in the range of 450 nm and a zeta potential of approx. -65 mV. The physical characteristics of the nanogels were clearly influenced by the ionic strength and temperature of the suspension. High deformability of the nanogel network was demonstrated by filtration through pores much narrower than the gel diameter. Temperature cycles in the range of 4°C to 37°C proved reversibility of size and zeta potential. The nanogels were stable in both simulated in vivo environment and in conditioned cell culture media. Exposure of seven human cancerous and non-cancerous cell lines to the nanogels, to identify the influence on the cell metabolic activity, revealed cell-type, nanogel dosage and exposure time dependence. However, nanogels prepared from animal and fungal chitosan showed similar behavior in vitro in all cell lines tested. The results obtained so far confirm fungal derived chitosan as an alternative to the animal derived chitosan. Nanogels carrying model protein antigen cargoes were taken up by porcine monocyte-derived dendritic cells, and kinetic analysis using an auto-quenched protein revealed a time-dependent endocytic processing of the nanogel cargo. These in vitro analyses were elaborated with an in vivo murine immunization experiment. Nanogels carrying ovalbumin (OVA) induced a dose-dependent antibody response over 6 weeks post-vaccination. An effective memory response was induced in nanogel-OVA immunized mice following a 0.1 µg OVA boost injection. Nanogels were also prepared carrying recombinant vaccine antigen against Neospora caninum. These induced a protective immune response following both intranasal and intraperitoneal vaccination in mice challenged with the tachyzoite form of the parasite. Overall, the results obtained in the framework of this research extend the knowledge on chitosan-based nanogels intended as nanocarriers for biomedical/pharmaceutical applications and contribute to further development of effective nanogel-based delivery systems.

EPFL2011

Stroke is a disease that causes the death of precious brain cells that will never grow back and which will affect one in four humans at some point in their life. While therapies and treatments for this debilitating condition are fairly standard, their outcomes are highly heterogeneous, with deficits all too often leading to permanent disability. These unsatisfactory outcomes point to the need for a paradigm shift towards precision medicine, where therapies and treatments are tailored to individual patients. This in turn requires a better understanding of the mechanisms underlying post-stroke impairment and recovery. Recent technological innovations provide an unprecedented opportunity to acquire a detailed picture of the anatomy and electrophysiology of the human brain non-invasively. Therefore, we apply multimodal methodologies to investigate the inner workings of the stroke-affected brain with a view to establishing biomarkers and creating stratifications that maximize the effectiveness of stroke therapy by making it personalized.In the first part of this thesis, network-theoretic models of the brain known as connectomes are created, under the assumption that these provide sufficiently detailed information about the individual patient to inform personalized recommendations. In particular, we leverage existing knowledge about how brain networks are organized into specialized modules connected by a "rich-club" of hubs. In a novel contribution to the field of connectomics, we combine these connectomes with detailed images of the lesion to obtain a network-theoretic lesion profile and a map of the non-lesioned part of the network, which we expect to be a better reflection of true brain connectivity. Using this methodology, we establish that the rich-club, in addition to being a source of network robustness, is also a source of vulnerability in that attacks against it lead to poor behavioral outcomes disproportionate to the size of the attacks.The creation of in-silico simulation of individual patients presents a great opportunity to quickly experiment with treatments, making it a potential game-changer in medical research. However, current technology is not able to faithfully capture the complexity of a whole human brain. The complex brain abnormalities inherent to stroke only add to the difficulty of the challenge. Any models one might wish to create must strike a balance between technological feasibility and sensitivity to inter-patient variability across a large parameter space. In the second part of this thesis, we investigate whether one major source of inter-patient variability, namely the size and location of the lesion, induces substantial variability in the effects of non-invasive brain stimulation to be included as factors in the design of stimulation protocols. Based on our modeling of the stimulation, personalizing stimulation protocols by taking the lesion into account produces little added value, except possibly when one is targeting brain areas close to the lesion and the lesion is significantly large.The proposed studies represent a step of the march towards precision medicine, by examining sources of variability in stroke patients and by associating them with variability in some outcomes of interest. Each step of this march brings stroke therapy farther from the status quo of homogeneous treatments and heterogeneous outcomes and closer to the ideal of heterogeneous treatments and homogeneously positive outcomes.

EPFL2022