Lens-free interferometric microscope for transparent materials

Roland Terborg

Dr. Valerio Pruneri

As health systems combat epidemics and infectious diseases, new forms of diagnostics must be developed to meet the growing demand for services, often in places without the necessary infrastructure. An emerging solution to this problem are Point of Care (POC) devices, which can provide rapid diagnostics without the need for specialized personnel or complex infrastructure. In this thesis, we demonstrate the development of a POC platform for the rapid and early detection of infections, in particular Sepsis, a whole-body inflammatory reaction with high mortality rates. The main components of this platform are: a lens-less interferometric microscope (LIM) and a microfluidic cartridge with a functionalized plasmonic chip for biomarker detection, free of additional markers. The LIM is also capable of measuring phase modulation in commercial plasmonic chips. More specifically, the thesis describes: • The development of the LIM with a large field of view and a large depth of field showing a sensitivity of 1nm along the beam propagation axis, which allows, for example, the measurement of ultrathin (2nm thick) and transparent silica microarrays and protein monolayers. • The generation of periodically structured light beams, obtained using a simple configuration that includes the LIM's birefringent elements. These can be applied not only to the detection of images and biomarkers, but also to additive manufacturing and surface microstructuring. • The phase measurement on commercial chips using surface plasmon resonance for the detection of changes in the refractive index of liquids. Phase measurements provide a sensitivity for refractive index changes that is approximately an order of magnitude higher than by intensity-based detection, under similar conditions. These results show a potential improvement in the sensitivity of standard systems used by the biomedical community. • The development of a POC device that comprises the LIM as a reader of gold plasmonic chips with specifically designed nano-hole arrays. The reading of the phase signal with the LIM shows an increase of an order of magnitude in sensitivity thanks to the enhanced interaction by localized surface plasmon resonance. Low concentrations of proteins and bacteria (as low as a single bacterium) are detected in real measurements, even in human samples. This platform has the potential to multiplex the signal for the simultaneous detection of thousands or even millions of different biomarkers. The LIM presented in this thesis is a highly sensitive, robust and high-throughput imaging system for the detection of small amounts of transparent materials (such as silica, proteins and bacteria), with applications in microscopy and biomedicine.

The LIM technology, which has been the main outcome of my doctoral thesis, is highly sensitive and robust, but at the same time simple and versatile. In the first tests at Hospital de Vall d'Hebrón, the LIM has shown a great potential as a point-of-care platform far the rapid diagnose of Sepsis. At ICFO's Innova,tion LaunchPad we are pushing the technology towards the market and expect to enter it within the next 3 years. The proposed platform will have a high impact in both, the economic and the social aspects

Health Systems; Epidemics; Infectious Diseases; Diagnostics; Growing Demand; Infrastructure; Point of Care (POC) Devices; Rapid Diagnostics; Specialized Personnel; Complex Infrastructure; POC Platform; Rapid Detection; Early Detection; Sepsis; Whole-Body Inflammatory Reaction; High Mortality Rates; Lens-less Interferometric Microscope (LIM); Microfluidic Cartridge; Functionalized Plasmonic Chip; Biomarker Detection; Marker-Free; Phase Modulation; Commercial Plasmonic Chips; Large Field of View; Large Depth of Field; Sensitivity; Beam Propagation Axis; Ultrathin Silica Microarrays; Transparent Silica Microarrays; Protein Monolayers; Periodically Structured Light Beams; Birefringent Elements; Image Detection; Biomarker Detection; Additive Manufacturing; Surface Microstructuring; Phase Measurement; Surface Plasmon Resonance (SPR); Refractive Index Changes; Intensity-Based Detection; Improved Sensitivity; Biomedical Community; Gold Plasmonic Chips; Nano-hole Arrays; Localized Surface Plasmon Resonance; Enhanced Interaction; Low Concentrations; Proteins; Bacteria Detection; Single Bacterium Detection; Human Samples; Multiplexed Signal; Simultaneous Detection; Thousands of Biomarkers; Millions of Biomarkers; Highly Sensitive Imaging System; Robust Imaging System; High-Throughput Imaging System; Small Amounts of Transparent Materials; Microscopy; Biomedicine.