PLASMONICS FOR HEALTHCARE & FUNDEMENTAL RESEARCH

PLASMONIC HAND-HELD BIOSENSORS FOR FIELD SETTINGS

In the conventional spectrometer-based read-out schemes utilize refractive index sensing, where the presence of the biomolecules is measured by monitoring spectral shifts within the optical response of the plasmonic structures. These platforms can enable analyte sensing i.e., viruses or bacteria, from biological media at clinically relevant concentrations with little to no sample preparation. Multiplexing and high-throughput capability of the biosensors can be improved via integrating large scale and highly dense plasmonic chips to imaging based platforms, i.e., CCD/CMOS cameras. This biosensors can be portable to be employed in the resource-poor settings by integrating plasmonic chip technology with lensfree telemedicine technology. This handheld design can be integrated with portable read-out-devices, e.g., a laptop or a cell-phone, which enables detection of biomolecules with a multiplexed manner in any environment lack of medical infrastructure. This system can also enable parallel detection of different biomolecules with ultra-thin layers as well as quantitative analyses of single-type biomolecules with large variety of concentrations.

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Cetin et al. Light: Science & Applications, 3, e122 (2014).

Cetin et al. Plasmonics, 12, 655 (2017).

Yanik et al. PNAS, 108, 11784 (2011).

Eksioglu et al. Plasmonics, 11, 851 (2016).

PLASMONICS FOR ULTRA-SENSITIVE BIODETECTION

The process of developing biosensors requires fundamental research on plasmonics so that new functionalities can be achieved that are not available with the conventional approaches. We utilize nanoplasmonics to develop ultra-sensitive spectroscopy and sensing technologies for real-time, label-free and high-throughput detection and analysis of very low quantities of biomolecules. In order to achieve large sensitivities, high-quality factor plasmonic structures supporting extremely sharp spectral features are explored, i.e., Fano-interference. High aspect-ratio plasmonic systems utilizing conducting layer could also support more advantageous far- and nearfield responses compared to their conventional counterparts on dielectric substrate. The sensing platforms utilizing these plasmonic structures allows better analyte-field overlap, which leads strong spectroscopy and sensing signals, easily distinguishable by the detectors.

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Cetin et al. Optics Express, 19, 22607 (2011).

Cetin et al. ACS Nano, 6, 9989 (2012).

Yilmaz et al. ACS Nano, 8, 4547 (2014).

VIBRATIONAL SPECTROSCOPY WITH PLASMONICS

Nearfield enhancement capability of nano-antennas could be further improved through new fabrication techniques. For example, plasmonic nanorod antennas realized with a nanostencil lithography technique, where the finite gap between the stencil and the substrate results nm-sized gold nanoparticles around the antennas. These nanoparticles improve the absorption signals by interacting with rectangular antennas within small gap regions. We also introduced a gold nanoring antenna system, standing on silicon nitride nanopedestal. We showed that the highly enhanced nearfields localized along the interface between metal and dielectric layers become accessible, when introducing a nanopedestal underneath. This configuration supports much larger absorption signal enhancements compared to its classical counterparts fabricated directly on a dielectric substrate.

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Cetin et al. Applied Physics B, 118, 29 (2015).

Cetin et al. Advanced Optical Materials, 2, 866 (2014).

MICROFLUIDICS / PLASMONICS INTEGRATION

We investigate fluidic systems integrated with plasmonic chip technology for efficient analyte-delivery, yielding ultra-fast sensor response compared to the conventional fluidic systems based on a flow-over scheme. Integrating microfluidics with plasmonic handheld technology, we also demonstrated real-time analyses of protein-protein interaction kinetics in a cost-effective and high-throughput manner. Utilizing robust algorithms, the microfluidic technology allows to monitor biomolecular binding interactions at pMolar levels.

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Cetin et al. ACS Photonics, 2, 1167 (2015).

Huang, et al. Lab on a Chip, 13, 4842 (2013).

GROWTH RATE CYTOMETER FOR CANCER THERAPEUTIC SUSCEPTIBILITY

Detection of clinical functional response in a patient following treatment initiation is currently measured indirectly by imaging or direct measurement of tumor burden. However, these assessments are slow and clinical indicators are only useful for making post-hoc treatment decisions. In the ideal scenario, therapeutic functional assays would be used to guide selection of treatment that would induce response and thereby avoid problematic side effects from inefficacious therapies. A straightforward approach for assaying single cell growth would be to seed individual cells in wells and monitor proliferation before and after delivery of a drug by microscopy. While this would be an improvement over bulk assays, a statistically robust proliferation assay requires large sample sizes and several cell doublings. Such an approach is problematic for most primary cells, which will not proliferate ex vivo, and even those cells that proliferate are subpopulations that do not necessarily represent the bulk. In order to address these problems, we have developed an approach that functionally assesses the therapeutic sensitivity of single cancer cells based on mass accumulation which is a property fundamentally linked to cell growth, as cell division requires the accumulation of biomass. The approach involves weighing individual cells repeatedly over a 15-minute period in a suspended microchannel resonator (SMR), either in the presence or absence of cancer therapeutics. Following the incubation of tumor cells with drug, the SMR can detect changes in the growth of single cells to predict therapeutic response without the need for extended culture. Recently, we have performed successful tests with the SMR technology on traditional cancer cell lines, patient-derived cell lines and primary cells.

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Cetin et al. Nature Communications, 8, 1613 (2017).

NOVEL NANO-FABRICATION TECHNIQUES

We introduced nano-manufacturing techniques which are highly advantageous over the conventional methods for fabrication of plasmonic structures. We introduced a high-throughput and lift-off free fabrication method based on deep ultraviolet (UV) lithography for nano-aperture designs. Compared to electron-beam lithography based fabrication techniques where lithography is sequentially applied on each chip, UV lithography could be performed on a whole silicon wafer which dramatically improves throughput. This fabrication method significantly reduces the manufacturing costs without losing the optical quality of the nano-structures. We also introduced a fabrication approach, which is highly suitable to fabricate high-aspect ratio nano-antennas. The approach is based on the assembly of nm-sized metallic nano-particles into the nano-vias by applying a potential between two parallel electrodes. Since this technique does not require a lift-off step, we can exploit the full thickness of the e-beam resist and fabricate tall nano-antennas relatively easily. This technique also allows the realization of multilayer metamaterials consisting of both metal and dielectric in different complex shapes.

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Coskun et al. Scientific Reports, 4, 6789 (2014).

Yilmaz et al. ACS Nano, 8, 4547 (2014).

ACTIVE PLASMONICS

For biosensing applications, it is critical to have optical responses at desired wavelengths for maximizing sensing signals. Recently, we introduced actively controlled plasmonic platforms that utilize materials with refractive indices, tunable with external mechanisms. For example, we developed an active plasmonic system, consisting of nanohole arrays integrated with a thermally controlled liquid crystal (LC) medium. The system shows extreme spectral tuning capabilities within a small temperature range by accessing different LC phases, i.e., nematic or isotropic. We also introduced electrically tunable plasmonic platforms, i.e., where the resonators operate both as a resonator and a field generator. The applied electric field orienting the LC molecules along the direction of the radial axis, yielding strong refractive index modulation compared to the classical ring resonators with two electrode configuration on side, where the modulation is only due to the partial alignment of LC molecules and the polarization of the electromagnetic excitations.

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Cetin et al. Physical Review A, 043812 (2010).

Cetin et al. Advanced Optical Materials, 1, 915 (2013).

Miquel et al. Advanced Optical Materials, 4, 1060 (2016).

PLASMONICS FOR CANCER IMMUNOTHERAPY

Toward a new route to application of plasmonics to ultra-sensitive cancer immunotherapy, we introduced a platform for adoptive cell transfer (ACT). Cancer immunotheraphy has emerged in the last decades as an alternative treatment for cancer, especially in metastatic and advanced stages. Efficiency of ACT therapy relies on exceptional ability of T-cells to target and kill cancer cells. T-cell recognition of cancer occurs when T-cell receptor (TCR) specifically interact with the peptide major histocompatibility complex (pMHC) of antigen-presenting cells. Our technology exploits plasmonic nanohole sensors that can evaluate TCR-pMHC interaction affinity and kinetics at clonal level. The system is composed of nanohole sensors functionalized with streptavidin for capturing pMHC and a Microwell, where CD8+ T cells are immobilized. T-cells are stained with NTAmers containing biotinylated pMHC. Upon addition of imidazole, NTAmers disintegrate leaving the pMHC monomers, which starts the natural dissociation from the cells. Spectral variations for the plasmonic response corresponding to the stained T-cell are clearly distinct from those of non-stained ones (cells without biotinylated pMHC), due to the capture of the pMHC disassociated from T-cells. This platform could be an alternative for ex-vivo cellular analysis and an ideal candidate for adoptive ACT immunotherapy.

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LIGHT SHAPING AND CONTROLLING VIA PLASMONICS

We introduced metallic nanoslit configurations enabling light focusing and scanning. In a symmetric 3-nanorod configuration, the focal position of the transmitted beam can be variable within a 0.5 - 3.5 um range. In a ladder configuration of rods, the transmitted beam can be deflected up to 23°. Horizontal displacement of rods allows fine-control of angular scanning up to 4°. We also proposed an all-optical method to actively control transmission of nanoslit arrays for scanning and lensing applications by two lateral control slits, where the whole system behaves like a T-junction.

Cetin et al. Photon. Nanostruct. Fund. App. 8, 7 (2010).

Cetin et al. Optics Letter, 35, 1980 (2010).

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