Onur Tokel

Advances in Plasmonic Technologies for Point of Care Applications

Demand for accessible and affordable healthcare for infectious and chronic diseases present significant challenges for providing high-value and effective healthcare. Traditional approaches are expanding to include point-of-care (POC) diagnostics, bedside testing, and community-based approaches to respond to these challenges.1 Innovative solutions utilizing recent advances in mobile technologies, nanotechnology, imaging systems, and microfluidic technologies are envisioned to assist this transformation. Infectious diseases have considerable economic and societal impact on developing settings. For instance, malaria is observed more commonly in sub-Saharan Africa and India.2 The societal impact of acquired immune deficiency syndrome (AIDS) and tuberculosis is high, through targeting adults in villages and leaving behind declining populations.3 In resource-constrained settings, it is estimated that about 32% of the disease burden is from communicable diseases such as respiratory infections, AIDS, and malaria, while 43% of the burden is from noncommunicable diseases, such as cardiovascular diseases, neuropsychiatric conditions, and cancer.4 Developing diagnostic platforms that are affordable, robust, and rapid-targeting infectious diseases is one of the top priorities for improving healthcare delivery in the developing world.5 The early detection and monitoring of infectious diseases and cancer through affordable and accessible healthcare will significantly reduce the disease burden and help preserve the social fabric of these communities. Further, improved diagnostics and disease monitoring technologies have potential to enhance foreign investment, trade, and mobility in the developing countries.6 Highly sensitive and specific lab assays such as cell culture methods, polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay (ELISA) are available for diagnosis of infectious diseases in the developed world. They require sample transportation, manual preparation steps, and skilled and well-trained technicians. These clinical conventional methods provide results in several hours to days, precluding rapid detection and response at the primary care settings. Another diagnostic challenge is identifying multiple pathogens. Since common symptoms like sore throat and fever can be caused by multiple infectious agents (e.g., bacteria and viruses), it is important to accurately identify the responsible agent for targeted treatment. Therefore, high-throughput sensors for multiplexed identification would help improve patient care.7 Medical instruments in centrally located institutions in the developed world rely on uninterrupted electricity and running water and require controlled environmental conditions. It may not be viable to satisfy some of these criteria in some POC settings, where well-trained healthcare personnel are not available and clean water access is unreliable.7,8 Further, in remote settings without infrastructure, rain and dust can act as contaminants.7 Diagnostic devices for POC testing in these settings are identified by the World Health Organization to be affordable, sensitive, user-friendly, specific to biological agents, and providing rapid response to small sample volumes.9 Optical biosensor devices are emerging as powerful biologic agent detection platforms satisfying these considerations.10 Optical sensing platforms employ various methods, including refractive index change monitoring, absorption, and spectroscopic-based measurements.11 Optical sensors that are based on refractive index monitoring cover a range of technologies, including photonic crystal fibers, nano/microring resonator structures, interferometric devices, plasmonic nano/micro arrays, and surface plasmon resonance (SPR)-based platforms.11,12 The latter two are plasmonic-based technologies. Plasmonics is an enabling optical technology with applications in disease monitoring, diagnostics, homeland security, food safety, and biological imaging applications. The plasmonic-based biosensor platforms along with the underlying technologies are illustrated in the Figure ​Figure1.1. Here, we reviewed SPR, localized surface plasmon resonance (LSPR), and large-scale plasmonic arrays (e.g., nanohole arrays). Figure 1 Plasmonic-based technologies for versatile biosensor applications. SPR stands for surface plasmon resonance, LSPR for localized surface plasmon resonance, SPRi for surface plasmon resonance imaging, and SERS for surface-enhanced Raman scattering.

Nanoplasmonic quantitative detection of intact viruses from unprocessed whole blood.

Infectious diseases such as HIV and hepatitis B pose an omnipresent threat to global health. Reliable, fast, accurate, and sensitive platforms that can be deployed at the point-of-care (POC) in multiple settings, such as airports and offices, for detection of infectious pathogens are essential for the management of epidemics and possible biological attacks. To the best of our knowledge, no viral load technology adaptable to the POC settings exists today due to critical technical and biological challenges. Here, we present for the first time a broadly applicable technology for quantitative, nanoplasmonic-based intact virus detection at clinically relevant concentrations. The sensing platform is based on unique nanoplasmonic properties of nanoparticles utilizing immobilized antibodies to selectively capture rapidly evolving viral subtypes. We demonstrate the capture, detection, and quantification of multiple HIV subtypes (A, B, C, D, E, G, and subtype panel) with high repeatability, sensitivity, and specificity down to 98 ± 39 copies/mL (i.e., HIV subtype D) using spiked whole blood samples and clinical discarded HIV-infected patient whole blood samples validated by the gold standard, i.e., RT-qPCR. This platform technology offers an assay time of 1 h and 10 min (1 h for capture, 10 min for detection and data analysis). The presented platform is also able to capture intact viruses at high efficiency using immuno-surface chemistry approaches directly from whole blood samples without any sample preprocessing steps such as spin-down or sorting. Evidence is presented showing the system to be accurate, repeatable, and reliable. Additionally, the presented platform technology can be broadly adapted to detect other pathogens having reasonably well-described biomarkers by adapting the surface chemistry. Thus, this broadly applicable detection platform holds great promise to be implemented at POC settings, hospitals, and primary care settings.

Portable Microfluidic Integrated Plasmonic Platform for Pathogen Detection

Timely detection of infectious agents is critical in early diagnosis and treatment of infectious diseases. Conventional pathogen detection methods, such as enzyme linked immunosorbent assay (ELISA), culturing or polymerase chain reaction (PCR) require long assay times, and complex and expensive instruments, which are not adaptable to point-of-care (POC) needs at resource-constrained as well as primary care settings. Therefore, there is an unmet need to develop simple, rapid, and accurate methods for detection of pathogens at the POC. Here, we present a portable, multiplex, inexpensive microfluidic-integrated surface plasmon resonance (SPR) platform that detects and quantifies bacteria, i.e., Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) rapidly. The platform presented reliable capture and detection of E. coli at concentrations ranging from ~105 to 3.2 × 107 CFUs/mL in phosphate buffered saline (PBS) and peritoneal dialysis (PD) fluid. The multiplexing and specificity capability of the platform was also tested with S. aureus samples. The presented platform technology could potentially be applicable to capture and detect other pathogens at the POC and primary care settings.

In-chip microstructures and photonic devices fabricated by nonlinear laser lithography deep inside silicon

Silicon is an excellent material for microelectronics and integrated photonics1–3, with untapped potential for mid-infrared optics4. Despite broad recognition of the importance of the third dimension5,6, current lithography methods do not allow the fabrication of photonic devices and functional microelements directly inside silicon chips. Even relatively simple curved geometries cannot be realized with techniques like reactive ion etching. Embedded optical elements7, electronic devices and better electronic–photonic integration are lacking8. Here, we demonstrate laser-based fabrication of complex 3D structures deep inside silicon using 1-µm-sized dots and rod-like structures of adjustable length as basic building blocks. The laser-modified Si has an optical index different to that in unmodified parts, enabling the creation of numerous photonic devices. Optionally, these parts can be chemically etched to produce desired 3D shapes. We exemplify a plethora of subsurface—that is, ‘in-chip’—microstructures for microfluidic cooling of chips, vias, micro-electro-mechanical systems, photovoltaic applications and photonic devices that match or surpass corresponding state-of-the-art device performances.By exploiting dynamics arising from nonlinear laser–material interactions, functional microelements and arbitrarily complex 3D architectures deep inside silicon are fabricated with 1 μm resolution, without damaging the silicon above or below.

Rich complex behaviour of self-assembled nanoparticles far from equilibrium

A profoundly fundamental question at the interface between physics and biology remains open: what are the minimum requirements for emergence of complex behaviour from nonliving systems? Here, we address this question and report complex behaviour of tens to thousands of colloidal nanoparticles in a system designed to be as plain as possible: the system is driven far from equilibrium by ultrafast laser pulses that create spatiotemporal temperature gradients, inducing Marangoni flow that drags particles towards aggregation; strong Brownian motion, used as source of fluctuations, opposes aggregation. Nonlinear feedback mechanisms naturally arise between flow, aggregate and Brownian motion, allowing fast external control with minimal intervention. Consequently, complex behaviour, analogous to those seen in living organisms, emerges, whereby aggregates can self-sustain, self-regulate, self-replicate, self-heal and can be transferred from one location to another, all within seconds. Aggregates can comprise only one pattern or bifurcated patterns can coexist, compete, endure or perish.

Buried waveguides written deep inside silicon

Silicon waveguides are widely used as optical interconnects and they are particularly important for Si-photonics. Si-based devices, along with other optical elements, are entirely fabricated on the top surface of Si wafers. However, further integration of photonic and electronic devices in the same chip requires a new approach. One alternative is to utilize the bulk of the wafer for fabricating photonic elements. Recently, we reported a direct-laser-writing method that exploits nonlinear interactions and can generate subsurface modifications inside silicon without damaging the surface [1]. Using this method, we fabricated several functional optical elements including gratings [1], lenses [2], and holograms [3]. In this work, we demonstrate optical waveguides entirely embedded in Si.

Laser-slicing of silicon with 3D nonlinear laser lithography

Recently, we have showed a direct laser writing method that exploits nonlinear interactions to form subsurface modifications in silicon. Here, we use the technique to demonstrate laser-slicing of silicon and its applications.

1.06μm–1.35μm Coherent pulse generation by a synchronously-pumped phosphosilicate Raman fiber laser

Rare-earth-doped fiber lasers are attractive for microscopy and imaging applications and have developed over the past decades rapidly. They are unable to cover near-infra-red region entirely and therefore Raman and parametric process are promising for producing new wavelengths which are out of emission band of the current fiber lasers.

Doppler effect on nanopatterning with nonlinear laser lithography

Just five years after invention of the laser, laser induced periodic structures (LIPSS) had been reported [1]. However, the structure period is not very uniform in LIPSS. Recently, with nonlinear laser lithography (NLL), long range ordered periodic surface structures had been maintained by exploiting various feedback mechanisms and nonlinearities [2]. Albeit, fine tuning of structure period remains challenging. Here, we present an analogy between Doppler effect and structure period of the NLL which adds a capability of changing the structure period.

Holograms Deep Inside Silicon

Through the Nonlinear Laser Lithography method, we demonstrate the first computer generated holograms fabricated deep inside Silicon. Fourier and Fresnel holograms are fabricated buried inside Si wafers, and a generation algorithm is developed for hologram fabrication.