Yunus Alapan

Extreme sensitivity biosensing platform based on hyperbolic metamaterials.

Optical sensor technology offers significant opportunities in the field of medical research and clinical diagnostics, particularly for the detection of small numbers of molecules in highly diluted solutions. Several methods have been developed for this purpose, including label-free plasmonic biosensors based on metamaterials. However, the detection of lower-molecular-weight (<500 Da) biomolecules in highly diluted solutions is still a challenging issue owing to their lower polarizability. In this context, we have developed a miniaturized plasmonic biosensor platform based on a hyperbolic metamaterial that can support highly confined bulk plasmon guided modes over a broad wavelength range from visible to near infrared. By exciting these modes using a grating-coupling technique, we achieved different extreme sensitivity modes with a maximum of 30,000 nm per refractive index unit (RIU) and a record figure of merit (FOM) of 590. We report the ability of the metamaterial platform to detect ultralow-molecular-weight (244 Da) biomolecules at picomolar concentrations using a standard affinity model streptavidin-biotin.

Heterogeneous Red Blood Cell Adhesion and Deformability in Sickle Cell Disease

We present a microfluidic approach that allows simultaneous interrogation of RBC properties in physiological flow conditions at a single cell level. With this method, we studied healthy hemoglobin A (HbA) and homozygous sickle hemoglobin (HbS) containing RBCs using whole blood samples from twelve subjects. We report that HbS-containing RBCs are heterogeneous in terms of adhesion and deformability in flow.

A multiband perfect absorber based on hyperbolic metamaterials.

In recent years, considerable research efforts have been focused on near-perfect and perfect light absorption using metamaterials spanning frequency ranges from microwaves to visible frequencies. This relatively young field is currently facing many challenges that hampers its possible practical applications. In this paper, we present grating coupled-hyperbolic metamaterials (GC-HMM) as multiband perfect absorber that can offer extremely high flexibility in engineering the properties of electromagnetic absorption. The fabricated GC-HMMs exhibit several highly desirable features for technological applications such as polarization independence, wide angle range, broad- and narrow- band modes, multiband perfect and near perfect absorption in the visible to near-IR and mid-IR spectral range. In addition, we report a direct application of the presented system as an absorption based plasmonic sensor with a record figure of merit for this class of sensors.

Enhancing the Angular Sensitivity of Plasmonic Sensors Using Hyperbolic Metamaterials

Surface plasmon resonance (SPR) sensors operate mainly on prism and grating coupling techniques, with spectral and angular scans being the two major interrogation schemes. Among them, the angular scan technique has several advantages including higher measurement precision owing to its higher signal-to-noise ratio. The currently available SPR sensor arrangements provide a maximum angular sensitivity of 500°-600° per RIU. Here, we report the study of grating coupled-hyperbolic metamaterial (GC-HMM) sensors with high angular sensitivity. The experimental studies show extraordinary angular sensitivities from visible to near infrared (NIR) wavelengths by exciting bulk plasmon polaritons associated with hyperbolic metamaterials, with a maximum of 7000° per RIU. This angular-scan plasmonic biosensor has been used for the detection of low molecular weight biomolecules such as biotin (244 Da) and high molecular weight macromolecules such as Cowpea mosaic virus (CPMV, 5.6 × 106 Da) at ultralow concentrations. The miniaturized sensing device can be integrated with microfluidic systems for the development of next-generation biosensors for lab-on-a-chip and point-of-care applications.

Three-Dimensional Printing Based Hybrid Manufacturing of Microfluidic Devices

Microfluidic platforms offer revolutionary and practical solutions to challenging problems in biology and medicine. Even though traditional micro/nanofabrication technologies expedited the emergence of the microfluidics field, recent advances in advanced additive manufacturing hold significant potential for single-step, stand-alone microfluidic device fabrication. One such technology, which holds a significant promise for next generation microsystem fabrication is three-dimensional (3D) printing. Presently, building 3D printed stand-alone microfluidic devices with fully embedded microchannels for applications in biology and medicine has the following challenges: (i) limitations in achievable design complexity, (ii) need for a wider variety of transparent materials, (iii) limited z-resolution, (iv) absence of extremely smooth surface finish, and (v) limitations in precision fabrication of hollow and void sections with extremely high surface area to volume ratio. We developed a new way to fabricate stand-alone microfluidic devices with integrated manifolds and embedded microchannels by utilizing a 3D printing and laser micromachined lamination based hybrid manufacturing approach. In this new fabrication method, we exploit the minimized fabrication steps enabled by 3D printing, and reduced assembly complexities facilitated by laser micromachined lamination method. The new hybrid fabrication method enables key features for advanced microfluidic system architecture: (i) increased design complexity in 3D, (ii) improved control over microflow behavior in all three directions and in multiple layers, (iii) transverse multilayer flow and precisely integrated flow distribution, and (iv) enhanced transparency for high resolution imaging and analysis. Hybrid manufacturing approaches hold great potential in advancing microfluidic device fabrication in terms of standardization, fast production, and user-independent manufacturing.

Micro- and nanodevices integrated with biomolecular probes

Understanding how biomolecules, proteins and cells interact with their surroundings and other biological entities has become the fundamental design criterion for most biomedical micro- and nanodevices. Advances in biology, medicine, and nanofabrication technologies complement each other and allow us to engineer new tools based on biomolecules utilized as probes. Engineered micro/nanosystems and biomolecules in nature have remarkably robust compatibility in terms of function, size, and physical properties. This article presents the state of the art in micro- and nanoscale devices designed and fabricated with biomolecular probes as their vital constituents. General design and fabrication concepts are presented and three major platform technologies are highlighted: microcantilevers, micro/nanopillars, and microfluidics. Overview of each technology, typical fabrication details, and application areas are presented by emphasizing significant achievements, current challenges, and future opportunities.

Dynamic deformability of sickle red blood cells in microphysiological flow.

In sickle cell disease (SCD), hemoglobin molecules polymerize intracellularly and lead to a cascade of events resulting in decreased deformability and increased adhesion of red blood cells (RBCs). Decreased deformability and increased adhesion of sickle RBCs lead to blood vessel occlusion (vaso-occlusion) in SCD patients. Here, we present a microfluidic approach integrated with a cell dimensioning algorithm to analyze dynamic deformability of adhered RBC at the single-cell level in controlled microphysiological flow. We measured and compared dynamic deformability and adhesion of healthy hemoglobin A (HbA) and homozygous sickle hemoglobin (HbS) containing RBCs in blood samples obtained from 24 subjects. We introduce a new parameter to assess deformability of RBCs: the dynamic deformability index (DDI), which is defined as the time-dependent change of the cells aspect ratio in response to fluid flow shear stress. Our results show that DDI of HbS-containing RBCs were significantly lower compared to that of HbA-containing RBCs. Moreover, we observed subpopulations of HbS containing RBCs in terms of their dynamic deformability characteristics: deformable and non-deformable RBCs. Then, we tested blood samples from SCD patients and analyzed RBC adhesion and deformability at physiological and above physiological flow shear stresses. We observed significantly greater number of adhered non-deformable sickle RBCs than deformable sickle RBCs at flow shear stresses well above the physiological range, suggesting an interplay between dynamic deformability and increased adhesion of RBCs in vaso-occlusive events.

Micro and Nano-scale Technologies for Cell Mechanics

Cell mechanics is a multidisciplinary field that bridges cell biology, fundamental mechanics, and micro and nanotechnology, which synergize to help us better understand the intricacies and the complex nature of cells in their native environment. With recent advances in nanotechnology, microfabrication methods and micro-electro-mechanical-systems (MEMS), we are now well situated to tap into the complex micro world of cells. The field that brings biology and MEMS together is known as Biological MEMS (BioMEMS). BioMEMS take advantage of systematic design and fabrication methods to create platforms that allow us to study cells like never before. These new technologies have been rapidly advancing the study of cell mechanics. This review article provides a succinct overview of cell mechanics and comprehensively surveys micro and nano-scale technologies that have been specifically developed for and are relevant to the mechanics of cells. Here we focus on micro and nano-scale technologies, and their applications in biology and medicine, including imaging, single cell analysis, cancer cell mechanics, organ-on-a-chip systems, pathogen detection, implantable devices, neuroscience and neurophysiology. We also provide a perspective on the future directions and challenges of technologies that relate to the mechanics of cells.

Emerging point-of-care technologies for sickle cell disease screening and monitoring

ABSTRACT Introduction: Sickle Cell Disease (SCD) affects 100,000 Americans and more than 14 million people globally, mostly in economically disadvantaged populations, and requires early diagnosis after birth and constant monitoring throughout the life-span of the patient. Areas covered: Early diagnosis of SCD still remains a challenge in preventing childhood mortality in the developing world due to requirements of skilled personnel and high-cost of currently available modalities. On the other hand, SCD monitoring presents insurmountable challenges due to heterogeneities among patient populations, as well as in the same individual longitudinally. Here, we describe emerging point-of-care micro/nano platform technologies for SCD screening and monitoring, and critically discuss current state of the art, potential challenges associated with these technologies, and future directions. Expert commentary: Recently developed microtechnologies offer simple, rapid, and affordable screening of SCD and have the potential to facilitate universal screening in resource-limited settings and developing countries. On the other hand, monitoring of SCD is more complicated compared to diagnosis and requires comprehensive validation of efficacy. Early use of novel microdevices for patient monitoring might come in especially handy in new clinical trial designs of emerging therapies.

Soft erythrocyte-based bacterial microswimmers for cargo delivery

Erythrocyte-based microswimmers offer superior efficiency, stability, and deformability for active and guided cargo delivery. Bacteria-propelled biohybrid microswimmers have recently shown to be able to actively transport and deliver cargos encapsulated into their synthetic constructs to specific regions locally. However, usage of synthetic materials as cargo carriers can result in inferior performance in load-carrying efficiency, biocompatibility, and biodegradability, impeding clinical translation of biohybrid microswimmers. Here, we report construction and external guidance of bacteria-driven microswimmers using red blood cells (RBCs; erythrocytes) as autologous cargo carriers for active and guided drug delivery. Multifunctional biohybrid microswimmers were fabricated by attachment of RBCs [loaded with anticancer doxorubicin drug molecules and superparamagnetic iron oxide nanoparticles (SPIONs)] to bioengineered motile bacteria, Escherichia coli MG1655, via biotin-avidin-biotin binding complex. Autonomous and on-board propulsion of biohybrid microswimmers was provided by bacteria, and their external magnetic guidance was enabled by SPIONs loaded into the RBCs. Furthermore, bacteria-driven RBC microswimmers displayed preserved deformability and attachment stability even after squeezing in microchannels smaller than their sizes, as in the case of bare RBCs. In addition, an on-demand light-activated hyperthermia termination switch was engineered for RBC microswimmers to control bacteria population after operations. RBCs, as biological and autologous cargo carriers in the biohybrid microswimmers, offer notable advantages in stability, deformability, biocompatibility, and biodegradability over synthetic cargo-carrier materials. The biohybrid microswimmer design presented here transforms RBCs from passive cargo carriers into active and guidable cargo carriers toward targeted drug and other cargo delivery applications in medicine.