Photothermal effects of terahertz-band and optical electromagnetic radiation on human tissues.

The field of wireless communication has witnessed tremendous advancements in the past few decades, leading to more pervasive and ubiquitous networks. Human bodies are continually exposed to electromagnetic radiation, but typically this does not impact the body as the radiation is non-ionizing and the waves carry low power. However, with progress in the sixth generation (6G) of wireless networks and the adoption of the spectrum above 100 GHz in the next few years, higher power radiation is needed to cover larger areas, exposing humans to stronger and more prolonged radiation. Also, water has a high absorption coefficient at these frequencies and could lead to thermal effects on the skin. Hence, there is a need to study the radiation effects on human tissues, specifically the photothermal effects. In this paper, we present a custom-built, multi-physics model to investigate electromagnetic wave propagation in human tissue and study its subsequent photothermal effects. The proposed finite-element model consists of two segments-the first one estimates the intensity distribution along the beam path, while the second calculates the increase in temperature due to the wave distribution inside the tissue. We determine the intensity variation in the tissue using the radiative transfer equation and compare the results with Monte Carlo analysis and existing analytical models. The intensity information is then utilized to predict the rise in temperature with a bio-heat transfer module, powered by Pennes' bioheat equation. The model is parametric, and we perform a systematic photothermal analysis to recognize the crucial variables responsible for the temperature growth inside the tissue, particularly for terahertz and near-infrared optical frequencies. Our numerical model can serve as a benchmark for studying the high-frequency radiation effects on complex heterogeneous media such as human tissue.

Capacitive interdigitated system of high osteoinductive/conductive performance for personalized acting-sensing implants.

Replacement orthopedic surgeries are among the most common surgeries worldwide, but clinically used passive implants cannot prevent failure rates and inherent revision arthroplasties. Optimized non-instrumented implants, resorting to preclinically tested bioactive coatings, improve initial osseointegration but lack long-term personalized actuation on the bone-implant interface. Novel bioelectronic devices comprising biophysical stimulators and sensing systems are thus emerging, aiming for long-term control of peri-implant bone growth through biointerface monitoring. These acting-sensing dual systems require high frequency (HF) operations able to stimulate osteoinduction/osteoconduction, including matrix maturation and mineralization. A sensing-compatible capacitive stimulator of thin interdigitated electrodes and delivering an electrical 60 kHz HF stimulation, 30 min/day, is here shown to promote osteoconduction in pre-osteoblasts and osteoinduction in human adipose-derived mesenchymal stem cells (hASCs). HF stimulation through this capacitive interdigitated system had significant effects on osteoblasts' collagen-I synthesis, matrix, and mineral deposition. A proteomic analysis of microvesicles released from electrically-stimulated osteoblasts revealed regulation of osteodifferentiation and mineralization-related proteins (e.g. Tgfb3, Ttyh3, Itih1, Aldh1a1). Proteomics data are available via ProteomeXchange with the identifier PXD028551. Further, under HF stimulation, hASCs exhibited higher osteogenic commitment and enhanced hydroxyapatite deposition. These promising osteoinductive/conductive capacitive stimulators will integrate novel bioelectronic implants able to monitor the bone-implant interface and deliver personalized stimulation to peri-implant tissues.

Towards an effective sensing technology to monitor micro-scale interface loosening of bioelectronic implants.

Instrumented implants are being developed with a radically innovative design to significantly reduce revision surgeries. Although bone replacements are among the most prevalent surgeries performed worldwide, implant failure rate usually surpasses 10%. High sophisticated multifunctional bioelectronic implants are being researched to incorporate cosurface capacitive architectures with ability to deliver personalized electric stimuli to peri-implant target tissues. However, the ability of these architectures to detect bone-implant interface states has never been explored. Moreover, although more than forty technologies were already proposed to detect implant loosening, none is able to ensure effective monitoring of the bone-implant debonding, mainly during the early stages of loosening. This work shows, for the first time, that cosurface capacitive sensors are a promising technology to provide an effective monitoring of bone-implant interfaces during the daily living of patients. Indeed, in vitro experimental tests and simulation with computational models highlight that both striped and circular capacitive architectures are able to detect micro-scale and macro-scale interface bonding, debonding or loosening, mainly when bonding is weakening or loosening is occurring. The proposed cosurface technologies hold potential to implement highly effective and personalized sensing systems such that the performance of multifunctional bioelectronic implants can be strongly improved. Findings were reported open a new research line on sensing technologies for bioelectronic implants, which may conduct to great impacts in the coming years.

Formation and manipulation of ferrofluid droplets with magnetic fields in a microdevice: a numerical parametric study.

We present a numerical model that describes the microfluidic generation and manipulation of ferrofluid droplets under an external magnetic field. We developed a numerical Computational Fluid Dynamics (CFD) analysis for predicting and optimizing continuous flow generation and processing of ferrofluid droplets with and without the presence of a permanent magnet. More specifically, we explore the dynamics of oil-based ferrofluid droplets within an aqueous continuous phase under an external inhomogeneous magnetic field. The developed model determines the effect of the magnetic field on the droplet generation, which is carried out in a flow-focusing geometry, and its sorting in T-junction channels. Three-channel depths (25 µm, 30 µm, and 40 µm) were investigated to study droplet deformation under magnetic forces. Among the three, the 30 µm channel depth showed the most consistent droplet production for the studied range of flow rates. Ferrofluids with different loadings of magnetic nanoparticles were used to observe the behavior for different ratios of magnetic and hydrodynamic forces. Our results show that the effect of these factors on droplet size and generation rate can be tuned and optimized to produce consistent droplet generation and sorting. This approach involves fully coupled magnetic-fluid mechanics models and can predict critical details of the process including droplet size, shape, trajectory, dispensing rate, and the perturbation of the fluid co-flow for different flow rates. The model enables better understanding of the physical phenomena involved in continuous droplet processing and allows efficient parametric analysis and optimization.

Numerical Analysis of Bead Magnetophoresis from Flowing Blood in a Continuous-Flow Microchannel: Implications to the Bead-Fluid Interactions.

In this work, we report a numerical flow-focused study of bead magnetophoresis inside a continuous-flow microchannel in order to provide a detailed analysis of bead motion and its effect on fluid flow. The numerical model involves a Lagrangian approach and predicts the bead separation from blood and their collection into a flowing buffer by the application of a magnetic field generated by a permanent magnet. The following scenarios are modelled: (i) one-way coupling wherein momentum is transferred from the fluid to beads, which are treated as point particles, (ii) two-way coupling wherein the beads are treated as point particles and momentum is transferred from the bead to the fluid and vice versa, and (iii) two-way coupling taking into account the effects of bead volume in fluid displacement. The results indicate that although there is little difference in the bead trajectories for the three scenarios, there is significant variation in the flow fields, especially when high magnetic forces are applied on the beads. Therefore, an accurate full flow-focused model that takes into account the effects of the bead motion and volume on the flow field should be solved when high magnetic forces are employed. Nonetheless, when the beads are subjected to medium or low magnetic forces, computationally inexpensive models can be safely employed to model magnetophoresis.

Capacitive technologies for highly controlled and personalized electrical stimulation by implantable biomedical systems.

Cosurface electrode architectures are able to deliver personalized electric stimuli to target tissues. As such, this technology holds potential for a variety of innovative biomedical devices. However, to date, no detailed analyses have been conducted to evaluate the impact of stimulator architecture and geometry on stimuli features. This work characterizes, for the first time, the electric stimuli delivered to bone cellular tissues during in vitro experiments, when using three capacitive architectures: stripped, interdigitated and circular patterns. Computational models are presented that predict the influence of cell confluence, cosurface architecture, electrodes geometry, gap size between electrodes and power excitation on the stimuli delivered to cellular layers. The results demonstrate that these stimulators are able to deliver osteoconductive stimuli. Significant differences in stimuli distributions were observed for different stimulator designs and different external excitations. The thickness specification was found to be of utmost importance. In vitro experiments using an osteoblastic cell line highlight that cosurface stimulation at a low frequency can enhance osteoconductive responses, with some electrode-specific differences being found. A major feature of this type of work is that it enables future detailed analyses of stimuli distribution throughout more complex biological structures, such as tissues and organs, towards sophisticated biodevice personalization.

Coherent Raman spectroscopic imaging to characterize microglia activation pathway.

Microglia are immune cells, which densely populate the central nervous system (CNS), and play essential role in suppression of neurodegenerative diseases, clearance of debris after CNS trauma, as well as serve as the last line of immune defense in response to any potential threat by being activated to eliminate diverse pathogens ranging from bacteria to cancer. The activated microglia cells are commonly used as a diagnostic biomarker of diverse brain conditions, however detection and classification of microglia activated phenotypes is a cumbersome and imprecise procedure. Here, we report on development of optical assay for detection and quantitative analysis of activated microglia. In this study, we investigated overall changes in the metabolism of microglia cells during their activation by monitoring the signal from cellular proteins and lipids using label-free coherent anti-Stokes Raman scattering imaging. Our data demonstrate that the activation of microglia in the presence of bacterial liposaccharide is accompanied by intense upregulation of synthesis of proteins and lipids. We further propose that elevated intracellular content of these types of macromolecules can serve as early supplementary marker for identification of active microglia cells in the brain samples by Raman imaging techniques.

Computational modeling and fluorescence microscopy characterization of a two-phase magnetophoretic microsystem for continuous-flow blood detoxification.

Magnetic beads can be functionalized to capture and separate target pathogens from blood for extracorporeal detoxification. The beads can be magnetically separated from a blood stream and collected into a coflowing buffer solution using a two-phase liquid-liquid continuous-flow microfluidic device in the presence of an external field. However, device design and process optimization, i.e. high bead recovery with minimum blood loss or dilution remain a substantial technological challenge. We introduce a CFD-based Eulerian-Lagrangian computational model that enables the rational design and optimization of such systems. The model takes into account dominant magnetic and hydrodynamic forces on the beads as well as coupled bead-fluid interactions. Fluid flow (Navier-Stokes equations) and mass transfer (Fick's law) between the coflowing fluids are solved numerically, while the magnetic force on the beads is predicted using analytical methods. The model is demonstrated via application to a prototype device and used to predict key performance metrics; degree of bead separation, flow patterns, and mass transfer, i.e. blood diffusion to the buffer phase. The impact of different process variables and parameters - flow rates, bead and magnet dimensions and fluid viscosities - on both bead recovery and blood loss or dilution is quantified for the first time. The performance of the prototype device is characterized using fluorescence microscopy and the experimental results are found to match theoretical predictions within an absolute error of 15%. While the model is demonstrated here for analysis of a detoxification device, it can be readily adapted to a broad range of magnetically-enabled microfluidic applications, e.g. bioseparation, sorting and sensing.

Theoretical study of the photothermal behaviour of self-assembled magnetic-plasmonic chain structures.

We study the field-directed self-assembly and photothermal behavior of one-dimensional (1D) chains of core-shell Fe3O4@Au magnetic-plasmonic nanoparticles. Monte Carlo analysis is used to predict the self-assembly of the nanoparticles when they are subjected to a uniform magnetic field and confined to a fluidic nanochannel. A coupled photonic and thermodynamic analysis is performed to analyze the optical and photothermal properties of the 1D chain structures. We show for the first time that the assembled chain structures exhibit a pronounced dip in their absorption spectrum at a wavelength that is strongly sensitive to changes in the refractive index of the surrounding medium. The plasmon enhanced features of these structures are well suited for a variety of theranostic modalities as we discuss.

Optimization of Optical Absorption of Colloids of SiO2@Au and Fe3O4@Au Nanoparticles with Constraints.

We study the optical response of monodisperse colloids of core-shell plasmonic nanoparticles and introduce a computational approach to optimize absorption for photothermal applications that require dilute colloids of non-interacting particles with a prescribed volume fraction. Since the volume fraction is held constant, the particle concentration is size-dependent. Optimization is achieved by comparing the absorption spectra of colloids as a function of particle size and structure. We demonstrate the approach via application to colloids of core-shell SiO2@Au and Fe3O4@Au nanoparticles with particle sizes that range from 5-100 nm and with the incident wavelength varying from 600-1200 nm. The absorption spectra are predicted using Mie theory and the analysis shows that there is a unique mix of parameters (core radius, shell thickness, wavelength) that maximize absorption, independent of the value of volume fraction. We show that lossy Fe3O4 cores produce a much broader absorption peak with much less sensitivity to variations in particle structure and wavelength than lossless SiO2 cores. This approach can be readily adapted to colloids of nanoparticles with arbitrary materials, shapes and structure using appropriate numerical methods to compute the absorption spectra. As such, it is useful for the rational design of colloids and process variables for a broad range of photothermal applications.

Theoretical Comparison of Optical Properties of Near-Infrared Colloidal Plasmonic Nanoparticles.

We study optical properties of near-infrared absorbing colloidal plasmonic nanostructures that are of interest for biomedical theranostic applications: SiO2@Au core-shell particles, Au nanocages and Au nanorods. Full-wave field analysis is used to compare the absorption spectra and field enhancement of these structures as a function of their dimensions and orientation with respect to the incident field polarization. Absorption cross-sections of structures with the same volume and LSPR wavelength are compared to quantify differential performance for imaging, sensing and photothermal applications. The analysis shows that while the LSPR of each structure can be tuned to the NIR, particles with a high degree of rotational symmetry, i.e. the SiO2@Au and nanocage particles, provide superior performance for photothermal applications because their absorption is less sensitive to their orientation, which is random in colloidal applications. The analysis also demonstrates that Au nanocages are advantaged with respect to other structures for imaging, sensing and drug delivery applications as they support abundant E field hot spots along their surface and within their open interior. The modeling approach presented here broadly applies to dilute colloidal plasmonic nanomaterials of arbitrary shapes, sizes and material constituents and is well suited for the rational design of novel plasmon-assisted theranostic applications.

New cosurface capacitive stimulators for the development of active osseointegrative implantable devices.

Non-drug strategies based on biophysical stimulation have been emphasized for the treatment and prevention of musculoskeletal conditions. However, to date, an effective stimulation system for intracorporeal therapies has not been proposed. This is particularly true for active intramedullary implants that aim to optimize osseointegration. The increasing demand for these implants, particularly for hip and knee replacements, has driven the design of innovative stimulation systems that are effective in bone-implant integration. In this paper, a new cosurface-based capacitive system concept is proposed for the design of implantable devices that deliver controllable and personalized electric field stimuli to target tissues. A prototype architecture of this system was constructed for in vitro tests, and its ability to deliver controllable stimuli was numerically analyzed. Successful results were obtained for osteoblastic proliferation and differentiation in the in vitro tests. This work provides, for the first time, a design of a stimulation system that can be embedded in active implantable devices for controllable bone-implant integration and regeneration. The proposed cosurface design holds potential for the implementation of novel and innovative personalized stimulatory therapies based on the delivery of electric fields to bone cells.

Tunable Bloch Wave Resonances and Bloch Gaps in Uniform Materials with Reconfigurable Boundary Profiles.

We study wave propagation in uniform materials with periodic boundary profiles and introduce for the first time Bloch resonances and Bloch gaps. Bloch resonances are due to transverse phase matching, i.e., the coupling of two transverse standing waves corresponding to different harmonics. These are distinct from well-known Bragg resonances that result from longitudinal phase matching. We show that Bloch gaps can be engineered over the entire first Brillouin zone up to an infinite wavelength, i.e., k_{x}=0, where k_{x} is the wave number in the direction of propagation. This is in contrast to Bragg gaps that open at a fixed wavelength, twice the period of the structure. Bloch resonances and gaps can be tuned by reconfiguring the boundary profile and we derive analytical expressions that predict these phenomena when the amplitude of the profile is small. The theory is fundamental as it broadly applies to wave phenomena that span the quantum to continuum scale with applications that range from condensed matter to acoustics. We validate the theory experimentally for the electromagnetic field at GHz frequencies. We also discuss potential photonic and electronic applications of the theory such as a white-light distributed feedback laser and a two-dimensional electron gas transistor.

Magnetic levitation-based electromagnetic energy harvesting: a semi-analytical non-linear model for energy transduction.

Magnetic levitation has been used to implement low-cost and maintenance-free electromagnetic energy harvesting. The ability of levitation-based harvesting systems to operate autonomously for long periods of time makes them well-suited for self-powering a broad range of technologies. In this paper, a combined theoretical and experimental study is presented of a harvester configuration that utilizes the motion of a levitated hard-magnetic element to generate electrical power. A semi-analytical, non-linear model is introduced that enables accurate and efficient analysis of energy transduction. The model predicts the transient and steady-state response of the harvester a function of its motion (amplitude and frequency) and load impedance. Very good agreement is obtained between simulation and experiment with energy errors lower than 14.15% (mean absolute percentage error of 6.02%) and cross-correlations higher than 86%. The model provides unique insight into fundamental mechanisms of energy transduction and enables the geometric optimization of harvesters prior to fabrication and the rational design of intelligent energy harvesters.

Designing ultrathin film composite membranes: the impact of a gutter layer.

Industrial membranes comprised of a thin selective layer (<100 nm) requires a gutter layer (<100 nm) between the selective layer and the porous support to achieve high permeance for gas separation. The gutter layer materials must be carefully chosen to enhance overall membrane performance, i.e., high permeance and high selectivity. However, the experimental determination of the optimum gutter layer properties is very challenging. Herein we address this need using a three dimensional (3D) computational model to systematically determine the effects of the gutter layer thickness and permeability on membrane performance. A key finding is that the introduction of a gutter layer between the selective layer and porous support can enhance the overall permeance of the penetrant by up to an order of magnitude, but this gain is accompanied by an undesired decrease in selectivity. The analysis also shows for the first time that a maximum increase in permeance with negligible decrease in selectivity is realized when the thickness of the gutter layer is 1-2 times the pore radius. The modeling approach provides clear and practical guidelines for designing ultrathin multilayer composite membranes to achieve high permeance and selectivity for low-cost and energy-efficient molecular separations.

Self-Assembly of Crystalline Structures of Magnetic Core-Shell Nanoparticles for Fabrication of Nanostructured Materials.

A theoretical study is presented of the template-assisted formation of crystalline superstructures of magnetic-dielectric core-shell particles. The templates produce highly localized gradient fields and a corresponding magnetic force that guides the assembly with nanoscale precision in particle placement. The process is studied using two distinct and complementary computational models that predict the dynamics and energy of the particles, respectively. Both mono- and polydisperse colloids are studied, and the analysis demonstrates for the first time that although the particles self-assemble into ordered crystalline superstructures, the particle formation is not unique. There is a Brownian motion-induced degeneracy in the process wherein various distinct, energetically comparable crystalline structures can form for a given template geometry. The models predict the formation of hexagonal close packed (HCP) and face centered cubic (FCC) structures as well as mixed phase structures due to in-plane stacking disorders, which is consistent with experimental observations. The polydisperse particle structures are less uniform than the monodisperse particle structures because of the irregular packing of different-sized particles. A comparison of self-assembly using soft- and hard-magnetic templates is also presented, the former being magnetized in a uniform field. This analysis shows that soft-magnetic templates enable an order-of-magnitude more rapid assembly and much higher spatial resolution in particle placement than their hard-magnetic counterparts. The self-assembly method discussed is versatile and broadly applies to arbitrary template geometries and multilayered and multifunctional mono- and polydisperse core-shell particles that have at least one magnetic component. As such, the method holds potential for the bottom-up fabrication of functional nanostructured materials for a broad range of applications. This work provides unprecedented insight into the assembly process, especially with respect to the viability and potential fundamental limitations of realizing structure-dependent material properties for applications.

Magnetofection Mediated Transient NANOG Overexpression Enhances Proliferation and Myogenic Differentiation of Human Hair Follicle Derived Mesenchymal Stem Cells.

We used magnetofection (MF) to achieve high transfection efficiency into human mesenchymal stem cells (MSCs). A custom-made magnet array, matching well-to-well to a 24-well plate, was generated and characterized. Theoretical predictions of magnetic force distribution within each well demonstrated that there was no magnetic field interference among magnets in adjacent wells. An optimized protocol for efficient gene delivery to human hair follicle derived MSCs (hHF-MSCs) was established using an egfp-encoding plasmid, reaching approximately ∼50% transfection efficiency without significant cytotoxicity. Then we applied the optimized MF protocol to express the pluripotency-associated transcription factor NANOG, which was previously shown to reverse the effects of organismal aging on MSC proliferation and myogenic differentiation capacity. Indeed, MF-mediated NANOG delivery increased proliferation and enhanced the differentiation of hHF-MSCs into smooth muscle cells (SMCs). Collectively, our results show that MF can achieve high levels of gene delivery to MSCs and, therefore, may be employed to moderate or reverse the effects of cellular senescence or reprogram cells to the pluripotent state without permanent genetic modification.

Maximizing derivable information from cytologic specimens for pathologic and molecular diagnostics.

INTRODUCTION: The advent of precision medicine will increase the demand for molecular testing on patient tumor specimens. Cytology specimens have been shown to be ideal substrates for molecular testing, but their often paucicellular nature can lead to conflicts in prioritizing sample management. A microfluidic platform was investigated to determine whether cytologic and molecular data could be procured from the same cells, obviating the need for partitioning a sample by multiplexing it instead. MATERIALS AND METHODS: Cytology samples were created from a tissue source, stained with a supravital dye, and enriched using immunomagnetic beads. These cells and the attached immunomagnetic beads were then run through a microfluidic channel, temporarily immobilized for cytologic examination, and then recovered. The cytologic characteristics of these cells was compared with cells from the same source prepared by conventional cytologic preparatory means. DNA was extracted from the cells recovered from the microfluidic channel and the nature of their integrity was assessed. RESULTS: Cytologic features between cells run in a microfluidic channel and prepared by conventional means were similar. The DNA recovered from the cells run through the microfluidic channel was of high molecular weight. CONCLUSIONS: Microfluidics enables multiplex testing of cytologic specimens, allowing for cytology-based diagnostic examination and recovery of high-quality DNA. This approach will be of particular benefit for cytology specimens that are paucicellular and will need molecular testing.

Template-assisted nano-patterning of magnetic core-shell particles in gradient fields.

A method is proposed for controlling the assembly of colloidal magnetic core-shell nanoparticles into patterned monolayer structures with nanoscale feature resolution. The method is based on magnetic field-directed self-assembly that is enhanced using soft-magnetic template elements. The elements are embedded in a nonmagnetic substrate and magnetized using a uniform bias field. A key feature of this approach is the combined use of a uniform field with induced gradient-fields produced by the template elements. This enables the customization of a force field with localized regions of attractive and repulsive magnetic forces that provide extraordinary control of particle motion during assembly. The method is demonstrated using a computational model that simulates the assembly process taking into account magnetic and hydrodynamic forces including interparticle interactions, Brownian diffusion, van der Waals force and effects of surfactants. The analysis shows that extended geometric patterns of particles can be assembled with nanoscale resolution, beyond that of the template elements, within milliseconds. This is achieved by tailoring key parameters including the template geometry to produce a force field that focuses the particles into prescribed patterns; the thickness of the dielectric particle shell to control the magnetic dipole-dipole force upon contact and the particle volume fraction to suppress undesired aggregation during assembly. The proposed method broadly applies to arbitrary template geometries and multi-layered core-shell particles with at least one magnetic component. It can enable the self-assembly of complex patterns of nanoparticles and open up opportunities for the scalable fabrication of multifunctional nanostructured materials for a broad range of applications.