Nanotechnology and Cancer Bioelectricity: Bridging the Gap Between Biology and Translational Medicine.

Bioelectricity is the electrical activity that occurs within living cells and tissues. This activity is critical for regulating homeostatic cellular function and communication, and disruptions of the same can lead to a variety of conditions, including cancer. Cancer cells are known to exhibit abnormal electrical properties compared to their healthy counterparts, and this has driven researchers to investigate the potential of harnessing bioelectricity as a tool in cancer diagnosis, prognosis, and treatment. In parallel, bioelectricity represents one of the means to gain fundamental insights on how electrical signals and charges play a role in cancer insurgence, growth, and progression. This review provides a comprehensive analysis of the literature in this field, addressing the fundamentals of bioelectricity in single cancer cells, cancer cell cohorts, and cancerous tissues. The emerging role of bioelectricity in cancer proliferation and metastasis is introduced. Based on the acknowledgement that this biological information is still hard to access due to the existing gap between biological findings and translational medicine, the latest advancements in the field of nanotechnologies for cellular electrophysiology are examined, as well as the most recent developments in micro- and nano-devices for cancer diagnostics and therapy targeting bioelectricity.

Passive Recording of Bioelectrical Signals from Non-Excitable Cells by Fluorescent Mirroring.

Bioelectrical variations trigger different cell responses, including migration, mitosis, and mutation. At the tissue level, these actions result in phenomena such as wound healing, proliferation, and pathogenesis. Monitoring these mechanisms dynamically is highly desirable in diagnostics and drug testing. However, existing technologies are invasive: either they require physical access to the intracellular compartments, or they imply direct contact with the cellular medium. Here, we present a novel approach for the passive recording of electrical signals from non-excitable cells adhering to 3D microelectrodes, based on optical mirroring. Preliminary results yielded a fluorescence intensity output increase of the 5,8% in the presence of a HEK-293 cell on the electrode compared to bare microelectrodes. At present, this technology may be employed to evaluate cell-substrate adhesion and monitor cell proliferation. Further refinements could allow extrapolating quantitative data on surface charges and resting potential to investigate the electrical phenomena involved in cell migration and cancer progression.

Wearable Smart Contact Lenses for Continual Glucose Monitoring: A Review.

Diabetes mellitus is a chronic disease requiring a careful management to prevent its collateral complications, such as cardiovascular and Alzheimer's diseases, retinopathy, nephropathy, foot and hearing impairment, and neuropathy. Self-monitoring of blood glucose at point-of-care settings is an established practice for diabetic patients. However, current technologies for glucose monitoring are invasive, costly, and only provide single snapshots for a widely varying parameter. On the other hand, tears are a source of physiological information that mirror the health state of an individual by expressing different concentrations of metabolites, enzymes, vitamins, salts, and proteins. Therefore, the eyes may be exploited as a sensing site with substantial diagnostic potential. Contact lens sensors represent a viable route for targeting minimally-invasive monitoring of disease onset and progression. Particularly, glucose concentration in tears may be used as a surrogate to estimate blood glucose levels. Extensive research efforts recently have been devoted to develop smart contact lenses for continual glucose detection. The latest advances in the field are reviewed herein. Sensing technologies are described, compared, and the associated challenges are critically discussed.

Smartphone-based colorimetric detection system for portable health tracking.

Colorimetric tests for at-home health monitoring became popular 50 years ago with the advent of the urinalysis test strips, due to their reduced costs, practicality, and ease of operation. However, developing digital systems that can interface these sensors in an efficient manner remains a challenge. Efforts have been put towards the development of portable optical readout systems, such as smartphones. However, their use in daily settings is still limited by their error-prone nature associated to optical noise from the ambient lighting, and their low sensitivity. Here, a smartphone application (Colourine) to readout colorimetric signals was developed on Android OS and tested on commercial urinalysis test strips for pH, proteins, and glucose detection. The novelty of this approach includes two features: a pre-calibration step where the user is asked to take a photo of the commercial reference chart, and a CIE-RGB-to-HSV color space transformation of the acquired data. These two elements allow the background noise given by environmental lighting to be minimized. The sensors were characterized in the ambient light range 100-400 lx, yielding a reliable output. Readouts were taken from urine strips in buffer solutions of pH (5.0-9.0 units), proteins (0-500 mg dL-1) and glucose (0-1000 mg dL-1), yielding a limit of detection (LOD) of 0.13 units (pH), 7.5 mg dL-1 (proteins) and 22 mg dL-1 (glucose), resulting in an average LOD decrease by about 2.8 fold compared to the visual method.

Lab-on-a-Contact Lens Platforms Fabricated by Multi-Axis Femtosecond Laser Ablation.

Contact lens sensing platforms have drawn interest in the last decade for the possibility of providing a sterile, fully integrated ocular screening technology. However, designing scalable and rapid contact lens processing methods while keeping a high resolution is still an unsolved challenge. In this article, femtosecond laser writing is employed as a rapid and precise procedure to engrave microfluidic networks into commercial contact lenses. Functional microfluidic components such as flow valves, resistors, multi-inlet geometries, and splitters are produced using a bespoke seven-axis femtosecond laser system, yielding a resolution of 80 µm. The ablation process and the tear flow within microfluidic structures is evaluated both experimentally and computationally using finite element modeling. Flow velocity drops of the 8.3%, 20.8%, and 29% were observed in valves with enlargements of the 100%, 200%, and 300%, respectively. Resistors yielded flow rate drops of 20.8%, 33%, and 50% in the small, medium, and large configurations, respectively. Two applications were introduced, namely a tear volume sensor and a tear uric acid sensor (sensitivity 16 mg L-1 ), which are both painless alternatives to current methods and provide reduced contamination risks of tear samples.

Microengineered poly(HEMA) hydrogels for wearable contact lens biosensing.

Microchannels in hydrogels play an essential role in enabling a smart contact lens. However, microchannels have rarely been created in commercial hydrogel contact lenses due to their sensitivity to conventional microfabrication techniques. Here, we report the fabrication of microchannels in poly(2-hydroxyethyl methacrylate) (poly(HEMA)) hydrogels that are used in commercial contact lenses with a three-dimensional (3D) printed mold. We investigated the corresponding capillary flow behaviors in these microchannels. We observed different capillary flow regimes in these microchannels, depending on their hydration level. In particular, we found that a peristaltic pressure could reinstate flow in a dehydrated channel, indicating that the motion of eye-blinking may help tears flow in a microchannel-containing contact lens. Colorimetric pH and electrochemical Na+ sensing capabilities were demonstrated in these microchannels. This work paves the way for the development of microengineered poly(HEMA) hydrogels for various biomedical applications such as eye-care and wearable biosensing.

Integration of paper microfluidic sensors into contact lenses for tear fluid analysis.

In this article, using the integration of paper microfluidics within laser-inscribed commercial contact lenses, we demonstrate the multiplexed detection of clinically relevant analytes including hydrogen ions, proteins, glucose, nitrites and l-ascorbic acid, all sampled directly from model tears. In vitro measurements involved the optimization of colorimetric assays, with readouts collected, stored and analyzed using a bespoke Tears Diagnostics smartphone application prototype. We demonstrate the potential of the device to perform discrete measurements either for medical diagnosis or disease screening in the clinic or at the point-of-care (PoC), with future applications including monitoring of ocular infections, uveitis, diabetes, keratopathies and assessing oxidative stress.

Dermal Tattoo Biosensors for Colorimetric Metabolite Detection.

Tattooing is a ubiquitous body modification involving the injection of ink and/or dye pigments into the dermis. Biosensors in the form of tattoos can be used to monitor metabolites in interstitial fluid. Here, minimally invasive, injectable dermal biosensors were developed for measuring pH, glucose, and albumin concentrations. The dermal pH sensor was based on methyl red, bromothymol blue, and phenolphthalein, which responded to a pH range from 5.0 to 9.0. The dermal glucose sensor consisted of glucose oxidase, 3,3',5,5'-tetramethylbenzidine, and peroxidase that detected concentrations up to 50.0 mmol L-1 . The dermal albumin sensor consisted of 3',3'',5',5''-tetrachlorophenol-3,4,5,6-tetrabromosulfophthalein to measure concentrations up to 5.0 g L-1 . The sensors were multiplexed in ex vivo skin tissue and quantitative readouts were obtained using a smartphone camera. These sensors can be used to manage of acid-base homeostasis, diabetes, and liver failure in point-of-care settings.

Contact Lens Technology: From Fundamentals to Applications.

Contact lenses are ocular prosthetic devices used by over 150 million people worldwide. Primary applications of contact lenses include vision correction, therapeutics, and cosmetics. Contact lens materials have significantly evolved over time to minimize adverse effects associated with contact lens wearing, to maintain a regular corneal metabolism, and to preserve tear film stability. This article encompasses contact lens technology, including materials, chemical and physical properties, manufacturing processes, microbial contamination, and ocular complications. The function and the composition of the tear fluid are discussed to assess its potential as a diagnostic media. The regulatory standards of contact lens devices with regard to biocompatibility and contact lens market are presented. Future prospects in contact lens technology are evaluated, with particular interest given to theranostic applications for in situ continuous monitoring the ocular physiology.

Real-time optical fiber sensors based on light diffusing microlens arrays.

The applications of optical fibers are impeded in implantable medical diagnostics due to incompatibility with biological tissues, and immune reaction in vivo. The utilization of biocompatible materials to construct a photonic sensing platform can reduce the immune response in in vivo medical diagnostics. Here, we developed real-time optical fiber sensors to determine the volumetric modulation of stimuli-responsive polymers. Asymmetric microlens structures were replicated on stimuli-sensitive hydrogels as stand-alone sensors and were chemically attached to the tips of silica and biocompatible optical fibers. Quantitative measurements were carried out using a smartphone to demonstrate the ease, simplicity, and practicality of the readout methodology. To demonstrate the utility in real-time sensing, the fiber probe was investigated in various concentrations of ethanol, propan-2-ol, and dimethyl sulfoxide. Also, the fiber probe showed a rapid response to pH in the acidic region with a sensitivity of 40 nW pH-1. To develop biocompatible probes for physiological applications, a microlens array-imprinted polymer was attached to the tip of a hydrogel optical fiber. The optical fiber probe in the refection configuration showed a sensitivity of 7 nW pH-1. The developed hydrogel fiber probes may have application in point-of-care diagnostics, continuous biomarker monitoring, and critical care sensing devices.

Contact lenses for continuous corneal temperature monitoring.

Temperature variation is a ubiquitous medical sign to monitor ocular conditions including dry eye disease (DED), glaucoma, carotid artery stenosis, diabetic retinopathy, and vascular neuritis. The ability to measure OST in real time is desirable in point-of-care diagnostics. Here, we developed minimally invasive contact lens temperature sensors for continuous monitoring of the corneal temperature. The contact lens sensor consisted of a laser patterned commercial contact lens embedding temperature-sensitive Cholesteric Liquid Crystals (CLCs), which exhibited a fully reversible temperature-dependent color change in the visible spectrum. The contact lens allowed the corneal temperature to be mapped in four key areas, at distances of 0.0, 1.0, 3.0, and 5.0 mm from the pupil's edge. Liquid crystals exhibited a wavelength shift from 738 ± 4 nm to 474 ± 4 nm upon increasing the temperature from 29.0 °C to 40.0 °C, with a time responsivity of 490 ms and a negligible hysteresis. Readouts were performed using a smartphone, which output RGB triplets associated to temperature values. Contact lens sensors based on CLCs were fitted and tested on an ex vivo porcine eye and readouts were compared with infrared thermal measurements, resulting in an average difference of 0.3 °C.

Anthocyanin-Functionalized Contact Lens Sensors for Ocular pH Monitoring.

Anthocyanins are bioactive compounds naturally found in a variety of leaves, fruits, and vegetables. Anthocyanin pigments undergo a modification in their chemical structure when exposed to different concentrations of hydrogen ions, and they were extensively studied to be used as active elements in biocompatible pH sensors. The ocular pH is a significant parameter to assess the ocular physiology in cases of postocular surgery, keratoconjunctivitis, and ocular rosacea. Contact lenses have the potential to be used as medical diagnostic devices for in situ continuous monitoring of the ocular physiology. Here, anthocyanin-functionalized contact lenses were developed as wearable sensors to monitor the ocular pH. Anthocyanin pigments were extracted from Brassica oleracea and used to functionalize the polymeric matrices of commercial soft contact lenses by soaking and drop-casting processes. Contact lenses responded to the physiological ocular pH of 6.5, 7.0, and 7.5, exhibiting a systematic color shift from pink (pH 6.5) to purple (pH 7.0) and blue (pH 7.5). The functionalization of contact lens sensors was evaluated as a function of the dye concentration. Quantitative values were obtained by comparing the RGB triplets of the colors obtained with the naturally extracted dye and with delphinidin chloride dye in 0.0 to 1.5 mmol L-1 aqueous solution. The functionalization of contact lenses was studied as a function of the soaking time, resulting in best results when soaking for 24 h. The dye leakage from the contact lenses in deionized water was evaluated, and a negligible leakage after 18 h was observed. Poly-2-hydroxy ethylmethacrylate contact lenses were fabricated and cross-linked with anthocyanin dye, resulting in a slight color shift upon pH changes from 6.5 to 7.4. Contact lens pH sensors may be used to continuously monitor the ocular pH at point-of-care settings.

A Self-Aligned High-Mobility Graphene Transistor: Decoupling the Channel with Fluorographene to Reduce Scattering.

The conduction channel of a graphene field-effect transistor (FET) is decoupled from the parasitic charge impurities of the underlying substrate. Fluorographene as a passivation layer is fabricated between the oxide substrate and channel, and a self-aligned gate-terminated FET is also fabricated. This approach significantly reduces the scattering and, as a result, the mobility increases ten fold.