Insertable Biosensors: Combining Implanted Sensing Materials with Wearable Monitors.

Insertable biosensor systems are medical diagnostic devices with two primary components: an implantable biosensor within the body and a wearable monitor that can remotely interrogate the biosensor from outside the body. Because the biosensor does not require a physical connection to the electronic monitor, insertable biosensor systems promise improved patient comfort, reduced inflammation and infection risk, and extended operational lifetimes relative to established percutaneous biosensor systems. However, the lack of physical connection also presents technical challenges that have necessitated new innovations in developing sensing chemistries, transduction methods, and communication modalities. In this review, we discuss the key developments that have made insertables a promising option for longitudinal biometric monitoring and highlight the essential needs and existing development challenges to realizing the next generation of insertables for extended-use diagnostic and prognostic devices.

Surface-Enhanced Spatially Offset Raman Spectroscopy in Tissue.

One aim of personalized medicine is to use continuous or on-demand monitoring of metabolites to adjust prescription dosages in real time. Surface-enhanced spatially offset Raman spectroscopy (SESORS) is an optical technique capable of detecting surface-enhanced Raman spectroscopy (SERS)-active targets under a barrier, which may enable frequent metabolite monitoring. Here we investigate how the intensity of the signal from SERS-active material varies spatially through tissue, both experimentally and in a computational model. Implant-sized, SERS-active hydrogel was placed under different thicknesses of contiguous tissue. Emission spectra were collected at the air-tissue boundary over a range of offsets from the excitation site. New features were added to the Monte Carlo light-tissue interaction model to modify the optical properties after inelastic scattering and to calculate the distribution of photons as they exit the model. The Raman signals were detectable through all barrier thicknesses, with strongest emission for the case of 0 mm offset between the excitation and detector. A steep decline in the signal intensities occurred for offsets greater than 2 mm. These results did not match published SORS work (where targets were much larger than an implant). However, the model and experimental results agree in showing the greatest intensities at 0 mm offset and a steep gradient in the intensities with increasing offset. Also, the model showed an increase in the number of photons when the new, longer wavelengths were used following the Stokes shift for scattering and the graphical display of the exiting photons was helpful in the determination and confirmation of the optimal offset.

Skin optical properties in the obese and their relation to body mass index: a review.

SIGNIFICANCE: Obesity is a worldwide epidemic contributing directly to several cardiovascular risk factors including hypertension and type 2 diabetes. Wearable devices are becoming better at quantifying biomarkers relevant for the management of health and fitness. Unfortunately, both anecdotal evidence and recent studies indicate that some wearables have higher levels of error when utilized by populations with darker skin tones and high body mass index (BMI). There is an urgent need for a better evaluation of the limits of wearable health technologies when used by obese individuals. AIMS: (1) To review the current know-how on changes due to obesity in the skin epidermis, dermis, and subcutis that could affect the skin optical properties; (2) for the green wavelength range, to evaluate the difference in absorption and scattering coefficients from the abdominal skin between individuals with and without elevated BMI. The changes include alterations in layer thickness and cell size, as well as significant differences in chromophores and scatterer content, e.g., water, hemoglobin, collagen, and lipids. APPROACH: We have summarized literature pertaining to changes in skin and its components in obesity and report the results of our search using articles published between years 1971 and 2020. A linear model was used to demonstrate the absorption and reduced scattering coefficient of the abdominal skin of individuals with and without elevated BMI in the green wavelength range (530 to 550 nm) that is typically found in most wearables. RESULTS: The general trends indicate a decrease in absorption for both dermis and subcutis and an increase in reduced scattering for both epidermis and dermis. At 544-nm wavelength, a typical wavelength used for photoplethysmography (PPG), the absorption coefficient's relative percentage difference between high and low BMI skin, was 49% in the subcutis, 19% in the dermis, and negligible in the epidermis, whereas the reduced scattering coefficient relative difference was 21%, 29%, and 165% respectively. CONCLUSIONS: These findings suggest that there could be significant errors in the output of optical devices used for monitoring health and fitness if changes due to obesity are not accounted for in their design.

Microparticle ratiometric oxygen sensors utilizing near-infrared emitting quantum dots.

Luminescent sensors incorporating two luminophores, an indicator and a reference, offer many advantages over intensity measurements from sensors made with one indicator dye. Quantum dots have yet to be widely employed as insensitive reference luminophores in such systems. This work describes the use of near-infrared emitting quantum dots in conjunction with a long-lifetime platinum(II) porphyrin phosphor in a microsphere-based, ratiometric oxygen sensor. The process for self-assembly of the nanocomposite system was developed, and the response and photostability of the prototypes were investigated. Results indicate the sensors possess excellent sensitivity (K(SV) = 0.00826 µM(-1)) at oxygen concentrations below 300 µM and were resistant to photobleaching. The sensor luminophores displayed minimal spectral overlap and little interference from excitation light, preventing the need for optical filters. A reversible photoenhancement of the quantum dot signal was also observed when exposed for extended periods of time. This work demonstrates the advantages of incorporating long-wavelength quantum dots into ratiometric intensity sensing schemes and highlights some key limitations that must be considered in their use.

Comparison of SERS pH probe responses after microencapsulation within hydrogel matrices.

SIGNIFICANCE: Personalized medicine requires the tracking of an individual's metabolite levels over time to detect anomalies and evaluate the body's response to medications. Implanted sensors offer effective means to continuously monitor specific metabolite levels, provided they are accurate, stable over long time periods, and do no harm. AIM: Four types of hydrogel embedded with pH-sensitive sensors were evaluated for their accuracy, sensitivity, reversibility, longevity, dynamic response, and consistency in static versus dynamic conditions and long-term storage. APPROACH: Raman spectroscopy was first used to calibrate the intensity of pH-sensitive peaks of the Raman-active hydrogel sensors in a static pH environment. The dynamic response was then assessed for hydrogels exposed to changing pH conditions within a flow cell. Finally, the static pH response after 5 months of storage was determined. RESULTS: All four types of hydrogels allowed the surface-enhanced Raman spectroscopy (SERS) sensors to respond to the pH level of the local environment without introducing interfering signals, resulting in consistent calibration curves. When the pH level changed, the probes in the gels were slow to reach steady-state, requiring several hours, and response times were found to vary among hydrogels. Only one type, poly(2-hydroxyethyl methacrylate) (pHEMA), lasted five months without significant degradation of dynamic range. CONCLUSIONS: While all hydrogels appear to be viable candidates as biocompatible hosts for the SERS sensing chemistry, pHEMA was found to be most functionally stable over the long interval tested. Poly(ethylene glycol) hydrogels exhibit the most rapid response to changing pH. Since these two gel types are covalently cross-linked and do not generally degrade, they both offer advantages over sodium alginate for use as implants.

High-throughput spectral system for interrogation of dermally-implanted luminescent sensors.

Ratiometric luminescent microparticle sensors have been developed for sensing biochemical targets such as glucose in interstitial fluid, enabling use of dermal implants for on-demand monitoring. For these sensor systems to be deployed in vivo, a matched optoelectronic system for interrogation of dermally-implanted sensors was previously designed, constructed, and evaluated experimentally. During evaluation experiments, it revealed that the system efficiency was compromised by losses due to fiber connections of a commercial spectrometer. In this work, a high-throughput spectral system was presented to solve the photon loss problem. This system was designed, constructed, and tested. The throughput was around hundred time more than the previous system we used, and it was cost-effective, as well. It enables use of an integrated system for excitation, collection and measurement of luminescent emission, and will be used as a tool for in vivo studies with animal models or human subjects.

Design of an optical system for interrogation of implanted luminescent sensors and verification with silicone skin phantoms.

Implantable luminescent sensors are being developed for on-demand monitoring of blood glucose levels. For these sensors to be deployed in vivo, a matched external hardware system is needed. In this paper, we designed a compact, low-cost optical system with highly efficient photon delivery and collection using advanced optical modeling software. Compared to interrogation with a fiber bundle, the new system was predicted to improve interrogation efficiency by a factor of 200 for native sensors; an improvement of 37 times was predicted for sensors implanted at a depth of 1 mm in a skin-simulating phantom. A physical prototype was tested using silicone-based skin phantoms developed specifically to mimic the scattering and absorbing properties of human skin. The experimental evaluations revealed that the prototype device performed in agreement with expectations from simulation results, resulting in an overall improvement of over 2000 times. This efficient system enables use of a low-cost commercial spectrometer for recording sensor emission, which was not possible using only fiber optic delivery and collection, and will be used as a tool for in vivo studies with animal models or human subjects.

Role of porosity in tuning the response range of microsphere-based glucose sensors.

Luminescent microspheres encapsulating glucose oxidase have recently been developed as implantable glucose sensors. Previous work has shown that the response range and sensitivity can be tuned by varying the thickness and composition of transport-controlling nanofilm coatings. Nevertheless, the linear response range of these sensors falls significantly below the desired clinical range for in vivo monitoring. We report here an alternative means of tuning the response range by adjusting microsphere porosity. A reaction-diffusion model was first used to evaluate whether increased porosity would be expected to extend the response range by decreasing the flux of glucose relative to oxygen. Sensors exhibiting linear response (R(2)>0.90) up to 600 mg/dL were then experimentally demonstrated by using amine-functionalized mesoporous silica microspheres and polyelectrolyte nanofilm coatings. The model was then used for sensor design, which led to the prediction that sensors constructed from ∼12 µm microspheres having an effective porosity between 0.005 and 0.01 and ∼65 nm transport-limiting coatings would respond over the entire physiological glucose range (up to 600 mg/dL) with maximized sensitivity.

Layer-by-layer assembly for drug delivery and related applications.

INTRODUCTION: High-performance drug delivery systems are always made through assembly and hybridization of multiple components, each of which possesses its own role within the unified delivery function. The layer-by-layer (LbL) adsorption technique offers huge freedom in material selection and flexibility of structural design, which are fully matched with the fabrication needs of drug delivery materials requiring complicated designs. AREAS COVERED: In this review, film-type LbL assemblies and their drug delivery application are focused on, with selected examples from recent years. In addition to a description of the general progress of this technique in bio-related areas, examples of the delivery of low-molecular-mass drugs, DNA, peptides and proteins are summarized, as well as recent advances in film structures composed of organic/inorganic hybrids. EXPERT OPINION: The authors expect that the highly versatile nature of the LbL assembly can overcome any remaining practical difficulties in delivering therapeutics, because the layer structure, component selection, and the surface nature including biocompatibility, degradability and size/dimension are all adjustable. Furthermore, the simple and inexpensive nature of this technique can also satisfy strict demands from an economic point of view.

High-efficiency optical systems for interrogation of dermally-implanted sensors.

Ratiometric Luminescent microparticle sensors have been developed for sensing biochemical targets such as glucose in interstitial fluid, enabling use of dermal implants for on-demand monitoring. For these sensor systems to be deployed in vivo, a matched optoelectronic system for interrogation of dermally-implanted sensors was previously designed, constructed, and evaluated experimentally. During evaluation experiments, it revealed that the system efficiency was compromised by losses due to fiber connections, the entrance aperture, and the entrance slit of the spectrometer. In this work, two optimization methods were investigated to overcome photon loss at fiber connections and internal trade-off between resolution and input light power of the current spectrometer: 1) Replacement of the CCD spectrometer with a two-detector system, enabling extraction of key spectral information by integrating signals over two wavelength regions (reference and sensing emission peaks); and 2) Free-space coupling of the optical probe to a custom low-resolution spectrometer. Photon loss was evaluated by experiments and simulations, preliminary hardware of two-detector system was constructed, and optimization simulations were performed to explore conceptual feasibility of the free-space coupling custom-designed spectrometer.

Three-dimensional, multiwavelength Monte Carlo simulations of dermally implantable luminescent sensors.

Dermally implanted luminescent sensors have been proposed for monitoring of tissue biochemistry, which has the potential to improve treatments for conditions such as diabetes and kidney failure. Effective in vivo monitoring via noninvasive transdermal measurement of emission from injected microparticles requires a matched optoelectronic system for excitation and collection of luminescence. We applied Monte Carlo modeling to predict the characteristics of output luminescence from microparticles in skin to facilitate hardware design. Three-dimensional, multiwavelength Monte Carlo simulations were used to determine the spatial and spectral distribution of the escaping luminescence for different implantation depths, excitation light source properties, particle characteristics, and particle packing density. Results indicate that the ratio of output emission to input excitation power ranged 10(-3) to 10(-6) for sensors at the upper and lower dermal boundaries, respectively, and 95% of the escaping emission photons induced by a 10-mm-diam excitation beam were confined within an 18-mm circle. Tightly packed sensor configurations yielded higher output intensity with fewer particles, even after luminophore concentration effects were removed. Most importantly, for the visible wavelengths studied, the ability to measure spectral changes in emission due to glucose changes was not significantly affected by absorption and scattering of tissue, which supports the potential to accurately track changes in luminescence of sensor implants that respond to the biochemistry of the skin.

Enhancing the longevity of microparticle-based glucose sensors towards 1 month continuous operation.

Luminescent microspheres encapsulating glucose oxidase have recently been reported as potential implantable sensors, but the operational lifetime of these systems has been limited by enzyme degradation. We report here that the longevity of these enzymatic microparticle-based sensors has been extended by the coimmobilization of glucose oxidase (GOx) and catalase (CAT) into the sensor matrix. A mathematical model was used to compare the response and longevity of the sensors with and without catalase. To experimentally test the longevity, sensors were continuously operated under normoglycemic dermal substrate concentrations and physiological conditions (5.5 mM glucose and 140 microM O(2), 37 degrees C and pH 7.4). The sensors incorporating CAT were experimentally shown to be approximately 5 times more stable than those without CAT; nevertheless, the response of sensors with CAT still changed by approximately 20%, when operated continuously for 7 days. The experimentally determined trends obtained for the variation in sensor response due to enzyme deactivation were in close agreement with modeling predictions, which also revealed a significant apparent loss in enzyme activity upon immobilization. It was further predicted via modeling that by incorporating 0.1 mM each of active GOx and CAT, the sensors will exhibit less than 2% variation in response over 1 month of continuous operation.

Experimental validation of an optical system for interrogation of dermally-implanted microparticle sensors.

Dermally-implanted microparticle sensors are being developed for on-demand monitoring of blood sugar levels. For these to be deployed in vivo, a matched optoelectronic system for delivery of excitation, collection and analysis of escaping fluorescent signal is needed. Previous studies predicted the characteristics of fluorescence from microparticle sensors to facilitate design of hardware system. Based on the results of simulations, we designed and constructed the optical part of this opto-electronic system. This study experimentally verified the simulation results and tested the capability of the designed optical system. Reliable skin phantoms sufficient for future dynamic tests were developed. Skin phantoms with different thicknesses were made and the optical properties of skin phantoms were determined with an integrating sphere system and Inverse Adding-Doubling method. Measurements of sensor emission spectrum through phantoms with different thicknesses were done with the designed optical system. Simulations for the experiment situation were performed. The experimental measurements agreed well with simulations in most cases. The results of hardware experiment and validation with skin phantoms provided us with critical information for future dynamic tests and animal experiments.

Optical instrument design for interrogation of dermally-implanted luminescent microparticle sensors.

Luminescence-based sensors have been developed in microparticle formats for biochemical targets such as glucose, enabling use of dermal implants for on-demand monitoring. For these to be deployed and interrogated in vivo, a matched optoelectronic system for delivery of excitation, collection and analysis of luminescence response is needed. In this work, simulations based on Monte Carlo ray-tracing were performed for models of luminescent microparticle materials embedded in skin. The spectral and spatial distribution of luminescence escaping the skin was determined for different concentrations, implantation depths, and input beam sizes. Results indicate that the implant environment does not significantly alter the measured spectral intensity ratios. The escaping emission light possesses measurable power and spectral information for quantitative analysis. Using these findings, an optical system has been designed specifically for sensor interrogation and response acquisition, and is currently implemented in hardware. Following benchtop validation and signal-to-noise maximization with tissue phantoms, the instrument will be used for measurement on sensors in rat subjects.

Polymer/colloid surface micromachining: micropatterning of hybrid multilayers.

Fabrication of multicomponent patterned films comprising polymer/nanoparticle multilayers using conventional lithography and bottom-up layer-by-layer nanofabrication techniques is described. The work is motivated by the potential to extend polymer surface micromachining capabilities toward construction of integrated systems by connecting discrete domains of active materials containing functional nanoparticles. Modified surfaces illustrate tunability of the physical (thickness, roughness, 3D structures) and chemical (inorganic/organic material combinations) properties of the nanocomposite micropatterns. Intriguing nanoscale phenomena were observed for the structures when the order of material deposition was changed; the final multilayer thickness and surface roughness and mechanical integrity of the patterns were found to be interdependent and related to the roughness of layers deposited earlier in the process.