Long-Term Evaluation of Inserted Nanocomposite Hydrogel-Based Phosphorescent Oxygen Biosensors: Evolution of Local Tissue Oxygen Levels and Foreign Body Response.

Phosphorescence-based oxygen-sensing hydrogels are a promising platform technology for an upcoming generation of insertable biosensors that are smaller, softer, and potentially more biocompatible than earlier designs. However, much remains unknown about their long-term performance and biocompatibility in vivo. In this paper, we design and evaluate a range of hydrogel sensors that contain oxygen-sensitive phosphors stabilized by micro- and nanocarrier systems. These devices demonstrated consistently good performance and biocompatibility in young adult rats for over three months. This study thoroughly establishes the biocompatibility and long-term suitability of phosphorescence lifetime sensors in vivo, providing the groundwork for expansion of this platform technology into a family of small, unobtrusive biosensors for a range of clinically relevant metabolites.

Implementing a Teaching Rural Mobile Health Clinic: Challenges and Adaptations.

In 2022, Penn State College of Medicine launched the LION Mobile Clinic, a teaching mobile health clinic offering preventive health services in rural Snow Shoe, Pennsylvania. We outline four challenges the clinic team faced in implementation, along with adaptations made to tailor the model to Snow Shoe's needs and opportunities.

Glucose biosensors based on Michael addition crosslinked poly(ethylene glycol) hydrogels with chemo-optical sensing microdomains.

Continuous glucose monitoring (CGM) devices have the potential to lead to better disease management and improved outcomes in patients with diabetes. Chemo-optical glucose sensors offer a promising, accurate, long-term alternative to the current CGMs that require frequent calibration and replacement. Recently, we have proposed glucose sensor designs using phosphorescence lifetime-based measurement of chemo-optical glucose sensing microdomains embedded within alginate hydrogels. Due to the poor long-term stability of calcium-crosslinked alginate, we propose poly(ethylene glycol) (PEG) hydrogels synthesized via thiol-Michael addition chemistry as an alternative hydrogel carrier. The objective of this study was to evaluate the suitability of Michael addition crosslinked PEG hydrogels compared to calcium crosslinked alginate hydrogels for encapsulating glucose-sensing microdomains. PEG hydrogels crosslinked via thiol-vinyl sulfone addition achieved gelation in under 5 minutes, resulting in an even distribution of sensing microdomains. The shear storage modulus of the PEG hydrogels was tunable from 2.2 ± 0.1 kPa to 9.5 ± 1.8 kPa, which was comparable to the alginate hydrogels (10.5 ± 0.8 kPa), and the inclusion of microdomains did not significantly impact stiffness. The high water content of PEG hydrogels resulted in high glucose permeability that closely corresponded to the glucose permeability of alginate (D = 0.09 and 0.12 cm2 s-1, respectively; p = 0.47), but the PEG hydrogels exhibited superior stability. Both PEG and alginate-embedded sensors exhibited a sensing range up to ∼200 mg dL-1 glucose. The lower limits of detection (LOD) for PEG and alginate-based glucose sensors were 19.8 and 20.6 mg dL-1 with a difference of just 4.2% variation. The small difference between PEG and alginate embedded sensors indicates that their sensing properties are primarily determined by the glucose sensing microdomains rather than the hydrogel matrix. Overall, the results of this study indicate that Michael addition-crosslinked PEG hydrogels are a promising platform for encapsulation of chemo-optical glucose sensing microdomains.

NIR Luminescent Oxygen-Sensing Nanoparticles for Continuous Glucose and Lactate Monitoring.

A highly sensitive, biocompatible, and scalable phosphorescent oxygen sensor formulation is designed and evaluated for use in continuous metabolite sensors for biological systems. Ethyl cellulose (EC) and polystyrene (PS) nanoparticles (NPs) stabilized with Pluronic F68 (PF 68), Polydimethylsiloxane-b-polyethyleneglycol methyl ether (PDMS-PEG), sodium dodecylsulfate (SDS), and cetyltimethylammonium bromide (CTAB) were prepared and studied. The resulting NPs with eight different surfactant−polymer matrix combinations were evaluated for physical properties, oxygen sensitivity, effect of changes in dispersion matrix, and cytotoxicity. The EC NPs exhibited a narrower size distribution and 40% higher sensitivity than PS, with Stern−Volmer constants (Ksv) 0.041−0.052 µM−1 for EC, compared to 0.029−0.034 µM−1 for PS. Notably, ethyl cellulose NPs protected with PF68 were selected as the preferred formulation, as they were not cytotoxic towards 3T3 fibroblasts and exhibited a wide phosphorescence lifetime response of >211.1 µs over 258−0 µM and ~100 µs over 2.58−0 µM oxygen, with a limit of detection (LoD) of oxygen in aqueous phase of 0.0016 µM. The EC-PF68 NPs were then efficiently encapsulated in alginate microparticles along with glucose oxidase (GOx) and catalase (CAT) to form phosphorescent nanoparticles-in-microparticle (NIMs) glucose sensing microdomains. The fabricated glucose sensors showed a sensitivity of 0.40 µs dL mg−1 with a dynamic phosphorescence lifetime range of 46.6−197.1 µs over 0−150 mg dL−1 glucose, with a glucose LoD of 18.3 mg dL−1 and maximum distinguishable concentration of 111.1 mg dL−1. Similarly, lactate sensors were prepared with NIMs microdomains containing lactate oxidase (LOx) and found to have a detection range of 0−14 mg dL−1 with LoD of 1.8 mg dL−1 and maximum concentration of 13.7 mg dL−1 with lactate sensitivity of 10.7 µs dL mg−1. Owing to its versatility, the proposed NIMs-based design can be extended to a wide range of metabolites and different oxygen-sensing dyes with different excitation wavelengths based on specific application.

Geometry design for a fully insertable glucose biosensor with multimodal optical readout.

Significance: Insertable optical continuous glucose monitors (CGMs) with wearable readers are a strong option for monitoring individuals with diabetes. However, a fully insertable CGM requires a small form factor while still delivering sufficient signal to be read through tissue by an external device. Previous work has suggested that a multimodal repeating unit (barcode) approach may meet these requirements, but the biosensor geometry must be optimized to meet performance criteria. Aim: This work details in silico trials conducted to evaluate the geometry of a fully insertable multimodal optical biosensor with respect to both optical output and species diffusion in vivo. Approach: Monte Carlo modeling is used to evaluate the luminescent output of three presupposed biosensor designs based on size constraints for an injectable and logical placement of the bar code compartments. Specifically, the sensitivity of the luminescent output to displacement of the biosensor in the X and Y directions, overall size of the selected design, and size of an individual repeating unit are analyzed. Further, an experimentally validated multiphysics model is used to evaluate the diffusion and reaction of glucose and oxygen within the biosensor to estimate the occurrence of chemical crosstalk between the assay components. Results: A stacked cylinder multimodal biosensor 4.4 mm in length with repeating units 0.36 mm in length was found to yield a greater luminescent output than the current "barcode" biosensor design. In addition, it was found that a biosensor with enzymatic elements does not significantly deplete glucose locally and thus does not impact the diffusion profile of glucose in adjacent compartments containing nonenzymatic assays. Conclusions: Computational modeling was used to design the geometry of a multimodal, insertable, and optical CGM to ensure that the optical output and chemical diffusion profile are sufficient for this device to function in vivo.

A Computational Modeling and Simulation Workflow to Investigate the Impact of Patient-Specific and Device Factors on Hemodynamic Measurements from Non-Invasive Photoplethysmography.

Cardiovascular disease is the leading cause of death globally. To provide continuous monitoring of blood pressure (BP), a parameter which has shown to improve health outcomes when monitored closely, many groups are trying to measure blood pressure via noninvasive photoplethysmography (PPG). However, the PPG waveform is subject to variation as a function of patient-specific and device factors and thus a platform to enable the evaluation of these factors on the PPG waveform and subsequent hemodynamic parameter prediction would enable device development. Here, we present a computational workflow that combines Monte Carlo modeling (MC), gaussian combination, and additive noise to create synthetic dataset of volar fingertip PPG waveforms representative of a diverse cohort. First, MC is used to determine PPG amplitude across age, skin tone, and device wavelength. Then, gaussian combination generates accurate PPG waveforms, and signal processing enables data filtration and feature extraction. We improve the limitations of current synthetic PPG frameworks by enabling inclusion of physiological and anatomical effects from body site, skin tone, and age. We then show how the datasets can be used to examine effects of device characteristics such as wavelength, analog to digital converter specifications, filtering method, and feature extraction. Lastly, we demonstrate the use of this framework to show the insensitivity of a support vector machine predictive algorithm compared to a neural network and bagged trees algorithm.

Silicone-containing thermoresponsive membranes to form an optical glucose biosensor.

Glucose biosensors that could be subcutaneously injected and interrogated without a physically connected electrode and transmitter affixed to skin would represent a major advancement in reducing the user burden of continuous glucose monitors (CGMs). Towards this goal, an optical glucose biosensor was formed by strategically tailoring a thermoresponsive double network (DN) membrane to house a phosphorescence lifetime-based glucose sensing assay. This membrane was selected based on its potential to exhibit reduced biofouling via 'self-cleaning' due to cyclical deswelling/reswelling in vivo. The membrane was strategically tailored to incorporate oxygen-sensitive metalloporphyrin phosphor, Pd meso-tetra(sulfophenyl)-tetrabenzoporphyrin ([PdPh4(SO3Na)4TBP]3) (HULK) and glucose oxidase (GOx). Specifically, electrostatic interactions and colvalent bonds were used to stabilize HULK and GOx within the membrane, respectively. Enhancing the oxygen permeability of the membrane was necessary to achieve sensitivity of HULK/GOx to physiological glucose levels. Thus, silicone microparticles were incorporated at two concentrations. Key properties of SiHy-0.25 and SiHy-0.5 microparticle-containing compositions were compared to a control having no microparticles (SiHy-0). The discrete nature of the silicone microparticles maintained the desired thermosensitivity profile and did not impact water content. While the modulus decreased with silicone microparticle content, membranes were more mechanically robust versus a conventional hydrogel. SiHy-0.25, owing to apparent phase separation, displayed greater glucose diffusion and oxygen permeability versus SiHy-0.5. Furthermore, SiHy-0.25 biosensors exhibited the greatest glucose sensitivity range of 100 to 300 mg dL-1versus only 100 to 150 mg dL-1 for both SiHy-0 and SiHy-0.5 biosensors.

Monte Carlo method for assessment of a multimodal insertable biosensor.

SIGNIFICANCE: Continuous glucose monitors (CGMs) are increasingly utilized as a way to provide healthcare to the over 10% of Americans that have diabetes. Fully insertable and optically transduced biosensors are poised to further improve CGMs by extending the device lifetime and reducing cost. However, optical modeling of light propagation in tissue is necessary to ascertain device performance. AIM: Monte Carlo modeling of photon transport through tissue was used to assess the luminescent output of a fully insertable glucose biosensor that uses a multimodal Förster resonance energy transfer competitive binding assay and a phosphorescence lifetime decay enzymatic assay. APPROACH: A Monte Carlo simulation framework of biosensor luminescence and tissue autofluorescence was built using MCmatlab. Simulations were first validated against previous research and then applied to predict the response of a biosensor in development. RESULTS: Our results suggest that a diode within the safety standards for light illumination on the skin, with far-red excitation, allows the luminescent biosensor to yield emission strong enough to be detectable by a common photodiode. CONCLUSIONS: The computational model showed that the expected fluorescent power output of a near-infrared light actuated barcode was five orders of magnitude greater than a visible spectrum excited counterpart biosensor.

A Glucose Biosensor Based on Phosphorescence Lifetime Sensing and a Thermoresponsive Membrane.

The adoption of existing continuous glucose monitors (CGMs) is limited by user burden. Herein, a design for a glucose biosensor with the potential for subcutaneous implantation, without the need for a transcutaneous probe or affixed transmitter, is presented. The design is based on the combination of an enzyme-driven phosphorescence lifetime-based glucose-sensing assay and a thermoresponsive membrane anticipated to reduce biofouling. The metalloporphyrin, Pd meso-tetra(sulfophenyl)-tetrabenzoporphyrin ([PdPh4 (SO3 Na)4 TBP]3 , HULK) as well as glucose oxidase (GOx) are successfully incorporated into the UV-cured double network (DN) membranes by leveraging electrostatic interactions and covalent conjugation, respectively. The oxygen-sensitive metalloporphyrin is incorporated at different levels within the DN membranes. These HULK-containing membranes retain the desired thermosensitivity, as well as glucose diffusivity and primary optical properties of the metalloporphyrin. After subsequently modifying the membranes with GOx, glucose-sensing experiments reveal that membranes prepared with the lowest GOx level exhibit the expected increase in phosphorescent lifetime for glucose concentrations up to 200 mg dL-1 . For membranes prepared with relatively higher GOx, oxygen-limited behavior is considered the source of diminished sensitivity at higher glucose levels. This proof-of-concept study demonstrates the promising potential of a biosensor design integrating a specific optical biosensing chemistry into a thermoresponsive hydrogel membrane.

Inorganic-Organic Interpenetrating Network Hydrogels as Tissue-Integrating Luminescent Implants: Physicochemical Characterization and Preclinical Evaluation.

Sensors capable of accurate, continuous monitoring of biochemistry are crucial to the realization of personalized medicine on a large scale. Great strides have been made to enhance tissue compatibility of long-term in vivo biosensors using biomaterials strategies such as tissue-integrating hydrogels. However, the low level of oxygen in tissue presents a challenge for implanted devices, especially when the biosensing function relies on oxygen as a measure-either as a primary analyte or as an indirect marker to transduce levels of other biomolecules. This work presents a method of fabricating inorganic-organic interpenetrating network (IPN) hydrogels to optimize the oxygen transport through injectable biosensors. Capitalizing on the synergy between the two networks, various physicochemical properties (e.g., swelling, glass transition temperature, and mechanical properties) are shown to be independently adjustable while maintaining a 250% increase in oxygen permeability relative to poly(2-hydroxyethyl methacrylate) controls. Finally, these gels, when functionalized with a Pd(II) benzoporphyrin phosphor, track tissue oxygen in real time for 76 days as subcutaneous implants in a porcine model while promoting tissue ingrowth and minimizing fibrosis around the implant. These findings support IPN networks for fine-tuned design of implantable biomaterials in personalized medicine and other biomedical applications.

A Versatile Multichannel Instrument for Measurement of Ratiometric Fluorescence Intensity and Phosphorescence Lifetime.

Optical biosensing is being actively investigated for minimally-invasive monitoring of key biomarkers both in vitro and in vivo. However, typical benchtop instruments are not portable and are not well suited to high-throughput, real-time analysis. This paper presents a versatile multichannel instrument for measurement of emission intensity and lifetime values arising from luminescent biosensor materials. A detailed design description of the opto-electronic hardware as well as the control software is provided, elaborating a flexible, user-configurable system that may be customized or duplicated for a wide range of applications. This article presents experimental measurements that prove the in vitro and in vivo functionality of the system. Such tools may be adopted for many research and development purposes, including evaluation of new biosensor materials, and may also serve as prototypes for future miniaturized handheld or wearable devices.

Sources of Inaccuracy in Photoplethysmography for Continuous Cardiovascular Monitoring.

Photoplethysmography (PPG) is a low-cost, noninvasive optical technique that uses change in light transmission with changes in blood volume within tissue to provide information for cardiovascular health and fitness. As remote health and wearable medical devices become more prevalent, PPG devices are being developed as part of wearable systems to monitor parameters such as heart rate (HR) that do not require complex analysis of the PPG waveform. However, complex analyses of the PPG waveform yield valuable clinical information, such as: blood pressure, respiratory information, sympathetic nervous system activity, and heart rate variability. Systems aiming to derive such complex parameters do not always account for realistic sources of noise, as testing is performed within controlled parameter spaces. A wearable monitoring tool to be used beyond fitness and heart rate must account for noise sources originating from individual patient variations (e.g., skin tone, obesity, age, and gender), physiology (e.g., respiration, venous pulsation, body site of measurement, and body temperature), and external perturbations of the device itself (e.g., motion artifact, ambient light, and applied pressure to the skin). Here, we present a comprehensive review of the literature that aims to summarize these noise sources for future PPG device development for use in health monitoring.

The efficacy of sustainability reporting towards cost of debt and equity reduction.

This paper empirically investigates the impact of overall sustainability reporting as well as its components (economic, environmental, and social sustainability reporting) on the cost of debt and equity capital for Malaysian oil and gas companies. The data was collected from 41 publicly listed oil and gas companies in Malaysia for the period from 2008 to 2017. Qualitative information was gathered for sustainability reporting and then converted into quantitative form by assigning weights according to the extent of reporting. The cost of capital information was sourced through Thomson Reuters Datastream. Panel data analysis was employed using generalized least square (GLS) random effects regression to examine the relationship between sustainability reporting and cost of capital. Firm reputation, size, and profitability were included as control variables. The findings indicate that overall sustainability reporting and one component, economic sustainability reporting, reduce both cost of debt and cost of equity. However, environmental sustainability reporting reduces only the cost of debt but does not reduce the cost of equity. Social sustainability reporting shows no effect on the cost of debt or equity. The findings of this paper should be useful for regulators, legislators, shareholders, creditors, and practitioners in pursuing sustainability practices that not only improve economic and environmental performance but also enhance overall performance by reducing the cost of capital. The results of the paper highlight that companies investing in sustainability can generate positive value through the enhancement of reputational capital. This study is the first to empirically investigate the relationship between overall sustainability reporting, including its three components, and the cost of both debt and equity capital.

An Optical Urate Biosensor Based on Urate Oxidase and Long-Lifetime Metalloporphyrins.

Gout is a condition that affects over 8 million Americans. This condition is characterized by severe pain, and in more advanced cases, bone erosion and joint destruction. This study explores the fabrication and characterization of an optical, enzymatic urate biosensor for gout management, and the optimization of the biosensor response through the tuning of hydrogel matrix properties. Sensors were fabricated through the co-immobilization of oxygen-quenched phosphorescent probes with an oxidoreductase within a biocompatible copolymer hydrogel matrix. Characterization of the spectral properties and hydrogel swelling was conducted, as well as evaluation of the response sensitivity and long-term stability of the urate biosensor. The findings indicate that increased acrylamide concentration improved the biosensor response by yielding an increased sensitivity and reduced lower limit of detection. However, the repeatability and stability tests highlighted some possible areas of improvement, with a consistent response drift observed during repeatability testing and a reduction in response seen after long-term storage tests. Overall, this study demonstrates the potential of an on-demand, patient-friendly gout management tool, while paving the way for a future multi-analyte biosensor based on this sensing platform.

Hydrogel Microdomain Encapsulation of Stable Functionalized Silver Nanoparticles for SERS pH and Urea Sensing.

Conceptual and commercial examples of implantable sensors have been limited to a relatively small number of target analytes, with a strong focus on glucose monitoring. Recently, surface-enhanced Raman spectroscopy (SERS) pH sensors were demonstrated to track acid-producing enzymatic reactions targeting specific analytes. We show here that SERS pH tracking in the basic regime is also possible, and can be used to monitor urea concentration. To accomplish this, we developed a hydrogel consisting of polyelectrolyte multilayer microcapsules containing a SERS-sensitive pH reporter (4-mercapopyridine capped silver nanoparticles modified with bovine serum albumin). This pH sensing material exhibited a sensitive Raman scattering response to a wide range of pH from 6.5-9.7. By incorporating urease into the hydrogel matrix, the new sensor was capable of distinguishing urea concentrations of 0, 0.1, 1, and 10 mM. We also found that bovine serum albumin (BSA) prevented severe aggregation of the nanoparticle-based pH sensor, which improved sensing range and sensitivity. Furthermore, BSA safeguarded the pH sensor during the encapsulation procedure. Together, the combination of materials represents a novel approach to enabling optical sensing of reactions that generate pH changes in the basic range.

Multidomain-Based Responsive Materials with Dual-Mode Optical Readouts.

Responsive materials designed to generate signals for both surface-enhanced Raman spectroscopy (SERS) and phosphorescence lifetime-"dual-mode"-measurements are described. To demonstrate this concept, we incorporated pH-sensitive and oxygen-sensitive microdomains into a single hydrogel that could be interrogated via SERS and phosphorescence lifetime, respectively. Microdomains consisted two populations of discrete microcapsules containing either (1) gold nanoparticles capped with pH-sensitive Raman molecules or (2) oxygen-sensitive benzoporphyrin phosphors. While the microdomain-embedded hydrogels presented an expected background luminescence, the pH-sensitive SERS signal was distinguishable for all tested conditions. Response characteristics of the dual sensor showed no significant difference when compared to standalone single-mode pH and oxygen sensors. In addition, the feasibility of redundant multimode sensing was proven by observing the reaction produced by glucose oxidase chemically cross-linked within the corresponding alginate matrix. Each optical mode showed a signal change proportional to glucose concentration with an opposite signal directionality. These results support the promise of micro-/nanocomposite materials to improve measurement accuracy using intrinsic multimode responses and built-in redundancy, concepts that have broad appeal in the chemical sensing and biosensing fields.

The Feasibility of Venovenous ECMO at Role-2 Facilities in Austere Military Environments.

INTRODUCTION: Venovenous extracorporeal membrane oxygenation (VV-ECMO) has been gaining use to bridge the recovery from acute respiratory distress syndrome (ARDS) refractory to conventional treatment. However, these interventions are often limited to higher echelons of military care. We present a case of lung salvage from severe ARDS in an Afghani soldier with VV-ECMO at a Role-2 (R2) facility in an austere military environment in Afghanistan. CASE: A 25-year-old Afghani soldier presented to an R2 facility with blast lung injury and multiple penetrating injuries following an explosion. The patient underwent immediate damage control laparotomy. The abdomen was left open for subsequent washouts and ongoing resuscitation. Due to his ineligibility for evacuation and worsening ARDS, despite 5 d of conventional ventilation strategies, he was started on VV-ECMO. The patient had immediate improvements in oxygenation, which continued for 10 d. Moreover, he underwent three transportations to the operating room without accidental decannulation or disruption of the VV-ECMO device. Despite significant improvements, the patient expired on postoperative day 15, due to an overwhelming intra-abdominal sepsis. CONCLUSION: As future advancements are sought, VV-ECMO may become a consideration for casualties with severe ARDS at the point of injury and at lower echelons of military care.

Medication Reconciliation in the Hospital: An Interactive Case-Based Session for Internal Medicine Residents.

Introduction: Medication reconciliation is a complex process of creating and maintaining the most accurate medication list for a patient to help guide therapy. Done incorrectly, the process of medication reconciliation can lead to medical error and result in adverse events for patients. Medication reconciliation on inpatient medicine service is often done by internal medicine residents. However, published reports of educational interventions for residents are limited. Methods: We created a 1-hour session that was experiential, case based, and targeted to the level of a first-year resident. In total, 31 internal medicine residents completed the curriculum, which involved either a 1-hour classroom group activity or an individual virtual activity. The curriculum was evaluated using standard forms with qualitative feedback regarding learner satisfaction, pre- and postsession confidence survey, and pre- and postsession patient chart audits. Results: Qualitative feedback demonstrated residents' positive experiences. There was no significant change in residents' confidence in portions of the medication reconciliation process. One month following the educational intervention, 100% of inpatient charts audited for review of the medication list were accurate, as compared to 67%-83% accuracy prior to the session. Discussion: This novel case-based medication reconciliation teaching session, targeted at learners in an internal medicine residency, can easily be implemented at other institutions using the institution-specific electronic health record. The session was well received by residents, and we observed improved accuracy in the medication reconciliation process done by residents.