Ahyeon Koh

Biocompatible materials for continuous glucose monitoring devices.

Diabetes mellitus is a worldwide epidemic characterized by chronic hyperglycemia that results from either a deficiency or tolerance in insulin.1 In the United States, 8.3% of the population currently has diabetes and that number is projected to increase to 1 in 3 adults by 2050 if current trends continue.2 As a consequence, diabetes is the seventh leading cause of death with an annual cost burden of

A soft, wearable microfluidic device for the capture, storage, and colorimetric sensing of sweat

174 billion in the United States, including

Local delivery of nitric oxide: targeted delivery of therapeutics to bone and connective tissues.

116 billion in direct medical expenses.2 Blood glucose levels in diabetics fluctuate significantly throughout the day, resulting in serious complications including heart attacks, strokes, high blood pressure, kidney failure, blindness and limb amputation.1–2 Portable glucose sensors give patients the ability to monitor blood glucose levels, manage insulin levels, and reduce the morbidity and mortality of diabetes mellitus. Traditional glucose monitoring techniques are primarily based on the use of electrochemical amperometric glucose sensors. In 1987, Medisense Inc. launched the first personal glucose testing device consisting of a test strip and reader. Over 40 different commercial pocket-sized monitors have been introduced since then.3 To date, the U.S. Food and Drug Administration (FDA) has approved >25 glucose monitors with the majority employing test strips consisting of either glucose dehydrogenase (GDH) or glucose oxidase (GOx) immobilized on a screen-printed electrode.4 The analysis is based on obtaining a small blood sample (<1 μL) through a finger prick that is subsequently introduced into the test strip via capillary action.3–4 While these monitors have augmented the health outcomes for people with diabetes by improving blood glucose management, such monitoring only provides instantaneous blood glucose concentrations that are unable to warn of hyperglycemic or hypoglycemic events in advance. Additionally, the sample collection (i.e., finger prick) method is inconvenient resulting in poor patient compliance. Analytical methods that enable continuous monitoring of blood glucose have thus been sought.5 Continuous glucose monitoring (CGM) provides real-time information on trends (i.e., whether the glucose levels are increasing or decreasing), magnitude, duration, and frequency of glucose fluctuations during the day.5–6 Ideally, analytically functional continuous glucose monitoring devices could be linked to an insulin delivery pump, creating an artificial pancreas.5–6 In this review, we describe progress in the development of continuous glucose monitoring technologies, specifically focusing on subcutaneous implantable electrochemical glucose sensors, which are widely studied and commercially available. We discuss the challenges associated with the development of biocompatible coatings for electrochemical glucose sensors. Borrowing from the ideas of David Williams, we consider sensor coatings to be “biocompatible” if they optimize the clinical relevance of the sensor, avoid any negative local and systemic effects, and elicit the most appropriate local tissue response adjacent to the implant.7

Fabrication of Nitric Oxide-Releasing Porous Polyurethane Membranes Coated Needle-Type Implantable Glucose Biosensors

A soft, skin-mounted microfluidic device captures microliter volumes of sweat and quantitatively measures biochemical markers by colorimetric analysis. Better health? Prepare to sweat Wearable technology is a popular way many people monitor their general health and fitness, tracking heart rate, calories, and steps. Koh et al. now take wearable technology one step further. They have developed and tested a flexible microfluidic device that adheres to human skin. This device collects and analyzes sweat during exercise. Using colorimetric biochemical assays and integrating smartphone image capture analysis, the device detected lactate, glucose, and chloride ion concentrations in sweat as well as sweat pH while stuck to the skin of individuals during a controlled cycling test. Colorimetric readouts showed comparable results to conventional analyses, and the sweat patches remained intact and functional even when used during an outdoor endurance bicycle race. The authors suggest that microfluidic devices could be used during athletic or military training and could be adapted to test other bodily fluids such as tears or saliva. Capabilities in health monitoring enabled by capture and quantitative chemical analysis of sweat could complement, or potentially obviate the need for, approaches based on sporadic assessment of blood samples. Established sweat monitoring technologies use simple fabric swatches and are limited to basic analysis in controlled laboratory or hospital settings. We present a collection of materials and device designs for soft, flexible, and stretchable microfluidic systems, including embodiments that integrate wireless communication electronics, which can intimately and robustly bond to the surface of the skin without chemical and mechanical irritation. This integration defines access points for a small set of sweat glands such that perspiration spontaneously initiates routing of sweat through a microfluidic network and set of reservoirs. Embedded chemical analyses respond in colorimetric fashion to markers such as chloride and hydronium ions, glucose, and lactate. Wireless interfaces to digital image capture hardware serve as a means for quantitation. Human studies demonstrated the functionality of this microfluidic device during fitness cycling in a controlled environment and during long-distance bicycle racing in arid, outdoor conditions. The results include quantitative values for sweat rate, total sweat loss, pH, and concentration of chloride and lactate.

The effect of nitric oxide surface flux on the foreign body response to subcutaneous implants.

Non-invasive treatment of injuries and disorders affecting bone and connective tissue remains a significant challenge facing the medical community. A treatment route that has recently been proposed is nitric oxide (NO) therapy. Nitric oxide plays several important roles in physiology with many conditions lacking adequate levels of NO. As NO is a radical, localized delivery via NO donors is essential to promoting biological activity. Herein, we review current literature related to therapeutic NO delivery in the treatment of bone, skin and tendon repair.

Fabrication of nitric oxide-releasing polyurethane glucose sensor membranes.

The active release of pharmaceutical agents and the use of porous sensor membranes represent the two most promising strategies for addressing the poor tissue biocompatibility of implantable glucose biosensors. Herein, we describe the combination of these approaches to create nitric oxide (NO)-releasing porous fiber mat-modified sensor membranes. An electrospinning method was used to directly modify needle-type glucose biosensors with the NO donor-loaded fibers. The resulting NO-releasing fiber mat (540 ± 139 nm fiber diameter, 94.1 ± 3.7% porosity) released ~100 nmol of NO per mg of polyurethane over 6 h while maintaining a porous structure without leaching of the NO donor, even in serum. The porous fiber membrane did not influence the analytical performance of the biosensor when ≤50 μm thick.

Nitric Oxide-Releasing Silica Nanoparticle-Doped Polyurethane Electrospun Fibers

Although the release of nitric oxide (NO) from biomaterials has been shown to reduce the foreign body response (FBR), the optimal NO release kinetics and doses remain unknown. Herein, polyurethane-coated wire substrates with varying NO release properties were implanted into porcine subcutaneous tissue for 3, 7, 21 and 42 d. Histological analysis revealed that materials with short NO release durations (i.e., 24 h) were insufficient to reduce the collagen capsule thickness at 3 and 6 weeks, whereas implants with longer release durations (i.e., 3 and 14 d) and greater NO payloads significantly reduced the collagen encapsulation at both 3 and 6 weeks. The acute inflammatory response was mitigated most notably by systems with the longest duration and greatest dose of NO release, supporting the notion that these properties are most critical in circumventing the FBR for subcutaneous biomedical applications (e.g., glucose sensors).

Glucose sensor membranes for mitigating the foreign body response

Despite clear evidence that polymeric nitric oxide (NO) release coatings reduce the foreign body response (FBR) and may thus improve the analytical performance of in vivo continuous glucose monitoring devices when used as sensor membranes, the compatibility of the NO release chemistry with that required for enzymatic glucose sensing remains unclear. Herein, we describe the fabrication and characterization of NO-releasing polyurethane sensor membranes using NO donor-modified silica vehicles embedded within the polymer. In addition to demonstrating tunable NO release as a function of the NO donor silica scaffold and polymer compositions and concentrations, we describe the impact of the NO release vehicle and its release kinetics on glucose sensor performance.

Ultrathin Injectable Sensors of Temperature, Thermal Conductivity, and Heat Capacity for Cardiac Ablation Monitoring

Electrospun polyurethane fibers doped with nitric oxide (NO)-releasing silica particles are presented as novel macromolecular scaffolds with prolonged NO-release and high porosity. Fiber diameter (119-614 nm) and mechanical strength (1.7-34.5 MPa of modulus) were varied by altering polyurethane type and concentration, as well as the NO-releasing particle composition, size, and concentration. The resulting NO-releasing electrospun nanofibers exhibited ~83% porosity with flexible plastic or elastomeric behavior. The use of N-diazeniumdiolate- or S-nitrosothiol-modified particles yielded scaffolds exhibiting a wide range of NO release totals and durations (7.5 nmol mg(-1)-0.12 μmol mg(-1) and 7 h to 2 weeks, respectively). The application of NO-releasing porous materials as coatings for subcutaneous implants may improve tissue biocompatibility by mitigating the foreign body response and promoting cell integration.

Needle-shaped ultrathin piezoelectric microsystem for guided tissue targeting via mechanical sensing

Continuous glucose monitoring devices remain limited in their duration of use due to difficulties presented by the foreign body response (FBR), which impairs sensor functionality immediately following implantation via biofouling and leukocyte infiltration. The FBR persists through the life of the implant, culminating with fibrous encapsulation and isolation from normal tissue. These issues have led researchers to develop strategies to mitigate the FBR and improve tissue integration. Studies have often focused on abating the FBR using various outer coatings, thereby changing the chemical or physical characteristics of the sensor surface. While such strategies have led to some success, they have failed to fully integrate the sensor into surrounding tissue. To further address biocompatibility, researchers have designed coatings capable of actively releasing biological agents (e.g., vascular endothelial growth factor, dexamethasone, and nitric oxide) to direct the FBR to induce tissue integration. Active release approaches have proven promising and, when combined with biocompatible coating materials, may ultimately improve the in vivo lifetime of subcutaneous glucose biosensors. This article focuses on strategies currently under development for mitigating the FBR.