Nitric oxide-releasing polyurethane membranes for implantable electrochemical glucose sensors

The development of novel biocompatible membranes is key to mitigating the host foreign body response (FBR) that limits the utility of implantable electrochemical biosensors for continuous glucose monitoring. Nitric oxide (NO)--an endogenously produced physiological mediator involved in wound healing, angiogenesis, and the inflammatory response--has been shown to reduce the FBR and may enhance sensor utility when released from sensor membranes. Nitric oxide-releasing glucose sensor membranes with tunable release kinetics and total payloads were fabricated utilizing polyurethane (PU) films doped with NO donor-modified silica nanoparticles. A wide range of NO-release fluxes (5−460 pmol cm-2 s-1) and durations (16 h to 14 d) were achieved by altering the type of dopant, as well as the PU sensor membrane composition and concentration. Sensor performance was affected by water uptake and membrane thickness regardless of the type of NO-release vehicle. To combine the potential benefits of both NO-release and porous scaffolds in one engineered material, NO-releasing fibrous PU membranes were fabricated via electrospinning. Electrospun PU fibers doped with NO-releasing silica particles exhibited a wide range of NO-release totals and durations (7.5-120 nmol mg-1 and 7 h to 14 d, respectively). These materials exhibited ~83% porosity with flexible plastic or elastomeric behavior, and a wide range of fiber diameters (119-614 nm) and mechanical strength (moduli of 1.7-34.5 MPa). Nitric oxide-releasing electrospun fibers were applied to needle-type glucose sensors as the outermost membrane. The NO-releasing dendrimer-doped PU fiber mats maintained their porosity in serum without dendrimer leaching. Sensor performance was not significantly impacted by the additional porous membrane (~50 μm thickness). The glucose sensitivity was 2.4 ± 1.6 nA/mM with a dynamic range 1-24 mM, indicating clinically acceptable performance. In vivo analytical sensor performance was assessed using NO-releasing membrane-modified glucose biosensors in a porcine model. The NO-releasing sensors were shown to continuously monitor glucose for one week with 91.8% of determinations indicated as clinically accurate and acceptable. This research illustrated the ability to create functional NO-releasing glucose sensors so future studies can focus on thoroughly evaluating the benefits of NO release and porosity on in vivo analytical performance.Doctor of Philosoph

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

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 NO per mg 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

Comparison of colorimetric analyses to determine cortisol in human sweat

Colorimetric analysis, which relies on a chemical reaction to facilitate a change in visible color, is a great strategy for detecting cortisol, which is necessary to diagnose and manage the wide variety of diseases related to the hormone, because it is simple in design, inexpensive, and reliable as a standard cortisol analysis technique. In this study, four different colorimetric cortisol analyses that use various chromogens, which include sulfuric acid, Porter−Silber reagent, Prussian blue, and blue tetrazolium, are studied. Modifications to the classic Porter−Silber method are made by increasing the carbon content of the alcohol and adding gold nanoparticles, which result in a twofold increase in reaction rate and a slight decrease in the limit of detection (LoD). After a comparison of the reaction rate, LoD, dynamic range, characteristic peaks, and color stability of all methods, blue tetrazolium demonstrates a low LoD (97 ng/mL), broad dynamic range (0.05−2 μg/mL), and quick reaction rate (color development as fast as 10 min), which are well within the requirements for human biofluids. Cortisol in artificial saliva and sweat and in human sweat was determined while confirming that no excipients or other biomarkers interfered with the reactions. Twenty-one human sweat samples were tested using blue tetrazolium and revealed a significant difference between male and female apocrine cortisol concentrations and showed a highly significant difference between apocrine and eccrine cortisol concentrations. Colorimetric methods of cortisol can compete with existing electrochemical sensors because of their similar accuracy and detection range in certain wearable biosensor applications. The simplicity of colorimetric methods advances potential applications in skin-interfaced bio-electronics and point-of-care devices

Sweat and saliva cortisol response to stress and nutrition factors

Cortisol is a biomarker for stress monitoring; however, the biomedical and clinical relevance is still controversial due to the complexity of cortisol secretion mechanisms and their circadian cycles as well as environmental factors that afect physiological cortisol level, which include individual mood and dietary intake. To further investigate this multifaceted relationship, a human pilot study examined cortisol concentration in sweat and saliva samples collected from 48 college-aged participants during aerobic exercise sessions along with mental distress and nutrition surveys. Enzyme-linked immunosorbent assays determined highly signifcant diferences between apocrine-dominant sweat (AP), saliva before exercise (SBE), and saliva after exercise (SAE) cortisol concentration (AP-SBE: p = 0.0017, AP-SAE: p = 0.0102). A signifcantly greater AP cortisol concentration was detected in males compared to females (p = 0.0559), and signifcant SAE cortisol concentration diferences were also recorded between recreational athletes and non-athletes (p= 0.044). However, Kessler 10 Psychological Distress Scale (K10) scores, an examination administered to deduce overall wellness, provided no signifcant diferences between males and females or athletes and non-athletes in distress levels, which statistically signifes a direct relationship to cortisol was not present. For further analysis, dietary intake from all participants was considered to investigate whether a multiplexed association was prevalent between nutrition, mood, and cortisol release. Signifcant positive correlations between AP cortisol, SAE cortisol, K10 scores, and fat intake among female participants and athletes were discovered. The various machine learning algorithms utilized the extensive connections between dietary intake, overall well-being, sex factors, athletic activity, and cortisol concentrations in various biofuids to predict K10 scores. Indeed, the understanding of physiochemical stress response and the associations between studied factors can advance algorithm developments for cortisol biosensing systems to mitigate stress-based illnesses and improve an individual’s quality of life

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

Non-invasive treatment of injuries and disorders affecting bones and connective tissue is a significant challenge facing the medical community. A treatment route that has recently been proposed is nitric oxide (NO) therapy. Nitric oxide plays several 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

Nitric Oxide-Releasing Silica Nanoparticle-Doped Polyurethane Electrospun Fibers

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 coating for subcutaneous implants may improve tissue biocompatibility by mitigating the foreign body response and promoting cell integration

Fabrication of nitric oxide-releasing polyurethane glucose sensor membranes

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

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

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)

Wearable Technology for Chronic Wound Monitoring: Current Dressings, Advancements, and Future Prospects

Chronic non-healing wounds challenge tissue regeneration and impair infection regulation for patients afflicted with this condition. Next generation wound care technology capable of in situ physiological surveillance which can diagnose wound parameters, treat various chronic wound symptoms, and reduce infection at the wound noninvasively with the use of a closed loop therapeutic system would provide patients with an improved standard of care and an accelerated wound repair mechanism. The indicating biomarkers specific to chronic wounds include blood pressure, temperature, oxygen, pH, lactate, glucose, interleukin-6 (IL-6), and infection status. A wound monitoring device would help decrease prolonged hospitalization, multiple doctors' visits, and the expensive lab testing associated with the diagnosis and treatment of chronic wounds. A device capable of monitoring the wound status and stimulating the healing process is highly desirable. In this review, we discuss the impaired physiological states of chronic wounds and explain the current treatment methods. Specifically, we focus on improvements in materials, platforms, fabrication methods for wearable devices, and quantitative analysis of various biomarkers vital to wound healing progress