Integrated sensing and delivery of oxygen for next-generation smart wound dressings.

Chronic wounds affect over 6.5 million Americans and are notoriously difficult to treat. Suboptimal oxygenation of the wound bed is one of the most critical and treatable wound management factors, but existing oxygenation systems do not enable concurrent measurement and delivery of oxygen in a convenient wearable platform. Thus, we developed a low-cost alternative for continuous O2 delivery and sensing comprising of an inexpensive, paper-based, biocompatible, flexible platform for locally generating and measuring oxygen in a wound region. The platform takes advantage of recent developments in the fabrication of flexible microsystems including the incorporation of paper as a substrate and the use of a scalable manufacturing technology, inkjet printing. Here, we demonstrate the functionality of the oxygenation patch, capable of increasing oxygen concentration in a gel substrate by 13% (5 ppm) in 1 h. The platform is able to sense oxygen in a range of 5-26 ppm. In vivo studies demonstrate the biocompatibility of the patch and its ability to double or triple the oxygen level in the wound bed to clinically relevant levels.

A mass-customizable dermal patch with discrete colorimetric indicators for personalized sweat rate quantification.

In this paper, we present a disposable, colorimetric, user-friendly and mass-customizable dermal patch for chronological collection and discrete real-time in situ measurement of sweat secretion over a small area of skin. The patch consists of a laminated filter paper patterned into radially arranged channels/fingers with water-activated dyes at their tips. As channels are filled during perspiration, their tips change color once fully saturated, providing easily identifiable levels of water loss which in turn can be mapped to personal dehydration levels. The patch can be manufactured at low cost in a variety of sizes to allow hydration monitoring for individuals participating in activities under different conditions (intensity, temperature, humidity, etc.). Furthermore, we describe an analytical model that enables mass customization of such a flexible wearable system accommodating a broad range of sweat rates and volumes to generate patch designs that are personalized to an individual's sweat rate, desired time of usage, and the temporal resolution of the required feedback. As a proof-of-concept demonstration, we characterized laser-fabricated patches that cover (7 cm × 5 cm) area of skin having various wicking materials, thicknesses (180-540 µm), and pore sizes (3-11 µm). Tests were conducted at various flow rates simulating different sweating intensities in the range of 1.5-15 mg/cm2/min. Experimental results for the case of a half-marathon runner targeting 90 min of usage and sweating at a rate of 1.5 mg/cm2/min indicated measurement accuracy of 98.3% when the patch is completely filled.

A pH-regulated drug delivery dermal patch for targeting infected regions in chronic wounds.

This work presents a low-cost, passive, flexible, polymeric pump for topical drug delivery which uses wound pH as a trigger for localized drug release. Its operation relies on a pH-responsive hydrogel actuator which swells when exposed to the alkaline pH of an infected wound. The pump enables slow release (<0.1 µL min-1) of aqueous anti-bacterial solution for up to 4 hours and sustains against up to 8 kPa of backpressure. Featuring a scalable layer-by-layer fabrication technique to expand the pump into a 2 × 2 array, the device can dispense 50 µl onto a 160 mm2 dermal coverage within 4 hours. Robustness tests show that when integrated within a medical adhesive, the device can be worn around the forearm and can withstand various daily activities (non-intensive) for up to 12 hours. In vitro experiments demonstrate a 58 times decrease of live P. aeruginosa after 24 hours of the pump assisted antibiotics treatment.

Laser-treated glass platform for rapid wicking-driven transport and particle separation in bio microfluidics.

In this work, we present a laser-based fabrication technique for direct patterning of micro-channels consisting of interconnected micro-cracks on soda-lime glass. Using a CO2 laser to deposit energy at a linear rate of 18.75 to 93.75 mJ mm-1, we were able to manipulate the micro-crack formation, while enabling rapid manufacturing and scalable production of cracked-glass microfluidic patterns on glass. At the higher end of the energy deposition rate (93.75 mJ mm-1), the laser fabricated microfluidic channels (1 mm wide and 20 mm long) had extremely fast wicking speeds (24.2 mm s-1, ×10 faster than filter paper) as a result of significant capillary action and laser-induced surface hydrophilization. At the lower end (18.75 mJ mm-1), 3-4 µm wide micro-cracked crevices resulted in an increased mesh/sieve density, hence, more efficiently filtering particle-laden liquid samples. The reproducibility tests revealed an averaged wicking speed of 10.6 ± 1.5 mm s-1 measured over 21 samples fabricated under similar conditions, similar to that of filter paper (∼85%). The micro-cracked channels exhibited a stable shelf life of at least 82 days with a wicking speed within 10-13 mm s-1.

Rapid prototyping of a novel and flexible paper based oxygen sensing patch via additive inkjet printing process.

A novel and flexible oxygen sensing patch was successfully developed for wearable, industrial, food packaging, pharmaceutical and biomedical applications using a cost-efficient and rapid prototypable additive inkjet print manufacturing process. An oxygen sensitive ink was formulated by dissolving ruthenium dye and ethyl cellulose polymer in ethanol in a 1 : 1 : 98 (w/w/w) ratio. The patch was fabricated by depositing the oxygen sensitive ink on a flexible parchment paper substrate using an inkjet printing process. A maximum absorbance from 430 nm to 480 nm and a fluorescence of 600 nm was observed for the oxygen sensitive ink. The capability of the oxygen sensitive patch was investigated by measuring the fluorescence quenching lifetime of the printed dye for varying oxygen concentration levels. A fluorescence lifetime decay (τ) from ≈4 µs to ≈1.9 µs was calculated for the printed oxygen sensor patch, for oxygen concentrations varying from ≈5 mg L-1 to ≈25 mg L-1. A sensitivity of 0.11 µs mg L-1 and a correlation coefficient of 0.9315 was measured for the printed patches. The results demonstrated the feasibility of employing an inkjet printing process for the rapid prototyping of flexible and moisture resistant oxygen sensitive patches which facilitates a non-invasive method for monitoring oxygen and its concentration levels.

Early Experience With Nonporous Polyethylene Barrier Sheet in Orbital Fracture Repair.

PURPOSE: The aim of this study was to evaluate the efficacy of the nonporous polyethylene barrier sheet as an alternative for nylon foil (SupraFOIL) implants in repair of orbital fractures. METHODS: This is a prospective, case series using the Stryker 0.4-mm-thick nonporous polyethylene barrier sheet in all patients over the age of 18 years presenting with orbital fractures from December 2014 to June 2015. Patient's age, location of fracture, etiology of injury, presence of preoperative restriction and diplopia, and postoperative diplopia and/or enophthalmos was recorded. Institutional review board approval was received, and consent was obtained from all participants. Patients were followed for at least 6 months when possible. Scanning electron microscopy was used to compare the thickness, surface characteristics, and porosity of the nonporous polyethylene barrier and nylon foil implants. Beam deflection testing was also performed to compare the biomechanical properties of each implant. RESULTS: Forty-six patients who underwent repair of orbital fractures with the nonporous polyethylene barrier sheet were included in this series. Average age was 43.3 years (range: 18-84 years). Twenty-six of 46 patients (56.5%) were males, and 20 (43.4%) were females. The most common causes of injuries were assault (38.3%), falls (25.5%), motor vehicle accident (14.9%), and sports related (10.5%). Twenty of 46 patients (43.4%) had isolated orbital floor, and 2 patients (4.3%) had isolated medial wall fractures. Fifteen patients (32.6%) had combined floor and medial wall fractures involving the inferomedial orbital strut, and 9 (19.6%) had floor fractures associated with zygomaticomaxillary complex or lateral wall fractures. Twenty-eight patients (60.9%) had preoperative diplopia. Timing of surgery was between 3 and 55 days, with the median of 11.5 days. Five of 46 patients (10.8%) had residual diplopia at their 1-week postoperative visit, 4 of those patients' diplopia had resolved at 2 months postoperatively. One patient had residual diplopia at 6-month follow up. Electron microscopy showed that the 0.4-mm nonporous polyethylene barrier implant was thinner (0.33 mm) than expected and thinner than 0.4-mm SupraFOIL (0.38 mm). Scanning electron microscopy exhibited that the surface of the nonporous polyethylene barrier was smooth and nonporous. Beam deflection testing showed that for small forces (<100 mN), the 2 materials behaved nearly identically, but at higher forces, the nonporous polyethylene implant exhibited less stiffness. CONCLUSIONS: The use of nonporous polyethylene barrier sheet implant for orbital fracture repair is a safe and effective alternative to nonporous nylon foil implants. There were no complications and one case of residual diplopia (2.1%) in this case series.

Comparison of Direct and Indirect Laser Ablation of Metallized Paper for Inexpensive Paper-Based Sensors.

In this work, we present a systematic study of laser processing of metallized papers (MPs) as a simple and scalable alternative to conventional photolithography-based processes and printing technologies. Two laser-processing methods are examined in terms of selectivity for the removal of the conductive aluminum film (25 nm) of an MP substrate; these processes, namely direct and indirect laser ablation (DLA and ILA), operate at wavelengths of 1.06 µm (neodymium-doped yttrium aluminum garnet) and 10.6 µm (CO2), respectively. The required threshold energy for each laser processing method was systematically measured using electrical, optical, and mechanical characterization techniques. The results of these investigations show that the removal of the metal coating using ILA is only achieved through partial etching of the paper substrate. The ILA process shows a narrow effective set of laser settings capable of removing the metal film while not completely burning through the paper substrate. By contrast, DLA shows a more defined and selective removal of the aluminum layer without damaging the mechanical and natural fibular structure of the paper substrate. Finally, as a proof of concept, interdigitated capacitive moisture sensors were fabricated by means of DLA and ILA onto the MP substrate, and their performance was assessed in the humidity range of 2-85%. The humidity sensitivity results show that the DLA sensors have a superior humidity sensing performance compared to the ILA sensors. The observed behavior is attributed to the higher water molecule absorption and induced capillary condensation within the intact cellulose network resulting from the DLA process (compared to the damaged one from the ILA process). The DLA process of MP should enable scalable production of low-cost, paper-based physical and chemical sensing systems for potential use in point-of-care diagnostics and food packaging.

Smart Bandage for Monitoring and Treatment of Chronic Wounds.

Chronic wounds are a major health concern and they affect the lives of more than 25 million people in the United States. They are susceptible to infection and are the leading cause of nontraumatic limb amputations worldwide. The wound environment is dynamic, but their healing rate can be enhanced by administration of therapies at the right time. This approach requires real-time monitoring of the wound environment with on-demand drug delivery in a closed-loop manner. In this paper, a smart and automated flexible wound dressing with temperature and pH sensors integrated onto flexible bandages that monitor wound status in real-time to address this unmet medical need is presented. Moreover, a stimuli-responsive drug releasing system comprising of a hydrogel loaded with thermo-responsive drug carriers and an electronically controlled flexible heater is also integrated into the wound dressing to release the drugs on-demand. The dressing is equipped with a microcontroller to process the data measured by the sensors and to program the drug release protocol for individualized treatment. This flexible smart wound dressing has the potential to significantly impact the treatment of chronic wounds.

Significant and safe reduction of propofol sedation dose for geriatric population undergoing pacemaker implantation: randomized clinical trial.

OBJECTIVE: A previous multidisciplinary pilot study based on computer simulations for the geriatric population showed that a dose of 0.5 mg/kg/h of propofol could sedate patients older than 65 for pacemaker implantation. The present study validates that the pacemaker implantation can be done in the elderly using 0.5-1 mg/kg/h of propofol with hemodynamic stability. METHODS: 66 patients from 65 to 88 years old scheduled for pacemaker implantation were randomly assigned one of three doses of propofol. The first group received 2 mg/kg/h of propofol (P2) that is within normal range of the sedation dose. The second group received 1 mg/kg/h (P1) dose and the third group received the dose of 0.5 mg/kg/h (P0.5) according to the simulation-predicted dose for geriatric populations. RESULTS: All patients kept MAP between 76 and 85 mmHg, with no hypotension episodes in any of the groups; therefore, they were all hemodynamically stable during the procedure. BIS was between 80 and 65 during the pacemaker implantation for the three groups, BIS of group P2 was significantly lower than the other groups. BIS in groups P1 and P0.5 was within the appropriated range for moderate sedation. Brice was positive for auditory recalls only when there was arousing noise in the operating room. CONCLUSIONS: Moderate sedation, adequate for pacemaker implantation, can be achieved infusing 0.5-1 mg/kg/h of propofol in elderly patients when the patient has proper analgesia management at the device implantation site. The second important condition is to avoid unnecessary and alerting auditory and mechanical stimuli in the operating room, so that the patient will remain calm.

Gradient-on-a-Chip with Reactive Oxygen Species Reveals Thresholds in the Nucleus Response of Cancer Cells Depending on the Matrix Environment.

Oxidative stress-mediated cancer progression depends on exposure to reactive oxygen species (ROS) in the extracellular matrix (ECM). To study the impact of ROS levels on preinvasive breast cancer cells as a function of ECM characteristics, we created a gradient-on-a-chip in which H2O2 progressively mixes with the cell culture medium within connected microchannels and diffuses upward into the ECM of the open cell culture window. The device utilizes a paper-based microfluidic bifurcating mixer insert to prevent leakage and favor an even fluid distribution. The gradient was confirmed by measuring H2O2 catalyzed into oxygen, and increasing oxidative DNA damage and protective (AOP2) response were recorded in 2D and ECM-based 3D cell cultures. Interestingly, the impact of ROS on nuclear shape and size (annunciating phenotypical changes) was governed by the stiffness of the collagen I matrix, suggesting the existence of thresholds for the phenotypic response to microenvironmental chemical exposure depending on ECM conditions.

Directly embroidered microtubes for fluid transport in wearable applications.

We demonstrate, for the first time, a facile and low-cost approach for integrating highly flexible and stretchable microfluidic channels into textile-based substrates. The integration of the microfluidics is accomplished by means of directly embroidering surface-functionalized micro-tubing in a zigzag/meander pattern and subsequently coating it with an elastomer for irreversible bonding. We show the utility of the embroidered micro-tubing by developing robust and stretchable drug-delivery and electronic devices. Controlled drug-delivery platforms with sustained release are achieved through selected laser ablated openings. We further demonstrate a wearable wireless resonant displacement sensor capable of detecting strains ranging from 0 to 60% with an average sensitivity of 45 kHz per % strain by filling the embroidered tubing with a liquid metal alloy, creating stretchable conductive microfluidics with <0.4 Ω resistance variations at their maximum stretchability (100%). The interconnects can withstand 1500 repeated stretch-and-release cycles at 30% strain with a less than 0.1 Ω change in resistance.

Skin Regeneration Using Dermal Substrates that Contain Autologous Cells and Silver Nanoparticles to Promote Antibacterial Activity: In Vitro Studies.

We hypothesized that the addition of silver nanoparticles (AgNP) to a dermal substrate would impart antibacterial properties without inhibiting the proliferation of contained cells. Our in vitro model was based on the commercial substrate, Integra. The substrate was prepared by simple immersion into 0 to 1% suspension of AgNP (75 or 200 nm diameter) followed by rinsing for 20 minutes and sterilization under an ultraviolet C lamp. A total of 107 human adipose stem cells per cubic centimeter were injected and after 1 hour, 6 × 105 keratinocytes/cm2 were seeded and cultured for up to 14 days. Constructs were evaluated using a metabolic assay (WST-1), and hematoxylin and eosin and immunoperoxidase staining. Bactericidal activity was measured using a log reduction assay against bacteria that are prevalent in burns. The presence of AgNP did not significantly change the metabolic activity of constructs after 14 days of culture, and the distribution of cells within the substrate was unchanged from the controls that did not have AgNP. Antibacterial activity of Integra containing AgNP (75 nm diameter) was concentration dependent. In conclusion, the addition of AgNP to the dermal substrate suppressed bacterial growth but did not significantly affect cell proliferation, and may represent an important property to incorporate into a future clinical skin regeneration system.

Highly Stretchable Potentiometric pH Sensor Fabricated via Laser Carbonization and Machining of Carbon-Polyaniline Composite.

The development of stretchable sensors has recently attracted considerable attention. These sensors have been used in wearable and robotics applications, such as personalized health-monitoring, motion detection, and human-machine interfaces. Herein, we report on a highly stretchable electrochemical pH sensor for wearable point-of-care applications that consists of a pH-sensitive working electrode and a liquid-junction-free reference electrode, in which the stretchable conductive interconnections are fabricated by laser carbonizing and micromachining of a polyimide sheet bonded to an Ecoflex substrate. This method produces highly porous carbonized 2D serpentine traces that are subsequently permeated with polyaniline (PANI) as the conductive filler, binding material, and pH-sensitive membrane. The experimental and simulation results demonstrate that the stretchable serpentine PANI/C-PI interconnections with an optimal trace width of 0.3 mm can withstand elongations of up to 135% and are robust to more than 12 000 stretch-and-release cycles at 20% strain without noticeable change in the resistance. The pH sensor displays a linear sensitivity of -53 mV/pH (r2 = 0.976) with stable performance in the physiological range of pH 4-10. The sensor shows excellent stability to applied longitudinal and transverse strains up to 100% in different pH buffer solutions with a minimal deviation of less than ±4 mV. The material biocompatibility is confirmed with NIH 3T3 fibroblast cells via PrestoBlue assays.

A paper-based in vitro model for on-chip investigation of the human respiratory system.

Culturing cells at the air-liquid interface (ALI) is essential for creating functional in vitro models of lung tissues. We present the use of direct-patterned laser-treated hydrophobic paper as an effective semi-permeable membrane, ideal for ALI cell culture. The surface properties of the paper are modified through a selective CO2 laser-assisted treatment to create a unique porous substrate with hydrophilic regions that regulate fluid diffusion and cell attachment. To select the appropriate model, four promising hydrophobic films were compared with each other in terms of gas permeability and long-term strength in an aqueous environment (wet-strength). Among the investigated substrates, parchment paper showed the fastest rate of oxygen permeability (3 times more than conventional transwell cell culture membranes), with the least variation in its dry and wet tensile strengths (124 MPa and 58 MPa, remaining unchanged after 7 days of submersion in PBS).The final paper-based platform provides an ideal, robust, and inexpensive device for generating monolayers of lung epithelial cells on-chip in a high-throughput fashion for disease modelling and in vitro drug testing.

Direct Laser Writing of Porous-Carbon/Silver Nanocomposite for Flexible Electronics.

In this Research Article, we demonstrate a facile method for the fabrication of porous-carbon/silver nanocomposites using direct laser writing on polymeric substrates. Our technique uses a combination of CO2 laser-induced carbonization and selective silver deposition on a polyimide sheet to create flexible highly conductive traces. The localized laser irradiation selectively converts the polyimide to a highly porous and conductive carbonized film with superhydrophilic wettability. The resulting pattern allows for selective trapping of aqueous silver ionic ink solutions into the carbonized regions, which are converted to silver nanoparticle fillers upon an annealing step. Elemental and surface morphology analysis via XRD and SEM reveals a uniform coating of Ag nanoparticles on the porous carbon. The Ag/C composite lowers the sheet resistance of the original laser carbonized polyimide from 50 to 0.02 Ω/□. The resulting patterns are flexible and electromechanically robust with less than 0.6 Ω variation in resistance after >15000 bending flexion cycles at a radius of curvature of 5 mm. Furthermore, using this technique, we demonstrate the fabrication of a wireless resonant pressure sensor capable of detecting pressures ranging from 0 to 97 kPa with an average sensitivity of -26 kHz/kPa.

A Smart Capsule With GI-Tract-Location-Specific Payload Release.

In this paper, we present a smart capsule for location-specific drug release in the gastrointestinal tract. Once activated through a magnetic proximity fuse, the capsule opens up and releases its powdered payload in a location specified by an implanted miniature magnetic marker or an externally worn larger magnet. The capsule (9 mm × 26 mm) comprises of two compartments: one contains a charged capacitor and a reed switch, while the second one houses the drug reservoir capped by a taut nylon thread intertwined with a nichrome wire. The nichrome wire is connected to the capacitor through the reed switch. The capacitor is charged to 2.7 V before ingestion and once within the proximity of the permanent magnet; the reed switch closes, discharging the capacitor through the nichrome wire, melting the nylon thread, detaching the cap, and emptying the drug reservoir.

Highly stretchable and sensitive unidirectional strain sensor via laser carbonization.

In this paper, we present a simple and low-cost technique for fabricating highly stretchable (up to 100% strain) and sensitive (gauge factor of up to 20 000) strain sensors. Our technique is based on transfer and embedment of carbonized patterns created through selective laser pyrolization of thermoset polymers, such as polyimide, into elastomeric substrates (e.g., PDMS or Ecoflex). Embedded carbonized materials are composed of partially aligned graphene and carbon nanotube (CNT) particles and show a sharp directional anisotropy, which enables the fabrication of extremely robust, highly stretchable, and unidirectional strain sensors. Raman spectrum of pyrolized carbon regions reveal that under optimal laser settings, one can obtain highly porous carbon nano/microparticles with sheet resistances as low as 60 Ω/□. Using this technique, we fabricate an instrumented latex glove capable of measuring finger motion in real-time.

Biodegradable nanofibrous polymeric substrates for generating elastic and flexible electronics.

Biodegradable nanofibrous polymeric substrates are used to fabricate suturable, elastic, and flexible electronics and sensors. The fibrous microstructure of the substrate makes it permeable to gas and liquid and facilitates the patterning process. As a proof-of-principle, temperature and strain sensors are fabricated on this elastic substrate and tested in vitro. The proposed system can be implemented in the field of bioresorbable electronics and the emerging area of smart wound dressings.

Flexible sensors for chronic wound management.

Chronic nonhealing wounds are a major source of morbidity and mortality in bed-ridden and diabetic patients. Monitoring of physical and chemical parameters important in wound healing and remodeling process can be of immense benefit for optimum management of such lesions. Low-cost flexible polymeric and paper-based substrates are attractive platforms for fabrication of such sensors. In this review, we discuss recent advances in flexible physiochemical sensors for chronic wound monitoring. After a brief introduction to wound healing process and commercial wound dressings, we describe various flexible biocompatible substrates that can be used as the base platform for integration of wound monitoring sensors. We will then discuss several fabrication methods that can be utilized to integrate physical and chemical sensors onto such substrates. Finally, we will present physical and chemical sensors developed for monitoring wound microenvironment and outline future development venues.

Disease-on-a-chip: mimicry of tumor growth in mammary ducts.

We present a disease-on-a-chip model in which cancer grows within phenotypically normal breast luminal epithelium on semicircular acrylic support mimicking portions of mammary ducts. The cells from tumor nodules developing within these hemichannels are morphologically distinct from their counterparts cultured on flat surfaces. Moreover, tumor nodules cocultured with the luminal epithelium in hemichannels display a different anticancer drug sensitivity compared to nodules cocultured with the luminal epithelium on a flat surface and to monocultures of tumor nodules. The mimicry of tumor development within the epithelial environment of mammary ducts provides a framework for the design and test of anticancer therapies.