Wearable and Flexible Ozone Generating System for Treatment of Infected Dermal Wounds.

Wound-associated infections are a significant and rising health concern throughout the world owing to aging population, prevalence of diabetes, and obesity. In addition, the rapid increase of life-threatening antibiotic resistant infections has resulted in challenging wound complications with limited choices of effective therapeutics. Recently, topical ozone therapy has shown to be a promising alternative approach for treatment of non-healing and infected wounds by providing strong antibacterial properties while stimulating the local tissue repair and regeneration. However, utilization of ozone as a treatment for infected wounds has been challenging thus far due to the need for large equipment usable only in contained, clinical settings. This work reports on the development of a portable topical ozone therapy system comprised of a flexible and disposable semipermeable dressing connected to a portable and reusable ozone-generating unit via a flexible tube. The dressing consists of a multilayered structure with gradient porosities to achieve uniform ozone distribution. The effective bactericidal properties of the ozone delivery platform were confirmed with two of the most commonly pathogenic bacteria found in wound infections, Pseudomonas aeruginosa and Staphylococcus epidermidis. Furthermore, cytotoxicity tests with human fibroblasts cells indicated no adverse effects on human cells.

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.

An Implantable Ultrasonically-Powered Micro-Light-Source (µLight) for Photodynamic Therapy.

Photodynamic therapy (PDT) is a promising cancer treatment modality that can selectively target unresectable tumors through optical activation of cytotoxic agents, thus reducing many side effects associated with systemic administration of chemotherapeutic drugs. However, limited light penetration into most biological tissues have so far prevented its widespread adoption beyond dermatology and a few other oncological applications in which a fiber optic can be threaded to the desired locations via an endoscopic approach (e.g., bladder). In this paper, we introduce an ultrasonically powered implantable microlight source, µLight, which enables in-situ localized light delivery to deep-seated solid tumors. Ultrasonic powering allows for small receiver form factor (mm-scale) and power transfer deep into the tissue (several centimeters). The implants consist of piezoelectric transducers measuring 2 × 2 × 2 mm3 and 2 × 4 × 2 mm3 with surface-mounted miniature red and blue LEDs. When energized with 185 mW/cm2 of transmitted acoustic power at 720 kHz, µLight can generate 0.048 to 6.5 mW/cm2 of optical power (depending on size of the piezoelectric element and light wavelength spectrum). This allows powering multiple receivers to a distance of 10 cm at therapeutic light output levels (a delivery of 20-40 J/cm2 light radiation dose in 1-2 hours). In vitro tests show that HeLa cells irradiated with µLights undergo a 70% decrease in average cell viability as compared to the control group. In vivo tests in mice implanted with 4T1-induced tumors (breast cancer) show light delivery capability at therapeutic dose levels. Overall, results indicate implanting multiple µLights and operating them for 1-2 hours can achieve cytotoxicity levels comparable to the clinically reported cases using external light sources.

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.

A Smart Capsule With a Hydrogel-Based pH-Triggered Release Switch for GI-Tract Site-Specific Drug Delivery.

In this paper, we present a smart capsule that can release its payload after a predetermined/adjustable delay subsequent to passing from the stomach into the small intestine. The described capsule (9 mm × 22 mm) comprises a pH-sensitive hydrogel-based switch, an electronic compartment containing a capacitor charged to 2.7 V, and a drug reservoir capped by a taut fusible thread intertwined with a nichrome wire. The nichrome wire, capacitor, and pH-responsive electrical switch are connected in series. The pH transition the capsule encounters when it enters the small intestine triggers controlled swelling of the pH-responsive hydrogel, which pushes a conductive elastic membrane to close an electrical switch. This initiates a sequence of events, i.e., the discharge of the capacitor, heating the nichrome wire, breakage of the fusible thread, and release of the payload stored in the capsule reservoir through the unlatched cap. The time lag between initiation of hydrogel swelling (by the near-neutral pH of the small intestine) and payload release is controlled by the deflection of the conductive elastic membrane and the gap separating the contacts. The release time can be set to within ±5 min after one hour in the small intestine (start of the swelling) increasing to ±40 min after 4 h.

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.

Fabrication and characterization of implantable flushable electrodes for electric field-mediated drug delivery in a brain tissue-mimic agarose gel.

Every forty minutes, one person dies in the USA due to glioblastoma multiforme; a deadly form of brain cancer with an average five-year survival rate less than 3%. The current standard of care for treatment involves surgical resection of the accessible tumor followed by radiation therapy and concomitant chemotherapy. Despite their potency, delivering chemotherapeutic agents to the brain is limited by the highly selective blood-brain barrier, which prevents molecules >500 Da from reaching the brain. Other techniques, such as convection-enhanced delivery, controlled release by drug-loaded wafers or intracerebroventricular infusion have limited clinical utility due to unpredictable targeting and volume of drug distribution. We introduce a novel drug delivery technique that can use direct current electric fields to deliver charged chemotherapeutics to the site of brain parenchyma after tumor resection. We fabricate and characterize an implantable drug delivery system using flushable electrodes to deliver the charged chemotherapeutic or doxorubicin (+1) in a brain tissue-mimic agarose gel (0.2% w/v) model by electrophoresis. The optimized capillary-embedded electrode system exhibited a sustained movement of charged doxorubicin through nearly 3.5 mm in four hours, a distance for achieving effective intratumoral concentrations.

Laser-Enabled Processing of Stretchable Electronics on a Hydrolytically Degradable Hydrogel.

Degradable electronics represent a rapidly emerging field of science and technology with the potential to serve short-term medical implantation applications where the device disappears once its function is complete. Despite many efforts in developing new types of degradable electronics, many of such systems are nonelastic and incompatible with the dynamic motion of native soft/elastic biological tissues. Herein, a photo-crosslinkable hydrogel with integrated electronics that are highly stretchable and degradable in liquid environments is demonstrated. The fabrication process takes advantage of facile laser micromachining of conductive patterns directly onto the hydrogel under ambient conditions and permanent hydrogel-hydrogel bonding. The robustness and degradation rate of hydrogel and the laser-processed encapsulated stretchable circuits is systematically investigated in different solutions under various conditions. Biocompatibility tests with non-neoplastic cells (HMT 3522 S1) and cancer cells (T4-2 and MDA-MB-231) are performed in 2D and 3D cell culture systems to confirm instead of evaluate the safety of the hydrogel and its byproducts during degradation as well as the zinc metal used in this technology. As a proof of concept, a stretchable hydrogel-based device that can be used for remote/wireless delivery of thermal energy into the tissue in contact with the hydrogel is fabricated.

An ultrasonically controlled switching system for power management in implantable devices.

In this paper, we present an ultrasonically controlled switching system that can save the battery power for implantable devices by turning the system on and off, on-demand. Ultrasonic control is employed to reduce the device size, increase the penetration depth, and reduce misalignment sensitivity associated with alternative techniques using permanent magnet and RF signal. As a proof-of-concept demonstration, a 665 kHz ultrasonic signal is used to activate a piezoelectric receiver which in turn switches a battery-powered RF system on-and-off. In-vitro tests show a reliable switching functionality at distances of up to 8 cm while consuming 43.5 nW (14.5 nA current consumption with 3 V power supply) when the system is in off-state, a factor of 10-100 times lower than the sleep-mode power consumption of typical RF SoC systems. The dimension of fabricated prototype is 6.3 × 16.7 × 2| mm3 allowing it to be easily incorporated into many existing implantable devices.

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.

Diaper-Embedded Urinary Tract Infection Monitoring Sensor Module Powered by Urine-Activated Batteries.

Urinary tract infection (UTI) is one of the most common infections in humans. UTI is easily treatable using antibiotics if identified in early stage. However, without early identification and treatment, UTI can be a major source of serious complications in geriatric patients, in particular, those suffering from neurodegenerative diseases. Also, for infants who have difficulty in describing their symptoms, UTI may lead to serious development of the disease making early identification of UTI crucial. In this paper, we present a diaper-embedded, wireless, self-powered, and autonomous UTI monitoring sensor module that allows an early detection of UTI with minimal effort. The sensor module consists of a paper-based colorimetric nitrite sensor, urine-activated batteries, a boost dc-dc converter, a low-power sensor interface utilizing pulse width modulation, and a Bluetooth low energy module for wireless transmission. Experimental results show a better detection of nitrite, a surrogate of UTI, than that of conventional dipstick testing. The proposed sensor module achieves a sensitivity of 1.35 ms/(mg/L) and a detection limit of 4 mg/L for nitrite.

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.