A Wirelessly Controlled Scalable 3D-Printed Microsystem for Drug Delivery.

Here we present a 3D-printed, wirelessly controlled microsystem for drug delivery, comprising a refillable microreservoir and a phase-change peristaltic micropump. The micropump structure was inkjet-printed on the back of a printed circuit board around a catheter microtubing. The enclosure of the microsystem was fabricated using stereolithography 3D printing, with an embedded microreservoir structure and integrated micropump. In one configuration, the microsystem was optimized for murine inner ear drug delivery with an overall size of 19 × 13 × 3 mm3. Benchtop results confirmed the performance of the device for reliable drug delivery. The suitability of the device for long-term subcutaneous implantation was confirmed with favorable results of implantation of a microsystem in a mouse for six months. The drug delivery was evaluated in vivo by implanting four different microsystems in four mice, while the outlet microtubing was implanted into the round window membrane niche for infusion of a known ototoxic compound (sodium salicylate) at 50 nL/min for 20 min. Real-time shifts in distortion product otoacoustic emission thresholds and amplitudes were measured during the infusion, demonstrating similar results with syringe pump infusion. Although demonstrated for one application, this low-cost design and fabrication methodology is scalable for use in larger animals and humans for different clinical applications/delivery sites.

Microengineered 3D Collagen Gels with Independently Tunable Fiber Anisotropy and Directionality.

Cellular processes, including differentiation, proliferation, and migration, have been linked to the alignment (anisotropy) and orientation (directionality) of collagen fibers in the native extracellular matrix (ECM). Given the critical role that biophysical cell-matrix interactions play in regulating biological functions, several microfluidic-based methods have been used to establish 3D collagen gels with defined fiber properties; these gels have helped to establish quantitative relationships between structural ECM cues and observed cell responses. Although existing microfluidic fabrication methods provide excellent definition over collagen fiber anisotropy, they have not demonstrated the independent control over fiber anisotropy and directionality necessary to replicate in vivo collagen architecture. Therefore, to advance collagen microengineering capabilities, we present a user-friendly technology platform that uses controlled fluid flows within a non-uniform microfluidic channel network to create collagen landscapes that can be tuned as a function of extensional strain rate. Herein, we demonstrate capabilities to i) control the degree of fiber anisotropy, ii) create spatial gradients in fiber anisotropy, iii) independently define fiber directionality, and iv) generate multi-material interfaces within a 3D environment. We then address the practical issue of integrating cells into microfluidic systems by using a peel-off template technique to provide direct access to microengineered collagen gels, and demonstrate that cells respond to the defined properties of the landscape. Finally, the platform's modular capability is highlighted by integrating a sub-micrometer thick porous parylene membrane onto the microengineered collagen as a method to define cell-substrate interactions.

A review of peristaltic micropumps.

This report presents a review of progress on peristaltic micropumps since their emergence, which have been widely used in many research fields from biology to aeronautics. This paper summarizes different techniques that have been used to mimic this elegant physiological transport mechanism that is commonly found in nature. The analysis provides definitions of peristaltic micropumps and their different features, distinguishing them from other mechanical micropumps. Important parameters in peristalsis are presented, such as the operating frequency, stroke volume, and various actuation sequences, along with introducing design rules and analysis for optimizing actuation sequences. Actuation methods such as piezoelectric, motor, pneumatic, electrostatic, and thermal are discussed with their advantages and disadvantages for application in peristaltic micropumps. This review evaluates research efforts over the past 30 years with comparison of key features and outputs, and suggestions for future development. The analysis provides a starting point for researchers designing peristaltic micropumps for a broad range of applications.

Microtechnologies for inner ear drug delivery.

PURPOSE OF REVIEW: Treatment of auditory dysfunction is dependent on inner ear drug delivery, with microtechnologies playing an increasingly important role in cochlear access and pharmacokinetic profile control. This review examines recent developments in the field for clinical and animal research environments. RECENT FINDINGS: Micropump technologies are being developed for dynamic control of flow rates with refillable reservoirs enabling timed delivery of multiple agents for protection or regeneration therapies. These micropumps can be combined with cochlear implants with integral catheters or used independently with cochleostomy or round window membrane (RWM) delivery modalities for therapy development in animal models. Sustained release of steroids with coated cochlear implants remains an active research area with first-time-in-human demonstration of reduced electrode impedances. Advanced coatings containing neurotrophin producing cells have enhanced spiral ganglion neuron survival in animal models, and have proven safe in a human study. Microneedles have emerged for controlled microperforation of the RWM for significant enhancement in permeability, combinable with emerging matrix formulations that optimize biological interaction and drug release kinetics. SUMMARY: Microsystem technologies are providing enhanced and more controlled access to the inner ear for advanced drug delivery approaches, alone and in conjunction with cochlear implants.

A 3D-Printed Modular Microreservoir for Drug Delivery.

Reservoir-based drug delivery microsystems have enabled novel and effective drug delivery concepts in recent decades. These systems typically comprise integrated storing and pumping components. Here we present a stand-alone, modular, thin, scalable, and refillable microreservoir platform as a storing component of these microsystems for implantable and transdermal drug delivery. Three microreservoir capacities (1, 10, and 100 µL) were fabricated with 3 mm overall thickness using stereolithography 3D-printing technology, enabling the fabrication of the device structure comprising a storing area and a refill port. A thin, preformed dome-shaped storing membrane was created by the deposition of parylene-C over a polyethylene glycol sacrificial layer, creating a force-free membrane that causes zero forward flow and insignificant backward flow (2% of total volume) due to membrane force. A septum pre-compression concept was introduced that enabled the realization of a 1-mm-thick septa capable of ~65000 leak-free refill punctures under 100 kPa backpressure. The force-free storing membrane enables using normally-open micropumps for drug delivery, and potentially improves the efficiency and precision of normally-closed micropumps. The ultra-thin septum reduces the thickness of refillable drug delivery devices, and is capable of thousands of leak-free refills. This modular and scalable device can be used for drug delivery in different laboratory animals and humans, as a sampling device, and for lab-on-a-chip and point-of-care diagnostics applications.

A nanoliter resolution implantable micropump for murine inner ear drug delivery.

Advances in protective and restorative biotherapies have created new opportunities to use site-directed, programmable drug delivery systems to treat auditory and vestibular disorders. Successful therapy development that leverages the transgenic, knock-in, and knock-out variants of mouse models of human disease requires advanced microsystems specifically designed to function with nanoliter precision and with system volumes suitable for implantation. Here we present results for a novel biocompatible, implantable, scalable, and wirelessly controlled peristaltic micropump. The micropump configuration included commercially available catheter microtubing (250 µm OD, 125 µm ID) that provided a biocompatible leak-free flow path while avoiding complicated microfluidic interconnects. Peristaltic pumping was achieved by sequentially compressing the microtubing via expansion and contraction of a thermal phase-change material located in three chambers integrated adjacent to the microtubing. Direct-write micro-scale printing technology was used to build the mechanical components of the micropump around the microtubing directly on the back of a printed circuit board assembly (PCBA). The custom PCBA was fabricated using standard commercial processes providing microprocessor control of actuation and Bluetooth wireless communication through an Android application. The results of in vitro characterization indicated that nanoliter resolution control over the desired flow rates of 10-100 nL/min was obtained by changing the actuation frequency. Applying 10× greater than physiological backpressures and ±â€¯3 °C ambient temperature variation did not significantly affect flow rates. Three different micropumps were tested on six mice for in vivo implantation of the catheter microtubing into the round window membrane niche for infusion of a known ototoxic compound (sodium salicylate) at 50 nL/min for 20 min. Real-time shifts in distortion product otoacoustic emission thresholds and amplitudes were measured during the infusion. There were systematic increases in distortion product threshold shifts during the 20-min perfusions; the mean shift was 15 dB for the most basal region. A biocompatibility study was performed to evaluate material suitability for chronic subcutaneous implantation and clinical translational development. The results indicated that the micropump components successfully passed key biocompatibility tests. A micropump prototype was implanted for one month without development of inflammation or infection. Although tested here on the small murine cochlea, this low-cost design and fabrication methodology is scalable for use in larger animals and for clinical applications in children and adults by appropriate scaling of the microtubing diameter and actuator volume.

Biocompatible Magnetic Nanocomposite Microcapsules as Microfluidic One-way Diffusion Blocking Valves with Ultra-low Opening Pressure.

A one-of-a-kind biocompatible magnetic nanocomposite microcapsule is developed as an in-line passive valve that can be integrated with micropumps and microfluidics. The magnetic nanocomposites act as the core for building a valve that utilizes the magnetic force attraction for sealing the microfluidic channels. The nanocomposites, molded with commercial microtubings, are prepared by incorporating Fe3O4 nanoparticles into polyethylene-glycol (PEG). Parylene-C provides a flexible, biocompatible shell and moisture barrier for the microcapsule that enables deformation and sealing to the microfluidic channel wall. The highly customizable valve design offers easy scalability, and simplicity for integration into microfluidic systems. The presented magnetically-responsive microcapsule demonstrates reliable performance as a passive one-way valve that exhibits unique features and capabilities including effective flow-rectification with steady flows, extremely low leakage flows from backpressures at a rate of 4.7 nL/min kPa-1, successfully block 99.96% of the diffusion, and extremely low inlet flow opening pressure of 2.1 kPa.

Inkjet Printed Polyethylene Glycol as a Fugitive Ink for the Fabrication of Flexible Microfluidic Systems.

This paper demonstrates a novel and simple processing technique for the realization of scalable and flexible microfluidic microsystems by inkjet-printing polyethylene-glycol (PEG) as a sacrificial template, followed by embedding in a structural layer (e.g. soft elastomers). The printing technology allows production of an array of PEG droplets simultaneously, reducing cost and manufacturing time. The PEG can be removed through heating above its phase-change temperature after the formation of the structural layer, with hydraulic flow removing the material. The developed technique allows easy modulation of the shape and dimensions of the pattern with the ability to generate complex architectures without using lithography. The method produces robust planar and multilayer microfluidic structures that can be realized on wide range of substrates. Moreover, microfluidics can be realized on other systems (e.g. electrodes and transducers) directly without requiring any bonding or assembling steps, which often limit the materials selection in conventional microfluidic fabrication. Multilayer Polydimethylsiloxane (PDMS) microfluidic channels were created using this technique to demonstrate the capability of the concept to realize flexible microfluidic electronics, drug delivery systems, and lab-on-a-chip devices. By utilizing conductive liquid metals (i.e. EGaIn) as the filling material of the channels, flexible passive resistive components and sensors have been realized.