Jason O. Fiering

Fabrication Methods and Performance of Low-Permeability Microfluidic Components for a Miniaturized Wearable Drug Delivery System

In this paper, we describe low-permeability components of a microfluidic drug delivery system fabricated with versatile micromilling and lamination techniques. The fabrication process uses laminate sheets which are machined using XY milling tables commonly used in the printed-circuit industry. This adaptable platform for polymer microfluidics readily accommodates integration with silicon-based sensors, printed-circuit, and surface-mount technologies. We have used these methods to build components used in a wearable liquid-drug delivery system for in vivo studies. The design, fabrication, and performance of membrane-based fluidic capacitors and manual screw valves provide detailed examples of the capability and limitations of the fabrication method. We demonstrate fluidic capacitances ranging from 0.015 to 0.15 muL/kPa, screw valves with on/off flow ratios greater than 38000, and a 45times reduction in the aqueous fluid loss rate to the ambient due to permeation through a silicone diaphragm layer.

Development of a Microfluidics-Based Intracochlear Drug Delivery Device

Background: Direct delivery of drugs and other agents into the inner ear will be important for many emerging therapies, including the treatment of degenerative disorders and guiding regeneration. Methods: We have taken a microfluidics/MEMS (MicroElectroMechanical Systems) technology approach to develop a fully implantable reciprocating inner-ear drug-delivery system capable of timed and sequenced delivery of agents directly into perilymph of the cochlea. Iterations of the device were tested in guinea pigs to determine the flow characteristics required for safe and effective delivery. For these tests, we used the glutamate receptor blocker DNQX, which alters auditory nerve responses but not cochlear distortion product otoacoustic emissions. Results: We have demonstrated safe and effective delivery of agents into the scala tympani. Equilibration of the drug in the basal turn occurs rapidly (within tens of minutes) and is dependent on reciprocating flow parameters. Conclusion: We have described a prototype system for the direct delivery of drugs to the inner ear that has the potential to be a fully implantable means for safe and effective treatment of hearing loss and other diseases.

Kinetics of reciprocating drug delivery to the inner ear.

Reciprocating drug delivery is a means of delivering soluble drugs directly to closed fluid spaces in the body via a single cannula without an accompanying fluid volume change. It is ideally suited for drug delivery into small, sensitive and unique fluid spaces such as the cochlea. We characterized the pharmacokinetics of reciprocating drug delivery to the scala tympani within the cochlea by measuring the effects of changes in flow parameters on the distribution of drug throughout the length of the cochlea. Distribution was assessed by monitoring the effects of DNQX, a reversible glutamate receptor blocker, delivered directly to the inner ear of guinea pigs using reciprocating flow profiles. We then modeled the effects of those parameters on distribution using both an iterative curve-fitting approach and a computational fluid dynamic model. Our findings are consistent with the hypothesis that reciprocating delivery distributes the drug into a volume in the base of the cochlea, and suggest that the primary determinant of distribution throughout more distal regions of the cochlea is diffusion. Increases in flow rate distributed the drug into a larger volume that extended more apically. Over short time courses (less than 2h), the apical extension, though small, significantly enhanced apically directed delivery of drug. Over longer time courses (>5h) or greater distances (>3mm), maintenance of drug concentration in the basal scala tympani may prove more advantageous for extending apical delivery than increases in flow rate. These observations demonstrate that this reciprocating technology is capable of providing controlled delivery kinetics to the closed fluid space in the cochlea, and may be suitable for other applications such as localized brain and retinal delivery.

Mastoid Cavity Dimensions and Shape: Method of Measurement and Virtual Fitting of Implantable Devices

Temporal bone implants can be used to electrically stimulate the auditory nerve, to amplify sound, to deliver drugs to the inner ear and potentially for other future applications. The implants require storage space and access to the middle or inner ears. The most acceptable space is the cavity created by a canal wall up mastoidectomy. Detailed knowledge of the available space for implantation and pathways to access the middle and inner ears is necessary for the design of implants and successful implantation. Based on temporal bone CT scans a method for three-dimensional reconstruction of a virtual canal wall up mastoidectomy space is described. Using Amira® software the area to be removed during such surgery is marked on axial CT slices, and a three-dimensional model of that space is created. The average volume of 31 reconstructed models is 12.6 cm3 with standard deviation of 3.69 cm3, ranging from 7.97 to 23.25 cm3. Critical distances were measured directly from the model and their averages were calculated: height 3.69 cm, depth 2.43 cm, length above the external auditory canal (EAC) 4.45 cm and length posterior to EAC 3.16 cm. These linear measurements did not correlate well with volume measurements. The shape of the models was variable to a significant extent making the prediction of successful implantation for a given design based on linear and volumetric measurement unreliable. Hence, to assure successful implantation, preoperative assessment should include a virtual fitting of an implant into the intended storage space. The above-mentioned three-dimensional models were exported from Amira to a Solidworks application where virtual fitting was performed. Our results are compared to other temporal bone implant virtual fitting studies. Virtual fitting has been suggested for other human applications.

A Si-based FPW sensor array system with polymer microfluidics integrated on a PCB

Many methods for fabricating structures for microfluidic-based sensors have been developed in recent years. However, little has been reported on effective methods for integrating these structures into electronic systems for analysis and fluidic delivery. This paper describes a straightforward and versatile fabrication platform for polymer microfluidics that readily accommodates integration with silicon-based sensors, printed circuit, and surface mount technologies. In particular, we have demonstrated a novel system for distributed fluid delivery to a flexural plate wave (FPW) chemical/biological sensor where micromachined fluidic components are combined in a single package with silicon die, multilayer printed circuit board, and surface mount electronics. In the same fabrication platform, we have demonstrated temperature control of the sensor with 0.1/spl deg/C precision using integrated metal thin-film heater and sensor elements. This is an important capability for FPW sensors to compensate for temperature-induced drift. We present results for the on-board microfluidic system where the sensor is used to detect changes in the composition of the supplied fluid.

Microfabricated infuse-withdraw micropump component for an integrated inner-ear drug-delivery platform

One of the major challenges in treatment of auditory disorders is that many therapeutic compounds are toxic when delivered systemically. Local intracochlear delivery methods are becoming critical in emerging treatments and in drug discovery. Direct infusion via cochleostomy, in particular, is attractive from a pharmacokinetics standpoint, as there is potential for the kinetics of delivery to be well-controlled. Direct infusion is compatible with a large number of drug types, including large, complex molecules such as proteins and unstable molecules such as siRNA. In addition, hair-cell regeneration therapy will likely require long-term delivery of a timed series of agents. This presents unknown risks associated with increasing the volume of fluid within the cochlea and mechanical damage caused during delivery. There are three key requirements for an intracochlear drug delivery system: (1) a high degree of miniaturization (2) a method for pumping precise and small volumes of fluid into the cochlea in a highly controlled manner, and (3) a method for removing excess fluid from the limited cochlear fluid space. To that end, our group is developing a head-mounted microfluidics-based system for long-term intracochlear drug delivery. We utilize guinea pig animal models for development and demonstration of the device. Central to the system is an infuse-withdraw micropump component that, unlike previous micropump-based systems, has fully integrated drug and fluid storage compartments. Here we characterize the infuse-withdraw capabilities of our micropump, and show experimental results that demonstrate direct drug infusion via cochleostomy in animal models. We utilized DNQX, a glutamate receptor antagonist that suppresses CAPs, as a test drug. We monitored the frequency-dependent changes in auditory nerve CAPs during drug infusion, and observed CAP suppression consistent with the expected drug transport path based on the geometry and tonotopic organization of the cochlea.

Rapid prototyping and parametric optimization of plastic acoustofluidic devices for blood–bacteria separation

Acoustic manipulation has emerged as a versatile method for microfluidic separation and concentration of particles and cells. Most recent demonstrations of the technology use piezoelectric actuators to excite resonant modes in silicon or glass microchannels. Here, we focus on acoustic manipulation in disposable, plastic microchannels in order to enable a low-cost processing tool for point-of-care diagnostics. Unfortunately, the performance of resonant acoustofluidic devices in plastic is hampered by a lack of a predictive model. In this paper, we build and test a plastic blood–bacteria separation device informed by a design of experiments approach, parametric rapid prototyping, and screening by image-processing. We demonstrate that the new device geometry can separate bacteria from blood while operating at 275% greater flow rate as well as reduce the power requirement by 82%, while maintaining equivalent separation performance and resolution when compared to the previously published plastic acoustofluidic separation device.

A new method to fabricate low-loss chip-scale RF inductors

A new method is presented for integrating high performance wire-based inductors into thin, planar, chip-scale formats. The method is designed for compatibility with commonly-used rapid prototyping tools, and fabrication can be automated for volume production. The chip-scale inductors are designed for inductances in the 1-10 nH range, self-resonant frequencies above 5 GHz, and quality factors exceeding 75-100. The process can produce a stand-alone chip or can be integrated with existing multi-chip modules and integrated circuits.

Optimum sensor placement in microchannel reactors: design tool applications

A computational analysis of a microchannel reacting flow that includes diffusion and heat transfer processes to determine design rules for sensor placement is described. The objective is to optimize the positioning of nanohole array sensors which measure concentration and temperature and to analyze the characteristics of the local quantities sensed by nanohole arrays. Because the position and minimum spacing of the sensors are limited by material and fabrication constraints, the computational analysis is used to verify the effectiveness and limitations of this approach. Thermal boundary analysis is performed to analyze the relation between the sensed layer (micro-sensing region) over the nanohole array sensors and the boundary layer development. The relationship between the sensor position and the nodes of the numerical solution that limit this design process are discussed.

Purification of Lymphocytes by Acoustic Separation in Plastic Microchannels

Emerging cell therapies have created new demands for instruments that will increase processing efficiency. Purification of lymphocytes prior to downstream steps of gene transfer currently relies on centrifugal separation, which has drawbacks in output sample purity and process automation. Here, we present an alternative approach to blood cell purification using acoustic forces in plastic microchannels. We provide details regarding the system’s ability to purify lymphocytes relative to other blood cell types while maintaining a high overall recovery, testing performance starting from leukapheresis product, buffy coat, and whole blood. Depending on settings, the device achieves for lymphocytes up to 97% purity and up to 68% recovery, and depletes 98% of monocytes while also reducing red cells and platelets. We expect that future scale-up of our system for increased throughput will enable its incorporation in the cell therapy workflow, and that it could ultimately reduce costs and expand access for patients.