Mark J. Mescher

Inner ear drug delivery for auditory applications

Many inner ear disorders cannot be adequately treated by systemic drug delivery. A blood-cochlear barrier exists, similar physiologically to the blood-brain barrier, which limits the concentration and size of molecules able to leave the circulation and gain access to the cells of the inner ear. However, research in novel therapeutics and delivery systems has led to significant progress in the development of local methods of drug delivery to the inner ear. Intratympanic approaches, which deliver therapeutics to the middle ear, rely on permeation through tissue for access to the structures of the inner ear, whereas intracochlear methods are able to directly insert drugs into the inner ear. Innovative drug delivery systems to treat various inner ear ailments such as ototoxicity, sudden sensorineural hearing loss, autoimmune inner ear disease, and for preserving neurons and regenerating sensory cells are being explored.

The MAC - a miniature atomic clock

The authors are developing a chip-scale atomic clock (CSAC), more than two orders of magnitude smaller and lower power than any existing technology. As an intermediate milestone, en route to the ultimate CSAC objectives, we have developed a miniature atomic clock (MAC), combining the low-power CSAC physics package with a low-parts count, low-power digital control and microwave system. The MAC is a complete packaged atomic clock, with overall size of 10 cm/sup 3/, power consumption >200 mW, and short-term stability /spl sigma//sub y/(/spl tau/)/spl sim/4/spl times/10/sup -10//spl tau//sup - 1/2 /. The MAC provides a valuable testbed for the further development and refinement of the CSAC physics package as well as for the development of the CSAC control electronics prior to undertaking the costly and time-consuming size-reduction effort which will be necessary to meet the ultimate CSAC objectives. The MAC itself may find applications in commercial and military timing systems which require the relatively small size and power consumption of the MAC now, rather than wait for the evolution of the 1 cm/sup 3/, 30 mW CSAC.

An ultra-low-power physics package for a chip-scale atomic clock

We report the design and measured thermal and mechanical performance of an ultra-low-power physics package for a chip-scale atomic clock (CSAC). This physics package enables communications and navigation systems that require a compact, low-power atomic frequency standard. The physics package includes a unique combination of thermal isolation, mechanical stability and robustness, and small package volume. We have demonstrated temperature control at a nominal operating temperature of 75/spl deg/C in a room-temperature, vacuum ambient requiring only 7mW of heating power. This represents a power reduction of over two orders of magnitude compared to the lowest-power existing commercial technology and more than an order of magnitude improvement over other CSAC development efforts.

VCSELs for atomic clocks

The spectroscopic technique of coherent population trapping (CPT) enables an all-optical interrogation of the groundstate hyperfine splitting of cesium (or rubidium), compared to the optical-microwave double resonance technique conventionally employed in atomic frequency standards. All-optical interrogation enables the reduction of the size and power consumption of an atomic clock by two orders of magnitude, and vertical-cavity surface-emitting lasers (VCSELs) are preferred optical sources due to their low power consumption and circular output beam. Several research teams are currently using VCSELs for DARPAs chip-scale atomic clock (CSAC) program with the goal of producing an atomic clock having a volume < 1 cm^3, a power consumption < 30 mW, and an instability (Allan deviation) < 1x10^-11 during a 1-hour averaging interval. This paper describes the VCSEL requirements for CPT-based atomic clocks, which include single mode operation, single polarization operation, modulation bandwidth > 4 GHz, low power consumption (for the CSAC), narrow linewidth, and low relative intensity noise (RIN). A significant manufacturing challenge is to reproducibly obtain the required wavelength at the specified VCSEL operating temperature and drive current. Data are presented that show the advantage of operating at the D1 (rather than D2) resonance of the alkali atoms. Measurements of VCSEL linewidth will be discussed in particular, since atomic clock performance is especially sensitive to this parameter.

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.

Proteomics analysis of perilymph and cerebrospinal fluid in mouse

Proteins in perilymph may alter the delivery profile of implantable intracochlear drug delivery systems through biofouling. Knowledge of protein composition will help anticipate interactions with delivered agents.

The Miniature Atomic Clock - Pre-Production Results

The authors have developed a miniature atomic clock (MAC) for applications requiring atomic timing accuracy in portable battery-powered applications. Recently, we have completed a pre-production build of 10 devices in order to evaluate unit-to-unit performance variations and to gain statistical confidence in the performance specifications, environmental sensitivity, and manufacturability.

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.

A portable and reconfigurable multi-organ platform for drug development with onboard microfluidic flow control.

The drug development pipeline is severely limited by a lack of reliable tools for prediction of human clinical safety and efficacy profiles for compounds at the pre-clinical stage. Here we present the design and implementation of a platform technology comprising multiple human cell-based tissue models in a portable and reconfigurable format that supports individual organ function and crosstalk for periods of up to several weeks. Organ perfusion and crosstalk are enabled by a precision flow control technology based on electromagnetic actuators embedded in an arrayed format on a microfluidic platform. We demonstrate two parallel circuits of connected airway and liver modules on a platform containing 62 electromagnetic microactuators, with precise and controlled flow rates as well as functional biological metrics over a two week time course. Technical advancements enabled by this platform include the use of non-sorptive construction materials, enhanced scalability, portability, flow control, and usability relative to conventional flow control modes (such as capillary action, pressure heads, or pneumatic air lines), and a reconfigurable and modular organ model format with common fluidic port architecture. We demonstrate stable biological function for multiple pairs of airway-liver models for periods of 2 weeks in the platform, with precise control over fluid levels, temperature, flow rate and oxygenation in order to support relevant use cases involving drug toxicity, efficacy testing, and organ-organ interaction.

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.