Biomedical Sensors and Subsystems
A Near Infrared Opto-mechanical Intracranial Pressure
Mostafa Ghannad-Rezaie and Nikos Chronis
(A) The near infrared pressure sensing technology. The external optical readout unit is used to collect spectroscopic data from the implanted the sensor in the near infrared (NI). (B) Cross sectional view (C) The working principle of the ICP sensor. (D) The microfabricated device sitting on a penny.
Intracranial pressure (ICP) monitoring is widely used to evaluate therapeutic interventions in patients with severe traumatic brain injuries (TBIs), hydrocephalus and other ICP-elevated disorders. These condition required frequent ICP measurement and brain imaging, usually MRI.
We present a new family of implantable, wireless, MRI compatible and power-free optical microsensors that can potentially be used to accurately monitor intracranial pressure (ICP) over long periods of time. These microsensors vertically integrate a glass mini-lens with a two wavelengths quantum dot micropillar that is photolithographically patterned on an ICP-exposed silicon nitride membrane. The operation principle is based on a novel opto-mechanical transduction scheme that converts ICP changes into changes in the intensity ratio of the two wavelengths, near infrared fluorescent light emitted from the quantum dots. These microsensors are microfabricated using silicon bulk micromachining and they operate at an ICP clinically relevant pressure dynamic range (0-40mmHg).
We believe that the proposed microsensors will open up a new direction not only in ICP monitoring but in other pressure-related biomedical applications.
BioBolt: A Minimally-Invasive Neural Interface for Wireless Epidural Recording by Intra-Skin Communication
Sun-Il Chang, Khaled AlAshmouny, and Euisik Yoon
Fabricated BioBolt and 16-Channel In-vivo Measurement
In this work, BioBolt: a distributed minimally-invasive neural interface for wireless epidural recording has been designed and developed. The main purpose of this work is to optimize the trade-off between the quality of neural information and the invasiveness of the neural interface systems. In order to achieve this goal, the proposed system has introduced several innovations as follows: The signals epidurallay recorded from the surface of dura mater are transmitted through the skin (ISCOM) to the external station. To secure the long-term reliability for chronic monitoring, the whole system will be subcutaneously implanted inside the cranium to eliminate any possible infections from external environments. Furthermore, in contrast with other implantable ECoG systems where the operation of the craniotomy is required, the handiness of the bolt-shaped system concept can differentiate the proposed system from other existing systems by providing the simple and safe operation protocol of implantation and explantation. Extreme low-power analog front-end including a low-noise preamplifier and analog-to-digital converter has been proposed to ensure a robust interface, because the neural potentials are vulnerable to external interference such as drift/offset from the cell-electrode interface and power line noise. With collaboration with Washington University, St. Louis, we successfully performed the in-vivo expereiment with Monkey without the power-line interference. The epidural electrode has been placed on the surface of dura mater of the monkey and the neural activities from sixteen channels were recorded simultaneously as shown in Figure 1.
Braille-Driven Aqueous Two-Phase System Droplet Microfluidic System
David Lai, John P. Frampton, Hari Sriram, and Shuichi Takayama
Aqueous Two Phase System monodisperse droplets of dextran-heavy phase in PEG-heavy phase with very low interfacial tension. Droplets in motion assume a teardrop shape due to high capillary number but conform to a spherical shape when flow is terminated.
A microfluidic system capable of creating aqueous two-phase system (ATPS) droplets where one aqueous phase forms droplets and the other aqueous phase forms the surrounding matrix. Unlike water-in-oil droplet systems, ATPS can have very low interfacial tensions that prevent spontaneous droplet formation through instabilities. We demonstrate the formation of ATPS droplet formation with the lowest interfacial tension to date and applied them to patterning alternating islands of two different cell types within a single microfluidic channel.
Micro- & Nanofluidics and Cellular Environomics
Toshiki Mastuoka, Byoung Choul Kim, and Shuichi Takayama
Figure. Size-adjustable elastomeric nanochannels. a, The system has an array of nanochannels spanning microscale inlet and outlet compartments separated by 500 μm. Fluorescein molecules introduced into the inlet are transported through the nanochannels by electrokinetic flows . b, Channel deformation at certain pressure resulted in stretching of single DNA
Fluidic transport through nanochannels offers new opportunities to probe fundamental nanoscale transport phenomena and to develop tools for manipulating DNA, proteins, small molecules and nanoparticles. We use nanoscale fracturing of oxidized poly(dimethylsiloxane) to conveniently fabricate nanofluidic systems with arrays of nanochannels to actively manipulate nanofluidic transport through dynamic modulation of the channel cross-section. The process is designed to achieve reversible nanochannel deformation using remarkably small forces. We demonstrate the versatility of the elastomeric nanochannels through tuneable sieving; trapping of nanoparticles and dynamic manipulation of the conformation of single DNA molecules.
Constant Flow-Driven Microfluidic Oscillator for Different Duty Cycles
Sung-Jin Kim, Ryuji Yokokawa, Sasha Cai Lesher-Perez, and Shuichi Takayama
Figure. (Left) Constant flow-driven microfluidic oscillator. To control duty cycle, the opening width of the valve is changed. (Right) Periodic staining of cell-nucleus. Fluorescent intensity-profile of a cell nucleus (see white arrow ) and the corresponding pressure profile at the source terminal of valve. Red region is valve-off state for the fluorescent solution, and clear solution flows during this time.
Cells exist in highly dynamic environments consistently being exposed to biochemical and physical stimulation. For cell study, we work on microfluidic devices that autonomously convert two constant flow inputs into an alternating oscillatory flow output. We accomplish this hardware embedded self-control programming using normally closed membrane valves that have an inlet, an outlet, and a membrane-pressurization chamber connected to a third terminal. Adjustment of threshold opening pressures in these 3-terminal flow switching valves enable adjustment of oscillation periods to between 57–360 s with duty cycles of 0.2–0.5. We also try to show the ability to use these oscillators to perform temporally patterned delivery of chemicals to living cells. The device only needs a syringe pump, thus removing the use of complex, expensive external actuators. These tunable waveform microfluidic oscillators are envisioned to facilitate cell-based studies that require temporal stimulation.
A 4 µW/Ch Fully Integrated Analog Front-End Scaled Toward Massive Parallel Neural Recording
Khaled Al-Ashmouny, Sun-Il Chang, and Euisik Yoon
A block diagram of a 2D probe integrable 128:16 channels front-end
We report an analog front-end prototype designed in 0.25μm CMOS process for hybrid integration into 3-D neural recording microsystems. For scaling towards massive parallel neural recording, the prototype has investigated some critical circuit challenges in power, area, interface, and modularity. The front-end features an extremely low power consumption (4μW/channel), optimized energy efficiency using moderate inversion in the low-noise amplifier (K of 5.98x108 and NEF of 2.9) and the programmable-gain amplifier, a minimized asynchronous interface (only 2 per 16 channels) for command and data capturing, a power-scalable sampling and digital operation (up to 50kS/s/channel), and a wide configuration range (9-bit) of gain and bandwidth. The implemented front-end module has achieved a reduction in noise-energy-area product by a factor of 5-25 times as compared to the state-of-the-art front-ends reported up to date.
Silicon and Parylene Intracortical Neural Probes for Chronically-Stable Recording
Daniel Egert, Rebecca L. Peterson, and Khalil Najafi
3-D drawing of silicon probes with integrated springs (left) and Parylene probes with implemented stiffeners and sharp tips (right).
Next-generation neuroprostheses assist functional motor control, aid the visually impaired or those suffering loss of hearing. A key feature for the control of neuroprostheses is the ability to record brain activity of awake, freely behaving hosts accurately enough such that action potentials from single neurons can be distinguished. To date only intracortical neural probes can provide that. The high spatial resolution of intracortical neural probes comes at the cost of a high degree of invasiveness; the host immune response often inhibits recording chronically.
This project pursues two technologies for neural probes that allow mitigating the immune response from the host to implanted neural probes and its impact on their performance. The developed neural probes consist of silicon or Parylene formed to millimeter-long needle-like shanks hosting multiple microelectrodes. One technology, based on silicon, supports individual electrodes that are placed at the end of very fine and flexible needle extensions to the shank that are deployed after implantation. The sites act like satellites, floating almost freely inside the brain tissue. These very small satellite electrodes are expected suffer less immune response. A second approach, based on Parylene, addresses a tradeoff between designing a shank large enough to be reliably implanted and the increase in tissue damage with size of the shank. The developed process technologies allow formation of sharp tips and the strategic design of the shank increases its mechanical robustness without significantly increasing its size.
This work is supported by the DARPA Hybrid Insect MEMS program under grant # N66001-07-1-2006.
CD4+ T-Cell Counting Biochip for Monitoring HIV/AIDS in Resource Limited Settings
Anurag Tripathi and Nikos Chronis
A Bio-MEMS Approach for CD4 Cell Count
Our aim is to develop an inexpensive lab-on-a-chip device for the point-of-care (POC) monitoring of HIV/AIDS in the resource limited settings of the world. CD4+ T cell (a type of white blood cell) count in human whole blood has been used conventionally as the metric for proliferation of HIV in an infected individual and its progression into AIDS. We are working towards developing a biochip (microfluidic device) which can perform CD4+ T-cell counting for HIV/AIDS monitoring.
We have developed a cell trapping biochip for capturing human white blood cells (WBCs). Our preliminary findings indicate that this biochip with a novel 3D trapping architecture enables to obtain a high (> 90%) trapping efficiency of WBCs. Our design for a compact point-of-care device for HIV/AIDS monitoring incorporates integration of the above biochip with an on-chip microcscopy technique, hence eliminating the need for bulky and expensive external microscopy setup. Towards this end, we have developed a high numerical aperture (NA) microlens array for on-chip imaging of micron sized objects. Employing these microlenses, we have demonstrated for the first time, use of microlenses for direct image formation on an inexpensive imaging sensor without the use of any intermediate optics. High NA (~0.5) microlenses were able to resolve 1µm resolution patterns comparable to the performance of conventional microscope objectives.
After their development and performance characterization, the biochip will be integrated with the on-chip microscopy module comprising the microlens array, laser for excitation and charged coupled device (CCD) sensor for image capture and analysis. This will form the first prototype of a standalone device for CD4+ T-cell counting.
High-Throughput Photodynamic Therapy (PDT) Screening Chip with Oxygen, Photosensitizer and Light Exposure Controls
Xia Lou, Gwangseong Kim, Yong-Eun Lee Koo, Raoul Kopelman, and Euisik Yoon
(a) PDT chip outlook and (b) typical high-throughput photosensitizer efficacy test result showing cell viability change under different PDT conditions
Photodynamic therapy (PDT) has emerged as a promising treatment for cancer since 1980s, especially with the advancement of new-generation photosensitizers (PS) and various PS delivery strategies. However, the experimental technologies for PDT lag behind to meet the need of huge number of screening tests for numerous photosensitizers developed recently in terms of specificity for target cancer cells and activating light delivery. In this project we developed a microfluidic chip that can provide the control of all these three crucial parameters in photodynamic therapy including the concentration of photosensitizers, oxygen levels and activating light intensity. By using the microfluidic gradient-generating networks, we can simultaneously provide nine different concentrations of photosensitizer. Also by imposing an extra gas layer in the top channel, we can provide different oxygen levels for each flow layer through molecular diffusion across the thin PDMS membrane which separates the two layers. Also exposure dose can be controlled by an LED light source. Methyleneblue (MB), which has been used for a variety of applications as photosensitizer, and rat C6 glioma tumor cells are adopted for PDT efficiency test. We observed distinctive viability for various Methyleneblue concentrations, oxygen levels and exposure doses. From this, we could determine the minimum (threshold) level of these parameters required for reaching certain effectiveness.
Ultrasonic Microresonators for Neuron Stimulation
Rahman Sabahi-Kaviani and Nikos Chronis
Neural Stimulation using MEMS ultrasound resonators
Neuron stimulation is recognized as a therapeutic tool for managing numerous neurological and psychiatric diseases. Different techniques for neuron stimulation have been suggested such as electrical, optical (optogenetics) and pharmaceutical methods. In addition to the current techniques, ultrasound can be a powerful neurostimulation tool. Its ability to interact with biological tissues, in addition to the fact that it transmits noninvasively through skull bones and other biological structures makes it a useful tool for neuronal excitation. The long-term goal of the proposed research is to develop novel, implantable, MEMS-based devices that can stimulate neurons using ultrasound waves. The proposed micro devices are miniaturized resonators that are injected into brain tissue. Excited at their resonance mode, they make physical contact with the neurons and exert mechanical force on them and therefore activating them.
Microrheometers for Simple and Complex Fluids
Eric Livak-Dahl and Mark A. Burns
New (left) and old (right) designs for microfluidic viscometers
The rheological properties of blood, such as viscosity and viscoelasticity, have been associated with a number of adverse cardiovascular conditions including stroke and hypertension. Other biological fluids such as protein solutions, sputum, nasal and cervical mucus, and synovial fluid can also be analyzed on the basis of their viscosity. While devices exist to measure these properties, most are bench-top instruments that can only be used in a laboratory setting. A microfabricated device, which could be used by a medical practitioner as a point-of-care device to quickly and easily measure the viscous and viscoelastic properties of the patient’s blood or other samples would be a very useful tool. We have already developed microscale devices to measure the viscosity of Newtonian fluids and the parameters of the power law model. We are presently working on developing devices that would measure the viscoelastic properties of samples, as well as nanoliter-volume droplet-based devices for probing samples over a wide range of shear rates, concentrations, and temperatures.
Micro- and Nano-structured Dynamic Fluidic Systems
Ramsey Zeitoun, Thomas Westrich, and Mark A. Burns
(left) View of the whole device; (center) schematic of stream flow paths; (right) image of streams narrowing in device
Co-flowing laminar streams in microfluidic devices are used to create microsecond mixers, produce materials and guide light. These tools can benefit from the high-throughput, controlled nature of microfluidic systems by miniaturizing, scaling, and understanding co-flow. This has been addressed by designing a three-dimensional microfluidic device to actively miniaturize co-flowing streams to thicknesses of less than one micron. This architecture allowed for devices to scale both the size and number of co-flows. Up to 64 submicron streams were generated in a single microchannel. The quality of produced co-flows was investigated with respect to limitations of diffusion at low flow rates and Dean flow alterations at high flow rates.
Dynamic Control of Nanoliter Droplet Volume and Composition
Ramsey Zeitoun, Marcus Goudie, and Mark A. Burns
Droplet ethanol concentration response to changing conditions in side channels
Nanoliter droplets in microfluidic devices can be used to perform thousands of controlled and independent chemical and biological experiments while minimizing reagents, cost and time. However, the absence of simple and versatile methods capable of controlling the contents of these nanoliter chemical systems limits their scientific potential. To address this, we have developed a simple method to continuously control nanoliter chemical systems by integrating a time-resolved convective flow signal across a permeable membrane wall. With this method, we can independently control the volume and concentration of nanoliter-sized drops without ever directly contacting the fluid. We achieved fluid introduction and removal rates ranging from .23 to 4.0 pL/s. Furthermore, we expanded this method to perform chemical processes. We precipitated silver chloride using a flow signal of sodium chloride and silver nitrate droplets. From there, we were able to separate sodium chloride reactants with a water flow signal and dissolve silver chloride solids with an ammonia hydroxide flow signal.
Microdroplet Enabled Parallel Co-Cultivation of Symbiotic Microbial Communities
Jihyang Park and Mark A. Burns
(left) Schematic of the interdependency between symbiotic microbes; (right) Three steps for analysis of symbiotic microbes
A microfluidic device for:
1. Encapsulation of subsets of microbiota - Multiple droplet generation by slanted T-junction geometry
2. Cultivation of microbial subsets - Monitoring of cell growth by microscopy
3. Analysis of cultivated communities
using monodispersed droplets in oil phase. The technology is being applied to cultivation of tunicate microbiota to isolate E.frumentensis, an anti-cancer drug producing bacterium.
Multi-Analyte Detection Using Asynchronous Magnetic Bead Rotation
Irene Sinn and Mark A. Burns
Bacterial growth increases the rotational period of the attached magnetic bead
A new diagnostic asynchronous magnetic bead rotation (AMBR) biosensor droplet microfluidic platform that can measure small cell population growth with high sensitivity has been reported to considerably reduce the time to determine antimicrobial susceptibility. With this platform, the growth, susceptibility, and minimum inhibitory concentration (MIC) of a small uropathogenic E. coli population that was confined in microfluidic droplets and exposed to concentrations above and below the MIC of gentamicin was measured. A 52% change in the sensor signal (i.e. rotational period) was observed within 15 minutes, thus allowing antimicrobial susceptibility test (AST) measurements to be performed within minutes. This reduction in the AST time may enable more appropriate therapies to be prescribed earlier, which consequently may help reduce the emergence and spread of antimicrobial resistance.
Single Cells to Spheroids: Adaptable Single Cell Handling in Microfluidics for Cancer Stem Cell Screening
Patrick Ingram, Jaehoon Chung, Kun Yang, Ronald Buckanovich, Max Wicha, and Euisik Yoon
(a) Single cell capture chip overview showing device inlets and outlets. (b) Expanded veiw of a portion of the single cell microwell array. Devices shows very high capture rates and efficiencies with very few wells being unoccupied.
In 1971 Nixon announced that the U.S. would fund an ambitious “War on Cancer,” and since that year, the U.S. has invested over $200 billion in cancer research. Despite this, we have only seen a 5% drop in the cancer death rate from 1950 to 2005. For years, conventional wisdom has considered size or mass reduction in the cancer as the standard for evaluating successful treatment, giving little thought to possible underlying cellular heterogeneity in the tumor. But in recent years several studies have found significant heterogeneity among cells that were previously treated as essentially copies of each other. Understanding and analyzing this heterogeneity and targeting specific cell subtypes such as cancer-stem cells have great potential for therapeutics. This presents a problem as this heterogeneity is still poorly understood, especially in its behavior in cancer.
With this in mind, we are developing high throughput microfluidic tools for single cell screening of cancer behavior. Our devices utilize a robust hydrodynamic capture scheme that sorts individual cells into separate wells requiring no external pumps or user input. Our systems are capable of measuring drug response, tracking division behavior, and even studying single cell derived spheroids through integration of hydrophobic base layers. Further work is being completed to increase capture rates and throughput of the system, as well as, make our system compatible with standard laboratory practices and robotics high throughput libraries.
Smart Rapid Palatal Expander for Pediatric Cleft Lip and Palate Patients
Venkatram Pepakayala, Dongmin Yoon, Yoonmyung Lee, Tao Li, Yogesh Gianchandani, David Blaauw, Sunil Kapila and Jeanne M. Nervina
Cleft lip and palate (CL/P) is the most prevalent craniofacial cleft type, appearing in 1 in 500-700 newborns. Alveolar bone graft surgery is just one of several surgeries CL/P patients undergo during infancy and childhood to correct the significant functional and esthetic deficits that result from clefting. Prior to this surgery, CL/P patients undergo rapid palatal expansion, which aligns the alveolar segments and provides sufficient space for the surgeon to place the bone graft. Conventional rapid palatal expanders (RPEs) are either tooth- or bone-borne and present obstacles to ideal treatment due to design constrictions. The goal of our proposed research is to design and fabricate a Smart Rapid Palatal Expander (S-RPE) that overcomes these obstacles. Our S-RPE has three key components: 1) The main mechanical frame that will apply stress to the palate by having a mechanical tensioning device, 2) A strain gage to measure the forces being applied by the tensioning device, 3) A microprocessor to read the strain gage measurement and store it in memory for wireless readout by an external device. The target of the S-RPE design is to significantly improve treatment outcomes of alveolar bone graft surgery and orthodontics in CL/P patients.