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ARO/NSF/SRC Technical Exchange Meeting
Cell-Semiconductor Interfaces and Hybrid Semiconductor-Biological Systems
Meeting Date: July 2 7 & 2 8 , 2016 Meeting Place : Georgia Institute of Technology, Atlanta, GA. Meeting Organizers : Hua Wang / Georgia Tech Dr. Joe Qiu / ARO Dr. Usha Varshney / NSF Dr. Victor Zhirnov / SRC Purpose Recently, there has been an increasing interest in hybrid biological-semiconductor platforms that can leverage both natural/synthetic biological processes and semiconductor technologies (Fig. 1). In such hybrid platforms, living cells and tissues can function as a “Biological Front-End” layer with the cellular biochemical processes serving as an organic interface to the external environment and performing biological sensing, actuation, signal processing, synthesis, and energy harvesting. In parallel, the underlying semiconductor platforms can form a “Semiconductor Back-End” layer for information computation, control, communication, storage, and energy supply. Most importantly, if reliable two-way communication schemes, for both information and energy, are achieved between the “Biological Front-End” and “Semiconductor Back-End” with a high spatiotemporal resolution and massively parallel operations, one can expect that a hybrid biotic- abiotic feedback system can be created. The hybrid biology-semiconductor systems can be employed in a broad spectrum of critical applications with ground-breaking scientific, economical, and societal impacts. Leveraging the built-in or synthetically programmed cellular machineries and their interactions with semiconductor platforms, these hybrid systems will potentially offer unprecedented capabilities far beyond conventional electronics-only devices. For example, advances in this field could stimulate developments of self- powered Intelligent Sensor Systems that integrate biological sensing functions and energy generation with inorganic information/computation capabilities to enable diverse new applications. Example applications include fast and high-throughput chemical screening for drug discovery, diagnosis and therapy planning Fig. 1. Hybrid biology-semiconductor platform.
for personalized medicine, detecting chemical and biological agents for defense and environmental needs, and novel microscopic biological actuators or robots. Current research on such hybrid biological-semiconductor platforms is still in its stage of infancy, and one of the major challenges in such hybrid biology-semiconductor systems lies in the information/energy interface between the cellular “Biological Front-End” layer and the “Semiconductor Back-End” layer. These technological challenges that must be addressed to develop such a hybrid system are daunting and encompass almost every facet of VLSI, nano-electronics, and bioengineering technologies. The meeting participants will examine these essential technologies from the point of view of what near-term advances may be achievable through focused investment in high-risk, high-reward applied research in the area of hybrid bioelectronics microsystems. This meeting will develop future research agendas with a particular focus on the interactions between the nano-electronics and the biological layers, which will enable the next-step scientific explorations on hybrid biological/nano-electronic devices/systems and insure the Nation long-term uncontested technology leadership. This meeting is also designed to identify and roadmap the technology capabilities that are needed to enable the production and deployment of hybrid biological-semiconductor microsystems by 2022. Format This is an invitation-only meeting where all the attendees are expected to actively participate. The 1.5- day technical exchange meeting will be constructed to include selected overview presentations and panel discussions. It will encourage and enable interactions by allotting sufficient time for in-depth panel-participant interactions. Participants will be asked to identify technologies and capabilities that may only be achievable through large, focused investment by funding agencies on both fundamental and applied research.
important in advanced man-made structures as it already is in molecular and cell biology. The fundamental laws of noise and thermodynamics set bounds on the energy, time, and space needed to compute at a given speed and precision, which biology is already remarkably close to. Based on the similarities between electronics and chemistry, it is possible to map circuits between electronic and biological domains in a rigorous fashion1,2. For example, logarithmic analog computation in living cells has been engineered with less than three transcription factors, almost two orders of magnitude more efficient than prior digital approaches, to build a ‘biomolecular slide rule’. Highly computationally intensive noisy DNA-protein and protein-protein networks can be rapidly simulated in mixed-signal supercomputing chips that naturally capture their noisiness, dynamics, and loading interactions at lightning-fast speeds. Hybrid cell-microelectronics systems could enable extremely low-energy and high-performance analog and digital computing. Possible first port of entry – point-of-care biomedical computing architectures^1. Fig. I. 1. Living cell as a information processing system^1 Biocompatible organic electronic materials Biocompatible organic materials are likely to play an important role in hybrid electronic-biological systems. Recently, electronically and ionically conducting polymers were used in an implantable device for local electrically controlled delivery of therapeutics in a living, awake, and freely moving animal ,
(Fig. I. 2). The conducting polymers form organic electronic ion pump allowing electronic pulses to be transduced into biological signals, in the form of ionic and molecular fluxes, which provide a new way of interfacing biology with electronics. Devices were implanted onto the spinal cord of rats, and local delivery of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) was initiated. The part of the device being inserted subarachnoidally onto the dorsal aspect of the spinal cord was 1.2 mm wide and about 6 cm long. Highly localized delivery resulted in a significant decrease in pain response with low dosage (less than 1% of the amount typically used in intrathecal administration) and no observable side effects. This work reported the first use of an implantable organic electronic device for therapeutic purposes. Fig. I. 2. Organic electronic pain therapy in vivo While the majority of current efforts in bioelectronic interfaces use animal cells, there are very promising opportunities in making bioelectronic interfaces with plants3,5. Plant cell bioelectronic research doesn’t have regulatory constraint as in some cases of animal cells. The roots, stems, leaves, and vascular circuitry of higher plants are responsible for conveying chemical signals that regulate growth and functions. This can be viewed as analogous to the contacts, interconnections, devices, and wires of discrete and integrated electronic circuits. Analog and digital organic electronic circuits and devices can be formed in living plants. Possible applications of integrated and distributed electronics in plants, include precision recording and regulation of physiology (e.g., electronic control of root growth rate), energy harvesting from photosynthesis, alternatives to genetic modification for plant optimization, etc. Experiments with Rosa floribunda (garden rose) demonstrated possibilities for creating electrically conducting channels by introducing and dispensing artificial electroactive materials into xylem (a transport tissue in plants). Electrically conducting polymer PEDOT-S:H was used to form extended continuous wires along the xylem channels. These long-range conducting PEDOT-S:H xylem wires, surrounded with cellular domains including confined electrolytic compartments, were shown to act as in situ organic electrochemical transistors. More complex xylem-templated circuits, namely, xylem logic has also been demonstrated3,5^ (Fig. I. 3).
Fig. I. 4. A perspective on using microfluidic lab-on-the chip platforms for precision diagnostics^6 Changes in electrical impedance produced by particles passing through a small aperture has also been applied for detection and analysis of different bio-molecules. The detection of target molecules is achieved by electrophoretically driving the molecules through nanometer-sized pores in thin membranes and simultaneously monitoring the modulation of nanopore ionic current. This method shows promise, e.g. for nanopore-based next generation DNA sequencing technology. Probability and state of different diseases, such as cancer can be assessed from patient’s genomic extracts. For example, the feasibility of cancer detection by analyzing DNA methylation on genomic extracts from bodily fluids using solid-state nanopores has been reported^9. Various dielectrics and metals have been used to make synthetic membranes for nanopores. However, the finite thickness (usually above 10 nm) of the fabricated membranes presents a limit on the spatial resolution of the measurements, making single nucleotide resolution difficult to achieve. 2D materials, such as graphene and MoS2 that come form single layer with the same order of thickness as the nucleotide separation in a DNA strand, are attractive solution to this problem. Integration of stacked graphene and MoS2 layers (Fig. I. 5) could enable identification of individual nucleobases in DNA6,^10. Fig. I. 5. MoS 2 nanoribbon on a graphene Al2O3 nanopore for DNA sensing
Interfacing Nanowires and Living Cells Using one-dimensional (1D) semiconductors, such as nanowires (NW) allows creating mechanical and electrical interface with single cells and even monitor subcellular processes (Fig. I. 6). The NW diameter can be as small as a few nm (comparable with the size of a single protein), while a typical length of the NW for biosensing applications is 1– 100 μm, and thus the NW can span a single cell. They could be used as (quasi) non-invasive probes to contact or even puncture through the cell’s membrane. Fig. I. 6. Interfacing inorganic nanowire arrays and living cells for a wide range of biological and biomedical applications11,12. Cell-penetrating inorganic nanowires can enable effective delivery of biomolecules, electrical and optical stimulation and recording of intracellular signals over a long period of time. Nanowire penetrations into cell through two mechanisms, namely through “impaling” as cells land onto a bed of nanowires, and through “adhesion-mediated” penetration, which occurs as cells spread on the substrate and generate adhesion force. Penetration is much more effective through the adhesion mechanism, with nanowire geometry and cell stiffness being critically important. Stiffer cells have higher penetration efficiency, but are more sensitive to nanowire geometry. Non-penetrating interfacing of high-density nanowire arrays with cells has also been demonstrated. It is based on interactions between the nanostructured substrate and the micro/nanoscale features of cell surfaces. Such interactions enable efficient capture of rare cells including circulating tumor cells and trafficking leukocytes from complex bio-specimens. It also serves as a platform for probing cell traction force and neuronal guidance. Nanowire substrate for rare tumor cell capture and quantitation in combination with laser scanning cytometry (LSC) technique allows for rapid, automated, high-content characterization of immobilized tumor cells.
(^1) Rahul Sarpeshkar (Dartmouth Coll), “Cell-Microelectronics Systems for Computation”, ARO/NSF/SRC Technical Exchange Meeting on Cell-Semiconductor Interfaces and Hybrid Semiconductor-Biological Systems, Atlanta, GA, July 27 & 28, 2016 (^2) J. J. Y. Teo, S. S. Woo, R. Sarpeshkar, “Synthetic Biology: A Unifying View and Review Using Analog Circuits”, IEEE Trans. Biomed. Circ. Systems 9 (2015) 453- 474 (^3) Daniel Simon (Linköping U – Sweden), “Electronic Plants”, ARO/NSF/SRC Technical Exchange Meeting on Cell-Semiconductor Interfaces and Hybrid Semiconductor-Biological Systems, Atlanta, GA, July 27 & 28, 2016 (^4) A. Jonsson, Z. Song, D. Nilsson, B. A. Meyerson, D. T. Simon, B. Linderoth, M. Berggren, ‘Therapy using implanted organic bioelectronics’, Science Advances 1 (2015) e (^5) E. Stavrinidou, R. Gabrielsson., E. Gomez, X. Crispin, O. Nilsson, D. Simon, M. Berggren, ‘Electronic plants’, Science Advances 1 (2015) e (^6) Rashid Bashir (U Illinois), “Micro- and Nanoelectronic Devices for Medicine and Biology”, ARO/NSF/SRC Technical Exchange Meeting on Cell-Semiconductor Interfaces and Hybrid Semiconductor-Biological Systems, Atlanta, GA, July 27 & 28, 2016 (^7) U. Hassan, R. Bashir, “Electrical cell counting process characterization in a microfluidic impedance cytometer”, Biomed Microdevices 16 (2014) 697-704. (^8) U. Hassan, N. N. Watkins, B. Reddy, G. Damhorst, R. Bashir, ‘Microfluidic differential immunocapture biochip for specific leukocyte counting’, Nature Protocols 11 (2016) 714– 726 (^9) J. Shim, Y. Kim, G. I. Humphreys, A. M. Nardulli, F. Kosari, G. Vasmatzis, W. R. Taylor, D. A. Ahlquist, S. Myong, R. Bashir, “Nanopore-Based Assay for Detection of Methylation in Double-Stranded DNA Fragments”, ACS NANO 9 (2015) 290- 300 (^10) S. Banerjee, J. Wilson, J. Shim, M. Shankla, E. A. Corbin, A. Aksimentiev, R. Bashir, “Slowing DNA Transport Using Graphene– DNA Interactions”, Adv. Funct. Mater. 25 (2015) 936- 946 (^11) Rong Fan (Yale U), “Interfacing Vertical Inorganic Nanowire Arrays with Living Cells for Cellular Function Analysis”, ARO/NSF/SRC Technical Exchange Meeting on Cell-Semiconductor Interfaces and Hybrid Semiconductor-Biological Systems, Atlanta, GA, July 27 & 28, 2016 (^12) M. Kwak, L. Han, J. J. Chen, R. Fan, “Interfacing Inorganic Nanowire Arrays and Living Cells for Cellular Function Analysis”, Small 11 (2015) 5600- 5610
Real-time bilateral interface between semiconductor platforms and
biology (Session II)
Contributors: Hua Wang / Georgia Tech Ken Shepard / Columbia U Brian Cunningham / UIUC Caroline Ajo-Franklin / LBNL Bozhi Tian / U Chicago Cells are highly complex systems that often exhibit multi-physics responses under external stimulus. This session will focus on technologies for creating interfaces that can provide (a) single-cell (<5-10μm/pixel) or sub-cell resolution (<1μm/pixel), (b) real-time two-way communication (sensing and actuation by both cells and microelectronics), (c) multi-modality interfacing with cells, (d) compatibility with high throughput massively parallel operations, and (e) possibility of production at commercial quantities. The nanometer-scale complementary metal-oxide semiconductor (CMOS) process is a potential candidate to realize cell-microelectronics interfaces. Electronics-based computations and signal processing, such as application of machine learning methods, may drastically relax the requirement on the physical interface and lead to further pixel miniaturization. In parallel, optoelectronics for interfacing with cells/tissues and various emerging technologies, such as nano-pores, silicon nanowires, and graphene biosensors, may greatly augment the CMOS. The topics discussed at this session included multi-modal cell-semiconductor interface for hybrid systems, electrochemical camera chip for imaging multiple metabolites in biofilms, nano-Biophotonics for cellular and molecular detections, e- nanoconduits to electronically interface cells with materials, and three-dimensional silicon for subcellular interfaces. Multi-Modality Cell-Semiconductor Interface for Hybrid Systems Cells are often viewed as the smallest building blocks of life that constitute all living organisms. Typical cell sizes highly depend on the cell types, which range from 100μm (human egg), to 8- 10 μm (human red blood cells), and down to 1- 2 μm ( E. coli bacteria). Despite of their small sizes, cells are highly complex systems with numerous molecules operating concurrently in hundreds of pathways most of which are carefully regulated to maintain the cell phenotypes and proper cellular functionalities. Understanding cells and leverage their built-in or synthetic functionalities will have a tremendous economic and scientific impacts. From the economic perspective, the cell biology and biotechnologies directly impact multiple large-volume and fast-growing markets in healthcare and pharmaceutical industries, such as cell-based assays dominated by drug discovery/testing ($18.3B by 2020^1 ), stem-cell development ($170.1B by 2020^2 ), and regenerative medicine ($67.5B by 2020^3 ). On the scientific impacts, cells offer a wide variety of natural or synthetic functionalities (e.g., sensing, actuation, synthesis, computation, processing, and even energy harvesting) and can serve as an organic and highly versatile interface to the external environment (Fig. II. 1).
Fig. II. 2. Multi-modal interfacing with cells is essential to capture complex cellular physiological changes and achieve holistic cellular characterization. In recent years, there have been substantial research investment on multi-modal cellular interface technologies using commercially available low-cost semiconductor technologies, such as CMOS. This area of research has been pioneered by Georgia Tech^5 -^10. It has been shown that multi-modal cellular sensing arrays are achieved in CMOS processes (Fig. II. 3). The achieved array scaled is from hundreds of pixels/chip to over 10k pixels/chip, and the chip size is from 2mm×2mm to 7mm×7mm to support tissue level field-of-view (FoV). Each pixel supports multiple sensing modalities, including cellular potential, current, impedance, optical, and thermal detections, and each pixel can be individually configured and addressed. The pixel size ranges from 80μm× 100 μm to 16μm× 16 μm, approaching single-cell resolution for mammalian cells. The CMOS cellular sensing arrays also contain signal conditioning and pre- processing circuitry on-chip. Biocompatible packaging using medical epoxy and low-cost polydimethylsiloxane (PDMS) has been demonstrated to match standard multi-well plate for cell analysis. Biocompatibility has been verified using various mammalian cells and bacteria. Fig. II. 3. Examples of CMOS multi-modal interfacing array chips for holistic cellular characterization, high throughput drug screening, and cell-based sensors. The CMOS multi-modal cellular sensing arrays have shown their use in a wide variety of cell-based assays, including real-time bioluminescence imaging, real-time cell impedance and cell detachment/migration assay, joint recording of extracellular potential and opto-mechanical potentials. These assays use various cell types, such as human ovarian cancer cell aggregates (HeyA8-F8), mouse/human neuron cell clusters, rat cardiomyocyte clusters, and E. coli bacteria^5 -^10. The joint recording of extracellular potential and opto-mechanical potentials is shown as an effective multi- parametric means for holistic cardiac cell characterizations and testing drug efficacy and cardiac toxicity.
It is believed that future hybrid cell-semiconductor systems will be a highly interdisciplinary field that require collaborative efforts and knowledge from areas such as electronics, device physics, micro- fabrication, biology, biochemistry, control theory, and signal process. Electrochemical camera chip for imaging multiple metabolites in biofilms Optical signals have been employed as the predominant means for interfacing the solid-state sensors and the cells for both in vivo imaging and molecular diagnostics. Light offers non-invasive interrogation, a diversity of developed and well established organic/inorganic chromophores, and also direct cell stimulation capability, e.g., optogenetics. However, optical interfacing has multiple disadvantages. Optical detection suffers from shot-noise and is mostly pronounced at high bandwidth. A single optical reporter only generate weak signal, which then solely relies on the electronics for signal amplification. In most cases, natural biophysical process do not generate light, and optical signals are only an indirect means for measurement and require labeling or genetic modification to add optical reporters. Moreover, most fluorescent measurements are restricted by photo-bleaching and cannot perform long- term real-time monitoring. Although multi-photon fluorescent excitations can alleviate this issue, it adds further complication on already complex optical measurement setups. In contrast, using electrical interface will address many aforementioned disadvantages of optical interfacing. In particular, electrical measurements naturally captures various electrochemical processes that are essential in cellular and molecular characterizations. However, electrical transduction inherently requires close proximity and experience form-factor mismatch and signaling/system mismatch. The former is because of the geometrical and mechanical property difference between the cells and electronics, which can be reconciled by making electronics miniaturizing or flexible/conformal to the biology. The latter mismatch is due to the fact that biology using ions for their signaling, while electronics use electronics. Thus, bioelectrical interfaces should be either based on charge detections or electrochemical reactions that convert ions to electrons. Two examples of bio-electrical interfaces are presented in this paper, i.e., a CMOS electrode array for electrochemical imaging of bio-films^11 , 12^ and a packaged system that harvest energy from ATP to power integrated electronics^13. In the first example, the CMOS electrode array employs a large number of working electrodes that share one pair of counter electrode and reference electrode. The working electrodes also share multiple trans- impedance amplifiers (TIAs) that provide low termination impedance and current sensing capability. The number of working electrodes have been demonstrated to be 60 electrodes/chip to 1824 electrodes/chip. Thus, the CMOS electrode array chip achieves 3-electrode potentiostat with up-to 1824 sensing sites by working electrode multiplexing, which supports whole-chip scanning frame rate of 1 frame/second. Such CMOS electrode array thus can detect electrochemical reactions of deposited bio- films with high spatiotemporal resolution and function as an “electrochemical camera.” Various electrochemical experiments have been demonstrated for detection of phenazines. Note that phenazines are a group of redox-active metabolites that are produced by Pseudomonas aeruginosa PA14, an opportunistic pathogen, which have drastic effects on community behavior in
enhanced microscopy, to potentially address applications such as disease diagnostics, life science research, and pharmaceutical screening. A common surface photonic structure is “guided mode resonator filter” that functions as an optical resonator (Q~850) for at least one wavelength. It is often constructed using periodically repeated structures that are coated with high refractive index material (SiN or TiO 2 ) between two materials with low refractive index (such as water, air, plastic, or SiO 2 ). It can be fabricated by nanoreplica molding that uses pre-patterned silicon master wafer as the mold to shape the liquid epoxy on a polyester sheet; the liquid epoxy is cued by UV light and then coated using high-refractive coating, such as TiO 2. Such nanoreplica molding can achieve mass production at ~0.5m/min rates as continuous rolls of polyester films. “Guided mode resonator filter” can also be fabricated on silicon substrates and glass wafers using post-processing lithography steps. The “guided mode resonator filter” can be utilized for label-free biomolecular sensing and PC-enhanced fluorescence detections that enhance both the excitation EM field and the fluorescent emission profile with directional enhancement. A major application drive on next-generation photonic crystals research is to realize PC-enabled point-of-care diagnostics, which will ultimately replace slow and label-intensive laboratory tests by automated assays using low-cost sensors with access to “cloud” computing for data analytics. Recently, a PC special cradle is developed to convert a common cell phone camera into a spectrometer. Detection of HIV virus through affinity-based binding has been demonstrated14, 15. Next, several detailed application examples are presented to showcase the use of photonic crystal structures in various biosensing. The first example is the PC-enhanced microscopy for label-free imaging of cell-surface interactions^16 , which utilizes the peak wavelength value (PWV) shift and peak intensity value (PIV) shift for surface-base label-free biosensing (Fig. II. 5). It has been shown that PC-enhanced microscopy can detect the surface attachments of various stem cell types and Au nano-rods^16 with improved contrast over conventional bright-field imaging. Fig. II. 5. PC Enhanced Microscopes for Cell-Surface Interaction Imaging. The second example is external cavity laser biosensors for small molecule drug screening17, 18^ (Fig. II. 6). The major challenge of drug screening is to efficiently search through libraries of chemical compounds to rule out most candidates and find those that have the desired interactions with the targets. The desired biosensor properties include high sensitivity, label-free detections, low-cost, and high
throughput to screen >100,000 compounds/day. Experimental results have shown that external cavity laser biosensors successfully detect dorzolamide within a mixture of 35 chemical compounds. Fig. II. 6. External Cavity Laser Biosensor. The third example is photonic crystal enhanced fluorescence for detection of cancer biomarker proteins 19 - (^21) (Fig. II. 7). The typical challenge of cancer biomarker detection is its extremely low concentration in blood circulation. It has been shown that PC-enhanced fluorescent imaging achieves better sensitivity than conventional unmodified glass-substrate of fluorescent imaging. Experimental results also achieve the lowest reported TNF-α detection concentration of 2.74pg/mL with replicate averaged SNR of 24.6. Similar enhanced fluorescent detections of various cancer biomarkers have been achieved by photonic crystal. Fig. II. 7. PC Enhanced Fluorescent Imaging for Cancer Biomarker Detections and Comparison with Unmodified Glass Substrate. e- Nanoconduits to Electronically Interface Cells with Materials This presentation focuses on the fundamental scientific aspects of electron transfer between living cells and external electrodes, which is essential for creating cell-semiconductor hybrid systems. There have been recurrent discussions and debates on the major mechanisms of electron transfers across the cell membranes. It is believed that both cross-membrane electron nano-conduit and extracellular redox groups serve as media for electron transfer across the cell membranes. This talk focuses on the fundamental science and application of cross-membrane electron nano-conduit.
Three-dimensional Silicon for Subcellular Interfaces This presentation focuses on using 3-D silicon structures, their material, geometric, mechanical properties, and their interactions with cells to achieve sub-cellular interfaces with bioelectric and/or biomechanical modalities. Three technology examples are shown. First, it is demonstrated that mesostructured silicon can be utilized to interface with lipid bilayers^26 (Fig. II. 9). Using mesoporous silica as the template, chemical vapor deposition system can implement the mesostructured silicon framework that show ordered nanowire array with amorphous properties. Mechanical tests show desired deformability of the silicon framework with its Young’s modulus of 1. GPa in air and 0.41 GPa in liquid, which supports certain flexibility of the silicon framework when interacting with cells. In contrast, bulk silicon are very rigid with Young’s modulus of 160~180 GPa. It is shown that when the mesostructured silicon framework is placed in close proximity to phospholipid bilayer, a fast temperature variation can induce noticeable capacitive currents (up-to 100pA) in the phospholipid bilayer. Note that such temperature variation can be triggered by focused laser illumination. Moreover, the resulting capacitive currents can be used to trigger action potential of the cells. Thus, using mesostructured silicon framework and laser illumination, one can realize a remotely laser-controlled bioelectric interface for action potential induction. This structure is different from commonly used optogenetics, since there is no need for genetic modification of the cells. It is shown that an average of 5.32μJ threshold energy is needed to reliably elicit action potentials. The elicited action potential can track the optical excitation up-to 15Hz. Fig. II. 9. A Silicon/Neuron Interface Using Mesostructured Silicon Framework. Next, it is shown that silicon nanowires with kinked geometry can be used to probe the cytoskeleton and measure the intracellular mechanical properties^27 (Fig. II. 10). When silicon nanowires are co-cultured with cells, it is observed that the nanowires will cluster in the perinuclear region of the cells. If the nanowires are designed with kinked and asymmetric shape, and their geometry can be monitored using high-resolution microscope, their geometrical bending during the cell co-culturing can measure the intracellular force with both amplitude and location properties over time. In experiments, a maximum intracellular force of 116.9pN is measured and shows significant spatiotemporal evolution of intracellular forces.
Fig. II. 10. Kinked Nanowires Allowed Intra-cellular Force Dynamics Study. In the third example, 3D silicon nanowires are shown to measure the mechanical properties of extracellular matrix^28 (Fig. II. 11). The silicon nanowires can be designed to have anisotropy in their shapes, which then experience difference in insertion force and detachment force when probing extracellular matrix, yield useful information of cells and their environments. Fig. II. 11. Anisotropy in 3D Silicon Nanowires May Yield Unidirectional Biointerfaces. In summary, 3D micromachined silicon or silicon nanostructures offer numerous new opportunities as biomaterials and cell-silicon interfaces with novel bioelectric and mechanical properties. ―――――――――――――――――― (^1) Cell-Based Assay Market by Product (Cell Lines, Reagents, Kits, Instruments, Software, Services), Applications (Research, Drug Discovery, ADME Studies, Toxicology), End User (Pharmaceutical Companies, Academics, CRO), & Region - Global Forecast to
(^2) Stem Cells Market Analysis By Product (Adult Stem Cells, Human Embryonic Cells, Pluripotent Stem Cell, Natural Rosette Cells), By Technology (Cell Acquisition, Cell Production, Cryopreservation, Expansion, Sub-Culture), By Application (Regenerative Medicine, Drug Discovery And Development) And Segment Forecasts To 2020 (^3) World Regenerative Medicines Market - Opportunities and Forecasts, 2013 - 2020 (^4) J. El-Ali, P. K. Sorger, K. F. Jensen, Cells on chips, Nature , vol. 442, pp. 403–411, 2006. (^5) J. Park, M. K. Aziz, S. Li, T. Chi, S. I. Grijalva, J. Sung, H. Cho, and H. Wang, “1024-Pixel CMOS Multi-Modality Joint Cellular Sensor/Stimulator Array for Real-Time Holistic Cellular Characterization and Cell-Based Drug Screening” IEEE Trans. Biomed. Circuits Syst., 201 8. (^6) T. Chi, J. S. Park, J. C. Butts, T. A. Hookway, A. Su, C. Zhu, M. P. Styczynski, T. C. McDevitt, and H. Wang, “A Multi-Modality CMOS Sensor Array for Cell-Based Assay and Drug Screening,” IEEE Trans. Biomed. Circuits Syst., vol. 9, no. 6, pp. 801-814, Dec.
