Publications by authors named "Jeffrey W Kysar"

27 Publications

  • Page 1 of 1

Design optimization of a cardiovascular stent with application to a balloon expandable prosthetic heart valve.

Mater Des 2021 Nov 10;209. Epub 2021 Jul 10.

Division of Cardiac, Thoracic and Vascular Surgery, Section of Pediatric and Congenital Cardiac Surgery, New-York Presbyterian - Morgan Stanley Children's Hospital, Columbia University Medical Center, New York, NY, USA.

A cardiovascular stent design optimization method is proposed with application to a pediatric balloon-expandable prosthetic heart valve. The prosthetic valved conduit may be expanded to a larger permanent diameter via subsequent transcatheter balloon dilation procedures. While multiple expandable prosthetic heart valves are currently at different stages of development, this work is focused on one particular design in which a stent is situated inside of an expandable polymeric valved conduit. Since the valve and conduit must be joined with a robust manufacturing technique, a polymeric glue layer is inserted between the two, which results in radial retraction of the valved region after expansion. Design of an appropriate stent is proposed to counteract this phenomenon and maintain the desired permanent diameter throughout the device after a single non-compliant balloon dilation procedure. The finite element method is used to compute performance metrics related to the permanent expansion diameter and required radial force. Additionally, failure due not only to high cycle fatigue but also due to ductile fracture is incorporated into the design study through the use of an existing ductile fracture criterion for metals. Surrogate models are constructed with the results of the high fidelity simulations and are subsequently used to numerically obtain a set of Pareto-optimal stent designs. Finally, a single design is identified by optimizing a normalized aggregate objective function with equal weighting of all design objectives.
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http://dx.doi.org/10.1016/j.matdes.2021.109977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336925PMC
November 2021

Impact of Systemic versus Intratympanic Dexamethasone Administration on the Perilymph Proteome.

J Proteome Res 2021 08 22;20(8):4001-4009. Epub 2021 Jul 22.

Department of Otolaryngology-Head and Neck Surgery, Columbia University Vagelos College of Physicians and Surgeons, New York, New York 10032, United States.

Glucocorticoids are the first-line treatment for sensorineural hearing loss, but little is known about the mechanism of their protective effect or the impact of route of administration. The recent development of hollow microneedles enables safe and reliable sampling of perilymph for proteomic analysis. Using these microneedles, we investigate the effect of intratympanic (IT) versus intraperitoneal (IP) dexamethasone administration on guinea pig perilymph proteome. Guinea pigs were treated with IT dexamethasone ( = 6), IP dexamethasone ( = 8), or untreated for control ( = 8) 6 h prior to aspiration. The round window membrane (RWM) was accessed via a postauricular approach, and hollow microneedles were used to perforate the RWM and aspirate 1 μL of perilymph. Perilymph samples were analyzed by liquid chromatography-mass spectrometry-based label-free quantitative proteomics. Mass spectrometry raw data files have been deposited in an international public repository (MassIVE proteomics repository at https://massive.ucsd.edu/) under data set # MSV000086887. In the 22 samples of perilymph analyzed, 632 proteins were detected, including the inner ear protein cochlin, a perilymph marker. Of these, 14 proteins were modulated by IP, and three proteins were modulated by IT dexamethasone. In both IP and IT dexamethasone groups, VGF nerve growth factor inducible was significantly upregulated compared to control. The remaining adjusted proteins modulate neurons, inflammation, or protein synthesis. Proteome analysis facilitated by the use of hollow microneedles shows that route of dexamethasone administration impacts changes seen in perilymph proteome. Compared to IT administration, the IP route was associated with greater changes in protein expression, including proteins involved in neuroprotection, inflammatory pathway, and protein synthesis. Our findings show that microneedles can mediate safe and effective intracochlear sampling and hold promise for inner ear diagnostics.
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http://dx.doi.org/10.1021/acs.jproteome.1c00322DOI Listing
August 2021

Simulation assisted design for microneedle manufacturing: Computational modeling of two-photon templated electrodeposition.

J Manuf Process 2021 Jun 16;66:211-219. Epub 2021 Apr 16.

Department of Chemical Engineering, Columbia University, New York, NY, 10027, USA.

Fully metallic micrometer-scale 3D architectures can be fabricated via a hybrid additive methodology combining multi-photon lithography with electrochemical deposition of metals. The methodology - referred to as two-photon templated electrodeposition (2PTE) - has significant design freedom that enables the creation of complicated, traditionally difficult-to-make, high aspect ratio metallic structures such as microneedles. These complicated geometries, combined with their fully metallic nature, can enable precision surgical applications such as inner ear drug delivery or fluid sampling. However, the process involves electrochemical deposition of metals into complicated 3D lithography patterns thicker than 500 μm. This causes potential and chemical gradients to develop within the 3D template, creating limitations to what can be designed. These limitations can be explored, understood, and overcome via numerical modeling. Herein we introduce a numerical model as a design tool that can predict growth for manufacturing complicated 3D metallic geometries. The model is successful in predicting the geometric result of 2PTE, and enables extraction of insights about geometric constraints through exploration of its mechanics.
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http://dx.doi.org/10.1016/j.jmapro.2021.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128138PMC
June 2021

Inner Ear Gene Delivery: Vectors and Routes.

Hearing Balance Commun 2020 25;18(4):278-285. Epub 2020 Aug 25.

Department of Otolaryngology -- Head and Neck Surgery, Columbia University Vagelos College of Physicians and Surgeons, New York, NY.

Objectives: Current treatments for hearing loss offer some functional improvements in hearing, but do not restore normal hearing. The aim of this review is to highlight recent advances in viral and non-viral vectors for gene therapy and to discuss approaches for overcoming barriers inherent to inner ear delivery of gene products.

Data Sources: The databases used were Medline, EMBASE, Web of Science, and Google Scholar. Search terms were [("cochlea*" or "inner ear" or "transtympanic" or "intratympanic" or "intracochlear" or "hair cells" or "spiral ganglia" or "Organ of Corti") and ("gene therapy" or "gene delivery")]. The references section of resulting articles was also used to identify relevant studies.

Results: Both viral and non-viral vectors play important roles in advancing gene delivery to the inner ear. The round window membrane is one significant barrier to gene delivery that intratympanic delivery methods attempt to overcome through diffusion and intracochlear delivery methods bypass completely.

Conclusions: Gene therapy for hearing loss is a promising treatment for restoring hearing function by addressing innate defects. Recent technological advances in inner ear drug delivery techniques pose exciting opportunities for progress in gene therapy.
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http://dx.doi.org/10.1080/21695717.2020.1807261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888570PMC
August 2020

Novel 3D-printed hollow microneedles facilitate safe, reliable, and informative sampling of perilymph from guinea pigs.

Hear Res 2021 02 2;400:108141. Epub 2020 Dec 2.

Department of Otolaryngology - Head and Neck Surgery, Columbia University Vagelos College of Physicians and Surgeons, 180 Fort Washington Avenue, Harkness Pavilion, 8th Floor, New York, NY 10032, United States; Department of Mechanical Engineering, Columbia University, New York, NY, United States. Electronic address:

Background: Inner ear diagnostics is limited by the inability to atraumatically obtain samples of inner ear fluid. The round window membrane (RWM) is an attractive portal for accessing perilymph samples as it has been shown to heal within one week after the introduction of microperforations. A 1 µL volume of perilymph is adequate for proteome analysis, yet the total volume of perilymph within the scala tympani of the guinea pig is limited to less than 5 µL. This study investigates the safety and reliability of a novel hollow microneedle device to aspirate perilymph samples adequate for proteomic analysis.

Methods: The guinea pig RWM was accessed via a postauricular surgical approach. 3D-printed hollow microneedles with an outer diameter of 100 µm and an inner diameter of 35 µm were used to perforate the RWM and aspirate 1 µL of perilymph. Two perilymph samples were analyzed by liquid chromatography-mass spectrometry-based quantitative proteomics as part of a preliminary study. Hearing was assessed before and after aspiration using compound action potential (CAP) and distortion product otoacoustic emissions (DPOAE). RWMs were harvested 72 h after aspiration and evaluated for healing using confocal microscopy.

Results: There was no permanent damage to hearing at 72 h after perforation as assessed by CAP (n = 7) and DPOAE (n = 8), and all perforations healed completely within 72 h (n = 8). In the two samples of perilymph analyzed, 620 proteins were detected, including the inner ear protein cochlin, widely recognized as a perilymph marker.

Conclusion: Hollow microneedles can facilitate aspiration of perilymph across the RWM at a quality and volume adequate for proteomic analysis without causing permanent anatomic or physiologic dysfunction. Microneedles can mediate safe and effective intracochlear sampling and show great promise for inner ear diagnostics.
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http://dx.doi.org/10.1016/j.heares.2020.108141DOI Listing
February 2021

Facile and quantitative estimation of strain in nanobubbles with arbitrary symmetry in 2D semiconductors verified using hyperspectral nano-optical imaging.

J Chem Phys 2020 Jul;153(2):024702

Department of Mechanical Engineering, Columbia University, New York, New York 10027, USA.

When layers of van der Waals materials are deposited via exfoliation or viscoelastic stamping, nanobubbles are sometimes created from aggregated trapped fluids. Though they can be considered a nuisance, nanobubbles have attracted scientific interest in their own right owing to their ability to generate large in-plane strain gradients that lead to rich optoelectronic phenomena, especially in the semiconducting transition metal dichalcogenides. Determination of the strain within the nanobubbles, which is crucial to understanding these effects, can be approximated using elasticity theory. However, the Föppl-von Kármán equations that describe strain in a distorted thin plate are highly nonlinear and often necessitate assuming circular symmetry to achieve an analytical solution. Here, we present an easily implemented numerical method to solve for strain tensors of nanobubbles with arbitrary symmetry in 2D crystals. The method only requires topographic information from atomic force microscopy and the Poisson ratio of the 2D material. We verify that this method reproduces the strain for circularly symmetric nanobubbles that have known analytical solutions. Finally, we use the method to reproduce the Grüneisen parameter of the E' mode for 1L-WS nanobubbles on template-stripped Au by comparing the derived strain with measured Raman shifts from tip-enhanced Raman spectroscopy, demonstrating the utility of our method for estimating localized strain in 2D crystals.
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http://dx.doi.org/10.1063/5.0012817DOI Listing
July 2020

Imaging strain-localized excitons in nanoscale bubbles of monolayer WSe at room temperature.

Nat Nanotechnol 2020 Oct 13;15(10):854-860. Epub 2020 Jul 13.

Department of Mechanical Engineering, Columbia University, New York, NY, USA.

In monolayer transition-metal dichalcogenides, localized strain can be used to design nanoarrays of single photon sources. Despite strong empirical correlation, the nanoscale interplay between excitons and local crystalline structure that gives rise to these quantum emitters is poorly understood. Here, we combine room-temperature nano-optical imaging and spectroscopic analysis of excitons in nanobubbles of monolayer WSe with atomistic models to study how strain induces nanoscale confinement potentials and localized exciton states. The imaging of nanobubbles in monolayers with low defect concentrations reveals localized excitons on length scales of around 10 nm at multiple sites around the periphery of individual nanobubbles, in stark contrast to predictions of continuum models of strain. These results agree with theoretical confinement potentials atomistically derived from the measured topographies of nanobubbles. Our results provide experimental and theoretical insights into strain-induced exciton localization on length scales commensurate with exciton size, realizing key nanoscale structure-property information on quantum emitters in monolayer WSe.
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http://dx.doi.org/10.1038/s41565-020-0730-5DOI Listing
October 2020

Drug delivery device for the inner ear: ultra-sharp fully metallic microneedles.

Drug Deliv Transl Res 2021 Feb;11(1):214-226

Department of Mechanical Engineering, Columbia University, 500 West 120th Street, New York, NY, 10027, USA.

Drug delivery into the inner ear is a significant challenge due to its inaccessibility as a fluid-filled cavity within the temporal bone of the skull. The round window membrane (RWM) is the only delivery portal from the middle ear to the inner ear that does not require perforation of bone. Recent advances in microneedle fabrication enable the RWM to be perforated safely with polymeric microneedles as a means to enhance the rate of drug delivery from the middle ear to the inner ear. However, the polymeric material is not biocompatible and also lacks the strength of other materials. Herein we describe the design and development of gold-coated metallic microneedles suitable for RWM perforation. When developing microneedle technology for drug delivery, we considered three important general attributes: (1) high strength and ductility material, (2) high accuracy and precision of fabrication, and (3) broad design freedom. We developed a hybrid additive manufacturing method using two-photon lithography and electrochemical deposition to fabricate ultra-sharp gold-coated copper microneedles with these attributes. We refer to the microneedle fabrication methodology as two-photon templated electrodeposition (2PTE). We demonstrate the use of these microneedles by inducing a perforation with a minimal degree of trauma in a guinea pig RWM while the microneedle itself remains undamaged. Thus, this microneedle has the potential literally of opening the RWM for enhanced drug delivery into the inner ear. Finally, the 2PTE methodology can be applied to many different classes of microneedles for other drug delivery purposes as well the fabrication of small scale structures and devices for non-medical applications. Graphical Abstract Fully metallic ultra-sharp microneedle mounted at end of a 24-gauge stainless steel blunt syringe needle tip: (left) Size of microneedle shown relative to date stamp on U.S. one-cent coin; (right) Perforation through guinea pig round window membrane introduced with microneedle.
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http://dx.doi.org/10.1007/s13346-020-00782-9DOI Listing
February 2021

Inner ear delivery: Challenges and opportunities.

Laryngoscope Investig Otolaryngol 2020 Feb 11;5(1):122-131. Epub 2019 Dec 11.

Department of Otolaryngology-Head and Neck Surgery Columbia University Vagelos College of Physicians and Surgeons New York New York.

Objectives: The treatment of inner ear disorders remains challenging due to anatomic barriers intrinsic to the bony labyrinth. The purpose of this review is to highlight recent advances and strategies for overcoming these barriers and to discuss promising future avenues for investigation.

Data Sources: The databases used were PubMed, EMBASE, and Web of Science.

Results: Although some studies aimed to improve systemic delivery using nanoparticle systems, the majority enhanced local delivery using hydrogels, nanoparticles, and microneedles. Developments in direct intracochlear delivery include intracochlear injection and intracochlear implants.

Conclusions: In the absence of a systemic drug that targets only the inner ear, the best alternative is local delivery that harnesses a combination of new strategies to overcome anatomic barriers. The combination of microneedle technology with hydrogel and nanoparticle delivery is a promising area for future investigation.

Level Of Evidence: NA.
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http://dx.doi.org/10.1002/lio2.336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042639PMC
February 2020

Anatomical and Functional Consequences of Microneedle Perforation of Round Window Membrane.

Otol Neurotol 2020 02;41(2):e280-e287

Department of Otolaryngology-Head and Neck Surgery, Columbia University Vagelos College of Physicians and Surgeons.

Hypothesis: Microneedles can create microperforations in the round window membrane (RWM) without causing anatomic or physiologic damage.

Background: Reliable delivery of agents into the inner ear for therapeutic and diagnostic purposes remains a challenge. Our novel approach employs microneedles to facilitate intracochlear access via the RWM. This study investigates the anatomical and functional consequences of microneedle perforations in guinea pig RWMs in vivo.

Methods: Single three-dimensional-printed, 100 μm diameter microneedles were used to perforate the guinea pig RWM via the postauricular sulcus. Hearing was assessed both before and after microneedle perforation using compound action potential and distortion product otoacoustic emissions. Confocal microscopy was used ex vivo to examine harvested RWMs, measuring the size, shape, and location of perforations and documenting healing at 0 hours (n = 7), 24 hours (n = 6), 48 hours (n = 6), and 1 week (n = 6).

Results: Microneedles create precise and accurate perforations measuring 93.1 ± 29.0 μm by 34.5 ± 16.8 μm and produce a high-frequency threshold shift that disappears after 24 hours. Examination of perforations over time demonstrates healing progression over 24 to 48 hours and complete perforation closure by 1 week.

Conclusion: Microneedles can create a temporary microperforation in the RWM without causing significant anatomic or physiologic dysfunction. Microneedles have the potential to mediate safe and effective intracochlear access for diagnosis and treatment of inner ear disease.
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http://dx.doi.org/10.1097/MAO.0000000000002491DOI Listing
February 2020

3D-Printed Microneedles Create Precise Perforations in Human Round Window Membrane in Situ.

Otol Neurotol 2020 02;41(2):277-284

Department of Otolaryngology-Head and Neck Surgery, Columbia University Vagelos College of Physicians and Surgeons.

Hypothesis: Three-dimensional (3D)-printed microneedles can create precise holes on the scale of micrometers in the human round window membrane (HRWM).

Background: An intact round window membrane is a barrier to delivery of therapeutic and diagnostic agents into the inner ear. Microperforation of the guinea pig round window membrane has been shown to overcome this barrier by enhancing diffusion 35-fold. In humans, the challenge is to design a microneedle that can precisely perforate the thicker HRWM without damage.

Methods: Based on the thickness and mechanical properties of the HRWM, two microneedle designs were 3D-printed to perforate the HRWM from fresh frozen temporal bones in situ (n = 18 total perforations), simultaneously measuring force and displacement. Perforations were analyzed using confocal microscopy; microneedles were examined for deformity using scanning electron microscopy.

Results: HRWM thickness was determined to be 60.1 ± 14.6 (SD) μm. Microneedles separated the collagen fibers and created slit-shaped perforations with the major axis equal to the microneedle shaft diameter. Microneedles needed to be displaced only minimally after making initial contact with the RWM to create a complete perforation, thus avoiding damage to intracochlear structures. The microneedles were durable and intact after use.

Conclusion: 3D-printed microneedles can create precise perforations in the HRWM without damaging intracochlear structures. As such, they have many potential applications ranging from aspiration of cochlear fluids using a lumenized needle for diagnosis and creating portals for therapeutic delivery into the inner ear.
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http://dx.doi.org/10.1097/MAO.0000000000002480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189659PMC
February 2020

Mechanical considerations for polymeric heart valve development: Biomechanics, materials, design and manufacturing.

Biomaterials 2019 12 17;225:119493. Epub 2019 Sep 17.

Division of Cardiac, Thoracic and Vascular Surgery, Section of Pediatric and Congenital Cardiac Surgery, New-York Presbyterian - Morgan Stanley Children's Hospital, Columbia University Medical Center, New York, NY, USA. Electronic address:

The native human heart valve leaflet contains a layered microstructure comprising a hierarchical arrangement of collagen, elastin, proteoglycans and various cell types. Here, we review the various experimental methods that have been employed to probe this intricate microstructure and which attempt to elucidate the mechanisms that govern the leaflet's mechanical properties. These methods include uniaxial, biaxial, and flexural tests, coupled with microstructural characterization techniques such as small angle X-ray scattering (SAXS), small angle light scattering (SALS), and polarized light microscopy. These experiments have revealed complex elastic and viscoelastic mechanisms that are highly directional and dependent upon loading conditions and biochemistry. Of all engineering materials, polymers and polymer-based composites are best able to mimic the tissue-level mechanical behavior of the native leaflet. This similarity to native tissue permits the fabrication of polymeric valves with physiological flow patterns, reducing the risk of thrombosis compared to mechanical valves and in some cases surpassing the in vivo durability of bioprosthetic valves. Earlier work on polymeric valves simply assumed the mechanical properties of the polymer material to be linear elastic, while more recent studies have considered the full hyperelastic stress-strain response. These material models have been incorporated into computational models for the optimization of valve geometry, with the goal of minimizing internal stresses and improving durability. The latter portion of this review recounts these developments in polymeric heart valves, with a focus on mechanical testing of polymers, valve geometry, and manufacturing methods.
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http://dx.doi.org/10.1016/j.biomaterials.2019.119493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948849PMC
December 2019

In-vitro perforation of the round window membrane via direct 3-D printed microneedles.

Biomed Microdevices 2018 06 8;20(2):47. Epub 2018 Jun 8.

Department of Mechanical Engineering, Columbia University, 220 Mudd Building 500 West 120th Street, New York, NY, 10027, USA.

The cochlea, or inner ear, is a space fully enclosed within the temporal bone of the skull, except for two membrane-covered portals connecting it to the middle ear space. One of these portals is the round window, which is covered by the Round Window Membrane (RWM). A longstanding clinical goal is to reliably and precisely deliver therapeutics into the cochlea to treat a plethora of auditory and vestibular disorders. Standard of care for several difficult-to-treat diseases calls for injection of a therapeutic substance through the tympanic membrane into the middle ear space, after which a portion of the substance diffuses across the RWM into the cochlea. The efficacy of this technique is limited by an inconsistent rate of molecular transport across the RWM. A solution to this problem involves the introduction of one or more microscopic perforations through the RWM to enhance the rate and reliability of diffusive transport. This paper reports the use of direct 3D printing via Two-Photon Polymerization (2PP) lithography to fabricate ultra-sharp polymer microneedles specifically designed to perforate the RWM. The microneedle has tip radius of 500 nm and shank radius of 50 μ m, and perforates the guinea pig RWM with a mean force of 1.19 mN. The resulting perforations performed in vitro are lens-shaped with major axis equal to the microneedle shank diameter and minor axis about 25% of the major axis, with mean area 1670 μ m. The major axis is aligned with the direction of the connective fibers within the RWM. The fibers were separated along their axes without ripping or tearing of the RWM suggesting the main failure mechanism to be fiber-to-fiber decohesion. The small perforation area along with fiber-to-fiber decohesion are promising indicators that the perforations would heal readily following in vivo experiments. These results establish a foundation for the use of Two-Photon Polymerization lithography as a means to fabricate microneedles to perforate the RWM and other similar membranes.
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http://dx.doi.org/10.1007/s10544-018-0287-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091873PMC
June 2018

Serrated needle design facilitates precise round window membrane perforation.

J Biomed Mater Res A 2016 07 11;104(7):1633-7. Epub 2016 Mar 11.

Department of Otolaryngology-Head and Neck Surgery, Columbia University College of Physicians and Surgeons, New York, New York.

The round window membrane (RWM) has become the preferred route, over cochleostomy, for the introduction of cochlear implant electrodes as it minimizes inner ear trauma. However, in the absence of a tool designed for creating precise perforation, current practices lead to tearing of the RWM and significant intracochlear pressure fluctuations. On the basis of RWM mechanical properties, we have designed a multi-serrated needle to create consistent holes without membrane tearing or damaging inner ear structures. Four and eight-serrated needles were designed and produced with wire electrical discharge machining (EDM). The needle's ability to create RWM perforations was tested in deidentified, commercially acquired temporal bones with the assistance of a micromanipulator. Subsequently, specimens were imaged under light and scanning electron microscopy (SEM). The needles created consistent, appropriately sized holes in the membrane with minimal tearing. While a four-serrated crown needle made rectangular/trapezoid perforations, the octagonal crown formed smooth oval holes within the membrane. Though designed for single use, the needle tolerated repeated use without significant damage. The serrated needles formed precise perforations in the RWM while minimizing damage during cochlear implantation. The octagonal needle design created the preferred oval perforation better than the quad needle. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1633-1637, 2016.
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http://dx.doi.org/10.1002/jbm.a.35692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508557PMC
July 2016

A dual wedge microneedle for sampling of perilymph solution via round window membrane.

Biomed Microdevices 2016 Apr;18(2):24

Department of Mechanical Engineering, Columbia University, 220 Mudd Building 500 West 120th Street, New York, NY, 10027, USA.

Precision medicine for inner-ear disease is hampered by the absence of a methodology to sample inner-ear fluid atraumatically. The round window membrane (RWM) is an attractive portal for accessing cochlear fluids as it heals spontaneously. In this study, we report on the development of a microneedle for perilymph sampling that minimizes the size of RWM perforation, facilitates quick aspiration, and provides precise volume control. Here, considering the mechanical anisotropy of the RWM and hydrodynamics through a microneedle, a 31G stainless steel pipe was machined into wedge-shaped design via electrical discharge machining. The sharpness of the needle was evaluated via a surface profilometer. Guinea pig RWM was penetrated in vitro, and 1 μL of perilymph was sampled and analyzed via UV-vis spectroscopy. The prototype wedge shaped needle was successfully fabricated with the tip curvature of 4.5 μm and the surface roughness of 3.66 μm in root mean square. The needle created oval perforation with minor and major diameter of 143 and 344 μm (n = 6). The sampling duration and standard deviation of aspirated volume were 3 s and 6.8 % respectively. The protein concentration was 1.74 mg/mL. The prototype needle facilitated precise perforation of RWMs and rapid aspiration of cochlear fluid with precise volume control. The needle design is promising and requires testing in human cadaveric temporal bone and further optimization to become clinically viable.
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http://dx.doi.org/10.1007/s10544-016-0046-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574191PMC
April 2016

Recoverable Slippage Mechanism in Multilayer Graphene Leads to Repeatable Energy Dissipation.

ACS Nano 2016 Feb 27;10(2):1820-8. Epub 2016 Jan 27.

Department of Mechanical Engineering, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208-3111, United States.

Understanding the deformation mechanisms in multilayer graphene (MLG), an attractive material used in nanodevices as well as in the reinforcement of nanocomposites, is critical yet challenging due to difficulties in experimental characterization and the spatiotemporal limitations of atomistic modeling. In this study, we combine nanomechanical experiments with coarse-grained molecular dynamics (CG-MD) simulations to elucidate the mechanisms of deformation and failure of MLG sheets. Elastic properties of graphene sheets with one to three layers are measured using film deflection tests. A nonlinear behavior in the force vs deflection curves for MLGs is observed in both experiments and simulations: during loading/unloading cycles, MLGs dissipate energy through a "recoverable slippage" mechanism. The CG-MD simulations further reveal an atomic level interlayer slippage process and suggest that the dissipated energy scales with film perimeter. Moreover, our study demonstrates that the finite shear strength between individual layers could explain the experimentally measured size-dependent strength with thickness scaling in MLG sheets.
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http://dx.doi.org/10.1021/acsnano.5b04939DOI Listing
February 2016

Silver/silver chloride microneedles can detect penetration through the round window membrane.

J Biomed Mater Res B Appl Biomater 2017 02 27;105(2):307-311. Epub 2015 Oct 27.

Department of Otolaryngology-Head and Neck Surgery, Columbia University College of Physicians and Surgeons, New York, New York.

Hypothesis: Silver-plated microneedles can be used to confirm penetration of semi-permeable membranes such as the round window membrane (RWM) by detection of voltage change at the moment of perforation.

Background: The introduction of microperforations in the RWM can significantly enhance intracochlear delivery of therapeutics. However, the moment of needle penetration through the RWM cannot be reliably detected by visualization or sensation alone. We explore the ability of electrochemical detection of penetration in defining the precise instant a microneedle enters the inner ear.

Methods: 0.2 mm diameter stainless steel Minutien pins were electroplated with copper, then silver. Pins were then soaked in bleach for 24 h to complete Ag/AgCl plating. Experiments were performed using a 3 mL Franz cell diffusion system with 1%, 2%, 3%, 4%, and 5% saline solution in the donor chamber and artificial perilymph solution in the receptor chamber separated by 5-μm pore synthetic membrane. Continuous voltage measurements were made throughout the process of membrane penetration by the microneedle (N = 6 for each saline concentration).

Results: Silver-plated needles were able to detect an instantaneous change in voltage when traversing the membrane from saline solution into artificial perilymph. As calculated, the magnitude of the change in voltage upon penetration increased with increasing saline concentration and was stable across trials.

Conclusion: Ag/AgCl coated microneedles are effective in detecting the moment of penetration across semi-permeable membranes. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 307-311, 2017.
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http://dx.doi.org/10.1002/jbm.b.33557DOI Listing
February 2017

Enhanced Glassy State Mechanical Properties of Polymer Nanocomposites via Supramolecular Interactions.

Nano Lett 2015 Aug 24;15(8):5465-71. Epub 2015 Jul 24.

†Department of Chemical Engineering, Columbia University, 500 W. 120th Street, New York, New York 10027, United States.

It is now well accepted that the addition of nanoparticles (NPs) can strongly affect the thermomechanical properties of the polymers into which they are incorporated. In the solid (glassy) state, previous work has implied that optimal mechanical properties are achieved when the NPs are well dispersed in the matrix and when there is strong interfacial binding between the grafted NPs and the polymer matrix. Here we provide strong evidence supporting the importance of intermolecular interactions through the use of NPs grafted with polymers that can hydrogen bond with the matrix, yielding to significant improvements in the measured mechanical properties. Our finding thus supports the previously implied central role of strong interfacial binding in optimizing the mechanical properties of polymer nanocomposites.
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http://dx.doi.org/10.1021/acs.nanolett.5b01859DOI Listing
August 2015

Microperforations significantly enhance diffusion across round window membrane.

Otol Neurotol 2015 Apr;36(4):694-700

*Department of Otolaryngology-Head and Neck Surgery, Columbia University College of Physicians and Surgeons; †Department of Mechanical Engineering; and ‡Department of Biomedical Engineering, Columbia University, New York, New York, U.S.A.

Hypothesis: Introduction of microperforations in round window membrane (RWM) will allow reliable and predictable intracochlear delivery of pharmaceutical, molecular, or cellular therapeutic agents.

Background: Reliable delivery of medications into the inner ear remains a formidable challenge. The RWM is an attractive target for intracochlear delivery. However, simple diffusion across intact RWM is limited by what material can be delivered, size of material to be delivered, difficulty with precise dosing, timing, and precision of delivery over time. Further, absence of reliable methods for measuring diffusion across RWM in vitro is a significant experimental impediment.

Methods: A novel model for measuring diffusion across guinea pig RWM, with and without microperforation, was developed and tested: cochleae, sparing the RWM, were embedded in 3D-printed acrylic holders using hybrid dental composite and light cured to adapt the round window niche to 3 ml Franz diffusion cells. Perforations were created with 12.5-μm-diameter needles and examined with light microscopy. Diffusion of 1 mM Rhodamine B across RWM in static diffusion cells was measured via fluorescence microscopy.

Results: The diffusion cell apparatus provided reliable and replicable measurements of diffusion across RWM. The permeability of Rhodamine B across intact RWM was 5.1 × 10(9-) m/s. Manual application of microperforation with a 12.5-μm-diameter tip produced an elliptical tear removing 0.22 ± 0.07% of the membrane and was associated with a 35× enhancement in diffusion (P < 0.05).

Conclusion: Diffusion cells can be applied to the study of RWM permeability in vitro. Microperforation in RWM is an effective means of increasing diffusion across the RWM.
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http://dx.doi.org/10.1097/MAO.0000000000000629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359065PMC
April 2015

Microanatomic analysis of the round window membrane by white light interferometry and microcomputed tomography for mechanical amplification.

Otol Neurotol 2014 Apr;35(4):672-8

*Department of Otolaryngology, New York University School of Medicine; †Department of Mechanical Engineering, Columbia University; and ‡Department of Otolaryngology, Columbia University College of Physicians and Surgeons, New York, New York, U.S.A.

Objective: The round window membrane (RWM) is increasingly becoming a target for amplification using active middle ear implants. However, the current strategy of using available transducer tips may have negative consequences for the RWM. We investigated the microanatomy of the RWM to establish a basis for the design of the transducer tip for the RWM driver.

Study Design: Using the guinea pig as an animal model, microcomputed tomography (μCT) and white light interferometry were used to study the topography of the RWM and RW niche (RWN). The curvatures of the RWM surface were calculated using the topography data.

Main Outcome Measures: The 3-dimensional structure of the scala tympani terminal, saddle-shaped surface topography, and surface curvature were determined.

Results: The size of the scala terminal was approximated as an ellipse for which the major and minor axes were 1.29 and 0.95 mm. The average minimum and maximum radii of curvature around the center of RWM were -0.44 and +0.70 mm along the minor and major axis.

Conclusion: The microanatomies of the RWM and RWN have important implications for the design of the transducer tip to maximize energy transfer while minimizing its distortion and permanent disruption. Our results suggest that the size of the transducer tip should be smaller than the minor axis of the scala terminal to avoid collision with the RWN. The driver should be designed to conform to the topography and radius of curvature of the center portion of the RWM, which for a guinea pig is 0.44 mm.
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http://dx.doi.org/10.1097/MAO.0000000000000193DOI Listing
April 2014

Strengthening effect of single-atomic-layer graphene in metal-graphene nanolayered composites.

Nat Commun 2013 ;4:2114

Graduate School of Energy Environment Water and Sustainability, Korea Advanced Institute of Science & Technology, Daejeon 305-701, Korea.

Graphene is a single-atomic-layer material with excellent mechanical properties and has the potential to enhance the strength of composites. Its two-dimensional geometry, high intrinsic strength and modulus can effectively constrain dislocation motion, resulting in the significant strengthening of metals. Here we demonstrate a new material design in the form of a nanolayered composite consisting of alternating layers of metal (copper or nickel) and monolayer graphene that has ultra-high strengths of 1.5 and 4.0 GPa for copper-graphene with 70-nm repeat layer spacing and nickel-graphene with 100-nm repeat layer spacing, respectively. The ultra-high strengths of these metal-graphene nanolayered structures indicate the effectiveness of graphene in blocking dislocation propagation across the metal-graphene interface. Ex situ and in situ transmission electron microscopy compression tests and molecular dynamics simulations confirm a build-up of dislocations at the graphene interface.
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http://dx.doi.org/10.1038/ncomms3114DOI Listing
December 2013

High-strength chemical-vapor-deposited graphene and grain boundaries.

Science 2013 May;340(6136):1073-6

Department of Mechanical Engineering, Columbia University, New York, NY 10027, USA.

Pristine graphene is the strongest material ever measured. However, large-area graphene films produced by means of chemical vapor deposition (CVD) are polycrystalline and thus contain grain boundaries that can potentially weaken the material. We combined structural characterization by means of transmission electron microscopy with nanoindentation in order to study the mechanical properties of CVD-graphene films with different grain sizes. We show that the elastic stiffness of CVD-graphene is identical to that of pristine graphene if postprocessing steps avoid damage or rippling. Its strength is only slightly reduced despite the existence of grain boundaries. Indentation tests directly on grain boundaries confirm that they are almost as strong as pristine. Graphene films consisting entirely of well-stitched grain boundaries can retain ultrahigh strength, which is critical for a large variety of applications, such as flexible electronics and strengthening components.
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http://dx.doi.org/10.1126/science.1235126DOI Listing
May 2013

Monolithic integration of nanoscale tensile specimens and MEMS structures.

Nanotechnology 2013 Apr 28;24(16):165502. Epub 2013 Mar 28.

Department of Mechanical Engineering, Columbia University, New York, NY 10027, USA.

Nanoscale materials often have stochastic material properties due to a random distribution of material defects and an insufficient number of defects to ensure a consistent average mechanical response. Current methods to measure the mechanical properties employ MEMS-based actuators. The nanoscale specimens are typically mounted manually onto the load platform, so the boundary conditions have random variations, complicating the experimental measurement of the intrinsic stochasticity of the material properties. Here we show methods for monolithic integration of a nanoscale specimen co-fabricated with the loading platform. The nanoscale specimen is gold with dimensions of ∼40 nm thickness, 350 ± 50 nm width, and 7 μm length and the loading platform is an interdigitated electrode electrostatic actuator. The experiment is performed in a scanning electron microscope and digital image correlation is employed to measure displacements to determine stress and strain. The ultimate tensile strength of the nanocrystalline nanoscale specimen approaches 1 GPa, consistent with measurements made by other nanometer scale sample characterization methods on other material samples at the nanometer scale, as well as gold samples at the nanometer scale. The batch-compatible microfabrication method can be used to create nominally identical nanoscale specimens and boundary conditions for a broad range of materials.
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http://dx.doi.org/10.1088/0957-4484/24/16/165502DOI Listing
April 2013

Mechanical properties of thin glassy polymer films filled with spherical polymer-grafted nanoparticles.

Nano Lett 2012 Aug 1;12(8):3909-14. Epub 2012 Aug 1.

Department of Chemical Engineering, Columbia University, New York, New York, USA.

It is commonly accepted that the addition of spherical nanoparticles (NPs) cannot simultaneously improve the elastic modulus, the yield stress, and the ductility of an amorphous glassy polymer matrix. In contrast to this conventional wisdom, we show that ductility can be substantially increased, while maintaining gains in the elastic modulus and yield stress, in glassy nanocomposite films composed of spherical silica NPs grafted with polystyrene (PS) chains in a PS matrix. The key to these improvements are (i) uniform NP spatial dispersion and (ii) strong interfacial binding between NPs and the matrix, by making the grafted chains sufficiently long relative to the matrix. Strikingly, the optimal conditions for the mechanical reinforcement of the same nanocomposite material in the melt state is completely different, requiring the presence of spatially extended NP clusters. Evidently, NP spatial dispersions that optimize material properties are crucially sensitive to the state (melt versus glass) of the polymeric material.
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http://dx.doi.org/10.1021/nl301792gDOI Listing
August 2012

Measurement of the elastic properties and intrinsic strength of monolayer graphene.

Science 2008 Jul;321(5887):385-8

Department of Mechanical Engineering, Columbia University, New York, NY 10027, USA.

We measured the elastic properties and intrinsic breaking strength of free-standing monolayer graphene membranes by nanoindentation in an atomic force microscope. The force-displacement behavior is interpreted within a framework of nonlinear elastic stress-strain response, and yields second- and third-order elastic stiffnesses of 340 newtons per meter (N m(-1)) and -690 Nm(-1), respectively. The breaking strength is 42 N m(-1) and represents the intrinsic strength of a defect-free sheet. These quantities correspond to a Young's modulus of E = 1.0 terapascals, third-order elastic stiffness of D = -2.0 terapascals, and intrinsic strength of sigma(int) = 130 gigapascals for bulk graphite. These experiments establish graphene as the strongest material ever measured, and show that atomically perfect nanoscale materials can be mechanically tested to deformations well beyond the linear regime.
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http://dx.doi.org/10.1126/science.1157996DOI Listing
July 2008

Viscoplastic and granular behavior in films of colloidal nanocrystals.

Phys Rev Lett 2007 Jan 9;98(2):026103. Epub 2007 Jan 9.

Department of Mechanical Engineering, Columbia University, New York, New York 10027, USA.

Nanoindentation measurements of electrophoretically deposited films of colloidal CdSe nanocrystals, capped by organic ligands, show the films have an elastic stiffness modulus of approximately 10 GPa and exhibit viscoplasticity. This mechanical response suggests polymeric features that are attributable to the ligands. After particle cross-linking and partial ligand removal, the films exhibit more features of granularity.
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http://dx.doi.org/10.1103/PhysRevLett.98.026103DOI Listing
January 2007

Raman microprobe analysis of elastic strain and fracture in electrophoretically deposited CdSe nanocrystal films.

Nano Lett 2006 Feb;6(2):175-80

Materials Research Science and Engineering Center, Columbia University, New York, New York 10027, USA.

The mechanical stability of nanocrystal films is critical for applications, yet largely unexplored. Raman microprobe analysis used here to probe the nanocrystal cores of thick, fractured electrophoretically deposited films of 3.2 nm diameter CdSe nanocrystals measures approximately 2.5% in-plane tensile strain in cores of unfractured films. The crack dimensions determine the overall in-plane film strain, approximately 11.7%, and the film biaxial modulus, approximately 13.8 GPa, from which the biaxial modulus of the trioctylphosphine oxide ligand matrix is inferred, approximately 5.1 GPa.
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http://dx.doi.org/10.1021/nl051921gDOI Listing
February 2006
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