Mechanical forces play important roles in the regulation of various biological processes at the molecular and cellular level, such as gene expression, adhesion, migration, and cell fate, which are essential to the maintenance of tissue homeostasis. In this review, we discuss emerging bioengineered tools enabled by microscale technologies for studying the roles of mechanical forces in cell biology. In addition to traditional mechanobiology experimental techniques, we review recent advances of microelectromechanical systems (MEMS)-based approaches for cell mechanobiology and discuss how microengineered platforms can be used to generate in vivo–like micromechanical environment in in vitro settings for investigating cellular processes in normal and pathophysiological contexts. These capabilities also have significant implications for mechanical control of cell and tissue development and cell-based regenerative therapies.

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Microengineered Platforms for Cell Mechanobiology

Improving access to effective and affordable healthcare has long been a global endeavor. In this quest, the development of cost-effective and easy-to-use medical testing equipment that enables rapid and accurate diagnosis is essential to reduce the time and costs associated with healthcare services. To this end, point-of-care (POC) diagnostics plays a crucial role in healthcare delivery in both developed and developing countries by bringing medical testing to patients, or to sites near patients. As the diagnosis of a wide range of diseases, including various types of cancers and many endemics, relies on optical techniques, numerous compact and cost-effective optical imaging platforms have been developed in recent years for use at the POC. Here, we review the state-of-the-art optical imaging techniques that can have a significant impact on global health by facilitating effective and affordable POC diagnostics.

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Optical imaging techniques for point-of-care diagnostics

The interplay between the mechanical properties of cells and the forces that they produce internally or that are externally applied to them play an important role in maintaining the normal function of cells. These forces also have a significant effect on the progression of mechanically related diseases. To study the mechanics of cells, a wide variety of tools have been adapted from the physical sciences. These tools have helped to elucidate the mechanical properties of cells, the nature of cellular forces, and mechanoresponses that cells have to external forces, i.e., mechanotransduction. Information gained from these studies has been utilized in computational models that address cell mechanics as a collection of biomechanical and biochemical processes. These models have been advantageous in explaining experimental observations by providing a framework of underlying cellular mechanisms. They have also enabled predictive, in silico studies, which would otherwise be difficult or impossible to perform with current experimental approaches. In this review, we discuss these novel, experimental approaches and accompanying computational models. We also outline future directions to advance the field of cell mechanics. In particular, we devote our attention to the use of microposts for experiments with cells and a bio-chemical-mechanical model for capturing their unique mechanobiological properties. [DOI: 10.1115/1.4025355]

Review on Cell Mechanics: Experimental and Modeling Approaches

We developed an ultrahigh speed, handheld swept source optical coherence tomography (SS-OCT) ophthalmic instrument using a 2D MEMS mirror. A vertical cavity surface-emitting laser (VCSEL) operating at 1060 nm center wavelength yielded a 350 kHz axial scan rate and 10 µm axial resolution in tissue. The long coherence length of the VCSEL enabled a 3.08 mm imaging range with minimal sensitivity roll-off in tissue. Two different designs with identical optical components were tested to evaluate handheld OCT ergonomics. An iris camera aided in alignment of the OCT beam through the pupil and a manual fixation light selected the imaging region on the retina. Volumetric and high definition scans were obtained from 5 undilated normal subjects. Volumetric OCT data was acquired by scanning the 2.4 mm diameter 2D MEMS mirror sinusoidally in the fast direction and linearly in the orthogonal slow direction. A second volumetric sinusoidal scan was obtained in the orthogonal direction and the two volumes were processed with a software algorithm to generate a merged motion-corrected volume. Motion-corrected standard 6 x 6 mm2 and wide field 10 x 10 mm2 volumetric OCT data were generated using two volumetric scans, each obtained in 1.4 seconds. High definition 10 mm and 6 mm B-scans were obtained by averaging and registering 25 B-scans obtained over the same position in 0.57 seconds. One of the advantages of volumetric OCT data is the generation of en face OCT images with arbitrary cross sectional B-scans registered to fundus features. This technology should enable screening applications to identify early retinal disease, before irreversible vision impairment or loss occurs. Handheld OCT technology also promises to enable applications in a wide range of settings outside of the traditional ophthalmology or optometry clinics including pediatrics, intraoperative, primary care, developing countries, and military medicine.

Handheld ultrahigh speed swept source optical coherence tomography instrument using a MEMS scanning mirror

Methods for probing mechanical responses of mammalian cells
to electrical excitations can improve our understanding of cellular
physiology and function. The electrical response of neuronal
cells to applied voltages has been studied in detail, but
less is known about their mechanical response to electrical
excitations. Studies using atomic force microscopes (AFMs)
have shown that mammalian cells exhibit voltage-induced
mechanical deflections at nanometre scales, but AFM
measurements can be invasive and difficult to multiplex. Here
we show that mechanical deformations of neuronal cells in
response to electrical excitations can be measured using piezoelectric
PbZr_xTi_(1-x)O_3 (PZT) nanoribbons, and we find that cells
deflect by 1 nm when 120 mV is applied to the cell membrane.
The measured cellular forces agree with a theoretical model in
which depolarization caused by an applied voltage induces a
change in membrane tension, which results in the cell altering
its radius so that the pressure remains constant across the
membrane. We also transfer arrays of PZT nanoribbons
onto a silicone elastomer and measure mechanical deformations
on a cow lung that mimics respiration. The PZT
nanoribbons offer a minimally invasive and scalable platform
for electromechanical biosensing.

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Piezoelectric nanoribbons for monitoring cellular deformations

A system for optical coherence tomographic imaging of turbid materials utilizing multiple channels of information comprising spatial, angle, spectral and polarization domains. The multichannel optical coherence tomographic methods can be incorporated into an endoscopic probe for imaging a patient. The endoscope comprises an optical fiber array and can comprise a plurality of optical fibers adapted to be disposed in the patient. The optical fiber array transmits the light from the light source Into the patient, and transmits the light reflected by the patient out of the patient. The plurality of optical fibers in the array are in optical communication with the light source. The multichannel optical coherence tomography system comprises a detector for receiving the light from the array and analyzing the light. The methods and apparatus may be applied for imaging a vessel, biliary, GU and/or Gl tract of a patient.

OCT using spectrally resolved bandwidth

Provided are forward-imaging optical coherence tomography (OCT) systems and probes. In one embodiment, a scanning reflector surface is configured to be rotated about two axes in a single operating plane to direct light transmitted along the sample path to a sample to be imaged.

Forward-imaging optical coherence tomography (OCT) systems and probes

A handheld, forward-imaging, laser-scanning confocal microscope (LSCM) demonstrating optical sectioning comparable with microtome slice thicknesses in conventional histology, targeted towards interventional imaging, is reported. Fast raster scanning (~2.5 kHz line scan rate, 3.0–5.0 frames per second) was provided by a 2-axis microelectromechanical system (MEMS) scanning mirror fabricated by a method compatible with complementary metal-oxide-semiconductor (CMOS) processing. Cost-effective rapid-prototyped packaging combined the MEMS mirror with micro-optical components into a probe with 18 mm outer diameter and 54 mm rigid length. ZEMAX optical design simulations indicate the ability of the handheld optical system to obtain lateral resolution of 0.31 and axial resolution of 2.85 µm. Lateral and axial resolutions are experimentally measured at 0.5 µm and 4.2 µm respectively, with field of view of 200 × 125 µm. Results of reflectance imaging of ex vivo swine liver, and fluorescence imaging of the expression of cytokeratin and mammaglobin tumor biomarkers in epithelial human breast tissue from metastatic breast cancer patients are presented. The results indicate that inexpensive, portable handheld optical microscopy tools based on silicon micromirror technologies could be important in interventional imaging, complementing existing coarse-resolution techniques to improve the efficacy of disease diagnosis, image-guided excisional microsurgery, and monitored photodynamic therapy.

Handheld histology-equivalent sectioning laser-scanning confocal optical microscope for interventional imaging.

We report on a fibre-based forward-imaging swept-source optical coherence tomography system using a high-reflectivity two-axis microelectromechanical scanning mirror for high-speed 3D in vivo visualization of cellular-scale architecture of biological specimens. The scanning micromirrors, based on electrostatic staggered vertical comb drive actuators, can provide ± 9° of optical deflection on both rotation axes and uniform reflectivity of greater than 90% over the range of imaging wavelengths (1260–1360 nm), allowing for imaging turbid samples with good signal-to-noise ratio. The wavelength-swept laser, scanning over 100 nm spectrum at 20 kHz rate, enables fast image acquisition at 10.2 million voxels s−1 (for 3D imaging) or 40 frames s−1 (for 2D imaging with 500 transverse pixels per image) with 8.6 µm axial resolution. Lateral resolution of 12.5 µm over 3 mm field of view in each lateral direction is obtained using ZEMAX optical simulations for the lateral beam scanning system across the scanning angle range of the 500 µm × 700 µm micromirror. We successfully acquired en face and tomographic images of rigid structures (scanning micromirror), in vitro biological samples (onion peels and pickle slices) and in vivo images of human epidermis over 2 × 1 × 4 mm3 imaging volume in real time at faster-than-video 2D frame rates. The results indicate that our system framework may be suitable for image-guided minimally invasive examination of various diseased tissues.

http://iopscience.iop.org/article/10.1088/1464-4258/10/4/044013/pdf

Karthik Kumar

Papers

OCT using spectrally resolved bandwidth

Forward-imaging optical coherence tomography (OCT) systems and probes

Handheld histology-equivalent sectioning laser-scanning confocal optical microscope for interventional imaging.

Fast 3D in vivo swept-source optical coherence tomography using a two-axis MEMS scanning micromirror

Forward-imaging optical coherence tomography (oct) systems and probe