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Research

We study the mechanical signals that govern cell-matrix and cell-cell interaction, mediated by cell-generated forces, extracellular matrix mechanics, and mechanical interaction between cells.

 

We focus on the following research directions:

Mechanical interaction between cells

We use computational finite element simulations and biological experiments to reveal how mechanical forces, generated by contractile cells, are transmitted across fibrous environments and how these forces impact cellular activity and collective behaviour. 

Related papers:

  • Assaf Nahum, Yoni Koren, Bar Ergaz, Sari Natan, Gad Miller, Yuval Tamir, Shahar Goren, Avraham Kolel, Sankar Jagadeeshan, Moshe Elkabets, Ayelet Lesman, Assaf Zaritsky. Inference of long-range cell-cell force transmission from ECM remodeling fluctuations. Commun Biol 6, 811 (2023). https://doi.org/10.1038/s42003-023-05179-1

  • Ran S. Sopher,  Shahar Goren, Yoni Koren,  Oren Tchaicheeyan, Ayelet Lesman. Intercellular Mechanical Signalling in a 3D Nonlinear Fibrous Network Model. Mechanics of Materials, Volume 184, September 2023. https://doi.org/10.1016/j.mechmat.2023.104739.

  • David Gomez, Eial Teomy, Ayelet Lesman, Yair Shokef. Target finding in fibrous biological environments. New J. Phys. New J. Phys. 22 103008 Oct 2020. https://doi.org/10.1088/1367-2630/abb64b

  • Sari Natan, Yoni Koren, Ortal Shelah, Shahar Goren, Ayelet Lesman. Long-range mechanical coupling of cells in 3D fibrin gels. Molecular Biology of the Cell, Volume 31, No. 14, July 2020. https://doi.org/10.1091/mbc.E20-01-0079.

  • Shahar Goren, Yoni Koren, Xinpeng Xu, Ayelet Lesman. Elastic Anisotropy Governs the Range of Cell-Induced Displacements. Biophysical Journal. March 2020 .Volume 118, Issue 5, 10 March 2020, Pages 1152-1164. https://doi.org/10.1007/s10439-019-02426-7

  • David Gomez, Sari Natan, Yair Shokef, Ayelet Lesman. Mechanical Interaction between Cells Facilitates Molecular Transport. Advanced Biosystems, Volume 3, Issue 12, November 2019. https://doi.org/10.1002/adbi.201900192

  • Amots Mann, Ran S Sopher, Shahar Goren, Ortal Shelah, Oren Tchaicheeyan, Ayelet Lesman. Force chains in cell-cell mechanical communication. Journal of the Royal Society Interface. 16 (159), Oct 2019.

  • Ran S Sopher, Hanan Tokash, Sari Natan, Mirit Sharabi, Ortal Shelah, Oren Tchaicheeyan, Ayelet Lesman. Nonlinear elasticity of the ECM fibers facilitates efficient inter-cellular communication. Biophysical J. 2;115(7):1357-1370, 2018.

Mechanical-communication-between-cells.png
Top: Covers of Molecular Biology of the Cell (left) and Biophysical Journal (right), showing pairs of green fluorescently-labeled fibroblasts, embedded within 3D fibrin gels, captured by confocal microscopy. When cells contract, they align and dense the gel fibers between them, resulting in long-range mechanical coupling.
Bottom: A computational finite element simulation of two contractile cells, generating mechanical coupling through the matrix fibers.

Together with Dr. Raya Sorkin (Chemistry, TAU), we use optical tweezers to measure force propagation in fibrous gels that are put under tension and become elastically anisotropic.

Force transmission in fibrous environments using optical tweezers

Related papers:

  • Shahar Goren, Maayan Levin, Guy Brand, Ayelet Lesman, Raya Sorkin. Probing Local Force Propagation in Tensed Fibrous Gels. Small, 2022, 2202573

0.75 micron polystyrene beads (orange) embedded in fibrin gel (green). Optical tweezers are used to apply localized forces and observe the material response.

Forces exerted by growing roots

Plant roots are considered one of the most efficient soil explorers. As opposed to the penetration strategy of other organisms, that is based on pushing through soil, roots penetrate by growing, adding new cells at the tip and elongating over a well-defined growth zone. In collaboration with Dr. Yasmin Meroz (Plant Sciences, TAU), we study the forces applied by plant roots in agar gel by traction force microscopy, and use finite element modeling to reveal the advantages of the growth mechanism.

3D displacement field of root of Arabidopsis plant growing within agar gel, generated using the Digital Volume Correlation algorithm. Displacements shown as a quiver plot, comparing  a sequence of images taken at different time points. Color scale on the left indicates the displacements in the gel.

Stretching Fibrous Hydrogels

External forces are an important factor in tissue formation, development, and maintenance. We have developed a method to stretch soft hydrogels, such as fibrin and collagen gels, from their circumference, using an elastic silicone strip. Advantages of this method include the ability to strain extremely soft hydrogels in 3D while executing in situ live microscopy, and the freedom to manipulate the geometry and size of the sample. By considering the design of various geometries, we use our method to program strain gradients along different chosen axes, providing a framework for engineering tissues with complex gradient structure, such that occur in interfacial tissues such as tendon-bone or cartilage-bone.

Related papers:

  • A. Kolel, B. Ergaz, S. Natan, S. Goren, O. Tchaicheeyan, A. Lesman. Strain Gradient Programming in 3D Fibrous Hydrogels to Direct Graded Cell Alignment. Small Methods, Vol 7, Issue 1. doi:10.1002/smtd.202201070, Nov. 2022.

  • A. Kolel, A. Roitblat Riba, S. Natan, O. Tchaicheeyan, E. Saias, A. Lesman. Controlled Strain of 3D Hydrogels under Live Microscopy Imaging. Journal of Visual Experiments, J. Vis. Exp. (166), e61671, doi:10.3791/61671, Sep. 2020.

  • Avishy Roitblat Riba, Sari Natan, Avraham Kolel, Hila Rushkin, Oren Tchaicheeyan, Ayelet Lesman. Straining 3D Hydrogels with Uniform Z-Axis Strains While Enabling Live Microscopy Imaging. Annals of Biomedical Engineering, 48, 868–880. December 2019. doi: 10.1007/s10439-019-02426-7

Application-of-external-forces-on-3D-hydrogels-stretcher-design.png
Application-of-external-forces-on-3D-hydrogels-fibrin-deformation.png
Top: Schematic of the stretching approach with the silicone strip (orange), circular gel (cut-out in the middle), and fabric extenders (green) that connect the silicone to the stretching device.
Bottom: Gel fiber alignment in response to external stretch. Images taken at the center of a fluorescently-labeled gel before and after stretch.

Related papers:

  • Nurit Bar-Shai, Orna Sharabani-Yosef, Meiron Zollmann, Ayelet Lesman, Alexander Golberg. Seaweed cellulose scaffolds derived from green macroalgae for tissue engineering. Scientific Reports. 2021 Jun 4;11(1):11843. doi: 10.1038/s41598-021-90903-2. PMID: 34088909.

Novel Biomaterials for Tissue Engineering

Coral-derived collagen fibers

In collaboration with Prof. Rami Haj-Ali (TAU, Mechanical Engineering), we extract centimeter-long collagen fibers from Sarcophyton soft corals, and wrap them around frames to create aligned fiber scaffolds. We study their biocompatibility and ability to support formation of various oriented tissues, such as skeletal muscle tissue.

Related papers:

  • Ortal Shelah, Shir Wertheimer, Rami Haj-Ali, Ayelet Lesman. Coral-derived Collagen Fibers for Engineering Aligned Tissues. Tissue Engineering Part A. July 2020, 27, 3-4. Feb 15, 2021. http://doi.org/10.1089/ten.tea.2020.0116

  • Shir Wertheimer, Mirit Sharabi, Ortal Shelah, Ayelet Lesman, Rami Haj-Ali. Bio-composites reinforced with unique coral collagen fibers: Towards biomimetic-based small diameter vascular grafts. Journal of the Mechanical Behavior of Biomedical Materials, April 2020, In Press.

Seaweed cellulose scaffolds from green macroalgae

In collaboration with Prof. Alexander Golberg (Porter environment, TAU), we apply decellularization-recellularization approach of marine macroalgae species Ulva sp. and Cladophora sp. to produce cellulose scaffolds for in-vitro mammalian cell growth. We test their biocompatibility for tissue engineering applications.

Extraction of collagen fibers from the coral
Seaweed-cellulose-scaffolds-from-green-macroalgae.png
The production of cellulose scaffolds from two types of green macro-algae (left): Ulva sp. (top) and Cladophora sp. (bottom). Fabrication samples (right).
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