An Anisotropic Biphasic Theory of Tissue-Equivalent Mechanics: The Interplay Among Cell Traction, Fibrillar Network Deformation, Fibril Alignment, and Cell Contact Guidance

1997 ◽  
Vol 119 (2) ◽  
pp. 137-145 ◽  
Author(s):  
V. H. Barocas ◽  
R. T. Tranquillo
Keyword(s):  
Contact Guidance ◽  
Deformation Tensor ◽  
Cell Contact ◽  
Cell Alignment ◽  
Collagen Gels ◽  
Cell Orientation ◽  
Collagen Network ◽  
Orientation Tensor ◽  
Tissue Equivalents ◽  
Cell Traction

We present a general mathematical theory for the mechanical interplay in tissue-equivalents (cell-populated collagen gels): Cell traction leads to compaction of the fibrillar collagen network, which for certain conditions such as a mechanical constraint or inhomogeneous cell distribution, can result in inhomogeneous compaction and consequently fibril alignment, leading to cell contact guidance, which affects the subsequent compaction. The theory accounts for the intrinsically biphasic nature of collagen gel, which is comprised of collagen network and interstitial solution. The theory also accounts for fibril alignment due to inhomogeneous network deformation, that is, anisotropic strain, and for cell alignment in response to fibril alignment. Cell alignment results in anisotropic migration and traction, as modeled by a cell orientation tensor that is a function of a fiber orientation tensor, which is defined by the network deformation tensor. Models for a variety of tissue-equivalents are shown to predict qualitatively the alignment that arises due to inhomogeneous compaction driven by cell traction.

A methodology for the systematic and quantitative study of cell contact guidance in oriented collagen gels. Correlation of fibroblast orientation and gel birefringence

1993 ◽  
Vol 105 (2) ◽  
pp. 317-331 ◽  
Author(s):  
S. Guido ◽  
R.T. Tranquillo
Keyword(s):  
Magnetic Field ◽  
Image Analysis ◽  
Collagen Gel ◽  
Time Lapse ◽  
Automated Image Analysis ◽  
Contact Guidance ◽  
Cell Contact ◽  
Collagen Gels ◽  
Cell Orientation ◽  
Observation Chamber

Despite the likely role of contact guidance in every physiological process involving cell migration, its study in a three-dimensional tissue-equivalent environment has been precluded, heretofore, by inherent difficulties in systematically preparing well-defined contact guidance fields and quantifying the resultant contact guidance. Here, we describe a novel use of a magnetic field to orient collagen fibrils during fibrillogenesis, entrapping cells dispersed in the collagen solution. Using computer-controlled staging and image analysis, we show from automated birefringence measurements of the resultant slab of cell-populated gel contained in a specially designed observation chamber that the fibril orientation is biased along the long axis of the chamber uniformly throughout the chamber. Further, we show that the degree of fibril orientation, and consequently the elicited contact guidance, can be controlled by independently varying the magnetic field strength or temperature during fibrillogenesis. We characterize the contact guidance response to the imposed contact guidance field by measuring cell orientation relative to the axis of fibril orientation from still images obtained in time-lapse via automated image analysis. We present the first quantitative correlation of contact guidance (based on cell orientation) with collagen fibril orientation (based on birefringence) for human foreskin fibroblasts cultured in a collagen gel, by using gels of varying orientation resulting from different magnetic field strengths and temperatures during fibrillogenesis, and by using sufficiently low cell concentrations and early observation times.

scholarly journals Cell contact guidance via sensing anisotropy of network mechanical resistance

2021 ◽  
Vol 118 (29) ◽  
pp. e2024942118
Author(s):  
Greeshma Thrivikraman ◽  
Alicja Jagiełło ◽  
Victor K. Lai ◽  
Sandra L. Johnson ◽  
Mark Keating ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Mammalian Cells ◽  
Dermal Fibroblasts ◽  
Contact Guidance ◽  
Cell Contact ◽  
Mechanical Resistance ◽  
Cell Orientation ◽  
Fibrin Gel ◽  
Anisotropy Index ◽  
The Cross

Despite the ubiquitous importance of cell contact guidance, the signal-inducing contact guidance of mammalian cells in an aligned fibril network has defied elucidation. This is due to multiple interdependent signals that an aligned fibril network presents to cells, including, at least, anisotropy of adhesion, porosity, and mechanical resistance. By forming aligned fibrin gels with the same alignment strength, but cross-linked to different extents, the anisotropic mechanical resistance hypothesis of contact guidance was tested for human dermal fibroblasts. The cross-linking was shown to increase the mechanical resistance anisotropy, without detectable change in network microstructure and without change in cell adhesion to the cross-linked fibrin gel. This methodology thus isolated anisotropic mechanical resistance as a variable for fixed anisotropy of adhesion and porosity. The mechanical resistance anisotropy |Y*|−1 − |X*|−1 increased over fourfold in terms of the Fourier magnitudes of microbead displacement |X*| and |Y*| at the drive frequency with respect to alignment direction Y obtained by optical forces in active microrheology. Cells were found to exhibit stronger contact guidance in the cross-linked gels possessing greater mechanical resistance anisotropy: the cell anisotropy index based on the tensor of cell orientation, which has a range 0 to 1, increased by 18% with the fourfold increase in mechanical resistance anisotropy. We also show that modulation of adhesion via function-blocking antibodies can modulate the guidance response, suggesting a concomitant role of cell adhesion. These results indicate that fibroblasts can exhibit contact guidance in aligned fibril networks by sensing anisotropy of network mechanical resistance.

scholarly journals Screening Platform for Cell Contact Guidance Based on Inorganic Biomaterial Micro/nanotopographical Gradients

2017 ◽  
Vol 9 (37) ◽  
pp. 31433-31445 ◽  
Author(s):  
Qihui Zhou ◽  
Olga Castañeda Ocampo ◽  
Carlos F. Guimarães ◽  
Philipp T. Kühn ◽  
Theo G. van Kooten ◽  
...  
Keyword(s):  
Contact Guidance ◽  
Cell Contact ◽  
Screening Platform

Stress-Dependent Effects of Platelet-Derived Growth Factor-BB on Fibroblast Migration and Traction Differ in Collagen and Fibrin

2000 ◽  
Author(s):  
David I. Shreiber ◽  
Paul A. J. Enever ◽  
Robert T. Tranquillo
Keyword(s):  
Type I Collagen ◽  
Cell Behavior ◽  
Environmental Cues ◽  
Type I ◽  
Collagen Gels ◽  
Fibrin Gels ◽  
Fibroblast Migration ◽  
Tissue Equivalents ◽  
Stress Dependent ◽  
Statistical Conclusion

Abstract We used our novel assays of cell behavior in tissue equivalents to study the dose-response effects of PDGF-BB on RDF migration and traction in mechanically stressed and stress-free type I collagen and fibrin gels. PDGF-BB increased fibroblast migration significantly in all assays, but the effects on traction depended on the presence of stress and the nature of the ECM. PDGF-BB decreased fibroblast traction in stressed collagen gels, but increased traction in stress-free gels. No statistical conclusion could be inferred for stressed fibrin gels, and increasing PDGF-BB decreased traction in stress-free fibrin gels. These results demonstrate the complex response of fibroblasts to environmental cues, and point to opportunities to orchestrate cell behavior to affect the outcome of wound healing.

The sequence of alignment of microtubules, focal contacts and actin filaments in fibroblasts spreading on smooth and grooved titanium substrata

1993 ◽  
Vol 106 (1) ◽  
pp. 343-354 ◽  
Author(s):  
C. Oakley ◽  
D.M. Brunette
Keyword(s):  
Actin Filaments ◽  
Human Gingival Fibroblasts ◽  
Contact Guidance ◽  
Gingival Fibroblasts ◽  
Cell Orientation ◽  
Cell Height ◽  
Focal Contacts ◽  
Microfilament Bundles ◽  
Titanium Surfaces ◽  
Oriented Parallel

Contact guidance refers to the reactions of cells with the topography of their substratum. Current hypotheses on the mechanism of contact guidance focus on the dynamic behaviour of the cytoskeletal components, but most observations have been made on cells that have already become oriented with topographic features of the substratum. The purpose of this study was to examine the sequence in which microtubules, focal contacts and microfilament bundles become aligned to the substratum topography as fibroblasts spread on grooved substrata. Human gingival fibroblasts were trypsinized and seeded onto grooved titanium surfaces produced by micromachining, as well as onto control smooth surfaces. After observation and photography of the spreading cells at times up to 6 hours, the cells were fixed and exposed to one or more of the following antibodies or fluorescent stains: phallacidin to stain actin filaments, monoclonal anti-tubulin, monoclonal anti-vinculin, anti-mouse IgG labelled with Texas-Red or FITC, and/or an aldehyde-reactive stain to identify the cell outline. The cells were photographed and cell area, shape and orientation were calculated. Cells were also examined with confocal microscopy to obtain optical sections so that cell height as well as the precise locations of the cytoskeletal components with respect to the vertical dimension of the grooved substrata could be determined. Microtubules were the first element to become oriented parallel to the direction of the grooves and were first aligned at the bottom of the grooves. This alignment of microtubules was evident as early as 20 minutes after plating and preceded the orientation of the cell as a whole. Aligned actin microfilament bundles were not observed until 40–60 minutes and were observed first at the wall-ridge edges. At early times, focal contacts were distributed radially, but only after 3 hours did the majority of cells demonstrate aligned focal contacts. If the first cytoskeletal component to become aligned is the prime determinant of cell orientation, then these data suggest that microtubules in human gingival fibroblasts may determine cell orientation on grooved titanium surfaces. By analogy with microtubule behaviour in other systems, we suggest that microtubule orientation on grooved substrata may occur as a result of the substratum establishing shear-free planes.

scholarly journals Alignment of Carbon Nanotubes: An Approach to Modulate Cell Orientation and Asymmetry

Nano LIFE ◽  
2014 ◽  
Vol 04 (01) ◽  
pp. 1450002 ◽  
Author(s):  
Qingsu Cheng ◽  
Greg M. Harris ◽  
Marc-Olivier Blais ◽  
Katy Rutledge ◽  
Ehsan Jabbarzadeh
Keyword(s):  
Stem Cells ◽  
Control Cell ◽  
Adhesion Formation ◽  
Embryonic Stem ◽  
Focal Adhesions ◽  
Biological Tissues ◽  
Spatiotemporal Pattern ◽  
Cell Alignment ◽  
Cell Orientation

Stem cells offer a promising tool in tissue engineering strategies, as their differentiated derivatives can be used to reconstruct most biological tissues. These approaches rely on controlling the biophysical cues that tune the ultimate fate of cells. In this context, significant effort has gone to parse out the role of conflicting matrix-elicited signals (e.g., topography and elasticity) in regulation of macroscopic characteristics of cells (e.g., shape and polarity). A critical hurdle, however, lies in our inability to recapitulate the nanoscale spatiotemporal pattern of these signals. The study presented in this manuscript took an initial step to overcome this challenge by developing a carbon nanotube (CNT)-based substrate for nanoresolution control of focal adhesion formation and cell alignment. The utility of this system was studied using human umbilical vascular endothelial cells (HUVECs) and human embryonic stem cells (hESCs) at a single cell level. Our results demonstrated the ability to control cell orientation by merely controlling the alignment of focal adhesions at a nanoscale size. Our long-term vision is to use these nanoengineered substrates to mimic cell orientation in earlier development and explore the role of polarity in asymmetric division and lineage specification of dividing cells.

Collagen Network Topology is Influenced by Collagen Concentration, But Not by Co-Gelation With Fibrin

2011 ◽  
Author(s):  
Victor K. Lai ◽  
Edward A. Sander ◽  
Spencer P. Lake ◽  
Robert T. Tranquillo ◽  
Victor H. Barocas
Keyword(s):  
Mechanical Properties ◽  
Healing Process ◽  
Biological Tissues ◽  
Wound Healing Process ◽  
Type I ◽  
Collagen Gels ◽  
Collagen Network ◽  
Modeling Framework ◽  
Collagen Concentration ◽  
Cardiovascular Tissue

Extracellular matrix (ECM) proteins (e.g. collagen, elastin) play an important role in biological tissues. In addition to conferring mechanical strength to a tissue, the ECM provides a biochemical environment essential for modulation of cellular responses such as growth and migration. Collagens are the dominant protein of the ECM, with collagen type I being most abundant. Our group and others have shown that the mechanical properties of a collagen I matrix change with collagen concentration, and when formed in the presence of a secondary fibril network such as fibrin [1]. We are interested in collagen-fibrin systems because our group uses fibrin as the starting scaffold material for cardiovascular tissue engineering, which produces interpenetrating collagen-fibrin matrices during the remodeling process as the fibrin network is degraded and replaced with cell-deposited collagen [2]. Fibrin and collagen networks are also present together around the thrombus during the wound healing process. Research has shown that ECM mechanical properties are correlated with their overall network structure characteristics such as fibril diameter [3]. Currently we have a modeling framework that generates an ECM microstructural network which can be used to predict the overall properties of a bioengineered tissue [4]. This framework allows exploration of the structure-function relation, but how the structure depends on composition remains poorly understood, especially in multi-component gels. Thus, the objective of this work was to quantify the collagen network architecture in pure collagen gels of different concentrations and in collagen-fibrin co-gels.

scholarly journals Tissue Equivalents: Template Curvature Influences Cell Alignment to Create Improved Human Corneal Tissue Equivalents (Adv. Biosys. 12/2017)

2017 ◽  
Vol 1 (12) ◽  
pp. 1770098
Author(s):  
Ricardo M. Gouveia ◽  
Elena Koudouna ◽  
James Jester ◽  
Francisco Figueiredo ◽  
Che J. Connon
Keyword(s):  
Corneal Tissue ◽  
Cell Alignment ◽  
Tissue Equivalents

Easy fabrication of aligned PLLA nanofibers-based 2D scaffolds suitable for cell contact guidance studies

2016 ◽  
Vol 62 ◽  
pp. 301-306 ◽  
Author(s):  
John Mohanraj ◽  
Luca Puzzi ◽  
Ennio Capria ◽  
Stefania Corvaglia ◽  
Loredana Casalis ◽  
...  
Keyword(s):  
Contact Guidance ◽  
Cell Contact
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