Research Papers

Adhesive Dynamics

[+] Author and Article Information
Daniel A. Hammer

Departments of Bioengineering and
Chemical and Biomolecular Engineering,
University of Pennsylvania,
Philadelphia, PA 19104
e-mail: hammer@seas.upenn.edu

Contributed by the Bioengineering Division of ASME for publication in the JOURNAL OF BIOMECHANICAL ENGINEERING. Manuscript received October 8, 2013; final manuscript received December 30, 2013; accepted manuscript posted January 2, 2014; published online February 5, 2014. Editor: Victor H. Barocas.

J Biomech Eng 136(2), 021006 (Feb 05, 2014) (10 pages) Paper No: BIO-13-1472; doi: 10.1115/1.4026402 History: Received October 08, 2013; Revised December 30, 2013; Accepted January 02, 2014

Adhesive dynamics (AD) is a method for simulating the dynamic response of biological systems in response to force. Biological bonds are mechanical entities that exert force under strain, and applying forces to biological bonds modulates their rate of dissociation. Since small numbers of events usually control biological interactions, we developed a simple method for sampling probability distributions for the formation or failure of individual bonds. This method allows a simple coupling between force and strain and kinetics, while capturing the stochastic response of biological systems. Biological bonds are dynamically reconfigured in response to applied mechanical stresses, and a detailed spatio-temporal map of molecules and the forces they exert emerges from AD. The shape or motion of materials bearing the molecules is easily calculated from a mechanical energy balance provided the rheology of the material is known. AD was originally used to simulate the dynamics of adhesion of leukocytes under flow, but new advances have allowed the method to be extended to many other applications, including but not limited to the binding of viruses to surface, the clustering of adhesion molecules driven by stiff substrates, and the effect of cell-cell interaction on cell capture and rolling dynamics. The technique has also been applied to applications outside of biology. A particular exciting recent development is the combination of signaling with AD (so-called integrated signaling adhesive dynamics, or ISAD), which allows facile integration of signaling networks with mechanical models of cell adhesion and motility. Potential opportunities in applying AD are summarized.

Copyright © 2014 by ASME
Your Session has timed out. Please sign back in to continue.


Hammer, D. A., and Apte, S. M., 1992, “Simulation of Cell Rolling and Adhesion on Surfaces in Shear Flow: General Results and Analysis of Selectin-Mediated Neutrophil Adhesion,” Biophys. J., 63, pp. 35–57. [CrossRef] [PubMed]
Lawrence, M. B., Berg, E. L., Butcher, E. C., and Springer, T. A., 1995, “Rolling of Lymphocytes and Neutrophils on Peripheral Node Addressing and Subsequent Arrest on ICAM-1 in Shear Flow,” Eur. J. Immunol., 25, pp. 1025–1031. [CrossRef] [PubMed]
Lawrence, M. B., McIntire, L. V., and Eskin, S. G., 1987, “Effect of Flow on Polymorphonuclear Leukocyte/Endothelial Cell Adhesion,” Blood, 70(5), pp. 1284–1290. [PubMed]
Tempelman, L. A., and Hammer, D. A., 1994, “Receptor-Mediated Binding of IgE-Sensitized Rat Basophilic Leukemia Cells to Antigen-Coated Substrates Under Hydrodynamic Flow,” Biophys. J., 66, pp. 1231–1243. [CrossRef] [PubMed]
Bell, G. I., 1978, “Models for the Specific Adhesion of Cells to Cells,” Science, 200, pp. 618–627. [CrossRef] [PubMed]
Beste, M. T., and Hammer, D. A., 2008, “Selectin Catch-Slip Kinetics Encode Shear Threshold Adhesive Behavior of Rolling Leukocytes,” Proc. Natl. Acad. Sci. U.S.A., 105(52), pp. 20716–20721. [CrossRef] [PubMed]
Hammer, D. A., and Lauffenburger, D. A., 1987, “A Dynamic Model for Receptor-Mediated Cell Adhesion to Surfaces,” Biophys. J., 52, pp. 475–487. [CrossRef] [PubMed]
Dembo, M., Torney, D. C., Saxman, K., and Hammer, D. A., 1988, “The Reaction-Limited Kinetics of Membrane-to-Surface Adhesion and Detachment,” Proc. R. Soc. London, Ser. B, 234, pp. 55–83. [CrossRef]
Chan, C. E., and Odde, D. J., 2008, “Traction Dynamics of Filopodia on Compliant Substrates,” Science, 322(5908), pp. 1687–1691. [CrossRef] [PubMed]
Bruehl, R. E., Springer, T. A., and Bainton, D. F., 1996, “Quantitation of L-Selectin Distribution on Human Leukocyte Microvilli by Immunogold Labeling and Electron Microscopy,” J. Histochem. Cytochem., 44(8), pp. 835–844. [CrossRef] [PubMed]
Picker, L. J., Warnock, R. A., Burns, A. R., Doerschuk, C. M., Berg, E. L., and Butcher, E. C., 1991, “The Neutrophil Selectin LECAM-1 Presents Carbohydrate Ligands to the Vascular Selectins ELAM-1 and GMP-140,” Cell, 66(5), pp. 921–933. [CrossRef] [PubMed]
Bussell, S. J., Koch, D. L., and Hammer, D. A., 1995, “The Effect of Hydrodynamic Interactions on the Diffusion of Integral Membrane Proteins. Diffusion in Plasma Membranes,” Biophys. J., 68, pp. 1836–1849. [CrossRef] [PubMed]
Chang, K. C., Tees, D. F. J., and Hammer, D. A., 2000, “The State Diagram for Cell Adhesion Under Flow: Leukocyte Rolling and Firm Adhesion,” Proc. Natl. Acad. Sci. U.S.A., 97(21), pp. 11262–11267. [CrossRef] [PubMed]
Alon, R., Hammer, D. A., and Springer, T. A., 1995, “Lifetime of the P-selectin: Carbohydrate Bond and its Response to Tensile Force in Hydrodynamic Flow,” Nature, 374, pp. 539–542. [CrossRef] [PubMed]
King, M. R., and Hammer, D. A., 2001, “Multiparticle Adhesive Dynamics. Interactions Between Stably Rolling Cells,” Biophys. J., 81(2), pp. 799–813. [CrossRef] [PubMed]
King, M. R., Kim, M. B., Sarelius, I. H., and Hammer, D. A., 2003, “Hydrodynamic Interactions Between Rolling Leukocytes in vivo,” Microcirculation, 10, pp. 401–409. [CrossRef] [PubMed]
Brunk, D. K., and Hammer, D. A., 1997, “Quantifying Rolling Adhesion With a Cell-Free Assay: E-Selectin and its Carbohydrate Ligands,” Biophys. J., 72(6), pp. 2820–2833. [CrossRef] [PubMed]
Chang, K. C., and Hammer, D. A., 2000, “Adhesive Dynamics Simulations of Sialyl-Lewis(x)/E-Selectin- Mediated Rolling in a Cell-Free System,” Biophys. J., 79(4), pp. 1891–1902. [CrossRef] [PubMed]
Lipowsky, H., Riedel, H. D., and Shi, G. S., 1991, “in vivo Mechanical Properties of Leukocytes During Adhesion to Venular Endothelium,” Biorheology, 28(1–2), pp. 53–64. [PubMed]
Evans, E., Leung, A., Hammer, D., and Simon, S., 2001, “Chemically Distinct Transition States Govern Rapid Dissociation of Single L-Selectin Bonds Under Force,” Proc. Natl. Acad. Sci. U.S.A., 98(7), pp. 3784–3789. [CrossRef] [PubMed]
Finger, E. B., Puri, K. D., Alon, R., Lawrence, M. B., von Andrian, U., and Springer, T. A., 1996, “Adhesion Through L-Selectin Requires a Threshold Hydrodynamic Shear,” Nature, 379, pp. 266–269. [CrossRef] [PubMed]
Chang, K.-C., and Hammer, D. A., 1999, “The Forward Rate of Binding of Surface-Tethered Reactants: Effect of Relative Motion Between Two Surfaces,” Biophys. J., 76, pp. 1280–1292. [CrossRef] [PubMed]
Caputo, K. E., Lee, D., King, M. R., and Hammer, D. A., 2007, “Adhesive Dynamics Simulations of the Shear Threshold Effect for Leukocytes,” Biophys. J., 92(3), pp. 787–797. [CrossRef] [PubMed]
Lu, C., Shimaoka, M., Ferzly, M., Oxvig, C., Takagi, J., and Springer, T. A., “An Isolated, Surface-Expressed I-Domain of the Integrin AlphaLbeta2 is Sufficient for Strong Adhesive Function When Locked in the Open Conformation With a Disulfide Bond,” Proc. Natl. Acad. Sci. U.S.A., 98, pp. 2387–2392. [CrossRef] [PubMed]
Eniola, A. O., Willcox, J., and Hammer, D. A., 2003, “Interplay Between Rolling and Firm Adhesion Elucidated With a Cell-Free System Engineered With Two Distinct Receptor-Ligand Pairs,” Biophys. J., 85, pp. 2720–2731. [CrossRef] [PubMed]
Bhatia, S. K., King, M. R., and Hammer, D. A., 2003, “The State Diagram for Cell Adhesion Mediated by Two Receptors,” Biophys. J., 84, pp. 2671–2690. [CrossRef] [PubMed]
Alon, R., and Ley, K., 2008, “Cells on the Run: Shear-Regulated Integrin Activation in Leukocyte Rolling and Arrest on Endothelial Cells,” Curr. Opin. Cell Biol., 20, pp. 1–8. [CrossRef]
Morrison, V. L., Macpherson, M. T., Savinko, T., San Lek, H., Prescott, A., and Fagerholm, S. C., 2013, “The Beta2 Integrin-kindlin-3 Interaction is Essential for T-cell Homing but Dispensable for T-Cell Activation in vivo,” Blood, 122(8), pp. 1428–1436. [CrossRef] [PubMed]
Krasik, E. F., Caputo, K. E., and Hammer, D. A., 2008, “Adhesive Dynamics Simulations of Neutrophil Arrest With Stochastic Activation,” Biophys. J., 95(4), pp. 1716–1728. [CrossRef] [PubMed]
Krasik, E. F., Yee, K. Y., and Hammer, D. A., 2006, “Adhesive Dynamics Simulation of Neutrophil Arrest With Deterministic Activation,” Biophys. J., 91, pp. 1145–1155. [CrossRef] [PubMed]
Caputo, K. E., and Hammer, D. A., 2008, “Adhesive Dynamics Simulation of G-protein-mediated Chemokine-activated Neutrophil Adhesion,” Biophys. J. (submitted).
Beste, M. T., Lee, D., King, M. R., Koretzky, G. A., and Hammer, D. A., 2012, “An Integrated Stochastic Model of ‘Inside-Out’ Integrin Activation and Selective T-lymphocyte Recruitment,” Langmuir, 28(4), pp. 2225–2237. [CrossRef] [PubMed]
Gillespie, D. T., 1975, “Exact Method for Numerically Simulating Stochastic Coalescence Process in a Cloud,” J. Atmos. Sci., 32(10), pp. 1977–1989. [CrossRef]
Shao, J.-Y., Ting-Beall, H. P., and Hochmuth, R. M., 1998, “Static and Dynamic Lengths of Neutrophil Microvilli,” Proc. Natl. Acad. Sci., 95, pp. 6797–6802. [CrossRef]
Jadhav, S., Eggleton, C. D., and Konstantopoulos, K., 2005, “A 3-D Computational Model Predicts That Cell Deformation Affects Selectin-Mediated Leukocyte Rolling,” Biophys. J., 88(1), pp. 96–104. [CrossRef] [PubMed]
Caputo, K. E., and Hammer, D. A., 2005, “Effect of Microvillus Deformability on Leukocyte Adhesion Explored Using Adhesive Dynamics Simulations,” Biophys. J., 89, pp. 187–200. [CrossRef] [PubMed]
Khismatullin, D. B., and Truskey, G. A., 2005, “Three-Dimensional Numerical Simulation of Receptor-Mediated Leukocyte Adhesion to Surfaces: Effects of Cell Deformability and Viscoelasticity,” Phys. Fluids, 17, p. 031505. [CrossRef]
King, M. R., Rodgers, S. D., and Hammer, D. A., 2001, “Hydrodynamic Collisions Suppress Fluctuations in the Rolling Velocity of Adhesive Blood Cells,” Langmuir, 17(14), pp. 4139–4143. [CrossRef]
King, M. R., and Hammer, D. A., 2001, “Multiparticle Adhesive Dynamics: Hydrodynamic Recruitment of Rolling Leukocytes,” Proc. Natl. Acad. Sci. U.S.A, 98(26), pp. 14919–14924. [CrossRef] [PubMed]
Isfahani, A. H., and Freund, J. B., 2012, “Forces on a Wall-Bound Leukocyte in a Small Vessel Due to Red Cells in the Blood Stream,” Biophys. J., 103(7), pp. 1604–1615. [CrossRef] [PubMed]
Mody, N. A., and King, M. R., 2007, “Influence of Brownian Motion on Blood Platelet Flow Behavior and Adhesive Dynamics Near a Planar Wall,” Langmuir, 23(11), pp. 6321–6328. [CrossRef] [PubMed]
Mody, N. A., and King, M. R., 2008, “Platelet Adhesive Dynamics. Part I: Characterization of Platelet Hydrodynamic Collisions and Wall Effects,” Biophys. J., 95(5), pp. 2539–2555. [CrossRef] [PubMed]
Mody, N. A., and King, M. R., 2008, “Platelet Adhesive Dynamics. Part II: High Shear-Induced Transient Aggregation via GPIbalpha-vWF-GPIbalpha Bridging,” Biophys. J., 95(5), pp. 2556–2574. [CrossRef] [PubMed]
Mody, N. A., Lomakin, O., Doggett, T. A., Diacovo, T. G., and King, M. R., 2005, “Mechanics of Transient Platelet Adhesion to von Willebrand Factor Under Flow,” Biophys. J., 88(2), pp. 1432–1443. [CrossRef] [PubMed]
Wang, W., Mody, N. A., and King, M. R., 2013, “Multiscale Model of Platelet Translocation and Collision,” J. Comput. Phys., 244, pp. 223–235. [CrossRef] [PubMed]
Fedosov, D. A., Caswell, B., and Karniadakis, G. E., 2010, “A Multiscale Red Blood Cell Model With Accurate Mechanics, Rheology, and Dynamics,” Biophys. J., 98(10), pp. 2215–2225. [CrossRef] [PubMed]
Fedosov, D. A., Caswell, B., and Karniadakis, G. E., 2011, “Wall Shear Stress-Based Model for Adhesive Dynamics of Red Blood Cells in Malaria,” Biophys. J., 100(9), pp. 2084–2093. [CrossRef] [PubMed]
Fedosov, D. A., Caswell, B., Suresh, S., and Karniadakis, G. E., 2011, “Quantifying the Biophysical Characteristics of Plasmodium-Falciparum-Parasitized Red Blood Cells in Microcirculation,” Proc. Natl. Acad. Sci. U.S.A., 108(1), pp. 35–39. [CrossRef] [PubMed]
Fedosov, D. A., Lei, H., Caswell, B., Suresh, S., and Karniadakis, G. E., 2011, “Multiscale Modeling of Red Blood Cell Mechanics and Blood Flow in Malaria,” PLoS Comput. Biol., 7(12), p. e1002270 [CrossRef]. [PubMed]
Pan, W., Fedosov, D. A., Caswell, B., and Karniadakis, G. E., 2011, “Predicting Dynamics and Rheology of Blood Flow: A Comparative Study of Multiscale and Low-Dimensional Models of Red Blood Cells,” Microvasc. Res., 82(2), pp. 163–170. [CrossRef] [PubMed]
English, T. J., and Hammer, D. A., 2005, “The Effect of Cellular Receptor Diffusion on Receptor-Mediated Viral Binding Using Brownian Adhesive Dynamics (BRAD) Simulations,” Biophys. J., 88(3), pp. 1666–1675. [CrossRef] [PubMed]
English, T. J., and Hammer, D. A., 2004, “Brownian Adhesive Dynamics (BRAD) for Simulating the Receptor-Mediated Binding of Viruses,” Biophys. J., 86(6), pp. 3359–3372. [CrossRef] [PubMed]
Paszek, M., Boettiger, D., Weaver, V. M., and Hammer, D. A., 2009, “Integrin Clustering is Driven by Mechanical Resistance From the Glycocalyx and the Substrate,” PLoS Comput. Biol., 5(12), p. e1000604. [CrossRef] [PubMed]
Wang, W., Mody, N. A., and King, M. K., 2013, “Multiscale Model of Platelet Translocation and Collision,” J. Comput. Phys., 244, pp. 223–235. [CrossRef] [PubMed]
Lei, H., and Karniadakis, G. E., 2013, “Probing Vasoocclusion Phenomena in Sickle Cell Anemia Via Mesoscopic Simulations,” Proc. Natl. Acad. Sci. U S A, 110(28), pp. 11326–11330. [CrossRef] [PubMed]
Hlavacek, W. S., Posner, R. G., and Perelson, A. S., 1999, “Steric Effects on Multivalent Ligand-Receptor Binding: Exclusion of Ligand Sites by Bound Cell Surface Receptors,” Biophys. J., 76(6), pp. 3031–3043. [CrossRef] [PubMed]
Trister, A. D., and Hammer, D. A., 2008, “Role of gp120 Trimerization on HIV Binding Elucidated With Brownian Adhesive Dynamics,” Biophys. J., 95(1), pp. 40–53. [CrossRef] [PubMed]
Chan, C. E., and Odde, D. J., 2008, “Traction Dynamics of Filopodia on Compliant Substrates,” Science, 322(5908), pp. 1687–1691. [CrossRef] [PubMed]
Paszek, M., Zahir, N., Johnson, K. R., Lakins, J. N., Rozenberg, G. I., Gefen, A., Reinhart-King, C. A., Margulies, S. S., Dembo, M., Boettinger, D., Hammer, D. A., and Weaver, V., 2005, “Tensional Homeostasis and the Malignant Phenotype,” Cancer Cell, 8, pp. 241–254. [CrossRef] [PubMed]
Timpe, L. C., Yen, R., Haste, N. V., Litsakos-Cheung, C., Yen, T. Y., and Macher, B. A., 2013, “Systemic Alteration of Cell-Surface and Secreted Glycoprotein Expression in Malignant Breast Cancer Cell Lines,” Glycobiology, 11, pp. 1240–1249. [CrossRef]
Ward, M. D., and Hammer, D. A., 1993, “Morphology of Cell-substratum Adhesion: Influence of Receptor Heterogeneity and Nonspecific Forces,” Cell Biophys., 20, pp. 177–222. [CrossRef]
Wang, Y.-K., and Chen, C. S., 2013, “Cell Adhesion and Mechanical Stimulation in the Regulation of Mesenchymal Stem Cell Differentiation,” Journal of Cellular and Molecular Medicine, 27(7), pp. 823–832.
Zhao, T., Li, Y., and Dinner, A. R., 2009, “How Focal Adhesion Size Depends on Integrin Affinity,” Langmuir, 25(3), pp. 1540–1546. [CrossRef] [PubMed]
Yang, M. T., Sniadecki, N. J., and Chen, C. S., 2007, “Geometric Considerations of Micro- to Nanoscale Elastomeric Post Arrays to Study Cellular Traction Forces,” Adv. Mater., 19(20), pp. 3119–3123. [CrossRef]
Gimona, M. R., Buccione, S. A., Courtneidge, and Linder, S., 2008, “Assembly and Biological Role of Podosomes and Invadopodia,” Curr. Opin. Cell Biol., 20(2), pp. 235–241. [CrossRef] [PubMed]


Grahic Jump Location
Fig. 1

Idealized rendering of a leukocyte in the original version of adhesive dynamics, where the leukocyte was modeled as a hard sphere with adhesive springs. The net motion of the cell comes from a balance of forces, easily derived from tracking the endpoints of each adhesion molecule. Figure reproduced from Ref. [1] with permission from Elsevier.

Grahic Jump Location
Fig. 2

The state diagram for leukocyte adhesion, reprinted from Ref. [13] with permission from the National Academy of Sciences. The dynamic states of leukocyte adhesion are calculated as a function of the unstressed off rate (kro) and reactive compliance (γ). Different dynamic states of adhesion are realized, including firm adhesion, transient or rolling adhesion, and no adhesion. Symbols represent independent measurements of kro- γ for molecules known to support rolling, consistent with the model predictions.

Grahic Jump Location
Fig. 3

A simulation of a single particle rolling in Couette flow on a P-selectin surface, reproduced from Ref. [15] with permission of Elsevier. Panel (a) shows the distribution of bonds in the reference frame of the cell, which is moving from left to right. Bonds are line segments that are color coded, where red indicates bonds that are under strain. Bond are convected from the back to the front of the contact zone. Panel (c) shows the total number of bonds as a function of time, which fluctuates. The number of bonds needed to support rolling is very small. Panel (b) shows the rolling velocity, which fluctuates and is anti-correlated with the bond number.

Grahic Jump Location
Fig. 4

The leukocyte activation diagram, calculated in Bhatia and Hammer [26]. This diagram calculates the state of adhesion as a function of the properties of integrin receptors, including the on rate, the density, and the strength of integrins that are necessary to stop a leukocyte. Any combination of these parameters to the right of the dotted line indicates a cell will adhere firmly if the reactive compliance is below the number indicated on the line, or above the integrin density or greater than the on rate associated with the line. Integrin activation is tantamount to increasing integrin density (such as increased expression of Mac-1), increasing the integrin on-rate (moving up on this diagram) or moving the dotted line to the left, which captures a larger region of the diagram in firm adhesion. Reprinted from [26] with permission of the National Academy of Sciences.

Grahic Jump Location
Fig. 5

Integrated adhesive dynamics (ISAD) for the simulation of T-cell adhesion under flow. Panel (a) shows the reaction pathways that are simulated as a part of ISAD, starting with the chemokine and ending at the activation of the integrin into a high strength state. Panel (b) shows the progressive accumulation of each important molecule, starting from the chemokine and culminating in the ligation of Rap1 at the integrin. Panel (c) shows the spatio-temporal dynamics of molecular engagement from adhesion molecules to signaling molecules in the vicinity of the contact zone (the circle) during the progressive activation of the cell. Image taken from Ref. [32] with permission of the American Chemical Society.

Grahic Jump Location
Fig. 6

Simulation by Jadhav and coworkers [35] on the effect of macroscopic deformation on the progressive rolling and firm adhesion of a cell, modeled with an elastic shell of varying stiffness. The calculations account for the deformation, spreading, increased contact zone and decreased rolling velocity for more deformable cells in higher shear fields. Reprinted from [35] with the permission of the authors and Elsevier.

Grahic Jump Location
Fig. 7

A simulation of the organization of TCR-gp120 bonds during the docking of HIV to the cell surface. Color coding indicates TCR that are bound to the same virus triskelion. The simulations indicate that after 12 s, the disorganized binding has minimized energy to lead to the formation of several well organized trimers. Figure reproduced from Ref. [57] with the permission of Elsevier.

Grahic Jump Location
Fig. 8

AD simulation of the clustering of integrin receptors against elastic substrate with a glycocalyx. Panel (a) shows a schematic of the simulation, and panel (b) shows the progressive accumulation of receptor clusters on the adhesive interface, driven by resistance from both the glycocalyx and the stiffness of the substrate. Image taken from Ref. [53].




Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging and repositioning the boxes below.

Related Journal Articles
Related eBook Content
Topic Collections

Sorry! You do not have access to this content. For assistance or to subscribe, please contact us:

  • TELEPHONE: 1-800-843-2763 (Toll-free in the USA)
  • EMAIL: asmedigitalcollection@asme.org
Sign In