About

Frederick C. MacKintosh is the Abercrombie Professor of Chemical and Biomolecular Engineering, as well as a Professor of Chemistry and Physics and Astronomy at Rice University. He received his Ph.D. in Theoretical Physics from Princeton University in 1989 and holds a B.S. in Physics and Mathematics from the University of Washington. His academic career includes positions at the University of Michigan’s Physics Department, where he served as an Assistant and then Associate Professor, and a professorship at Vrije Universiteit in Amsterdam, where he was a Professor of Theoretical Physics. Dr. MacKintosh's research focuses on the fundamental material properties of biological and soft matter networks. His key achievements include the development of models of elasticity and dynamics of biopolymer gels, as well as combined experimental and theoretical advances in micro rheology, non-equilibrium motor-activated gels, and active diffusion in cells. He has also contributed to the understanding of affine to non-affine transitions and critical behavior in fiber networks.

Research topics

• Materials science
• Composite material
• Physics
• Genetics
• Biophysics
• Cell biology
• Condensed matter physics
• Biology

Selected publications

• Actin and vimentin jointly control cell viscoelasticity and compression stiffening

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-02 · 8 citations

  preprintOpen access

  Abstract The mechanical properties of cells are governed by the cytoskeleton, a dynamic network of actin filaments, intermediate filaments, and microtubules. Understanding the individual and collective mechanical contributions of these three different cytoskeletal elements is essential to elucidate how cells maintain mechanical integrity during deformation. Here we use a custom single-cell rheometer to identify the distinct contributions of actin and vimentin to the viscoelastic and nonlinear elastic response of cells to uniaxial compression. We used mouse embryonic fibroblasts (MEFs) isolated from wild type (WT) and vimentin knockout (vim -/-) mice in combination with chemical treatments to manipulate actin polymerization and contractility. We show through small amplitude oscillatory measurements and strain ramp tests that vimentin, often overlooked in cellular mechanics, plays a role comparable to actin in maintaining cell stiffness and resisting large compressive forces. However, actin appears to be more important than vimentin in determining cellular energy dissipation. Finally we show by comparing wild type and enucleated cells that compression stiffening originates from the actin and vimentin cytoskeleton, while the nucleus appears to play little role in this. Our findings provide insight into how cytoskeletal networks collectively determine the mechanical properties of cells, providing a basis to understand the role of the cytoskeleton in the ability of cells to resist external as well as internal forces. Significance statement A cell’s response to mechanical stress is largely governed by the actin and vimentin cytoskeletal networks, but their relative contribution to cell viscoelasticity and response to large deformations are poorly characterized. We reveal that actin and vimentin networks have an almost equal contribution to cellular stiffness and the cell’s ability to strain-stiffen under uniaxial compression. This work underscores the cytoskeleton’s central role in cellular mechanics and the mechanical synergy between the cytoskeletal networks, providing a framework for understanding how cellular components coordinate to maintain structural integrity and respond to different mechanical environments.

  PublisherDOI

• Plectin affects cell viscoelasticity at small and large deformations

  Biophysical Journal · 2025-09-05

  articleOpen access

  cells, suggesting a more sparse cytoskeletal network. Confocal imaging indicated that this was due to a marked change in the architecture of the vimentin network, from a fine meshwork in wild-type cells to a bundled network in the plectin knockout cells. Our findings therefore indicate that plectin is an important regulator of the organization and viscoelastic properties of the cytoskeleton in fibroblasts. Our findings emphasize that mechanical integration of the different cytoskeletal networks present in cells is important for regulating the versatile mechanical properties of cells.

  PublisherDOI

• Tissue-like compression stiffening in biopolymer networks induced by aggregated and irregularly shaped inclusions

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-06

  preprintOpen access

  Biological tissues experience mechanical compression under various physiological and pathological conditions and often exhibit compression stiffening, in which their stiffness increases during compression, a phenomenon that plays a crucial role in regulating cell behavior and maintaining mechanical homeostasis. However, most isolated biopolymer networks, such as fibrin and collagen hydrogels that form the extracellular matrix and actin network that forms the internal cytoskeleton, undergo compression softening, raising questions about how tissues achieve compression stiffening despite the softening properties of their extracellular and intracellular matrix components. Previous studies have shown that spherical inclusions at large volume fractions can induce compression stiffening in biopolymer networks, but they do not account for the effects of aggregation and irregular morphologies of cellular assemblies or other components in tissues. Here, we demonstrate a novel mode of compression stiffening induced by aggregated or irregularly shaped inclusions that occurs at significantly lower volume fractions. Using carbonyl iron particles and coffee ground particles, we find that the morphological diversity of inclusions enables tissue-like compression stiffening at a low volume fraction of inclusions. Through a set of experiments and computational analyses, we demonstrate that these particles can percolate at low volume fractions. We further show that the percolation of stiff inclusions creates a stress-supporting network and enables tension-dominated stress propagation in fibrin fibers, both of which drive macroscopic stiffening during compression. These findings provide insights into the regulation of tissue stiffness and have implications for designing biomaterials with physiologically relevant mechanical properties for biomedical applications. Significance Statement: Biological tissues experience a variety of mechanical forces. Many tissues, such as brain, liver, fat, and blood clots, become stiffer under physiological compressive loads, a property known as compression stiffening. In contrast, most biopolymer networks, which are the primary structural components for tissues, soften under compression. Here, we show that incorporating a small amount of aggregated or irregularly shaped particles into biopolymer gels induces robust compression stiffening. These inclusions percolate through the gel and rearrange non-affinely under compression, stretching surrounding fibers and contributing to mechanical reinforcement. Together, these effects reproduce tissue-like compression stiffening. Our findings not only provide new physical models for understanding tissue mechanics but also offer insights for designing biomaterials to achieve physiologically relevant mechanical responses.

  PublisherOA PDFDOI

• Plectin affects cell viscoelasticity at small and large deformations

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-30 · 1 citations

  preprintOpen access

  ABSTRACT Plectin is a giant protein of the plakin family that crosslinks the cytoskeleton of mammalian cells. It is expressed in virtually all tissues and its dysfunction is associated with various diseases such as skin blistering. There is evidence that plectin regulates the mechanical integrity of the cytoskeleton in diverse cell and tissue types. However, it is unknown how plectin modulates the mechanical response of cells depending on the frequency and amplitude of mechanical loading. Here we demonstrate the role of plectin in the viscoelastic properties of fibroblasts at small and large deformations by quantitative single-cell compression measurements. To identify the importance of plectin, we compared the mechanical properties of wild type ( Plec +/+ ) fibroblasts and plectin knockout ( Plec −/− ) fibroblasts. We show that plectin knockout cells are nearly 2-fold softer than wild type cells, but their strain-stiffening behaviour is similar. Plectin deficiency also caused faster viscoelastic stress relaxation at long times. Fluorescence recovery after photobleaching experiments indicated that this was due to 3-fold faster actin turnover. Short-time poroelastic relaxation was also faster in Plec −/− cells as compared to Plec +/+ cells, suggesting a more sparse cytoskeletal network. Confocal imaging indicated that this was due to a marked change in the architecture of the vimentin network, from a fine meshwork in wild type cells to a bundled network in the plectin knockout cells. Our findings therefore indicate that plectin is an important regulator of the organization and viscoelastic properties of the cytoskeleton in fibroblasts. Our findings emphasize that mechanical integration of the different cytoskeletal networks present in cells is important for regulating the versatile mechanical properties of cells. SIGNIFICANCE Mammalian cells combine superior mechanical strength with the ability to actively deform themselves. They owe this paradoxical mechanical behaviour to their cytoskeleton, an intracellular web of protein filaments that includes actin filaments and intermediate filaments. It is known that both cytoskeletal filament types contribute to cell stiffness on their own, but the impact of their mechanical integration via cytoskeletal crosslinker proteins remains unknown. Here we test the effect of crosslinking of actin and vimentin intermediate filaments by the crosslinker protein plectin in fibroblasts by single-cell compression measurements. By comparing normal cells and cells in which plectin is knocked out, we find that plectin significantly increases cell stiffness and provides a protective mechanism against actin network disruption by compressive loading.

  PublisherOA PDFDOI

• Criticality Enhances the Reinforcement of Disordered Networks by Rigid Inclusions

  Physical Review X · 2025-07-14 · 1 citations

  articleOpen accessSenior author

  The mechanical properties of biological materials are spatially heterogeneous. Typical tissues are made up of a spanning fibrous extracellular matrix in which various inclusions, such as living cells, are embedded. While the influence of embedded inclusions on the stiffness of common elastic materials such as rubber has been studied for decades and can be understood in terms of the volume fraction and shape of inclusions, the same is not true for disordered filamentous and fibrous networks. Recent work has shown that, in isolation, such networks exhibit unusual viscoelastic behavior indicative of an underlying mechanical phase transition controlled by network connectivity and strain. How this behavior is modified when inclusions are present is unclear. Here, we present a theoretical and computational study of the influence of rigid inclusions on the mechanics of disordered elastic networks near the connectivity-controlled central-force rigidity transition. Combining scaling theory and coarse-grained simulations, we predict and confirm an anomalously strong dependence of the composite stiffness on inclusion volume fraction, beyond that seen in ordinary composites. This stiffening exceeds the well-established volume-fraction-dependent stiffening expected in conventional composites, e.g., as an elastic analog of the classic volume-fraction-dependent increase in the viscosity of liquids first identified by Einstein. We show that this enhancement is a consequence of the interplay between interparticle spacing and an emergent correlation length, leading to an effective finite-size scaling imposed by the presence of inclusions. We outline the expected scaling of the linear shear modulus and strain fluctuations with the inclusion volume fraction and network connectivity, confirm these predictions in simulations, and discuss potential experimental tests and implications for our predictions in real systems.

  PublisherDOI

• Actin and vimentin jointly control cell viscoelasticity and compression stiffening

  Molecular Biology of the Cell · 2025-12-16

  articleOpen access

  The mechanical properties of cells are governed by the cytoskeleton, a dynamic network of actin filaments, intermediate filaments, and microtubules. Understanding the individual and collective mechanical contributions of these three different cytoskeletal elements is essential to elucidate how cells maintain mechanical integrity during deformation. Here, we use a custom single-cell rheometer to identify the distinct contributions of actin and vimentin to the viscoelastic and nonlinear elastic response of cells to uniaxial compression. We used mouse embryonic fibroblasts (MEF) isolated from wild-type (WT) and vimentin knockout (vim −/− ) mice in combination with chemical treatments to manipulate actin polymerization and contractility. We show through small amplitude oscillatory measurements and strain ramp tests that vimentin, often overlooked in cellular mechanics, plays a role comparable with actin in maintaining cell stiffness and resisting large compressive forces. However, actin appears to be more important than vimentin in determining cellular energy dissipation. Finally, we show by comparing WT and enucleated cells that compression stiffening originates from the actin and vimentin cytoskeleton, while the nucleus appears to play little role in this. Our findings provide insight into how cytoskeletal networks collectively determine the mechanical properties of cells, providing a basis to understand the role of the cytoskeleton in the ability of cells to resist external as well as internal forces.

  PublisherOA PDFDOI

• Criticality enhances the reinforcement of disordered networks by rigid inclusions

  arXiv (Cornell University) · 2024-07-28

  preprintOpen accessSenior author

  The mechanical properties of biological materials are spatially heterogeneous. Typical tissues are made up of a spanning fibrous extracellular matrix in which various inclusions, such as living cells, are embedded. While the influence of inclusions on the stiffness of common elastic materials such as rubber has been studied for decades and can be understood in terms of the volume fraction and shape of inclusions, the same is not true for disordered filamentous and fibrous networks. Recent work has shown that, in isolation, such networks exhibit unusual viscoelastic behavior indicative of an underlying mechanical phase transition controlled by network connectivity and strain. How this behavior is modified when inclusions are present is unclear. Here, we present a theoretical and computational study of the influence of rigid inclusions on the mechanics of disordered elastic networks near the connectivity-controlled central force rigidity transition. Combining scaling theory and coarse-grained simulations, we predict and confirm an anomalously strong dependence of the composite stiffness on inclusion volume fraction, beyond that seen in ordinary composites. This stiffening exceeds the well-established volume fraction-dependent stiffening expected in conventional composites, e.g., as an elastic analogue of the classic volume fraction dependent increase in the viscosity of liquids first identified by Einstein. We show that this enhancement is a consequence of the interplay between inter-particle spacing and an emergent correlation length, leading to an effective finite-size scaling imposed by the presence of inclusions. We outline the expected scaling of the shear modulus and strain fluctuations with the inclusion volume fraction and network connectivity, confirm these predictions in simulations, and discuss potential experimental tests and implications for our predictions in real systems.

  PublisherOA PDFDOI

• Nonlinear Poisson effect in affine semiflexible polymer networks

  Physical review. E · 2024-07-26 · 3 citations

  articleSenior author

  Stretching an elastic material along one axis typically induces contraction along the transverse axes, a phenomenon known as the Poisson effect. From these strains, one can compute the specific volume, which generally either increases or, in the incompressible limit, remains constant as the material is stretched. However, in networks of semiflexible or stiff polymers, which are typically highly compressible yet stiffen significantly when stretched, one instead sees a significant reduction in specific volume under finite strains. This volume reduction is accompanied by increasing alignment of filaments along the strain axis and a nonlinear elastic response, with stiffening of the apparent Young's modulus. For semiflexible networks, in which entropic bending elasticity governs the linear elastic regime, the nonlinear Poisson effect is caused by the nonlinear force-extension relationship of the constituent filaments, which produces a highly asymmetric response of the constituent polymers to stretching and compression. The details of this relationship depend on the geometric and elastic properties of the underlying filaments, which can vary greatly in experimental systems. Here, we provide a comprehensive characterization of the nonlinear Poisson effect in an affine network model and explore the influence of filament properties on essential features of both microscopic and macroscopic response, including strain-driven alignment and volume reduction.

  PublisherDOI

• Effects of local incompressibility on the rheology of composite biopolymer networks

  The European Physical Journal E · 2024-05-01 · 1 citations

  articleSenior author
  PublisherDOI

• Capturing the slow relaxation time of superparamagnetic colloids in time-varying fields

  arXiv (Cornell University) · 2024-02-09 · 1 citations

  preprintOpen access

  Superparamagnetic colloids present interesting assembly dynamics and propulsion in time-varying magnetic fields due to their magnetic relaxation. However, little is known about the mechanisms governing this magnetic relaxation, which is commonly attributed to the interactions and polydispersity of the ferromagnetic nanoparticles distributed within the colloid. We measure this relaxation from the effective potential between colloids subjected to rotating magnetic fields. Remarkably, our results indicate the presence of magnetic relaxation times much longer than what has been reported, which furthers our understanding of the magnetization of colloids in complex magnetic fields.

  PublisherOA PDFDOI

Recent grants

• Mechanical Phase Transitions and Critical Fluctuations in Fiber Networks

  NSF · $537k · 2022–2026

• Mechanical phase transitions and the rheology of stiff polymers

  NSF · $464k · 2018–2022

Frequent coauthors

• Christoph F. Schmidt

  Duke University

  124 shared

• Jordan L. Shivers

  University of Chicago

  71 shared

• Chase P. Broedersz

  Ludwig-Maximilians-Universität München

  70 shared

• Gijsje H. Koenderink

  Delft University of Technology

  67 shared

• Abhinav Sharma

  University of Augsburg

  63 shared

• Tomer Markovich

  56 shared

• Sadjad Arzash

  Syracuse University

  49 shared

• Alex J. Levine

  41 shared

Labs

• Frederick C. MacKintosh LabPI

Education

• PhD, Physics

  Princeton University