Our publications are classified into four areas: (1) Polymers and Soft Matter, (2) Advanced (Bio)Manufacturing, (3) Biomaterials, and (4) Bioengineering. Some of them are theoretical works or experimental works including theoretical component. Please click tags to sort papers of each category and Google Scholar for citations.
2024
12.
Zhi Jian He, Baiqiang Huang,, Li Heng Cai
Bottlebrush polyethylene glycol nanocarriers translocate across human airway epithelium via molecular architecture-enhanced endocytosis Journal Article
In: ACS Nano, vol. 18, iss. 27, pp. 17586–17599, 2024.
Abstract | Links | Tags: Bioengineering, Biomaterials
@article{He2024a,
title = {Bottlebrush polyethylene glycol nanocarriers translocate across human airway epithelium via molecular architecture-enhanced endocytosis},
author = {Zhi Jian He, Baiqiang Huang, and Li Heng Cai},
doi = {10.1021/acsnano.4c01983},
year = {2024},
date = {2024-01-01},
urldate = {2024-01-01},
journal = {ACS Nano},
volume = {18},
issue = {27},
pages = {17586–17599},
abstract = {Pulmonary drug delivery is critical for the treatment of respiratory diseases. However, the human airway surface presents multiple barriers to efficient drug delivery. Here, we report a bottlebrush poly(ethylene glycol) (PEG-BB) nanocarrier that can translocate across all barriers within the human airway surface. Guided by a molecular theory, we design a PEG-BB molecule consisting of a linear backbone densely grafted by many (∼1000) low molecular weight (∼1000 g/mol) polyethylene glycol (PEG) chains; this results in a highly anisotropic, wormlike nanocarrier featuring a contour length of ∼250 nm, a cross-section of ∼20 nm, and a hydrodynamic diameter of ∼40 nm. Using the classic air-liquid-interface culture system to recapitulate essential biological features of the human airway surface, we show that PEG-BB rapidly penetrates through endogenous airway mucus and periciliary brush layer (mesh size of 20-40 nm) to be internalized by cells across the whole epithelium. By quantifying the cellular uptake of polymeric carriers of various molecular architectures and manipulating cell proliferation and endocytosis pathways, we show that the translocation of PEG-BB across the epithelium is driven by bottlebrush architecture-enhanced endocytosis. Our results demonstrate that large, wormlike bottlebrush PEG polymers, if properly designed, can be used as a carrier for pulmonary and mucosal drug delivery.},
keywords = {Bioengineering, Biomaterials},
pubstate = {published},
tppubtype = {article}
}
Pulmonary drug delivery is critical for the treatment of respiratory diseases. However, the human airway surface presents multiple barriers to efficient drug delivery. Here, we report a bottlebrush poly(ethylene glycol) (PEG-BB) nanocarrier that can translocate across all barriers within the human airway surface. Guided by a molecular theory, we design a PEG-BB molecule consisting of a linear backbone densely grafted by many (∼1000) low molecular weight (∼1000 g/mol) polyethylene glycol (PEG) chains; this results in a highly anisotropic, wormlike nanocarrier featuring a contour length of ∼250 nm, a cross-section of ∼20 nm, and a hydrodynamic diameter of ∼40 nm. Using the classic air-liquid-interface culture system to recapitulate essential biological features of the human airway surface, we show that PEG-BB rapidly penetrates through endogenous airway mucus and periciliary brush layer (mesh size of 20-40 nm) to be internalized by cells across the whole epithelium. By quantifying the cellular uptake of polymeric carriers of various molecular architectures and manipulating cell proliferation and endocytosis pathways, we show that the translocation of PEG-BB across the epithelium is driven by bottlebrush architecture-enhanced endocytosis. Our results demonstrate that large, wormlike bottlebrush PEG polymers, if properly designed, can be used as a carrier for pulmonary and mucosal drug delivery.
11.
Zhi Jian He, Catherine Chu, Riley Dickson, Kenichi Okuda, Li-Heng Cai
A gel-coated air-liquid-interface culture system with tunable substrate stiffness matching healthy and diseased lung tissues Journal Article
In: American journal of physiology. Lung cellular and molecular physiology, vol. 326, no. 3, pp. L292–L302, 2024.
Abstract | Links | Tags: Bioengineering, Biomaterials
@article{He2024,
title = {A gel-coated air-liquid-interface culture system with tunable substrate stiffness matching healthy and diseased lung tissues},
author = {Zhi Jian He and Catherine Chu and Riley Dickson and Kenichi Okuda and Li-Heng Cai},
url = {https://doi.org/10.1152/ajplung.00153.2023},
year = {2024},
date = {2024-01-01},
urldate = {2024-01-01},
journal = {American journal of physiology. Lung cellular and molecular physiology},
volume = {326},
number = {3},
pages = {L292–L302},
abstract = {Since its invention in the late 1980s, the air-liquid-interface (ALI) culture system has been the standard in vitro model for studying human airway biology and pulmonary diseases. However, in a conventional ALI system, cells are cultured on a porous plastic membrane that is much stiffer than human airway tissues. Here, we develop a gel-ALI culture system by simply coating the plastic membrane with a thin layer of hydrogel with tunable stiffness matching that of healthy and fibrotic airway tissues. We determine the optimum gel thickness that does not impair the transport of nutrients and biomolecules essential to cell growth. We show that the gel-ALI system allows human bronchial epithelial cells (HBECs) to proliferate and differentiate into pseudostratified epithelium. Furthermore, we discover that HBECs migrate significantly faster on hydrogel substrates with stiffness matching that of fibrotic lung tissues, highlighting the importance of mechanical cues in human airway remodeling. The developed gel-ALI system provides a facile approach to studying the effects of mechanical cues in human airway biology and in modeling pulmonary diseases.},
keywords = {Bioengineering, Biomaterials},
pubstate = {published},
tppubtype = {article}
}
Since its invention in the late 1980s, the air-liquid-interface (ALI) culture system has been the standard in vitro model for studying human airway biology and pulmonary diseases. However, in a conventional ALI system, cells are cultured on a porous plastic membrane that is much stiffer than human airway tissues. Here, we develop a gel-ALI culture system by simply coating the plastic membrane with a thin layer of hydrogel with tunable stiffness matching that of healthy and fibrotic airway tissues. We determine the optimum gel thickness that does not impair the transport of nutrients and biomolecules essential to cell growth. We show that the gel-ALI system allows human bronchial epithelial cells (HBECs) to proliferate and differentiate into pseudostratified epithelium. Furthermore, we discover that HBECs migrate significantly faster on hydrogel substrates with stiffness matching that of fibrotic lung tissues, highlighting the importance of mechanical cues in human airway remodeling. The developed gel-ALI system provides a facile approach to studying the effects of mechanical cues in human airway biology and in modeling pulmonary diseases.
2023
10.
Jinchang Zhu, Li-Heng Cai
All-aqueous printing of viscoelastic droplets in yield-stress fluids Journal Article
In: Acta Biomaterialia, vol. 165, no. 2023, pp. 60–71, 2023.
Abstract | Links | Tags: Advanced (Bio)Manufacturing, Bioengineering, Theory
@article{Zhu2023,
title = {All-aqueous printing of viscoelastic droplets in yield-stress fluids},
author = {Jinchang Zhu and Li-Heng Cai},
url = {https://doi.org/10.1016/j.actbio.2022.09.031},
doi = {10.1016/j.actbio.2022.09.031},
year = {2023},
date = {2023-01-01},
urldate = {2023-01-01},
journal = {Acta Biomaterialia},
volume = {165},
number = {2023},
pages = {60–71},
publisher = {Elsevier Ltd},
abstract = {All-aqueous printing of viscoelastic droplets (aaPVD) in yield-stress fluids is the core of an emerging voxelated bioprinting technology that enables the digital assembly of spherical bio-ink particles (DASP) to create functional tissue mimics. However, the mechanism of aaPVD is largely unknown. Here, by quantifying the dynamics of the whole printing process in real-time, we identify two parameters critical to aaPVD: (1) acceleration of print nozzle, and (2) droplet/nozzle diameter ratio. Moreover, we distinguish three stages associated with aaPVD: droplet generation, detachment, and relaxation. To generate a droplet of good roundness, the ink should be a highly viscous shear-thinning fluid. Using particle image velocimetry and scaling theory, we establish a universal description for the droplet displacements at various printing conditions. Along the direction of nozzle movement, the droplet displacement is determined by the detachment number, a dimensionless parameter defined as the ratio between the dragging force from the nozzle and the confinement force from the supporting matrix. Perpendicular to the direction of nozzle movement, the droplet displacement is determined by the Oldroyd number, a dimensionless parameter that describes the yielded area of the supporting matrix near the print nozzle. For a relaxed droplet, the droplet tail length is independent of droplet/nozzle diameter ratio but determined by the nozzle acceleration. We conclude that printing droplets of good fidelity requires a relatively large droplet/nozzle diameter ratio and intermediate nozzle accelerations. These ensure that the droplet is more solid-like to not flow with the nozzle to form a tadpole-like morphology and that the confinement force from the yield-stress fluid is large enough to prevent large droplet displacement. Our results provide the knowledge and tools for in situ generating and depositing highly viscoelastic droplets of good roundness at prescribed locations in 3D space, which help establish the foundational science for voxelated bioprinting. Statement of significance: Analogues of pixels to two-dimensional (2D) pictures, voxels – in the form of small cubes or spheres – are the basic units of three-dimensional (3D) objects. All-aqueous printing of viscoelastic droplets (aaPVD) is the core of voxelated bioprinting, an emerging technology that uses spherical bio-ink voxels as building blocks to create 3D tissue mimics. Unlike existing technologies relying on the classic Rayleigh-Plateau instability to generate droplets, aaPVD exploits previously unexplored nonlinear fluid dynamics of complex fluids to precisely manipulate viscoelastic droplets in 3D space. The developed knowledge and tools not only help advance biomanufacturing but also stimulate new research directions in soft matter and complex fluids.},
keywords = {Advanced (Bio)Manufacturing, Bioengineering, Theory},
pubstate = {published},
tppubtype = {article}
}
All-aqueous printing of viscoelastic droplets (aaPVD) in yield-stress fluids is the core of an emerging voxelated bioprinting technology that enables the digital assembly of spherical bio-ink particles (DASP) to create functional tissue mimics. However, the mechanism of aaPVD is largely unknown. Here, by quantifying the dynamics of the whole printing process in real-time, we identify two parameters critical to aaPVD: (1) acceleration of print nozzle, and (2) droplet/nozzle diameter ratio. Moreover, we distinguish three stages associated with aaPVD: droplet generation, detachment, and relaxation. To generate a droplet of good roundness, the ink should be a highly viscous shear-thinning fluid. Using particle image velocimetry and scaling theory, we establish a universal description for the droplet displacements at various printing conditions. Along the direction of nozzle movement, the droplet displacement is determined by the detachment number, a dimensionless parameter defined as the ratio between the dragging force from the nozzle and the confinement force from the supporting matrix. Perpendicular to the direction of nozzle movement, the droplet displacement is determined by the Oldroyd number, a dimensionless parameter that describes the yielded area of the supporting matrix near the print nozzle. For a relaxed droplet, the droplet tail length is independent of droplet/nozzle diameter ratio but determined by the nozzle acceleration. We conclude that printing droplets of good fidelity requires a relatively large droplet/nozzle diameter ratio and intermediate nozzle accelerations. These ensure that the droplet is more solid-like to not flow with the nozzle to form a tadpole-like morphology and that the confinement force from the yield-stress fluid is large enough to prevent large droplet displacement. Our results provide the knowledge and tools for in situ generating and depositing highly viscoelastic droplets of good roundness at prescribed locations in 3D space, which help establish the foundational science for voxelated bioprinting. Statement of significance: Analogues of pixels to two-dimensional (2D) pictures, voxels – in the form of small cubes or spheres – are the basic units of three-dimensional (3D) objects. All-aqueous printing of viscoelastic droplets (aaPVD) is the core of voxelated bioprinting, an emerging technology that uses spherical bio-ink voxels as building blocks to create 3D tissue mimics. Unlike existing technologies relying on the classic Rayleigh-Plateau instability to generate droplets, aaPVD exploits previously unexplored nonlinear fluid dynamics of complex fluids to precisely manipulate viscoelastic droplets in 3D space. The developed knowledge and tools not only help advance biomanufacturing but also stimulate new research directions in soft matter and complex fluids.
2021
9.
Jing Xia, Li-Heng Cai, Huayin Wu, Frederick C. MacKintosh, David A. Weitz
Anomalous mechanics of Zn2+-modified fibrin networks Journal Article
In: Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 10, pp. e2020541118, 2021.
Abstract | Links | Tags: Bioengineering
@article{Xia2021,
title = {Anomalous mechanics of Zn2+-modified fibrin networks},
author = {Jing Xia and Li-Heng Cai and Huayin Wu and Frederick C. MacKintosh and David A. Weitz},
doi = {10.1073/pnas.2020541118},
year = {2021},
date = {2021-01-01},
urldate = {2021-01-01},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {118},
number = {10},
pages = {e2020541118},
abstract = {Fibrin is the main component of blood clots. The mechanical properties of fibrin are therefore of critical importance in successful hemostasis. One of the divalent cations released by platelets during hemostasis is Zn2+; however, its effect on the network structure of fibrin gels and on the resultant mechanical properties remains poorly understood. Here, by combining mechanical measurements with three-dimensional confocal microscopy imaging, we show that Zn2+ can tune the fibrin network structure and alter its mechanical properties. In the presence of Zn2+, fibrin protofibrils form large bundles that cause a coarsening of the fibrin network due to an increase in fiber diameter and reduction of the total fiber length. We further show that the protofibrils in these bundles are loosely coupled to one another, which results in a decrease of the elastic modulus with increasing Zn2+ concentrations. We explore the elastic properties of these networks at both low and high stress: At low stress, the elasticity originates from pulling the thermal slack out of the network, and this is consistent with the thermal bending of the fibers. By contrast, at high stress, the elasticity exhibits a common master curve consistent with the stretching of individual protofibrils. These results show that the mechanics of a fibrin network are closely correlated with its microscopic structure and inform our understanding of the structure and physical mechanisms leading to defective or excessive clot stiffness.},
keywords = {Bioengineering},
pubstate = {published},
tppubtype = {article}
}
Fibrin is the main component of blood clots. The mechanical properties of fibrin are therefore of critical importance in successful hemostasis. One of the divalent cations released by platelets during hemostasis is Zn2+; however, its effect on the network structure of fibrin gels and on the resultant mechanical properties remains poorly understood. Here, by combining mechanical measurements with three-dimensional confocal microscopy imaging, we show that Zn2+ can tune the fibrin network structure and alter its mechanical properties. In the presence of Zn2+, fibrin protofibrils form large bundles that cause a coarsening of the fibrin network due to an increase in fiber diameter and reduction of the total fiber length. We further show that the protofibrils in these bundles are loosely coupled to one another, which results in a decrease of the elastic modulus with increasing Zn2+ concentrations. We explore the elastic properties of these networks at both low and high stress: At low stress, the elasticity originates from pulling the thermal slack out of the network, and this is consistent with the thermal bending of the fibers. By contrast, at high stress, the elasticity exhibits a common master curve consistent with the stretching of individual protofibrils. These results show that the mechanics of a fibrin network are closely correlated with its microscopic structure and inform our understanding of the structure and physical mechanisms leading to defective or excessive clot stiffness.
8.
Yinan Shen, Huayin Wu, Peter J. Lu, Dianzhuo Wang, Marjan Shayegan, Hui Li, Weichao Shi, Zizhao Wang, Li-Heng Cai, Jing Xia, Meng Zhang, Ruihua Ding, Harald Herrmann, Robert Goldman, Fred C. Mackintosh, Arturo Moncho-Jordá, David A. Weitz
Effects of vimentin intermediate filaments on the structure and dynamics of in vitro multicomponent interpenetrating cytoskeletal networks Journal Article
In: Physical Review Letters, vol. 127, no. 10, pp. 108101, 2021.
Abstract | Links | Tags: Bioengineering
@article{Shen2021,
title = {Effects of vimentin intermediate filaments on the structure and dynamics of in vitro multicomponent interpenetrating cytoskeletal networks},
author = {Yinan Shen, Huayin Wu, Peter J. Lu and Dianzhuo Wang and Marjan Shayegan and Hui Li and Weichao Shi and Zizhao Wang and Li-Heng Cai and Jing Xia and Meng Zhang and Ruihua Ding and Harald Herrmann and Robert Goldman and Fred C. Mackintosh and Arturo Moncho-Jordá and David A. Weitz},
url = {https://doi.org/10.1103/PhysRevLett.127.108101},
year = {2021},
date = {2021-01-01},
urldate = {2021-01-01},
journal = {Physical Review Letters},
volume = {127},
number = {10},
pages = {108101},
publisher = {American Physical Society},
abstract = {We investigate the rheological properties of interpenetrating networks reconstituted from the main cytoskeletal components: filamentous actin, microtubules, and vimentin intermediate filaments. The elastic modulus is determined largely by actin, with little contribution from either microtubules or vimentin. However, vimentin dramatically impacts the relaxation, with even small amounts significantly increasing the relaxation time of the interpenetrating network. This highly unusual decoupling between dissipation and elasticity may reflect weak attractive interactions between vimentin and actin networks.},
keywords = {Bioengineering},
pubstate = {published},
tppubtype = {article}
}
We investigate the rheological properties of interpenetrating networks reconstituted from the main cytoskeletal components: filamentous actin, microtubules, and vimentin intermediate filaments. The elastic modulus is determined largely by actin, with little contribution from either microtubules or vimentin. However, vimentin dramatically impacts the relaxation, with even small amounts significantly increasing the relaxation time of the interpenetrating network. This highly unusual decoupling between dissipation and elasticity may reflect weak attractive interactions between vimentin and actin networks.
2020
7.
Yongcheng Wang, Ting Cao, Jina Ko, Yinan Shen, Will Zong, Kuanwei Sheng, Wenjian Cao, Sijie Sun, Li-Heng Cai, Ying Lin Zhou, Xin Xiang Zhang, Chenghang Zong, Ralph Weissleder, David Weitz
Dissolvable Polyacrylamide Beads for High-Throughput Droplet DNA Barcoding Journal Article
In: Advanced Science, vol. 7, no. 8, pp. 1–8, 2020.
Abstract | Links | Tags: Bioengineering
@article{Wang2020,
title = {Dissolvable Polyacrylamide Beads for High-Throughput Droplet DNA Barcoding},
author = {Yongcheng Wang and Ting Cao and Jina Ko and Yinan Shen and Will Zong and Kuanwei Sheng and Wenjian Cao and Sijie Sun and Li-Heng Cai and Ying Lin Zhou and Xin Xiang Zhang and Chenghang Zong and Ralph Weissleder and David Weitz},
doi = {10.1002/advs.201903463},
year = {2020},
date = {2020-02-01},
urldate = {2020-02-01},
journal = {Advanced Science},
volume = {7},
number = {8},
pages = {1–8},
publisher = {John Wiley & Sons, Ltd},
abstract = {Droplet-based single cell sequencing technologies, such as inDrop, Drop-seq, and 10X Genomics, are catalyzing a revolution in the understanding of biology. Barcoding beads are key components for these technologies. What is limiting today are barcoding beads that are easy to fabricate, can efficiently deliver primers into drops, and thus achieve high detection efficiency. Here, this work reports an approach to fabricate dissolvable polyacrylamide beads, by crosslinking acrylamide with disulfide bridges that can be cleaved with dithiothreitol. The beads can be rapidly dissolved in drops and release DNA barcode primers. The dissolvable beads are easy to synthesize, and the primer cost for the beads is significantly lower than that for the previous barcoding beads. Furthermore, the dissolvable beads can be loaded into drops with >95% loading efficiency of a single bead per drop and the dissolution of beads does not influence reverse transcription or the polymerase chain reaction (PCR) in drops. Based on this approach, the dissolvable beads are used for single cell RNA and protein analysis.},
keywords = {Bioengineering},
pubstate = {published},
tppubtype = {article}
}
Droplet-based single cell sequencing technologies, such as inDrop, Drop-seq, and 10X Genomics, are catalyzing a revolution in the understanding of biology. Barcoding beads are key components for these technologies. What is limiting today are barcoding beads that are easy to fabricate, can efficiently deliver primers into drops, and thus achieve high detection efficiency. Here, this work reports an approach to fabricate dissolvable polyacrylamide beads, by crosslinking acrylamide with disulfide bridges that can be cleaved with dithiothreitol. The beads can be rapidly dissolved in drops and release DNA barcode primers. The dissolvable beads are easy to synthesize, and the primer cost for the beads is significantly lower than that for the previous barcoding beads. Furthermore, the dissolvable beads can be loaded into drops with >95% loading efficiency of a single bead per drop and the dissolution of beads does not influence reverse transcription or the polymerase chain reaction (PCR) in drops. Based on this approach, the dissolvable beads are used for single cell RNA and protein analysis.
6.
Ruihua Ding, K. -C. Kuo-Chan Hung, Anindita Mitra, L. W. Lloyd W Ung, Daniel Lightwood, Ran Tu, Dale Starkie, Li-Heng Cai, Linas Mazutis, Shaorong Chong, D. A. Weitz, J. A. Heyman
Rapid isolation of antigen-specific B-cells using droplet microfluidics Journal Article
In: RSC Advances, vol. 10, no. 45, pp. 27006–27013, 2020.
Abstract | Links | Tags: Bioengineering
@article{Ding2020,
title = {Rapid isolation of antigen-specific B-cells using droplet microfluidics},
author = {Ruihua Ding and K. -C. Kuo-Chan Hung and Anindita Mitra and L. W. Lloyd W Ung and Daniel Lightwood and Ran Tu and Dale Starkie and Li-Heng Cai and Linas Mazutis and Shaorong Chong and D. A. Weitz and J. A. Heyman},
doi = {10.1039/d0ra04328a},
year = {2020},
date = {2020-01-01},
urldate = {2020-01-01},
journal = {RSC Advances},
volume = {10},
number = {45},
pages = {27006–27013},
publisher = {Royal Society of Chemistry},
abstract = {© The Royal Society of Chemistry. Monoclonal antibodies are powerful tools for scientific research and are the basis of numerous therapeutics. However, traditional approaches to generate monoclonal antibodies against a desired target, such as hybridoma-based techniques and display library methods, are laborious and suffer from fusion inefficiency and display bias, respectively. Here we present a platform, featuring droplet microfluidics and a bead-based binding assay, to rapidly identify and verify antigen-binding antibody sequences from primary cells. We used a defined mixture of hybridoma cells to characterize the system, sorting droplets at up to 100 Hz and isolating desired hybridoma cells, comprising 0.1% of the input, with a false positive rate of less than 1%. We then applied the system to once-frozen primary B-cells to isolate rare cells secreting target-binding antibody. We performed RT-PCR on individual sorted cells to recover the correctly paired heavy- and light-chain antibody sequences, and we used rapid cell-free protein synthesis to generate single-chain variable fragment-format (scFv) antibodies from fourteen of the sorted cells. Twelve of these showed antigen-specific binding by ELISA. Our platform facilitates screening animal B-cell repertoires within days at low cost, increasing both rate and range of discovering antigen-specific antibodies from living organisms. Further, these techniques can be adapted to isolate cells based on virtually any secreted product. This journal is},
keywords = {Bioengineering},
pubstate = {published},
tppubtype = {article}
}
© The Royal Society of Chemistry. Monoclonal antibodies are powerful tools for scientific research and are the basis of numerous therapeutics. However, traditional approaches to generate monoclonal antibodies against a desired target, such as hybridoma-based techniques and display library methods, are laborious and suffer from fusion inefficiency and display bias, respectively. Here we present a platform, featuring droplet microfluidics and a bead-based binding assay, to rapidly identify and verify antigen-binding antibody sequences from primary cells. We used a defined mixture of hybridoma cells to characterize the system, sorting droplets at up to 100 Hz and isolating desired hybridoma cells, comprising 0.1% of the input, with a false positive rate of less than 1%. We then applied the system to once-frozen primary B-cells to isolate rare cells secreting target-binding antibody. We performed RT-PCR on individual sorted cells to recover the correctly paired heavy- and light-chain antibody sequences, and we used rapid cell-free protein synthesis to generate single-chain variable fragment-format (scFv) antibodies from fourteen of the sorted cells. Twelve of these showed antigen-specific binding by ELISA. Our platform facilitates screening animal B-cell repertoires within days at low cost, increasing both rate and range of discovering antigen-specific antibodies from living organisms. Further, these techniques can be adapted to isolate cells based on virtually any secreted product. This journal is
2018
5.
Brian Button, Henry P. Goodell, Eyad Atieh, Yu-Cheng Cheng Chen, Robert Williams, Siddharth Shenoy, Elijah Lackey, Nathan T. Shenkute, Li-Heng Cai, Robert G. Dennis, Richard C. Boucher, Michael Rubinstein
Roles of mucus adhesion and cohesion in cough clearance Journal Article
In: Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 49, pp. 12501–12506, 2018.
Abstract | Links | Tags: Bioengineering
@article{Button2018,
title = {Roles of mucus adhesion and cohesion in cough clearance},
author = {Brian Button and Henry P. Goodell and Eyad Atieh and Yu-Cheng Cheng Chen and Robert Williams and Siddharth Shenoy and Elijah Lackey and Nathan T. Shenkute and Li-Heng Cai and Robert G. Dennis and Richard C. Boucher and Michael Rubinstein},
doi = {10.1073/pnas.1811787115},
year = {2018},
date = {2018-12-01},
urldate = {2018-12-01},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {115},
number = {49},
pages = {12501–12506},
publisher = {National Academy of Sciences},
abstract = {Clearance of intrapulmonary mucus by the high-velocity airflow generated by cough is the major rescue clearance mechanism in subjects with mucoobstructive diseases and failed cilial-dependent mucus clearance, e.g., subjects with cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Previous studies have investigated the mechanical forces generated at airway surfaces by cough but have not considered the effects of mucus biophysical properties on cough efficacy. Theoretically, mucus can be cleared by cough from the lung by an adhesive failure, i.e., breaking mucus-cell surface adhesive bonds and/or by cohesive failure, i.e., directly fracturing mucus. Utilizing peel-testing technologies, mucus-epithelial surface adhesive and mucus cohesive strengths were measured. Because both mucus concentration and pH have been reported to alter mucus biophysical properties in disease, the effects of mucus concentration and pH on adhesion and cohesion were compared. Both adhesive and cohesive strengths depended on mucus concentration, but neither on physiologically relevant changes in pH nor bicarbonate concentration. Mucus from bronchial epithelial cultures and patient sputum samples exhibited similar adhesive and cohesive properties. Notably, the magnitudes of both adhesive and cohesive strength exhibited similar velocity and concentration dependencies, suggesting that viscous dissipation of energy within mucus during cough determines the efficiency of cough clearance of diseased, hyperconcentrated, mucus. Calculations of airflow-induced shear forces on airway mucus related to mucus concentration predicted substantially reduced cough clearance in small versus large airways. Studies designed to improve cough clearance in subjects with mucoobstructive diseases identified reductions of mucus concentration and viscous dissipation as key therapeutic strategies.},
keywords = {Bioengineering},
pubstate = {published},
tppubtype = {article}
}
Clearance of intrapulmonary mucus by the high-velocity airflow generated by cough is the major rescue clearance mechanism in subjects with mucoobstructive diseases and failed cilial-dependent mucus clearance, e.g., subjects with cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Previous studies have investigated the mechanical forces generated at airway surfaces by cough but have not considered the effects of mucus biophysical properties on cough efficacy. Theoretically, mucus can be cleared by cough from the lung by an adhesive failure, i.e., breaking mucus-cell surface adhesive bonds and/or by cohesive failure, i.e., directly fracturing mucus. Utilizing peel-testing technologies, mucus-epithelial surface adhesive and mucus cohesive strengths were measured. Because both mucus concentration and pH have been reported to alter mucus biophysical properties in disease, the effects of mucus concentration and pH on adhesion and cohesion were compared. Both adhesive and cohesive strengths depended on mucus concentration, but neither on physiologically relevant changes in pH nor bicarbonate concentration. Mucus from bronchial epithelial cultures and patient sputum samples exhibited similar adhesive and cohesive properties. Notably, the magnitudes of both adhesive and cohesive strength exhibited similar velocity and concentration dependencies, suggesting that viscous dissipation of energy within mucus during cough determines the efficiency of cough clearance of diseased, hyperconcentrated, mucus. Calculations of airflow-induced shear forces on airway mucus related to mucus concentration predicted substantially reduced cough clearance in small versus large airways. Studies designed to improve cough clearance in subjects with mucoobstructive diseases identified reductions of mucus concentration and viscous dissipation as key therapeutic strategies.
2016
4.
Liyuan Zhang, Li-Heng Cai, Philipp S. Lienemann, Torsten Rossow, Ingmar Polenz, Queralt Vallmajo-Martin, Martin Ehrbar, Hui Na, David J. Mooney, David A. Weitz
One-step microfluidic fabrication of polyelectrolyte microcapsules in aqueous conditions for protein release Journal Article
In: Angewandte Chemie – International Edition, vol. 55, no. 43, pp. 13470–13474, 2016.
Abstract | Links | Tags: Bioengineering, Biomaterials
@article{Zhang2016,
title = {One-step microfluidic fabrication of polyelectrolyte microcapsules in aqueous conditions for protein release},
author = {Liyuan Zhang and Li-Heng Cai and Philipp S. Lienemann and Torsten Rossow and Ingmar Polenz and Queralt Vallmajo-Martin and Martin Ehrbar and Hui Na and David J. Mooney and David A. Weitz},
doi = {10.1002/anie.201606960},
year = {2016},
date = {2016-01-01},
urldate = {2016-01-01},
journal = {Angewandte Chemie - International Edition},
volume = {55},
number = {43},
pages = {13470–13474},
abstract = {We report a microfluidic approach for one-step fabrication of polyelectrolyte microcapsules in aqueous conditions. Using two immiscible aqueous polymer solutions, we generate transient water-in-water-in-water double emulsion droplets and use them as templates to fabricate polyelectrolyte microcapsules. The capsule shell is formed by the complexation of oppositely charged polyelectrolytes at the immiscible interface. We find that attractive electrostatic interactions can significantly prolong the release of charged molecules. Moreover, we demonstrate the application of these microcapsules in encapsulation and release of proteins without impairing their biological activities. Our platform should benefit a wide range of applications that require encapsulation and sustained release of molecules in aqueous environments.},
keywords = {Bioengineering, Biomaterials},
pubstate = {published},
tppubtype = {article}
}
We report a microfluidic approach for one-step fabrication of polyelectrolyte microcapsules in aqueous conditions. Using two immiscible aqueous polymer solutions, we generate transient water-in-water-in-water double emulsion droplets and use them as templates to fabricate polyelectrolyte microcapsules. The capsule shell is formed by the complexation of oppositely charged polyelectrolytes at the immiscible interface. We find that attractive electrostatic interactions can significantly prolong the release of charged molecules. Moreover, we demonstrate the application of these microcapsules in encapsulation and release of proteins without impairing their biological activities. Our platform should benefit a wide range of applications that require encapsulation and sustained release of molecules in aqueous environments.
3.
Karin Wang, Li-Heng Cai, Bo Lan, Jeffrey J. Fredberg
Hidden in the mist no more: physical force in cell biology Journal Article
In: Nature Methods, vol. 13, no. 2, pp. 124–125, 2016.
Abstract | Links | Tags: Bioengineering
@article{Wang2016,
title = {Hidden in the mist no more: physical force in cell biology},
author = {Karin Wang and Li-Heng Cai and Bo Lan and Jeffrey J. Fredberg},
doi = {10.1038/nmeth.3744},
year = {2016},
date = {2016-01-01},
urldate = {2016-01-01},
journal = {Nature Methods},
volume = {13},
number = {2},
pages = {124–125},
abstract = {To drive its migration through a fibrillar matrix—and thus to spread, invade or metastasize—a cancer cell must exert physical forces. The first visualization of these forces in three dimensions reveals surprising migration dynamics.},
keywords = {Bioengineering},
pubstate = {published},
tppubtype = {article}
}
To drive its migration through a fibrillar matrix—and thus to spread, invade or metastasize—a cancer cell must exert physical forces. The first visualization of these forces in three dimensions reveals surprising migration dynamics.
2014
2.
Ashley G. Henderson, Camille Ehre, Brian Button, Lubna H. Abdullah, Li-Heng Cai, Margaret W. Leigh, Genevieve C. DeMaria, Hiro Matsui, Scott H. Donaldson, C. William Davis, John K. Sheehan, Richard C. Boucher, Mehmet Kesimer
Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressure Journal Article
In: Journal of Clinical Investigation, vol. 124, no. 7, pp. 3047–3060, 2014.
Abstract | Links | Tags: Bioengineering
@article{Henderson2014,
title = {Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressure},
author = {Ashley G. Henderson and Camille Ehre and Brian Button and Lubna H. Abdullah and Li-Heng Cai and Margaret W. Leigh and Genevieve C. DeMaria and Hiro Matsui and Scott H. Donaldson and C. William Davis and John K. Sheehan and Richard C. Boucher and Mehmet Kesimer},
doi = {10.1172/JCI73469},
year = {2014},
date = {2014-01-01},
urldate = {2014-01-01},
journal = {Journal of Clinical Investigation},
volume = {124},
number = {7},
pages = {3047–3060},
abstract = {The pathogenesis of mucoinfective lung disease in cystic fibrosis (CF) patients likely involves poor mucus clearance. A recent model of mucus clearance predicts that mucus flow depends on the relative mucin concentration of the mucus layer compared with that of the periciliary layer; however, mucin concentrations have been difficult to measure in CF secretions. Here, we have shown that the concentration of mucin in CF sputum is low when measured by immunologically based techniques, and mass spectrometric analyses of CF mucins revealed mucin cleavage at antibody recognition sites. Using physical size exclusion chromatography/differential refractometry (SEC/dRI) techniques, we determined that mucin concentrations in CF secretions were higher than those in normal secretions. Measurements of partial osmotic pressures revealed that the partial osmotic pressure of CF sputum and the retained mucus in excised CF lungs were substantially greater than the partial osmotic pressure of normal secretions. Our data reveal that mucin concentration cannot be accurately measured immunologically in proteolytically active CF secretions; mucins are hyperconcentrated in CF secretions; and CF secretion osmotic pressures predict mucus layer-dependent osmotic compression of the periciliary liquid layer in CF lungs. Consequently, mucin hypersecretion likely produces mucus stasis, which contributes to key infectious and inflammatory components of CF lung disease.},
keywords = {Bioengineering},
pubstate = {published},
tppubtype = {article}
}
The pathogenesis of mucoinfective lung disease in cystic fibrosis (CF) patients likely involves poor mucus clearance. A recent model of mucus clearance predicts that mucus flow depends on the relative mucin concentration of the mucus layer compared with that of the periciliary layer; however, mucin concentrations have been difficult to measure in CF secretions. Here, we have shown that the concentration of mucin in CF sputum is low when measured by immunologically based techniques, and mass spectrometric analyses of CF mucins revealed mucin cleavage at antibody recognition sites. Using physical size exclusion chromatography/differential refractometry (SEC/dRI) techniques, we determined that mucin concentrations in CF secretions were higher than those in normal secretions. Measurements of partial osmotic pressures revealed that the partial osmotic pressure of CF sputum and the retained mucus in excised CF lungs were substantially greater than the partial osmotic pressure of normal secretions. Our data reveal that mucin concentration cannot be accurately measured immunologically in proteolytically active CF secretions; mucins are hyperconcentrated in CF secretions; and CF secretion osmotic pressures predict mucus layer-dependent osmotic compression of the periciliary liquid layer in CF lungs. Consequently, mucin hypersecretion likely produces mucus stasis, which contributes to key infectious and inflammatory components of CF lung disease.
2012
1.
B. Button, L. -H. Cai, C. Ehre, M. Kesimer, D. B. Hill, J. K. Sheehan, R. C. Boucher, M. Rubinstein
A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia Journal Article
In: Science, vol. 337, no. 6097, pp. 937–941, 2012.
Abstract | Links | Tags: Bioengineering
@article{Button2012,
title = {A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia},
author = {B. Button and L. -H. Cai and C. Ehre and M. Kesimer and D. B. Hill and J. K. Sheehan and R. C. Boucher and M. Rubinstein},
doi = {10.1126/science.1223012},
year = {2012},
date = {2012-08-01},
urldate = {2012-08-01},
journal = {Science},
volume = {337},
number = {6097},
pages = {937–941},
abstract = {Mucus clearance is the primary defense mechanism that protects airways from inhaled infectious and toxic agents. In the current gel-on-liquid mucus clearance model, a mucus gel is propelled on top of a “watery” periciliary layer surrounding the cilia. However, this model fails to explain the formation of a distinct mucus layer in health or why mucus clearance fails in disease. We propose a gel-on-brush model in which the periciliary layer is occupied by membrane-spanning mucins and mucopolysaccharides densely tethered to the airway surface. This brush prevents mucus penetration into the periciliary space and causes mucus to form a distinct layer. The relative osmotic moduli of the mucus and periciliary brush layers explain both the stability of mucus clearance in health and its failure in airway disease.},
keywords = {Bioengineering},
pubstate = {published},
tppubtype = {article}
}
Mucus clearance is the primary defense mechanism that protects airways from inhaled infectious and toxic agents. In the current gel-on-liquid mucus clearance model, a mucus gel is propelled on top of a “watery” periciliary layer surrounding the cilia. However, this model fails to explain the formation of a distinct mucus layer in health or why mucus clearance fails in disease. We propose a gel-on-brush model in which the periciliary layer is occupied by membrane-spanning mucins and mucopolysaccharides densely tethered to the airway surface. This brush prevents mucus penetration into the periciliary space and causes mucus to form a distinct layer. The relative osmotic moduli of the mucus and periciliary brush layers explain both the stability of mucus clearance in health and its failure in airway disease.