Elliot Elson | Washington University in St. Louis (original) (raw)

Papers by Elliot Elson

Advances in Bioengineering, 1999

We investigated the contractile force response to epidermal growth factor (EGF) stimulation in 3T... more We investigated the contractile force response to epidermal growth factor (EGF) stimulation in 3T3-derived NR6 fibroblast cells in order to determine significant pathways of biochemical signaling that mediate the response. We examined the force generating specificity of the EGF receptor (EGFR) signaling mechanism by using mutant NR6 fibroblasts expressing variations of the EGFR construct. The wild-type (WT) cell presented the complete internalizing EGFR signaling construct while the c’973 cell presented an internalization-defective EGFR construct, and the M721 cell presented a kinase-defective EGFR construct making it signaling inert. Additionally we examined the roles of the phospholipasc C-γ (PLCγ) pathway by using the PLC inhibitor U73122 (1 μM) and the mitogen activated protein kinase (MAPK) pathway using the inhibitor PD98059 (10 μM) in the observed contractile force responses. We found that the WT cells showed a rapid but transient force increase within the first hour post-sti...

Annals of Biomedical Engineering, Oct 11, 2006

Bioartificial tissues are useful model systems for studying cell and extra-cellular matrix mechan... more Bioartificial tissues are useful model systems for studying cell and extra-cellular matrix mechanics. These tissues provide a 3D environment for cells and allow tissue components to be easily modified and quantified. In this study, we fabricated bioartificial tissue rings from a 1 ml solution containing one million cardiac fibroblasts and 1 mg collagen. After 8 days, rings compacted to <1% of original volume and cell number increased 2.4 fold. We initiated continuous cyclic stretching of the rings after 2, 4, or 8 days of incubation, while monitoring the tissue forces. Peak tissue force during each cycle decreased rapidly after initiating stretch, followed by further slow decline. We added 2 µM Cytochalasin-D to some rings prior to initiation of stretch to determine the force contributed by the matrix. Cell force was estimated by subtracting matrix force from tissue force. After 12 h, matrix force-strain curves were highly nonlinear. Cell force-strain curves were linear during loading and showed hysteresis indicating viscoelastic behavior. Cell stiffness increased with stretching frequency from 0.001-0.25 Hz. Cell stiffness decreased with stretch amplitude (5-25%) at 0.1 Hz. The trends in cell stiffness do not fit simple viscoelastic models previously proposed, and suggest possible strain-amplitude related changes during cyclic stretch.

Journal of The Mechanical Behavior of Biomedical Materials, Aug 1, 2018

Characterizing how a tissue's constituents give rise to its viscoelasticity is important for unco... more Characterizing how a tissue's constituents give rise to its viscoelasticity is important for uncovering how hidden timescales underlie multiscale biomechanics. These constituents are viscoelastic in nature, and their mechanics must typically be assessed from the uniaxial behavior of a tissue. Confounding the challenge is that tissue viscoelasticity is typically associated with nonlinear elastic responses. Here, we experimentally assessed how fibroblasts and extracellular matrix (ECM) within engineered tissue constructs give rise to the nonlinear viscoelastic responses of a tissue. We applied a constant strain rate, "triangular-wave, " loading, and interpreted responses using the Fung quasi-linear viscoelastic (QLV) material model. Although the Fung QLV model has several well-known weaknesses, it was well suited to the behaviors of the tissue constructs, cells, and ECM tested. Cells showed relatively high damping over certain loading frequency ranges. Analysis revealed that, even in cases where the Fung QLV model provided an excellent fit to data, the the time constant derived from the model was not in general a material parameter. Results have implications for design of protocols for the mechanical characterization of biological materials, and for the mechanobiology of cells within viscoelastic tissues.

American Society of Mechanical Engineers, Bioengineering Division (Publication) BED, Dec 1, 2001

Previous studies indicate that organ fibroblasts play an important role in wound healing, collage... more Previous studies indicate that organ fibroblasts play an important role in wound healing, collagen production, remodeling processes and pathogenesis of progressive heart, lung, renal and hepatic fibrotic diseases. Several studies suggest a possible inhibitory role for adenosine in the regulation of fibroblast proliferation. The effect of adenosine A 2 agonists on proliferation and differentiation of chick embryo skin/muscle fibroblasts was studied in collagen-based 3-dimensional tissue constructs and also in plated monolayer cells. Materials and Methods: Chick embryo primary fibroblasts were plated in separate groups and were synchronized by growth arrest before stimulation by different doses of adenosine, and A 2 receptor agonists, CV1808, NECA and an A 2 receptor antagonist, CGS15943, and control, in the presence of serum or serum free medium. The cell counts for each treatment of monolayer fibroblasts were compared to determine fibroblast proliferation. Western blot analysis, immunostaining and myofibroblast size measurements were conducted to measure the effect of adenosine on the fibroblast differentiation into myofibroblasts. Cell proliferation was also gauged with DNA assays in the 3-D constructs. Results: Adenosine agonists at low doses significantly reduced fibroblast proliferation in monolayer and 3-D cell culture in the presence of 5% Fetal Calf Serum (FCS) demonstrating a potential antifibrotic activity possibly by activation of the A 2B receptor. Western blot analysis and immunostaining of cells revealed no significant inhibition of the expression of α-smooth muscle actin on a per cell basis by adenosine agonists. Cell size measurements indicated increased numbers of smaller fibroblasts suggesting that adenosine may inhibit the conversion of fibroblasts to myofibroblasts. Conclusion: This study suggests that agents that increase tissue cAMP levels may be of beneficial therapeutic value in organ tissue fibrosis.

Biophysical Journal, 2014

MicroRNAs regulate a large number of genes in metazoan organisms by accelerating mRNA degradation... more MicroRNAs regulate a large number of genes in metazoan organisms by accelerating mRNA degradation and inhibiting translation. Although the

Biophysical Journal, Jun 1, 2017

Measurement of the sizes of nanoscopic particles is a difficult challenge, especially in two-dime... more Measurement of the sizes of nanoscopic particles is a difficult challenge, especially in two-dimensional systems such as cell membranes. We have extended inverse fluorescence correlation spectroscopy (iFCS) to endow it with unique advantages for measuring particle size from the nano-to the microscale. We have augmented iFCS with an analysis of moments of fluorescence fluctuations and used it to measure stages of phase separation in model lipid bilayer membranes. We observed two different pathways for the growth of phase domains. In one, nanoscopic gel domains appeared first and then gradually grew to micrometer size. In the other, the domains reached micrometer size quickly, and their number gradually increased. These measurements demonstrate the value of iFCS measurements through their ability, to our knowledge, to provide new information about the mechanism of lipid phase separation and potentially about the physical basis of naturally occurring nanodomains such as lipid rafts.

Annals of Biomedical Engineering, May 1, 2004

ABSTRACT Remodeling of arteries in response to altered loads is an area of intense interest to ca... more ABSTRACT Remodeling of arteries in response to altered loads is an area of intense interest to cardio-vascular clinicians and researchers. In humans, changes due to cardiovascular diseases (e.g. aortic dilatation) may occur slowly over many years, and mathematical models that describe the remodeling response are needed for predicting the course, and possible treatment, of these diseases. Recently, Humphrey and co-workers have proposed constrained mixture models [1] that consider local stresses in the arterial wall to be the sum of contributions from collagen, elastic fibers, and vascular smooth muscle cells (VSMCs). While numerous studies (e.g., [2]) have considered the active response of VSMCs in large arteries under quasi-static conditions, little is known about the mechanical response of VSMCs to continuous cyclic stretch. We have chosen 3-D bio-artificial tissue constructs as a model system in which to study the response of VSMCs to continuous cyclic stretch. However, VSMCs undergo a shift from a contractile phenotype to a de-differentiated phenotype during culture [3]. Some investigators have suggested that serum deprivation can induce re-differentiation toward a more contractile phenotype [4, 5]. The goal of our study was to compare the effect of incubation conditions on the active responses of VSMCs in 3-D tissue constructs to continuous cyclic stretch.

Biophysical Journal, Jul 1, 2020

Analysis of fluctuations arising as fluorescent particles pass through a focused laser beam has e... more Analysis of fluctuations arising as fluorescent particles pass through a focused laser beam has enabled quantitative characterization of a broad range of molecular kinetic processes. Two key mathematical frameworks that have enabled these quantifications are fluorescence correlation spectroscopy (FCS) and photon counting histogram (PCH) analysis. Although these frameworks are effective and accurate when the focused laser beam is well approximated by an infinite Gaussian beam with a waist that is small compared to the size of the region over which the fluorescent particles can diffuse, they cannot be applied to situations in which this region is bounded at the nanoscale. We therefore derived general forms of the FCS and PCH frameworks for bounded systems. The finite-domain form of FCS differs from the classical form in its boundary and initial conditions and requires development of a new Fourier space solution for fitting data. Our finite-domain FCS predicts simulated data accurately and reduces to a previous model for the special case when the system is much larger than the Gaussian beam and can be considered to be infinite. We also derived the PCH form for the bounded systems. Our approach enables estimation of the concentration of diffusing fluorophores within a finite domain for the first time, to our knowledge. The method opens the possibility of quantification of kinetics in several systems for which this has never been possible.

Pflügers Archiv: European Journal of Physiology, Apr 27, 1998

Acta Biomaterialia, Jun 1, 2016

The ways that fibroblasts remodel their environment is central to wound healing, development of m... more The ways that fibroblasts remodel their environment is central to wound healing, development of musculoskeletal tissues, and progression of pathologies such as fibrosis. However, the changes that fibroblasts make to the material around them and the mechanical consequences of these changes have proven difficult to quantify, especially in a realistic, viscoelastic three dimensional culture environments, leaving a critical need for quantitative data. Here, we observed the mechanisms and quantified the mechanical effects of fibroblast remodeling in engineered tissue constructs (ETCs) comprised of reconstituted rat tail (type I) collagen and human fibroblast cells. To study the effects of remodeling on tissue mechanics, stress-relaxation tests were performed on ETCs cultured for 24, 48, and 72 hours. ETCs were treated with deoxycholate and tested again to assess the ECM response. Viscoelastic relaxation spectra were obtained using the generalized Maxwell model. Cells exhibited viscoelastic damping at two finite time constants over which the ECM showed little damping, approximately 0.2 s and 10-30 s. Different finite time constants in the range of 1-7000 s were attributed to ECM relaxation. Cells remodeled the ECM to produce a relaxation time constant on the order of 7000 s, and to merge relaxation finite time constants in the 0.5-2 s range into a single time content in the 1 s range. Results shed light on hierarchical deformation mechanisms in tissues, and on pathologies related to collagen relaxation such as diastolic dysfunction.

Archives of Physiology and Biochemistry, Aug 12, 2020

Human induced pluripotent stem cells (hIPSCs) have initiated a higher degree of successes in dise... more Human induced pluripotent stem cells (hIPSCs) have initiated a higher degree of successes in disease modelling, preclinical evaluation of drug therapy and pharmaco-toxicological testing. Since the discovery of iPSCs in 2006, many advanced techniques have been introduced to differentiate iPSCs to cardiomyocytes, which have been progressively improved. The disease models from iPSC-induced cardiomyocytes (iPSC-CM) have been successfully helping to study a variety of cardiac diseases such as long QT syndrome, drug-induced long QT, different cardiomyopathies related to mutations in mitochondria or desmosomal proteins and other rare genetic diseases. IPSC-CMs have also been used to screen the role of chemicals in cardiovascular drug discovery and individualisation of drug dosages. In this review, the quality of current procedures for characterisation and maturation of iPSC-CM lines will be discussed. Also, we will focus on time efficiency and cost of standard differentiation methods after reprogramming.

In the present study, we developed the fluorescence correlation spectroscopy theory for closed sy... more In the present study, we developed the fluorescence correlation spectroscopy theory for closed systems with either periodic or reflective boundaries. The illumination could be any arbitrary function. We tested our theory with simulated data of both boundary conditions. We also tested the theory with experimental data of membrane nanotubes, whose circular direction is a closed system. The result shows that the correlation function for nanotubes falls between 1D and 2D diffusion model. The fitting with our model gives an accurate recovery of the diffusion time and nanotube radius. We also give some examples of single molecule experiments for which our theory can be potentially useful. 122 .

ASME 2008 Summer Bioengineering Conference, Parts A and B, Jun 25, 2008

ABSTRACT Remodeling of arteries in response to altered loads is an area of intense interest to ca... more ABSTRACT Remodeling of arteries in response to altered loads is an area of intense interest to cardio-vascular clinicians and researchers. In humans, changes due to cardiovascular diseases (e.g. aortic dilatation) may occur slowly over many years, and mathematical models that describe the remodeling response are needed for predicting the course, and possible treatment, of these diseases. Recently, Humphrey and coworkers have proposed constrained mixture models [1] that can describe these acute and chronic changes[2, 3]. These models consider local stresses in the arterial wall to be the sum of individual contributions from collagen, elastic fibers, and vascular smooth muscle cells (VSMCs) Therefore, the mechanical behavior of VSMCs (presumed to be mechanically in parallel) should be independent of the exact composition of the extracellular matrix (ECM) at any specified stage of tissue remodeling. Previously we have studied the mechanics of VSMCs in 3-D bio-artificial tissue constructs made with collagen [4]. In this study, we made 3-D constructs using fibrin, and investigated whether VSMC morphology and mechanics are dependent on the ECM composition. Because previous studies have shown that VSMCs respond to cyclic stretch by increasing alignment and extra-cellular matrix production[5], we measured the mechanical responses of the VSMCs under continuous cyclic stretch.

Nature, May 1, 1990

SCIENTIFIC CORRESPONDENCE late Ca 2 + and the substrates (arginine and NADPH) needed for NO synth... more SCIENTIFIC CORRESPONDENCE late Ca 2 + and the substrates (arginine and NADPH) needed for NO synthesis but will produce •NO or 0; only when oxygen is supplied by reperfusion. Intravenously administered superoxide dismutase may reduce ischaemic injury by scavenging 0,before it reacts with •NO to form ONOO-. This hypothesis is consistent with current data showing the reduction of ischaemic injury by superoxide dismutase, desferrioxamine and •OH scavengers, but it also predicts that increased amounts of nitrate, nitrite and nitrosamines should be detectable in ischaemic tissue and its venous drainage.

Journal of Biomedical Optics, 2010

Journal of Biomechanical Engineering, 2019

Phase separation of lipid species is believed to underlie formation of lipid rafts that enable th... more Phase separation of lipid species is believed to underlie formation of lipid rafts that enable the concentration of certain surface receptors. However, the dynamics and stabilization of the resulting surface domains are unclear. We developed a methodology for collapsing giant unilamellar vesicles (GUVs) into supported bilayers in a way that keeps membrane nanodomains stable and enables their imaging. We used a combination of fluorescence and atomic force microscopy (AFM) of this system to uncover how a surprising phase separation occurs on lipid vesicles, in which two different gel phases of the same lipid co-exist. This unusual phase behavior was evident in binary GUVs containing 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC) and either 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). The approach showed that one of the phases is stabilized by lipid patches that become ejected from the membrane, thereby enabling the stabiliz...

Journal of the mechanical behavior of biomedical materials, Jan 17, 2015

Viscoelastic relaxation spectra are essential for predicting and interpreting the mechanical resp... more Viscoelastic relaxation spectra are essential for predicting and interpreting the mechanical responses of materials and structures. For biological tissues, these spectra must usually be estimated from viscoelastic relaxation tests. Interpreting viscoelastic relaxation tests is challenging because the inverse problem is expensive computationally. We present here an efficient algorithm that enables rapid identification of viscoelastic relaxation spectra. The algorithm was tested against trial data to characterize its robustness and identify its limitations and strengths. The algorithm was then applied to identify the viscoelastic response of reconstituted collagen, revealing an extensive distribution of viscoelastic time constants.

Experimental Cell Research, 1981

... IN THE RESPONSE OF SEVERAL CELL TYPES TO INHIBITION OF SURFACE RECEPTOR MOBILITY BY LOCAL CON... more ... IN THE RESPONSE OF SEVERAL CELL TYPES TO INHIBITION OF SURFACE RECEPTOR MOBILITY BY LOCAL CONCANAVALINA BINDING YOAV I. HENIS and ... a Zeiss Universal fluorescence microscope to a spot of 1.9 jiim radius (using an x40 water immersion lens) for all ...

Advances in Bioengineering, 1999

We investigated the contractile force response to epidermal growth factor (EGF) stimulation in 3T... more We investigated the contractile force response to epidermal growth factor (EGF) stimulation in 3T3-derived NR6 fibroblast cells in order to determine significant pathways of biochemical signaling that mediate the response. We examined the force generating specificity of the EGF receptor (EGFR) signaling mechanism by using mutant NR6 fibroblasts expressing variations of the EGFR construct. The wild-type (WT) cell presented the complete internalizing EGFR signaling construct while the c’973 cell presented an internalization-defective EGFR construct, and the M721 cell presented a kinase-defective EGFR construct making it signaling inert. Additionally we examined the roles of the phospholipasc C-γ (PLCγ) pathway by using the PLC inhibitor U73122 (1 μM) and the mitogen activated protein kinase (MAPK) pathway using the inhibitor PD98059 (10 μM) in the observed contractile force responses. We found that the WT cells showed a rapid but transient force increase within the first hour post-sti...

Annals of Biomedical Engineering, Oct 11, 2006

Bioartificial tissues are useful model systems for studying cell and extra-cellular matrix mechan... more Bioartificial tissues are useful model systems for studying cell and extra-cellular matrix mechanics. These tissues provide a 3D environment for cells and allow tissue components to be easily modified and quantified. In this study, we fabricated bioartificial tissue rings from a 1 ml solution containing one million cardiac fibroblasts and 1 mg collagen. After 8 days, rings compacted to <1% of original volume and cell number increased 2.4 fold. We initiated continuous cyclic stretching of the rings after 2, 4, or 8 days of incubation, while monitoring the tissue forces. Peak tissue force during each cycle decreased rapidly after initiating stretch, followed by further slow decline. We added 2 µM Cytochalasin-D to some rings prior to initiation of stretch to determine the force contributed by the matrix. Cell force was estimated by subtracting matrix force from tissue force. After 12 h, matrix force-strain curves were highly nonlinear. Cell force-strain curves were linear during loading and showed hysteresis indicating viscoelastic behavior. Cell stiffness increased with stretching frequency from 0.001-0.25 Hz. Cell stiffness decreased with stretch amplitude (5-25%) at 0.1 Hz. The trends in cell stiffness do not fit simple viscoelastic models previously proposed, and suggest possible strain-amplitude related changes during cyclic stretch.

Journal of The Mechanical Behavior of Biomedical Materials, Aug 1, 2018

Characterizing how a tissue's constituents give rise to its viscoelasticity is important for unco... more Characterizing how a tissue's constituents give rise to its viscoelasticity is important for uncovering how hidden timescales underlie multiscale biomechanics. These constituents are viscoelastic in nature, and their mechanics must typically be assessed from the uniaxial behavior of a tissue. Confounding the challenge is that tissue viscoelasticity is typically associated with nonlinear elastic responses. Here, we experimentally assessed how fibroblasts and extracellular matrix (ECM) within engineered tissue constructs give rise to the nonlinear viscoelastic responses of a tissue. We applied a constant strain rate, "triangular-wave, " loading, and interpreted responses using the Fung quasi-linear viscoelastic (QLV) material model. Although the Fung QLV model has several well-known weaknesses, it was well suited to the behaviors of the tissue constructs, cells, and ECM tested. Cells showed relatively high damping over certain loading frequency ranges. Analysis revealed that, even in cases where the Fung QLV model provided an excellent fit to data, the the time constant derived from the model was not in general a material parameter. Results have implications for design of protocols for the mechanical characterization of biological materials, and for the mechanobiology of cells within viscoelastic tissues.

American Society of Mechanical Engineers, Bioengineering Division (Publication) BED, Dec 1, 2001

Previous studies indicate that organ fibroblasts play an important role in wound healing, collage... more Previous studies indicate that organ fibroblasts play an important role in wound healing, collagen production, remodeling processes and pathogenesis of progressive heart, lung, renal and hepatic fibrotic diseases. Several studies suggest a possible inhibitory role for adenosine in the regulation of fibroblast proliferation. The effect of adenosine A 2 agonists on proliferation and differentiation of chick embryo skin/muscle fibroblasts was studied in collagen-based 3-dimensional tissue constructs and also in plated monolayer cells. Materials and Methods: Chick embryo primary fibroblasts were plated in separate groups and were synchronized by growth arrest before stimulation by different doses of adenosine, and A 2 receptor agonists, CV1808, NECA and an A 2 receptor antagonist, CGS15943, and control, in the presence of serum or serum free medium. The cell counts for each treatment of monolayer fibroblasts were compared to determine fibroblast proliferation. Western blot analysis, immunostaining and myofibroblast size measurements were conducted to measure the effect of adenosine on the fibroblast differentiation into myofibroblasts. Cell proliferation was also gauged with DNA assays in the 3-D constructs. Results: Adenosine agonists at low doses significantly reduced fibroblast proliferation in monolayer and 3-D cell culture in the presence of 5% Fetal Calf Serum (FCS) demonstrating a potential antifibrotic activity possibly by activation of the A 2B receptor. Western blot analysis and immunostaining of cells revealed no significant inhibition of the expression of α-smooth muscle actin on a per cell basis by adenosine agonists. Cell size measurements indicated increased numbers of smaller fibroblasts suggesting that adenosine may inhibit the conversion of fibroblasts to myofibroblasts. Conclusion: This study suggests that agents that increase tissue cAMP levels may be of beneficial therapeutic value in organ tissue fibrosis.

Biophysical Journal, 2014

MicroRNAs regulate a large number of genes in metazoan organisms by accelerating mRNA degradation... more MicroRNAs regulate a large number of genes in metazoan organisms by accelerating mRNA degradation and inhibiting translation. Although the

Biophysical Journal, Jun 1, 2017

Measurement of the sizes of nanoscopic particles is a difficult challenge, especially in two-dime... more Measurement of the sizes of nanoscopic particles is a difficult challenge, especially in two-dimensional systems such as cell membranes. We have extended inverse fluorescence correlation spectroscopy (iFCS) to endow it with unique advantages for measuring particle size from the nano-to the microscale. We have augmented iFCS with an analysis of moments of fluorescence fluctuations and used it to measure stages of phase separation in model lipid bilayer membranes. We observed two different pathways for the growth of phase domains. In one, nanoscopic gel domains appeared first and then gradually grew to micrometer size. In the other, the domains reached micrometer size quickly, and their number gradually increased. These measurements demonstrate the value of iFCS measurements through their ability, to our knowledge, to provide new information about the mechanism of lipid phase separation and potentially about the physical basis of naturally occurring nanodomains such as lipid rafts.

Annals of Biomedical Engineering, May 1, 2004

ABSTRACT Remodeling of arteries in response to altered loads is an area of intense interest to ca... more ABSTRACT Remodeling of arteries in response to altered loads is an area of intense interest to cardio-vascular clinicians and researchers. In humans, changes due to cardiovascular diseases (e.g. aortic dilatation) may occur slowly over many years, and mathematical models that describe the remodeling response are needed for predicting the course, and possible treatment, of these diseases. Recently, Humphrey and co-workers have proposed constrained mixture models [1] that consider local stresses in the arterial wall to be the sum of contributions from collagen, elastic fibers, and vascular smooth muscle cells (VSMCs). While numerous studies (e.g., [2]) have considered the active response of VSMCs in large arteries under quasi-static conditions, little is known about the mechanical response of VSMCs to continuous cyclic stretch. We have chosen 3-D bio-artificial tissue constructs as a model system in which to study the response of VSMCs to continuous cyclic stretch. However, VSMCs undergo a shift from a contractile phenotype to a de-differentiated phenotype during culture [3]. Some investigators have suggested that serum deprivation can induce re-differentiation toward a more contractile phenotype [4, 5]. The goal of our study was to compare the effect of incubation conditions on the active responses of VSMCs in 3-D tissue constructs to continuous cyclic stretch.

Biophysical Journal, Jul 1, 2020

Analysis of fluctuations arising as fluorescent particles pass through a focused laser beam has e... more Analysis of fluctuations arising as fluorescent particles pass through a focused laser beam has enabled quantitative characterization of a broad range of molecular kinetic processes. Two key mathematical frameworks that have enabled these quantifications are fluorescence correlation spectroscopy (FCS) and photon counting histogram (PCH) analysis. Although these frameworks are effective and accurate when the focused laser beam is well approximated by an infinite Gaussian beam with a waist that is small compared to the size of the region over which the fluorescent particles can diffuse, they cannot be applied to situations in which this region is bounded at the nanoscale. We therefore derived general forms of the FCS and PCH frameworks for bounded systems. The finite-domain form of FCS differs from the classical form in its boundary and initial conditions and requires development of a new Fourier space solution for fitting data. Our finite-domain FCS predicts simulated data accurately and reduces to a previous model for the special case when the system is much larger than the Gaussian beam and can be considered to be infinite. We also derived the PCH form for the bounded systems. Our approach enables estimation of the concentration of diffusing fluorophores within a finite domain for the first time, to our knowledge. The method opens the possibility of quantification of kinetics in several systems for which this has never been possible.

Pflügers Archiv: European Journal of Physiology, Apr 27, 1998

Acta Biomaterialia, Jun 1, 2016

The ways that fibroblasts remodel their environment is central to wound healing, development of m... more The ways that fibroblasts remodel their environment is central to wound healing, development of musculoskeletal tissues, and progression of pathologies such as fibrosis. However, the changes that fibroblasts make to the material around them and the mechanical consequences of these changes have proven difficult to quantify, especially in a realistic, viscoelastic three dimensional culture environments, leaving a critical need for quantitative data. Here, we observed the mechanisms and quantified the mechanical effects of fibroblast remodeling in engineered tissue constructs (ETCs) comprised of reconstituted rat tail (type I) collagen and human fibroblast cells. To study the effects of remodeling on tissue mechanics, stress-relaxation tests were performed on ETCs cultured for 24, 48, and 72 hours. ETCs were treated with deoxycholate and tested again to assess the ECM response. Viscoelastic relaxation spectra were obtained using the generalized Maxwell model. Cells exhibited viscoelastic damping at two finite time constants over which the ECM showed little damping, approximately 0.2 s and 10-30 s. Different finite time constants in the range of 1-7000 s were attributed to ECM relaxation. Cells remodeled the ECM to produce a relaxation time constant on the order of 7000 s, and to merge relaxation finite time constants in the 0.5-2 s range into a single time content in the 1 s range. Results shed light on hierarchical deformation mechanisms in tissues, and on pathologies related to collagen relaxation such as diastolic dysfunction.

Archives of Physiology and Biochemistry, Aug 12, 2020

Human induced pluripotent stem cells (hIPSCs) have initiated a higher degree of successes in dise... more Human induced pluripotent stem cells (hIPSCs) have initiated a higher degree of successes in disease modelling, preclinical evaluation of drug therapy and pharmaco-toxicological testing. Since the discovery of iPSCs in 2006, many advanced techniques have been introduced to differentiate iPSCs to cardiomyocytes, which have been progressively improved. The disease models from iPSC-induced cardiomyocytes (iPSC-CM) have been successfully helping to study a variety of cardiac diseases such as long QT syndrome, drug-induced long QT, different cardiomyopathies related to mutations in mitochondria or desmosomal proteins and other rare genetic diseases. IPSC-CMs have also been used to screen the role of chemicals in cardiovascular drug discovery and individualisation of drug dosages. In this review, the quality of current procedures for characterisation and maturation of iPSC-CM lines will be discussed. Also, we will focus on time efficiency and cost of standard differentiation methods after reprogramming.

In the present study, we developed the fluorescence correlation spectroscopy theory for closed sy... more In the present study, we developed the fluorescence correlation spectroscopy theory for closed systems with either periodic or reflective boundaries. The illumination could be any arbitrary function. We tested our theory with simulated data of both boundary conditions. We also tested the theory with experimental data of membrane nanotubes, whose circular direction is a closed system. The result shows that the correlation function for nanotubes falls between 1D and 2D diffusion model. The fitting with our model gives an accurate recovery of the diffusion time and nanotube radius. We also give some examples of single molecule experiments for which our theory can be potentially useful. 122 .

ASME 2008 Summer Bioengineering Conference, Parts A and B, Jun 25, 2008

ABSTRACT Remodeling of arteries in response to altered loads is an area of intense interest to ca... more ABSTRACT Remodeling of arteries in response to altered loads is an area of intense interest to cardio-vascular clinicians and researchers. In humans, changes due to cardiovascular diseases (e.g. aortic dilatation) may occur slowly over many years, and mathematical models that describe the remodeling response are needed for predicting the course, and possible treatment, of these diseases. Recently, Humphrey and coworkers have proposed constrained mixture models [1] that can describe these acute and chronic changes[2, 3]. These models consider local stresses in the arterial wall to be the sum of individual contributions from collagen, elastic fibers, and vascular smooth muscle cells (VSMCs) Therefore, the mechanical behavior of VSMCs (presumed to be mechanically in parallel) should be independent of the exact composition of the extracellular matrix (ECM) at any specified stage of tissue remodeling. Previously we have studied the mechanics of VSMCs in 3-D bio-artificial tissue constructs made with collagen [4]. In this study, we made 3-D constructs using fibrin, and investigated whether VSMC morphology and mechanics are dependent on the ECM composition. Because previous studies have shown that VSMCs respond to cyclic stretch by increasing alignment and extra-cellular matrix production[5], we measured the mechanical responses of the VSMCs under continuous cyclic stretch.

Nature, May 1, 1990

SCIENTIFIC CORRESPONDENCE late Ca 2 + and the substrates (arginine and NADPH) needed for NO synth... more SCIENTIFIC CORRESPONDENCE late Ca 2 + and the substrates (arginine and NADPH) needed for NO synthesis but will produce •NO or 0; only when oxygen is supplied by reperfusion. Intravenously administered superoxide dismutase may reduce ischaemic injury by scavenging 0,before it reacts with •NO to form ONOO-. This hypothesis is consistent with current data showing the reduction of ischaemic injury by superoxide dismutase, desferrioxamine and •OH scavengers, but it also predicts that increased amounts of nitrate, nitrite and nitrosamines should be detectable in ischaemic tissue and its venous drainage.

Journal of Biomedical Optics, 2010

Journal of Biomechanical Engineering, 2019

Phase separation of lipid species is believed to underlie formation of lipid rafts that enable th... more Phase separation of lipid species is believed to underlie formation of lipid rafts that enable the concentration of certain surface receptors. However, the dynamics and stabilization of the resulting surface domains are unclear. We developed a methodology for collapsing giant unilamellar vesicles (GUVs) into supported bilayers in a way that keeps membrane nanodomains stable and enables their imaging. We used a combination of fluorescence and atomic force microscopy (AFM) of this system to uncover how a surprising phase separation occurs on lipid vesicles, in which two different gel phases of the same lipid co-exist. This unusual phase behavior was evident in binary GUVs containing 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC) and either 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). The approach showed that one of the phases is stabilized by lipid patches that become ejected from the membrane, thereby enabling the stabiliz...

Journal of the mechanical behavior of biomedical materials, Jan 17, 2015

Viscoelastic relaxation spectra are essential for predicting and interpreting the mechanical resp... more Viscoelastic relaxation spectra are essential for predicting and interpreting the mechanical responses of materials and structures. For biological tissues, these spectra must usually be estimated from viscoelastic relaxation tests. Interpreting viscoelastic relaxation tests is challenging because the inverse problem is expensive computationally. We present here an efficient algorithm that enables rapid identification of viscoelastic relaxation spectra. The algorithm was tested against trial data to characterize its robustness and identify its limitations and strengths. The algorithm was then applied to identify the viscoelastic response of reconstituted collagen, revealing an extensive distribution of viscoelastic time constants.

Experimental Cell Research, 1981

... IN THE RESPONSE OF SEVERAL CELL TYPES TO INHIBITION OF SURFACE RECEPTOR MOBILITY BY LOCAL CON... more ... IN THE RESPONSE OF SEVERAL CELL TYPES TO INHIBITION OF SURFACE RECEPTOR MOBILITY BY LOCAL CONCANAVALINA BINDING YOAV I. HENIS and ... a Zeiss Universal fluorescence microscope to a spot of 1.9 jiim radius (using an x40 water immersion lens) for all ...