scholarly journals Combinatorial Screen of Dynamic Mechanical Stimuli for Predictive Control of MSC Mechano-Responsiveness

2020 ◽  
Author(s):  
Haijiao Liu ◽  
Jenna F. Usprech ◽  
Prabu Karthick Parameshwar ◽  
Yu Sun ◽  
Craig A. Simmons
Keyword(s):  
Predictive Control ◽  
Mechanical Stimulation ◽  
Interactive Effect ◽  
Mechanical Stimuli ◽  
Dynamic Mechanical ◽  
Response Data ◽  
Stimulation Parameters ◽  
Deformable Membrane ◽  
Matrix Production ◽  
The Individual

AbstractMechanobiological-based control of mesenchymal stromal cells (MSCs) to aid in the engineering and regeneration of load-bearing tissues requires systematic investigations of specific dynamic mechanical stimulation protocols. Using deformable membrane microdevice arrays paired with combinatorial experimental design and modeling, we systematically probed the individual and integrative effects of mechanical stimulation parameters (strain magnitude (STRAIN), rate at which strain is changed (RATE) and duty period (DUTY)) on myofibrogenesis and matrix production of MSCs in 3D hydrogels. These functions were found to be dominantly influenced by a novel and higher-order interactive effect between STRAIN and DUTY. Empirical models based on our combinatorial cue-response data predicted an optimal loading regime in which STRAIN and DUTY were increased synchronously over time, which was validated to most effectively promote MSC matrix production. These findings inform the design of loading regimes for MSC-based engineered tissues and validate a broadly applicable approach to probe multifactorial regulating effects of microenvironmental and mechanobiological cues.

scholarly journals Combinatorial screen of dynamic mechanical stimuli for predictive control of MSC mechano-responsiveness

2021 ◽  
Vol 7 (19) ◽  
pp. eabe7204
Author(s):  
Haijiao Liu ◽  
Jenna F. Usprech ◽  
Prabu Karthick Parameshwar ◽  
Yu Sun ◽  
Craig A. Simmons
Keyword(s):  
Mechanical Stimulation ◽  
Interactive Effect ◽  
Three Dimensional ◽  
Mechanical Stimuli ◽  
Dynamic Mechanical ◽  
Response Data ◽  
Deformable Membrane ◽  
Matrix Production ◽  
Strain Magnitude ◽  
The Individual

Mechanobiological-based control of mesenchymal stromal cells (MSCs) to facilitate engineering and regeneration of load-bearing tissues requires systematic investigations of specific dynamic mechanical stimulation protocols. Using deformable membrane microdevice arrays paired with combinatorial experimental design and modeling, we probed the individual and integrative effects of mechanical stimulation parameters (strain magnitude, rate at which strain is changed, and duty period) on myofibrogenesis and matrix production of MSCs in three-dimensional hydrogels. These functions were found to be dominantly influenced by a previously unidentified, higher-order interactive effect between strain magnitude and duty period. Empirical models based on our combinatorial cue-response data predicted an optimal loading regime in which strain magnitude and duty period were increased synchronously over time, which was validated to most effectively promote MSC matrix production. These findings inform the design of loading regimes for MSC-based engineered tissues and validate a broadly applicable approach to probe multifactorial regulating effects of mechanobiological cues.

scholarly journals Design, Implementation, and Validation of a Piezoelectric Device to Study the Effects of Dynamic Mechanical Stimulation on Cell Proliferation, Migration and Morphology

Sensors ◽  
2020 ◽  
Vol 20 (7) ◽  
pp. 2155 ◽  
Author(s):  
Dahiana Mojena-Medina ◽  
Marina Martínez-Hernández ◽  
Miguel de la Fuente ◽  
Guadalupe García-Isla ◽  
Julio Posada ◽  
...  
Keyword(s):  
Mechanical Stimulation ◽  
Cell Monolayer ◽  
Mechanical Stimuli ◽  
Mechanical Parameters ◽  
Dynamic Stimuli ◽  
New Device ◽  
Dynamic Mechanical ◽  
Cell Functions ◽  
Biochemical Signals

Cell functions and behavior are regulated not only by soluble (biochemical) signals but also by biophysical and mechanical cues within the cells’ microenvironment. Thanks to the dynamical and complex cell machinery, cells are genuine and effective mechanotransducers translating mechanical stimuli into biochemical signals, which eventually alter multiple aspects of their own homeostasis. Given the dominant and classic biochemical-based views to explain biological processes, it could be challenging to elucidate the key role that mechanical parameters such as vibration, frequency, and force play in biology. Gaining a better understanding of how mechanical stimuli (and their mechanical parameters associated) affect biological outcomes relies partially on the availability of experimental tools that may allow researchers to alter mechanically the cell’s microenvironment and observe cell responses. Here, we introduce a new device to study in vitro responses of cells to dynamic mechanical stimulation using a piezoelectric membrane. Using this device, we can flexibly change the parameters of the dynamic mechanical stimulation (frequency, amplitude, and duration of the stimuli), which increases the possibility to study the cell behavior under different mechanical excitations. We report on the design and implementation of such device and the characterization of its dynamic mechanical properties. By using this device, we have performed a preliminary study on the effect of dynamic mechanical stimulation in a cell monolayer of an epidermal cell line (HaCaT) studying the effects of 1 Hz and 80 Hz excitation frequencies (in the dynamic stimuli) on HaCaT cell migration, proliferation, and morphology. Our preliminary results indicate that the response of HaCaT is dependent on the frequency of stimulation. The device is economic, easily replicated in other laboratories and can support research for a better understanding of mechanisms mediating cellular mechanotransduction.

scholarly journals A Role for Acid-sensing Ion Channel 3, but Not Acid-sensing Ion Channel 2, in Sensing Dynamic Mechanical Stimuli

2010 ◽  
Vol 113 (3) ◽  
pp. 647-654 ◽  
Author(s):  
Jasenka Borzan ◽  
Chengshui Zhao ◽  
Richard A. Meyer ◽  
Srinivasa N. Raja
Keyword(s):  
Ion Channel ◽  
Nerve Injury ◽  
Mechanical Stimulation ◽  
Knockout Mice ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Mechanical Stimuli ◽  
Baseline Sensitivity ◽  
Male And Female ◽  
Dynamic Mechanical

Background Acid-sensing ion channels 2 and 3 (ASIC2 and ASIC3, respectively) have been implicated as putative mechanotransducers. Because mechanical hyperalgesia is a prominent consequence of nerve injury, we tested whether male and female ASIC2 or ASIC3 knockout mice have altered responses to mechanical and heat stimuli at baseline and during the 5 weeks after spinal nerve ligation. Methods Age-matched, adult male and female ASIC2 knockout (n=21) and wild-type (WT; n=24) mice or ASIC3 knockout (n=20) and WT (n=19) mice were tested for sensitivity to natural stimuli before and after spinal nerve ligation surgery. All animals were first tested for baseline sensitivity to mechanical and heat stimuli and in a novel dynamic mechanical stimulation test. The same testing procedures were then repeated weekly after spinal nerve injury. Results Compared with their respective WT counterparts, ASIC2 and ASIC3 knockout mice had normal baseline sensitivity to standard mechanical and heat stimuli. However, when exposed to a novel stroking stimulus to test sensitivity to dynamic mechanical stimulation, ASIC3 knockout mice were significantly more sensitive than were WT mice. After spinal nerve ligation, ASIC2 and ASIC3 knockout mice developed mechanical and heat hyperalgesia comparable with that of their respective WT controls. In addition, in both experiments, female mice were more sensitive than male mice to heat at baseline and after the nerve injury. Conclusions We conclude that ASIC2 and ASIC3 channels are not directly involved in the development or maintenance of neuropathic pain after spinal nerve ligation. However, the ASIC3 channel significantly modulates the sensing of dynamic mechanical stimuli in physiologic condition.

scholarly journals A Novel Bioreactor for the Mechanical Stimulation of Clinically Relevant Scaffolds for Muscle Tissue Engineering Purposes

Processes ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 474
Author(s):  
Silvia Todros ◽  
Silvia Spadoni ◽  
Edoardo Maghin ◽  
Martina Piccoli ◽  
Piero G. Pavan
Keyword(s):  
Mechanical Stimulation ◽  
Strain Range ◽  
Tensile Tests ◽  
Muscular Tissue ◽  
Fe Model ◽  
Mechanical Stimuli ◽  
Physiological Strain ◽  
Cellular Alignment ◽  
Stimulation Of

Muscular tissue regeneration may be enhanced in vitro by means of mechanical stimulation, inducing cellular alignment and the growth of functional fibers. In this work, a novel bioreactor is designed for the radial stimulation of porcine-derived diaphragmatic scaffolds aiming at the development of clinically relevant tissue patches. A Finite Element (FE) model of the bioreactor membrane is developed, considering two different methods for gripping muscular tissue patch during the stimulation, i.e., suturing and clamping with pliers. Tensile tests are carried out on fresh and decellularized samples of porcine diaphragmatic tissue, and a fiber-reinforced hyperelastic constitutive model is assumed to describe the mechanical behavior of tissue patches. Numerical analyses are carried out by applying pressure to the bioreactor membrane and evaluating tissue strain during the stimulation phase. The bioreactor designed in this work allows one to mechanically stimulate tissue patches in a radial direction by uniformly applying up to 30% strain. This can be achieved by adopting pliers for tissue clamping. Contrarily, the use of sutures is not advisable, since high strain levels are reached in suturing points, exceeding the physiological strain range and possibly leading to tissue laceration. FE analysis allows the optimization of the bioreactor configuration in order to ensure an efficient transduction of mechanical stimuli while preventing tissue damage.

scholarly journals Causal mediation analysis with multiple causally non-ordered mediators

2015 ◽  
Vol 27 (1) ◽  
pp. 3-19 ◽  
Author(s):  
Masataka Taguri ◽  
John Featherstone ◽  
Jing Cheng
Keyword(s):  
Indirect Effect ◽  
Interactive Effect ◽  
Mediation Effect ◽  
Mediation Effects ◽  
Mediation Analyses ◽  
Intermediate Variable ◽  
Causal Mediation ◽  
Health Studies ◽  
Using Data ◽  
The Individual

In many health studies, researchers are interested in estimating the treatment effects on the outcome around and through an intermediate variable. Such causal mediation analyses aim to understand the mechanisms that explain the treatment effect. Although multiple mediators are often involved in real studies, most of the literature considered mediation analyses with one mediator at a time. In this article, we consider mediation analyses when there are causally non-ordered multiple mediators. Even if the mediators do not affect each other, the sum of two indirect effects through the two mediators considered separately may diverge from the joint natural indirect effect when there are additive interactions between the effects of the two mediators on the outcome. Therefore, we derive an equation for the joint natural indirect effect based on the individual mediation effects and their interactive effect, which helps us understand how the mediation effect works through the two mediators and relative contributions of the mediators and their interaction. We also discuss an extension for three mediators. The proposed method is illustrated using data from a randomized trial on the prevention of dental caries.

scholarly journals Effect of mechanical loading on insulin-like growth factor-I gene expression in rat tibia

2007 ◽  
Vol 192 (1) ◽  
pp. 131-140 ◽  
Author(s):  
Christianne M A Reijnders ◽  
Nathalie Bravenboer ◽  
Annechien M Tromp ◽  
Marinus A Blankenstein ◽  
Paul Lips
Keyword(s):  
Bone Formation ◽  
Mrna Expression ◽  
Mechanical Loading ◽  
Mechanical Stimulation ◽  
Molecular Mechanisms ◽  
Bone Marrow Cells ◽  
Mechanical Stimuli ◽  
Igf I ◽  
Female Wistar Rats ◽  
Tibia Shaft

Mechanical loading plays an essential role in maintaining skeletal integrity. Mechanical stimulation leads to increased bone formation. However, the cellular and molecular mechanisms that are involved in the translation of mechanical stimuli into bone formation, are not completely understood. Growth factors and osteocytes, which act as mechanosensors, play a key role during the bone formation after mechanical stimulation. The aim of this study was to characterize the role of IGF-I in the translation of mechanical stimuli into bone formation locally in rat tibiae. Fifteen female Wistar rats were randomly assigned to three groups (n = 5): load, sham-loaded, and control. The four-point bending model of Forwood and Turner was used to induce a single period of mechanical loading on the tibia shaft. The effects of mechanical loading on IGF-I mRNA expression were determined with non-radioactive in situ hybridization on decalcified tibiae sections, 6 h after the loading session. Endogenous IGF-I mRNA was expressed in trabecular and cortical osteoblasts, some trabecular and sub-endocortical osteocytes, intracortical endothelial cells of blood vessels, and periosteum. Megakaryocytes, macrophages, and myeloid cells also expressed IGF-I mRNA. In the growth plate, IGF-I mRNA was located in proliferative and hypertrophic chondrocytes. Mechanical loading did not affect the IGF-I mRNA expression in osteoblasts, bone marrow cells, and chondrocytes, but the osteocytes at the endosteal side of the shaft showed a twofold increase of IGF-I mRNA expression. The proportion of IGF-I mRNA positive osteocytes in loaded tibiae was 29.3 ± 12.9% (mean ± s.d.; n = 5), whereas sham-loaded and contra-lateral control tibiae exhibited 16.7 ± 4.4% (n = 5) and 14.7 ± 4.2% (n = 10) respectively (P < 0.05). Lamellar bone formation after a single mechanical loading session was observed at the endosteal side of the shaft. In conclusion, a single loading session results in a twofold up-regulation of IGF-I mRNA synthesis in osteocytes which are present in multiple layers extending into the cortical bone of mechanically stimulated tibia shaft 6 h after loading. This supports the hypothesis that IGF-I, which is located in osteocytes, is involved in the translation of mechanical stimuli into bone formation.

scholarly journals Localized mechanical stimulation of single cells with engineered spatio-temporal profile

Lab on a Chip ◽  
2018 ◽  
Vol 18 (19) ◽  
pp. 2955-2965 ◽  
Author(s):  
M. Monticelli ◽  
D. S. Jokhun ◽  
D. Petti ◽  
G. V. Shivashankar ◽  
R. Bertacco
Keyword(s):  
Cell Culture ◽  
Mechanical Stimulation ◽  
Single Cells ◽  
Mechanical Stimuli ◽  
Temporal Profile ◽  
A Cell ◽  
Spatio Temporal ◽  
Stimulation Of

We introduce a new platform for mechanobiology based on active substrates, made of Fe-coated polymeric micropillars, capable to apply mechanical stimuli with tunable spatio-temporal profile on a cell culture.

Stretch-Activated Calcium Signal Propagation Following Mechanical Stimulation of Focal Adhesions

2007 ◽  
Author(s):  
Warren C. Ruder ◽  
Erica D. Pratt ◽  
Nailah Z. Brandy ◽  
David A. LaVan ◽  
Philip R. LeDuc ◽  
...  
Keyword(s):  
Mechanical Stimulation ◽  
Focal Adhesions ◽  
Signal Propagation ◽  
Cell Types ◽  
Calcium Signal ◽  
Matrix Remodeling ◽  
Mechanical Stimuli ◽  
Cellular Processes ◽  
Unique Manner ◽  
Tissue Matrix

Cells translate environmental mechanical stimuli into biochemical reactions that govern a range of cellular processes such as proliferation, death and tissue matrix remodeling. Mechanical activation of individual focal adhesions formed between the cell and its environment directly correspond to several internal responses. Intracellular calcium concentration, [Ca2+]in, has been shown to profoundly change during force sensing. In order to understand this dynamic in cells, we compared calcium mobilization resulting from chemical stimulation and that resulting from mechanical stimulation. We have analyzed the response of fibroblasts to membrane displacements of over 5 μm resulting in eventual spikes in [Ca2+]in. Our data initially indicates that fibroblasts may process mechanical calcium events in unique manner in comparison to other cell types. This finding has implications in a range of fields including mechanobiology and magnetics based activation.

A comparative study of the changes in receptive-field properties of multireceptive and nocireceptive rat dorsal horn neurons following noxious mechanical stimulation

1989 ◽  
Vol 62 (4) ◽  
pp. 854-863 ◽  
Author(s):  
J. M. Laird ◽  
F. Cervero
Keyword(s):  
Dorsal Horn ◽  
Mechanical Stimulation ◽  
Receptive Fields ◽  
Mechanical Stimulus ◽  
Mechanical Stimuli ◽  
Dorsal Horn Neurons ◽  
Mechanical Threshold ◽  
Before And After ◽  
Low Threshold ◽  
Noxious Mechanical Stimulation

1. Single-unit electrical activity has been recorded from 42 dorsal horn neurons in the sacral segments of the rat's spinal cord. The sample consisted of 20 multireceptive (class 2) cells with both A- and C-fiber inputs and 22 nocireceptive (class 3) cells. All neurons had cutaneous receptive fields (RFs) on the tail. 2. The RF sizes of the cells and their response thresholds to mechanical stimulation of the skin were determined before and after each of a series of 2-min noxious mechanical stimuli. Up to five such stimuli were delivered at intervals ranging from 10 to 60 min. In most cases, only one cell per animal was tested. 3. The majority of neurons were tested in barbiturate-anesthetized animals. However, to test whether or not this anesthetic influenced the results obtained, experiments were also performed in halothane-anesthetized and decerebrate-spinal preparations. The results from these experiments are considered separately. 4. All of the neurons responded vigorously to the first noxious pinch stimulus and all but one to the rest of the stimuli in the series. The responses of the neurons varied from stimulus to stimulus, but there were no detectable trends in the two groups of cells. 5. The RFs of the class 2 cells showed large increases (624.3 +/- 175.8 mm2, mean +/- SE) after the application of the pinch stimuli. The RFs of the class 3 neurons, which were initially smaller than those of the class 2 cells, either did not increase in size or showed very small increases after the pinch stimuli (38.3 +/- 11.95 mm2, mean +/- SE). 6. Some cells in both groups (6/10 class 2 cells and 7/16 class 3 cells) showed a decrease in mechanical threshold as a result of the noxious mechanical stimulus, but none of the class 3 cells' thresholds dropped below 20 mN into the low-threshold range. 7. The results obtained in the halothane-anesthetized and decerebrate-spinal animals were very similar to those seen in the barbiturate-anesthetized experiments, with the exception that in the decerebrate-spinal animals, the RFs of the class 2 cells were initially larger and showed only small increases.(ABSTRACT TRUNCATED AT 400 WORDS)

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