Effect of in vivo flow dynamics on angiogenesis by computational modeling

Author(s):  
Siavash Ghaffari ◽  
Richard L. Leask ◽  
Elizabeth A.V. Jones
Micromachines ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 386
Author(s):  
Ana Santos ◽  
Yongjun Jang ◽  
Inwoo Son ◽  
Jongseong Kim ◽  
Yongdoo Park

Cardiac tissue engineering aims to generate in vivo-like functional tissue for the study of cardiac development, homeostasis, and regeneration. Since the heart is composed of various types of cells and extracellular matrix with a specific microenvironment, the fabrication of cardiac tissue in vitro requires integrating technologies of cardiac cells, biomaterials, fabrication, and computational modeling to model the complexity of heart tissue. Here, we review the recent progress of engineering techniques from simple to complex for fabricating matured cardiac tissue in vitro. Advancements in cardiomyocytes, extracellular matrix, geometry, and computational modeling will be discussed based on a technology perspective and their use for preparation of functional cardiac tissue. Since the heart is a very complex system at multiscale levels, an understanding of each technique and their interactions would be highly beneficial to the development of a fully functional heart in cardiac tissue engineering.


1997 ◽  
Vol 272 (5) ◽  
pp. H2107-H2114 ◽  
Author(s):  
D. C. Poole ◽  
T. I. Musch ◽  
C. A. Kindig

As muscles are stretched, blood flow and oxygen delivery are compromised, and consequently muscle function is impaired. We tested the hypothesis that the structural microvascular sequellae associated with muscle extension in vivo would impair capillary red blood cell hemodynamics. We developed an intravital spinotrapezius preparation that facilitated direct on-line measurement and alteration of sarcomere length simultaneously with determination of capillary geometry and red blood cell flow dynamics. The range of spinotrapezius sarcomere lengths achievable in vivo was 2.17 +/- 0.05 to 3.13 +/- 0.11 microns. Capillary tortuosity decreased systematically with increases of sarcomere length up to 2.6 microns, at which point most capillaries appeared to be highly oriented along the fiber longitudinal axis. Further increases in sarcomere length above this value reduced mean capillary diameter from 5.61 +/- 0.03 microns at 2.4-2.6 microns sarcomere length to 4.12 +/- 0.05 microns at 3.2-3.4 microns sarcomere length. Over the range of physiological sarcomere lengths, bulk blood flow (radioactive microspheres) decreased approximately 40% from 24.3 +/- 7.5 to 14.5 +/- 4.6 ml.100 g-1.min-1. The proportion of continuously perfused capillaries, i.e., those with continuous flow throughout the 60-s observation period, decreased from 95.9 +/- 0.6% at the shortest sarcomere lengths to 56.5 +/- 0.7% at the longest sarcomere lengths and was correlated significantly with the reduced capillary diameter (r = 0.711, P < 0.01; n = 18). We conclude that alterations in capillary geometry and luminal diameter consequent to increased muscle sarcomere length are associated with a reduction in mean capillary red blood cell velocity and a greater proportion of capillaries in which red blood cell flow is stopped or intermittent. Thus not only does muscle stretching reduce bulk blood (and oxygen) delivery, it also alters capillary red blood cell flow dynamics, which may further impair blood-tissue oxygen exchange.


1995 ◽  
Vol 74 (3) ◽  
pp. 1222-1243 ◽  
Author(s):  
P. Mukherjee ◽  
E. Kaplan

1. We investigated the time domain transformation that thalamocortical relay cells of the cat lateral geniculate nucleus (LGN) perform on their retinal input, and used computational modeling to explore the biophysical properties that determine the dynamics of the LGN relay cells in vivo. 2. We recorded simultaneously the input (S potentials) and output (action potentials) of 50 cat LGN relay cells stimulated by drifting sinusoidal gratings of varying temporal frequency. The temporal modulation transfer functions (TMTFs) of the neurons were derived from these data. The burstiness of the LGN spike trains was also assessed using objective criteria. 3. We found that the form of the TMTF was quite variable among cells, ranging from low-pass to strongly band-pass. The optimal temporal frequency of band-pass neurons was between 2 and 8 Hz. In addition, the TMTF of some cells was nonstationary: their temporal tuning changed with time. 4. The temporal tuning of a cell was directly related to the degree of burstiness of its spike train. Tonically firing relay cells had low-pass TMTFs, whereas the most bursty neurons exhibited the most sharply band-pass transfer functions. This was also true for single cells that altered their temporal tuning: a shift to more band-pass tuning was associated with increased burstiness of the spike train, and vice versa. 5. We constructed a computer simulation of the LGN relay cell. The model was a simplified five-channel version of the thalamocortical neuron model of McCormick and Huguenard. It incorporated the quantitative kinetics of the Ca2+ T channel, as well as the Hodgkin-Huxley Na+ and K+ channels, as the only active membrane currents. To simulate the in vivo dynamics of the relay cell, the input to the model consisted of trains of synaptic potentials, recorded as S potentials in our physiological experiments. 6. When the resting membrane potential of the model neuron was relatively depolarized, the model's TMTF was low-pass, with no bursting evident in the simulated spike train. At hyperpolarized resting membrane potentials, however, the modeled TMTF was band-pass, with frequent burst discharges. Thus the biophysical model reproduced not only the range of dynamics seen in real LGN relay cells, but also the dependence of the overall dynamics on the burstiness of the spike train. However, neither of these phenomena could be simulated without the T channel. Thus the simulations demonstrated that the T-type Ca2+ channel was necessary and sufficient to explain the LGN dynamics observed in physiological experiments.(ABSTRACT TRUNCATED AT 400 WORDS)


2018 ◽  
Vol 81 (4) ◽  
pp. 2759-2773 ◽  
Author(s):  
Jan N. Rose ◽  
Sonia Nielles‐Vallespin ◽  
Pedro F. Ferreira ◽  
David N. Firmin ◽  
Andrew D. Scott ◽  
...  

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Kirti Kandhwal Chahal ◽  
Jie Li ◽  
Irina Kufareva ◽  
Donald Durden ◽  
Robert Wechsler Reya ◽  
...  

Abstract INTRODUCTION Dysregulation of the 7-transmembrane receptors Smoothened (SMO) and other components of the Hedgehog (Hh) signaling pathway causes several cancers, including medulloblastoma (MB) and glioblastoma. However, SMO-specific antagonists produced mixed results in clinical trials, marked by a limited efficacy and a high rate of acquired resistance in tumors. METHODS Computational modeling of protein docking sites, analytical configuration modeling of crystallographic data, and in Vitro and in Vivo xenograft experiments. RESULTS Using computational modeling of SMO structure, we discovered that Nilotinib, an FDA-approved receptor tyrosine kinase inhibitor, directly binds to SMO. Furthermore, Nilotinib was more efficacious than the SMO-specific antagonist Vismodegib in inhibiting cell growth and Gli-1 mRNA and protein levels in Hh-dependent MB cells and glioblastoma cells. It also reduced tumor growth in the Hh-dependent MB and glioblastoma mouse xenograft models. These results indicate that in addition to its ability to inhibit several tyrosine kinase-mediated proliferative pathways, Nilotinib is active against the Hh pathway. CONCLUSION The newly discovered extension of Nilotinib target profile holds promise for the treatment of Hh-dependent cancers. It also calls for comprehensive characterization of pharmacology for other drugs and incorporation of their multitarget profiles into drug-disease matching criteria for personalized medicine.


Circulation ◽  
1998 ◽  
Vol 98 (25) ◽  
pp. 2873-2882 ◽  
Author(s):  
Eliezer Be’eri ◽  
Stephan E. Maier ◽  
Michael J. Landzberg ◽  
Taylor Chung ◽  
Tal Geva

2015 ◽  
Vol 242 ◽  
pp. 97-105 ◽  
Author(s):  
David E. Cepeda ◽  
Leah Hains ◽  
David Li ◽  
Joseph Bull ◽  
Stephen I. Lentz ◽  
...  

2013 ◽  
Vol 46 (2) ◽  
pp. 266-275 ◽  
Author(s):  
Marvin J. Slepian ◽  
Yared Alemu ◽  
João Silva Soares ◽  
Richard G. Smith ◽  
Shmuel Einav ◽  
...  

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