A combined experimental and computational framework to evaluate the behavior of therapeutic cells for peripheral nerve regeneration

Abstract

Recent studies have explored the potential of tissue-mimetic scaffolds in encouraging nerve regeneration. One of the major determinants of the regenerative success of cellular nerve repair constructs (NRCs) is the local microenvironment, particularly native low oxygen conditions which can affect implanted cell survival and functional performance. In vivo, cells reside in a range of environmental conditions due to the spatial gradients of nutrient concentrations that are established. Here we evaluate in vitro the differences in cellular behavior that such conditions induce, including key biological features such as oxygen metabolism, glucose consumption, cell death, and vascular endothelial growth factor secretion.Experimental measurements are used to devise and parameterize a mathematical model that describes the behavior of the cells. The proposed model effectively describes the interactions between cells and their microenvironment and could in the future be extended, allowing researchers to compare the behavior of different therapeutic cells. Such a combinatorial approach could be used to accelerate the clinical translation of NRCs by identifying which critical design features should be optimized when fabricating engineered nerve repair conduits.

Mathematical modelling with Bayesian inference to quantitatively characterize therapeutic cell behaviour in nerve tissue engineering

“…The stabilized gel, on the other hand is composed of approximately 5-10% collagen [20], and between approximately 1:5% and 15% cells in volume (depending on the initial cell density) so that we expect the diffusion coefficient in the gel (D g ) to be smaller than in the media. We use Stokes-Einstein Law to obtain a first approximation of the diffusion coefficient, which falls reasonably close to the range of values reported in the literature for oxygen [13,51], glucose [13,52] and VEGF [13,53,54]. royalsocietypublishing.org/journal/rsif J. R. Soc.…”

“…To describe cell death, we follow the approach of Eleftheriadou et al . [13] and prescribeQ=C¯cell(δ0+δnormaloxCnormalox,1/2C¯ox+Cox,1/2+δnormalgluCnormalglu,1/2C¯glu+Cglu,1/2),where δ 0 is the baseline death rate and where δ ox and δ glu are coefficients for cell death in low oxygen and glucose concentrations environment, respectively.…”

“…Cell density in the gel was estimated after 24 h ( §2.1.4). Sections 2.1.1 to 2.1.4 focus on F7 cell experiments; the counterpart data for dADSC and CTX cells have already been published [8,13].…”

“…C glu Þ relate high proliferation rates to high oxygen and glucose concentrations without adding new parameters into the model. To describe cell death, we follow the approach of Eleftheriadou et al [13] and prescribe…”

“…One popular class of mathematical models used in tissue engineering are cell-solute models [8,[11][12][13]. Such models consist of a set of continuous, coupled and generally nonlinear, partial differential equations describing the interplay between nutrients, the cell population(s) and the cell secretome in a given tissue.…”