Stem cell mechanoadaptation and scaffolddesign optimization

Raphael MarkwalderMechBio Team, Graduate School of Biomedical Engineering UNSW

IntroductionWith the elderly population rising and athletes pushing their bodies towards lim-its that have never been explored yet, tissue failure occurs more often than ever.The soft tissue repair global market is expected to reach $21.3 billion by 2023 [1],whereas more than two million bone grafts are conducted every year worldwide[2]. In this context, tissue engineering offers great solutions of repair thanks toauto-, allo- and xeno-grafts. Nevertheless, these grafts face inherent drawbacksas shortage, low biocompatibility and potential for disease transmission. This re-search thus aims to optimize scaffold designs for engineered tissue with regards tostem cell mechanoadaptation.

Stem cell mechanoadaptationTo assess the stem cell adapting morphology, mesenchyme stem cells (MSCs) wereseeded following distinct protocols, at different densities that are low, high andvery high density, and on both normal dishes and ones coated with a suitable com-pliance substrate (polydimethylsiloxane PDMS) to account for mechanical forcesacting within the extracellular compartments of the cells in a more realistic way.The shape of both MSCs cytoplasm and nucleus were determined by normalizingthe ratio of their surface area and volume by an isovolumetric sphere.

Figure 1: Stem cell cytoplasm and nucleus morphologies with regards to seeding density and protocol.

Based on both the virtual power and dissipation principles, MSCs bulk mod-ulus evolution could be evaluated, assuming stem cells are homogeneous linearisotropic materials.

dKK = βoutK − βEK, where βEK =3

2(1

3I1)

2 and βoutK =γ

2

( pK

)n

Figure 2: Bulk modulus evolution with time for STD cellsseeded at VHD on normal dish. Cells are assumed to behomogeneous linear isotropic materials.

I1 and p = 3K0ε0 being respectivelythe first invariant of the strain tensorand the hydrostatic pressure computedthanks to linear elasticity theory. Theevolution seems to be consistent withbiophysical behavior as it converges to-wards a steady state. MSCs stiffnesseither increases or decreases dependingon the remodeling stimulus. Note thatthis was observable for MSCs seededon both substrates as well as cells mod-eled as viscoelastic material thanks toMaxwell model.

At a longer length scale, cellular movements resemble random particles in a fluid.Thus, the diffusion-convection governing equation can be applied to approximateMSCs behavior by which they migrate and proliferate on substrates such as tissueengineering scaffolds.

∂c

∂t− κ∇2c + α · ∇c = ψc

ψ = ψ(1− cc)− ν

c· |∇c|

Using adequate spatial and time discretization to solve the differential equation,the MSCs proliferation could be compared to measurements in culture well. Themigration process was also shown to differ when the MSCs are seeded on nor-mal or PDMS substrate and is taken into account in the model. Furthermore, therole of chemotaxis and durotaxis on probabilities of oriented migration might beimplemented thanks to a reaction term.

Figure 3: Measurements (left) and model (right) proliferation curves for C3H/10T1/2 multipotent progenitor cellsseeded on normal dish at LD, HD and VHD.

Figure 4: Stem cells migration pattern when seeded at LD under biharmonic functions on normal dish (left) and PDMScoated dish (right)

Scaffold design optimizationThe scaffold designs were inspired by ma-rine plants such as the Euplectella aspergillumOkeanos. By reproducing cubic features of differ-ent porosity in a linear pattern, they were build tomimic dimensions of a cranial defect tissue tem-plate from a previous study.

Figure 5: The scaffold consists in the as-sembly of same basic cubic features.

In order to drive stem cells towards the targeted phenotype, CFD and FE studieswere conducted to analyze scaffolds performance through permeability, wall shearstress and mechanical strength.

Figure 6: Fluid shear stress delivered to stem cells seeded on scaffold walls derived from CFD analysis (top) andstructure mechanical strength derived from FEM analysis (bottom).

ConclusionMSCs adaptation is eventually driven by energy costs minimization, whose pro-cess triggers specific phenotype. Thus, tissue engineering should benefit fromstem cell mechanoadaptation knowledge to optimize scaffold design according toits targeted in vivo application as well as to emulate native tissue environment andmechanical properties.

References[1] A.B. Jones and J.M. Smith. Soft tissue repair global market - forecast to 2023. 2017.

[2] Ian L Valerio John P Fisher Ruchi Mishra, Tyler Bishop and David Dean. The potential impactof bone tissue engineering in the clinic. Regenerative Medicine, 2016.

EPFL Supervisor: Prof. Dominique PiolettiUNSW Supervisor: Prof. Melissa Knothe Tate Master Thesis Acknowledgement: Dr. Vittorio Sansalone