Buckling instability in tumor spheroids

P. Ciarletta1,2∗

1
CNRS and Institut Jean le Rond d’Alembert, UMR 7190,

Université Paris 6, 4 place Jussieu case 162,

75005 Paris, France

2
MOX - Politecnico di Milano and Fondazione CEN,

piazza Leonardo da Vinci 32, 20133 Milano, Italy

Abstract

A growing tumor is subjected to intrinsic physical forces, arising from the cellular

turnover in a spatially constrained environment. This work demonstrates that such

residual solid stresses can provoke a buckling instability in heterogeneous tumor

spheroids. The growth rate ratio between the outer shell of proliferative cells and

the inner necrotic core is the control parameter of this instability. The buckled

morphology is found to depend both on the elastic and the geometric properties

of the tumor components, suggesting a key role of residual stresses for promoting

tumor invasiveness.

Keywords: Elastic stability, Stroh formulation, spherical harmonics, solid tumor

∗
Corresponding author. E-mail: ciarletta@dalembert.upmc.fr

1
Supplementary Material

1 Linear stability analysis of a heterogeneous solid

tumor in buckling

1.1 Definition of the elastic model

Let me consider a spherical solid tumor initially made of an inner necrotic core and an
outer shell of proliferative shell, indicated with subscripts/superscripts c and s, respec-

tively, in the following. Using the spherical coordinate system, the spatial (resp. material)
position vector is indicated by x(r, θ, ϕ)(resp.X(R, Θ, Φ)), so that Ri ,Ro (resp. ri ,ro ) are

the inner and outer radii in the reference (resp. spatial) configuration, and F = ∂x/∂X

is the deformation gradient. Being Rc and Rs the radial coordinates in the reference

configuration, the inner and outer shell grow homogeneously and isotropically at growth

rates gc and gs , respectively, so that:

√
rc = gc Rc ; rs = 3 gs3 Rs3 − (gs3 − gc3 )Ri3 (1)

where the incompressibility constraint is taken into account.

In the following, let gc Ri be the unit length, so that g = gs /gc is the dimensionless

parameters representing the differential growth inside the tumor. Let both material be
neo-Hookean, and µc , µs indicate the shear moduli, the Cauchy stress tensors read:

(0) T
σ i = µi Fi F(0) i − pi I with i = (c, s) (2)

(0)
where Fi are the deformation gradients of the respective base solutions and pi are the
hydrostatic pressures arising from the incompressibility constraint.

2
The equilibrium equations div(σ i ) = 0 in spherical coordinates read:

(r2 (σ i )rr ),r − r((σ i )θθ + (σ i )ϕϕ ) = 0 (3)

Therefore, the inner core undergoes a homogeneous deformation with r = gc R for avoiding
singularities at the origin, and a biaxial stress state is given by:

σ c = (µc − pc )I (4)

On the outer shell the deformation is radially inhomogeneous (i.e. (rs /(gc Ri ))3 = g 3 (Rs /Ri )3 -

g 3 + 1) because of the spatial constraint on growth, so that:

(σ s )jj = µs λ2j − ps with j = (r, θ, ϕ) (5)

where the principal stretches read λr = gs−1 r,R and λθ = λϕ = gs−1 r/R. Using the previous

relation, the equilibrium equation for the stress reads:

( ∫ )
ro λ2ϕ − λ2r
ps = µs λ2r +2 dr (6)
r r

where we used the stress-free boundary condition (σ s )rr (ro ) = 0, with ro = rs (Ro ).

Moreover, imposing the continuity of the stress at the interface ri = (gc Ri ), we get:

pc = µc + ps − µs λ2r at r = ri (7)

The residual stress distribution inside the tumor rim is sketched in Figure 1. In particular,
if gs /gc > 1 a compressive tangential stress arise within the tumor, so it is worthwhile
investigating if a buckling instability may arise.

Therefore, once derived the governing equation determining the basic spherical solution
of the elastic problem we can now perform a linear stability analysis for detecting the loss

3
 Σrr ΣΘΘ
-0.96
0.25
-0.98
0.20 -1.00
0.15 -1.02
0.10 -1.04
0.05 -1.06
r r
1.02 1.04 1.06 1.08 1.10 1.12 1.02 1.04 1.06 1.08 1.10 1.12

Figure 1: Residual stress distribution in a tumor rim with Ro /Ri = 1.08, µc = µs , and
gs /gc = 1.2.

of spherical symmetry due to growth.

1.2 Incremental deformations and linear stability analysis

Let us consider an infinitesimal change of the deformation mapping from x = χ(X) to

′ ′
x = χ (X), defined as:
′
δx = δχ = χ (X) − χ(X) (8)

Neglecting displacement terms of order |δx|2 and higher, δx can be regarded as an in-

cremental deformation with respect to the configuration mapped by χ(X). Choosing to

express such incremental deformation as a function of the actual position x, from standard
vectorial algebra the deformation gradient F can be defined as follows:

′
dx dx d(δx) dx
F= = + = F(0) + δFF(0) (9)
dX dX dx dX

where a prismatic incremental deformation gradient δF in spherical coordinates reads:

 
uθ −v
 ur r
0 
 
δF = 
 vr
vθ +u
r
0 
 (10)
 
u+v cot θ
0 0 r

4
In the previous equation I set δχ = u(r, θ)er + v(r, θ)eθ , so that u, v are the displacement
fields along er and eθ , respectively. Therefore, I neglected the displacement field over
eϕ as it gives rise to decoupled incremental equations, thus not influencing the following
bifurcation analysis (Ben Amar and Goriely, 2005).
The incompressibility relation imposes the vanishing of the incremental volume δJ, which
is given at first order by:

vθ + u u + v cot θ
δJ = JδFF(0) : (F(0) )−1 = JδF : I = ur + + =0 (11)
r r

The incremental constitutive equation for the nominal stress tensor δS can be written
with respect to the actual configuration as follows:

δS = L : δF + pδF − δpI (12)

where δp is the incremental hydrostatic pressure, and L represents the fourth-order tensor

of instantaneous moduli, being the push-forward of the fixed reference elasticity tensor.
In absence of body forces, I can therefore postulate the equilibrium equation of the incre-

mental nominal stress δS referred to the actual configuration, as follows:

div(δS) = 0 (13)

while the incremental boundary conditions in presence of a generic traction T at a surface

∂Ωl , having unit normal n in the current configuration, can be written as:

δST n = TδFT n − δTn at ∂Ωl (14)

In the case of our problem, one must therefore introduce the four deformation fields (ui , vi )
with i = (c, s) and the nominal stress tensors δSi satisfying the bulk relations given by

5
eqs.(11, 13). The boundary conditions impose the continuity of the displacement and
stress fields at the interface, being:

u c = us ; vc = vs ; (δSTc − δSTs )er = 0 at r = ri (15)

while for avoiding singularities at the core center one must impose:

uc = v c = 0 at r = 0 (16)

Finally, eq.(14) at the free surface can be written as:

δST
s n = 0 at r = ro (17)

The incremental form of the linear stability analysis will be solved in the following using
a simplified representation, also know as the Stroh formulation of the problem.

1.3 Stroh formulation of the problem

In order to fulfill Eq.(11-13), one can develop the incremental deformation and defor-

mation fields using variable separation as a function of spherical harmonics (Norris and

Shuvalov, 2012). Without loss of generality one can therefore impose:

{ui (r, θ), (σi )rr (r, θ)} = {Ui (r), Σirr (r)}Pm (cos θ) (18)

{ }
Vi (r) Σirθ (r) dPm (cos θ)
{vi (r, θ), (σi )rθ (r, θ)} = √ ,√ (19)
m(m + 1) m(m + 1) dθ

where Pm indicates the Legendre polynomial of order m, fulfilling the following identity:

d2 Pm (cos θ) dPm (cos θ)

+ cot θ + m(m + 1)Pm (cos θ) = 0 (20)
dθ2 dθ

6
Taking into account Eqs.(12, 20), the increment δpi of the generic Lagrange multiplier pi
can be expressed by the constitutive equation for Σirr , as follows:

′
δpi (r, θ) = (−Σirr + (Lirrrr + pi )Ui )Pm (cos θ) (21)

where prime denotes differentiation over the function argument.

Setting the displacement-traction vector η i = [Ui , Vi , r2 Σirr , r2 Σirθ ]T , and using Eqs.(11,
12,13), the Stroh formulation of the stability problem reads:

 
′  N1 N2 
η = Nη =  η (22)
N3 −N1
T

where:
 √     
m(m+1)
 − 2r   0 0   δ1 δ2 
N1 =  √ r
; N2 =  ; N3 =   (23)
m(m+1)p
− rLirθrθ
p
rLirθrθ
0 1
r 2 Lirθrθ
δ2 δ3

and:
 ( )

 δ1 = 4Lirrrr + m(m + 1)Liθrθr + 2Liθθθθ + pi 6 − Lirθrθ m(m+1)pi


 √ p2 −2Lirrrr Lirθrθ −Lirθrθ (Liθrθr +Liθθθθ +3pi )
 δ2 = m(m + 1) · i


Lirθrθ

 δ3 = Liθrθr − Liθθθθ + m(1 + m)(Lirrrr + Liθθθθ ) + (−1 + 2m(1 + m))pi − p2i
Lirθrθ
(24)
Therefore one can solve the first-order differential equation system for the core nucleus
and the tumor proliferative shell with the boundary conditions given by Eqs.(15-17).

1.4 Exact solution for the inner core

In alternative to the Stroh formulation, the elastic problem can be transformed into a
forth-order differential equation with mixed boundary conditions. This can be done by

7
obtaining V (r), (r2 Σrr ), (r2 Σrθ ) from the first, the second and the forth of Eq.(22),
respectively. After these substitutions, the third of Eq.(22) can be rewritten as:

( ′
( ′′ ′′′ ′′′′
))
a0 (r)Ui + r a1 (r)Ui + r a2 (r)Ui + r(a3 (r)Ui + ra4 (r)Ui ) =0 (25)

with:

( ′ ′ )
a0 (r) = −(m2 + m − 2) (m2 + m − 1)Lθrθr + Lθθθθ + r(Lθrθr − Lθθθθ + rpi )
a1 (r) = 2m(m + 1)Lrrrr + 2Lθrθr + 2(m2 + m − 1)Lθθθθ
′ ′ ′ ′ ′′ ′ ′′
+r(m(m + 1)Lrrrr − 9Lrθrθ + Lθrθr + (m2 + m − 1)Lθθθθ − 3rLrθrθ + 3pi + rpi ))
a2 (r) = m(m + 1)Lrrrr − 12Lrθrθ + Lθrθr + (m2 + m + 1)Lθθθθ
′ ′ ′
+r(−11Lrθrθ − rLrθrθ + pi )
′
a3 (r) = −2(4Lrθrθ + rLrθrθ )

a4 (r) = −Lrθrθ
(26)
In particular, recalling the inner tumour core undergoes a homogeneous deformation

and using Eq.(7), the boundary value problem in Eq.(25) simplifies as:

( ′
( ′′ ′′′ ′′′′
))
−m(m+2)(m2 −1)Uc +r 4m(m + 1)Uc − r −2(m2 + m − 6)Uc + r(8Uc + rUc ) = 0

(27)
Avoiding singular displacements at r = 0, the solution of Eq.(27) is given by:

Uc (r) = C1 rm+1 + C2 rm−1

C1 (3+m)r m+1 +C2 (1+m)rm−1
Vc (r) = √
m(m+1)
(28)
pc (C1 (m2 −3)r m +C2 (−1+m2 )rm−2 )+(m+1)µc ((m−1)C2 rm−2 +(m+3)C1 r m )
2
r Σcrt (r) = √
m(m+1)
pc m(C1 (m+1)r m +C 2 (m−1)r
m−2 )+µ (C (−6−3m+m2 )r m +m(m−1)C r m−2 )
r2 Σcrr (r) = c
m
1 2

where C1 and C2 are arbitrary constant parameters, and assuming m ≥ 2.

8
2 Results

2.1 Numerical solution using the determinant method

The boundary value problem for the growing shells, expressed by Eq.(22) in the Stroh
formulation, can be solved using the determinant method.
In practice, let me consider two independents sets (C1a , C2a ) and (C1b , C2b ) to be intro-
duced as arbitrary values (C1 , C2 ) in the solution of the inner core. Accordingly, from
Eq.(28) two independent sets η 0a and η 0b of boundary conditions can be derived at r = Rc .
Therefore, the solution η s for the proliferative tumor shell can be expressed as:

η s = βa η sa + βb η sb (29)

where βa , βb are arbitrary constants, and η sa , η sb are the numerical solution obtained

using the initial conditions given by η 0a and η 0b , respectively. In this way, the boundary

conditions given by Eqs.(15,16) are identically satisfied.

Finally, one must impose that the solution in Eq. (29) satisfies the other boundary

conditions in Eq. (17) at r = ri , which rewrites:

 
 (s0rr (ro ))a (s0rθ (ro ))a 
f (gr ) = det  =0 at r = ro (30)
(s0rr (ro ))b (s0rθ (ro ))b

where (s0jl )k = rs2 (Σsk )jl , j, l = r, θ, k = {a, b}, with (Σsk )jl being the incremental stresses
numerically calculated at r = ri from η sk , using the initial value η 0k ar r = ri . Thus, the
bifurcation threshold g(H, m) can be calculated with the help of few cycles of iteration:
first iterations on the aspect ratio H = R0 /Ri and the wavenumber m, and then iteration
on the bifurcation parameter g until the stop condition f (g) = 0 in Eq. (30) is reached.
In Figure 2, the instability thresholds found with this numerical procedure are shown for
µs /µc = 10 versus the aspect ratio 1 < Ro /Ri ≤ 2, as for higher H the procedure can run

9
into numerical stiffness.
gs
m
gc
1.5
15
1.4
1.3 10
1.2
5
1.1
RoRi RoRi
1.0 1.2 1.4 1.6 1.8 2.0 1.0 1.2 1.4 1.6 1.8 2.0

Figure 2: Marginal stability curves for gs /gc (left, thick line) and m (right) versus the
aspect ratio Ro /Ri , calculated for µs /µc = 10. The thin solid lines represent the critical
thresholds gs /gc for different values of the wavenumber m = 2, .., 20.

Using this simple numerical scheme, the threshold growth rate value can be calculated
as a function of H and m, but no information about the deformed shape of the growing

tumor and the distribution of incremental stresses is obtained. For doing so, a more robust

numerical procedure can be implemented after transformation of the Stroh formulation

of the problem.

2.2 Numerical solution using the conditional impedance matrix

First, let me define us = [Us (r), Vs (r)]T and Σs = [Σsrr (r), Σsrθ (r)]T as the displacement
and traction vectors, respectively, such that:

η s = [us , r2 Σs ]T (31)

According to Shuvalov (2003), the elastic solution can be expressed as follows:

 
 M1 (r, ro ) M2 (r, ro ) 
η s (r) = M(r, ro )η s (ro ) =   η s (ro ) (32)
M3 (r, ro ) M4 (r, ro )

10
where M(r, ro ) is the conditional matrix, such that M(ro , ro ) is equal to the identity
matrix. Accordingly, it is possible to define a functional relation between the traction
and the displacements vectors, reading:

r2 Σs = Zs us (33)

where Zs = M3 (r, ro )M−1 s

1 (r, ro ) = Z (r, ro ) is the impedance matrix, whose expression

is therefore conditional to the boundary condition Σs (ro ) = 0. Substituting Eq.(33) in

Eq.(22) for eliminating the dependence on us , the equation system can be transformed as
a Riccati differential equation for Zs , being:

d s
Z = N3 − NT1 Zs − Zs N1 − Zs N2 Zs , with Zs (rs ) = 0 (34)
dr

As highlighted by Destrade et al. (2009), Zs is real since N2 , N3 are both hermitian

matrices. Using the exact solution for the inner core in Eq.(28) and expressing it as

r2 Σc = Zin uc , the inner impedance matrix Zin at r = ri reads:

 √ 
−2mpc +(3+m(3+2m))µc m(1+m)(mpc −(3+m)µc )
 
Zin =  √
mri mri
m(1+m)(mpc −(3+m)µc )
 (35)
−pc +2(1+m)µc
mri ri

Furthermore, the boundary conditions in Eq.(15), imposing uc = us and Σc = Σs at

r = ri , can be written as:

det(Zs − Zin ) = 0 at r = ri (36)

Therefore, the incremental elastic problem can be solved by numerically integrating the
impedance matrix Zs in Eq.34 using the stop condition given by Eq.(36) for deriving the
threshold value g(H, m). The variability of the buckling thresholds with the shear moduli
ratio µs /µc is depicted in Figure 3

11
 15

m
10

0.5 1.0 5.0 10.0 50.0 100.0

Μs
Μc

Figure 3: Logarithmic plots of the marginal stability curves for gs /gc (left) and m (right)
versus the shear moduli ratio µs /µc . The solid lines represent the instability thresholds
for Ro /Ri = 1.05(blue), 1, 5(purple), 2(yellow), 3(green).

In this way, the ratio between the radial and the tangential displacements at r = ri is
given by:
Uc (ri ) Z s (Rc ) − Z12
in s
Z22 (Rc ) − Z22
in
= − 12 = − (37)
Vc (ri ) s
Z11 (Rc ) − Z11
in s
Z21 (Rc ) − Z21
in

In order to avoid numerical stiffness problems, the overall displacement and stress fields
can be calculated by a successive numerical integration of the conditional impedance ma-

trix Zc based on the boundary conditions at r = ri . Transforming the Stroh formulation

in Eq.(22) using the conditional relation (r2 Σs ) = Zsc us with Zsc = Zsc (r, ri ), the full so-

lution is given by simultaneous integration at the given threshold g(H, m) of the following

equations:

d sc
Z = N3 − NT1 Zsc − Zsc N1 − Zsc N2 Zsc , with Zsc (ri ) = Zs (ri ) (38)
dr

[ ]T
d s Zs12 (Rc ) − Zin
u = N1 us + N2 Zsc us , with u (rc ) = −ϵ s
s 12
,ϵ (39)
dr Z11 (rc ) − Zin
11

where ϵ is the small amplitude of the inner tangential displacement, which cannot be fixed
s s
by the linear stability analysis, and Z11 (ri ), Z12 (ri ) are the numerical values obtained at
ri by the previous integration on Zs . The initial conditions of Eqs.(38, 39) are imposed

12
taking into account the boundary condition at ri using Eq.(15, 37). An example of the
tumor displacement fields calculated at instability threshold is shown in Figure (4).

U V
r
0.5 1.0 1.5 2.0 2.5 3.0 r
0.5 1.0 1.5 2.0 2.5 3.0
-0.02
-0.01
-0.04
-0.02
-0.06
-0.03
-0.08

Figure 4: Radial and tangential displacement at instability threshold calculated in a tumor

rim with Ro /Ri = 2, µc = µs , m = 10 and gs /gc = 1.6789.

2.3 WKB approximation of the elastic solution for the outer

shell

In order to validate the numerical results, it is useful to obtain an analytical approximation

of the elastic solution for the outer shell. Using Eqs.(1,6) in Eq.(25), and recalling that
for a neo-Hookean material Lijkl = δjl Fiα Fkα , the coefficients of the forth-order ordinary

differential equations for Us simplify as:

a0 (r) = −(m2 + m − 2) (10a3 − 14a2 r3 + am(1 + m)r6 − m(1 + m)r9 )

a1 (r) = 2 (a3 (10 + m + m2 ) − a2 (14 + m + m2 )r3 − 3a(−2 + m + m2 )r6 + 2m(1 + m)r9 )

a2 (r) = (r3 − a) (a2 (10 + m + m2 ) − 2a(2 + m + m2 )r3 + 2(−6 + m + m2 )r6 )
a3 (r) = −8(r3 − a)2 r3
a4 (r) = −(r3 − a)3
(40)

with a = −(g 3 −1)(ri )3 . In particular, one can notice that if m ≫ 1 than the coefficients a3
and a4 are much smaller than the others, which is the typical differential equation structure
where a boundary layer occurs. In this case, one can look for a WKB approximation of

13
Eq.(25), having the following expression:

∫ S0(s)
Uswkb (r) = e r ( m +S1(s))ds (41)

where S0 and S1 are generic approximating functions. Substituting Eq.(41) into Eqs.(25,
40), the boundary value problem is transformed into a couple of polynomial equations
at the first two orders in 1/m, for m → ∞. The solution of such equations gives four
combinations of S0 and S1 as follows:

1 3r6 − 4ar3 + 2a3

S0(r) = ; S1(r) = (42)
r r(2r6 − 3ar2 + a2 )

1 r6 − ar3 + a3
S0(r) = − ; S1(r) = (43)
r r(2r6 − 3ar2 + a2 )

r2 3r5
S0(r) = ; S1(r) = (44)
r3 − a r(2r6 − 3ar2 + a2 )

r2 r2 (r3 + a)
S0(r) = − ; S1(r) = (45)
r3 − a r(2r6 − 3ar2 + a2 )

so that the WKB approximation from Eq.(41) rewrites:

1 1 m m
rm+2 (r3 − a) 3 r1−m (r3 − a) 3 (r3 − a)1− 3 (r3 − a)1+ 3
Uswkb (r) = D1 · √ + D2 · √ + D3 · √ + D4 · √
2r3 − a 2r3 − a 2r3 − a 2r3 − a
(46)

where D1 , D2 , D3 , D4 are arbitrary constant parameters.

Using the WKB approximation and the inner core solution, one has 6 parameters, which
can be collected in a vector b = [C1 , C2 , D1 , D2 , D3 , D4 ]T . The 6 boundary conditions
can be written as H · b, so that the numerical thresholds g can be found by solving
det H = 0 at given m. As shown in Figure (5), the growth threshold calculated with the
WKB approximation works very well for a short wavelength instability (high values of
m).Finally, a comparison of the tumor morphology at instability threshold is shown in
Figure (6).

14
 gs
gc
1.7

1.6

1.5

1.4

1.3
Ro
1.0 1.2 1.4 1.6 1.8 2.0 Ri

Figure 5: Numerical solutions (solid lines) and WKB approximation (dashed lines) of the
growth instability versus the aspect ratio Ro /Ri for a tumor rim with µc = µs . The curves
are calculated for m = 10(blue) and m = 20(red).

U V
r
1.5 2.0 2.5 3.0 r
-0.02 1.5 2.0 2.5 3.0
-0.01
-0.04
-0.02
-0.06
-0.03
-0.08
Figure 6: Comparison of the radial and tangential displacements obtained with the nu-
merical method (solid lines) and the WKB approximation (dashed lines) at the instability
threshold calculated in a tumor rim with Ro /Ri = 2, µc = µs , m = 10 and gs /gc = 1.6789.

Acknowledgements

Partial funding by the European Community grant ERG-256605, FP7 program, and by
the NSF grant PHY05-51164 are gratefully acknowledged.

References

Ben Amar, M., Goriely, A., 2005. Growth and instability in elastic tissues. J. Mech. Phys.
Solids 53, 2284-2319.

15
Destrade, M., Ní Annadih, A, Coman, C.D., 2009. Beding instabilities of soft biological
tissues. Int, J. Solids Struct. 46, 4322-4330.

Norris, A.N., Shuvalov, A.L., 2012. Elastodynamics of radially inhomogeneous spherically

anisotropic elastic materials in the Stroh formalism. Proc. R. Soc. A 468, 467-484.

Shuvalov, A.L., 2003. A sextic formalism for the three-dimensional elastodynamics of

cylindrically anisotropic radially inhomogeneous materials. Proc. Roy. Soc. Lond. A

459, 1611-1639.

16