Incompressible limit of a mechanical model for tissue growth with non-overlapping constraint. *
Sophie Hecht, Nicolas Vauchelet (LAGA)

TL;DR
This paper proves that a tissue growth model with a non-overlapping constraint converges to a Hele-Shaw free boundary problem in the incompressible limit, despite using a singular pressure law.
Contribution
It introduces a non-overlapping constraint into a tissue growth model and shows convergence to the Hele-Shaw problem even with a singular pressure law.
Findings
The model converges to the Hele-Shaw free boundary problem.
The non-overlapping constraint is preserved in the limit.
Singular pressure laws can enforce non-overlapping constraints.
Abstract
A mathematical model for tissue growth is considered. This model describes the dynamics of the density of cells due to pressure forces and proliferation. It is known that such cell population model converges at the incompressible limit towards a Hele-Shaw type free boundary problem. The novelty of this work is to impose a non-overlapping constraint. This constraint is important to be satisfied in many applications. One way to guarantee this non-overlapping constraint is to choose a singular pressure law. The aim of this paper is to prove that, although the pressure law has a singularity, the incompressible limit leads to the same Hele-Shaw free boundary problem.
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Taxonomy
TopicsMathematical Biology Tumor Growth · Navier-Stokes equation solutions · Thermoelastic and Magnetoelastic Phenomena
Incompressible limit of a mechanical model for tissue growth with non-overlapping constraint.
111S.H. acknowledges support from the Imperial/Crick PhD program. N.V. acknowledges partial support from the ANR blanche project Kibord No ANR-13-BS01-0004 funded by the French Ministry of Research. Part of this work has been done while N.V. was a CNRS fellow at Imperial College, he is really grateful to the CNRS and to Imperial College for the opportunity of this visit. The authors would like to express their sincere gratitude to Pierre Degond for his help and its suggestions during this work.
Sophie Hecht Francis Crick Institute, 1 Midland Rd, Kings Cross, London NW1 1AT, UK - Imperial College London, South Kensington Campus London SW7 2AZ, UK email([email protected])
Nicolas Vauchelet LAGA - UMR 7539, Institut Galilée, Université Paris 13, 99 avenue Jean-Baptiste Clément, 93430 Villetaneuse - France, email([email protected])
Abstract
A mathematical model for tissue growth is considered. This model describes the dynamics of the density of cells due to pressure forces and proliferation. It is known that such cell population model converges at the incompressible limit towards a Hele-Shaw type free boundary problem. The novelty of this work is to impose a non-overlapping constraint. This constraint is important to be satisfied in many applications. One way to guarantee this non-overlapping constraint is to choose a singular pressure law. The aim of this paper is to prove that, although the pressure law has a singularity, the incompressible limit leads to the same Hele-Shaw free boundary problem.
Keywords: Nonlinear parabolic equation; Incompressible limit; Free boundary problem; Tissue growth modelling.
AMS Subject Classification: 35K55; 76D27; 92C50.
1 Introduction
Mathematical models are now commonly used in the study of growth of cell tissue. For instance, a wide literature is now available on the study of the tumor growth through mathematical modeling and numerical simulations [2, 3, 14, 18]. In such models, we may distinguish two kinds of description: Either they describe the dynamics of cell population density (see e.g. [6, 8]), or they consider the geometric motion of the tissue through a free boundary problem of Hele-Shaw type (see e.g. [16, 15, 11, 18]). Recently the link between both descriptions has been investigated from a mathematical point of view thanks to an incompressible limit [22].
In this paper, we depart from the simplest cell population model as proposed in [7]. In this model the dynamics of the cell density is driven by pressure forces and cell multiplication. More precisely, let us denote by the cell density depending on time and position , and by the mechanical pressure. The mechanical pressure depends only on the cell density and is given by a state law . Cell proliferation is modelled by a pressure-limited growth function denoted . Mechanical pressure generates cells displacement with a velocity whose field is computed thanks to the Darcy’s law. After normalizing all coefficients, the model reads
[TABLE]
The choice has been taken in [22, 23, 24]. This choice allows to recover the well-known porous medium equation for which a lot of nice mathematical properties are now well-established (see e.g. [26]). The incompressible limit is then obtained by letting going to .
However, this state law does not prevent cells to overlap. In fact, it is not possible with this choice to avoid the cell density to take value above (which corresponds here to the maximal packing density after normalization). A convenient way to avoid cells overlapping is to consider a pressure law which becomes singular when the cell density approaches . Such type of singularity is encountered, for instance, in the kinetic theory of dense gases where the interaction between molecules is strongly repulsive at very short distance [9]. Similar singular pressure laws have been also considered in [12, 13] to model collective motion, in [4, 5] to model the traffic flow, and in [21] to model crowd motion (see also the review article [19]). Then, in order to fit this non-overlapping constraint, we consider the following simple model of pressure law given by
[TABLE]
Finally, the model under study in this paper reads, for ,
[TABLE]
This system is complemented by an initial data denoted . The aim of this paper is to investigate the incompressible limit of this model, which consists in letting going to [math] in the latter system.
At this stage, it is of great importance to observe that from (1.1), we may deduce an equation for the pressure by simply multiplying (1.1) by and using the relation from (1.2),
[TABLE]
Formally, we deduce from (1.3) that when , we expect to have the relation
[TABLE]
Moreover, passing formally to the limit into (1.2), it appears clearly that . We deduce from this relation that if we introduce the set , then we obtain a free boundary problem of Hele-Shaw type: On , we have and , whereas on . Thus although the pressure law is different, we expect to recover the same free boundary Hele-Shaw model as in [22].
The incompressible limit of the above cell mechanical model for tumor growth with a pressure law given by has been investigated in [22] and in [23] when taking into account active motion of cells. In [24], the case with viscosity, where the Darcy’s law is replaced by the Brinkman’s law, is studied. We mention also the recent works [17, 20] where the incompressible limit with more general assumptions on the initial data has been investigated. However, in all these mentionned works the pressure law do not prevent the non-overlapping of cells. Up to our knowledge, this work is the first attempt to extend the previous result with this constraint, i.e. with a singular pressure law as given by (1.2).
The outline of the paper is the following. In the next section we give the statement of the main result in Theorem 2.1, which is the convergence when goes to [math] of the mechanical model (1.1)–(1.2) towards the Hele-Shaw free boundary system. The rest of the paper is devoted to the proof of this result. First, in section 3 we establish some a priori estimate allowing to obtain space compactness. Then, section 4 is devoted to the study of the time compactness. Thanks to compactness results, we can pass to the limit in system (1.1)–(1.2) in section 5, up to the extraction of a subsequence. Finally the proof of the complementary relation (1.4) is performed in section 6.
2 Main result
The aim of this paper is to establish the incompressible limit of the cell mechanical model with non-overlapping constraint (1.1)–(1.2). Before stating our main result, we list the set of assumptions that we use on the growth fonction and on the initial data. For the growth function, we assume
[TABLE]
The quantity , for which the growth stops, is commonly called the homeostatic pressure [25]. This set of assumptions on the growth function is quite similar to the one in [22], except for the bound on the growth term which is needed here due to the singularity in the pressure law.
For the initial data, we assume that there exists such that for all ,
[TABLE]
Notice that this set of assumptions imply that is uniformly bounded in .
We are now in position to state our main result.
Theorem 2.1
Let , . Let and satisfy assumptions (2.5) and (2.6) respectively. After extraction of subsequences, both the density and the pressure converge strongly in as to the limit and , which satisfy
[TABLE]
and
[TABLE]
Moreover, we have the relation
[TABLE]
and the complementary relation
[TABLE]
This result extends the one in [22] to singular pressure laws with non-overlapping constraint. We notice that we recover the same limit model whose uniqueness has already been stated in [22, Theorem 2.4].
Although our proof follows the idea in [22], several technical difficulties must be overcome due to the singularity of the pressure law. Indeed, we first recall that with the choice , equation (1.1) may be rewritten as the porous medium equation . A lot of estimates are known and well established for this equation (see [26]), in particular a semiconvexity estimate is used in [22] which allows to obtain estimate on the time derivative and thus compactness. With our choice of pressure law, (1.1) should be consider as a fast diffusion equation. Thus we have first to state a comparison principle to obtain a priori estimates (see Lemma 3.2). Unlike in [22], we may not use a semiconvexity estimate to obtain estimate on the time derivative. To do so, we use regularizing effects (see section 4). Then the convergence proof has to be adapted for these new estimates.
Finally, we illustrate the comparison between the two pressure laws and by a numerical simulation. We display in Figure 1 the density computed thanks to a discretization with an upwind scheme of (1.1). In Figure 1-left, the pressure law is as in (1.2) with . In Figure 1-right, the pressure law is with . We take as growth function (which satisfies obviously assumption (2.5) with ). The dashed lines in these plots correspond to the constant value . As expected, we observe that the density is bounded by in the case of the pressure law whereas it takes values greater than for the pressure law . This observation illustrates the fact that the choice of the pressure law does not prevent from overlapping.
3 A priori estimates
3.1 Nonnegativity principle
The following Lemma establishes the nonnegativity of the density.
Lemma 3.1
Let be a solution to (1.1) such that and . Then, for all , .
Proof.
We have the equation
[TABLE]
We use the Stampaccchia method. We multiply by , then using the notation for the negative part, we get
[TABLE]
We integrate in space, using assumption (2.5), we deduce
[TABLE]
So, after a time integration
[TABLE]
With the initial condition , we deduce . ∎
3.2 A priori estimates
In order to use compactness results, we need first to find a priori estimates on the pressure and the density. We first observe that we may rewrite system (1.1) as, by using (1.2),
[TABLE]
with .
Lemma 3.2
Let us assume that (2.5) and (2.6) hold. Let be a solution to (3.12)–(1.2). Then, for all , we have the uniform bounds in ,
[TABLE]
More generally, we have the comparison principle: If , are respectively subsolution and supersolution to (3.12), with initial data , as in (2.6) and satisfying . Then for all , .
Finally, we have that is uniformly bounded in and is uniformly bounded in .
Proof.
Comparison principle.
Let be a subsolution and a supersolution of (3.12), we have
[TABLE]
Notice that, since the function is nondecreasing, the sign of is the same as the sign of . Moreover,
[TABLE]
so for and is the positive part, the so-called Kato inequality reads . Thus multiplying the latter equation by , we obtain
[TABLE]
From assumption (2.5), we have that is nonincreasing. Thus, since is increasing, we deduce that the last term of the right hand side is nonpositive. Since is uniformly bounded we obtain
[TABLE]
After an integration over ,
[TABLE]
Then, integrating in time, we deduce
[TABLE]
Since we have , we deduce that for all , .
** bounds.**
We define , such that , then applying the comparison principle with , we deduce, using also the assumption on the initial data (2.6) that for all , Moreover, since [math] is clearly a subsolution to (3.12), we also have by the comparison priniciple . Since , we have which implies
[TABLE]
** bound of .**
By nonnegativity, after a simple integration in space of equation (1.1), we deduce
[TABLE]
where we use (2.5). Integrating in time give the bound,
[TABLE]
Then, using by (1.2), we get from the bound , which has been proved above,
[TABLE]
Estimates on the derivative.
We derive equation (3.12) with respect to for ,
[TABLE]
Multiplying by sign, we get
[TABLE]
We can remark that , so, by the same token as above, we have
[TABLE]
Moreover, , thus . By assumption (2.5), we know that
[TABLE]
we deduce
[TABLE]
After an integration in time and space,
[TABLE]
This latter inequality provides us with a uniform bound on the space derivative of in . Then
[TABLE]
We split the integral in two: Either and then ; or .
[TABLE]
where we have used the estimate (3.14) for the last inequality. Then, integrating in time, we deduce, using again the estimate (3.14)
[TABLE]
It concludes the proof. ∎
3.3 Compact support
The following Lemma proves that assuming that the initial data is compactly supported, then the pressure is compactly supported for any time with a control of the growth of the support.
Lemma 3.3** **(Finite speed of propagation)
Under the same assumptions as in Theorem 2.1, we have that with , where is the ball of center [math] and radius .
Proof.
Using the equation on (1.3),
[TABLE]
Let us introduce for ,
[TABLE]
with . Then is compactly supported in with We have
[TABLE]
and
[TABLE]
Then, for all ,
[TABLE]
In other words, is a supersolution for the equation for the pressure. Let us show that it implies that . We define . We know that
[TABLE]
Then, on the one hand, multiplying (3.15) with by we get
[TABLE]
On the other hand, from (1.1),
[TABLE]
By the comparison principle (see Lemma 3.2), we have
[TABLE]
Thus, for all ,
[TABLE]
and is compactly supported in provided we choose large enough such that , which can be done thanks to our assumption on the initial data (2.6).
Since is uniformly bounded in , we may iterate the process on . After several iterations, we reach the time and prove the result on . ∎
3.4 estimate for
In the following Lemma, we state a uniform estimate on the gradient of the pressure.
Lemma 3.4** **( estimate for )
Under the same assumptions as in Theorem 2.1, we have a uniform bound on in .
Proof.
For a given function we have, multiplying (1.1) by ,
[TABLE]
Let be an antiderivative of , we have thanks to an integration by parts
[TABLE]
We choose such as , i.e. . After straightforward computations, we find and . It gives
[TABLE]
We integrate in time, using also the expression of in (1.2),
[TABLE]
Then, to have a bound on the -norm of , it suffices to prove a uniform control on . We have
[TABLE]
The second term of the right hand side is small when is small thanks to the bound on , thus it is uniformly bounded. Using the expression of in (1.2), we get
[TABLE]
Then, since and since is uniformly bounded on , we get
[TABLE]
We conclude thanks to Lemma 3.3, which provides a uniform control on the support of . ∎
4 Regularizing effect and time compactness
As already noticed in [23], regularizing effects, similar to the ones observed for the heat equation [1, 10], allow to deduce estimates on the time derivatives.
Lemma 4.1
Under the assumptions (2.5) and (2.6), the weak solution satisfies the estimates
[TABLE]
for a large enough (independent of ) constant .
Proof.
Let us denote , the equation on the pressure (1.3) reads
[TABLE]
The proof is divided into several steps. We first find a lower bound for by using the comparison principle. Then we deduce estimates on the density and on the pressure.
1st step. Thanks to (4.16), we deduce an equation satisfied by . On the one hand, by multiplying (4.16) by , we deduce, since is decreasing from (2.5)
[TABLE]
On the other hand, we have
[TABLE]
Thus, with (4.17), we deduce that satisfies
[TABLE]
By definition of , we have . Thus we deduce that
[TABLE]
where we have used the notation
[TABLE]
Following an idea of [10] which has been generalized in [23], we introduce the function
[TABLE]
where the function will be defined later such that is a subsolution for (4.18). We compute
[TABLE]
Using again equation (4.16), we have
[TABLE]
By definition of in (4.19), we deduce with (4.21),
[TABLE]
We may rearrange it into
[TABLE]
Let us choose
[TABLE]
where is chosen large enough (independent of ) such that
[TABLE]
Thanks to this choice, we have
[TABLE]
and
[TABLE]
Finally, we obtain from (4.22)
[TABLE]
where we use the fact that by definition (4.20) we have (recalling also that is decreasing by assumption (2.5)).
Thus, by the sub- and super-solution technique, we deduce, using also (4.18) that
[TABLE]
2nd step. Using again equation (4.16), we get from (4.24)
[TABLE]
which is the first inequality of Lemma 4.1. Finally, by definition (1.2), we have also . Thus
[TABLE]
where we use the definition (1.2) for the last identity. We conclude easily the proof. ∎
Thanks to this latter Lemma, we may deduce uniform estimates on the time derivative of and .
Lemma 4.2
For any , we have that is uniformly bounded in and is uniformly bounded in .
Proof.
We use the equality , where we recall that denotes the negative part. Thus
[TABLE]
where we have used equation (3.13) to bound the first term and Lemma 4.1 for the second term. By the same token, we have
[TABLE]
We conclude the proof thanks to the estimates on and in obtained in Lemma 3.2. ∎
5 Convergence
This section is devoted to the proof of Theorem 2.1 apart from the complementary relation (2.11) which is postponed to the next section.
Since the sequences and are bounded in , due to Lemma 3.2 and 4.2, we may apply the Helly theorem and recover strong convergence in , up to an extraction. If we want to extend this local convergence to a global convergence in we need to prove that we can control the mass in an initial strip and in the tail. Indeed, let , ,
[TABLE]
Since we have strong convergence of in ,
[TABLE]
Then we have to control the two other terms in the right hand side.
The control of the initial strip comes from the estimate of ,
[TABLE]
For the control of the tail we consider such that , for and for . We define . Then
[TABLE]
where the notation stand for a generic nonnegative constant. Moreover, using equation (3.12), we deduce
[TABLE]
Then, integrating on , we get
[TABLE]
By assumption (2.6), since the initial data is uniformly compactly supported, we deduce that the right hand side tends to [math] as goes to and goes to [math]. Then is a Cauchy sequence in . It implies its convergence in . The convergence of the pressure follows from the same kind of computation. The only difference is for the control of the tail and which is directly given by the estimate
[TABLE]
Therefore, we can extract subsequences and pass to the limit in the equation
[TABLE]
which implies
[TABLE]
This is the relation (2.10). We can also pass to the limit in the uniform estimate of Lemma 3.2 which provides (2.7) and .
Limit model.
We first recall that from (3.12), we have
[TABLE]
We get,
[TABLE]
Thus, the term in the Laplacien converges strongly to as goes to [math]. Then, thanks to the strong convergence of and , we deduce that in the sense of distribution satisfies (2.8). Moreover, due to the uniform estimate on in of Lemma 3.4, we can show, by passing into the limit in a product of a weak-strong convergence, that in the sense of distribution satisfies (2.9).
Time continuity.
Let us define , . For a given , we consider a smooth function on such that , for and for . We have
[TABLE]
We have
[TABLE]
with a function which is zero on . Thus, as for the control of the tail, for large enough, we have, uniformly for ,
[TABLE]
In addition, we know from Lemma 4.1 (and the bound on ) that , so . Then, since ,
[TABLE]
Then, using equation (2.8) and an integration by parts, we obtain
[TABLE]
Then we can choose close enough such that
[TABLE]
We conclude that .
Initial trace
For any test function , we have from (3.12),
[TABLE]
Letting going to [math], we obtain with (2.6),
[TABLE]
Letting we can conclude that .
6 Complementary relation
In this section we prove the complementary relation
[TABLE]
In the weak sense, this identity reads, for any test function ,
[TABLE]
The proof is divided into two steps.
1st step. In this first step we prove the inequality in (6.25). We start with the pressure equation (1.3) that we multiply by
[TABLE]
We multiply by a test function and integrate,
[TABLE]
where we use an integration by parts for the last identity. From the estimates in Lemma 3.2, we have
[TABLE]
We deduce that for any test function ,
[TABLE]
Since we have strong convergence of and weak convergence of , we can pass into the limit in the last two term in (6.26),
[TABLE]
Now we are looking for the limit of the first term in (6.26). We have . By weak convergence of and with Jensen inequality (since is convex),
[TABLE]
Thus, we conclude from (6.26) that
[TABLE]
which is a first inequality for (6.25).
2nd step. Now we want to show the reverse inequality, i.e.
[TABLE]
We know that
[TABLE]
with Thanks to the inequality , and the strong convergence , we know that as . Because
[TABLE]
we deduce from Lemma 3.2 that . It gives us compactness in space but not in time. Thus, following the idea of [22], we use a regularization process ’à la Steklov’.
Let introduce a time regularizing kernel such that . Then with the notations , , where the convolution holds only in the time variable,
[TABLE]
We denote , then
[TABLE]
Since and are uniformly bounded in from Lemma 3.2, is bounded in and we can extract a converging subsequence, still denoted , converging towards in for fixed. Moreover
[TABLE]
We multiply (6.27) by ,
[TABLE]
Then, passing to the limit , we obtain, thanks to the above remark
[TABLE]
So we are left to prove that for any , we have
[TABLE]
We compute for a fixed ,
[TABLE]
where is a constant such that .
For the first term we have
[TABLE]
For the second term, we have
[TABLE]
and . Let and the smallest time in its support, we then have for
[TABLE]
So integrating on
[TABLE]
Then
[TABLE]
where we use the bound on in Lemma 4.2.
For the third term, since , for any test function as above,
[TABLE]
So for all test function as above, and all ,
[TABLE]
Now it remain to pass to the limit in the regularization process. Thanks to an integration by parts,
[TABLE]
From the estimate on (Lemma 3.4) and the estimate on (Lemma 3.2), we deduce that we can pass to the limit and get
[TABLE]
Finally, from (2.10), we have . It concludes the proof.
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