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A systematic review of modeling and simulation approaches in designing targeted treatment technologies for Leukemia Cancer in low and middle income countries

  • Virtual experimentation is a widely used approach for predicting systems behaviour especially in situations where resources for physical experiments are very limited. For example, targeted treatment inside the human body is particularly challenging, and as such, modeling and simulation is utilised to aid planning before a specific treatment is administered. In such approaches, precise treatment, as it is the case in radiotherapy, is used to administer a maximum dose to the infected regions while minimizing the effect on normal tissue. Complicated cancers such as leukemia present even greater challenges due to their presentation in liquid form and not being localised in one area. As such, science has led to the development of targeted drug delivery, where the infected cells can be specifically targeted anywhere in the body.

    Despite the great prospects and advances of these modeling and simulation tools in the design and delivery of targeted drugs, their use by Low and Middle Income Countries (LMICs) researchers and clinicians is still very limited. This paper therefore reviews the modeling and simulation approaches for leukemia treatment using nanoparticles as an example for virtual experimentation. A systematic review from various databases was carried out for studies that involved cancer treatment approaches through modeling and simulation with emphasis to data collected from LMICs. Results indicated that whereas there is an increasing trend in the use of modeling and simulation approaches, their uptake in LMICs is still limited. According to the review data collected, there is a clear need to employ these tools as key approaches for the planning of targeted drug treatment approaches.

    Citation: Henry Fenekansi Kiwumulo, Haruna Muwonge, Charles Ibingira, John Baptist Kirabira, Robert Tamale. Ssekitoleko. A systematic review of modeling and simulation approaches in designing targeted treatment technologies for Leukemia Cancer in low and middle income countries[J]. Mathematical Biosciences and Engineering, 2021, 18(6): 8149-8173. doi: 10.3934/mbe.2021404

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  • Virtual experimentation is a widely used approach for predicting systems behaviour especially in situations where resources for physical experiments are very limited. For example, targeted treatment inside the human body is particularly challenging, and as such, modeling and simulation is utilised to aid planning before a specific treatment is administered. In such approaches, precise treatment, as it is the case in radiotherapy, is used to administer a maximum dose to the infected regions while minimizing the effect on normal tissue. Complicated cancers such as leukemia present even greater challenges due to their presentation in liquid form and not being localised in one area. As such, science has led to the development of targeted drug delivery, where the infected cells can be specifically targeted anywhere in the body.

    Despite the great prospects and advances of these modeling and simulation tools in the design and delivery of targeted drugs, their use by Low and Middle Income Countries (LMICs) researchers and clinicians is still very limited. This paper therefore reviews the modeling and simulation approaches for leukemia treatment using nanoparticles as an example for virtual experimentation. A systematic review from various databases was carried out for studies that involved cancer treatment approaches through modeling and simulation with emphasis to data collected from LMICs. Results indicated that whereas there is an increasing trend in the use of modeling and simulation approaches, their uptake in LMICs is still limited. According to the review data collected, there is a clear need to employ these tools as key approaches for the planning of targeted drug treatment approaches.



    1. Introduction

    In this paper, we consider the following Cahn-Hilliard systems with dynamic boundary conditions and time periodic conditions, say (P), which consists of the following equations:

    utΔμ=0in Q:=Ω×(0,T), (1.1)
    μ=κ1Δu+ξ+π(u)f,ξβ(u)in Q, (1.2)
    uΓ=u|Γ,μΓ=μ|Γon Σ:=Γ×(0,T), (1.3)
    uΓt+νμΔΓμΓ=0on Σ, (1.4)
    μΓ=κ1νuκ2ΔΓuΓ+ξΓ+πΓ(uΓ)fΓ,ξΓβΓ(uΓ)on Σ, (1.5)
    u(0)=u(T)in Ω,uΓ(0)=uΓ(T)on Γ (1.6)

    where 0<T<+, Ω is a bounded domain of Rd (d=2,3) with smooth boundary Γ:=Ω, κ1,κ2 are positive constants, ν is the outward normal derivative on Γ, u|Γ,μ|Γ stand for the trace of u and μ to Γ, respectively, Δ is the Laplacian, ΔΓ is the Laplace-Beltrami operator (see, e.g., [21]), and f:QR, fΓ:ΣR are given data. Moreover, β,βΓ:R2R are maximal monotone operators and π,πΓ:RR are Lipschitz perturbations.

    The Cahn-Hilliard equation [8] is a description of mathematical model for phase separation, e.g., the phenomenon of separating into two phases from homogeneous composition, the so-called spinodal decomposition. In (1.1)–(1.2), u is the order parameter and μ is the chemical potential. Moreover, it is well known that the Cahn-Hilliard equation is characterized by the nonlinear term β+π. It plays an important role as the derivative of the double-well potential W. The well-known example of nonlinear terms is W(r)=(1/4)(r21)2, namely W(r)=r3r for rR, this is called the prototype double well potential. Other examples are stated later. As the abstract mathematical result, Kenmochi, Niezgódka and Pawłow study the Cahn-Hilliard equation with constraint by subdifferential operator approach [24] (see also [25]). Essentially we apply the same method in this paper.

    In terms of (1.3)–(1.5), we consider the dynamic boundary condition as being uΓ,μΓ unknown functions on the boundary. The dynamic boundary condition is treated in recent years, for example, for the Stefan problem [1,2,14], wider the degenerate parabolic equation [3,15,16] and the Cahn-Hilliard equation [11,12,17,18,19,20,22,29]. To the best our knowledge, the type of dynamic boundary conditions on the Cahn-Hilliard equation like (P) is formulated in [17,20]. Recently, the well-posedness with singular potentials is discussed in [11]; the maximal Lp regularity in bounded domains is treated in [22]; the related new model is also introduced in [29]. Based on the result [11], we also used the property of dynamic boundary conditions, more precisely, we set up the function space which satisfies that the total mass is equal to 0. At the sight of (P), we consider the same type of equations (1.1)–(1.2) on the boundary. In other words, (1.1)–(1.5) is a transmission problem connecting Ω and Γ. The nonlinear term βΓ+πΓ on boundary is also the derivative of the double-well potential WΓ, that is, we treat different nonlinear terms W and WΓ in Ω and on Γ, respectively. In this case, it is necessary to assume some compatibility condition (see, e.g., [9,11]), stated (A4).

    Focusing on (1.6), the study of time periodic problems of the Cahn-Hilliard equation is treated in [26,27,28,31]. In particular, Wang and Zheng discuss the existence of time periodic solutions of the Cahn-Hilliard equation with the Neumann boundary condition [31]. The authors employ the method of [4]. Note that the authors impose two assumptions for a maximal monotone graph, specifically, a restriction of effective domains and the following growth condition for the maximal monotone graph β:

    ˆβ(r)cr2for all rR,

    for some positive constant c. However, the above assumption is too restrictive for some physical applications. In this paper, we follow the method of [31] and apply the abstract theory of evolution equations by using the viscosity approach and the Schauder fixed point theorem in the level of approximate problems. Moreover, by virtue of the viscosity approach, we also can apply the abstract result [4]. Note that, the growth condition is not need to solve the Cahn-Hilliard equation (see, e.g., [11]), therefore, setting the appropriate convex functional and using the Poincaré-Wirtinger inequality, we can relax the growth condition for the time periodic problem. Thanks to this, we can choose various kinds of nonlinear diffusion terms β+π and βΓ+πΓ. On the other hand, a restriction of effective domains is essential to show the existence of solutions of (P).

    The present paper proceeds as follows.

    In Section 2, a main theorem and a definition of solutions are stated. At first, we prepare the notation used in this paper and set appropriate function spaces. Next, we introduce the definition of periodic solutions of (P) and the main theorems are given there. Also, we give examples of double-well potentials.

    In Section 3, in order to pass to the limit, we set convex functionals and consider approximate problems. Next, we obtain the solution of (P)ε by using the Schauder fixed point theorem. Finally, we deduce uniform estimates for the solution of (P)ε.

    In Section 4, we prove the existence of periodic solutions by passing to the limit ε0.

    A detailed index of sections and subsections follows.

    1. Introduction

    2. Main results

      2.1. Notation

      2.2. Definition of the solution and main theorem

    3. Approximate problems and uniform estimates

      3.1. Abstract formulation

      3.2. Approximate problems for (P)

      3.3. Uniform estimates

    4. Proof of convergence theorem


    2. Main results


    2.1. Notation

    We introduce the spaces H:=L2(Ω), HΓ:=L2(Γ), V:=H1(Ω), VΓ:=H1(Γ) with standard norms ||H, ||HΓ, ||V, ||VΓ and inner products (,)H, (,)HΓ, (,)V, (,)VΓ, respectively. Moreover, we set H:=H×HΓ and

    V:={z:=(z,zΓ)V×VΓ : z|Γ=zΓ a.e. on Γ}.

    H and V are then Hilbert spaces with inner products

    (u,z)H:=(u,z)H+(uΓ,zΓ)HΓfor all u:=(u,uΓ),z:=(z,zΓ)H,(u,z)V:=(u,z)V+(uΓ,zΓ)VΓfor all u:=(u,uΓ),z:=(z,zΓ)V.

    Note that zV implies that the second component zΓ of z is equal to the trace of the first component z of z on Γ, and zH implies that zH and zΓHΓ are independent. Throughout this paper, we use the bold letter u to represent the pair corresponding to the letter; i.e., u:=(u,uΓ).

    Let m:HR be the mean function defined by

    m(z):=1|Ω|+|Γ|{Ωzdx+ΓzΓdΓ}for all zH,

    where |Ω|:=Ω1dx,|Γ|:=Γ1dΓ. Then, we define H0:={zH:m(z)=0}, V0:=VH0. Moreover, V,V0 denote the dual spaces of V,V0, respectively; the duality pairing between V0 and V0 is denoted by ,V0,V0. We define the norm of H0 by |z|H0:=|z|H for all zH0 and the bilinear form a(,):V×VR by

    a(u,z):=κ1Ωuzdx+κ2ΓΓuΓΓzΓdΓfor all u,zV.

    Then, for all zV0, |z|V0:=a(z,z) becomes a norm of V0. Also, we let F:V0V0 be the duality mapping, namely,

    Fz,˜zV0,V0:=a(z,˜z)for all z,˜zV0.

    We note that the following the Poincaré-Wirtinger inequality holds: There exists a positive constant cP such that

    |z|2VcP|z|2V0for all zV0 (2.1)

    (see [11,Lemma A]). Moreover, we define the inner product of V0 by

    (z,˜z)V0:=z,F1˜zV0,V0for all z,˜zV0.

    Also, we define the projection P:HH0 by

    Pz:=zm(z)1for all zH,

    where 1:=(1,1). Then, since P is a linear bounded operator, the following property holds: Let {zn}nN be a sequence in H such that znz weakly in H for some z, then we infer that

    PznPzweakly in H0as n. (2.2)

    Then, we have V0↪↪H0↪↪V0, where "↪↪" stands for compact embedding (see [11,Lemmas A and B]).


    2.2. Definition of the solution and main theorem

    In this subsection, we define our periodic solutions for (P) and then we state the main theorem.

    Firstly, from (1.1) and (1.4), the following total mass conservation holds:

    m(u(t))=m(u(0))for all t[0,T].

    Therefore, for any given m0intD(βΓ), we define the periodic solution satisfying the total mass conservation m(u(t))=m0 for all t[0,T]. We use the following notation: the variable v:=um01; the datum f:=(f,fΓ); the function π(z):=(π(z),πΓ(zΓ)) for zH. Moreover, we set the space W:=H2(Ω)×H2(Γ).

    Definition 2.1. For any given m0intD(βΓ), the triplet (v,μ,ξ) is called the periodic solution of (P) if

    vH1(0,T;V0)L(0,T;V0)L2(0,T;W),μL2(0,T;V),ξ=(ξ,ξΓ)L2(0,T;H),

    and they satisfy

    v(t),zV0,V0+a(μ(t),z)=0for all zV0, (2.3)
    (μ(t),z)H=a(v(t),z)+(ξ(t)m(ξ(t))1+π(v(t)+m01)f(t),z)Hfor all zV (2.4)

    for a.a. t(0,T), and

    ξβ(v+m0)a.e. in Q,ξΓβΓ(vΓ+m0)a.e. on Σ

    with

    v(0)=v(T)in H0. (2.5)

    Remark 2.1. We can see that μ:=(μ,μΓ) satisfies

    μ=κ1Δu+ξm(ξ)+π(u)fa.e. in Q,μΓ=κ1νuκ2ΔΓuΓ+ξΓm(ξ)+πΓ(uΓ)fΓa.e. on Σ,

    where u=v+m0 and uΓ=vΓ+m0, because of the regularity vL2(0,T;W).

    Remark 2.2. In (2.4), this is different from the following definition of [11,Definition 2.1]:

    (μ(t),z)H=a(v(t),z)+(ξ(t)+π(v(t)+m01)f(t),z)Hfor all zV (2.6)

    for a.a. t(0,T). However, by setting ˜μ:=μ+m(ξ)1, ˜μ satisfies ˜μL2(0,T;V) and (2.6). Hence, in other words, we can employ (2.6) as definition of (P) replaced by (2.4).

    We assume that

    (A1) fL2(0,T;V) and f(t)=f(t+T) for a.a. t[0,T];

    (A2) π,πΓ:RR are locally Lipschitz continuous functions;

    (A3) β,βΓ:R2R are maximal monotone operators, which is the subdifferential

    β=Rˆβ,βΓ=RˆβΓ

    of some proper lower semicontinuous convex functions ˆβ,ˆβΓ:R[0,+] satisfying ˆβ(0)=ˆβΓ(0)=0 with domains D(β) and D(βΓ), respectively;

    (A4) D(βΓ)D(β) and there exist positive constants ρ and c0 such that

    |β(r)|ρ|βΓ(r)|+c0for all rD(βΓ); (2.7)

    (A5) D(β),D(βΓ) are bounded domains with non-empty interior, i.e., ¯D(β)=[σ,σ] and ¯D(βΓ)=[σΓ,σΓ] for some constants σ,σ,σΓ and σΓ with <σσΓ<σΓσ<.

    The minimal section β of β is defined by β(r):={qβ(r):|q|=minsβ(r)|s|} for rR. Also, βΓ is defined similarly. In particular, (A3) yields 0β(0). The assumption (A5) is not imposed in [11]. However, it is essential to obtain uniform estimates in Section 3. This is a difficulty of time periodic problems. Also, the assumption of compatibility of β and βΓ (A4) is the same as in [9,11].

    Now, we give some examples of the nonlinear perturbation terms which satisfies the above assumptions:

    β(r)=βΓ(r)=(α1/2)ln((1+r)/(1r)), π(r)=πΓ(r)=α2r for all rD(β)=D(βΓ)=(1,1) and 0<α1<α2 for the logarithmic double well potential W(r)=WΓ(r)=(α1/2){(1r)ln((1r)/2)+(1+r)ln((1+s)/2)}+(α2/2)(1r2). The condition α1<α2 ensures that W,WΓ have double-well forms (see, e.g., [10]).

    β(r)=βΓ(r)=I[1,1](r), π(r)=πΓ(r)=r for all rD(β)=D(βΓ)=[1,1] for the singular potential W(r)=WΓ(r)=I[1,1](r)r2/2, where I[1,1] is the subdifferential of the indicator function I[1,1] of the interval [1,1] (namely, I[1,1](r)=0 if r[1,1] and I[1,1](r)=+ otherwise).

    β(r)=βΓ(r)=I[1,1](r)+r3, π(r)=πΓ(r)=r for all rD(β)=D(βΓ)=[1,1] for the modified prototype double well potential W(r)=WΓ(r)=I[1,1](r)+(1/4)(r21)2r2/2.

    Our main theorem is given now.

    Theorem 2.1. Under the assumptions (A1)– (A5), for any given m0intD(βΓ), there exist at least one periodic solution of (P) such that m(u(t))=m0 for all t[0,T].

    Remark 2.3. We note that periodic solutions of (P) is not uniquely determined. It is due to the usage of the Gronwall inequality. Indeed, in [11,Theorem 2.1], the continuous dependent on the data is proved, that is, the uniqueness of the solution to a Cauchy problem is obtained. However, in this periodic problem (P), even if we use the same method, the continuous dependent can not be obtained because of Lipschitz perturbations π and πΓ. Without the perturbations, we can obtain the uniqueness (see Section 3).


    3. Approximate problems and uniform estimates

    In this section, we consider approximate problems and obtain uniform estimates to show the existence of periodic solutions of (P). Hereafter, we fix a given constant m0intD(βΓ).


    3.1. Abstract formulation

    In order to prove the main theorem, we apply the abstract theory of evolution equations. To do so, we define a proper lower semicontinuous convex functional φ:H0[0,+] by

    φ(z):={κ12Ω|z|2dx+κ22Γ|ΓzΓ|2dΓ            +Ωˆβ(z+m0)dx+ΓˆβΓ(zΓ+m0)dΓ                    ifzV0 with ˆβ(z+m0)L1(Ω), ˆβΓ(zΓ+m0)L1(Γ),+               otherwise.

    Next, for each ε(0,1], we define a proper lower semicontinuous convex functional φε:H0[0,+] by

    φε(z):={κ12Ω|z|2dx+κ22Γ|ΓzΓ|2dΓ            +Ωˆβε(z+m0)dx+ΓˆβΓ,ε(zΓ+m0)dΓifzV0,+otherwise,

    where ˆβε,ˆβΓ,ε are Moreau-Yosida regularizations of ˆβ,ˆβΓ defined by

    ˆβε(r):=infsR{12ε|rs|2+ˆβ(s)}=12ε|rJε(r)|2+ˆβ(Jε(r)),ˆβΓ,ε(r):=infsR{12ερ|rs|2+ˆβΓ(s)}=12ερ|rJΓ,ε(r)|2+ˆβΓ(JΓ,ε(r)),

    for all rR, where ρ is a constant as in (2.7) and Jε,JΓ,ε:RR are resolvent operators given by

    Jε(r):=(I+εβ)1(r),JΓ,ε(r):=(I+ερβΓ)1(r)

    for all rR. Moreover, βε,βΓ,ε:RR are Yosida approximations for maximal monotone operators β,βΓ, respectively:

    βε(r):=1ε(rJε(r)),βΓ,ε(r):=1ερ(rJΓ,ε(r))

    for all rR. Then, we easily see that βε(0)=βΓ,ε(0)=0 holds from the definition of the subdifferential. It is well known that βε,βΓ,ε are Lipschitz continuous with Lipschitz constants 1/ε,1/(ερ), respectively. Here, we have following properties:

    0ˆβε(r)ˆβ(r),0ˆβΓ,ε(r)ˆβΓ(r)for all rR.

    Hence, 0φε(z)φ(z) holds for all zH0. These properties of Yosida approximation and Moreau-Yosida regularizations are as in [5,6,23]. Moreover, thanks to [9,Lemma 4.4], we have

    |βε(r)|ρ|βΓ,ε(r)|+c0for all rR (3.1)

    with the same constants ρ and c0 as in (2.7).

    Now, for each ε(0,1], we also define two proper lower semicontinuous convex functionals ˜φ,ψε:H0[0,+] by

    ˜φ(z):={κ12Ω|z|2dx+κ22Γ|ΓzΓ|2dΓifzV0,+otherwise

    and

    ψε(z):=Ωˆβε(z+m0)dx+ΓˆβΓ,ε(zΓ+m0)dΓ

    for all zH0, respectively. Then, from [11,Lemma C], the subdifferential A:=H0˜φ on H0 is characterized by

    Az=(κ1Δz,κ1νzκ2ΔΓzΓ)with z=(z,zΓ)D(A)=WV0.

    Moreover, the representation of the subdifferential H0ψε is given by

    H0ψε(z)=Pβε(z+m01)for all zH0,

    where βε(z+m01):=(βε(z+m0),βΓ,ε(zΓ+m0)) for z=(z,zΓ)H0. This is proved by the same way as in [16,Lemma 3.2]. Noting that it holds that D(H0ψε)=H0 and A is a maximal monotone operator; indeed it follows from the abstract monotonicity methods (see, e.g., [5,Sect. 2.1]) that A+H0ψε is also a maximal monotone operator. Moreover, by a simple calculation, we deduce that (A+H0ψε)H0φε. Hence,

    H0φε(z)=(A+H0ψε)(z) (3.2)

    for any zH0 (see, e.g., [13]).


    3.2. Approximate problems for (P)

    Now, we consider the following approximate problem, say (P)ε: for each ε(0,1] find vε:=(vε,vΓ,ε) satisfying

    εvε(t)+F1vε(t)+H0φε(vε(t))         +P(˜π(vε(t)+m01))=Pf(t)in H0for a.a. t(0,T), (3.3)
    vε(0)=vε(T)in H0. (3.4)

    where, for all zH, ˜π(z):=(˜π(z),˜πΓ(zΓ)) is a cut-off function of π,πΓ given by

    ˜π(r):={0if rσ1,π(σ)(rσ+1)if σ1rσ,π(r)if σrσ,π(σ)(rσ1)if σrσ+1,0if rσ+1 (3.5)

    and

    ˜πΓ(r):={0if rσΓ1,πΓ(σΓ)(rσ+1)if σΓ1rσΓ,πΓ(r)if σΓrσΓ,πΓ(σΓ)(rσ1)if σΓrσΓ+1,0if rσΓ+1 (3.6)

    for all rR, respectively. We establish the above cut-off function by referring to [31].

    From now, we show the next proposition of the existence of the periodic solution for (P)ε.

    Proposition 3.1. Under the assumptions (A1)–(A5), for each ε(0,1], there exist at least one function

    vεH1(0,T;H0)L(0,T;V0)L2(0,T;W)

    such that vε satisfies (3.3) and (3.4).

    The proof of Proposition 3.1 is given later. In order to show the Proposition 3.1, we use the method in [31], that is, we employ the fixed point argument. To do so, we consider the following problem: for each ε(0,1] and gL2(0,T;V0),

    (F1+εI)vε(t)+φε(vε(t))=g(t)in H0for a.a. t(0,T), (3.7)
    vε(0)=vε(T)in H0. (3.8)

    Now, we can apply the abstract theory of doubly nonlinear evolution equations respect to the time periodic problem [4] for (3.7), (3.8) because the operator εI+F1 and φε are coercive in H0. It is an important assumption to apply Theorem 2.2 in [4]. Moreover, the function vε satisfying (3.7) and (3.8) is uniquely determined. Indeed, let v1ε,v2ε be periodic solutions of the problem (3.7) and (3.8). Then, at the time t(0,T), taking the difference (3.7) for v1ε and v2ε, respectively, we have

    ε(v1ε(t)v2ε(t))+F1(v1ε(t)v2ε(t))+φε(v1ε(t))φε(v2ε(t))=0in H0 (3.9)

    for a.a. t(0,T). Now, we test (3.9) at time t(0,T) by v1ε(t)v2ε(t). Then, we deduce that

    12ddt(ε|v1ε(t)v2ε(t)|2H0+|v1ε(t)v2ε(t)|2V0)+12|v1ε(t)v2ε(t)|2V00

    for a.a. t(0,T), because of (3.2) and the monotonicity of β,βΓ. Therefore, by integrating it over [0,T] with respect to t, it follows from (2.1) that

    T0|v1ε(t)v2ε(t)|2Vdt0.

    It implies that the function vε satisfying (3.7) and (3.8) is unique.

    Hence, we obtain the next proposition.

    Proposition 3.2. For each ε(0,1] and gL2(0,T;V0), there exists a unique function vε such that (3.7) and (3.8) are satisfied.

    We apply the Schauder fixed point theorem to prove Proposition 3.1. To this aim, we set

    Y1:={ˉvεH1(0,T;H0)L(0,T;V0):ˉvε(0)=ˉvε(T)}.

    Firstly, for each ˉvεY1, we consider the following problem, say (Pε;ˉvε):

    εvε(s)+F1vε(s)+φε(vε(s))+P(˜π(ˉvε(s)+m01))=Pf(s)in H0 (3.10)

    for a.a. s(0,T), with

    vε(0)=vε(T)in H0.

    Next, we obtain estimates of the solution of (Pε;ˉvε) to apply the Schauder fixed point theorem. Note that we can allow the dependent of ε(0,1] for estimates of Lemma 3.1 because we use the Schauder fixed point theorem in the level of approximation.

    Lemma 3.1. Let vε be the solution of problem (Pε;ˉvε). Then, there exist positive constants C1ε,C2,C3ε such that

    εT0|vε(s)|2H0ds+T0|vε(s)|2V0dsC1ε, (3.11)
    T0|vε(s)|2V0ds+T0Ωˆβε(vε(s)+m0)dxds+T0ΓˆβΓ,ε(vΓ,ε(s)+m0)dsC2 (3.12)

    and

    12|vε(t)|2V0+Ωˆβε(vε(t)+m0)dx+ΓˆβΓ,ε(vΓ,ε(t)+m0)dΓC3ε (3.13)

    for all t[0,T].

    Proof. At first, for each ˉvεY1, there exists a positive constant M, depending only on σ,σΓ,σ and σΓ, such that

    |˜π(ˉvε(t)+m01)|2H0Mfor all t[0,T]. (3.14)

    Now, testing (3.10) at time s(0,T) by vε(s) and using the Young inequality, we infer that

    ε|vε(s)|2H0+|vε(s)|2V0+ddsφε(vε(s))=(Pf(s)P(˜π(ˉvε(s)+m01)),vε(s))H012|f(s)|2V+12|vε(s)|2V0+M2ε+ε2|vε(s)|2H0

    for a.a. s(0,T). Therefore, we have that

    ε|vε(s)|2H0+|vε(s)|2V0+2ddsφε(vε(s))|f(s)|2V+Mε (3.15)

    for a.a. s(0,T). Then, integrating it over (0,T) with respect to s and using the periodic property, we see that

    εT0|vε(s)|2H0ds+T0|vε(s)|2V0dsT0|f(s)|2Vds+MTε,

    which implies the first estimate (3.11).

    Next, testing (3.10) at time s(0,T) by vε(s) and from (3.1), we deduce that

    12dds|vε(s)|2V0+ε2dds|vε(s)|2H0+φε(vε(s))(Pf(s)P(˜π(ˉvε(s)+m01)),vε(s))H0+φε(0)2cP|f(s)|2H0+14cP|vε(s)|2H0+2cPM+φ(0)2cP|f(s)|2H0+14|vε(s)|2V0+2cPM+φ(0)2cP|f(s)|2H0+12φε(vε(s))+2cPM+φ(0)

    for a.a. s(0,T), thanks to the definition of the subdifferential. From the definition of φε, it follows that

    12dds|vε(s)|2V0+ε2dds|vε(s)|2H0+14|vε(s)|2V0+12Ωˆβε(vε(s)+m0)dx+12ΓˆβΓ,ε(vΓ,ε(s)+m0)dΓ2cP|f(s)|2H0+2cPM+Ωˆβε(m0)dx+ΓˆβΓ,ε(m0)dΓ

    for a.a. s(0,T). Integrating it over (0,T) and using the periodic property, we see that

    12T0|vε(s)|2V0ds+T0Ωˆβε(vε(s)+m0)dxds+T0ΓˆβΓ,ε(vΓ,ε(s)+m0)dΓds4cP|f|2L2(0,T;H0)+4cPTM+T|Ω||ˆβ(m0)|+T|Γ||ˆβΓ(m0)|.

    Hence, there exist a positive constant C2 such that the second estimate (3.12) holds.

    Next, for each s,t[0,T] such that st, we integrate (3.15) over [s,t] with respect to s. Then, by neglecting the first two positive terms, we have

    φε(vε(t))φε(vε(s))+12T0|f(s)|2Vds+MT2ε

    for all s,t[0,T], namely,

    12|vε(t)|2V0+Ωˆβε(vε(t)+m0)dx+ΓˆβΓ,ε(vΓ,ε(t)+m0)dΓ12|vε(s)|2V0+Ωˆβε(vε(s)+m0)dx+ΓˆβΓ,ε(vΓ,ε(s)+m0)dΓ+12T0|f(s)|2Vds+MT2ε (3.16)

    for all s,t[0,T]. Now, integrating it over (0,t) with respect to s, we deduce that

    t2|vε(t)|2V0+tΩˆβε(vε(t)+m0)dx+tΓˆβΓ,ε(vΓ,ε(t)+m0)dΓ12T0|vε(s)|2V0ds+T0Ωˆβε(vε(s)+m0)dxds+T0ΓˆβΓ,ε(vΓ,ε(s)+m0)dΓds+T2T0|f(s)|2Vds+MT22ε (3.17)

    for all t[0,T]. In particular, putting t:=T and dividing (3.17) by T, it follows that

    12|vε(T)|2V0+Ωˆβε(vε(T)+m0)dx+ΓˆβΓ,ε(vΓ,ε(T)+m0)dΓ12TT0|vε(s)|2V0ds+1TT0Ωˆβε(vε(s)+m0)dxds+1TT0ΓˆβΓ,ε(vΓ,ε(s)+m0)dΓds+12T0|f(s)|2Vds+MT2ε. (3.18)

    Hence, combining the second estimate (3.12) and (3.18), we see that

    12|vε(T)|2V0+Ωˆβε(vε(T)+m0)dx+ΓˆβΓ,ε(vΓ,ε(T)+m0)dΓC2T+12T0|f(s)|2Vds+MT2ε.

    Moreover, from the periodic property, we infer that

    12|vε(0)|2V0+Ωˆβε(vε(0)+m0)dx+ΓˆβΓ,ε(vΓ,ε(0)+m0)dΓC2T+12T0|f(s)|2Vds+MT2ε. (3.19)

    Now, let s be 0 in (3.16). Then, owing to (3.19), we deduce that

    12|vε(t)|2V0+Ωˆβε(vε(t)+m0)dx+ΓˆβΓ,ε(vΓ,ε(t)+m0)dΓC2T+|f|2L2(0,T;V)+MTε

    for all t[0,T]. Thus, there exists a positive constant C3ε such that the final estimate (3.13) holds.

    In terms of (3.11), one key point to prove the estimate is exploiting (3.14). The estimate (3.14) is arised from the form of cut-off functions (3.5) and (3.6). The form of cut-off functions depends on the assumption (A5) essentially. However, considered the same estimate in [11,Lemma 4.1], it is not imposed the assumption. They use the Gronwall inequality to obtain the estimate because the initial value is given data. On the other hand, we can not obtain it even though we use the Gronwall inequality, because the initial value is not given. For this reason, it is necessary to impose (A5). This is a difficult point to solve this time periodic problem (P).

    Now, we show the existence of solutions of the approximate problem (P)ε.

    Proof of Proposition 3.1. We apply the Schauder fixed point theorem. To do so, we set

    Y2:={ˉvεY1:supt[0,T]|ˉvε(t)|2V0+ε|ˉvε|2H1(0,T;H0)Mε},

    where Mε is a positive constant and be determined by Lemma 3.1. Then, the set Y2 is non-empty compact convex on C([0,T];H0). Now, from Proposition 3.2, for each ˉvεY2, there exists a unique solution vε of (Pε;ˉvε). Moreover, from Lemma 3.1, it holds vεY2. Here, we define the mapping S:Y2Y2 such that, for each ˉvεY2, corresponding ˉvε to the solution vε of (Pε;ˉvε). Then, the mapping S is continuous on Y2 with respect to topology of C([0,T];H0). Indeed, let {ˉvε,n}nNY2 be ˉvε,nˉvε in C([0,T];H0) and {vε,n}nN be the sequence of the solution of (Pε;ˉvε,n). From Lemma 3.1, there exist a subsequence {nk}kN, with nk as k, and vεH1(0,T;H0)L(0,T;V0) such that

    vε,nkvεweakly star in H1(0,T;H0)L(0,T;V0). (3.20)

    Hence, from (3.20) and the Ascoli-Arzelà theorem (see, e.g., [30]), there exists a subsequence (not relabeled) such that

    vε,nkvεin C([0,T];H0) (3.21)

    as k. Also, we have

    vε,nkvεweakly in L2(0,T;H0) (3.22)

    as k. Because we have vε,nk(0)=vε,nk(T), it implies vε(0)=vε(T) in H0. Hereafter, we show that vε is the solution of (Pε;ˉvε). Since vε,nk is the solution of (Pε;ˉvε,nk), we see that

    T0(Pf(s)P(˜π(ˉvε,nk(s)+m01))εvε,nk(s)F1vε,nk(s),η(s)vε,nk(s))H0dsT0φε(η(s))dsT0φε(vε,nk(s))ds (3.23)

    for all ηL2(0,T;H0), thanks to the definition of the subdifferential φε. Moreover, it follows from ˉvε,nkˉvε in C([0,T];H0) that

    P(˜π(ˉvε,nk+m01))P(˜π(ˉvε+m01))in C([0,T];H0). (3.24)

    Thus, on account of (3.20)–(3.24), taking the upper limit as k in (3.23) and using

    lim infkT0φε(vε,nk(s))dsT0φε(vε(s))ds,

    we infer that

    T0(Pf(s)P(˜π(ˉvε(s)+m01))εvε(s)F1vε(s),η(s)vε(s))H0dsT0φε(η(s))dsT0φε(vε(s))ds

    for all ηL2(0,T;H0). Hence, we see that the function vε is the solution of (Pε;ˉvε). As a result, it follows from the uniqueness of the solution of (Pε;ˉvε) that

    S(ˉvε,nk)=vε,nkvε=S(ˉvε)in C([0,T];H0)

    as k. Therefore, the mapping S is continuous with respect to C([0,T];H0). Thus, from the Schauder fixed point theorem, there exists a fixed point on Y2, namely, the problem (P)ε admits a solution vε. Finally, from the fact that φε(vε)L2(0,T;H0), which implies vεL2(0,T;W).

    Now, we consider the chemical potential μ:=(μ,μΓ) by approximating. For each ε(0,1], we set the approximate sequence

    με(s):=εvε(s)+φε(vε(s))+˜π(vε(s)+m01)f(s) (3.25)

    for a.a. s(0,T). From (3.2), we can rewrite (3.25) as

    με(s)=εvε(s)+Avε(s)+Pβε(vε(s)+m01)+˜π(vε(s)+m01)f(s) (3.26)

    for a.a. s(0,T). Then, we rewrite (3.3) as

    F1vε(s)+με(s)ωε(s)1=0in V

    for a.a. s(0,T), where

    ωε(s):=m(˜π(vε(s)+m01)f(s))

    for a.a. s(0,T). Therefore, we have Pμε=μεωε1L2(0,T;V0) and ωεL2(0,T). Then, it holds μεL2(0,T;V) and

    vε(s)+FPμε(s)=0in V0 (3.27)

    for a.a. s(0,T).


    3.3. Uniform estimates

    In this subsection, we obtain uniform estimates independent of ε(0,1]. We refer to [31] to obtain uniform estimates.

    Lemma 3.2. There exists a positive constant M1, independent of ε(0,1], such that

    12T0|vε(s)|2V0ds+T0Ωˆβε(vε(s)+m0)dxds+T0ΓˆβΓ,ε(vΓ,ε(s)+m0)dΓdsM1. (3.28)

    Proof. From (3.5), (3.6) and the assumption (A3), note that ˜π,˜πΓ are globally Lipschitz continuous on R. We denote Lipschitz constants of ˜π,˜πΓ by ˜L,˜LΓ, respectively. Moreover, we can take the primitive function ˆ˜π of ˜π satisfying

    Ωˆ˜π(vε(s))dx0

    for a.a. s(0,T). Analogously, we define ˆ˜πΓ. Now, we test (3.3) at time s(0,T) by vε(s) and use the Young inequality. Then, we deduce that

    12dds|vε(s)|2V0+ε2dds|vε(s)|2H0+φε(vε(s))(Pf(s)P(˜π(vε(s)+m01)),vε(s))H0+φε(0)cP|f(s)|2H+14cP|vε(s)|2H0+cPM+φ(0)14|vε(s)|2V0+cP|f(s)|2H+cPM+φ(0)12φε(vε(s))+cP|f(s)|2H+cPM+φ(0)

    for a.a. s(0,T). Namely, we have

    12dds|vε(s)|2V0+ε2dds|vε(s)|2H0+14|vε(s)|2V0+12Ωˆβε(vε(s)+m0)dx+12ΓˆβΓ,ε(vΓ,ε(s)+m0)dΓcP|f(s)|2H+cPM+φ(0)

    for a.a. s(0,T). Integrating it over (0,T) and using the periodic property, we see that

    12T0|vε(s)|2V0+T0Ωˆβε(vε(s)+m0)dxds+T0ΓˆβΓ,ε(vΓ,ε(s)+m0)dΓds2cP|f|2L2(0,T;H)+2cPTM+2Tφ(0).

    This yields that the estimate (3.28) holds.

    Lemma 3.3. There exists a positive constant M2, independent of ε(0,1], such that

    εT0|vε(s)|2H0ds+12T0|vε(s)|2V0dsM2.

    Proof. We test (3.3) at time s(0,T) by vε(s). Then, by using the Young inequality, we see that

    ε|vε(s)|2H0+|vε(s)|2V0+ddsφε(vε(s))+ddsΩˆ˜π(vε(s)+m0)dx+ddsΓˆ˜πΓ(vΓ,ε(s)+m0)dΓ=(Pf(s),vε(s))H012|f(s)|2V+12|vε(s)|2V0

    for a.a. s(0,T). This implies that

    ε|vε(s)|2H0+12|vε(s)|2V0+ddsφε(vε(s))+ddsΩˆ˜π(vε(s)+m0)dx+ddsΓˆ˜πΓ(vΓ,ε(s)+m0)dΓ12|f(s)|2V (3.29)

    for a.a. s(0,T). Therefore, by integrating it over (0,T) with respect to s and using the periodic property, we can conclude.

    Lemma 3.4. There exists a positive constant M3, independent of ε(0,1], such that

    12|vε(t)|2V0+Ωˆ˜π(vε(t)+m0)dx+Γˆ˜πΓ(vΓ,ε(t)+m0)dΓM3 (3.30)

    for all t[0,T].

    Proof. For each s,t[0,T] such that st, we integrate (3.29) over [s,t]. Then, by neglecting the first two positive terms, we see that

    φε(vε(t))+Ωˆ˜π(vε(t)+m0)dx+Γˆ˜πΓ(vΓ,ε(t)+m0)dΓφε(vε(s))+Ωˆ˜π(vε(s)+m0)dx+Γˆ˜πΓ(vΓ,ε(s)+m0)dΓ+12T0|f(s)|2V0ds

    for all s,t[0,T]. Now, integrating it over (0,t) with respect to s, it follows that

    t2|vε(t)|2V0+tΩˆβε(vε(t)+m0)dx+tΓˆβΓ,ε(vΓ,ε(t)+m0)dΓ12T0|vε(s)|2V0ds+T0Ωˆβε(vε(s)+m0)dxds+T0ΓˆβΓ,ε(vΓ,ε(s)+m0)dΓds+T0Ωˆ˜π(vε(s)+m0)dxds+T0Γˆ˜πΓ(vΓ,ε(s)+m0)dΓds+T2T0|f(s)|2V0ds (3.31)

    for all t[0,T]. Here, note that we have

    |ˆ˜π(r)|r0|˜π(τ)|dτ˜L|r|0|τ|dτ+r0|˜π(0)|dτ˜L2r2+|˜π(0)||r| (3.32)

    for r>0. Then we can easily show that (3.32) holds for any rR. Similarly, we have

    |ˆ˜πΓ(r)|˜LΓ2r2+|˜πΓ(0)||r|for all rR.

    Then, by using the Young inequality, we infer that

    Ωˆ˜π(vε(s)+m0)dxΩ(˜L2|vε(s)+m0|2+|˜π(0)||vε(s)+m0|)dx˜LΩ|vε(s)+m0|2dx+12˜L|˜π(0)|2|Ω|2˜LΩ|vε(s)|2dx+2m20|Ω|+12˜L|˜π(0)|2|Ω| (3.33)

    for a.a. s[0,T]. Similarly, we have

    Γˆ˜πΓ(vΓ,ε(s)+m0)dΓ2˜LΓΓ|vΓ,ε(s)|2dΓ+2m20|Γ|+12˜LΓ|˜πΓ(0)|2|Γ| (3.34)

    for a.a. s[0,T]. Thus, on account of (3.31)–(3.34), we deduce that

    t2|vε(t)|2V0+tΩˆβε(vε(t)+m0)dx+tΓˆβΓ,ε(vΓ,ε(t)+m0)dΓ12T0|vε(s)|2V0ds+T0Ωˆβε(vε(s)+m0)dxds+T0ΓˆβΓ,ε(vΓ,ε(s)+m0)dΓds+2˜LΩ|vε(s)|2dx+2˜LΓΓ|vΓ,ε(s)|2dΓ+T2T0|f(s)|2V0ds+˜M4(12+ˆLcP)T0|vε(s)|2V0ds+T0Ωˆβε(vε(s)+m0)dxds+T0ΓˆβΓ,ε(vΓ,ε(s)+m0)dΓds+T2T0|f(s)|2V0ds+˜M4

    for all t[0,T], where ˆL:=max{2˜L,2˜LΓ} and

    ˜M4:=2m20|Ω|+12˜L|˜π(0)|2|Ω|+2m20|Γ|+12˜LΓ|˜πΓ(0)|2|Γ|.

    In particular, putting t:=T and dividing it by T, it follows that

    12|vε(T)|2V0+Ωˆβε(vε(T)+m0)dx+ΓˆβΓ,ε(vΓ,ε(T)+m0)dΓ1T(12+ˆLcP)T0|vε(s)|2V0ds+1TT0Ωˆβε(vε(s)+m0)dxds+1TT0ΓˆβΓ,ε(vΓ,ε(s)+m0)dΓds+12T0|f(s)|2V0ds+˜M4T. (3.35)

    Combining (3.28) and (3.35), there exists a positive constant ˜M3 such that

    12|vε(T)|2V0+Ωˆβε(vε(T)+m0)dx+ΓˆβΓ,ε(vΓ,ε(T)+m0)dΓ˜M3.

    From the periodic property, we have

    φε(vε(0))=12|vε(0)|2V0+Ωˆβε(vε(0)+m0)dx+ΓˆβΓ,ε(vΓ,ε(0)+m0)dΓ˜M3. (3.36)

    Now, integrating (3.29) by (0,t) with respect to s, it follows from (3.33)–(3.34) that

    φε(vε(t))+Ωˆ˜π(vε(t)+m0)dx+Γˆ˜πΓ(vΓ,ε(t)+m0)dΓφε(vε(0))+Ωˆ˜π(vε(0)+m0)dx+Γˆ˜πΓ(vΓ,ε(0)+m0)dΓ+12T0|f(s)|2V0ds(1+2ˆLcP)φε(vε(0))+12T0|f(s)|2V0ds+˜M4 (3.37)

    for all t[0,T]. Therefore, by virtue of (3.36)–(3.37), there exists a positive constant M3 such that the estimate (3.30) holds.

    Lemma 3.5. There exists a positive constant M4, independent of ε(0,1], such that

    δ0T0|βε(vε(s)+m0)|2L1(Ω)ds+δ0T0|βΓ,ε(vΓ,ε(s)+m0)|2L1(Γ)dsM4 (3.38)

    for some positive constants δ0.

    Proof. We employ the method of [11,Lemmas 4.1,4.3], indeed we impose same assumptions as [11] for β,βΓ and being m0intD(βΓ). Therefore, we can also exploit the following inequalities stated in [18,Sect. 5]: for each ε(0,1], there exist two positive constants δ0 and c1 such that

    βε(r)(rm0)δ0|βε(r)|c1,βΓ,ε(r)(rm0)δ0|βΓ,ε(r)|c1

    for all rR. Hence, it follows that

    (βε(uε(s)),vε(s))Hδ0Ω|βε(uε(s))|dxc1|Ω|+δ0Γ|βΓ,ε(uΓ,ε(s))|dΓc1|Γ| (3.39)

    for a.a. s(0,T). On the other hand, we test (3.3) at time s(0,T) by vε(s). Then, from (3.2), we see that

    (εvε(s),vε(s))H0+(vε(s),vε(s))V0+(Avε(s),vε(s))H0+(Pβε(uε(s)),vε(s))H0(f(s)˜π(uε(s)),vε(s))H. (3.40)

    Hence, from (3.39)–(3.40) and the maximal monotonicity of A, by squaring we have

    (δ0Ω|βε(uε(s))|dx+δ0Γ|βΓ,ε(uΓ,ε(s))|dΓ)23c21(|Ω|+|Γ|)2+9(|f(s)|2H+|π(uε(s))|2H+ε2|vε(s)|2H0)|vε(s)|2H0+3|vε(s)|2V0|vε(s)|2V0

    for a.a. s(0,T). Therefore, from the Lipschitz continuity of ˜π,˜πΓ and Lemma 3.4, by integrating it over (0,T) with respect to s, there exists a positive constant M4 such that the estimate (3.38) holds.

    Lemma 3.6. There exists a positive constants M5, independent of ε(0,1], such that

    T0|με(s)|2VdsM5. (3.41)

    Proof. Firstly, by using the Lipschitz continuity of ˜π,˜πΓ and the Hölder inequality, it follows from (2.1) and Lemma 3.4 that there exists a positive constant M5 such that

    |m(˜π(vε(s)+m01))|1|Ω|+|Γ|{Ω|˜π(vε(s)+m0)|dx+Γ|˜πΓ(vΓ,ε(s)+m0)|dΓ}1|Ω|+|Γ|{˜L|Ω|12|vε(s)|2H+˜L|Ω||m0|+|Ω||˜π(0)|+˜LΓ|Γ|12|vΓ,ε(s)|2HΓ+˜LΓ|Γ||m0|+|Γ||˜πΓ(0)|}1|Ω|+|Γ|M5{|vε(s)|2V0+1}1|Ω|+|Γ|M5(M3+1)=:˜M5 (342)

    for a.a. s(0,T). Therefore, owing to (3.42) we deduce that

    |m(με(s))|2=|m(˜π(vε(s)+m01)f(s))|22˜M25+4(|Ω|+|Γ|)2(|f(s)|L1(Ω)+|fΓ(s)|L1(Γ))=:ˆM5

    for a.a. s(0,T). Next, from (2.1), (3.27) and the fact Pμε(s)=με(s)m(με(s))1 for a.a. s(0,T), we deduce that

    T0|με(s)|2Vds2T0|Pμε(s)|2Vds+2T0|m(με(s))1|2Vds2cPT0|Pμε(s)|2V0ds+2(|Ω|+|Γ|)T0|m(με(s))|2ds2cPT0|vε(s)|2V0ds+2T(|Ω|+|Γ|)ˆM25.

    Thus, from Lemma 3.3, there exists a positive constant M5 such that the estimate (3.41) holds.

    Lemma 3.7. There exists a positive constant M6, independent of ε(0,1], such that

    12T0|βε(vε(s)+m0)|2Hds+14ρT0|βε(vΓ,ε(s)+m0)|2HΓdsM6. (3.43)

    Proof. From the definition of με, we can infer that

    με=εtvεκ1Δvε+βε(vε+m0)m(βε(vε+m01))+˜π(vε+m0)fa.e. in Q, (3.44)
    μΓ,ε=εtvΓ,ε+κ1νvεκ2ΔΓvΓ,ε+βΓ,ε(vΓ,ε+m0)m(βε(vε+m01))+˜πΓ(vΓ,ε+m0)fΓa.e. on Σ. (3.45)

    Now, it follows from (3.38) that there exists a positive constant ˜M6 such that

    |m(βε(vε(s)+m01))|22(|Ω|+|Γ|)2(|βε(vε+m0)|L1(Ω)+|βΓ,ε(vΓ,ε(s)+m0)|L1(Γ))˜M6 (3.46)

    for a.a. s(0,T). Moreover, we test (3.44) at time s(0,T) by βε(vε(s)+m0) and exploit (3.45). Then, on account of the fact (βε(vε+m0))|Γ=βε(vΓ,ε+m0), by integrating over Ω we deduce that

    κ1Ωβε(vε(s)+m0)|vε(s)|2dx+κ2Γβε(vΓ,ε(s)+m0)|ΓvΓ,ε(s)|2dΓ+|βε(vε(s)+m0)|2H+ΓβΓ,ε(vΓ,ε(s)+m0)βε(vΓ,ε(s)+m0)dΓ(f(s)+με(s)εvε(s)˜π(vε(s)+m0),βε(vε(s)+m0))H+(m(βε(vε(s)+m01)),βε(vε(s)+m0))H+(fΓ(s)+μΓ,ε(s)εvΓ,ε(s)˜πΓ(vΓ,ε(s)+m0),βε(vΓ,ε(s)+m0))HΓ+(m(βε(vε(s)+m01)),βε(vΓ,ε(s)+m0))HΓ (3.47)

    for a.a. s\in (0, T). Now, from (3.1), since the both signs of \beta _{\varepsilon }(r) and \beta _{\Gamma, \varepsilon }(r) are same for all r\in \mathbb{R}, we infer that

    \begin{eqnarray} \int_{\Gamma }\beta _{\Gamma, \varepsilon }\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr)\beta _{\varepsilon }\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr)d\Gamma & = &\int_{\Gamma }\bigl|\beta _{\Gamma, \varepsilon }\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr)\bigr|\bigl|\beta _{\varepsilon }\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr)\bigr|d\Gamma \nonumber \\ &\geq &\frac{1}{2\rho }\int_{\Gamma }\bigl|\beta _{\varepsilon }\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr)\bigr|^{2}d\Gamma -\frac{c_{0}^{2}}{2\rho }|\Gamma |. \label{sign} \end{eqnarray} (3.48)

    Also, it holds

    \int_{\Omega }\beta _{\varepsilon }'\bigl(v_{\varepsilon }(s)+m_{0}\bigr)\bigl|\nabla v_{\varepsilon }(s)\bigr|^{2}dx\geq 0, \quad \int_{\Gamma }\beta _{\Gamma, \varepsilon }'\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr)\bigl|\nabla _{\Gamma }v_{\Gamma, \varepsilon }(s)\bigr|^{2}d\Gamma \geq 0. (3.49)

    Moreover, by using the Young inequality, the Lipschitz continuity of \widetilde{\pi }, \widetilde{\pi }_{\Gamma } and (3.46), there exists a positive constant \hat{M}_{6} such that

    \begin{eqnarray} &&\bigl(f(s)+\mu _{\varepsilon }(s)-\varepsilon v_{\varepsilon }'(s)-\widetilde{\pi }\bigl(v_{\varepsilon }(s)+m_{0}\bigr), \beta _{\varepsilon }\bigl(v_{\varepsilon }(s)+m_{0}\bigr)\bigr)_{H} \nonumber \\ &&\quad \quad \quad +\bigl(m\bigl(\boldsymbol{\beta }_{\varepsilon }\bigl(\boldsymbol{v}_{\varepsilon }(s)+m_{0}\boldsymbol{1}\bigr)\bigr), \beta _{\varepsilon }\bigl(v_{\varepsilon }(s)+m_{0}\bigr)\bigr)_{H} \nonumber \\ &&\quad \leq \frac{1}{2}\bigl|\beta _{\varepsilon }\bigl(v_{\varepsilon }(s)+m_{0}\bigr)\bigr|_{H}^{2} +4\bigl|f(s)\bigr|_{H}^{2}+4\bigl|\mu _{\varepsilon }(s)\bigr|_{H}^{2} +4\varepsilon ^{2}\bigl|v_{\varepsilon }'(s)\bigr|_{H}^{2} +4\bigl|\widetilde{\pi }\bigl(v_{\varepsilon }(s)+m_{0}\bigr)\bigr|_{H}^{2} \nonumber \\ &&\quad \quad \quad +\bigl|m\bigl(\boldsymbol{\beta }_{\varepsilon }\bigl(\boldsymbol{v}_{\varepsilon }(s)+m_{0}\boldsymbol{1}\bigr)\bigr)\bigr|_{H}^{2} \nonumber \\ &&\quad \leq \frac{1}{2}\bigl|\beta _{\varepsilon }\bigl(v_{\varepsilon }(s)+m_{0}\bigr)\bigr|_{H}^{2} +\hat{M}_{6}\bigl(\bigl|f(s)\bigr|_{H}^{2}+\bigl|\mu _{\varepsilon }(s)\bigr|_{H}^{2} +\varepsilon ^{2}\bigl|v_{\varepsilon }'(s)\bigr|_{H}^{2}+\bigl|v_{\varepsilon }(s)\bigr|_{H}^{2}+1\bigr) \nonumber \\ &&\quad \quad \quad +|\Omega |\tilde{M}_{6} \label{homg} \end{eqnarray} (3.50)

    and

    \begin{eqnarray} &&\bigl(f_{\Gamma }(s)+\mu _{\Gamma, \varepsilon }(s)-\varepsilon v_{\Gamma, \varepsilon }'(s)-\widetilde{\pi }_{\Gamma }\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr), \beta _{\varepsilon }\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr)\bigr)_{H_{\Gamma }} \nonumber \\ &&\quad \quad \quad +\bigl(m\bigl(\boldsymbol{\beta }_{\varepsilon }\bigl(\boldsymbol{v}_{\varepsilon }(s)+m_{0}\boldsymbol{1}\bigr)\bigr), \beta _{\varepsilon }\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr)\bigr)_{H} \nonumber \\ &&\quad \leq \frac{1}{4\rho }\bigl|\beta _{\varepsilon }\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr)\bigr|_{H_{\Gamma }}^{2} +2\rho \bigl|f_{\Gamma }(s)\bigr|_{H}^{2}+2\rho \bigl|\mu _{\Gamma, \varepsilon }(s)\bigr|_{H_{\Gamma }}^{2} +2\rho \varepsilon ^{2}\bigl|v_{\Gamma, \varepsilon }'(s)\bigr|_{H_{\Gamma }}^{2} \nonumber \\ &&\quad \quad \quad +2\rho \bigl|\widetilde{\pi }_{\Gamma }\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr)\bigr|_{H_{\Gamma }}^{2} +2\rho \bigl|m\bigl(\boldsymbol{\beta }_{\varepsilon }\bigl(\boldsymbol{v}_{\varepsilon }(s)+m_{0}\boldsymbol{1}\bigr)\bigr)\bigr|_{H_{\Gamma }}^{2} \nonumber \\ &&\quad \leq \frac{1}{4\rho }\bigl|\beta _{\varepsilon }\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr)\bigr|_{H_{\Gamma }}^{2} +2\rho |\Gamma |\tilde{M}_{6} \nonumber \\ &&\quad \quad \quad +\rho \hat{M}_{6}\bigl(\bigl|f_{\Gamma }(s)\bigr|_{H_{\Gamma }}^{2}+\bigl|\mu _{\Gamma, \varepsilon }(s)\bigr|_{H_{\Gamma }}^{2} +\varepsilon ^{2}\bigl|v_{\Gamma, \varepsilon }'(s)\bigr|_{H_{\Gamma }}^{2} +\bigl|v_{\Gamma, \varepsilon }(s)\bigr|_{H_{\Gamma }}^{2}+1\bigr) \label{hgomg} \end{eqnarray} (3.51)

    for a.a. s\in (0, T). Thus, from Lemmas 3.3, 3.4 and (2.1), by combining from (3.47)–(3.51) and integrating it over (0, T), we can conclude the existence of the constant M_{6} satisfying (3.43).

    Lemma 3.8. There exists a positive constant M_{7}, independent of \varepsilon \in (0, 1], such that

    \kappa _{1}\int_{0}^{T}\bigl|\Delta v_{\varepsilon }(s)\bigr|_{H}^{2}ds +\int_{0}^{T}\bigl|v_{\varepsilon }(s)\bigr|_{H^{\frac{3}{2}}(\Omega )}^{2}ds +\int_{0}^{T}\bigl|\partial _{\boldsymbol{\nu }}v_{\varepsilon }(s)\bigr|_{H_{\Gamma }}^{2}ds \leq M_{7}. (3.52)

    This lemma is proved exactly the same as in [11, Lemmas 4.4] because the necessary uniform estimates to prove it is obtained by Lemmas 3.3, 3.4, 3.6 and 3.7. Sketching simply, comparing in (3.44) we deduce that |\Delta v_{\varepsilon }|_{L^{2}(0, T; H)} is uniformly bounded. Moreover, by using the theory of the elliptic regularity (see, e.g., [7,Theorem 3.2,p. 1.79]), we see that |v_{\varepsilon }|_{L^{2}(0, T; H^{3/2}(\Omega))} is also uniformly bounded. Thus, using both uniformly boundeds, we can conclude that (3.52) holds.

    Lemma 3.9. There exists a positive constant M_{8}, independent of \varepsilon \in (0, 1], such that

    \int_{0}^{T}\bigl|\beta _{\Gamma, \varepsilon }\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr)\bigr|_{H_{\Gamma }}^{2}ds \leq M_{8}. (3.53)

    Proof. We test (3.45) at time s\in (0, T) by \beta _{\Gamma, \varepsilon }(v_{\Gamma, \varepsilon }(s)+m_{0}) and integrating it over \Gamma . Then, by using the Young inequality and the Lipschitz continuity of \widetilde{\pi }_{\Gamma }, there exists a positive constant \tilde{M}_{8} such that

    \begin{eqnarray} &&\kappa _{2}\int_{\Gamma }\beta _{\Gamma, \varepsilon }'\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr)\bigl|\nabla _{\Gamma }v_{\Gamma, \varepsilon }(s)\bigr|^{2}d\Gamma +\bigl|\beta _{\Gamma, \varepsilon }\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr)\bigr|_{H_{\Gamma }}^{2} \nonumber \\ &&\quad = \bigl(f_{\Gamma }(s)+\mu _{\Gamma }(s)-\varepsilon v_{\Gamma, \varepsilon }'(s)-\partial _{\boldsymbol{\nu }}v_{\varepsilon }(s) -\widetilde{\pi }_{\Gamma }\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr), \beta _{\Gamma, \varepsilon }\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr)\bigr)_{H_{\Gamma }} \nonumber \\ &&\quad \leq \frac{1}{2}\bigl|\beta _{\Gamma, \varepsilon }\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr)\bigr|_{H_{\Gamma }}^{2} +\bigl|m\bigl(\boldsymbol{\beta }_{\varepsilon }\bigl(\boldsymbol{v}_{\varepsilon }(s)+m_{0}\boldsymbol{1}\bigr)\bigr)\bigr|_{H_{\Gamma }}^{2} \nonumber \\ &&\quad \quad \quad +\tilde{M}_{8}\bigl(\bigl|f_{\Gamma }(s)\bigr|_{H_{\Gamma }}^{2} +\bigl|\mu _{\Gamma }(s)\bigr|_{H_{\Gamma }}^{2} +\varepsilon ^{2}\bigl|v_{\Gamma, \varepsilon }'(s)\bigr|_{H_{\Gamma }}^{2} +\bigl|\partial _{\boldsymbol{\nu }}v_{\varepsilon }(s)\bigr|_{H_{\Gamma }}^{2} +\bigl|v_{\Gamma, \varepsilon }(s)\bigr|_{H_{\Gamma }}^{2}+1\bigr) \nonumber \\ &&\quad \leq \frac{1}{2}\bigl|\beta _{\Gamma, \varepsilon }\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr)\bigr|_{H_{\Gamma }}^{2} +|\Gamma |\tilde{M}_{6} \nonumber \\ &&\quad \quad \quad +\tilde{M}_{8}\bigl(\bigl|f_{\Gamma }(s)\bigr|_{H_{\Gamma }}^{2} +\bigl|\mu _{\Gamma }(s)\bigr|_{H_{\Gamma }}^{2} +\varepsilon ^{2}\bigl|v_{\Gamma, \varepsilon }'(s)\bigr|_{H_{\Gamma }}^{2} +\bigl|\partial _{\boldsymbol{\nu }}v_{\varepsilon }(s)\bigr|_{H_{\Gamma }}^{2} +\bigl|v_{\Gamma, \varepsilon }(s)\bigr|_{H_{\Gamma }}^{2}+1\bigr) \nonumber \\ \label{es8ine} \end{eqnarray} (3.54)

    for a.a. s\in (0, T). Note that it holds

    \kappa _{2}\int_{\Gamma }\beta _{\Gamma, \varepsilon }'\bigl(v_{\Gamma, \varepsilon }(s)+m_{0}\bigr)\bigl|\nabla _{\Gamma }v_{\Gamma, \varepsilon }(s)\bigr|^{2}d\Gamma \geq 0.

    Thus, on account of Lemmas 3.3, 3.4, 3.6 and 3.8, by integrating (3.54) over (0, T), we can find a positive constant M_{7} such that the estimate (3.53) holds.

    Lemma 3.10. There exists a positive constant M_{9}, independent of \varepsilon \in (0, 1], such that

    \int_{0}^{T}\bigl|\boldsymbol{v}_{\varepsilon }(s)\bigr|_{\boldsymbol{W}}^{2}ds \leq M_{9}.

    This lemma is also proved the same as in [11,Lemmas 4.5]. The key point to prove it is that we can obtain the uniform estimate of |\Delta _{\Gamma }v_{\Gamma, \varepsilon }|_{L^{2}(0, T; H_{\Gamma })} by comparing in (3.45). We omit the proof.


    4. Proof of convergence theorem

    In this section, we obtain the existence of periodic solutions of (P) by performing passage to the limit for the approximate problem (P)_{\varepsilon }. The convergence theorem is also nearly the same [11,Sect. 4]. The different point from [11] is that the component of the periodic solution of (P) satisfies (2.4) and the periodic property (2.5).

    Thanks to the previous estimates in Lemmas from 3.3 to 3.10, there exist a subsequence \{\varepsilon _{k}\}_{k\in \mathbb{N}} with \varepsilon _{k}\to 0 as k\to \infty and some limits functions \boldsymbol{v}\in H^{1}(0, T; \boldsymbol{V}_{0}^{*})\cap L^{\infty }(0, T; \boldsymbol{V}_{0})\cap L^{2}(0, T; \boldsymbol{W}), \boldsymbol{\mu }\in H^{1}(0, T; \boldsymbol{V}), \xi \in L^{2}(0, T; H) and \xi _{\Gamma }\in L^{2}(0, T; H_{\Gamma }) such that

    \boldsymbol{v}_{\varepsilon _{k}}\to \boldsymbol{v} \quad {\rm weakly~star~in~} H^{1}(0, T; \boldsymbol{V}_{0}^{*})\cap L^{\infty }(0, T; \boldsymbol{V}_{0})\cap L^{2}(0, T; \boldsymbol{W}), (4.1)
    \varepsilon _{k}\boldsymbol{v}_{\varepsilon _{k}}\to 0 \quad {\rm strongly~in~} H^{1}(0, T; \boldsymbol{H}_{0}),
    \boldsymbol{\mu }_{\varepsilon _{k}}\to \boldsymbol{\mu } \quad {\rm weakly~in~} L^{2}(0, T; \boldsymbol{V}),
    \beta _{\varepsilon _{k}}(u_{\varepsilon _{k}})\to \xi \quad {\rm weakly~in~} L^{2}(0, T; H), (4.2)
    \beta _{\Gamma, \varepsilon _{k}}(u_{\Gamma, \varepsilon _{k}})\to \xi _{\Gamma } \quad {\rm weakly~in~} L^{2}(0, T; H_{\Gamma }) (4.3)

    as k\to \infty . Owing to (4.1) and a well-known compactness results (see, e.g., [30]), we obtain

    \boldsymbol{v}_{\varepsilon _{k}}\to \boldsymbol{v} \quad {\rm strongly~in~} C([0, T]; \boldsymbol{H}_{0})\cap L^{2}(0, T; \boldsymbol{V}_{0}) (4.4)

    as k\to \infty . This yeilds that

    \boldsymbol{u}_{\varepsilon _{k}}\to \boldsymbol{u}: = \boldsymbol{v}+m_{0}\boldsymbol{1} \quad {\rm strongly~in~} C([0, T]; \boldsymbol{H}_{0})\cap L^{2}(0, T; \boldsymbol{V}_{0}) (4.5)

    as k\to \infty . Therefore, from (4.5) and the Lipschitz continuity of \widetilde{\pi }, \widetilde{\pi }_{\Gamma }, we deduce that

    \widetilde{\boldsymbol{\pi }}(\boldsymbol{u}_{\varepsilon _{k}})\to \widetilde{\boldsymbol{\pi }}(\boldsymbol{u}) \quad {\rm strongly~in~} C([0, T]; \boldsymbol{H})

    as k\to \infty . Hence, by passing to the limit in (3.26) and (3.27), we obtain (2.3) and the following weak formulation:

    \bigl(\boldsymbol{\mu }(t), \boldsymbol{z}\bigr)_{\boldsymbol{H}} = a\bigl(\boldsymbol{v}(t), \boldsymbol{z}\bigr) +\bigl(\boldsymbol{\xi }(t)-m\bigl(\boldsymbol{\xi }(t)\bigr)\boldsymbol{1} +\widetilde{\boldsymbol{\pi }}\bigl(\boldsymbol{u}(t)\bigr)-\boldsymbol{f}(t), \boldsymbol{z}\bigr)_{\boldsymbol{H}} \quad {\rm for~all~}z\in \boldsymbol{V} (4.6)

    for a.a. t\in (0, T), where \boldsymbol{\xi }: = (\xi, \xi _{\Gamma }), because of the property (2.2) of linear bounded operator \boldsymbol{P}. Now, we can infer v+m_{0}\in D(\beta) and v_{\Gamma }+m_{0}\in D(\beta _{\Gamma }). Hence, from the form (2.5) and (3.6), we deduce that \widetilde{\pi }(v+m_{0}) = \pi (v+m_{0}) a.e. in Q and \widetilde{\pi }_{\Gamma }(v_{\Gamma }+m_{0}) = \pi _{\Gamma }(v_{\Gamma }+m_{0}) a.e. on \Sigma . This implies that we obtain (2.4) replaced by (4.6). Moreover, it follows from (4.4) that

    \boldsymbol{v}(0) = \boldsymbol{v}(T) \quad {\rm in~}\boldsymbol{H}_{0}.

    Also, due to (4.2), (4.3), (4.5) and the monotonicity of \beta , from the fact [5,Prop. 2.2,p. 38] we obtain

    \xi \in \beta (v+m_{0}) \quad {\rm a.e.~in~}Q, \quad \xi _{\Gamma }\in \beta _{\Gamma }(v_{\Gamma }+m_{0}) \quad {\rm a.e.~on~}\Sigma .

    Thus, we complete the proof of Theorem 2.1.


    Acknowledgments

    The author is deeply grateful to the anonymous referees for reviewing the original manuscript and for many valuable comments that helped to clarify and refine this paper.


    Conflict of interest

    The author declares no conflicts of interest in this paper.




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