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Active bacteriophage biocontrol and therapy on sub-millimeter scales towards removal of unwanted bacteria from foods and microbiomes

  • Bacteriophages can be used as antibacterial agents as a form of biological control, e.g., such as phage therapy. With active treatment, phages must “actively” produce new virions, in situ, to attain “inundative” densities, i.e., sufficient titers to eradicate bacteria over reasonable timeframes. Passive treatment, by contrast, can be accomplished using phages that are bactericidal but incapable of generating new phage virions in situ during their interaction with target bacteria. These ideas of active versus passive treatment come from theoretical considerations of phage therapy pharmacology, particularly as developed in terms of phage application to well-mixed cultures consisting of physically unassociated bacteria. Here I extend these concepts to bacteria which instead are physically associated. These are bacteria as found making up cellular arrangements or bacterial microcolonies—collectively, clonal bacterial “clumps”. I consider circumstances where active phage replication would be required to effect desired levels of bacterial clearance, but populations of bacteria nevertheless are insufficiently prevalent to support phage replication to bacteria-inundative densities across environments. Clumped bacteria, however, may still support active treatment at more local, i.e., sub-millimeter, within-clump spatial scales, and potential consequences of this are explored mathematically. Application is to the post-harvest biocontrol of foodborne pathogens, and potentially also to precise microbiome editing. Adequate infection performance by phages in terms of timely burst sizes, that is, other than just adsorption rates and bactericidal activity, thus could be important for treatment effectiveness even if bacterial densities overall are insufficient to support active treatment across environments. Poor phage replication during treatment of even low bacterial numbers, such as given food refrigeration during treatment, consequently could be problematic to biocontrol success. In practical terms, this means that the characterization of phages for such purposes should include their potential to generate new virions under realistic in situ conditions across a diversity of potential bacterial targets.

    Citation: Stephen T. Abedon. Active bacteriophage biocontrol and therapy on sub-millimeter scales towards removal of unwanted bacteria from foods and microbiomes[J]. AIMS Microbiology, 2017, 3(3): 649-688. doi: 10.3934/microbiol.2017.3.649

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  • Bacteriophages can be used as antibacterial agents as a form of biological control, e.g., such as phage therapy. With active treatment, phages must “actively” produce new virions, in situ, to attain “inundative” densities, i.e., sufficient titers to eradicate bacteria over reasonable timeframes. Passive treatment, by contrast, can be accomplished using phages that are bactericidal but incapable of generating new phage virions in situ during their interaction with target bacteria. These ideas of active versus passive treatment come from theoretical considerations of phage therapy pharmacology, particularly as developed in terms of phage application to well-mixed cultures consisting of physically unassociated bacteria. Here I extend these concepts to bacteria which instead are physically associated. These are bacteria as found making up cellular arrangements or bacterial microcolonies—collectively, clonal bacterial “clumps”. I consider circumstances where active phage replication would be required to effect desired levels of bacterial clearance, but populations of bacteria nevertheless are insufficiently prevalent to support phage replication to bacteria-inundative densities across environments. Clumped bacteria, however, may still support active treatment at more local, i.e., sub-millimeter, within-clump spatial scales, and potential consequences of this are explored mathematically. Application is to the post-harvest biocontrol of foodborne pathogens, and potentially also to precise microbiome editing. Adequate infection performance by phages in terms of timely burst sizes, that is, other than just adsorption rates and bactericidal activity, thus could be important for treatment effectiveness even if bacterial densities overall are insufficient to support active treatment across environments. Poor phage replication during treatment of even low bacterial numbers, such as given food refrigeration during treatment, consequently could be problematic to biocontrol success. In practical terms, this means that the characterization of phages for such purposes should include their potential to generate new virions under realistic in situ conditions across a diversity of potential bacterial targets.


    Recently fractional calculus has gotten much attention from researchers like traditional calculus. The mentioned area has the ability to describe real-world phenomena in more excellent ways. Also, such derivatives have numerous applications in the description of those systems with memory effects. Due to various applications, the said calculus has been used to investigate various infectious disease models like in [1,2,3]. Also, in the field of physics, engineering, and cosmology, fractional calculus has very well been used. For instance, we refer [4,5,6]. It has been shown that in many applications, the use of fractional calculus provides more realistic models than those obtained via classical ordinary derivatives. Due to this reason, the study of fractional models has received great attention from many researchers in the last few years. As the fractional order derivatives have important characteristics known as the memory effect which ordinary derivatives do not involve. Also, fractional differential operators are nonlocal as compared to the local behavior of integer derivatives. Recently researchers have published some very important results in this regard like [7,8]. Also, authors [9] have published some new results on the numerical scheme for fractional order SEIR epidemic of measles. Here it is remarked that some authors have discussed the geometry of fractional order derivatives. For instance, authors [10] have suggested a geometric interpretation of the fractional derivatives which is based on modern differential geometry and the geometry of jet bundles. In fact, the fractional differential operators are definite integrals that create the complete accumulation or spectrum of the function on whose these applications include the corresponding integer-order counterpart of a special case. In the same way, authors [11] have given the definition of the geometric interpretation of gradient of order (0,1]. In this way, they have suggested some geometric interpretations of the differentiability of real order.

    Different problems under the concept of fractional calculus have been studied for the existing theory and stability analysis. One of the important areas is devoted to investigating hybrid problems under the aforesaid concepts. In this regard, different problems under boundary and initial conditions have been studied by using nonlinear analysis and tools of advanced functional analysis. In the present time class of fractional differential equations devoted to the quadratic perturbation of nonlinear differential equations (called hybrid differential equations) has attracted much attention from researchers. This is due to the fact that they include several dynamical systems as special cases. For instance, Dhage and Lakshmikantham [12] discussed the existence theory of the following problem of hybrid differential equations

    ddt[u(t)f(t,u(t))]=g(t,u(t)),a.e.t[t0,t0+a],

    where

    fC([t0,t0+a]×R,R{0}), and gC([t0,t0+a]×R,R).

    They used hybrid fixed point theory to establish the existence of solutions to the proposed problems. In the same way, Dhage and Jadhav[13] studied the existence and uniqueness results for the ordinary first-order hybrid differential equation with perturbation of second type given by

    ddt[u(t)f(t,u(t))]=g(t,u(t)),a.e.t[t0,t0+a],u(t0)=u0,

    where f,gC([t0,t0+a]×R,R). Motivated from the mentioned mentioned work, Lu et al.[14] studied the following class of FHDEs by replacing the ordinary derivative by Caputo fractional type with 0<σ1 as

    cDσ[u(t)f(t,u(t))]=g(t,u(t)),a.e.t[t0,t0+a],u(t0)=u0.

    They used the hybrid fixed point theory of Dhage to study the existence and uniqueness of the solution to the mentioned problem.

    In the last few years, hybrid fixed point theory has been used to study different problems of hybrid nature for the existence theory in [15,16,17,18]. Also, using the aforementioned tools, authors have established various results devoted to existence theory for different boundary value problems of HFDEs in [19,20,21,22,23]. Also, some authors have studied integral-type FHDEs in [24,25]. Authors [26] have studied a system of FHDEs of thermostats type by using a fixed point approach. Furthermore, authors [27] have investigated a class of FHDEs under mixed-type hybrid integral boundary conditions. In the same way authors in [28,29,30,31,32] have used the tools of nonlinear functional analysis for studying various problems and systems of HFDEs. Here, we remark that authors [33] established a review of the analytical solutions for some generalized classes. In the same line, a class of HFDEs has also been considered in [34]. Authors in [35,36,37] have studied different boundary value problems of fractional order using topological degree theory for the existence theory. Here it should be kept in mind that a hybrid system is a dynamic system that interacts with continuous and discrete dynamics. For, example, the novel multiplex engineering systems involve numerous kinds of process and abstract decision-making units that present the image of various systems simultaneously exhibiting continuous and discrete time dynamics (see details in [38]). Further, the applications of hybrid systems can be found in embedded control systems also (see [39]).

    The existence theory of solutions to nonlinear problems is an important area of research in the current scenario. Because the said theory predicts the existence of a solution to a dynamic problem whether it has a solution or not. Usually, for the said theory fixed point theory has been used very well. But fixed point theory needs strong compact conditions which restricted its use in some situations. Also, to deal HFDEs, Dhage established some hybrid-type fixed point theorems to study the existence and uniqueness of the solution to the mentioned problems. However, it also needs the same strong compact conditions. To relax, the criteria and replace strong compact conditions with some weaker compactness, the degree theory has been introduced. It has a sophisticated tool to be used to investigate numerous nonlinear problems of integral, differential, and difference equations for their corresponding solution. The mentioned theory has been used very well for usual problems of fractional order equations. However, in the case of HFDEs, it has not been used properly. For some important contributions by using degree theory to study various problems in fractional calculus, we refer few papers as [40,41,42,43].

    In this work, we study a more general class of nonlinear boundary value problems (BVPs) consisting of a more general class of nth order S-HFDEs) together subject to nonlinear boundary conditions. Also, we choose the general case in which the nonlinear functions involved depend on the non-integer order derivatives. Further, necessary conditions required for the uniqueness of a solution to the proposed problem, we implement Caratheódory conditions along with techniques of measure of non-compactness and degree theory. Some new and interesting results are developed. Also, a result devoted to U-H stability is derived for the considered problem. Our proposed problem is stated as

    cDϑ[cDωu(t)m1Iβihi(t,u(t),Dρu(t))f(t,u(t),Dρu(t))]=g(t,u(t),Iγu(t)),tI=[0,1]u(0)=ψ1(u(η)),u(0)=0,u(0)=0,....,u(n1)(0)=0,u(1)=ψ2(u(η)), (1.1)

    where 0<ϑ1,n1<ω,βi, γn,n2<ρn1 with n2, 0<η<1, the functions f:I×R×RR{0},hi:I×R×RR(i=1,2,....,m) and g:I×R×RR satisfy the Caratheódory conditions. Moreover, ψ1,ψ2:RR are nonlinear functions. Also, the notation cD denotes the Caputo fractional order derivative and I represents fractional integral. Here, we use the tools mentioned in [44,45,46] to establish a detailed analysis of the considered problem. Also, stability is an important aspect of qualitative theory. In this regard, U-H stability analysis has also considered for some problems of HFDEs. For instance, see [47,48].

    The present article is organized as: Section 1 is devoted to the introduction. Section 2 is related to basic results from fractional calculus and degree theory. Section 3 is devoted to the first part of our main results. Section 4 is related to the second part of our main results. The section is consisted of applications to verify our results. Section 6 is devoted to a brief conclusion.

    Here it should be kept in mind that we have used the following basic definitions from [1,2] of fractional order derivative and integration.

    Definition 2.1. If ϑ>0, then the fractional order integration of a function uL1([0,1]) is given by

    Iϑ0+u(t)=1Γ(ω)t0(ts)ω1u(s)ds.

    Definition 2.2. The fractional derivative in Caputo sense of a function u over the interval [0,1] is defined as

    cDϑu(t)=1Γ(mϑ)t0(ts)nϑ1θ(n)(s)ds,

    where n1=[ϑ].

    Theorem 2.3. The solution of

    Iϑ[cDϑu(t)]=y(t),n1<ϑn,

    is derived as

    Iϑ[cDϑu(t)]=y(t)+Citn1,

    for arbitrary CiR, i=0,1,2,,n1=[ϑ].

    Let E={uC(I):cDω1uC(I)} is Banach space under the norm uρ=max0t1|u(t)|+max0t1|cDρu|.

    Let P represents family of all bounded sub sets of E, then we define the following measure of non-compactness.

    Definition 2.4. [44] The measure due to non-compactness μ:PR+ is Kuratowski measure which is defined as

    μ(S)=inf{ϱ>0 where  SP such that diameterofSϱ}.

    Definition 2.5. [25] If T1,T2:EE are μ-Lipschtiz with constants C and C respectively, then T1+T2:EE is μ-Lipschitz with constant C+C.

    Definition 2.6. [25] If T1:SE is compact, then T1 is μ-Lipschitz with constant C=0.

    Definition 2.7. [25] If T1:SE is Lipschitz with constant C, then T1 is μ-Lipschitz with the same constant C.

    We need the given theorem.

    Theorem 2.8. [25] Let T:EE be μ-condensing and

    S={uE:withλ[0,1]asu=λTu}.

    If S is a bounded set in E, so we can find r>0, such that SDr(0), then the degree

    deg(IλT,Dr(0),0)=1,  for all  λ[0,1].

    Thus T has at least one fixed point and the set of the fixed points of T lies in Dr(0).

    Here, we derive first part of our main results.

    Lemma 3.1. The solution of (1.1) can be described as

    u(t)=IωΨ(t,u(t),cDρu(t))+m1Iωβihi(t,u(t),cDρu(t))+ψ1(u(η))+Iωf(t,u(t),cDρ1u(t))Iωf(1,u(1),cDρu(1))(ψ2(u(η))ψ1(u(η))IωΨ(1,u(1),cDρu(1))Iωf(1,u(1),cDρu(1))m1Iω+βihi(1,u(1),cDρu(1)), (3.1)

    such that

    Ψ(t,u(t),cDρu(t))=f(t,u(t),cDρu(t))Iϑg(t,u(t),Iγu(t)),
    Iωψ(1,u(1),cDρu(1)),Iωf(1,u(1),cDρu(1))

    represent value of integral

    IωΨ(t,u(t),cDρu(t)),Iωf(1,u(1),cDρu(1))

    at t=1 and Iω+βihi(1,u(1),cDρu(1)) denotes the value of the integral Iω+βihi(t,u(t),cDρu(t)) at t=1, for i=1,2,3,...m.

    Proof. On using Iϑ at both sides of (1.1), one has

    cDωu(t)m1Iβihi(t,u(t),cDρu(t))=f(t,u(t),cDρu(t))Iϑg(t,u(t),Iγu(t))+C0f(t,u(t),cDρu(t))=Ψ(t,u(t),cDρu(t))+C0f(t,u(t),cDρu(t)).

    Hence, we obtain

    cDωu(t)=m1Iβihi(t,u(t),cDρu(t))+Ψ(t,u(t),cDρu(t))+C0f(t,u(t),cDρu(t)).

    Using Iω and the semi group property of integrals, one has

    u(t)=m1Iω+βihi(t,u(t),cDρu(t))+IωΨ(t,u(t),cDρu(t))+C0Iωf(t,u(t),cDρu(t))+C1+C2t++Cntn1.

    Taking jth order ordinary derivative, one has

    uj(t)=Iω+βijhi(t,u(t),cDρu(t))+IωjΨ(t,u(t),cDρu(t))+C0Iωjf(t,u(t),cDρu(t))+n1Cii!tij(ij+1)!.

    Also, u(0)=0,u(0)=0,...,un1(0)=0 yield C2=0,C3=0,....,Cn=0. Thus

    u(t)=m1Iω+βihi(t,u(t),cDρu(t))+IωΨ(t,u(t),cDρu(t))+C0Iωf(t,u(t),cDρu(t))+C1. (3.2)

    Further u(0)=ψ1(u(η)) yields C1=ψ1(u(η)) and using u(1)=ψ2(u(η)), one has

    ψ2(u(η))=u(1)=IωΨ(1,u(1),cDρu(1))+m1Iω+βihi(1,u(1),cDρu(1))+C0Iωf(1,u(1),cDρu(1))+ψ1(u(η)),

    which implies

    [ψ2(u(η))ψ1(u(η))IωΨ(1,u(1),cDρu(1))m1Iω+βihi(1,u(1),cDρu(1))]=C0Iωf(1,u(1),cDρu(1)).

    Hence, we get the given result

    C0=[ψ2(u(η))ψ1(u(η))IωΨ(1,u(1),cDρu(1))m1Iω+βih(1,u(1),cDρu(1))]Iωf(1,u(1),cDρu(1)).

    Hence, (3.2) becomes

    u(t)=IωΨ(t,u(t),cDρu(t))+m1Iω+βihi(t,u(t),cDρu(t))+Iωf(t,u(t),cDρu(t))Iωf(1,u(1),cDρu(1))×(ψ2(u(η))IωΨ(1,u(1),cDρu(1))Iωf(1,u(1),cDρu(1))+ψ1(u(η))m1Iωβihi(1,u(1),cDρu(1)))=IωΨ(t,u(t),cDρu(t))+m1Iω+βihi(t,u(t),cDρu(t))+ψ1(u(η))+Iωf(t,u(t),cDρu(t))Iωf(1,u(1),cDρu(1))(ψ2(u(η))ψ1(u(η))IωΨ(1,u(1),cDρu(1))Iωf(1,u(1),cDρu(1))m1Iω+βihi(1,u(1),cDρu(1))),

    which can be rewritten as

    u(t)=IωΨ(t,u(t),cDρu(t))+m1Iω+βihi(t,u(t),cDρu(t))+ψ1(u(η))+Iωf(t,u(t),cDρu(t))Iωf(1,u(1),cDρu(1))(ψ2(u(η))ψ1(u(η))IωΨ(1,u(1),cDρu(1))Iωf(1,u(1),cDρu(1))m1Iω+βihi(1,u(1),cDρu(1))). (3.3)

    From (3.3), it follows that

    cDρu(t)=IωρΨ(t,u(t),cDρu(t))+m1Iω+βiρhi(t,u(t),cDρu(t))+Iωρf(t,u(t),cDρu(t))Iωf(1,u(1),cDρu(1))(ψ2(u(η))ψ1(u(η)). (3.4)

    Let define A,B,C:EE by A=ˉA+ψ1(u(η)),C=(ψ2(u(η))ψ1(u(η)))ˉC, where

    (ˉAu)(t)=IωΨ(t,u(t),cDρu(t))+m1Iω+βihi(t,u(t),cDρu(t)),(Bu)(t)=Iωf(t,u(t),cDρu(t))Iωf(1,u(1),cDρu(1)),(ˉCu)(t)=IωΨ(1,u(1),cDρu(1))+Iωf(1,u(1),cDρu(1))+m1Iω+βihi(1,u(1),cDρu(1))), (3.5)

    then (3.3) takes the form of the operator equation

    u(t)=Au(t)+Bu(t)Cu(t)=Tu(t),tI, (3.6)

    and fixed points of the operator Eq (3.6) are solutions of the BVP (1.1). Further, from (3.4), it follows that

    cDρ(ˉAu)(t)=IωρΨ(t,u(t),cDρu(t))+m1Iω+βiρhi(t,u(t),cDρu(t)),cDρ(Bu)(t)=Iωρf(t,u(t),cDρu(t))Iωf(1,u(1),cDρu(1)),cDρ(ˉCu)(t)=0. (3.7)

    Using (3.5), and (3.7), we obtain

    |(ˉAu)(t)||IωΨ(t,u(t),cDρu(t))|+m1|Iω+βihi(t,u(t),cDρu(t))|,|cDρ(ˉAu)||IωρΨ(t,u(t),cDρu(t))|+m1|Iω+βiρhi(t,u(t),cDρu(t))|,|(Bu)(t)||Iωf(t,u(t),cDρu(t))||Iωf(1,u(1),cDρu(1))|,|cDρ(Bu)(t)||Iωρf(t,u(t),cDρu(t))||Iωf(1,u(1),cDρu(1))|,|(ˉCu)(t)|=|IωΨ(1,u(1),cDρu(1))|+|Iωf(1,u(1),cDρu(1))|+m1|Iω+βihi(1,u(1),cDω1u(1)))|,|cDρ(ˉCu)(t)|=0. (3.8)

    The following data depended results need to be hold to establish our main results.

    (H1) f,hi,g fulfill the criteria of Caratheódory conditions.

    (H2) For constants τ1,τ2,d1,d2,c1,c2, one has

    |ψi(u1(t))ψi(u2(t))|τi|u1u2|,i=1,2|ψi(u)|ci|u|+di,i=1,2.

    (H3) Let we have continuous mappings θi,μ,δ:IR, with 0<ξ,λ, such that for uE that

    |hi(t,u(t),cDρu(t))||θi(t)|(u+cDρu)+ξ=|θi(t)|uρ+ξ,|f(t,u(t),cDρu(t))||μ(t)|(u+cDρu)+λ=|μ(t)|uρ+λ,|g(t,u(t),Iγu(t))|δ(t).

    (H4) There exists τi>0, such that for u1,u2E,

    |f(t,u1(t),cDρu1(t))f(t,u2(t),cDρu2(t))|μ0u1u2ρ,|hi(t,u1(t),cDρu1(t))hi(t,u2(t),cDρu2(t))|θiu1u2ρ,|g(t,u1(t),(t))g(t,u2(t),Iγu2(t))|δ0u1u2,|ψi(u1(t))ψi(u2(t))|τi|u1u2|,i=1,2,

    where

    μ0=maxtIμ(t),δ0=maxtIδ(t),θi=maxtI|θi(t)|,i=1,2,3,,m.

    Under the hypothesis (H3), we have the following relation

    |Ψ(t,u(t),cDρu(t))|δ0Γ(ϑ+1)(μ0uρ+λ),|IωΨ(t,u(t),cDρu(t))|δ0Γ(ω+1)Γ(ϑ+1)(μ0uρ+λ),|IωρΨ(t,u(t),cDρu(t))|δ0Γ(ωρ+1)Γ(ϑ+1)(μ0uρ+λ),|Iωf(t,u(t),cDρu(t))|1Γ(ω+1)(μ0uρ+λ),|Iω+βihi(t,u(t),cDρu(t))|1Γ(ω+βi+1)(θiuρ+ξ),|Iω+βiρhi(t,u(t),cDρu(t))|1Γ(ω+βiρ+1)(θiuρ+ξ). (3.9)

    Using (3.8), and (3.9) together with the hypothesis H2,H3, we obtain the following relations

    |(ˉAu)(t)|δ0(μ0uρ+λ)Γ(ϑ+1)Γ(ω+1)+m1(θiuρ+ξ)Γ(ω+βi+1),|cDρ(ˉAu)|δ0(μ0uρ+λ)Γ(ϑ+1)Γ(ωρ+1)+m1(θiuρ+ξ)Γ(ω+βiρ+1),|(Bu)(t)|(μ0uρ+λ)ΛΓ(ω+1),|cDρ(Bu)(t)|(μ0uρ+λ)ΛΓ(ωρ+1),|(ˉCu)(t)δ0(μ0||u||ρ+λ)Γ(ω+1)Γ(ϑ+1)+m1(θiu||ρ+ξ)Γ(ω+βi+1),|cDρ(ˉCu)(t)|=0, (3.10)

    where Λ=|IωΨ(1,u(1),cDρu(1)). Thus, under the hypothesis H4, we have the following relation

    |Iϑg(t,u1(t),Iγu1(t))Iϑg(t,u2(t),Iγu2(t))|ρ0Γ(ϑ+1)u1u2,|Ψ(t,u1(t),cDρu1(t))Ψ(t,u2(t),cDρu2(t))|(δμ+ρ0(uρ+λ))Γ(ϑ+1)u1u2ρ. (3.11)

    Further, we have

    IωΨ(t1,u(t1),cDρu(t1))IωΨ(t2,u(t2),cDρu(t2))=1Γ(ω)[t10(t1s)ω1Ψ(s,u(s),cDρu(s))dst20(t2s)ω1Ψ(s,u(s),cDρu(s))ds]=1Γ(ω)[t10((t1s)ω1(t2s)ω1)Ψ(s,u(s),cDρu(s)ds+t2t1((t2s)ω1(t2s)ω1)Ψ(s,u(s),cDρu(s))ds].

    Thus, one has

    |IωΨ(1t,u(t1),cDρu(t1))IωΨ(t2,u(t2),cDρu(t2))|Ψ(s,u(s),cDρu(s)Γ(ω+1)(2(t2t1)ω+tω1tω2),

    which in view of (3.9) implies that

    |IωΨ(t1,u(t1),cDρu(t1))IωΨ(t2,u(t2),cDρu(t2))|δ0(μ0uρ+λ)Γ(ϑ+1)Γ(ω+1)(2(t2t1)ω+tω1tω2). (3.12)

    Similarly, in view of (3.9), we obtain

    |IωρΨ(t1,u(t1),cDρu(t1))IωρΨ(t2,u(t2),cDρu(t2))|δ0(μ0uρ+λ)Γ(ϑ+1)Γ(ωρ)(2(t2t1)ωρ+tωρ1tωρ2), (3.13)
    |Iω+βihi(t1,u(t1),cDρu(t1))Iω+βihi(t2,u(t2),cDρu(t2))|(θiuρ+ξ)Γ(ω+βi+1)(2(t2t1)ω+βi+tω+βi1tω+βi2), (3.14)
    |Iω+βiρhi(t1,u(t1),cDρu(t1))Iω+βiρhi(t2,u(t2),cDρu(t2))|(θiuρ+ξ)Γ(ω+βiρ+1)(2(t2t1)ω+βiρ+tω+βiρ1tω+βiρ2), (3.15)
    |Iωf(t1,u(t1),cDρu(t1))Iωf(t2,u(t2),cDρu(t2))|((μ0uρ+λ)Γ(ω+1)(2(t2t1)ω+tω1tω2), (3.16)
    |Iωρf(t1,u(t1),cDρu(t1))Iωρf(t2,u(t2),cDρu(t2))|((μ0uρ+λ)Γ(ωρ+1)(2(t2t1)ωρ+tωρ1tωρ2). (3.17)

    Hence, it follows that

    |Au1(t)Au2(t)|1Γ(ω+1)|Ψ(t,u1(t),Dρu1(t))Ψ(t,u2(t),Dρu2(t))|+m1|hi(t,u1(t),Dρu1(t))hi(t,u2(t),Dρu2(t))|Γ(ω+βi+1)+|ψ1(u1)(η)ψ1(u2)(η)|,

    which in view (3.11), and H4 implies that

    |Au1(t)Au2(t)|(δμ+ρ0(uρ+λ)Γ(ω+1)Γ(ϑ+1)u1u2ρ+m1|θi|u1u2ρΓ(ω+βi+1)+τ1u1u2((δμ+ρ0(uρ+λ)Γ(ω+1)Γ(ϑ+1)+m1|θi|Γ(ω+βi+1)+τ1)u1u2ρ. (3.18)

    In addition, we have

    |DρAu1(t)DρAu2(t)|Iωρ|Ψ(t,u1(t),Dρu1(t))Ψ(t,u2(t),Dρu2)(t)|+m1Iω+βiρ|(hi(t,u1(t),Dρu1(t))hi(t,u2(t),Dρu2(t))|,

    which in view (3.11), and H4 implies that

    |DρAu1(t)DρAu2(t)|(δμ+ρ0(uρ+λ)Γ(ωρ+1)Γ(ϑ+1)u1u2ρ+m1|θi|u1u2ρΓ(ω+βiρ+1)=((δμ+ρ0(uρ+λ)Γ(ωρ+1)Γ(ϑ+1)+m1|θi|Γ(ω+βiρ+1))u1u2ρ. (3.19)

    From (3.23), and (3.19), it follows that

    Au1(t)Au2(t)ρ((δμ+ρ0(uρ+λ)Γ(ϑ+1)(1Γ(ω+1)+1Γ(ωρ+1))+m1(|θi|Γ(ω+βi+1)+|θi|Γ(ω+βiρ+1))+τ1)u1u2ρ=κ1u1u2ρ, (3.20)

    where κ1=(δμ+ρ0(uρ+λ)Γ(ϑ+1)(1Γ(ω+1)+1Γ(ωρ+1))+m1(|θi|Γ(ω+βi+1)+|θi|Γ(ω+βiρ+1))+τ1. Now

    |Bu1(t)Bu2(t)|Iω|(f(t,u1(t),Dρu1(t))f(t,u2(t),Dρu2(t))Λ,|DρBu1(t)DρBu2(t)|Iωρ|(f(t,u1(t),Dρu1(t))f(t,u2(t),Dρu2(t))|Λ,

    using H4 yields

    |Bu1(t)Bu2(t)|μu1u2ΛΓ(ω+1),|DρBu1(t)DρBu2(t)|μu1u2ΛΓ(ωρ+1).

    Hence, it follows that

    Bu1Bu2ρμΛ(1Γ(ω+1)+1Γ(ωρ+1))u1u2ρ=κ2u1u2ρ, (3.21)

    whereκ2=μΛ(1Γ(ω+1)+1Γ(ωρ+1)).

    |Cu1(t)Cu2(t)||ψ2(u1)ψ2(u2)|+|ψ1(u1)ψ1(u2)|+|IωΨ(1,u1(1),Dρu1(1))IωΨ(1,u1(1),Dρu1(1))|+|Iωf(1,u1(1),Dρu1(1))Iωf(1,u1(1),Dρu1(1))|+m1|Iω+βihi(1,u1(1),Dρu1(1))Iω+βihi(1,u1(1),Dρu1(1))|. (3.22)

    Using(3.11), and H4, we obtain

    |Cu1(t)Cu2(t)|(τ1+τ2)|u1u2|+(δμ+ρ0(uρ+λ)Γ(ω+1)Γ(ϑ+1)u1u2ρ+μ0Γ(w+1)u1u2ρ+m1θiu1u2ρΓ(ω+βi+1)((δμ+ρ0(uρ+λ)Γ(ω+1)Γ(ϑ+1)+μ0Γ(w+1)+m1|θi|Γ(ω+βi+1)+τ1+τ2)u1u2ρ=κ3u1u2ρ, (3.23)

    where κ3=(δμ+ρ0(uρ+λ)Γ(ω+1)Γ(ϑ+1)+μ0Γ(w+1)+m1|θi|Γ(ω+βi+1)+τ1+τ2.

    Theorem 3.2. Under the hypothesis H1H3, the operator ˉA is compact and satisfies the following growth condition ˉAuρΔ1uρ+Δ2, where

    Δ1=δ0μ0Γ(ϑ+1)(1Γ(ω+1)+1Γ(ωρ+1))+m1(θiΓ(ω+βi+1)+θiΓ(ω+βiρ+1)), (3.24)

    and

    Δ2=δ0λΓ(ϑ+1)(1Γ(ω+1)+1Γ(ωρ+1))+m1(ξΓ(ω+βi+1)+ξΓ(ω+β1ρ+1)). (3.25)

    Proof. Here (ˉAu)(t)=IωΨ(t,u(t),cDρu(t))+m1Iω+βihi(t,u(t),cDρu(t)), clearly, ˉA is continuous on E. Now, for uE, using (3.10), we have

    ˉAuρ=ˉAu+cDρˉAuδ0(μ0uρ+λ)Γ(ϑ+1)(1Γ(ω+1)+1Γ(ωρ+1))+m1(θiuρ+ξ))(1Γ(ω+βi+1)+1Γ(ω+βiρ+1))=(δ0μ0Γ(ϑ+1)(1Γ(ω+1)+1Γ(ωρ+1))+m1(θiΓ(ω+βi+1)+θiΓ(ω+βiρ+1)))uρ+δ0λΓ(ϑ+1)(1Γ(ω+1)+1Γ(ωρ+1))+m1(ξΓ(ω+βi+1)+ξΓ(ω+β1ρ+1)).

    Hence

    AuρΔ1uρ+Δ2. (3.26)

    (3.26) yields that ˉA is uniformly bounded for bounded set on E. Let, t1<t2I, and consider

    |ˉA(u)t2ˉA(u)t1|+|(cDρˉAu)t2(cDρˉAu)t1||IωΨ(t1,u(t1),cDρu(t1))IωΨ(t2,u(t2),cDρu(t2))|+m1|Iω+βihi(t1,u(t1),cDρu(t1)Iω+βihi(t2,u(t2),cDρu(t2)|.

    In view of (3.12), and (3.14), we obtain

    |ˉA(u)t2ˉA(u)t1|δ0Γ(ϑ+1)(μ0uρ+λ)Γ(ω+1)(2(t2t1)ω+tω1tω2)+m1(θiuρ+ξ)Γ(ω+βi+1)(2(t2t1)ω+βi+tω+βi1tω+βi2),, (3.27)

    in view of (3.13), and (3.15), we obtain

    |cDρˉA(u)t2cDρˉA(u)t1||IωρΨ(t1,u(t1),cDρu(t1))IωρΨ(t2,u(t2),cDρu(t2))|+m1|Iω+βiρhi(t1,u(t1),cDρu(t1)Iω+βiρhi(t2,u(t2),cDρu(t2)|δ0Γ(ϑ+1)(μ0uρ+λ)Γ(ωρ)(2(t2t1)ωρ+tωρ1tωρ2)+m1(θiuρ+ξ)Γ(ω+βiρ+1)(2(t2t1)ω+βiρ+tω+βiρ1tω+βiρ2). (3.28)

    From (3.27) and (3.28), it follows that

    ˉA(u)t2ˉA(u)t1ρ=ˉA(u)t2ˉA(u)t1+(cDρˉAu)t2(cDρˉAu)t10 as t1t2. (3.29)

    Thus ˉA is equi continuous, and by Arzelá- Ascoli theorem ˉA is relatively compact. Hence, ˉA is μ- Lipschtiz with constant 0.

    Lemma 3.3. Under the hypothesis H1H3, the operator A is μ-Lipschtiz with constant τ1 and satisfes the following growth condition

    Auρ(Δ1+c1)uρ+(Δ2+d1). (3.30)

    Proof. By H2, the operator ψ1(η) is μ-Lipschtiz with constant τ1 and by Lemma (3.2), the operator ˉA is μ-Lipschtiz with constant 0. Hence, the operator A=ˉA+ψ1(η) is μ-Lipschtiz with constant τ1. Since, ˉAuρΔ1uρ+Δ2 by Lemma (3.2), it follows that Auρ(Δ1+c1)uρ+(Δ2+d1).

    Lemma 3.4. Under the hypothesis H1H3, the operator B is continuous and compact.

    Proof. Here, (Bu)(t)=Iωf(t,u(t),cDρu(t))Iωf(1,u(1),cDρu(1)). Clearly, B is continuous on E and bounded as

    |(Bu)(t)|=||Iωf(t,u(t),cDρu(t))|Λ1. (3.31)

    For equi-continuity, choose t1<t2I, and consider

    |B(u)t2B(u)t1|+|(cDρBu)t2(cDρBu)t1||Iωf(t2,u(t2),cDρu(t2))Iωf(t1,u(t1),cDρu(t1))|Λ.

    In view of (3.16), we obtain

    |B(u)t2B(u)t1|((μ0uρ+λ)Γ(ω+1)Λ(2(t2t1)ω+tω1tω2), (3.32)

    in view of (3.17), we obtain

    |cDρB(u)t2cDρB(u)t1|((μ0uρ+λ)Γ(ωρ+1)Λ(2(t2t1)ωρ+tωρ1tωρ2). (3.33)

    From (3.32) and (3.33), it follows that

    B(u)t2B(u)t1ρ=B(u)t2B(u)t1+(cDρBu)t2(cDρBu)t10 as t1t2. (3.34)

    Therefore, B is equi continuous. Therefore, using Arzelá- Ascoli theorem, B is compact.

    Lemma 3.5. Under the hypothesis H1H3, the operator ˉC is compact and satisfies the following growth condition

    ˉCuρΔ3uρ+Δ4, (3.35)

    where

    Δ3=δ0μ0Γ(ω+1)Γ(ϑ+1)+μ0Γ(ω+1)+m1(θiΓω+βi+1),

    and

    Δ4=λδ0Γ(ω+1)Γ(ϑ+1)+λΓ(ω+1)+m1ξΓ(ω+βi+1).

    Proof. The continuity of ˉC follows from the definition of ˉC. In addition, we have

    |ˉCu(t)||IωΨ(1,u(1),cDρu(1))|+|Iωf(1,u(1),cDρu(1))|+m1|Iω+βihi(1,u(1),cDρu(1)))|

    which is in view of (3.9) implies that

    |ˉCu(t)|δ0(μ0uρ+λ)Γ(ω+1)Γ(ϑ+1)+1Γ(ω+1)(μ0uρ+λ)+m1(θiuρ+ξ)Γ(ω+βi+1).

    Hence, it follows that

    ˉC(u)ρδ0(μ0uρ+λ)Γ(ω+1)Γ(ϑ+1)+1Γ(ω+1)(μ0uρ+λ)+m1(θiuρ+ξ)Γ(ω+βi+1). (3.36)

    The equi-continuity of ˉC follows from the fact that

    |ˉC(u)t2ˉC(u)t1|=0, for all t1,t2I.

    Hence, ˉC is compact and it follows that ˉC is μ-Lipschtiz with constant 0.

    Lemma 3.6. Under the hypothesis H1H3, the operator C is μ-Lipschtiz with constant τ and satisfies the following growth condition

    Cuρ(Δ3+c1)uρ+(Δ4+d1). (3.37)

    Proof. Define F(u)=ψ2(u(η))ψ1(u(η)), for u1,u2E, consider

    |F(u2)tF(u1)t||ψ1(u2(η))ψ1(u1(η))|+|ψ2(u2(η))ψ2(u1(η))|,

    which in view of H2 implies that

    |F(u2)tF(u1)t|(τ1+τ2)u2u1=τu2u1,

    τ=τ1+τ2. Since C=(ψ2(u(η))ψ1(u(η)))ˉC=F(u)ˉC and by Lemma 3.5 ˉC is μ-Lipschtiz with constant 0. Hence, C is μ-Lipschtiz with constant τ. Further, ˉCuρΔ3uρ+Δ4 by Lemma 3.5, it follows that

    Cuρ(Δ3+c1)uρ+(Δ4+d1). (3.38)

    Choose the parameters such that Δ1+Δ3+2c1+c2<1. Choose Rmax{τ1+τ,Δ2+Δ4+2d1+d21(Δ1+Δ3+2c1+c2)}. Define S={uE:uρR}, then S is closed, convex and bounded subset of E.

    Theorem 3.7. Under the assumptions (H1)(H3), the system (3.6) has at least one solution uE provided Δ1+Δ3+2c1+c2<1.

    Proof. By Lemma 3.3, the operator A is μ-Lipschitz with constant τ1. Using Lemma 3.6, the operator C is μ-Lipschitz with constant τ. By Lemma 3.4, the operator B is compact. Now for vS and uE, consider the equation u=Au+BvCu, which implies that

    uρAu||ρ+ByρCuρ.

    Using (3.30), (3.31) and (3.37), we obtain

    uρ(Δ1+c1)uρ+(Δ2+d1)+(Δ3+c1+c2)uρ+(Δ4+d1+d2).

    That implies

    (1(Δ1+Δ3+2c1+c2))uρ(Δ2+Δ4+2d1+d2).

    Hence, it follows that

    uρΔ2+Δ4+2d1+d2(1(Δ1+Δ3+2c1+c2)R

    which implies that uS. Further we have M=Buρ=1 and Rτ1+τ. Finally from above, we conclude that (3.6) has at least one solution uE.

    Theorem 3.8. Under the assumptions (H1)–(H4), the system (3.6) has a unique solution in S provided that

    κ1+κ2((Δ3+c1)R+(Δ4+d1))+k3<1. (3.39)

    Proof. For u1,u2S, Consider

    T(u2)T(u1)ρ=Au2+Bu2Cu2(Au1+Bu1Cu1)ρAu2Au1ρ+Cu1ρBu2Bu1ρ+Bu2ρCu2Cu1ρ. (3.40)

    By (3.20), (3.21), and (3.23), we have

    Au2A(u1)ρκ1u1u2ρ,Bu2B(u1)ρκ2u1u2ρ,Cu2C(u1)ρκ3u1u2ρ. (3.41)

    Using (3.41) in (3.40), we obtain

    Tu2Tu1ρκ1u1u2ρ+Cu1ρκ2u1u2ρ+κ3u1u2ρBu2ρ

    which in view of (3.31), and (3.38) implies that

    Tu2Tu1ρκ1u1u2ρ+((Δ3+c1)uρ+(Δ4+d1))κ2u1u2ρ+κ3u1u2ρ.

    Further, the above relation implies that

    Tu1Tu2ρ(κ1+κ2((Δ3+c1)uρ+(Δ4+d1))+k3)u1u2ρ(κ1+κ2((Δ3+c1)R+(Δ4+d1))+k3)u1u2ρ, (3.42)

    and uniqueness follows by the Banach contraction principle.

    U-H stability result is developed for (1.1). For detail introduction and results of U-H stability, we refer [47,48].

    Definition 4.1. The problem (3.6) is said to be U-H stable, if there exists a constant ζ>0, such that for a given φ>0, and for each solution u of the inequality

    u(Au+BuCu)ρ<φ, (4.1)

    there exists a solution ˉu(t) of (3.6). Then one has

    ˉu(t)=Aˉu(t)+Bˉu(t)Cˉu(t),

    such that

    uˉuρ<φζ.

    Theorem 4.2. Under the assumptions (H2) and (H4), the problem (1.1) is U-H stable provided k+k1<1.

    Proof. Let uE satisfies the inequality (4.1), and ˉuE be a solution of (1.1) which satisfies the Eq (3.6). Consider

    uˉuρ=u(Aˉu+BˉuCˉu)ρu(Au+BuCu)ρ+(Au+BuCu)(Aˉu+BˉuCˉu)ρ<φ+TuTˉuρ. (4.2)

    Now using (3.42) and (4.1), we obtain

    uˉuρφ+(κ1+κ2((Δ3+c1)R+(Δ4+d1))+k3)u1u2ρ=φ+Ku1u2ρ, (4.3)

    where K=κ1+κ2((Δ3+c1)R+(Δ4+d1))+k3. Hence, it follows that

    uˉuρ<φζ, where ζ=11K.

    Here, we present an application to demonstrate our results.

    Example 5.1. Consider the following problem by taking n=2 as

    cD0.5[cD1.5u(t)m1I1.5hi(t,u(t),cD1.5u(t))f(t,u(t),cD1.5u(t))]=g(t,u(t),I1.5u(t)),tI=[0,1],u(0)=ψ1(u(0.5)),u(0)=0,u(1)=ψ2(u(0.5)). (5.1)

    Consider

    hi(t,u(t),cD1.5u(t))=sin|u(t)|+sin|cD1.5u(t)|100+t2,f(t,u(t),cD1.5u(t))=sin|u(t)|+|cD1.5u(t)|50+et2,g(t,u(t),I1.5u(t))=|u(t)|+I1.5u(t)150+t,ψ1(u(0.5))=sin|u(0.5)|50, ψ2(u(0.5)=sin|u(0.5)|50.

    It is easy to show that the conditions of Theorem 3.2 and 3.8 are satisfied. Therefore, the given problem (5.1) has at least one solution. Further, the solution uniqueness condition also holds. Also, one can obviously verified the condition of U-H stability given in Theorem 4.2.

    In this manuscript, a nonlinear problem of S-HFDEs has been investigated by using a sophisticated tool known as topological degree theory. We have used a degree of non-compactness along with Caratheódory condition to establish appropriate results for the qualitative theory. Usually, fixed point theory involves strong compact conditions which require more restrictions on the nonlinear operators. Therefore, to replace the strong compact condition with some weaker compact condition, the proposed degree theory is a powerful tool. The concerned tool has the ability to relax the criteria and hence can be applied to large numbers of nonlinear problems of differential and integral equations. On the other hand, stability is an important consequence of nonlinear analysis. Therefore, a result based on U-H concepts for stability has been established. Finally, to verify our obtained results, we have given an illustrative problem. In the future, the degree theory will be applied in hybrid problems of fractal-fractional differential equations which have the ability to describe complex and irregular geometry in more diligent ways. Also, the mentioned degree theory has not yet been used in dealing with non-singular type hybrid fractional differential equations. Therefore, the aforesaid area will be our next target.

    All the authors are thankful to Prince Sultan University for paying the APC and support through TAS research lab.

    The authors declare no conflict of interest.

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