Self-Propelled Vesicles Induced by the Mixing of ... - ACS Publications

Feb 29, 2016 - University, Machikaneyamacho 1-3, Toyonaka City, Osaka ... Department of Chemical Engineering & Materials Science, Doshisha University,...
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Self-Propelled Vesicles Induced by the Mixing of Two Polymeric Aqueous Solutions through a Vesicle Membrane Far from Equilibrium Takahiko Ban,*,† Takashi Fukuyama,† Shouta Makino,† Erika Nawa,‡ and Yuichiro Nagatsu§ †

Division of Chemical Engineering, Department of Materials Engineering Science, Graduate School of Engineering Science, Osaka University, Machikaneyamacho 1-3, Toyonaka City, Osaka 560-8531, Japan ‡ Department of Chemical Engineering & Materials Science, Doshisha University, Tatara Miyakodani 1-3, Kyotanabe, Kyoto 610-0321, Japan § Department of Chemical Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan S Supporting Information *

ABSTRACT: This study describes the development of self-propelled vesicles using transient interfacial energy in an aqueous two-phase system composed of polyethylene glycol (PEG), dextran (DEX), and water. The transient interfacial energy was generated at the mixing boundary between the PEG and DEX solutions when the two miscible liquids were in contact with each other far from equilibrium. Vesicles encapsulating 20 wt % DEX solution traveled spontaneously when the PEG concentration in the environmental media was >15 wt %. The motility of the vesicles varied with the permeability of the vesicle membrane. The permeability increased significantly when the concentration of PEG was >15 wt %. PEG had a profound effect not only on mass transfer through the membrane but also on the motility of the vesicles.

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INTRODUCTION The motion of vesicles has fundamental significance for the origin of force generation in cellular motility,1−3 coupling behavior between motility and shape deformation,4,5 and cell division,6−8 and it is potentially useful in many applications, including targeted drug delivery systems9,10 and bioreactors.11,12 However, vesicles cannot utilize their interfacial energy for self-propulsion, because they have extremely low interfacial energies, in comparison with that of droplets in immiscible liquid systems at the macroscopic scale. Thus, selfpropulsion of vesicles requires the interaction of specially treated vesicle membranes with their environmental media. There have been some reports discussing the use of the active motion of vesicles utilized for direct conversion of chemical energy to kinetic energy, even in homogeneous concentration fields, for example, using actin polymerization of a vesicle coated with a protein,1,2 and electrostatic adhesion of negatively charged vesicles onto a positively charged supported bilayer.3 In this study, we have developed a new method to propel vesicles using the transient interfacial energy generated by the mixing of two polymeric aqueous solutions without pretreatment of the vesicle membrane. The mixing of miscible liquids generates a concentration gradient in the boundary between the two liquids, giving rise to a transient interfacial energy in the mixing zone,13−15 and the resulting interfacial energy induces a convective flow.16−24 This phenomenon, which is called the Korteweg effect, occurs when two miscible liquids are in © 2016 American Chemical Society

contact with each other far from equilibrium. We have recently reported the self-propulsion of soft matter at the macroscopic scale driven by the Korteweg effect using an aqueous two-phase system (ATPS).23,24 The ATPS was composed of a lighter polyethylene glycol (PEG)-rich phase and a heavier dextran (DEX)- or salt-rich phase at equilibrium. Droplets of the heavier phase of the ATPS were found to move spontaneously, even in a homogeneous concentration field when formed in a PEG solution with a different composition from the equilibrium composition. The advantages of the ATPS are that is less harmful to biological systems, in comparison with organic solvent systems, and that is applicable to lipid bilayer membranes.8,25 If permeable vesicles encapsulating the heavier phase of the ATPS are formed in the lighter phase of the ATPS far from equilibrium and mutual dissolution proceeds through the vesicle interface, then the vesicles themselves should be able to move because of the Korteweg effect. However, bilayer vesicle membranes inhibit mass transfer of macromolecules between an inner aqueous phase and an outer aqueous phase, because vesicles consist of hydrophobic long tails. PEG is used to cause the leakage of contents from vesicles.26−29 The above strategy was harnessed for the propulsion of vesicles. Received: January 12, 2016 Revised: February 29, 2016 Published: February 29, 2016 2574

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Figure 1. (a) Schematic illustration of the reverse emulsion method used to create vesicles containing DEX. (b) Illustration of the microslide used for observation of vesicle motion.

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portion of the PEG solution was pushed out of an opposite filling port of the microslide. The filling ports then were closed with plugs after the vesicle solution was filled in half of the microslide. The vesicle activity on the PEG solution side was observed using a fluorescent microscope (Keyence, Model BZ-8100) in an air-conditioned environment at 25 ± 1 °C. In a preliminary experiment, vesicles were prepared using a PEG + Na2SO4 system, which delivered a higher self-propulsion performance, in comparison with the PEG + DEX system. However, the osmotic concentration of the PEG + Na2SO4 system was too high to create stable vesicles, with breakage of vesicles occurring frequently. Therefore, the PEG + DEX system was chosen for use. Permeability of the Vesicle Membrane. To calculate the permeability of the vesicle membrane, the change in the fluorescence intensity of the vesicles was measured in an air-conditioned environment at 25 ± 1 °C when vesicles encapsulating 20 wt % DEX solution labeled with 0.005 wt % FITC−dextran (Mw = 40 000) were formed in different PEG solutions. The exposure time of the light used for excitation was 4 s. The reduction in fluorescence intensity with time corresponded to leakage of the FITC−dextran. From this, the permeability (p) was calculated using the following equation:32,33

EXPERIMENTAL SECTION

Materials and Methods. Didodecyl dimethylammonium bromide (DDAB) was purchased from TCI. Dextran (Dextran 40, Mr ≈ 40 000) and fluorescein isothiocyanate−dextran (FITC-dextran, Mw = 40 000) were purchased from Sigma Chemical Co. Polyethylene glycol (PEG 4000, Mw = 3000) and decane were purchased from Wako Pure Chemical Industries. Preparation of Vesicles. An example showing the composition conditions that induce the Korteweg effect follows. Mixing of a 7 wt % DEX solution with an equal amount of a 10 wt % PEG solution yields phase separation into a lighter phase consisting of 1.95 wt % DEX + 12.5 wt % PEG, and a heavier phase consisting of 21.5 wt % DEX + 2.41 wt % PEG.30 If a droplet of the heavier phase is formed in a PEG solution with a composition different from the lighter phase, mutual dissolution proceeds and spontaneous convection occurs around the droplet, which can lead to spontaneous motion of the droplet. Note that the minor component, which is DEX for the lighter phase and PEG for the heavier phase, has no effect on the droplet motion. For the PEG 4000/DEX 40 000 system, the PEG concentration of the lighter phase is 10−15 wt % at equilibrium, whereas the DEX concentration of the heavier phase is 16−25 wt %.30 In this study, we used a 20 wt % DEX solution as the inner aqueous phase of vesicles and PEG solutions at various concentrations as outer phases. As shown in Figure 1, unilamellar vesicles were created using a reverse emulsion method.11,12 To prepare the inner aqueous phase of vesicles, 2.5 g of DDAB was added to an equal amount of decane.31 The decane solution was sonicated in an ultrasonic cleaning bath for 30 min, and 2.5 g of an aqueous solution consisting of 20 wt % DEX was added to the decane solution. The decane solution was sonicated for an additional 30 min to create a DDAB emulsion containing DEX. An aqueous solution of DDAB (1 mL, 1.2 mM) was prepared in a 5 mL test tube. An equal amount of DDAB emulsion was poured over the DDAB aqueous solution. The reverse emulsions transferred through a monolayer of DDAB at the oil/water interface, forming vesicles in the lower phase. The vesicle solution of the lower phase was removed by micropipette 10−15 min after initial contact. The vesicle solution (75 μL) was introduced into a filling port of the microslide (ibidi, μ-Slide I 0.6 Luer Uncoated, 50 mm × 5 mm × 600 μm = 150 μL in volume) that had been filled with a PEG solution in advance. A

I C = = e−pαt I0 C0

(1)

where I and C are the fluorescence intensity of the vesicles and the concentration of the fluorescent dye inside the vesicles, respectively, and α is the specific surface area of the vesicles. The subscript “0” refers to the initial values. The calculation of the specific surface area was based on the assumption that the vesicles were spherical.

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RESULTS AND DISCUSSION First, it was demonstrated using a numerical simulation that a droplet in a ternary system composed of three species (denoted as A, B, and C) can move spontaneously, even in a homogeneous concentration field under a dissolution process. Assuming that (i) the fluid flow is slow enough to neglect the convective terms in the Navier−Stokes equation, and (ii) the ternary fluid is incompressible and has the same density, 2575

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Figure 2. Concentration field of composition A at four times (t ̃ = 1, 5, 9, and 12), when a single droplet with initial composition, ϕA,drop = 0.5, ϕB,drop = 0.3, was formed in a continuous phase with initial composition ϕA,cont = 0.1, ϕB,cont = 0.1.

molecular weight, diffusion coefficient, and viscosity, we have the following conservation equations for mass and momentum:20 (2)

∇·v = 0 ∂ϕi ∂t

Fi =

1 + v·∇ϕi = − ∇·ji ρ

η∇2 v − ∇p = −

∑

(7)

where Mw is the molecular weight and r is the position. This force is proportional to the concentration gradient and chemical potential, and acts in the direction of increasing concentration. The molar Gibbs free energy in the ternary system is defined as34

(3)

Fi

i = A,B

g = gA ϕA + gBϕB + gCϕC + RT (ϕA ln ϕA + ϕB ln ϕB + ϕC ln ϕC)

(4)

where v is the average velocity, ϕi the molar fraction of component i, ji the diffusion flux of component i, η the viscosity, p the pressure, and Fi the body force of component i. When cross diffusion is ignored, ji in the ternary system is determined through the relation34 jA = −ρϕA ϕBD∇(μA − μB ) − ρϕA ϕCD∇(μA − μC )

(5a)

jB = −ρϕBϕA D∇(μB − μA ) − ρϕBϕCD∇(μB − μC )

(5b)

jC = −ρϕCϕA D∇(μC − μA ) − ρϕCϕBD∇(μC − μB )

(5c)

+ RT (ΨABϕA ϕB + ΨACϕA ϕC + ΨBCϕBϕC) + RT[KAB∇ϕA ∇ϕB + KAC∇ϕA ∇ϕC + KBC∇ϕB∇ϕC] ⎤ ⎡1 1 1 + RT ⎢ KAA(∇ϕA )2 + KBB(∇ϕB)2 + K CC(∇ϕC)2 ⎥ ⎦ ⎣2 2 2

(8)

where gi is the molar free energy of the pure species, Ψij the Flory parameter, and Kij the gradient energy parameter. The molar fractions are subjected to the constraint that ϕA + ϕB + ϕC = 1. Thus, the number of independent component variables is reduced to two. Now the analysis is restricted to two-dimensional systems, so that the velocity can be expressed in terms of a stream function ψ, i.e., vx = ∂ψ/∂y, vy = −∂ψ/∂x. Using the scaling r̃ = r/a, t ̃ = Dt/a2, and ψ̃ = Caψ/D,1 we obtain

where ρ is the density, D the diffusion coefficient, and μi the generalized chemical potential of component i, defined as the functional derivative of the molar Gibbs free energy of a nonuniform system for a ternary mixture (G = ∫ g dV):20

δ[G /(RT )] μi = δϕi

⎛ ρRT ⎞ ρ δG =⎜ ⎟μ ∇ ϕ Mw δr ⎝ Mw ⎠ i i

∂ϕA = ∇̃ψ ̃ × ∇̃ϕA + ∇̃ ·{∇̃ϕA + ϕA ϕB[(ΨAC + ΨBC − ΨAB)∇̃ϕA ∂t ̃ + 2ΨBC∇̃ϕB + ∇̃(k12∇̃ϕA + k 22∇̃ϕB)]

(6)

where g is the generalized specific free energy, R the gas constant, and T the temperature. The body force Fi driven by the Korteweg effect is described by the following equation:20

− ϕA (1 − ϕA )[(ΨAC + ΨBC − ΨAB)∇̃ϕB + 2ΨAC∇̃ϕA + ∇̃(k11∇̃ϕA + k12∇̃ϕB)]} 2576

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Figure 3. Velocity field corresponding to Figure 2.

∂ϕB = ∇̃ψ ̃ × ∇̃ϕB + ∇̃ · {∇̃ϕB + ϕA ϕB[(ΨAC + ΨBC − ΨAB)∇̃ϕB ∂t ̃ + 2ΨAC∇̃ϕA + ∇̃(k11∇̃ϕA + k12∇̃ϕB)]

solution with a different composition from the equilibrium composition (see Figure S1 and Movie S1 in the Supporting Information). A locally generated convection current was caused by the mixing of the miscible solutions, and then the droplet was transported by the asymmetric convection.23 This convection effect was exploited for the self-propulsion of vesicles. Vesicles composed of DDAB were prepared to encapsulate the DEX solution by a reverse emulsion method.11,12 Figure 4 displays successive images of a moving vesicle encapsulating 20 wt % dextran labeled with 0.001 wt % FITC−dextran immersed

− ϕB(1 − ϕB)[(ΨAC + ΨBC − ΨAB)∇̃ϕA + 2ΨBC∇̃ϕB + ∇̃(k12∇̃ϕA + k 22∇̃ϕB)]}

(10)

4 2 2 ∇̃ ψ̃ = −Ca−1∇̃(k11∇̃ ϕA + k12∇̃ ϕB) × ∇̃ϕA 2 2 − Ca−1∇̃(k12∇̃ ϕA + k 22∇̃ ϕB) × ∇̃ϕB

(11)

where k11 = KAA + KCC − 2KAC, k12 = KAB + KCC − KAC − KBC, k22 = KBB + KCC − 2KBC, and Ca−1 =

a 2 ⎛ ρ ⎞⎛ RT ⎞ ⎟ ⎜ ⎟⎜ D ⎝ η ⎠⎝ M w ⎠

kij is expressed as a function of Ψij.34 Thus, the parameters in the governing equations are Ca−1 and Ψij. The governing equations (eqs 9−11) were solved according to the numerical scheme reported by Vladimirova at Ca−1 = 10−4, ΨAB = 6, ΨAC = 6, and ΨBC = 3.20 Figure 2 shows the time evolution of the concentration field of composition A. The numerical simulation clarifies how the main driving force is generated. In the initial state, the droplet is slightly deformed. Absorbing materials from the surrounding media, the droplet gradually becomes tense and decreases its surface area, because the concentration gradient formed around the droplet exerts a transient interfacial energy on the droplet. An asymmetric concentration field is formed around the droplet, inducing an asymmetric velocity field (Figure 3). The driving force due to the Korteweg effect leads to the motion of the droplet toward the narrower region of the ditch. We have demonstrated self-propulsion of a millimeter-sized droplet composed of the heavier phase of ATPS, even in a homogeneous concentration field when formed in a PEG

Figure 4. Fluorescent images of a 20 wt % dextran 40 000-containing vesicle labeled with 0.001 wt % FITC−dextran 40 000 in a solution of 20 wt % PEG 4000. The images were taken at 0.5 s intervals and have been superimposed in the same image. The arrows represent the direction of vesicle movement. Scale bar = 20 μm. 2577

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over 6 s, as calculated by a simple estimation from Einstein’s equation. Therefore, passive motion is considered to be due to the convection of the entire solution. For CPEG ≤ 15 wt %, the velocity of the active motion decreased suddenly and was comparable to that of passive motion. Figure 6 shows the MSD ⟨L2⟩ of the passive and active motions, corresponding to Figure 5. The MSD of active motion

in 20 wt % PEG solution. The vesicles showed a variety of motions, such as uniform motion, reciprocatory motion, zigzag motion, and sudden cessation of motion (see Movies S2 and S3 in the Supporting Information). Vesicles sometimes showed intermittent motion and moved again after cessation of motion. The average persistence time of continuous movement was 5− 15 s, and this value increased slightly with increasing PEG concentration (see Figure S2 in the Supporting Information). The intermittent motion of the vesicles was observed over a period of 1 h, commencing after the vesicle solution was mixed with the PEG solution in a microslide. Particle tracking and subsequent statistical analysis35,36 was carried out. Mean-square displacement (MSD) was calculated from the trajectory of the moving vesicles by dividing it into passive and active motions. In this study, passive motion refers to slow uniform motion without changes in direction, whereas active motion refers to fast motion accompanied by many changes in direction (see Movies S2 and S3). Figure 5 shows

Figure 6. Mean-squared displacement as a function of time for vesicles trajectories relating to passive (dashed lines) and active motions (solid lines) shown in Figure 5.

was extremely high, compared to that of passive motion. The active motion of vesicles could be divided into two main types, based on the MSD calculated from the trajectory of the moving vesicles, as well as ballistic and reciprocatory motions. In reciprocatory motion, ⟨L2⟩ showed an oscillatory behavior that did not originate from rotational diffusion, because its characteristic time scale τR (defined as τR = 8πηR3/(kBT) ≈ 500−10 000 s, where η is the viscosity of water and the term kBT represents the thermal energy)35 was much longer than the observation time. The oscillatory behavior of self-propelled vesicles is different distinctive features, compared to vesicle motion based on the actin polymerization,1,2 electrostatic interactions,3 and ATPS droplets at the macroscopic scale.24 Actively moving vesicles were deformable and not spherical in shape (see Movie S3), whereas passively moving vesicles did not exhibit deformation. The deformation may cause an imbalance of the transient interfacial energy around vesicles, leading to self-propulsion. The deformation of the moving vesicles may induce the oscillatory behavior. Increase in the PEG concentration resulted in a decrease in the reciprocatory motion. Increase in the viscosity of the solution may inhibit spontaneous change in the shape of the vesicles. On the other hand, the nondeformed vesicles were found to drift only under the influence of the convective flow of the entire solution. However, we have not found conclusive evidence suggesting that the active motion of the vesicles solely originates from spontaneous changes in shape, because the change in the shape of the vesicles could not be characterized quantitatively, because of the low time resolution of the microscope (7.5 frames per second). However, we do understand that, for

Figure 5. Trajectories of three vesicles over 6 s, showing passive and active motions in PEG solutions of different concentrations.

typical trajectories of passive and active motions. The moving distance of passive motion was 50 μm/s (∼25 body lengths per second). The vesicles driven by the Korteweg effect were quite fast, in comparison with movement based on actin polymerization1,2 and the electrostatic interactions,3 which displayed velocities of ∼0.01 μm/s and 5 μm/s, respectively. On the other hand, the average velocity of passive motion was 1−6 μm/s and decreases with increasing PEG concentration. To investigate the effect of PEG concentration on the permeability of the vesicle membrane, the change in fluorescence intensity over time was monitored using a fluorescent microscope (see Figures S3 and S4 in the Supporting Information). Figure 8 shows the effect of PEG concentration on the permeability, which was found to increase with increasing PEG concentration and could be fitted by two lines having different slopes. A discontinuous change in the slope was observed at PEG concentrations in the range of 15− 20 wt %, shifting to a steeper slope at the higher concentrations.

dramatically at p > 0.2 μm/s. Increasing the PEG concentration promoted the exchange of molecules through the vesicle membrane. Mutual dissolution of the two polymeric solutions occurred around the vesicles, allowing them to use the transient interfacial energy exerted by the Korteweg effect. Generally, the self-propulsion of vesicles driven by concentration differences is thought to be due to an osmotic pressure. Nardi et al. estimated that the speed of vesicles driven by osmotic pressure was ∼10−3 μm/s,37 which is far less than the speed observed in this work. PEG produced two different effects required for selfpropulsion: the leakage of macromolecules and the generation of the Korteweg effect. Therefore, the mixing of the two polymeric aqueous solutions served as an efficient driving force for the propulsion of vesicles, even in highly viscous solutions.

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CONCLUSIONS We demonstrated that vesicles encapsulating dextran (DEX) solutions could be transported by the Korteweg effect in a polyethylene glycol (PEG) solution. The motility of the vesicles was dependent on the permeability of the vesicle membrane. The permeability increased discontinuously with increasing PEG concentration, and the motility of the vesicles was observed to change beyond the discontinuous point. There are no restrictions on the types of chemicals that could be used for the generation of the Korteweg effect, because the effect can be generated as long as a system passes through a series of nonequilibrium states far from equilibrium.22−24 In addition, our method for the self-propulsion of vesicles does not require the use of specific materials extracted from microorganisms, pretreatment of supported substrates, or external power sources. This indicates the method’s broad utility for the design of artificial chemotactic systems at the nanoscale. It is possible that microcapsules, aqueous gels, liposomes, etc., impregnated with biocompatible materials will be used in biological organisms by using the Korteweg effect to create controlled delivery systems.

Figure 8. Effect of PEG concentration on the permeability of the vesicle membrane. 2579

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.langmuir.6b00105. Movie file describing a moving droplet with an initital composition of CPEG,drop = 2.4 wt %, CDEX,drop = 21.5 wt %, immersed in a 20 wt % PEG solution (Movie S1) (AVI) Movie file describing a fluorescent image of a moving vesicle encapsulating 20 wt % DEX 40 000 labeled with 0.001 wt % FITC−dextran 40 000 in a 20 wt % PEG solution (Movie S2) (AVI) Movie file describing a moving vesicle encapsulating 20 wt % DEX in a 20 wt % PEG solution (Movie S3) (AVI) Movie file describing the budding dynamics of a vesicle encapsulating 20 wt % DEX in a 5 wt % PEG solution (Movie S4) (AVI) Descriptions of the calculation of the driving force, the permeability of the vesicle membrane, and the dynamics of ATPS droplets at the macroscopic scale (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +81-6-6850-6625. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by JSPS KAKENHI Grant Number 21685020. REFERENCES

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DOI: 10.1021/acs.langmuir.6b00105 Langmuir 2016, 32, 2574−2581

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DOI: 10.1021/acs.langmuir.6b00105 Langmuir 2016, 32, 2574−2581