WO2024069343A1

WO2024069343A1 - Method and system for forming micro-capsules comprising a core surrounded by a shell

Info

Publication number: WO2024069343A1
Application number: PCT/IB2023/059434
Authority: WO
Inventors: Jieke JIANG; Claas Willem VISSER; Tom KAMPERMAN; Albert Thijs Poortinga
Original assignee: Universiteit Twente; Iamfluidics Holding B.V.; Bether Encapsulates B.V.
Priority date: 2022-09-26
Filing date: 2023-09-25
Publication date: 2024-04-04

Abstract

A system for forming micro-capsules comprising a core surrounded by a shell comprises a liquid container (1) and jet means (30) for generating and maintaining a liquid jet. The liquid container is connected to supply means (10,15) for supplying a shell liquid to a fill level of said container. The container is bound by a wall (4) having at least one opening (5) below said fill level that is substantially leak-free to said shell liquid. The jet means are connected to a liquid source (20,25) for supplying a liquid flow of a core liquid and comprise a nozzle (30) for ejecting a jet of said core liquid along a jet propagation path (35). The nozzle opens below said fill level (2) within said container at a distance from said opening (5) and is directed to said opening such that said jet propagation path crosses said opening.

Description

Method and system for forming micro-capsules comprising a core surrounded by a shell

The present invention relates to a method and system for forming micro-capsules comprising a core surrounded by a shell.

Micro-capsules having a liquid or solid core and a solid shell of hydrophobic or hydrophilic nano-particles are broadly used for the protection and controlled release of active compounds in pharmacy, life science, agriculture, and food. One widely applied example comprises a Pickering emulsion. Typically, a mechanically and chemically stable shell protects active molecules in the core of a particle. Controlled porosity, degradation or fracture of the shell results in the release of the core at a desired moment or location. For example, tailored core-shell capsules were employed for pulsatile release at 1, 2, and 5 weeks after a single co-injection of a model vaccine encapsulated by varying micro-capsules.

Recently, core-shell particles enabled several novel features and functionalities. For instance, water micro-droplets coated with hydrophobic nano-particles, also known as "dry water" or "liquid marbles", have been used for enhanced gas storage, improved hydrating properties of cosmetics, and pressure-triggered release of adhesives. Liquid marbles were also used as 3D micro-bioreactors to investigate cellular behaviour in complex 3D environments that mimic the multi-scale arrangements of native extracellular matrix. Furthermore, water micro-droplets encapsulated by porous hydrophobic coatings enable the promising concept of anti-bubbles, i.e. liquid droplets surrounded by an air layer. This was shown to enable controlled burst release of actives via ultrasound actuation. Particles with an aqueous core and a solid shell are also desired in pharmacy, food, agriculture, life science, and cosmetics. Here, the core and the shell are tuned according to the specific application.

Encapsulating aqueous cores with tuneable solid shells is still challenging since there is lack of suitable processing method to produce controllable capsules in scale. In bulk emulsification, a particle suspension or polymer solution (the precursor for the shell layer), is mechanically mixed with the core liquid to form an emulsion followed by a drying step to evaporate the solvent. This method is scalable and is capable of handling suspensions with high concentrations of particles, but provides limited control over the size and morphology of the capsules. As an alternative, micro-capsules with a narrow size distribution and well-controlled morphologies may be obtained by means of micro-fluidic chips for particle loadings up to 0.2 w/v%. The dripping mechanism that forms double emulsions, however, only functions at low throughput (0.3-1.5 rnL/h). Jet-based ejection from coaxial nozzles that eject jets into the air or inkjet printing provides high throughput and precisely tuneable size and morphology of the capsules. A drawback, however, is that the required co-axial nozzles easily get clogged, especially when the suspension has a high loading of particles with the potential to aggregate caused by the surface roughness and stickiness. Similarly, European patent application EP 3.436.188 describes a process of jetting crossing liquid jets in air to form precisely controlled micro-capsules at the collision spot that are substantially mono-disperse. Also this known process, however, is limited as far as the production rate and allowed viscosity of the liquid jets are concerned.

However, the narrow orifice that typically separates the outer surface of the core nozzle and the inner surface of the shell nozzle by a distance AR is prone to clogging by particles that may block the flow. This significantly limits the composition of the shell liquid. Moreover nozzle clogging events also increase in core-shell nozzles when using volatile solvents such as ethanol or acetone due to their rapid evaporation from a small wetted surface that may cause precipitation of any solid shell liquid components.

Submerged jetting from a liquid bath is less prone to such clogging. In that case a nozzle is placed just below the surface of a liquid bath or a liquid film of the shell liquid. Although clogging of the shell liquid is prevented, a large suspension container is nevertheless challenging to stabilize, because the suspended nano- or microscale particles may sink, stick to each other, or form a gel network. Furthermore, jetting from a submerged bath must be directed against the direction of gravity and the micro-capsules obtained this way are far from identical.

Clogging is still a major problem in formulation of micro-capsules, especially since particles that form networks or jam due to their roughness, size or stickiness, such as colloidal silica nano-particles, are often desired in the composition of either their core, shell or both. Clog-free jetting of suspensions, therefore, remains a major challenge on the road to scalable fabrication of controlled micro-capsules with particle-based shells. It is inter alia an object of the present invention to provide a method for the controlled production of micro-capsules that is scalable to an unprecedented level while maintaining control over the properties, size and morphology of the resulting micro-particles of micro-metre to millimetre size.

In order to achieve the afore mentioned object, a method of the type as described in the opening paragraph according to the invention comprises the steps of: providing a liquid container for holding a shell liquid, said container being bound by at least one wall having locally at least one opening to an external atmosphere that is leak free to said shell liquid; maintaining said shell liquid within said container in contact with said wall and extending over said at least one leak-free opening; providing at least one jet of said core liquid, propagating along a propagation path; directing said at least one jet of said core liquid through said shell liquid such that a centre line of said propagation path crosses a leak-free opening of said at least one leak-free opening; and collecting said micro capsules beyond said leak-free opening and along said propagation path as they are delivered by said at least one jet of said core liquid surrounded by said shell liquid.

A system for forming micro-capsules comprising a core surrounded by a shell, according to the present invention comprises a liquid container and jet means for generating and maintaining a liquid jet, wherein said liquid container is connected to supply means for supplying a shell liquid to a fill level of said container, wherein said container is bound by a wall having at least one opening to an external atmosphere below said fill level that is substantially leak-free to said shell liquid, wherein said jet means are connected to a liquid source for supplying a liquid flow of a core liquid, wherein said jet means comprise a nozzle for ejecting a jet of said core liquid along a jet propagation path of said nozzle, wherein said nozzle opens below said fill level within said container, and wherein said nozzle is directed with respect to said opening such that a centre line of said jet propagation path crosses said opening.

The method and system may be applied stationary, upright or inclined with respect to gravity, allowing the microcapsules gaining momentum from gravitation. Alternatively the system and method might also be applied dynamically, particularly rotating around a centre to impose momentum on the microcapsules as they are delivered due to centrifugal forces. The shell liquid container may be closed except for the at least one leak-free opening in the wall. In this respect leak-free means that the shell liquid will not exit the container by gravitational and/or wetting, but remains instead confined to the container by capillary force. Accordingly, no shell liquid flows or leaks out unless driven by the core liquid jet. The shell liquid merely forms a suspension layer, not a co-flowing sheath or jet, and it is the capillary force that will maintain this layer inside the container apart from being dragged out by the core liquid jet.

The container can be an open container such as a ring-shaped holder, for retaining the shell liquid. This particular type of container design allows a clogging-free reaction or solidification in an open space between the core and the shell liquid. This renders the method and system particularly applicable for liquids with a relatively high particle loading ratio.

Said nozzle may be suspended adjustably in order to be able to change its angle (of inclination) and/or distance with respect to said opening. An outlet of said nozzle may be at a distance in front of said opening, within said opening or even sticking out a little beyond said opening. The micro-capsules may be collected to feed a further nozzle of a further system according to the invention, delivering a further, different, shell liquid layer surrounding the microcapsules produced by the previous system.

According to the invention the core liquid is being jetted in a bath of the shell liquid that is being held substantially stationary in said container. The jet is driven solely by inertia of the core nozzle and the nozzle is wetting to the shell liquid in the container. The container has at least one opening below a fill level of said container that is sufficiently small to be nevertheless leak-free to said shell liquid due to the surface tension of said shell liquid. The surface tension of said shell liquid confines the shell liquid to the container despite the presence of the opening(s) thus preventing the shell liquid from leaking out.

Once the jet of core liquid crosses the shell liquid, however, it is being enveloped by the shell liquid before it crosses the opening. The shell liquid is being held substantially stationary during the formation of the micro-capsules. Even relatively viscous liquid may be employed without deteriorating the performance and throughput of the method and system, as the shell liquid need not be forced through any narrow channel or duct. The compound jet of core liquid surrounded by shell liquid is broken up into substantially identical micro-capsules by means of appropriate break-up and/or actuating means. The jet of said core liquid may already comprise a composite jet, particularly a co-axial jet, of multiple liquids or layers. Suitable means are present to collect said substantially identical micro-capsules that are formed this way from said compound jet. The micro-capsules may particularly comprise air shells, Pickering emulsions and/or colloidosomes.

The method and system according to the invention happen to enable clog-free continuous jetting of dense suspensions with particle loading and viscosity up to 10 w/v% and 1 Pa-s, respectively. By enveloping a core liquid jet with a shell layer of a suspension, the method and system according to the invention particularly enable a reliable production of micro-capsules at per-nozzle throughput over two orders of magnitude faster than known chip micro-fluidics.

Lacking a requirement of flowing nano-particle suspensions through micro-scale channels, the invention broadens significantly the choice of the shell materials for functional capsules. Consequently, more concentrated slurries can be jetted to create highly controllable microcapsules with emerging properties. The invention may for instance be used for a high-throughput fabrication of mono-disperse micro-capsules with shells composed of highly concentrated bio-compatible silica nano-particles and biodegradable polyflactic acid) polymers. Drying these capsules results in air-coated capsules (particle-stabilized anti-bubbles) for ultrasound-triggered release of a core compound.

The leak-free nature of the at least one opening in said wall is due to the retention by the surface tension by said shell liquid in combination with the dimensions of said opening. In this respect, specific embodiments of the method and system according to the invention are characterized in that said at least one opening has at least one maximum cross sectional dimension d according to the following formula:

O' d = 2. R < 2. -

P- 9- in which o is the surface tension of the shell liquid, p represents the density of the shell liquid, h is a fill level of the container and g is the gravitational acceleration. A ratio between the diameter of the core nozzle diameter and the diameter of the leak-free opening is particularly smaller than 0,3, specifically less than 0,1. According to the invention it appears possible to direct the jet downwards or vertically through the shell liquid and the opening to thereby gain a beneficial effect from gravity. To that end, a preferred embodiment of the method according to the invention is characterized in that said wall is a bottom or side wall of said container, and said at least one jet of said core liquid is directed trough said shell liquid substantially vertically, and preferably downwards along with gravity. To that end, a system according to the invention is characterized in that said wall comprises a bottom or side wall of said container, and said nozzle opens vertically, and preferably downwards along with gravity. In this case, the momentum and resulting flow rate at which the micro-capsules emerge outside the opening(s) is not only delivered by the intrinsic liquid pressure of the core jet of core liquid travelling through the shell liquid but also gained in part from gravity as the micro-capsules propagate downwards.

The method and system according to the invention enable a parallel production that will increase the production rate. To that end, a preferred embodiment of the method according to the invention is characterized in that said at least one opening comprises multiple openings in said wall that are leak-free to said shell liquid. Similarly, a preferred embodiment of the system according to the invention is characterized in that said at least one opening comprises multiple openings in said wall that are leak-free to said shell liquid, each of said openings having at least one nozzle of said at least one nozzle directed to it. Each of these openings may be used concurrently for the production of micro-capsules to enhance the overall production rate.

A further particular embodiment of the system according to the invention that allows for an increase in a concurrent production of micro-capsules is characterized in that said at least one nozzle comprises multiple nozzles that are directed to a common opening in said wall that is leak-free to said shell liquid. The opening in the wall of the container is in that case share by multiple nozzles to deliver multiple micro-capsules parallel to one another.

Although many nozzle configurations may be used in the system and method according to the invention, a particularly practical setup of the system according to the invention is characterized in that said nozzle comprises at least one capillary duct having a liquid channel extending axially from an inlet to an outlet, said outlet having a line of sight with one of said at least one substantially leak-free opening in said wall. The cross section of the capillary duct may be adjusted or may be adjustable to the intended size of the micro-capsules.

A first further embodiment of the system according to the invention that allows a concurrent formation of micro-capsules parallel to one another is thereby characterized in that said nozzle comprises multiple capillary ducts having a line of sight with a common substantially leak-free opening. A second further embodiment of the system according to the invention is characterized in that said nozzle comprises multiple capillary ducts each having a line of sight with one of said multiple substantially leak-free openings in said wall. Preferably the system according to the invention is thereby characterized in that said bottom of said container comprises multiple openings that are leak-free to said shell liquid, wherein said openings are at least four times an inner diameter of the nozzle spaced apart.

The invention particularly allows the use of a shell liquid of considerable viscosity. In this respect a particular embodiment of the method according to the invention is characterized in that said shell liquid has a viscosity that is larger than a viscosity of said core liquid, while an even more particular embodiment is characterized in that said shell liquid has a viscosity in a range from 0.001 Pa.s to 10 Pa.s, particularly of more than 0.01 Pa.s, even more particularly of more than 0.1 Pa.s, and specifically exceeding 0.3 Pa.s or even exceeding 1 Pa.s.

These relatively high viscosity within the shell layer allow the production of substantially mono-disperse micro-capsules that are so far hard or impossible to realize on an economically feasible scale.

In this respect a particular embodiment of the method according to the invention is characterized in that the said shell liquid comprises a nano-particle suspension having a solid to liquid concentration exceeding 0,2%, particularly of up to 10 w/v%. For non-sticky particles, such as glass beads, it is expected that even rates up to 80% w/v can be reached

A further particular embodiment of the method according to the invention is characterized in that said shell liquid comprises a polymer solution having a polymer to liquid concentration of up to 30 w/v%. A further particular embodiment of the method according to the invention is characterized in that said core fluid is modulated, particularly actuated or vibrated, to render micro-capsules having a similar size of between 15 micron and 5 millimetre and are generated at a core flow rate exceeding 1,5 ml/hour, particularly up to 4 ml/min, for 15 micron particles. The latter is of the order of more than 100 times higher than conventional microfluidic chip methods. When the core fluid is modulated at a suitable frequency, this will create micro capsules of a substantially identical size. Said size may be the true diameter in air of substantially spherical capsules, or otherwise may be defined by their Feret diameter. Size measurements include, but are not limited to, dynamic image analysis, laser diffraction, and dynamic light scattering.

Hereinafter, the invention will be described in further detail with reference to a number of specific embodiments and an accompanying drawing. In the drawing:

Figure 1 shows a schematic setup of a first embodiment of a system according to the invention;

Figure 2 is a side view of a second embodiment of the system according to the invention;

Figure 3 is a bottom view of the embodiment of figure 2;

Figure 4 is a perspective view of a third embodiment of a system according to the invention;

Figure 5 is a side view of a fourth embodiment of the system according to the invention;

Figure 6 is a microscope image of a compound jet containing mono-disperse compound droplets generated by the process according to the invention;

Figure 7 is a microscope image of microcapsules with silica shell fabricated by the process according to the invention;

Figure 8 is a SEM image that indicates that the shell of the capsules of figure 7 is composed of silica nano-particles;

Figure 9A-9B shows microscope images of capsules before and after their shell breaks by mechanically pressing. The released water is visible after breaking (figure 9B), indicating the capsules successfully encapsulated liquid;

Figure IDA shows a microscope image of large amount of compound capsules that were produced by JetALL within seconds;

Figure 10B shows a microscope image of monodisperse capsules in oil. Figure IOC shows a size distribution of the diameters of the capsules of figure 10A and

10B;

Figure 11 shows a microscope image of small PLA capsules with diameters of around 100 micron;

Figure 12 shows PLA capsules made from concentrated (30 w/v%) PLA solution, indicating the compatibility of JetALL with highly concentrated polymer solutions;

Figure 13 shows self-standing PLA capsules in air, after their removal from a bath;

Figure 14 shows a microscope image of a Pickering emulsion (silica-coated water droplets

Figure 15 shows a high-resolution image that indicates that silica capsules have a colloidosome structure;

Figure 16 shows a microscope image of silica capsules in the air;

Figure 17 shows schematically a setup for a symmetry control of the capsules by in-air collision by a side jet;

Figure 18 shows symmetric capsules that were made without the side jet;

Figure 19 shows asymmetric capsules with a shell, having a thin and thick side;

Figure 20 shows capsules with openings that are induced by the collision of a side jet with high surface tension.

Figure 21 shows the formation of an underwater air-shell outside a hydrophobic capsule;

Figure 22 shows microscope images of prepared hybrid capsules in the air;

Figure 23,24 show microscope images at varying magnifications of the capsules of figure 22 after being immersed in water. The air layer was clearly visualized in the high magnification picture, confirming the formation of an air-shell that tolerates the water pressure; and

Figure 25-28 provide time-lapse images showing the ultrasound-triggered release of encapsulated red dye from the air-shells at 0, 18, 24 and 58 second after ultrasonic exposure.

It is noted that the figures are drawn purely schematically and not necessarily to a same scale.

In particular, certain dimensions may have been exaggerated to a more or lesser extent to aid the clarity of any features. Similar parts are generally indicated by a same reference numeral throughout the figures. Figure 1 shows the basic setup of an embodiment of a system according to the invention. The system comprises a container 1 of a stable shell liquid that is maintained by a suitable container 1 having a fill level 2. The container 1 is formed out of a suitable plastic and has one or more vertical walls 3 and the bottom 4. During operation the fill level 2 is maintained by suitable recharging means like a pump 15 that provides a supply of shell liquid from a first storage tank 10 triggered by a level sensor (not shown) and a control unit (not shown).

The system further comprises a supply of a core liquid from a second storage tank 20 that is being delivered by a second liquid pump 25 to a nozzle 30. The nozzle 30 comprises a stainless steel or glass capillary duct with an ultimate inner diameter of approximately 100 micron. For instance a syringe needle may be used as (part of) the nozzle and a syringe pump may be used for the second liquid pump. The capillary duct receives said core liquid at an inlet 31 under elevated pressure to deliver a liquid jet at its outlet 32 along a jet propagation path 35. The nozzle is submerged within the container 1 below said fill level 2 such that the outlet 32 of the duct 30 will open into the shell liquid. The capillary duct is fully wetted by the liquid in which it is submerged. The contact angle of the liquid in container 1 on the surface of the capillary duct is less than 90 °.

At least one of the walls of the container 1, particularly the bottom 4, is provided locally with an opening 5 that is sufficiently small to allow the surface tension of the shell liquid to retain the shell liquid within the container 1. As a result the opening 5 is effectively leak-free to the shell liquid. The nozzle 30 is directed to said opening such that the jet propagation path 35 crosses the opening. This forces the jet of the core liquid to travel through said shell liquid within said container 1 and ensures that the jet of core liquid is being surrounded by a layer of shell liquid to form a co-axial compound jet, consisting of a core of core liquid surrounded by shell liquid.

Suitable actuation means 50 are provided to break-up the compound liquid jet into an interrupted jet of almost identical consecutive micro-droplets that emerge beyond the opening 5. The surface tension of the shell liquid forces the shell liquid around the core as the compound liquid jet breaks up to create these substantially equal micro-capsule, having a kernel of the core liquid and a shell of said shell liquid, that may maintain its initial properties or may enter into a chemical or physical change once it has been formed. The actuation means comprise for instance a ultra-sonic actuator, like a piezo electric vibrator element or other resonator. In this example a piezo element 50 is attached to the nozzle to generate a vibration in the direction perpendicular or parallel to the jet propagation path. The piezo element is driven by a signal of the sine wave from a function generator and a high voltage amplifier. The piezoelectric element is turned on after the second liquid pump 25 is on and the frequency is tuned until a train of mono-disperse droplets is visualized. Typically, the required frequency is within the range of 0.5 to 6 kHz. The nozzle 30 maintains a distance to the opening. The resulting vibration forces the break-up of the liquid jet into droplets of a substantially equal size.

To illustrate the process according to the invention the container 1 is filled with a silica suspension that is continuously refilled to its fill level by the supply means 10,15. The surface tension of this liquid is sufficient to retain the suspension within the container 1 rendering the opening 5 in the bottom 4 of the container 1 effectively leak-free. An aqueous core liquid is stored in the second storage tank 20 and fed under pressure to the nozzle by the syringe pump 25. This liquid is ejected as a core liquid jet by the nozzle 30 through the suspension in the container 1 and through the opening 5 in the bottom of the container 1. The suspension forms a laminar flow layer surrounding the core liquid jet and a compound jet is generated.

Controlled break-up of the compound liquid jet is achieved by vibrating the nozzle by means of the piezo element 50 to produce a train mono-disperse micro-droplets of an aqueous liquid core, as shown in figure 6. After having travelled through the suspension, the ejected liquid jet appeared to be surrounded successfully with the suspension layer to form micro-capsules of the aqueous liquid core surrounded by a silica nano-particle-laden shell formed by said suspension, as shown in Figure 7. The ejected compound droplets travel through the air to be partially solidified by evaporation, thermal solidification, solvent diffusion, polymerization or any other means of solidification.

Collecting these compound droplets in a miscible liquid bath 40 results in the formation of solid micro-capsules via rapid solvent extraction. SEM pictures of the dried capsules in figure 8 show that the shell is assembled by the silica nano-particles. Furthermore, hybrid shells composed of biodegradable polymer, polylactic acid (PLA), and silica nano-particles were successfully achieved with the illustrated method and system according to the invention. To demonstrate that the capsules contain liquid cores, they were broken by mechanical compression. Figure 9 shows a microscope image of the capsules after breaking the shell by mechanically pressing. The released encapsulated liquid was visible after breaking, indeed revealing that the former capsules successfully encapsulated this liquid.

A further upscaling of the process and system according to the invention is shown in the embodiment of figure 2 in side view and in figure 3 in bottom view. According to this embodiment multiple nozzles 31,32,33 are jetting through one liquid layer simultaneously, each with a line of sight of the jet propagation path directed to a common opening 50 in the bottom of the container 1. The three nozzles are of the same kind as that of figure 1 and are fed concurrently with a pressurized core liquid from a storage supply. The container 1 is filled with the shell liquid 10 that will surround the respective core jets that are released by the nozzles 31..33 and travel through the shell liquid on their way to or through the opening 50.

Preferably the container 1 is formed as a narrow gutter having a relatively small transverse dimension or width was compared to its longer longitudinal dimension or length I, as can be seen in the top view of figure 3. The opening in the bottom is a narrow slit 50 and the nozzles 31-33 are spaced apart over a distance A of at least 3 mm in order to avoid a mutual influence. This distance A is likewise observed towards the walls of the container. The slit 50 has at least one maximum cross sectional dimension d of the order of 3 mm that meets: d = 2. R <

' '^{n w} '^ch ° '^s the ^{su r}f^ace tension of the shell liquid, p represents the density of the shell liquid, h is a fill level of the container, particularly a maximum fill level of the container, and g is the gravitational acceleration. This allows the surface tension to retain the liquid within the container 1 such that the opening 50 will be in effect leak-free to the liquid 10.

Figure 4 shows a third embodiment of the system according to the invention that likewise allows for a parallel performance of the method according to the invention. The container 1 of this embodiment is basically cylindrical in shape and comprises an array of leak-free openings 5 at its bottom. Each opening 5 in said bottom has an individual nozzle 30 associated with it, similar to the embodiment of figure 3, that will receive a core liquid concurrently under pressure from a core liquid supply. The container 1 is filled to a defined fill level with an appropriate shell liquid that is constantly or intermittently replenished as required to maintain said fill level. A fourth embodiment of a system according to the invention is shown in figure 5. According to this embodiment a single opening 50 in the bottom of the container 1 is shared in common by multiple nozzles 31..33. Instead of one such opening 50 with multiple nozzles, the container 1 may also have multiple openings each with multiple nozzles to allow for a further upscaling of the throughput if the system. The nozzles associated with individual opening may be fed with the same core liquid or may each be supplied with another core liquid in order to obtain a mixture of different micro-capsules having a same shell layer but different cores.

The process according to the invention is compatible with various materials to fabricate capsules with high tunability. As shown in figures 10A-10C, scalable production of monodisperse (coefficient of variation < 10%) water-laden capsules with colloidal si I ica/P LA shells were achieved. The process according to the invention does not need the formation of a double emulsion, which allows a wide and almost unlimited variety of combinations of shell materials and the core material. As an example, small capsules possessing pure PLA shells with diameters of around 100 micron were fabricated, as shown in figure 11. Similarly, a precursor containing a much higher loading of PLA (30 w/v%) was successfully processed to make the PLA capsules (Figure 12). Those capsules are mechanically robust even after being taken out from the collection bath into air (Figure 13). Furthermore, the process according to the invention allows the self-assembly of silica particles to form Pickering emulsions or colloidosomes, as is shown in Figure 14.

The detailed microscope image in Figure 15 indicates the silica particles inside the shell layer formed a so-called colloidosome structure. After retrieving the capsules from the bath, the silica capsules form self-standing translucent micro-containers (Figure 16). If surfactants are added instead of nano-particles, simple emulsions are formed. Remarkably, the symmetry and thickness of the shell layer can be tuned by introducing a side jet for in-air collision of the jetted compound droplets as schematically shown in Figure 17. Compared to symmetric capsules that are obtained without the side jet (Figure 18), the introduction of a side jet produces an asymmetric shell, as shown in figure 19, that has a considerably thinner side that could be leveraged e.g. for accelerated release. A high surface tension side jet will create an opening on the collided capsules, as shown in figure 20, which can for example be used in self-propelled micro-robotics. Hydrophobic nano-particle covered capsules have unique properties in contact-less liquid transportation and triggered release. The process according to the invention enables the formation of densely coated stable colloidosome, which can be transformed into nano- particle-coated capsules. Capsules with hydrophobic shells composed of nano-particles can be created by the process according to the invention and immersed in aqueous medium, resulting in ultrasound-triggerable capsules (also called particle-stabilized anti bubbles) as shown in figure 21. The process according to the invention allows high-throughput fabrication of these air-shells of the order of 3000 capsules per second by jetting of concentrated suspensions of hydrophobic silica particles around an aqueous core without clogging. These capsules were dried (Figure 22) and immersed into water, resulting in an air-layer outside the capsules (Figure 23). The formation of the silver-colour reflection indicates a stable air layer formed outside the capsules (Figure 24). The formation of this air layer resembles the formation of so-called diving bells that is observed for aquatic insects.

Notably, by adding PLA, the hydrophobicity of the shell reduces and, as a result, the air layer will collapse after one hour, providing release of the liquid core. Pure hydrophobic silica was used to form a more stable air layer. The resulted air-shell successfully encapsulated the liquid core containing red food dye for up to 70 hours of contact with water. Afterward, sonication was used to release the encapsulated liquid core with red dye. As shown in Figure 25-28, during sonification, the air layer of the capsules was released, forming large visible air pockets. Meanwhile, the silica shell was ruptured to release the encapsulated liquid core. The high-throughput production of well-controlled micro-capsules with such an air-shell may be applied successfully in the field of controlled release of compounds, CO2 electrolysis for renewable fuels or adsorption of volatile organic compounds.

In conclusion, the process and system according to the invention provide inter alia a robust route for the rapid fabrication of controlled micro-capsules with aqueous cores and hydrophobic shells that consist of nano-particles and polymers. The invention provides an at least substantially clog-free method for jetting suspensions with high concentrations of solid particles (e.g. up to 10 w/v% silica) and polymers (e.g. up to 30 w/v% PLA). Micro-capsules may be produced at high rate with an aqueous core that appear robust enough to be dried in the air. Especially, super-hydrophobic capsules with air-shells can be fabricated by invention at high throughput. Conceptually, the present invention combines the key features of jetting from a coaxial core-shell nozzles and those of submerged jetting from a liquid bath. The invention thereby combines the benefits associated with any of these techniques, notably a large flow rate combined with a highly mono-disperse production in size and morphology, without inheriting their limitations. Such scalable and flexible fabrication of controlled, particle-coated microcapsules will play a key role in drug delivery, preservation of food, gas sensing and storage, and liquid transportation.

Claims

Claims:

1. Method for forming micro-capsules, said micro-capsules comprising a core surrounded by a shell, said method comprising the steps of: providing a liquid container for holding a shell liquid, said container being bound by at least one wall having locally at least one opening to an external atmosphere that is leak-free to said shell liquid; maintaining said shell liquid within said container in contact with said wall and extending over said at least one leak-free opening; providing at least one jet of said core liquid, propagating along a propagation path; directing said at least one jet of said core liquid through said shell liquid such that a centre line of said propagation path crosses a leak-free opening of said at least one leak-free opening; and collecting said micro-capsules beyond said leak-free opening and along said propagation path as they are delivered by said at least one jet of said core liquid surrounded by said shell liquid.

2. Method according to claim 1, wherein said at least one opening has at least one maximum cross sectional dimension d according to the following formula: d = 2R < 2.^-^ , in which o is the surface tension of the shell liquid, p represents the density of the shell liquid, h is a fill level, particularly a maximum fill level, of the container, and g is the gravitational acceleration.

3. Method according to claim 1 or 2, wherein said wall is a bottom or side wall of said container, and wherein said at least one jet of said core liquid is directed trough said shell liquid downwards, and preferably substantially vertically along with gravity.

4. Method according to claim 1, 2 or 3, wherein said at least one opening comprises multiple openings in said wall that are leak-free to said shell liquid.

5. Method according to anyone of the preceding claims, wherein said shell liquid has a viscosity that is larger than a viscosity of said core liquid.

6. Method according to claim 5, wherein said shell liquid has a viscosity in a range from 0.001 Pa.s to 10 Pa.s, particularly of more than 0.01 Pa.s, even more particularly of more than 0.1 Pa.s, and specifically exceeding 0.3 Pa.s or even exceeding 1 Pa.s.

7. Method according to anyone of the preceding claims, wherein said shell liquid comprises a nano-particle suspension having a solid to liquid concentration exceeding 0,2

particularly of up to 10 w/v%.

8. Method according to anyone of the preceding claims, wherein said shell liquid comprises a polymer solution having a polymer to liquid concentration of up to 30 w/v%.

9. Method according to anyone of the preceding claims, wherein said core fluid is modulated, particularly actuated or vibrated, to render micro capsules having a similar size of between 15 micron and 5 millimetre and are generated at a flow rate exceeding 1,5 ml/hour.

10. Method according to anyone of the preceding claims, wherein said micro capsules are generated at a production rate of between 1,5 ml/hour and 4 ml/hour.

11. System for forming micro-capsules comprising a core surrounded by a shell, said system comprising a liquid container and jet means for generating and maintaining a liquid jet, wherein said liquid container is connected to supply means for supplying a shell liquid to a fill level of said container, wherein said container is bound by a wall having at least one opening to an external atmosphere below said fill level that is substantially leak-free to said shell liquid, wherein said jet means are connected to a liquid source for supplying a liquid flow of a core liquid, wherein said jet means comprise a nozzle for ejecting a jet of said core liquid along a jet propagation path, wherein said nozzle opens below said fill level within said container, and wherein said nozzle is directed with respect to said opening such that a centre line of said jet propagation path crosses said opening.

12. System according to claim 11, wherein said at least one opening has at least one maximum cross sectional dimension d according to the following formula: d = 2R < 2.-^-^, in which a is the surface tension of the shell liquid, p represents the density of the shell liquid, h is a fill level of the container, particularly a maximum fill level of the container, and g is the gravitational acceleration.

13. System according to claim 11 or 12, wherein said wall comprises a bottom or side wall of said container, and wherein said nozzle opens downwards and preferably substantially vertically along with gravity.

14. System according to anyone of claims 11 to 13, wherein said at least one opening comprises multiple openings in said wall that are leak-free to said shell liquid, each of said openings having at least one nozzle of said at least one nozzle directed to it.

15. System according to anyone of claims 11 to 14, wherein said at least one nozzle comprises multiple nozzles that are directed to a common opening in said wall that is leak-free to said shell liquid.

16. System according to anyone of claims 11 to 15, wherein said nozzle comprises at least one capillary duct having a liquid channel extending axially from an inlet to an outlet, said outlet having a line of sight with one of said at least one substantially leak-free opening in said wall.

17. System according to claim 16, wherein said nozzle comprises multiple capillary ducts having a line of sight with a common substantially leak-free opening.

18. System according to claim 16, wherein said nozzle comprises multiple capillary ducts each having a line of sight with one of said multiple substantially leak-free openings in said wall.

19. System according to anyone of claim 13, wherein said liquid container comprises a container having opposite longitudinal walls that are connected by said bottom, wherein said bottom has a width between said walls that is smaller than a length of said bottom along said walls.

20. System according to anyone of claims 11 to 19, characterized in that said bottom of said container comprises multiple openings that are leak-free to said shell liquid, wherein said openings are at least four times an inner diameter of the nozzle spaced apart.