RU2633655C1 - Device for dosed opening of microcapsules - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: device for dosed opening of microcapsules comprises a substrate and at least one well for the microcapsule, at least one first conductive layer located on the substrate, at least one dielectric layer located on the first conductive layer, at least one second conductive layer located on the dielectric layer. The well is formed in the dielectric layer between the electrically conductive layers, and the second conductive layer is provided with at least one opening located above the well and having a diameter corresponding to the well diameter.

EFFECT: ensuring of a possibility of increasing the accuracy of the required substance dosage.

4 cl, 3 dwg

Description

The invention relates to the field of nanotechnology and can be used to create a reusable system for targeted delivery of drugs by controlled (dosed according to a specific program) receipt of a medicinal substance extracted from the volume of one or more microcapsules by opening them with an electric field.

A known hybrid system for the release of the delivered substance from microobjects (liposomes) by exposure to an electric field (Gulyaev Yu.V., Cherepenin V.A., Vdovin V.A., Taranov I.V., Faykin V.V. et al. Remote activation using a pulsed electric field of nanocomposite microcapsules based on complexes of lipids, polymers and conductive nanoparticles // Journal of Radioelectronics (electronic journal) - 2014. - No. 11. - P.1-32, ISSN 1684-1719 [Electronic resource] http : //jre.cplire.ru/jre/nov14/9/text.pdf (accessed: 03/22/2016)). This system of targeted drug delivery is based on the interaction of liposomes, the membranes of which include conductive particles, with an electric field. The key point in this method is a significant change in the surface structure of liposomes as a result of such an interaction, which in turn leads to the release of substances encapsulated in liposomes.

The disadvantage of this system is that the magnitude of the electric field (i.e., its critical values at which liposome decapsulation occurs) and the pulse energy can be not only sufficient, but also excessively large, capable of affecting not only microcapsules with drugs, but and other microobjects - elements of cellular structures or blood cells. During a short pulse, neither the magnitude of the field, nor the time of its action is corrected, and the process is actually uncontrollable. Thus, for each case, an additional procedure is required to determine the critical values of the external electric field.

The prototype of the claimed technical solution is a biological microfluidic chip, the design of which was developed by the authors of the patent “Biological microfluidic chip and related methods” (see international patent application No. WO / 2010/149292, IPC B01L 3/00, C12M 3/00, publ. 12/29/2010). This invention consists of a substrate containing several microfluidic ports, which are a collection of holes on the surface of the substrate. There are many holes on it, isolated from each other by one or more walls, connected by channels.

However, a significant drawback and fundamental limitation of this invention is the need to use heat-sensitive microobjects (photosynthetic bodies) to enable opening of microcapsules by heating. A completely logical consequence of heating will be the opening of not only microcapsules with drugs, but also damage to other micro-objects and system elements - red blood cells, platelets, and other adjacent cell structures and even whole organs. Undesirable overheating can cause a violation of their functions, up to irreversible degradation and destruction. In addition to the above, another significant drawback should be noted: the described invention does not imply repeated use, the authors not only did not establish this functional property, but also did not even analyze such a possibility. In addition, the design described in the patent is quite voluminous, which complicates its integration into the bloodstream or individual organs. The design has a complex device, its formation requires the use of three-dimensional technology (for example, 3D printing, the creation of three-dimensional templates and complex three-dimensional equipment) and it is not intended to use a well-developed planar technology.

The objective of the invention is to develop a device for storing microcapsules with drugs (in specially formed holes) and their metered opening by local exposure to an external electric field.

The technical result achieved by using the inventive device is to increase the accuracy of the dosage of the required substance due to the possibility of selective opening of microcapsules with drugs.

The specified technical result is achieved in that the device for the metered opening of the microcapsules containing the substrate and at least one well for the microcapsule, according to the solution, the device contains at least one first electrically conductive layer located on the substrate, at least one dielectric a layer located on the first conductive layer, at least one second conductive layer located on the dielectric layer, and the hole is made in the dielectric layer between the conductive layers, and the second conductive layer is provided with at least one hole located above the hole and having a diameter corresponding to the diameter of the hole. The device comprises a second dielectric layer located between the dielectric layer with the holes and the first electrically conductive layer located on the substrate. The device contains a membrane located on the second conductive layer and made permeable to the contents of the microcapsule. The substrate is made in the form of a tube with a diameter equal to the diameter of a blood vessel, while the first electrically conductive layer is located on the inner surface of the tube.

The invention is illustrated by drawings, where in FIG. 1 shows a variant of a device with three holes, a top view; in FIG. 2 - section AA, passing through the wells into which microcapsules of different diameters are placed; in FIG. 3 is a top view of a device with six holes.

The positions in the drawing indicate:

1. substrate;

2. the first conductive layer;

3. the first dielectric layer;

4. a second dielectric layer;

5. hole;

6. a second electrically conductive layer for forming a potential difference in the first well;

7. a second electrically conductive layer for forming a potential difference in the second well;

8. a second electrically conductive layer for forming a potential difference in the third well.

The inventive device is the following design.

On the substrate 1, the material of which can also be different depending on the specific application, there is a continuous first conductive layer 2. It is a continuous electrode in the form of lines or lines, on it there is a first dielectric layer 3 and a second dielectric layer 4. In the upper second dielectric layer 4 there are isolated wells, or cavities with certain sizes 5. The upper dielectric layer is covered with second conductive layers 6, 7, 8 with holes for free penetration of microcapsules with sizes It is smaller than the diameter of the holes. Through these openings, microcapsules of an appropriate size are drawn into the region between the electrodes and held there until they are opened. The first and second electrically conductive layers 2, 6, 7, 8, formed in the form of intersecting strips lying in different layers, not electrically connected to each other. Between the conductive layers are dielectric layers, which serve to create a strictly fixed distance between the conductive layers.

As an example in FIG. Figure 1 shows such a system in which the dielectric layers are made of various materials with different thicknesses, which allows not only to form a hole of a certain size, but also to obtain reliable insulation of the lower electrode, which avoids electrochemical reactions on the surface of the electrodes and affects microcapsules with drugs exclusively electric field, excluding the flow of electronic and ion currents and the associated undesirable heating of system elements, including microcapsules with drugs.

Not only crystalline or solid-state substrates, but also flexible ones, for example polymer substrates, can be used in the construction as a base material; as an option, they can be biocompatible, built into the bloodstream, applied to the surfaces of organs, onto skin integuments, fixed on top with a band-aid or having adhesive layer permeable to microcapsules.

Wells can be created using various methods: etching through a mask, applying layers through a mask, laser perforation, or some other method or technology. Wells can have different diameters and depths, which allows you to selectively manipulate and open microcapsules of various sizes with different contents. Each of the holes in the system can be filled with microcapsules of the appropriate size. Wells after refilling with microcapsules can be covered with a thin membrane permeable to drugs, which allows the use of this device extracorporeally, without the participation of liquid (blood or lymph) as a drug carrier. In this case, after the voltage is applied, the microcapsules are opened, and the drug goes out, the dosage occurs through the skin. This may be applicable to volatile, aromatic and other drugs that can enter the bloodstream through the skin.

A voltage can be applied to any of the holes (to the corresponding electrodes), which leads to the opening of the microcapsule located in this hole.

Before using the system, its wells must be filled with microcapsules. The wells are refilled by flushing the system with the wells in a solution containing microcapsules, the diameter of which corresponds to the diameter and depth of the system holes.

The design includes the ability to differentiate microcapsules in size and charge.

If it is necessary to introduce or control the opening of single microcapsules, it is necessary to create a system of holes with a diameter and depth approximately equal to the diameter of the used microcapsules containing the drug substance.

In one well system, wells of various diameters and depths can be formed, which allows filling different sized wells with microcapsules of various sizes. In this case, the system is refilled in several stages: first, they are filled into larger holes with the corresponding larger microcapsules. After all the large holes are occupied, the smaller holes are refilled by flushing the system in solution with smaller microcapsules. The procedure is repeated until all the wells of the system are filled, or until all the necessary microcapsules are present in the corresponding wells.

If necessary, microcapsules with substantially smaller sizes can be introduced into wells with a large diameter and depth. In this case, several microcapsules placed at random will be in the same hole at the same time.

If it is necessary to place microcapsules in a single hole in the form of a sequential chain aligned perpendicular to the plane of the base, the diameter of the hole should correspond to the diameter of the microcapsule, and the depth should be several times greater than the diameter (i.e., the depth of the hole should be as many times the diameter of the hole how many microcapsules should fit in one well). The increase in depth is achieved by varying the thickness of the dielectric layer (one or more).

To expand the functionality of the patent device, it is possible to create a system of layers of different thicknesses, in which the wells of different layers are combined so that smaller microcapsules can freely pass through the upper layers, reach their layer and are placed in a hole of an appropriate size. In this case, holes of a smaller diameter are formed in the layers lying below, and holes of a larger diameter in the layers lying above. The electrodes supplying voltage to each layer, in this case, are wired like a multi-level wiring in microcircuit chips. The number of pairs of dielectric and electrically conductive layers can be many, which makes it possible to selectively act on microcapsules lying between selected pairs of electrically conductive layers to open these microcapsules, while it is not necessary that the voltage be applied to the pairs of the nearest conductive layers.

To achieve a more efficient filling of the wells with microcapsules, a small potential can additionally be applied to the lower electrode to create a retracting field (i.e., the potential of the lower electrode should have the sign opposite to the sign of the surface potential of the microcapsule). Using the potential of a different sign allows you to separate the process of filling holes with microcapsules of different signs. Microobjects of different sizes (in particular, microcapsules) can be placed in the wells, the diameter of the microcapsule should be 5-10% less than the diameter of the holes.

After refueling the system with microcapsules, the system is ready for use.

The selectivity of opening the microcapsules is determined by the choice of electrically conductive layers 2, 6-8, between which the capsule (one or more) is located, and the application of the required voltage to them.

In FIG. 2 shows one of the modifications of the device with well systems. This modification of the device allows you to open certain capsules when external voltage is connected to a certain second conductive layer 6-8, this will allow you to vary the operation of the device and open the capsules both all at the same time or separately (i.e., specific). At the intersection of the lines of the electrically conductive layers there is a specially fixed microcapsule, which is exposed to an electric field, in the case of applying a potential difference to the corresponding pair - one electrode from the first conductive layer and one electrode from the second conductive layer.

For opening the microcapsules, a constant and / or alternating voltage supplied to the electrically conductive layers can be used, the value of which will be sufficient to violate the integrity or decompression of the shell. To create voltage on the electrically conductive layers of the hole system, a special voltage control system can be used - a conversion circuit combined with the hole system and placed on the basis of or representing an additional device (chip, microcontroller, etc.) made separately and connected to the hole system by conductors .

Electrical power for the operation of the control system and the system of holes can be carried out by an alternating electromagnetic field (inductively through the skin), using electrochemical cells, by supplying energy in the form of light with further conversion using photovoltaic cells and other methods.

It is assumed that the voltage control system should be able to control the voltage (or potential distribution) on any selected pair of electrically conductive layers. In this case, the electrically conductive layers to which the voltage can be applied can lie both in different layers and in one layer, depending on the desired effect: either to draw microcapsules into the corresponding wells, or to open the microcapsules already filled into the wells, or to clean holes from the decay products of microcapsules.

Physico-chemical processes that occur when creating voltage for opening microcapsules can be described as follows.

When sufficient voltage is applied to the electrically conductive layers between which the charged microcapsule is located, local changes in the acidity of the solution occur under the influence of an electric field. In areas adjacent to the conductive layers: an applied external electric field leads to the drift of cations and anions to the corresponding conductive layers. Over time, anions and cations accumulate in these regions (in this case, a change in their local concentrations can reach 1–2 or more orders of magnitude). At the same time, a change in acidity occurs in these areas: in the corresponding electrically conductive layers, the pH index shifts toward acidic or alkaline values. A local change in acidity in turn leads to a change in charge in the polar groups of surfactant molecules, from which microcapsule membranes are formed. Due to this, the Coulomb repulsion of molecules is enhanced. The membranes of the microcapsules become more discharged, which, in turn, leads to an increase in their permeability and promotes the outflow of the contents (PM) from the microcapsule to the outside and enters the external environment (for example, into the bloodstream or lymph system).

The device can be rolled up or in the form of a tube, the diameter of which is equal to or comparable with the diameter of blood vessels, and can be integrated into one of these vessels similarly to embedding stents. In this case, the first electrically conductive layer is located on the inner surface of the tube, which ensures electrical isolation of the system of electrically conductive layers between which current can flow from the walls of blood vessels.

Refueling of such a device can be carried out without removing the device from the body, for which two microcapillaries are introduced into the section of the vessel above and below the bloodstream, connected to special containers (containing solutions with microcapsules) through a peristaltic pump; the section of the vessel above and below the capillaries is temporarily pulled over and a solution with appropriate microcapsules is pumped through the closed volume; the pumping procedure is carried out until the wells of the device are filled with the necessary microcapsules. Monitoring the filling of device holes with microcapsules with a drug can be done by measuring the capacitive parameters of each of the holes; when a microcapsule enters a well, capacitive parameters can change quite sharply, which will make it possible to track the act of a microcapsule entering a well.

Claims (4)

1. A device for the dosed opening of microcapsules containing a substrate and at least one well for a microcapsule, characterized in that the device contains at least one first conductive layer located on the substrate, at least one dielectric layer located on the first conductive layer, at least one second conductive layer located on the dielectric layer, the hole is made in the dielectric layer between the conductive layers, and the second conductive layer is provided ene at one opening positioned above the hole and having a diameter corresponding to the diameter of the hole. 2. The device according to claim 1, characterized in that it contains a second dielectric layer located between the dielectric layer with the holes and the first electrically conductive layer located on the substrate. 3. The device according to claim 1, characterized in that it contains a membrane located on the second conductive layer and made permeable to the contents of the microcapsule. 4. The device according to claim 1, characterized in that the substrate is made in the form of a tube with a diameter equal to the diameter of a blood vessel, while the first electrically conductive layer is located on the inner surface of the tube.

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