JPH0441420A - Self-propelled intelligent material - Google Patents

Abstract

PURPOSE:To obtain the subject material, capable of expressing function while moving in intellectual response to environment sensed with itself by integrating a micro-sensor with a micro-actuator in a self-organizing system. CONSTITUTION:A liposome prepared by integrating three of a lipid double membrane, a micro-sensor and a micro-actuator in a self-organizing system, forming closed vesicles and holding a drug therein. The material is capable of sensing a substance specific for cells of affected parts with the own micro- sensor, judging the target site of the target cell based on concentration gradient of the aforementioned substance, interlocking with the micro-sensor, actuating the own micro-actuator, thereby accurately approaching to the affected parts and releasing the drug held in the interior thereto. A micro-sensor responsive to stimulation from the external world such as molecules, ions, heat, light or pH is used as the micro-sensor and the micro-actuator is constructed from a biological model of muscular contracting and ciliary movement, etc. The application to drug.delivery.systems, methods for forming patterns, biocomputers, etc., is expected from the aforementioned material.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a self-propelled intelligent material that expresses (actuates) functions while moving in response to the environment it senses (sensing). .

[Summary of the invention]

The present invention aims to realize a self-propelled intelligent material that is extremely small and can actively move by integrating at least a micro sensor and a micro actuator in a self-organizing manner.

[Prior Art] In the fields of industrial machinery, medical welfare equipment, etc., there is an increasing demand for compact actuators (power sources) with advanced functions. The mainstream of conventional small actuators is electric motors that can be easily controlled digitally, but their energy conversion efficiency is said to be proportional to the 2/3 power of the volume, achieving multiple degrees of freedom, high output, and miniaturization at the same time. It is almost impossible to do so. Even if a small, high-power machine with multiple degrees of freedom were realized, a dedicated high-performance computer would need to be constantly running to control it, and the system as a whole would not become larger or more complex. This suggests that future actuators will have to be based on completely different principles and be intelligent.

In recent years, the concept of intelligent materials inspired by biological functions, structures, movements, etc. has been proposed and is attracting attention.

This is a material that embodies the functions of a detection means (sensor), an information processing means (processor), and an active means (actuator or effector) in a single material, and also aims to link these functions with each other. It is.

In the conventional thinking, these champions were independent devices, but
According to the concept of intelligent materials, these elements are integrated and can naturally behave in response to the environment. Therefore, there are great expectations for its application to new drug delivery systems, artificial organs, bioreactors, biosensors, biocomputers, structural materials, and the like.

Artificial organs are a promising application field for intelligent materials. For example, the pancreas detects blood sugar levels on the surface of β-cells in the islets of Langerhans, and controls the release of insulin stored in the endoplasmic reticulum within the cells according to the detected levels. Conventional artificial pancreases, which are being developed for the purpose of treating diabetes, are equipped with blood sugar sensors,
It consists of devices such as a microcomputer, an insulin pump, and a battery that serves as a power source. But if intelligent membranes were developed that automatically changed their insulin permeability depending on blood sugar levels, these devices would no longer be necessary.

Furthermore, if an artificial bone that grows or disappears with the growth state of the living bone can be created using intelligent materials, there will be no need for re-surgery as the living body grows or heals.

Alternatively, in structural materials with defects such as cracks, self-diagnosis is possible, such as informing the outside of the deterioration by coloring or emitting electrons at the tips of the cracks, and automatically filling the cracks by eluting the incubating components. Self-healing properties can also be expected.

In this way, the ultimate form of intelligent materials, which are expected to have a variety of applications, is thought to be a type of molecular machine. However, it is extremely difficult to synthesize this as a molecule using current technology, so attempts are being made to design molecular aggregates as a more realistic approach.

For example, molecules that react with specific substances and release hydrogen, such as those found in certain enzymes, are used as microsensors, and polymers that expand and contract due to changes in local pH are used as microactuators.
Wrapping these in a polymer net to form microcapsules is considered to be a relatively feasible means.

[Problem to be solved by the invention]

As mentioned above, it is an intelligent material that has been considered for a variety of application fields, but the functions of microactuators that have traditionally been assumed are static images such as releasing a stored substance at a fixed location. However, the concept of an intelligent material acting as an active moving organ and freely moving the intelligent material itself has not been proposed.Furthermore, the concept of an aggregated state of microsensors and microactuators being confined in a microcapsule has not been proposed. It is difficult to create extremely small intelligent materials at the micron or submicron level because this is achieved through physical methods and there is no thermodynamic necessity for the aggregated state.

Therefore, an object of the present invention is to provide a self-propelled intelligent material that is minute and can actively move beyond the limits of conventional technology.

[Means to solve the problem]

The self-propelled intelligent material according to the present invention is proposed to achieve the above-mentioned object, and is characterized in that at least a microsensor and a microactuator are integrated in a self-organized manner. be.

[Operation] Self-organizing integration in the present invention means assembling a thermodynamically stable structure as if it were a single organization using materials that have mutual affinity. Therefore, it is possible to easily construct an intelligent material that is much smaller than the conventional method of simply physically confining a microsensor and a microactuator that do not have any special interaction in a microcapsule. Furthermore, the microsensor and microactuator that are integrally assembled in this manner can sensitively respond to changes in each other directly or indirectly through the tissue that connects them.

Furthermore, the micro actuators in the intelligent material of the present invention function as a kind of movement organ, so they can always be actively moved, quickly move to the desired location, and allow the intelligent material to concentrate on the intended work. It becomes possible to do so.

〔Example〕

Hereinafter, preferred embodiments of the present invention will be described.

Example 1 This example is an example of constructing a closed vesicle that can provide a novel drug delivery system by applying the present invention.

The closed vesicles in this example are based on liposomes. In the field of drug delivery systems, methods have already been put into practical use to impart sustained release properties and cell specificity to drugs using liposomes as carriers. Liposomes can gradually release drugs during blood circulation, partially migrate from blood vessels to tissues where they release drugs, or can be enzymatically absorbed by phagocytes or fused to other cells. while releasing the drug. In conventional techniques, a certain degree of cell selectivity or organ selectivity has been achieved by adjusting the liposome size and membrane charge, or by modifying the liposome surface with an antibody that functions as a microsensor.

However, the liposome described in this example is not simply composed of a lipid bilayer membrane or has a microsensor such as an antibody added thereto, but is also equipped with a microactuator.

The microsensor and microactuator do not necessarily need to be separate structures, and a single substance may have both functions. Furthermore, a drug is retained inside the liposome. The above microsensors and microactuators are made of lipids, 15! It may be a substance that has been modified so that the constituent components of normal biological membranes such as lipids, proteins, and glycoproteins can express a specific function, or it may be a substance that does not inhibit membrane formation or exhibit toxicity. They may be selected from materials other than biological materials within a range, and the number and arrangement of these materials in the membrane are not particularly limited. For example, a single microactuator can imitate the flagellar movement of bacteria or protozoa, and multiple microactuators can imitate protozoan ciliary movement or amoeboid movement.

By the way, the above-mentioned microsensors include those that respond to all kinds of external stimuli such as molecules, ions, heat, light, pH, air, magnetism, sound, pressure, etc. Taking identification as an example, Hormone Tori Sebuta,
The first idea is to apply the specific interactions observed between antigens and antibodies, enzymes and substrates, etc. to sensor functions. In this case, each of the above-mentioned substances or modified substances thereof may be embedded in the lipid bilayer membrane as a microsensor.

Alternatively, sensing is possible without relying on specific interactions that naturally exist in living organisms.

For example, a site where cancer cells proliferate has a higher temperature and lower pH than a normal site, so a heat sensor or a pH sensor can be used to identify the affected area. It is also possible to label cells of interest with a fluorescent antibody and detect the fluorescence using an optical sensor.

On the other hand, various types of microactuators are conceivable, but at present, they are suggested more by biological models than by microsensors. In this case, biological models include muscle contraction, flagellar movement of bacteria and sperm, ciliary movement, and amoeboid movement seen in protozoa, phagocytes, and the like. As is well known, muscle contraction is caused by sliding motion between two types of proteins, actin and myosin. Regarding bacterial flagellar movement, for example,
Biophysics” Vol. 26, No. 2, pp. 73-82 (1986)
As reviewed in 2010, it has been revealed that there is a flagellar motor made of protein at the base of the flagellum, which uses hydrogen ions as energy to rotate the flagellum. In addition, ciliary movement in protozoa consists of an effective stroke in which sliding occurs between microtubules inside the cilia with a (9+2) structure, causing the cilia to bend, and an effective stroke that propagates toward the tip of the cilia and then returns to its original position. This is due to repeated recovery strokes. Furthermore, in amoeboid movement, plasma flow occurs due to the interaction of contractile proteins using ATP as an energy source, and as a result, the cell membrane moves the cell body while extending pseudopodia.

Here, as a microactuator that obtains propulsive force by utilizing the sliding motion between proteins, it is conceivable to use a higher-order structure in which two rod-shaped proteins are arranged back to back due to interaction, for example. When the relative positions of two proteins shift two-dimensionally, a rotational moment about the center of gravity of the higher-order structure is generated. If the direction of the deviation is opposite, the rotational moment will also be in the opposite direction. By repeating the occurrence of such deviation, a plane wave is generated, and a propulsion force can be obtained.

Alternatively, in the above-mentioned higher-order structure, if one protein stretches, the other contracts, and one protein contracts, the other stretches, and if this action is repeated, a bending motion similar to that of a bimetal can be expected.

Furthermore, as microactuators that do not use biomaterials, those that apply mechanochemical systems and mechanothermal systems are highly feasible.

A mechanochemical system is a system that converts chemical energy into mechanical energy. For example, a crosslinked polymer having methacrylic acid in its main chain has -C in its side chain in an alkaline solution.
Most of the OOH groups dissociate, causing electrostatic repulsion within the molecules and causing swelling; however, in an acidic solution, most of them recombine, causing the repulsion to disappear and the gel to shrink. In addition to this, mechanochemical systems based on operating principles such as redox, photoisomerization, and phase transition can be considered.

On the other hand, a mechanothermal system is a system that converts thermal energy into mechanical energy. For example, a typical example is the phase transition between martensite and austenite phases in shape memory alloys.

Among the lipids, phospholipids, which are the main constituent lipids of biological membranes, are used as molecules constituting the lipid bilayer membrane, which is the main component of the liposome in this example.

Generally, zwitterionic lecithin (phosphatidylcholine) and sphingomyelin, anionic phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine having a -grade amino group, and the like are used. Furthermore, cholesterol or the like may be added as a neutral lipid to stabilize the membrane.

Although the above are natural lipids derived from biological membranes, artificial lipids can also be introduced. For example, stearylamine dicetyl phosphate sulfolipids can be used to control surface charge, and long-chain alkyl glucosides with myristyl, heptyl, stearyl, etc. It can also be used as a lipid.

The method for preparing liposomes is not particularly limited in the present invention, and can be appropriately selected from various known methods depending on the desired shape and size.

The simplest case is when a microsensor and a microactuator can be incorporated simultaneously during the formation of a lipid bilayer. In this case, (1) dissolve the lipid, microsensor, and microactuator as described above in an organic solvent in a suitable container, remove the organic solvent by evaporation, and form a thin lipid film on the vessel wall.
However, after forming a microsensor and microactuator), a drug solution is injected into a container and stirred with a mixer; ■ A method in which an organic solvent containing lipids, microsensors, microactuators, and drugs is irradiated with ultrasonic waves. , ■ A method of forming mixed micelles by coexisting a surfactant such as sodium cholate or sodium deoxycholate in the organic solvent in (■) above, and removing the surfactant by dialysis (cholate dialysis method), ■ Chloroform A method of preparing an emulsion using a solution of a lipid dissolved in ether and a buffer solution and evaporating the solvent (reverse-phase evaporation method); A method such as evaporation can be applied.

However, when microsensors and microactuators are made of materials such as proteins and glycoproteins, the use of organic solvents or ultrasonic irradiation causes large vibrations that can lead to denaturation. It is desirable to introduce microsensors and microactuators after the formation of the microsensors and microactuators. For example, a method in which an antibody bound to a hydrophobic group is introduced onto a liposome by cholic acid dialysis, or a method in which an antibody is introduced into a sugar chain portion of a glycoprotein that has been introduced in advance can be referred to. In this case, the microsensors and microactuators may penetrate the lipid bilayer membrane or be buried only in the surface monolayer, depending on the distribution of hydrophilic and hydrophobic regions in their structure. I can do it.

Regardless of which method is applied, the lipid bilayer membrane 5 microsensor and microactuator are ultimately integrated in a self-organized manner to form a closed vesicle in which the drug is retained. This is a feature of the liposome of this example.

In such liposomes, the functions of the microsensors and microactuators are highly linked. The information detected by the microsensor is generated by changes in the interfacial potential of the lipid bilayer membrane, pH changes, osmotic pressure changes, structural changes in the lipid bilayer membrane due to gel-liquid crystal phase transition due to temperature, or structural changes in the microsensor itself. It is transmitted to the microactuator in some way, such as by an induced change in the shape of the lipid bilayer membrane. In a highly biomimetic system, microsensors and microactuators may move two-dimensionally within the membrane and dynamically transmit information through association and dissociation.

The type of drug held within the liposome is also not particularly limited.

The liposome configured in this way uses its own microsensor to detect a substance specific to cells in the affected area, and based on the concentration gradient of the substance, determines the location of the target cell,
By operating its own micro actuator in conjunction with a micro sensor, it accurately approaches the colored area, where it releases the drug held inside. Therefore, not only does it have no effect on normal cells, but it also makes it possible to intensively release the drug closer to the affected area than with conventional drug delivery systems. Therefore, high therapeutic efficiency can be expected with a small amount of drug, and
It is extremely effective in suppressing side effects when administering powerful anticancer drugs.

Example 2 This example is an example of constructing a closed vesicle that can provide a novel pattern forming method by applying the present invention.

The closed vesicle of this example is basically a liposome in which a microsensor and a microactuator are integrated in a self-organizing manner, as in Example 1, but it retains a resist material inside.

The microsensor detects a marker provided in advance on the substrate on which a pattern is to be formed, and the actuator actively moves the liposome to the marker position based on the detection information of the microsensor, and the resist material is applied there. Release and attach. At this time, the marker may be of any type, such as light, heat, or magnetism, as long as it can be detected by a microsensor.This allows pattern formation on the order of nanometers.

In recent years, in the field of semiconductor device manufacturing, design rules have become increasingly finer, as seen in VLSI and ULSI, and research is now focused on microfabrication not only at the submicron level but also at the quarter micron level. Targeted.

Conventionally, the key to these microfabrication techniques has been lithography technology in which a predetermined resist pattern is formed by irradiation with light or electron beams. For example, in photolithography that uses light, short-wavelength light sources such as excimer laser light are increasingly being used, but along with this, the effects of the thickness and level difference of the photoresist layer have become significant. The resolution limit is about 0.3 μm.

In addition, in the case of electron beam lithography that uses an electron beam,
Although the resolution limit increases to 10 nm, it requires a large amount of capital investment, including the need for vacuum equipment.

On the other hand, if a novel pattern forming method is provided using the self-propelled intelligent material of the present invention, it will be possible to form patterns down to the molecular size level without using expensive equipment.

Example 3 This example is an example in which a type of circuit network is constructed by realizing a chain structure in which liposomes as described above are further bonded in a self-organizing manner.

The liposome used in this example is a cell-simulating device that has a microsensor, a microactuator, and an appropriate marker that can be detected by the microsensor. The above microsensors include S,,S,.

1.・,S7, the above marker has M, ,M2. -・・１
M.

There are many types of cell dislocation devices in which these microsensors and markers are freely combined. Here, between the microsensor and the marker, S, -M+
, sz-M! ,-, ,S,-M,.

When a certain correspondence relationship is established, each cell pseudo device swims around due to the operation of its microactuator, searches for cell pseudo devices that have markers that can be detected by its own microsensor, and connects them to create a chain. It grows into a structure.

Such circuit networks have extremely unique features not found in conventional electrical or electronic circuits. First, by changing the combination of the microsensors and markers, any arrangement can be realized.

Furthermore, it is also possible to form a branch structure by using a plurality of microsensors or markers in one cell-simulating device, or by overlapping correspondence relationships. Furthermore, a defect occurring in a part of the circuit network can be repaired by adding a new cell reversal device to replace the cell reversal device at the defective site. Furthermore, if microsensors and markers can be chemically changed by a learning effect or the like after the circuit network is completed, it becomes possible to change the circuit characteristics without destroying the structure of the circuit network.

The above circuit network can also be expected to be applied to biocomputers modeled on neural networks.

[Effects of the Invention] As is clear from the above description, the self-propelled intelligent material of the present invention is much smaller than the conventional material, and each of the microsensors and microactuators are made of a single tissue. As a member of the group, they exhibit closely linked behavior and perform accurate movements. The self-propelled intelligent material can be used as a novel drug delivery system, patterning method,
This will pave the way for biocomputers, etc.

Claims (1)

[Claims] A self-propelled intelligent material comprising at least a microsensor and a microactuator integrated in a self-organized manner.