Injector, method for forming cap using same, and method for reducing intercellular fluid accumulated in object

Abstract

The present invention provides at least the following. That is, an injector capable of forming a void in an object is provided. The problem is solved by an injector that injects a liquid and a gas into a subject from an injector main body without performing injection through a predetermined structure in a state in which the predetermined structure is inserted into the subject, the injector being provided with: an accommodating part that accommodates the liquid and the gas; a nozzle unit communicating with the accommodating unit and having an ejection port for ejecting the liquid and the gas toward the object; and a pressurizing unit that pressurizes the liquid and the gas accommodated in the accommodating unit during operation to eject the liquid and the gas from the ejection port toward the object, the volume ratio of the gas to the total volume of the liquid and the gas being greater than 60% and 80% or less.

Description

Technical Field

[0001] This disclosure relates to an injector, a method for forming a void using the injector, and a method for reducing the accumulation of interstitial fluid in an object. Background Technology

[0002] As injectors for injecting medication into a target, there are needle injectors that inject via a needle and needleless injectors that inject without a needle. Additionally, catheters equipped with a needle and a drive source, or multi-hole needles, can also be used to deliver medication to the target.

[0003] In needle-free injectors, sometimes the injectable component is ejected by applying pressure to a chamber containing the injectable solution using pressurized gas, a spring, or electromagnetic force. For example, a configuration has been adopted in which multiple nozzle holes are formed inside the injector body, and a piston is arranged corresponding to each nozzle hole and driven during ejection (Patent Document 1). This configuration attempts to achieve uniform injection to the target by simultaneously ejecting the injectable solution from multiple nozzle holes. In this case, highly efficient cell transduction was achieved by injecting a plasmid containing the luciferase gene into rats.

[0004] In addition, pressurized gas can be used as the power source for ejecting the injection liquid in a needle-free injector. For example, a pressurization method in which the pressure is increased instantaneously at the initial stage of ejection and then gradually reduced over 40 to 50 msec has been demonstrated (Patent Document 2).

[0005] On the other hand, methods of injecting medication by mixing air into the solution are known. For example, when administering azacitidine, a treatment for myelodysplastic syndrome, subcutaneously using a needle injector, if the medication is administered conventionally without mixing in air, side effects such as redness at the injection site, pain at the injection site, and bruising at the injection site can occur, causing discomfort to the patient. In contrast, it has been reported that administering the medication by mixing in air can prevent contact between the epithelium and the medication, thereby reducing side effects (Non-Patent Literature 1).

[0006] Furthermore, methods for injecting a solution containing biomolecules and a given gas into an injection target are known. It has also been disclosed that, according to this method, the proportion of functional biomolecules in the injection target is increased (Patent Document 3).

[0007] Lymphedema is a type of intercellular edema. It is primarily caused by factors such as obstructed lymphatic flow resulting from cancer treatment, and typically occurs in the hands and feet.

[0008] Currently, treatments for lymphedema include complex therapies that combine compression therapy, exercise therapy, lifestyle guidance, skin care, and lymphatic drainage, as well as surgical treatments that eliminate lymphatic stasis through lymphatic vessel-venous anastomosis.

[0009] Existing technical documents

[0010] Patent documents

[0011] Patent Document 1: Japanese Patent Application Publication No. 2004-358234

[0012] Patent Document 2: U.S. Patent Application Publication No. 2005 / 0010168

[0013] Patent Document 3: International Publication No. 2022 / 149550

[0014] Non-patent literature

[0015] Non-patent literature 1: Can. Oncol. Nurs. J., 22(4): 222-34, 2012 Summary of the Invention

[0016] The problem that the invention aims to solve

[0017] The objectives of this disclosure are at least as follows: First, to provide an injector capable of forming voids in an object. Second, to provide a novel method for forming voids. Third, to provide a novel method for reducing intercellular fluid.

[0018] Methods for solving problems

[0019] In order to solve the above-mentioned problems, the inventors conducted in-depth research and found that the above-mentioned problems can be solved by using a given injector.

[0020] That is, the main point of this disclosure is as follows.

[0021] [1] An injector that injects liquids and gases into an object from an injector body without injecting via the given structure in a state in which a given structure is inserted into the object.

[0022] The above-mentioned injector has the following features:

[0023] A container holding the aforementioned liquid and the aforementioned gas;

[0024] A nozzle portion communicating with the aforementioned receiving portion and having an ejection outlet for ejecting the aforementioned liquid and gas toward the aforementioned object; and

[0025] During operation, a pressurized part pressurizes the liquid and gas contained in the aforementioned containment section and ejects the liquid and gas from the aforementioned ejection port toward the aforementioned object.

[0026] The volume of the gas is greater than 60% and less than 80% relative to the total volume of the liquid and the gas.

[0027] [2] According to the injector described in [1], wherein,

[0028] The gas mentioned above is air.

[0029] [3] According to the injector described in [1] or [2], wherein,

[0030] The above-mentioned object injection is performed by injecting the object through jet injection.

[0031] [4] The injector according to any one of [1] to [3], wherein,

[0032] The ejection velocities of the aforementioned liquid and gas are greater than 83.3 μL / s.

[0033] [5] The injector according to any one of [1] to [4], wherein,

[0034] The liquid mentioned above contains functional substances found in living organisms.

[0035] [6] According to the injector described in [5], wherein,

[0036] The aforementioned functional substances in living organisms are selected from one or more of nucleic acids, peptides, proteins, and low molecular weight compounds.

[0037] [7] An injector for reducing the accumulation of intercellular fluid in an object, which injects liquids and gases into the object from the injector body without injecting via the given structure in a state in which a given structure is inserted into the object.

[0038] The above-mentioned injector has the following features:

[0039] A container holding the aforementioned liquid and the aforementioned gas;

[0040] A nozzle portion communicating with the aforementioned receiving portion and having an ejection outlet for ejecting the aforementioned liquid and gas toward the aforementioned object; and

[0041] A pressurized part that, during operation, pressurizes the liquid and gas contained in the aforementioned containment section and ejects the liquid and gas from the aforementioned ejection port toward the aforementioned object.

[0042] [8] According to the injector described in [7], wherein,

[0043] The volume of the gas is 30% or more and 80% or less relative to the total volume of the liquid and the gas.

[0044] [9] The injector according to [7] or [8], wherein,

[0045] The gas mentioned above is air.

[0046]

[10] The injector according to any one of [7] to [9], wherein,

[0047] The above-mentioned object injection is performed by injecting the object into the object via jet injection.

[0048]

[11] The injector according to any one of [7] to

[10] , wherein,

[0049] The ejection velocities of the aforementioned liquid and gas are greater than 83.3 μL / s.

[0050]

[12] The injector according to any one of [7] to

[11] , wherein,

[0051] The liquid mentioned above contains functional substances found in living organisms.

[0052]

[13] According to the injector described in

[12] , wherein,

[0053] The aforementioned functional substances in living organisms are selected from one or more of nucleic acids, peptides, proteins, and low molecular weight compounds.

[0054]

[14] A method for forming a void using an injector,

[0055] The aforementioned injector injects liquids and gases into an object from the injector body without injecting via the given structure into the object, provided that a given structure is inserted within the object.

[0056] The above-mentioned injector has the following features:

[0057] A container holding the aforementioned liquid and the aforementioned gas;

[0058] A nozzle portion communicating with the aforementioned receiving portion and having an ejection outlet for ejecting the aforementioned liquid and gas toward the aforementioned object; and

[0059] During operation, a pressurized part pressurizes the liquid and gas contained in the aforementioned containment section and ejects the liquid and gas from the aforementioned ejection port toward the aforementioned object.

[0060] The above-mentioned formation methods include:

[0061] The process of containing the above-mentioned liquid and gas in the above-mentioned container;

[0062] The process of pressurizing the liquid and gas contained in the aforementioned containment, and

[0063] The process of injecting the above-mentioned liquid and gas into the above-mentioned object,

[0064] The viscoelasticity of the injection site of the above-mentioned object at 25°C is above 47% and below 82%.

[0065]

[15] According to the method for forming the void described in

[14] , wherein,

[0066] In the above-mentioned injection process, the injection is performed on the object by jet injection.

[0067]

[16] According to the method for forming the void as described in

[14] or

[15] , wherein,

[0068] The volume of the gas is 30% or more and 80% or less relative to the total volume of the liquid and the gas.

[0069]

[17] The method for forming a void according to any one of

[14] to

[16] , wherein,

[0070] The gas mentioned above is air.

[0071]

[18] The method for forming a void according to any one of

[14] to

[17] , wherein,

[0072] The ejection velocities of the aforementioned liquid and gas are greater than 83.3 μL / s.

[0073]

[19] The method for forming a void according to any one of

[14] to

[18] , wherein,

[0074] The relaxation time of the injection site of the above-mentioned object was greater than 0.89 ms and less than 4.39 ms when viscoelasticity was measured at 25°C.

[0075]

[20] A method for reducing intercellular fluid accumulation in an object using an injector,

[0076] The aforementioned injector injects liquids and gases into an object from the injector body without injecting via the given structure into the object, provided that a given structure is inserted within the object.

[0077] The above-mentioned injector has the following features:

[0078] A container holding the aforementioned liquid and the aforementioned gas;

[0079] A nozzle portion communicating with the aforementioned receiving portion and having an ejection outlet for ejecting the aforementioned liquid and gas toward the aforementioned object; and

[0080] During operation, a pressurized part pressurizes the liquid and gas contained in the aforementioned containment section and ejects the liquid and gas from the aforementioned ejection port toward the aforementioned object.

[0081] The methods described above for reducing the accumulation of intercellular fluid in the target include:

[0082] The process of containing the above-mentioned liquid and gas in the above-mentioned container;

[0083] The process of pressurizing the liquid and gas contained in the aforementioned containment, and

[0084] The process of injecting the aforementioned liquid and gas into the aforementioned object.

[0085]

[21] According to the method described in

[20] , wherein,

[0086] The above-mentioned objects are mammals other than humans.

[0087]

[22] According to the method described in

[20] or

[21] , wherein,

[0088] In the above-mentioned injection process, the injection is performed on the object by jet injection.

[0089]

[23] The method according to any one of

[20] to

[22] , wherein,

[0090] The volume of the gas is 30% or more and 80% or less relative to the total volume of the liquid and the gas.

[0091]

[24] The method according to any one of

[20] to

[23] , wherein,

[0092] The gas mentioned above is air.

[0093]

[25] The method according to any one of

[20] to

[24] , wherein,

[0094] The ejection velocities of the aforementioned liquid and gas are greater than 83.3 μL / s.

[0095]

[26] The method according to any one of

[20] to

[25] , wherein,

[0096] The liquid mentioned above contains functional substances found in living organisms.

[0097]

[27] According to the method described in

[26] , wherein,

[0098] The aforementioned functional substances in living organisms are selected from one or more of nucleic acids, peptides, proteins, and low molecular weight compounds.

[0099]

[28] The method according to any one of

[20] to

[27] further comprises:

[0100] The process of injecting a solution or cells containing functional substances from a living organism into a cavity formed by the above-described injection process.

[0101] The effects of the invention

[0102] This disclosure can at least achieve the effect of creating voids in a given object. Additionally, it can provide new methods for reducing intercellular fluid. Attached Figure Description

[0103] Figure 1 This is a diagram illustrating a simplified configuration of an injector according to one embodiment of the present disclosure.

[0104] Figure 2 The image shows a tissue section from Experiment 1 viewed under a stereomicroscope (the attached image is a substitute photograph).

[0105] Figure 3 The image shows a tissue section from Experiment 2 observed under a stereomicroscope (the attached image is a substitute photograph).

[0106] Figure 4 The image shows a tissue section from Experiment 3 under a stereomicroscope (the attached image is a substitute photograph).

[0107] Figure 5 The image shows a tissue section from Experiment 4 under a stereomicroscope (the attached image is a substitute photograph).

[0108] Figure 6 It is a coordinate graph showing the relative values ​​of the tail diameter on day 21 and day 28 after skin peeling.

[0109] Figure 7 This is an image observed under a stereomicroscope after liquid and gas were injected into konjac jelly at a gas ratio of 50% (attached as a substitute photograph).

[0110] Figure 8 This is an image observed under a stereomicroscope after liquid and gas were injected into konjac jelly at a gas ratio of 60% (attached as a substitute photograph).

[0111] Figure 9 This is an image observed under a stereomicroscope after liquid and gas were injected into konjac jelly at a gas ratio of 80% (attached as a substitute photograph).

[0112] Figure 10 These are images of the liquid and gas injected into a 0.7% agarose gel at a gas ratio of 80% (attached as a substitute photograph).

[0113] Figure 11 These are images of the liquid and gas injected into a 0.5% agarose gel at a gas ratio of 80% (the attached image is a substitute photograph).

[0114] Figure 12 This is an image of the observation after liquid and gas are injected into marshmallows at a 50% gas ratio (attached as a substitute photograph).

[0115] Figure 13 This is an image of the observation after liquid and gas are injected into marshmallows at a gas ratio of 60% (attached as a substitute photograph).

[0116] Figure 14 This is an image of the observation after liquid and gas are injected into marshmallows at a gas ratio of 80% (attached as a substitute photograph).

[0117] Figure 15 This is a stereomicroscopic image of a section of a pig after a 50% gas-liquid mixture was injected into its abdomen (attached as a substitute photograph). Detailed Implementation

[0118] Each embodiment and its combination is an example, and appropriate additions, omissions, substitutions, and other modifications can be made to the structure without departing from the spirit of this disclosure. This disclosure is limited only by the scope of the claims and is not limited to the embodiments. Furthermore, the various methods disclosed in this specification can also be combined with any other features disclosed in this specification.

[0119] In addition, the numerical range represented by "~" refers to the range of values ​​recorded before and after "~" as the lower and upper limits. "A~B" means above A and below B.

[0120] This disclosure includes: an invention of an injector (first embodiment), an invention of an injector for reducing intercellular fluid accumulation in a target (second embodiment), an invention of a method for forming a gap using an injector (third embodiment), an invention of a method for reducing intercellular fluid accumulation in a target using an injector (fourth embodiment), and a method for reducing intercellular fluid accumulation in a target (fifth embodiment).

[0121] <First Implementation>

[0122] The first embodiment of this disclosure is an injector that injects liquids and gases into an object from an injector body without injecting via the given structure into the object.

[0123] The injector includes:

[0124] A container holding the aforementioned liquid and the aforementioned gas;

[0125] A nozzle portion communicating with the aforementioned receiving portion and having an ejection outlet for ejecting the aforementioned liquid and gas toward the aforementioned object; and

[0126] A pressurized part that, during operation, pressurizes the liquid and gas contained in the aforementioned containment section and ejects the liquid and gas from the aforementioned ejection port toward the aforementioned object.

[0127] In this embodiment, by presenting the liquid and the gas in the aforementioned containment portion, the gas can be dissolved in the liquid while being pressurized, and the liquid can be injected into the object. It can be inferred that after injection into the object, by depressurizing while partially restoring the gas dissolved in the liquid back to gas, numerous microbubbles can be generated, thereby forming multiple voids in the object through the shearing action of these bubbles. These voids typically have a maximum diameter of approximately 10 μm to approximately 1000 μm, and sometimes larger voids can be formed due to the interconnection of multiple voids. The formation of the voids can be confirmed using a stereomicroscope or similar device.

[0128] This gap can be used, for example, as a flow path or storage container for any liquid or gas.

[0129] [liquid]

[0130] In this embodiment, the liquid contained in the containment section can be, for example, water, preferably a liquid isotonic with the animal's body fluids. Specifically, physiological saline, Ringer's solution, lactated Ringer's solution, acetate Ringer's solution, bicarbonate Ringer's solution, etc., can be suitable. These can be prepared by known methods or commercially available products can be used.

[0131] The injector of this embodiment can inject liquids that may contain, as needed, conventional additives and oils such as functional substances in living organisms, buffers, isotonics, pH adjusters, antioxidants, thickeners, stabilizers, wetting agents, emulsifiers, and binders. However, even without these, it can still create voids in a given object and reduce intercellular fluid.

[0132] There are no particular limitations on the functional substances in a living organism, as long as they exert physiological activity in the organism. The aforementioned functional substances in a living organism can be one or more. These functional substances can be natural substances or artificially synthesized substances.

[0133] The aforementioned functional substances in living organisms are preferably selected from one or more of nucleic acids, peptides, proteins, and low molecular weight compounds.

[0134] Examples of nucleic acids include DNA, RNA, and PNA. Furthermore, these nucleic acids can be either those containing a protein-coding portion or those not containing a protein-coding portion (non-coding nucleic acids).

[0135] Examples of peptides and proteins include: antigens (i.e., substances that produce antibodies against a peptide or protein), antibodies, peptide vaccines, protein vaccines, peptide hormones, protein hormones, growth factors, cytokines, coagulation factors, serum albumin, digestive enzymes, anti-inflammatory peptides, and anti-inflammatory proteins.

[0136] As proteins, the extracellular matrix can also be used. The extracellular matrix is ​​a non-cellular component of the human body and is expected to act as a scaffold for cells, helping to maintain space. Examples of extracellular matrix include collagen, fibronectin, and laminin.

[0137] Low molecular weight compounds generally refer to compounds with a molecular weight of 2000 or less, but are not limited to this; in this field, compounds that can be treated as low molecular weight compounds are included. Preferred molecular weight ranges for low molecular weight compounds include, for example, 50 or more, and 100 or more. Additionally, ranges include 2000 or less, and 1000 or less. That is, ranges include 50 to 2000, 50 to 1000, and 100 to 2000.

[0138] In this disclosure, physiological activity refers to the effect on specific physiological regulatory functions of an organism. Evaluation indicators of physiological activity can be appropriately set according to the purpose, and can be any of qualitative or quantitative indicators, preferably quantitative indicators. For example, specific mRNA levels, protein levels, cytokine levels, antibody titers, or the number of cells of a specific cell type can be used as indicators. These quantitative indicators can be quantified using methods known in the art.

[0139] Especially when the functional substance in an organism is a nucleic acid containing a portion encoding a protein, the amount of protein encoded by that nucleic acid can be quantified and used as an indicator of physiological activity. Furthermore, the activity of the protein can be quantitatively evaluated. For example, if the protein is a luciferase, its physiological activity can be evaluated by measuring the intensity of bioluminescence.

[0140] When the functional substance in a living organism is nucleic acid, this nucleic acid can be introduced into a viral vector or loaded onto lipid nanoparticles and contained in the aforementioned liquid, or neither a viral vector nor lipid nanoparticles can be used. By not using viral vectors or lipid nanoparticles, the possibility of inducing side effects such as anaphylaxis in subjects can be reduced.

[0141] The content of the above-mentioned functional substances in the biological body relative to the total amount of liquid can be appropriately set based on the type of the above-mentioned functional substances in the biological body, the target, and the physiological activity exerted by the above-mentioned functional substances in the target in which they are injected.

[0142] As buffers, the following can be used: buffers containing phosphate (e.g., phosphate buffer, phosphate-buffered saline (PBS) (which can be PBS(+) or PBS(-)), Duchenne phosphate-buffered saline (D-PBS), citrate / phosphate buffer, citrate / phosphate buffered saline, etc.), citrate buffer, tris(hydroxymethyl)aminomethane-HCl buffer (Tris hydrochloric acid buffer), acetate buffer, GOOD buffer (e.g., HEPES-NaOH buffer, etc.), amino acid buffers (e.g., glycine-hydrochloric acid buffer, glycine-NaOH buffer, diglypeptide-NaOH buffer, diglypeptide-KOH buffer, etc.), imidazole buffer, etc.

[0143] From a generality point of view, a buffer solution using phosphate is preferred.

[0144] Examples of isotonic agents include ionic isotonic agents and nonionic isotonic agents.

[0145] Examples of ionic isotonic agents include salts such as sodium chloride, potassium chloride, calcium chloride, and magnesium chloride.

[0146] Examples of nonionic isotonic agents include: glycerol, propylene glycol, polyethylene glycol, glucose, sorbitol, mannitol, trehalose, maltose, and sucrose.

[0147] From a generality perspective, sodium chloride is preferred.

[0148] Examples of pH adjusters include: hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.

[0149] Examples of antioxidants include ascorbic acid, sodium sulfite, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, and tocopherol.

[0150] Examples of thickeners include: alginate, polyethylene glycol, hydroxypropyl methylcellulose, and sodium carboxymethyl cellulose.

[0151] Examples of oils include sesame oil, soybean oil, rapeseed oil, and olive oil. Additionally, glycerol, which constitutes oils, can also be used. It is expected that by leaving these oils in the resulting pores, they will help maintain the pore structure.

[0152] [gas]

[0153] In this embodiment, the gas contained in the containment section is not particularly limited, and air can be used as an example. The air can be ordinary air, and its composition is not particularly limited. For example, a mixture of approximately 80% nitrogen and approximately 20% oxygen can be used. Other examples of the gas include nitrogen, oxygen, ozone, carbon dioxide, hydrogen, and carbon monoxide, and mixtures of any two or more of these can be used. Furthermore, in a preferred embodiment, the gas is either free of microorganisms or is a gas in which microorganisms are dead even if they are present.

[0154] The proportion of the gas volume relative to the total volume of the liquid and the gas is not particularly limited, but is preferably 30% or more, more preferably greater than 60%. Furthermore, it is preferably less than 100%, more preferably 80% or less. That is, preferred ranges for the proportion of the gas volume include 30% or more and less than 100%, 30% or more and less than 80%, and greater than 60% and less than 80%. When the gas volume is within this range, it is easier to form multiple voids in the object.

[0155] [object]

[0156] The injector in this embodiment can inject either biological or non-biological objects. The object in this embodiment can be, for example, one or more selected from cells, cell sheets, cell blocks, tissues, organs (skin, organs, etc.), organ systems, or individuals (organisms). Alternatively, it can be one or more selected from tissues, organs (skin, organs, etc.), organ systems, or individuals (organisms). It can be any system, such as an in vitro system, an in vivo system, or an exvivo system. The cell blocks mentioned above can be cell blocks obtained through three-dimensional culture, and the organs (skin, organs, etc.) mentioned above can be organoids.

[0157] Furthermore, when injecting the aforementioned objects, injection can be performed into the subordinate layers they contain. That is, for example, when the object is an individual (organism), injection can be performed into the tissues contained in that individual (organism), or into the cells contained in that individual (organism), or into both. Similarly, when the object is a tissue, injection can be performed into the cells contained in that tissue, or into the extracellular matrix contained in that tissue, or into both.

[0158] Furthermore, in this embodiment, when the object is selected from one or more of cells, cell sheets, cell blocks, tissues, organs (skin, organs, etc.), or organ systems, it can be selected from one or more of cells, cell sheets, cell blocks, tissues, organs (skin, organs, etc.), or organ systems in a state existing in an individual (organism), or it can be selected from one or more of cells, cell sheets, cell blocks, tissues, organs (skin, organs, etc.), or organ systems in a state not existing in an individual (organism) (e.g., a state of being removed from an individual (organism), separated, or prepared outside an individual (organism)).

[0159] In addition, the objects in this embodiment can be one or more of the following: cells, cell sheets, cell blocks, tissues, organs (skin, organs, etc.) and organ systems derived from iPS cells (artificial pluripotent stem cells). They can be in a state existing in an individual (organism) or in a state not existing in an individual (organism) (e.g., a state of being removed or separated from an individual (organism) or a state of being prepared outside an individual (organism).

[0160] The aforementioned individuals (organisms) are preferably mammals. There are no particular restrictions on the mammals mentioned; humans and other mammals besides humans can be included. Examples of mammals other than humans include: mice, rats, guinea pigs, hamsters, cattle, goats, sheep, pigs, monkeys, dogs, and cats.

[0161] The aforementioned organs can be selected from one or more of the following: joint cavity, eyeball, skin, muscle, bone, cartilage, bone marrow, ligament, brain, spinal cord, lung, liver, heart, kidney, pancreas, gallbladder, digestive tract, bladder, reproductive organs, lymph nodes, lymphatic network and blood vessels, as well as tumors arising from any of these. Examples of reproductive organs include the testes and ovaries.

[0162] Furthermore, regardless of whether the object in this embodiment is any of the objects described above, when injecting a cell, it can be injected into the cytoplasm of the cell, or into the nucleus of the cell, or into both the cytoplasm and the nucleus of the cell.

[0163] Furthermore, the object in this embodiment is not particularly limited, but is preferably selected from one or more of the intradermal space, subcutaneous space, and underlying muscle layer of the skin of an individual mammal (organism). In this case, the liquid and gas are injected into the skin by ejecting them from the injector onto the skin surface, and a method can be used to inject one or more of the intradermal space, subcutaneous space, and underlying muscle layer of the skin.

[0164] In particular, this embodiment is preferably applied to areas of skin in mammals where intercellular edema has occurred.

[0165] When liquid and gas are injected into a site of intercellular edema using the injector of this embodiment, multiple pores are created. These pores can be considered as flow paths for intercellular fluid, reducing the amount of locally accumulated intercellular fluid.

[0166] The viscoelastic modulus of the injection site of the object at 25°C is preferably 47% or more and 82% or less. The viscoelastic modulus is a value obtained by the following formula, which represents the ratio of the viscous element to the elastic element of the object.

[0167] Viscoelastic modulus = (viscous strain) / (viscous strain + elastic strain)

[0168] The value is 0% for an ideal elastomer and 100% for an ideal viscous body.

[0169] The viscoelastic modulus of the object at 25°C is preferably 47% or more and 71% or less.

[0170] The relaxation time of the injection site of the object when the viscoelasticity was measured at 25°C is preferably 0.89ms or more and 4.39ms or less, more preferably 0.89ms or more and 3.11ms or less.

[0171] The relaxation time is the time constant of the stress relaxation behavior of a viscoelastic body, and is an exponent representing the vibrational frequency characteristics of a viscoelastic material. It can be calculated using the following formula.

[0172] Relaxation time = (Viscous data) / (Elastic data)

[0173] Viscoelasticity and relaxation time can be measured according to the operating instructions of Vesmeter (for biological measurement, E-100HS, WAVECYBERCORP.). Specifically, at room temperature (25°C), the Vesmeter probe can be placed vertically above the object to be measured, and the same location can be measured 4 to 35 times, with the average value taken as the measured value.

[0174] [Injector]

[0175] As described above, the injector of this embodiment includes a receiving portion that contains liquid and gas, a nozzle portion that communicates with the receiving portion and has an ejection outlet for ejecting the liquid and gas to the object, and a pressurizing portion that, during operation, pressurizes the liquid and gas contained in the receiving portion to eject the liquid and gas from the ejection outlet to the object, and injects the liquid and gas to the object by ejecting the liquid and gas from the ejection outlet of the nozzle portion.

[0176] In this embodiment, the injector injects the liquid and gas into the object from the injector body without injecting via the given structure, provided that a given structure is inserted into the object. The injector of this embodiment, for example, when the distance from the injector body to the object is large, may include a structure that guides the liquid and gas from the injector body to the object; for example, it may include a given structure such as a conduit. Therefore, the injector of this embodiment may or may not include such a given structure.

[0177] In the injector of this embodiment, the energy imparted to the pressurizing section for pressurizing liquids and gases can be applied using energy impartation methods based on known pressurization techniques. One example of the imparted energy is chemically generated energy, such as combustion energy generated by the oxidation reaction of gunpowder / explosives. Alternatively, the energy for pressurization can be generated electrically, for example, by a piezoelectric element or electromagnetic actuator driven by an input power source. Furthermore, the energy for pressurization can also be generated physically, for example, by the elastic energy of an elastomer or the internal energy of a compressed object such as compressed gas. In short, any energy can be used as long as it enables the ejection of the liquid from the injector. Additionally, the energy for pressurization can be a composite energy formed by appropriately combining the aforementioned combustion energy, electrical energy, elastic energy, and other internal energies.

[0178] In summary, the pressurization unit can utilize the pressure generated by the combustion of gunpowder ignited by the ignition device, or it can utilize the pressure generated when compressed gas is released. Furthermore, the pressurization unit can utilize the pushing force of a compression spring, or it can utilize electromagnetic force; for example, it can utilize a linear electromagnetic actuator. Preferably, the pressurization unit utilizes at least the pressure generated by the combustion of gunpowder ignited by the ignition device; however, it can also be used in combination with any of the other pressurization methods described above.

[0179] When the pressurization section utilizes the pressure generated by the combustion of gunpowder, the gunpowder can be, for example, any one of the following: zirconium and potassium perchlorate (ZPP), titanium hydride and potassium perchlorate (THPP), titanium and potassium perchlorate (TiPP), aluminum and potassium perchlorate (APP), aluminum and bismuth oxide (ABO), aluminum and molybdenum oxide (AMO), aluminum and copper oxide (ACO), aluminum and iron oxide (AFO), or a combination of multiple of these gunpowders. A characteristic of these gunpowders is that even though their combustion products are gaseous at high temperatures, they do not contain gaseous components at room temperature; therefore, the combustion products condense immediately after ignition.

[0180] Furthermore, when the pressurization section utilizes the energy generated by the combustion of a gas generating agent as the ejection energy, various gas generating agents already used in single-base smokeless powder (GG), airbag gas generators, and seatbelt pretensioner gas generators can be used as the gas generating agent. Examples of single-base smokeless powder include, for instance, a single-base smokeless powder containing 98% by mass of nitrocellulose, 0.8% by mass of diphenylamine, and 1.2% by mass of potassium sulfate.

[0181] Hereinafter, the syringe 1 (needle-free syringe) will be described as an example of the injector in this embodiment, with reference to the accompanying drawings. It should be noted that the following configuration is merely an example and is not limited thereto. It should be noted that the terms "front end side" and "base end side" are used to indicate the relative positional relationship of the syringe 1 in the longitudinal direction. The "front end side" refers to the position of the syringe 1 near the front end, i.e., near the injection port 31a, as described later, and the "base end side" refers to the direction in the longitudinal direction of the syringe 1 opposite to the "front end side," i.e., the direction towards the drive section 7. Furthermore, in this example, the combustion energy of the gunpowder ignited by the ignition device is used as the injection energy for pressurization, but this disclosure is not limited to this.

[0182] (Composition of syringe 1)

[0183] Figure 1This is a diagram showing a simplified configuration of syringe 1, and also a cross-sectional view along the length of syringe 1. Syringe 1 is constructed by mounting syringe assembly 10 onto housing (syringe housing) 2. Syringe assembly 10 is obtained by assembling a sub-assembly consisting of a syringe barrel 3 and a plunger 4, and a sub-assembly consisting of a syringe body 6, a piston 5, and a drive unit 7 into one unit.

[0184] As described above, the syringe assembly 10 is configured to be freely detachable from the housing 2. The receiving portion 32 formed between the syringe barrel 3 and the plunger 4 included in the syringe assembly 10 is filled with liquid and gas. The syringe assembly 10 is a disposable unit used after each injection of the liquid and gas. It should be noted that the receiving portion 32 may include a first receiving portion for gas and a second receiving portion for liquid. On the other hand, the housing 2 side includes a battery 9, which supplies power to the igniter 71 included in the drive unit 7 of the syringe assembly 10. Power is supplied from the battery 9 by the user pressing a button 8 provided on the housing 2, thereby connecting the electrodes on the housing 2 side and the electrodes on the drive unit 7 side of the syringe assembly 10 via wiring. It should be noted that the shape and position of the electrodes on the housing 2 side and the electrodes on the drive unit 7 side of the syringe assembly 10 are designed so that they automatically contact each other when the syringe assembly 10 is installed on the housing 2. Furthermore, the outer casing 2 is a reusable unit as long as there is residual power in the battery 9 sufficient to supply power to the drive unit 7. It should be noted that in the outer casing 2, if the battery 9 is depleted, simply replacing the battery 9 allows the outer casing 2 to continue to be used.

[0185] Next, the details of the syringe assembly 10 will be explained. First, the sub-assembly including the syringe barrel 3 and the plunger 4 will be described. The syringe barrel 3 has a receiving portion 32 formed inside, which serves as a space to contain the liquid and the gas. More specifically, as... Figure 1 As shown, the plunger 4 is configured to slide freely along the inner wall surface extending axially in the syringe barrel 3, and the inner wall surface of the syringe barrel 3 and the plunger 4 define the receiving portion 32. Furthermore, the syringe barrel 3 has a nozzle portion 31 communicating with the receiving portion 32, and an injection outlet 31a is formed at the front end of the nozzle portion 31. The nozzle portion 31 is a flow path whose cross-sectional area gradually decreases from the receiving portion 32 side towards the injection outlet 31a side, used to guide the liquid and gas filled in the receiving portion 32 to the injection outlet 31a. Figure 1 In the example shown, the shape of the front end of the plunger 4 is basically the same as the shape of the nozzle 31.

[0186] Next, the sub-assembly comprising the syringe body 6, piston 5, and drive unit 7 will be described. The piston 5, for example, is made of metal and is configured to slide within a through hole formed inside the syringe body 6, pressurized by combustion products (combustion gases) generated by the igniter 71 of the drive unit 7. The syringe body 6 is a generally cylindrical component that houses the piston 5 in a manner that allows it to slide freely along its axially extending inner wall surface. It should be noted that the piston 5 can be made of resin; in this case, metal can be used in conjunction with parts requiring heat resistance and pressure resistance. Furthermore, as... Figure 1 As shown, piston 5 and plunger 4 are connected as one unit.

[0187] Next, the drive unit 7 will be explained. For example... Figure 1 As shown, the drive unit 7 is fixed to the base end side with reference to the through hole in the syringe body 6. The drive unit 7 has an igniter 71, which is an electric igniter. The igniter 71 is arranged facing the interior of the through hole in the syringe body 6, and contains igniting powder inside. Various gunpowders as described above can be used as igniting powder. Alternatively, the igniting powder can be contained, for example, in a gunpowder cup formed of a suitable thin-walled metal.

[0188] In the syringe 1 configured as described above, the volume of gas contained in the receiving part 32 is adjusted to, for example, more than 30% and less than 80% of the volume of the receiving part 32.

[0189] Next, the working function of the syringe 1 described above will be explained. For example... Figure 1As shown, with the syringe assembly 10 installed on the housing 2, liquid and gas can be drawn from the nozzle 31's outlet 31a. This allows liquid and gas to be filled into the receiving portion 32. After this state, for example, with the syringe 1's outlet 31a in contact with an object, when the user presses the button 8 on the housing 2, this triggers the supply of power from the battery 9 to the igniter 71 of the drive unit 7, activating the igniter 71. When the igniter 71 is activated, the ignition propellant is ignited and burns, generating combustion products (flame, combustion gases, etc.). As a result, for example, the propellant cup of the igniter 71 may crack, releasing combustion gases into the through hole in the syringe body 6. This causes a rapid increase in pressure within the through hole of the syringe body 6, pressing the piston 5 towards the front end of the syringe body 6. Consequently, the piston 5 slides along the inner wall of the through hole in the syringe body 6 towards the front end. As described above, since the plunger 4 and piston 5 are integrated, the plunger 4 also slides along the inner wall of the syringe 3 in conjunction with the piston 5. That is, the plunger 4 is pressed against the nozzle 31 located at the front end of the syringe 3, thereby reducing the volume of the container 32 containing liquid and gas and rapidly pressurizing it. As a result, the liquid and gas filled in the container 32 are forced into the nozzle 31 and ejected from the injection port 31a under high pressure. Thus, liquid and gas can be injected into the target.

[0190] In addition, Figure 1 The syringe body 6 shown does not contain any additional gunpowder components. However, to adjust the pressure changes applied to the liquid and gas via the piston 5, a gas generating agent, which generates gas by combustion of the combustion products produced by the gunpowder in the igniter 71, can be placed inside the igniter 71 and the through hole of the syringe body 6. The composition of the gas generating agent placed inside the igniter 71 is known technology, as disclosed in International Publication No. 01-031282 and Japanese Patent Application Publication No. 2003-25950. As an example of a gas generating agent, a single-base smokeless gunpowder containing 98% by mass of nitrocellulose, 0.8% by mass of diphenylamine, and 1.2% by mass of potassium sulfate can be cited. Various gas generating agents already used in airbag gas generators and seatbelt pretensioner gas generators can also be used. By adjusting the size, shape, and especially the surface shape of the gas generating agent placed in the through hole, the combustion end time of the gas generating agent can be changed. Therefore, the pressure change applied to the liquid and gas can be set as a desired change, that is, a change that allows the liquid and gas to properly reach the target. In this embodiment, a gas generator or the like used as needed is also included in the drive unit 7. In this embodiment, a "pressurization unit" is constituted by including a plunger 4 and a piston 5.

[0191] In this embodiment, the liquid and gas can be injected into the object via a jet injection device.

[0192] Here, in this disclosure, "jet injection" refers to an injection characterized by liquid and gas being ejected from an injection port toward an object, thereby forming a through-hole penetrating the inner and outer boundaries of the object, generating a high-pressure ultramicrofluidic stream capable of injecting liquid and gas into the object through the through-hole. For example, in the case of an individual mammal (organism), it refers to an injection characterized by generating a high-pressure ultramicrofluidic stream capable of penetrating, for example, the skin of the individual mammal (organism).

[0193] The injector of this embodiment is typically capable of ejecting the liquid and gas at an ejection rate greater than 83.3 μL / s. The ejection rate is preferably 200 μL / s or more, more preferably 250 μL / s or more, further preferably 300 μL / s or more, even more preferably 350 μL / s or more, even more preferably 400 μL / s or more, and most preferably 500 μL / s or more. Furthermore, there is no particular upper limit, and rates of 5000 μL / s or less can be cited. That is, preferred ranges for ejection velocities include greater than 83.3 μL / s and less than 5000 μL / s, greater than 200 μL / s and less than 5000 μL / s, greater than 250 μL / s and less than 5000 μL / s, greater than 300 μL / s and less than 5000 μL / s, greater than 350 μL / s and less than 5000 μL / s, greater than 400 μL / s and less than 5000 μL / s, and greater than 500 μL / s and less than 5000 μL / s.

[0194] When the ejection velocity is within the above range, it is easy to make the injection into the object a jet injection.

[0195] In this disclosure, the ejection velocity is the velocity of the liquid as it exits the ejection port, and can be calculated, for example, by dividing the ejected volume by the time required from the start to the end of ejection. The time required from the start to the end of ejection can be measured, for example, by photographing the liquid ejecting from the ejection port using an imaging device such as a high-speed camera.

[0196] The injection speed can be set within the above range by adjusting the injection energy accordingly based on the shape and material of the nozzle and the volume and viscosity of the liquid.

[0197] The amount of liquid injected into the object can be determined according to the volume of the container and the volume of the gas contained in the container.

[0198] Examples of the liquid injection volume into the target include, for example, 10 μL or more, 50 μL or more, or 100 μL or more. Alternatively, examples include 50 mL or less, 10 mL or less, or 5 mL or less. That is, examples include 10 μL to 50 mL, 50 μL to 10 mL, and 100 μL to 5 mL.

[0199] The time required to inject the liquid into the object is simply the time required to eject the specified amount of liquid at the specified ejection rate; there is no particular limitation. Examples include 0.001 seconds or more, 0.005 seconds or more, or 0.01 seconds or more. Alternatively, examples include 100 seconds or less, 50 seconds or less, or 10 seconds or less. In other words, examples include 0.001 to 100 seconds, 0.005 to 50 seconds, and 0.01 to 10 seconds.

[0200] <Second Implementation>

[0201] The second embodiment of this disclosure is an injector for reducing the accumulation of intercellular fluid in an object, which injects liquids and gases into the object from the injector body without injecting via the given structure in a state where a given structure is inserted into the object.

[0202] The above-mentioned injector has the following features:

[0203] A container holding the aforementioned liquid and the aforementioned gas;

[0204] A nozzle portion communicating with the aforementioned receiving portion and having an ejection outlet for ejecting the aforementioned liquid and gas toward the aforementioned object; and

[0205] A pressurized part that, during operation, pressurizes the liquid and gas contained in the aforementioned containment section and ejects the liquid and gas from the aforementioned ejection port toward the aforementioned object.

[0206] When a portion of a lymphatic vessel is removed or damaged during procedures such as cancer treatment, the flow of lymph fluid (also known as intercellular fluid) is obstructed, leading to localized accumulation and sometimes intercellular edema. This condition is called lymphedema.

[0207] When liquid and gas are injected into a site of intercellular edema using the injector of this embodiment, multiple pores are created. These pores can be considered as flow paths for the intercellular fluid, thereby reducing the local accumulation of intercellular fluid. In this way, the injector of this embodiment can be used as an injector for reducing the accumulation of intercellular fluid in a subject. Furthermore, when the intercellular fluid is derived from lymphatic vessels, it can also be used as an injector for treating lymphedema.

[0208] Regarding the liquid, gas, object, and injector in this embodiment, the description of the first embodiment is referenced. When the liquid contains a functional substance found in living organisms, collagen is preferably the functional substance.

[0209] <Third Implementation Method>

[0210] The third embodiment of this disclosure is a method for forming a void using an injector.

[0211] The aforementioned injector injects liquids and gases into an object from the injector body without injecting via the given structure into the object, provided that a given structure is inserted within the object.

[0212] The injector comprises:

[0213] A container holding the aforementioned liquid and the aforementioned gas;

[0214] A nozzle portion communicating with the aforementioned receiving portion and having an ejection outlet for ejecting the aforementioned liquid and gas toward the aforementioned object; and

[0215] During operation, a pressurized part pressurizes the liquid and gas contained in the aforementioned containment section and ejects the liquid and gas from the aforementioned ejection port toward the aforementioned object.

[0216] The above-mentioned formation methods include:

[0217] The process of containing the above-mentioned liquid and gas in the above-mentioned container;

[0218] The process of pressurizing the liquid and gas contained in the aforementioned containment, and

[0219] The process of injecting the above-mentioned liquid and gas into the above-mentioned object,

[0220] The viscoelasticity of the above-mentioned objects at 25°C is above 47% and below 82%.

[0221] Regarding the liquid, gas, object, and injector in this embodiment, the description of the first embodiment is referenced.

[0222] The process of containing the liquid and gas in the container is not particularly limited. It can be a process of containing the liquid and gas in the container by drawing them from the outside of the injector through the injection port of the nozzle.

[0223] The energy imparting based on the pressurization unit in the process of pressurizing the liquid and gas contained in the aforementioned containment section can be achieved using an energy imparting method based on known pressurization techniques. Specifically, the description of the injector in the first embodiment is referenced.

[0224] Examples of the process of injecting the liquid and gas into the object include: using the ejection energy generated by pressurizing the liquid and gas through the nozzle while the ejection port is in contact with the object, to eject the liquid and gas.

[0225] The steps of containing the liquid and gas in the container, pressurizing the liquid and gas contained in the container, and injecting the liquid and gas into the object can be performed once or multiple times. Furthermore, when performing the injection step multiple times, the injection sites on the object can be the same or different.

[0226] <Fourth Implementation>

[0227] The fourth embodiment of this disclosure is a method for reducing the accumulation of intercellular fluid in a target using an injector.

[0228] The aforementioned injector injects liquids and gases into an object from the injector body without injecting via the given structure into the object, provided that a given structure is inserted within the object.

[0229] The above-mentioned injector has the following features:

[0230] A container holding the aforementioned liquid and the aforementioned gas;

[0231] A nozzle portion communicating with the aforementioned receiving portion and having an ejection outlet for ejecting the aforementioned liquid and gas toward the aforementioned object; and

[0232] During operation, a pressurized part pressurizes the liquid and gas contained in the aforementioned containment section and ejects the liquid and gas from the aforementioned ejection port toward the aforementioned object.

[0233] The above reduction methods include:

[0234] The process of containing the above-mentioned liquid and gas in the above-mentioned container;

[0235] The process of pressurizing the liquid and gas contained in the aforementioned containment, and

[0236] The process of injecting the aforementioned liquid and gas into the aforementioned object.

[0237] In cases where the intercellular fluid originates from lymphatic vessels, the method described in this embodiment can be used as a treatment for lymphedema.

[0238] Regarding the liquid, gas, object, and injector in this embodiment, the description of the first embodiment is referenced.

[0239] The process of containing the liquid and gas in the container, the process of pressurizing the liquid and gas contained in the container, and the process of injecting the liquid and gas into the object are described in accordance with the description of the third embodiment.

[0240] The reduction method of this embodiment may further include a step of injecting a solution or cells containing functional substances in the body into the voids formed by the above-described injection step.

[0241] By utilizing the voids created by the injection process described above as reservoirs for solutions or cells containing functional substances within organisms, these solutions can be locally distributed and retained.

[0242] A solution containing a functional substance from within a living organism can be exemplified by a solution obtained by dissolving (in this disclosure, this includes suspending or emulsifying) a functional substance from within a living organism that can be used in the first embodiment in a liquid that can be used in the first embodiment. When the liquid contains a functional substance from within a living organism, the functional substance from within the liquid may be the same as or different from the functional substance from within the solution.

[0243] The cells used in the process of injecting a solution or cells containing functional substances from a living organism can be cells removed from an organism or cultured cells derived from stem cells such as iPS cells (artificial pluripotent stem cells). Furthermore, the cells can be in the form of cell sheets, cell blocks, etc. The aforementioned cell blocks can be cell blocks obtained through three-dimensional culture.

[0244] The process of injecting a solution or cells containing functional substances from a living organism can be performed using the aforementioned injector, or other injectors. Examples of other injectors include syringes comprising a syringe plunger and an injection needle, but are not limited to these.

[0245] The process of injecting a solution or cells containing functional substances from the organism into the cavity formed by the above-described injection process can be performed once or multiple times.

[0246] <Fifth Implementation>

[0247] The fifth embodiment of this disclosure is a method for reducing intercellular fluid accumulation in an object requiring treatment, the method comprising: injecting a composition comprising liquid and gas into an injection site of the object.

[0248] In this embodiment, the injection can be performed using a needle-free injector. Alternatively, the injection can be performed using the injector described in the first embodiment.

[0249] In this embodiment, the liquid may be pressurized. Furthermore, the method of this embodiment may further include pressurizing the liquid and the gas in an injector.

[0250] Regarding the liquid, gas, object, and injector in this embodiment, the description of the first embodiment is referenced.

[0251] Example

[0252] The present disclosure will now be described in detail with reference to embodiments. However, the present disclosure is not limited to the embodiments described below.

[0253] [Experiment 1: Creating cavities in the intradermal space of rats or pigs]

[0254] (Target population)

[0255] Rats: Female SD rats, 8 weeks old, were used. They were anesthetized, shaved, and placed flat with their flanks facing upwards. The drugs were administered to the flanks.

[0256] Pigs: SPF livestock pigs were used. They were anesthetized, shaved, and placed flat on their backs with the abdomen facing upwards. The medication was administered to the abdomen or groin.

[0257] (Methods for filling and administering liquids and gases)

[0258] As an injector, it used a Figure 1 The injector with the structure shown was used. PBS (NACALAI TESQUE, 14249-95) solution was drawn from the nozzle of the injector's housing. Then, without drawing PBS solution, the plunger was pulled up further to fill the air in a typical laboratory environment. The volumes of liquid and gas drawn are shown in Table 1. After confirming the presence of air on the plunger side and PBS solution on the nozzle tip side, the medication was administered to the subject.

[0259]

[0260] After administration of the drug, the patient was euthanized by bloodletting while under anesthesia.

[0261] Skin was recovered centered at the drug administration site and fixed in 10% neutral buffered formaldehyde solution (NACALAI TESQUE, 37152-51) for 1–3 nights. The skin was then washed twice with PBS and immersed in fresh PBS. Skin removed from PBS was then immersed in ethanol for dehydration and defatting. Substitution with xylene and paraffin was then performed. The tissue was embedded in paraffin and thinly sectioned. The resulting sections were deparaffinized using xylene and ethanol. Wood cinnamic acid staining was performed, followed by eosin staining after washing with water and destaining with ethanol. Ethanol-based dehydration was then performed. After substitution with xylene, the tissue was mounted on glass slides using mounting medium. Microscopic observation was then performed.

[0262] Images of the sections were obtained using a KEYENCE All-in-One fluorescence microscope (BZ-X710).

[0263] like Figures 2-5 As shown, image observation confirmed the formation of voids throughout the dermis.

[0264] [Experiment 2: Drug administration to reduce tail edema in rats]

[0265] Rats were anesthetized, and the skin at a distance of 10 mm from the base of the tail was dissected and excised in a 5 mm band along the long axis. Then, the lymphatic vessels and veins located on the tail side of the dissected area were cauterized with an electrocautery device. The treated rats were then fed until edema was confirmed.

[0266] Liquid and gas were administered to four sites, staggered 90 degrees circumferentially, at the site where the skin had been peeled off. The volumes of the liquid and gas were 30 μL and 20 μL, respectively (gas ratio 40%).

[0267] Twenty-eight days after administration, the patient was euthanized and samples were taken.

[0268] After the aforementioned tail skin stripping was formed, lactated Ringer's solution (LRS), lactated Ringer's solution containing 5% glycerin, lactated Ringer's solution containing 5% sesame oil (Sesame), or collagen solution containing 5% sesame oil (ColSes) were injected on days 21, 22, and 23. Here, the collagen solution was prepared by mixing a 1% solution of atelocollagen from Nipponham pig skin, 10x Minimum Essential Medium (MEM), and a remodeling buffer (containing 2.2 g of sodium bicarbonate and 4.77 g of HEPES dissolved in 100 mL of 0.05N NaOH aqueous solution) in an 8:1:1 ratio. The diameter at a distal 5 mm position was compared between days 21 and 28 post-skin stripping. The results are shown below. Figure 6 .

[0269] Compared to the non-injected group (Cont), the tail diameters of the injected groups were significantly smaller. Error bars represent standard deviations. Sample sizes were: Cont: 9, Glycerin: 9, LRS: 6, Sesami: 6, ColSes: 6.

[0270] 30 μL each of lactated Ringer's solution, glycerin, sesame oil, and collagen were mixed with 20 μL of air and injected, and the results showed that lymphedema was improved.

[0271] [Experiment 3: Void formation for various drug administration subjects]

[0272] (Target population)

[0273] Mice: Bulb / c mice, female, 8 weeks old. They were anesthetized, shaved, placed face up, fixed, and administered drugs or assays to the flanks.

[0274] Pigs: SPF livestock pigs were used. Anesthesia was administered, and after shaving, the pigs were placed flat with their abdomen facing upwards. Drug administration or testing was performed on the abdomen or groin. Alternatively, after shaving, the pigs were placed prone, and drug administration or testing was performed on their backs. Abdominal administration or testing included administration or testing performed under normal conditions and administration or testing performed with air introduced into the abdominal cavity to tighten the skin. In tables and figures, the former is indicated as "(without air)" and the latter as "(with air)".

[0275] Konjac Jelly: (Registered Trademark), Mannanlife Corporation. When measuring physical properties, one sheet of Pro-Wipe (Daio Paper Co., Ltd.) was placed on the konjac jelly, and the measurements were taken from above.

[0276] Agarose gel (0.5%, 0.7% or 1%): Agarose (Agarose ME (medium immersion) Classic Type 100G, NACALAI TESQUE, 01158-56) was added to PBS to achieve the above concentrations, heated in a microwave oven, and then allowed to stand at 4°C to achieve the desired concentrations.

[0277] Marshmallow: White Marshmallow (EIWA Co., Ltd.) was administered.

[0278] (Methods for determining physical properties)

[0279] The measurements were performed according to the operating instructions of the Vesmeter (for biological assays, E-100HS, WAVECYBER CORP.). Specifically, at room temperature (25°C), the Vesmeter probe was placed vertically above the object being measured, and measurements were taken 4 to 35 times at the same location. The average value was taken as the measured value.

[0280] (Methods for filling and administering liquids and gases)

[0281] As an injector, it used a Figure 1 The injector has the structure shown. A given volume of D-PBS (-) (NACALAI TESQUE, 14249-24) containing 1% malachite green (NACALAI TESQUE, malachite green oxalate, 21015-12) is drawn from the nozzle of the injector's container. Then, without drawing the solution, the plunger is pulled up to the 100 μL mark to fill the container with air, as is typical in a laboratory setting. This brings the volume of air in the container to 30-80%. After confirming the presence of air on the plunger side and the presence of D-PBS solution on the nozzle tip side, the medication is administered to the subject.

[0282] (Observation after administration of liquid and gaseous drugs)

[0283] Konjac jelly was prepared into approximately 7 mm slices including the administration site and observed under a microscope. Agarose gel was prepared and administered in 50 mL centrifuge tubes, and observed visually from the outside of the tubes. Marshmallows were longitudinally cut with the center of the administration site marked, and observed visually.

[0284] The mice and pigs were prepared in the same manner as in Experiment 1 and observed under a microscope.

[0285] The observed images of each object are shown in Figures 7-15 .

[0286] The formation of voids was evaluated according to the following criteria.

[0287] A: Multiple voids are formed within the object. In konjac jelly, agarose, and marshmallows, this refers to the state where multiple voids, observed as bubbles, are visible within the malachite green color.

[0288] B: A large void is formed within the object. In konjac jelly, agarose, and marshmallows, this refers to the state of a void observed within the malachite green color.

[0289] C: No gaps were formed.

[0290] Table 2 shows the results of measurements of gas ratio, Vesmeter-based hardness, elasticity, viscosity coefficient, viscoelasticity, relaxation time, and evaluation of void formation. For the groin region of pigs, measurements were taken from multiple individuals, and the results were distinguished as groin region 1 and groin region 2, respectively.

[0291]

[0292] As shown in Table 2, voids were formed for objects with a viscoelasticity of 47% or higher and 82% or lower at 25°C and a relaxation time of 0.89 ms or higher and 4.39 ms or lower.

Claims

1. An injector that injects a liquid and a gas into an object from an injector main body without performing injection via a given structure in a state in which the given structure is inserted into the object, the injector comprising: a storage portion that stores the liquid and the gas; a nozzle portion that communicates with the storage portion and has a discharge port for discharging the liquid and the gas toward the object; and a pressurizing portion that, in operation, discharges the liquid and the gas from the discharge port toward the object by pressurizing the liquid and the gas stored in the storage portion, wherein a ratio of a volume of the gas to a total volume of the liquid and the gas is greater than 60% and is 80% or less.

2. The injector according to claim 1, wherein the gas is air.

3. The injector according to claim 1 or 2, wherein the injection into the object is injection into the object by jet injection.

4. The injector according to claim 1 or 2, wherein a discharge speed of the liquid and the gas is greater than 83.3 μL / s.

5. The injector according to claim 1 or 2, wherein the liquid contains a biological in vivo functional substance.

6. The injector according to claim 5, wherein the biological in vivo functional substance is one or more selected from the group consisting of a nucleic acid, a peptide, a protein, and a low-molecular compound.

7. An injector for reducing intercellular fluid accumulated in an object, the injector injecting a liquid and a gas into an object from an injector main body without performing injection via a given structure in a state in which the given structure is inserted into the object, the injector comprising: a storage portion that stores the liquid and the gas; a nozzle portion that communicates with the storage portion and has a discharge port for discharging the liquid and the gas toward the object; and a pressurizing portion that, in operation, discharges the liquid and the gas from the discharge port toward the object by pressurizing the liquid and the gas stored in the storage portion.

8. The injector according to claim 7, wherein a ratio of a volume of the gas to a total volume of the liquid and the gas is 30% or more and 80% or less.

9. The injector according to claim 7 or 8, wherein the gas is air.

10. The injector according to claim 7 or 8, wherein the injection into the object is injection into the object by jet injection.

11. The injector according to claim 7 or 8, wherein a discharge speed of the liquid and the gas is greater than 83.3 μL / s.

12. The injector according to claim 7 or 8, wherein the liquid contains a biological in vivo functional substance.

13. The injector according to claim 12, wherein the biological in vivo functional substance is one or more selected from the group consisting of a nucleic acid, a peptide, a protein, and a low-molecular compound.

14. A method of forming a void using an injector that injects a liquid and a gas into an object from an injector main body without performing injection via a given structure in a state in which the given structure is inserted into the object, the injector comprising: a storage portion that stores the liquid and the gas; a nozzle portion that communicates with the storage portion and has a discharge port for discharging the liquid and the gas toward the object; and a pressurizing portion that, in operation, discharges the liquid and the gas from the discharge port toward the object by pressurizing the liquid and the gas stored in the storage portion. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ A container holding the liquid and the gas; A nozzle portion communicating with the receiving portion and having an ejection outlet for ejecting the liquid and the gas toward the object; and During operation, a pressurized part ejects the liquid and gas contained in the containment from the ejection port toward the target by pressurizing the liquid and gas contained in the containment. The forming method includes: The process of containing the liquid and the gas in the containment portion The process of pressurizing the liquid and the gas contained in the containment, and The process of injecting the liquid and the gas into the object. The viscoelasticity of the injection site of the object at 25°C is above 47% and below 82%.

15. The method for forming a void according to claim 14, wherein, In the injection process, the injection is performed by jet injection into the object.

16. The method for forming a void according to claim 14 or 15, wherein, The volume of the gas relative to the total volume of the liquid and the gas is more than 30% and less than 80%.

17. The method for forming a void according to claim 14 or 15, wherein, The gas is air.

18. The method for forming a void according to claim 14 or 15, wherein, The ejection velocities of the liquid and the gas are greater than 83.3 μL / s.

19. The method for forming a void according to claim 14 or 15, wherein, The relaxation time of the injection site of the object was measured at 25°C to be greater than 0.89 ms and less than 4.39 ms.

20. A method for reducing the accumulation of intercellular fluid in an object using an injector. The injector injects liquids and gases into the object from the injector body, without injecting via the given structure into the object where a given structure is inserted. The injector comprises: A container holding the liquid and the gas; A nozzle portion communicating with the receiving portion and having an ejection outlet for ejecting the liquid and the gas toward the object; and During operation, a pressurized part ejects the liquid and gas contained in the containment from the ejection port toward the target by pressurizing the liquid and gas contained in the containment. The method for reducing the accumulation of intercellular fluid in the object includes: The process of containing the liquid and the gas in the containment portion The process of pressurizing the liquid and the gas contained in the containment, and The process of injecting the liquid and the gas into the object.

21. The method according to claim 20, wherein, The subject is a mammal other than a human.

22. The method according to claim 20 or 21, wherein, In the injection process, the injection is performed by jet injection into the object.

23. The method according to claim 20 or 21, wherein, The volume of the gas relative to the total volume of the liquid and the gas is more than 30% and less than 80%.

24. The method according to claim 20 or 21, wherein, The gas is air.

25. The method according to claim 20 or 21, wherein, The ejection velocities of the liquid and the gas are greater than 83.3 μL / s.

26. The method according to claim 20 or 21, wherein, The liquid contains functional substances found in living organisms.

27. The method according to claim 26, wherein, The functional substances in the organism are selected from one or more of nucleic acids, peptides, proteins, and low molecular weight compounds.

28. The method according to claim 20 or 21, further comprising: The process of injecting a solution or cells containing functional substances from a living organism into a cavity formed by performing the injection process.

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