JP7845880B2 - A medical device for administering a liquid containing humoral factors produced by cells to a target site. - Google Patents

Description

This invention relates to a medical device for administering a liquid containing humoral factors produced by cells to a target site.

In recent years, various attempts have been made to transplant cells to repair damaged tissues. For example, fetal cardiomyocytes, skeletal muscle blasts, mesenchymal stem cells, cardiac stem cells, ES cells, and iPS cells have been attempted to repair myocardial tissue damaged by ischemic heart diseases such as angina pectoris and myocardial infarction (Non-Patent Literature 1).
As part of these efforts, cell structures formed using scaffolds and sheet-like cell cultures formed from cells in a sheet-like structure have been developed (Non-Patent Literature 2). Another example of repairing damaged tissues through cell transplantation is CD34-positive cell therapy for severe lower limb diseases. In this therapy, CD34-positive cells are dissolved in physiological saline and injected intramuscularly into dozens of locations on both legs that are in a severe ischemic state (Non-Patent Literature 3).

Various attempts have been made regarding methods and devices for administering cells for transplantation. Patent Document 1 describes a cell implantation device capable of implanting cells within a body cavity. This device comprises a tubular device body connectable to a device delivery portion, and a cell storage portion connected to the device body and consisting of a cell storage bag capable of containing cells. The device describes how humoral factors released from cells stored in the bag are passed through the bag to act on the target site.

Patent Document 2 describes a cell suspension delivery device. This device has multiple projections for perforating one or more layers of a blood vessel from within the lumen of the blood vessel, and delivers a cell suspension to one or more layers of the blood vessel or perivascular tissue through these projections.
Patent Document 3 describes a medical system comprising a medical access port and a transport device. In such a system, the medical access port is an implantable access port including a needle consisting of a needle shaft and a removable needle tip, and it is described that fluid is extracted from a target through the transport device, the access port body and the needle by the needle penetrating through the skin to the outside of the body, and that fluid or cells are introduced into the target through such a pathway.

Japanese Patent Publication No. 2014-79480 Special Publication No. 2020-500669 Patent No. 6879946

Haraguchi et al., Stem Cells Transl Med. 2012 Feb;1(2):136-41 Sawa et al., Surg Today. 2012 Jan;42(2):181-4 Fujita et al., Circulation Journal Vol.78, February 2014: 490-501

The inventors of this invention faced the problem that, as described above, administering cells into tissues often requires repeated administration numerous times, placing a significant burden on the subject. Therefore, the present invention aims to solve this problem and provide a medical device that can reduce the frequency of cell administration with a simple mechanism.

The inventors, through diligent research to solve the above problems, discovered that the problems could be solved by gradually releasing cells from a storage area to the target site. Based on this finding, further research led to the completion of the present invention.

In other words, the present invention relates to the following:
[1] A medical device for administering a liquid containing humoral factors produced by cells to a target site,
The medical device comprises a storage section for storing a cell suspension and a clamping section for fixing the storage section near a target site, wherein the storage section has a structure that releases a liquid containing humoral factors produced by cells.
[2] The medical device according to [1], wherein the clamping portion includes an opening that allows fluid communication with the storage portion, and a liquid containing humoral factors produced by cells released from the storage portion is administered to the target site through the opening.
[3] The medical device according to [1] or [2], wherein the storage section further comprises an injection section for injecting a cell suspension.
[4] The medical device according to any one of [1] to [3], wherein the reservoir is configured to be expandable and contractible, and when the reservoir is expanded, it is configured to release a liquid containing humoral factors produced by cells.

[5] A medical device according to any one of [1] to [4], wherein the injection section is configured to prevent contamination by contaminants.
[6] A medical device described in any one of [1] to [5], wherein the target site is a blood vessel.
[7] A method of administering a liquid containing a humoral factor produced by cells to a target site,
A medical device comprising a storage section for storing a cell suspension and a clamping section for fixing the storage section near a target site, wherein the storage section has a structure that releases a liquid containing humoral factors produced by cells.
The method comprising the steps of exposing a target area and fixing a clamping portion, on which a storage portion is fixed, near the target area.

According to the present invention, since a liquid containing humoral factors produced by cells in a cell suspension stored in a reservoir fixed near the target site can be gradually administered to the target site, the frequency of administration procedures such as surgery and injection can be reduced, thereby reducing the burden on the subject. Furthermore, according to the present invention, after the cell suspension in the reservoir decreases due to administration, the cell suspension can be replenished from outside the body, further reducing the frequency of administration procedures.

Figure 1 is a conceptual diagram of a medical device according to the first embodiment of the present invention. This is a conceptual diagram showing an example of use of a medical device according to the first embodiment of the present invention.

In one aspect, the present invention relates to a medical device for administering a liquid containing humoral factors produced by cells to a target site, comprising a storage portion for storing a cell suspension and a clamping portion for fixing the storage portion near a target site, wherein the storage portion has a structure that releases a liquid containing humoral factors produced by cells.

In the present invention, "liquid containing humoral factors produced by cells" refers to a liquid containing any humoral factors produced by cells contained in a cell suspension. Examples of liquids containing humoral factors produced by cells include physiological saline, PBS, and culture media containing humoral factors produced by cells. In the present invention, the liquid containing humoral factors produced by cells also includes cell suspensions.
Examples of humoral factors produced by cells include cell growth factors, differentiation-inducing factors, hematopoietic factors, and various cytokines. Specifically, examples of humoral factors include HGF, VEGF, and SDF-1.

In the present invention, "cell suspension" refers to a state in which cells are suspended in any medium. The cells may be single cells or cells may be linked together via intervening substances. The cells may contain any gene or a viral vector containing any gene. The cells may also be cell cultures. In the present invention, cell cultures refer to, and are not limited to, those obtained through the cell culture step, but include spheroids, sheet-like cell cultures, and fragments of sheet-like cell cultures.
In the present invention, the medium for suspending cells is not limited to these, but examples include water, physiological saline, culture medium, buffer, diluent, cell preservation solution, and swelling bodies such as gels.

In this invention, "sheet-like cell culture" refers to a sheet-like structure in which cells are interconnected. The cells may be directly connected to each other (including through cellular elements such as adhesion molecules) and/or via intervening substances. The intervening substance is not particularly limited as long as it can connect cells at least physically (mechanically), but examples include extracellular matrix. The intervening substance is preferably cell-derived, particularly derived from the cells constituting the cell culture. While the cells are connected at least physically (mechanically), they may also be functionally connected, for example, chemically or electrically. The sheet-like cell culture may consist of one cell layer (monolayer) or two or more cell layers (layered (multilayer) structure, for example, two, three, four, five, six layers, etc.). Furthermore, the sheet-like cell culture may have a three-dimensional structure with a thickness exceeding the thickness of a single cell, without the cells exhibiting a clear layered structure. For example, in a vertical cross-section of a sheet-like cell culture, the cells may not be uniformly aligned horizontally, but rather arranged unevenly (e.g., in a mosaic pattern).

The sheet-like cell culture preferably does not contain a scaffold (support). Scaffolds are sometimes used in the art to adhere cells to their surface and/or interior, and to maintain the physical integrity of the sheet-like cell culture. For example, membranes made of polyvinylidene difluoride (PVDF) are known; however, the sheet-like cell culture of the present invention can maintain its physical integrity without such a scaffold. Furthermore, the sheet-like cell culture of the present invention preferably consists only of cell-derived materials constituting the sheet-like cell culture, and does not contain any other materials.

In this invention, "fragments of sheet-like cell culture" refers to fragments obtained by fragmenting a sheet-like cell culture into multiple fragments. The size of the fragments is not limited to this, but it is preferable that the majority of the fragments are small enough not to enter microvessels and to pass through the inside of an injection needle. Such a size is, for example, an average length of the diagonal of the sheet-like plane of 30 μm to 1000 μm, preferably 100 μm to 500 μm. In this invention, fragmentation can be performed by any known method that yields fragments of sheet-like cell culture, for example, by suspending a medium containing the sheet-like cell culture using a syringe and needle or pipette.

The cells included in the cell suspension of the present invention are not particularly limited as long as they produce humoral factors, and examples include adherent cells. Adherent cells include, for example, adherent somatic cells. Examples of somatic cells include myoblasts (e.g., skeletal myoblasts), muscle satellite cells, mesenchymal stem cells (e.g., those derived from bone marrow, adipose tissue, peripheral blood, skin, hair follicles, muscle tissue, endometrium, placenta, umbilical cord blood, etc.), tissue stem cells such as cardiomyocytes, fibroblasts, and cardiac stem cells, embryonic stem cells, pluripotent stem cells such as iPS (induced pluripotent stem) cells, synovial cells, chondrocytes, epithelial cells (e.g., oral mucosal epithelial cells, retinal pigment epithelial cells, nasal mucosal epithelial cells, etc.), endothelial cells (e.g., vascular endothelial cells, etc.), hepatocytes (e.g., hepatocytes, etc.), pancreatic cells (e.g., islet cells, etc.), renal cells, adrenal cells, periodontal ligament cells, gingival cells, periosteal cells, and skin cells. Somatic cells may be those differentiated from iPS cells (iPS cell-derived cells), and examples include iPS cell-derived cardiomyocytes, fibroblasts, myoblasts, epithelial cells, endothelial cells, hepatocytes, pancreatic cells, renal cells, adrenal cells, periodontal ligament cells, gingival cells, periosteal cells, skin cells, synovial cells, and chondrocytes. Cells include suspension cells. Examples of suspension cells include T lymphocytes and B lymphocytes.
Preferably, the cells contained in the cell suspension of the present invention are cells capable of promoting angiogenesis, for example, cells capable of secreting angiogenesis-promoting factors, such as cytokines such as VEGF. In such cases, the liquid containing humoral factors produced by the cells is a liquid containing cells capable of promoting angiogenesis, for example, angiogenesis-promoting factors, such as cytokines such as VEGF.

In the present invention, the "storage section" refers to a section that stores a cell suspension. The storage section of the present invention has a structure that releases a liquid containing humoral factors produced by cells. Examples of materials for the storage section include elastic resin materials. Such elastic resin materials are not limited and include, for example, polyamide, polyamide elastomer, polyolefin, polyolefin elastomer, polyester, polyester elastomer, polyurethane, polyurethane elastomer, polyimide, polyvinyl chloride, fluororesin, silicone rubber, latex rubber, etc., and one or more of these can be used in combination. In another example, a biodegradable polymer can be used as the material for the storage section. Such biodegradable polymers are not limited and include, for example, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, polycaprolactone, lactic acid-caprolactone copolymer, glycolic acid-caprolactone copolymer, poly-γ-glutamic acid, etc., and one or more of these can be used in combination. A structure that releases a fluid containing humoral factors produced by cells may, for example, have a reservoir with an opening. The diameter of such an opening is 1 to 500 μm, preferably 10 to 50 μm.

In one embodiment, the reservoir is configured to be expandable and contractible. The expandable and contractible reservoir is formed, for example, by fusing one end of a tubular elastic resin material (such as silicone) and fixing the other end to a tube or the like. The reservoir can be expanded by delivering a fluid for expansion into the reservoir through such a tube. In this embodiment, the reservoir is not fixed to the clamping portion when contracted, but can be fixed to the clamping portion by expanding. Furthermore, in this embodiment, the reservoir can be configured as a valve structure that does not release liquid containing cell-produced humoral factors when contracted, but releases liquid containing cell-produced humoral factors when expanded. Additionally, by providing a valve structure made of a rubber-like material inside the area where the liquid containing cell-produced humoral factors is released, a structure capable of releasing liquid containing cell-produced humoral factors can be created.

In the present invention, the "clamping portion" refers to a member that fixes the reservoir portion near the target site. The clamping portion has a leg portion on its lower surface and an arm portion on its upper surface. The leg portion fixes the clamping portion itself near the target site in the tissue, and the arm portion further fixes the reservoir portion to the clamping portion itself. The clamping portion of the present invention is responsible for fixing the reservoir portion and fixing it to the target site on its upper and lower surfaces, respectively, so that the reservoir portion does not compress or damage the target site, such as a blood vessel, due to changes in shape caused by the expansion or contraction of the reservoir portion. In one embodiment, the leg portion is configured to clamp tissue in the body, preferably a tubular structure in the body such as a blood vessel or lymphatic vessel. The leg portion of the clamping portion may be configured to clamp a blood vessel by force such as a spring, like a clip, or it may be curved to follow the surface of the blood vessel wall and configured to fit the circumferential direction of the blood vessel. The tip of the leg may have a sharp structure, for example, to allow for puncture of surrounding tissue, in order to fix the clamping portion to the surrounding tissue of tubular structures such as blood vessels.
The clamping portion of the present invention may have openings. These openings refer to flow paths within the clamping portion and are located on the arm side and on the front or side of the clamping portion. The openings on the arm side allow for fluid communication with the reservoir. Multiple openings may be located on the arm side, allowing for fluid communication with locations that release fluid containing humoral factors produced by multiple cells in the reservoir. The fluid containing humoral factors produced by cells released from the reservoir flows from the arm side opening into the opening and can be administered to the target site through the front or side opening of the clamping portion. Multiple openings may be located on the front or side of the clamping portion. In such cases, the fluid containing humoral factors produced by cells is administered to the target site through multiple openings on the front or side of the opening.

The medical device of the present invention may further include an injection section. The injection section refers to a component configured to inject a cell suspension into the reservoir. The injection section may be a tubular body that is in fluid communication with the reservoir. For example, if the reservoir is configured to be expandable and contractible, a tube for delivering fluid for expansion, fixed to one end of a tubular elastic resin material, may be used as the injection section.
In one embodiment, the injection unit is configured to prevent contamination by contaminants. For example, the injection unit has a lid, which can be used to close the injection port when not injecting a cell suspension.

In this invention, the "target site" refers to the site within the target tissue where a fluid containing humoral factors produced by cells is administered. Examples of target sites in tissue include, in living organisms, areas where injury (wound) exists or its vicinity. While injury (wound) is not limited to these, it includes vascular injury and stenosis. In such cases, the target site in tissue is in the tissue near the blood vessel, preferably between the blood vessel wall and the surrounding tissue. In one embodiment, the target site in tissue is the vascular sheath surrounding the vascular tissue. In this case, the clamping portion fixes itself to the blood vessel near the target site and further fixes the reservoir portion.

In the present invention, a liquid containing cellular humoral factors is administered into the target tissue, preferably into the tissue surrounding the target blood vessel, and more preferably into the tissue surrounding the blood vessel near the lesion site of a patient with a lower limb disease. In one embodiment, the liquid containing cellular humoral factors is administered to a patient with peripheral artery disease in a lesion site where blood flow is impaired, for example, into the tissue surrounding the blood vessel in the adductor muscles of the thigh of the lower limb. In this embodiment, the medical device of the present invention can be configured to have an elongated reservoir and be fixed over a long distance along the blood vessel by multiple clamping parts in order to administer the liquid containing cellular humoral factors to a wide area of tissue surrounding the blood vessel in the lower limb. In one embodiment, by administering the liquid containing cellular humoral factors into the tissue surrounding the blood vessel near the lesion site, blood flow can be improved by, for example, 35%, 40%, or 45% compared to a healthy state, for example, 7 days after administration. In one embodiment, administering a fluid containing humoral factors produced by cells into the tissue surrounding blood vessels near the lesion site can improve blood flow by approximately 1.5 times, 2 times, or 2.5 times compared to control saline solution.

In one embodiment, the recipient of a liquid containing humoral factors produced by cells using the medical device of the present invention has a disease of the lower limbs. Diseases of the lower limbs include all diseases affecting the lower limbs. Examples of such diseases, but not limited to these, include peripheral artery disease, varicose veins, deep vein thrombosis, and diabetic foot lesions. Preferably, the disease of the lower limbs in the present invention is a disease in which blood vessels in the lower limbs are narrowed or blocked, and blood flow to the lower limbs is impaired, for example, peripheral artery disease. In the present invention, peripheral artery disease includes, but is not limited to, lower limb obstructive arteriosclerosis, Buerger's disease, collagen disease, and in particular severe lower limb obstructive arteriosclerosis is referred to as severe lower limb ischemia.
While not bound by any particular theory, the effect of the fluid containing humoral factors produced by cells administered by the medical device of the present invention on lower limb diseases is thought to be due to cytokines such as VEGF contained in the fluid containing humoral factors produced by the administered cells acting directly and/or indirectly on cells in the ischemic area, thereby promoting angiogenesis.

In another aspect, the present invention relates to a method for administering a liquid containing
In the present invention, exposing the target site means, for example, exposing the target site to which a fluid containing humoral factors produced by cells will be administered by making an incision in the body surface. Preferably, the target site is a blood vessel, and the body surface is incised until a portion of the circumferential direction of the blood vessel is exposed.

The medical device of the present invention can be fixed near the target site after an incision has been made and exposed, and then sutured in a manner that allows the medical device to be implanted in the body. This allows for the continuous administration of a liquid containing humoral factors produced by cells from the medical device to the target site even after suturing.
In one embodiment, the medical device provided in the method of the present invention further includes an injection section of a tubular body in fluid communication with a reservoir. In this embodiment, after fixing the medical device of the present invention near the target site, the exposed target site can be sutured closed, leaving only the tip of the injection section outside the body. In this case, the cell suspension in the reservoir can be replenished from outside the body after it has decreased due to the release of fluid containing humoral factors produced by the cells. In this way, the frequency of operations for administering fluid containing humoral factors produced by the cells can be reduced.

The following describes a medical device 1 according to a preferred embodiment of the present invention. Figure 1 shows a conceptual diagram of the first embodiment of the present invention. In the figures of this disclosure, the size of each component is exaggerated as appropriate for the sake of clarity, and the illustrated components do not represent their actual size.
As shown in Figure 1, the medical device 1 of the present invention includes a storage section 2 for storing a cell suspension and a clamping section 3 for fixing the storage section 2 near the target site. The size of the storage section 2 can be changed according to the size and extent of the target site. Depending on the size of the storage section 2, multiple clamping sections 3 can be used to firmly fix the storage section 2 near the target site. The clamping section 3 has an arm on its upper side and a leg on its lower side, with the arm fixing the storage section 2 and the leg fixing itself near the target site. The storage section 2 has a structure that releases a liquid containing humoral factors produced by cells, allowing the liquid containing humoral factors produced by cells to be released from the storage section 2 to the outside.

The clamping portion 3 may further have an opening 3a. The opening 3a is in fluid communication with the storage portion 2. The liquid containing humoral factors produced by the cells that exits the storage portion 2 passes through the opening 3a, which allows for changes in the administration location and the direction in which the liquid containing humoral factors produced by the cells exits.
As shown in Figure 1, the storage section 2 is connected to an injection section 4, a tubular body that is fluidly connected to the lumen of the storage section 2, and the cell suspension S can be injected into the storage section 2 from the injection port at the tip of the injection section 4. A plate-like body 6 for fixing the injection port can be attached to the tip of the injection section 4, as shown in Figure 1.

To administer a fluid containing humoral factors produced by cells near a blood vessel using the medical device 1 shown in Figure 1, first, as shown in Figure 2a, an incision is made in the body surface to expose the target blood vessel B. The exposure of the target blood vessel B can be performed in the same manner as the step of harvesting an autologous vein to be used for bypass surgery. At this time, it is not necessary to expose the entire circumferential surface of blood vessel B; it is sufficient to expose only a part of it. Next, as shown in Figure 2b, the clamping part 3, which has the constricted reservoir part 2 set on it, is positioned so that the curve of its lower surface clamps onto blood vessel B. The clamping part 3 is fixed to the target site around blood vessel B by inserting its legs at both ends into the surrounding tissue of blood vessel B.
Once all the clamping parts 3 (only one is shown in Figure 2) are fixed in the desired position, the cell suspension S is then injected from the injection part 4 into the storage part 2, as shown in Figure 2c, to expand the storage part 2. As the storage part 2 expands, it becomes firmly fixed to the arms of the clamping parts 3. As the storage part 2 expands, it also extends a projection toward the opening 3a of the clamping part 3. When the storage part 2 is sufficiently expanded, the tip of the projection opens, and the lumen of the storage part 2 and the opening 3a of the clamping part 3 become fluidly connected, and the liquid containing humoral factors produced by the cells released from the storage part 2 begins to flow into the opening 3a of the clamping part 3.

When the fluid containing humoral factors produced by the cells begins to be released from the front side of the opening 3a, the incision is sutured, leaving only the tip of the injection section 4 on the body surface, as shown in Figure 2d. At this time, the injection section 4 exposed to the outside of the body surface may be configured to be fixed in a desired position on the body surface by a plate-shaped fixing device near the tip. As shown in Figure 2e, when the cell suspension S in the storage section 2 decreases, the cell suspension S in the storage section 2 can be replenished by injecting more cell suspension S from the injection section 4. At this time, the injection section 4 may have a lid 5 to close the injection port for injecting the cell suspension S. Except when injecting the cell suspension S, the lid 5 prevents dirt, bacteria, etc., from contaminating the storage section and prevents the cell suspension S in the storage section 3 from leaking out of the body.

In other words, the medical device of the present invention can be used sequentially by the following steps.
(1) Provide medical device 1.
(2) Make an incision on the body surface so that blood vessel B is exposed.
(3) A clamping section 3 with a constricted storage section 2 is placed near blood vessel B.
(4) The cell suspension S is injected from the injection section 4 into the storage section 2 to expand the storage section 2.
(5) Leave only the tip of the injection site 4 outside the body and suture the incision.
In the procedure described above, the clamping portion 3 was positioned near the blood vessel B before expanding the reservoir portion 2. However, the reservoir portion 2 may be expanded beforehand, and the clamping portion 3 with the expanded reservoir portion 2 set in place may be positioned near the blood vessel B. Alternatively, the reservoir portion 2 may be expanded by suturing the incision while the reservoir portion 2 is still contracted, and then injecting the cell suspension S from outside the body. Furthermore, the reservoir portion 2 may be expanded by injecting any expansion fluid in addition to the cell suspension S.

As described above, the medical device of the present invention allows for the gradual administration of a liquid containing humoral factors produced by cells in a cell suspension stored in a reservoir fixed near the target site. This reduces the frequency of administration procedures such as surgery and injections, thereby reducing the burden on the patient. Furthermore, according to the present invention, after the cell suspension in the reservoir decreases due to administration, additional cell suspension can be replenished from outside the body, further reducing the frequency of administration procedures.

1 Medical device 2 Storage section 3 Clamping section 3a Opening 4 Injection section 5 Lid 6 Plate-shaped body S Cell suspension B Blood vessel

Claims (6)

A medical device for administering a liquid containing humoral factors produced by cells to a target site,
It includes a storage section for storing a cell suspension and a clamping section for fixing the storage section near the target site, and the storage section has a structure that releases a liquid containing humoral factors produced by cells.
The clamping portion is configured to grip tubular structures within the body.
The aforementioned medical device. The medical device according to claim 1, wherein the clamping portion includes an opening that allows fluid communication with the storage portion, and a liquid containing humoral factors produced by cells released from the storage portion is administered to the target site through the opening. The medical device according to claim 1 or 2, wherein the storage section further includes an injection section for injecting a cell suspension. A medical device according to any one of claims 1 to 3, wherein the reservoir is configured to be expandable and contractible, and the reservoir is configured to release a liquid containing humoral factors produced by cells when expanded. The medical device according to any one of claims 1 to 4, wherein the injection section is configured to prevent contamination by contaminants. A medical device according to any one of claims 1 to 5, wherein the target site is a blood vessel.