Patent Application
20130218262
The present invention relates to a sheet to be bonded (adhered) to living tissue and a device for bonding the sheet to living tissue. More specifically, the invention pertains to a medical sheet which can be bonded to the inside of a body lumen and a device for delivering and bonding the sheet to the inside of the body lumen.
An example of a known therapeutic device for use inside a body lumen is a tubular stent which is set indwelling in a blood vessels. Japanese Patent Laid-open No. 2009-131672 discloses an example of a stent. A stent is ordinarily used in the following manner. First, a blood vessel at the patient's leg or arm is minutely incised, and an introducer sheath (introducer) is set in the incision. While a guide wire is precedingly advanced through the lumen of the introducer sheath, a radially contracted stent is inserted into the blood vessel by a balloon catheter or the like. Thereafter, the stent is expanded at a target position by a balloon or the like so that the stent is set indwelling in the blood vessel.
Upon being indwelled in the blood vessel, the stent functions to support a stenosed part from the inside or to obstruct an entrance to an aneurysm.
Such a stent is commonly formed in a tubular shape. Even in a situation where only a part of the circumferential extent of a blood vessel is troubled, therefore, the stent makes contact with the whole 360 degree circumferential extent of the blood vessel, and is indwelled over a wide area that includes healthy parts of the blood vessel.
Once the stent is indwelled, the stent continues to be present in the blood vessel, without being taken out. The stent is considered to be foreign matter and so when the stent is present in a blood vessel, a thrombus may be generated due to the stent. Therefore, the patient must continue to be medicated with an antiplatelet agent as an antithrombogenic treatment. Although there is present a drug-eluting stent having a drug contained in a stent, the period over which the drug is being eluted is limited.
A biological adhesive sheet, and a device for bonding (adhering) the sheet to living tissue, are configured to reduce the influence on a living tissue and enhance safety.
A biological adhesive sheet positionable in a living body in contact with living tissue of the living body comprises a substrate formed of a biocompatible material, and a plurality of spaced apart projections formed of a biocompatible material and projecting from a surface of the substrate, with the plurality of spaced apart projections being contactable with the living tissue. The biological adhesive sheet is bondable to the living tissue by van der Waals forces when the spaced apart projections contact the living tissue.
The biological adhesive sheet is bonded to living tissue by the van der Waals force by putting the plurality of projections in contact with the living tissue. Therefore, there is no need for other configuration for holding the bonded state of the biological adhesive sheet and so the influence on the living tissue can be reduced and safety can be enhanced. Especially, in a therapy of the inside of a body lumen where a stent is ordinarily needed, the influence on healthy parts of the tube (vessel) can be reduced. Specifically, when a stent is used in a lumen, there arise situations in which even if only a part of the circumferential extent of the tube (vessel) is troubled, the stent makes contact with a full 360 degree circumferential extent of the tube and the stent is left indwelling in a wide range (region or area) inclusive of healthy parts of the tube. When the biological adhesive sheet is used, on the other hand, the sheet can be bonded by the van der Waals force, without utilizing any radial forces as in the case of a stent, so that only the troubled part of the tube can be covered and thereby treated. Thus, the influence on the healthy parts of the tube (vessel) can be minimized.
The projections are preferable arranged on the surface of the substrate in a density of one or more projections per 1 μm2 and have a length of 1 to 500 μm and a maximum outside diameter of 5 nm to 1 μm. The biological adhesive sheet can thus exhibit a good adhesive force to a living tissue.
The substrate and the projections are each formed of a biodegradable polymer, and the bonded biological adhesive sheet disappears through decomposition over time, whereby the period of medication with an antiplatelet agent can be shortened.
With the substrate and the projections both formed of biodegradable polymer such that the substrate disappears through decomposition earlier than the projections, the substrate will disappear through decomposition before the deterioration of the adhesive force owing to the projections. This can help restrain peeling of the substrate.
The biodegradable polymer is preferably one or more selected from the group consisting of polylactic acid, polylactic acid stereo complex, polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, polyhydroxybutyric acid, polymalic acid, poly-α-amino acid, collagen, laminin, heparan sulfate, fibronectin, vitronectin, chondroitin sulfate, hyaluronic acid, polycaprolactone, and polyamino acid, and so the biological adhesive sheet is decomposed favorably after being bonded to living tissue.
The substrate can be a porous body. This can make it possible to promote the regeneration of a living tissue to which the biological adhesive sheet is bonded, and to permit the biological adhesive sheet to be speedily covered with the living tissue.
At least one of the substrate and the projections can contain a biologically active agent. This thus makes it possible to treat living tissue to which the biological adhesive sheet is bonded, or to restrain obstruction or the like from occurring at an application site in the case where the biological adhesive sheet is disposed inside a body lumen.
The substrate can be a tubular base (or tubular body), with the projections projecting outwardly from the outer circumferential surface of the tubular base. In this way, the biological adhesive sheet can be indwelled rather safely inside a body lumen, for example, a blood vessel by the van der Waals force while reducing the influence on the living tissue.
The substrate can also be provided with a plurality of through slits so that the biological adhesive sheet can be bonded while enlarging the substrate according to a living tissue to which the biological adhesive sheet is applied. Especially in the case where the substrate is a tubular base (or tubular body), the biological adhesive sheet can be bonded while enlarging the base according to the inside diameter of a body lumen to which the biological adhesive sheet is applied.
According to another aspect, a device for delivering a biological adhesive sheet to a site in a living body comprises a tube possessing a size which is insertable into a living body, and a tubular holding section disposed at a distal portion of the tube and possessing an outer circumferential surface. The tubular holding section is elastically expandable from a contracted state to an expanded state, and is contractable from the expanded state to the contracted state, with the outer circumferential surface of the tubular holding section being configured to hold the biological adhesive sheet to be bonded to living tissue in the living body. The device also includes an outer sheath covering the outer circumferential surface of the tubular holding section and holding the tubular holding section in the contracted state, with the outer sheath and the tubular holding section being relatively axially movable to permit the outer sheath to be moved to a position uncovering at least a part of the tubular holding section to allow the part of the tubular holding section to expand outwardly to the expanded state. In addition, an inflatable and deflatable balloon is located at a distal portion of the tube.
The balloon is inflatable and deflatable inside the holding section, thus allowing the biological adhesive sheet to be rather assuredly bonded to a living tissue by pressing the biological adhesive sheet by the balloon in the condition where the biological adhesive sheet is tentatively fixed to the living tissue by the holding section.
According to a further aspect, a method comprises inserting a biological adhesive sheet into a living body, wherein the biological adhesive sheet includes a substrate formed of a biocompatible material and a plurality of spaced apart projections formed of a biocompatible material and projecting from a surface of the substrate. The method additionally involves positioning the biological adhesive sheet adjacent living tissue in the living body, and bringing the spaced apart projections of the biological adhesive sheet into contact with the living tissue in the living body to bond the biological adhesive sheet to the living tissue by van der Waals forces.
Embodiments of the biological adhesive sheet and device for bonding such sheet will be described below with reference to the accompanying drawing figures. To help facilitate an understanding of the disclosure here, dimensional ratios in the drawings may be exaggerated so as to be different from actual ratios.
A biological adhesive sheet 10 according to a first embodiment representing one example of the biological adhesive sheet disclosed here is a flexible medical sheet to be bonded to a living tissue M, and is one that exhibits an adhesive force both in gas and in liquid, without application of any separate adhesive to an adhesion surface. In the case where a stronger adhesive force is required, a stronger adhesive force can be obtained by making a surface of the biological adhesive sheet 10 a more hydrophilic surface. The living tissue M to which the biological adhesive sheet 10 is to be bonded is not specifically restricted. By way of example, the living tissue M may be a lesion in a lumen such as blood vessel, bile duct, trachea, esophagus, urethra, etc. or the inside of nasal cavity, lung or the like. Particularly, examples of use of the biological adhesive sheet in a lumen include adhesion to cover a lesion for reinforcing or supplementing a weakened or defective blood vessel, heart or the like, adhesion to close an entrance to an aneurysm or varix or the like, and adhesion to cover a vulnerable plaque formed in a blood vessel for the purpose of preventing lipid in the vulnerable plaque from flowing into the blood vessel. The term legion refers to, for example, any localized, abnormal structural change in the body.
The biological adhesive sheet 10 has a configuration as shown in
The thickness B of the substrate 12 is preferably appropriately selected according to the application site of the living tissue M and the use of the biological adhesive sheet 10. For example, the thickness B is 3 to 3000 μm, preferably 30 to 300 μm.
The shape of the substrate 12 is not particularly limited, and is preferably modified appropriately according to the shape of the lesion of the living tissue M to which the biological adhesive sheet 10 is to be applied. For example, the shape may be a circle, a rectangle or the like.
The size of the substrate 12 is not specifically restricted, and is preferably modified appropriately according to the width of the lesion of the living tissue M to which the biological adhesive sheet 10 is to be applied. For example, the maximum width C is 5 to 50 mm. The size of the substrate 12 can be selectively modified, for example, by preliminarily preparing a plurality of biological adhesive sheets 10 differing in size, or by cutting a large biological adhesive sheet 10 to a desired size.
The projections 13 possess a columnar shape (in this embodiment, a cylindrical shape). The maximum outside diameter D of the projections 13 is 5 nm to 1 μm, more preferably 0.1 to 0.5 μm. The height H of the projections 13 is 1 to 500 μm, more preferably 10 to 50 μm. The pitch P of the projections (i.e., the spacing between adjacent projections) 13 is 0 to 1 μm, more preferably 0.05 to 0.5 μm. The maximum outside diameter here means the length (dimension) of a longest part in a section orthogonal to the extending direction (projecting direction) of the projection 13, and can be used even if the projections 13 are not circular in cross-sectional shape.
The projections 13 are formed in a density of one or more projections per 1 μm2, more preferably 50 or more projections per 1 μm2. Where the projections 13 are shaped and sized as above-mentioned, an adhesive force can be exhibited based on the van der Waals force, both in gas and in liquid.
The pattern in which the projections 13 are arranged is not limited to a specific pattern. Although the projections 13 are arranged regularly in this embodiment, they may be arranged irregularly.
The projections 13 extend perpendicularly from the substrate 12 in this embodiment, but they may also be inclined relative to the substrate 12 as in another example shown in
In addition, the projections 13 need not necessarily be arranged so they all extend in the same direction. For example, the projections 13 can be arranged so that they are inclined in different directions depending on the part of the adhesion surface 11 of the substrate 12.
Where the plurality of projections 13 extend in the same direction (at the same inclination angle), upon adhesion to a living tissue M, the projections 13 tend to be aligned in one direction, as shown in
When the projections 13 are inclined in different directions depending on the part in the adhesion surface 11 of the substrate 12, this makes it difficult for the biological adhesive sheet 10 to peel off. This is effective in application of the biological adhesive sheet 10 to a part where inadvertent peeling is undesirable or a part where forces are exerted irregularly.
In addition, the shape of the projections 13 is not restricted to the cylindrical shape. For example, the shape may be a columnar shape with a polygonal section. The individual projections 13 may not necessarily have the same cross-sectional shape from the proximal end portion connected to the substrate 12 to the distal portion. For instance, the projection 13 may be configured so that the cross-section at its distal portion is greater or smaller than the cross-section at its proximal portion.
The substrate 12 and the projections 13 are each formed of a biocompatible material. Preferably, at least one of them is formed of a biodegradable polymer. More preferably, both the substrate 12 and the projections 13 are formed of biodegradable polymers. In addition, at least one of the substrate 12 and the projections 13 may contain a biologically active agent, such as immunosuppressors and carcinostatic agents.
As the biodegradable polymer, for example, those which are high in stability in vivo are preferred. For instance, the biodegradable polymer is preferably at least one selected from the group consisting of polylactic acid, polylactic acid stereo complex, polyglycolic acid, a copolymer of polylactic acid and polyglycolic acid, polyhydroxybutyric acid, polymalic acid, poly-α-amino acid, collagen, laminin, heparan sulfate, fibronectin, vitronectin, chondroitin sulfate, hyaluronic acid, polycaprolactone, and polyamino acid. Taking into consideration its decomposition in vivo, the biodegradable polymer is preferably one that is safe medically. As the most preferred of these polymers, polylactic acid and its derivatives are used optimally.
The biocompatible material is not specifically restricted so long as it is biocompatible. Examples of other biocompatible materials than the above-mentioned biodegradable polymers include Teflon (registered trademark), polyurethane, and silicones.
The biologically active agent is not specifically restricted insofar as it is a substance that acts on the living tissue M. Especially where the biological adhesive sheet 10 is used so it is indwelled in a lumen, it is preferably one that has a restenosis-restraining effect or an inflammation-restraining effect. Examples of the biologically active agent include carcinostatic agent, immunosuppressor, antibiotic, antirheumatic, antithrombogenic agent, HMG-CoA reductase inhibitor, ACE inhibitor, calcium antagonist, antilipemic agent, integrin inhibitor, antiallergic agent, antioxidant, GPIIbIIIa antagonist, retinoid, flavonoid, carotinoid, lipid improver, DNA synthesis inhibitor, tyrosine kinase inhibitor, antiplatelet agent, blood vessel smooth muscle proliferative inhibitor, antiflammatory agent, bio-derived material, interferon, and NO production promoting substance.
The carcinostatic agent is preferably, for example, vincristin, vinblastin, vindesin, irinotecan, pirarubicin, paclitaxel, docetaxel, methotrexate, or the like.
The immunosuppressor is preferably, for example, sirolimus, everolimus, pimecrolimus, sirolimus derivatives such as ABT-578, AP23573, CCI-779, etc., tacrolimus, azathioprine, cicrosporin, cyclophosphamide, mycophenolate mofetil, gusperimus, mizoribin, or the like.
The antibiotic is preferably, for example, mitomycin, adriamycin, doxorubicin, actinomycin, daunorubicin, idarubicin, pirarubicin, aclarubicin, epirubicin, peplomycin, zinostatin stimalamer, or the like.
The antirheumatic is preferably, for example, methotrexate, sodium thiomalate, penicillamine, lobenzarit, or the like.
The antithrombogenic agent is preferably, for example, heparin, aspirin, antithrombin preparation, ticlopidine, hirudin, or the like.
The HMG-CoA reductase inhibitor is preferably, for example, cerivastatin, cerivastatin sodium, atorvastatin, rosuvastatin, pitavastatin, fluvastatin, fluvastatin sodium, simvastatin, lovastatin, pravastatin, or the like.
The ACE inhibitor is preferably, for example, quinapril, perindopril erbumine, trandolapril, cilazapril, temocapril, delapril, enalapril maleate, lisinopril, captopril, or the like.
The calcium antagonist is preferably, for example, hifedipine, nilvadipine, diltiazem, benidipine, nisoldipine, or the like.
The antilipemic agent is preferably, for example, probucol.
The integrin inhibitor is preferably, for example, AJM300.
The antiallergic agent is preferably, for example, tranilast.
The antioxidant is preferably, for example, α-tocopherol.
The GPIIbIIIa antagonist is preferably, for example, abciximab.
The retinoid is preferably, for example, all-trans-retinoic acid.
The flavonoid is preferably, for example, epigallocatechin, anthocyanine, or proanthocyanidine.
The carotinoid is preferably, for example, β-carotene, or lycopene.
The lipid improver is preferably, for example, eicosapentanoic acid.
The DNA synthesis inhibitor is preferably, for example, 5-FU.
The tyrosine kinase inhibitor is preferably, for example, genistein, tyrphostin, erbstatin, staurosporine, or the like.
The antiplatelet agent is preferably, for example, ticlopidine, cilostazol, or clopidogrel.
The antiflammatory agent is preferably, for example, steroids such as dexamethasone, and prednisolone.
The bio-derived material is preferably, for example, EGF (epidermal growth factor), VEGF (vascular endothelial growth factor), HGF (hepatocyte growth factor), PDGF (platelet derived growth factor), BFGF (basic fibrolast growth factor), or the like.
The interferon is preferably, for example, interferon-γ1a.
The NO production promoting substance is preferably, for example, L-alginine.
Whether the biologically active agent is one kind of biologically active agent or is a combination of two or more different kinds of biologically active agents should be appropriately selected according to the individual case.
The biological adhesive sheet 10 according to this embodiment is adhered (bonded) to a living tissue by the van der Waals force by having the plurality of projections 13 in contact with the living tissue, as above-mentioned. Therefore, other features or ways of holding the adhered state are not needed, and it is possible to reduce the influence on the living tissue and to enhance safety. Especially, with therapy applied to the inside of a lumen in which a stent is ordinarily necessary, the influence on healthy parts of the tube (vessel) can be reduced. Specifically, when a stent is used or indwelled inside a lumen, the stent makes contact with a 360 degree circumferential extent of the tube or tubular living tissue (lumen), even in situations where only a part of the circumferential extent of the tube or tubular living tissue (lumen)is troubled. The stent is thus left indwelling over a greater extent (greater circumferential extent) than may otherwise be needed, including healthy parts of the tube or tubular living tissue (lumen). When the biological adhesive sheet 10 is used, on the other hand, it can be adhered to a desired part by the adhesive force of the adhesion surface 11 itself, without utilizing radial forces as in the case of a stent. In this case, therefore, only the troubled part of the tube (lumen) can be covered and treated, while minimizing the influence on the healthy parts of the tube.
Depending on the part to which the biological adhesive sheet 10 is adhered, over time the biological adhesive sheet 10 thus adhered, for example, to the inside wall of a blood vessel becomes embedded by being covered with the living tissue M.
In addition, where the substrate 12 and the projections 13 are each formed of a biodegradable polymer, the adhered adhesive sheet 10 disappears by being decomposed over time. In the case where the biological adhesive sheet 10 is adhered for example to the inside wall of a blood vessel, therefore, the period of medication with an antiplatelet agent for restraining generation of a thrombus due to the presence of the foreign matter can be shortened.
In addition, in the case where the substrate 12 and the projections 13 are both formed of biodegradable polymers such that the substrate 12 will disappear through decomposition earlier than the projections 13, the substrate 12 can be restrained from peeling before the adhesive force is lost by disappearance of the projections 13 through decomposition. The decomposition of the substrate 12 earlier than the projections 13 in this way can be realized, for example, by applying biodegradable polymers differing in decomposition time to the substrate 12 and the projections 13, respectively. For example, a configuration may be adopted in which the projections 13 are formed of polycaprolactone or its derivative whereas the substrate 12 is formed of polylactic acid and its derivative.
As a further example of the biological adhesive sheet shown in
In addition, where at least one of the substrate 12 and the projections 13 contains a biologically active agent, it is possible to treat a lesion to which the biological adhesive sheet 10 is applied, and to restrain obstruction or the like from occurring at the application site in the case where the biological adhesive sheet 10 is disposed to the inside of a body lumen.
Set forth next is a description of a device for bonding a sheet (sheet bonding device) 20 for delivering a patch to a lesion A of a blood vessel and adhering the patch to the lesion A, using the biological adhesive sheet 10 according to this embodiment as the patch to be adhered so as to cover the lesion A.
As shown in
A medium lumen L2 exists between the outer tube 22 and the inner tube 21, and a fluid is flowable through this medium lumen L2 for inflation/deflation of the balloon 25. The medium lumen L2 is in fluid-tight communication with the inside of the balloon 25.
The balloon 25 is so structured that it is deflated or folded on the outer circumference of the inner tube 21 when not inflated, and it is inflated when an inflation fluid is introduced from an external fluid supply device 27 into the balloon 25 through the medium lumen L2.
Materials constituting the inner tube 21 and the outer tube 22 are each preferably a material having a certain degree of flexibility. Examples of materials, that can be used include thermoplastic resins (which are ordinarily plastics), and thermosetting resins or thermo-crosslinkable resins such as rubber. Specific examples of the materials include: various thermoplastic resins and their polymeric derivatives, such as polyesters such as polyethylene terephthalate, polybutylene terephthalate, etc. and polyester elastomers using such polyesters as hard segments; polyolefins such as polyethylene, polypropylene, etc. and polyolefin elastomers; copolymeric polyolefins produced using a metallocene catalyst; vinyl polymers such as polyvinyl chloride, PVDC, PVDF, etc.; polyamides, inclusive of nylons, and polyamide elastomers (PAE); polyimides; polystyrene; SEBS resins; polyurethane; polyurethane elastomers; ABS resins; acrylic resins; polyarylates; polycarbonates; polyoxymethylene (POM); polyvinyl alcohol (PVA); fluoro-resins (ETFE, PFA, PTFE); ethylene-vinyl acetate saponified products; ethylene vinyl alcohol; ethylene vinyl acetate; carboxymethyl cellulose, methyl cellulose, cellulose acetate; vinyl polysulfones; liquid crystal polymers (LCP); polyether sulfones (PES); polyether ether ketones (PEEK); polyphenylene oxide (PPO); and polyphenylene sulfide (PPS). Other examples include thermosetting or crosslinkable resins such as vulcanized rubbers, silicone resins, epoxy resins, two-part reactive polyurethane resins, etc. Further, polymer alloys containing any of the above-mentioned thermoplastic resins and thermosetting or crosslinkable resins can also be used, and resin solutions prepared by dissolving these resins in solvent may also be used. The outside diameter of the outer tube 22 is 0.5 to 5 mm, preferably 1 to 3 mm.
Examples of the material which can be used to form the balloon 25 include ethylene-butylene-styrene block copolymers obtained by mixing polyethylene and ionomer with a low-molecular polystyrene and optionally with polypropylene; similar mixed materials obtained by replacing ethylene and butylenes in the above-mentioned polymers with butadiene or isoprene; polyvinyl chloride; polyurethane; (co)polyesters; polyamides and polyamide elastomers; thermoplastic rubbers; silicone-polycarbonate copolymer; and ethylene-vinyl acetate copolymers. The size of the balloon 25 depends on the part where the biological adhesive sheet 10 is to be used, and is not particularly limited. When inflated, the balloon 25 is preferably about 0.5 to 50 mm in outer diameter, more preferably about 1 to 5 mm in outer diameter.
The outer sheath 26 has such a structure that the outer tube 22 and the holding section 24 in a contracted state can be contained in the outer sheath 26. The outer sheath 26 is formed of a material which is low in the van der Waals force and which is difficult to adhere by the van der Waals force, in order that the biological adhesive sheet 10 held by the holding section 24 will not adhere to the outer sheath 26. The material is, for example, PTFE. The outside diameter of the outer sheath 26 is 1 to 10 mm, preferably 2 to 4 mm.
The holding section 24 is formed in a meshed tubular form from an elastic material. The holding section 24 is contained in the outer sheath 26 by being contracted elastically. The holding section 24 is elastically self-expandable so that when the outer sheath 26 is moved backward, the restraint on the holding section 24 by the outer sheath 26 is released. The structure of the holding section 24 need not necessarily be a meshed structure. The structure of the holding section 24 is not specifically limited insofar as the holding section 24 is self-expandable and can hold the biological adhesive sheet 10. The material of the holding section 24 is not particularly limited, so long as it can be elastically expanded and contracted. Examples of the material of the holding section 24 include stainless steel, and superelastic alloys (e.g., Ni—Ti alloy).
A procedure for delivering the biological adhesive sheet 10 in a blood vessel and bonding it to a lesion A by the sheet bonding device 20 described above will now be set forth.
First, a plurality of biological adhesive sheets 10 are disposed on an outer circumferential surface of the radially contracted holding section 24 in an axially aligned state, with their adhesion surfaces on the outside (i.e., with the projections 13 extending outwardly away from the holding section). Thereafter, the holding section 24 is contained in the outer sheath 26, whereby the biological adhesive sheets 10 are stored between the holding section 24 and the outer sheath 26. In this instance, each of the biological adhesive sheets 10 is preferably held onto the holding section 24 by, for example, having a part thereof trapped in a gap in the meshed structure of the holding section 24. Alternatively, the biological adhesive sheets 10 may be adhered to the outer circumferential surface of the holding section 24 by an adhesive having a feeble adhesive force (relatively weak adhesive force). Although the adhesion surface 11 of the biological adhesive sheet 10 makes contact with the inside surface of the outer sheath 26, the adhesion surface 11 of the biological adhesive sheet 10 is not adhered to the inside surface of the outer sheath 26, since the outer sheath 26 is made of PTFE. While three biological adhesive sheets 10 are arrayed on the outer circumferential surface of the holding section 24 in the drawings, the number of biological adhesive sheets 10 may be two or less, or may be four or more.
Next, a blood vessel at the patient's leg or arm is minutely incised, an introducer sheath is set at the incision, and a guide wire W is precedingly advanced to a target position through a lumen of the introducer sheath under radioscopy. Then, the guide wire W is inserted and passed in the guide wire lumen L1 of the sheet bonding device 20, and the sheet bonding device 20 is moved along the guide wire W. In this instance, the biological adhesive sheets 10 are delivered while being contained between the holding section 24 and the outer sheath 26. Then, after the biological adhesive sheet 10 on the most distal side of the plurality of biological adhesive sheets 10 held on the holding section 24 is delivered into the vicinity of the lesion A of a blood vessel, as shown in
Next, the inflation fluid is discharged from the inside of the balloon 25 through the medium lumen L2 by the fluid supply device 27, thereby deflating the balloon 25. Then, as shown in
According to the sheet bonding device 20 in this embodiment, the expandable and contractible holding section 24 with the biological adhesive sheets 10 held on the outer circumferential surface thereof is contained in a contracted state in the outer sheath 26. Therefore, the biological adhesive sheets 10 can be relatively easily delivered to target positions. Furthermore, by moving the outer sheath 26 in the axial direction, the holding section 24 is permitted to expand by its self-expanding function. Therefore, the biological adhesive sheets 10 held on the outer circumferential surface of the holding section 24 can be rather easily adhered to the living tissue by operating the device on the proximal side. In addition, since the balloon 25 is provided, the biological adhesive sheets 10 can be adhered to the living tissue more assuredly by operations on the proximal side.
The balloon 25 is capable of inflation and deflation inside the holding section 24. This helps ensure that, with the biological adhesive sheet 10 tentatively fixed to the living tissue M by the holding section 24, the biological adhesive sheet 10 can be pressed by the balloon 25, to be assuredly adhered to the living tissue M. The balloon 25 may not necessarily be capable of inflation and deflation inside the holding section 24. For example, a configuration can be adopted in which a balloon is disposed inside a holding section so that it can be moved forward and backward in the axial direction, and the balloon can be inflated and deflated in the state of being exposed from the outer sheath by moving it to the distal side relative to the holding section. In addition, if the biological adhesive sheet 10 can be firmly adhered to the living tissue M by only the holding section 24, a configuration may be adopted in which only the holding section 24 is provided without providing any balloon 25. A configuration also may be adopted in which the holding section 24 is not provided, and the biological adhesive sheet 10 is adhered while being delivered by the balloon 25 alone.
Now, an example of the method of manufacturing the biological adhesive sheet 10 will be described below.
First, a polymethyl methacrylate resin (PMMA) supported on a silicon wafer is formed with a fine pattern 31 of pores on the order of several hundreds of nanometers by electron beam lithography, to produce a mold 30 (see
Next, the above-mentioned biodegradable polymer (or biocompatible material) as the material for the substrate 12 and the projections 13 is dissolved in a solvent in a concentration of 0.001 to 1 wt %, to obtain a solvent phase. As the solvent, chloroform or the like can be applied.
Subsequently, the mold 30 is held horizontal so that its surface formed with the fine pattern 31 is oriented upward. The material in the solvent phase is poured into the mold 30 so that the material enters into the fine pattern 31, and, further, the material in an amount corresponding to the thickness B of the substrate 12 is poured as shown in
After the material(s) is solidified, the solidified material(s) is detached from the mold 30, to obtain a biological adhesive sheet 10 having a plurality of projections 13 formed on a substrate 12.
The method for processing the pattern on the order of several hundreds of nanometers is not restricted to the above-mentioned method. For example, nanoimprint, soft lithography, shaping by use of a fine cutting tool (e.g., diamond cutting tool), and the like can also be applied. The method is preferably selected appropriately according to the condition of the biological adhesive sheet 10 such as shape, dimension, material and the like.
A biological adhesive sheet according to a second embodiment representing another example of the invention disclosed here is a medical tubular body or biological adhesive tube 50 to be adhered particularly to the inside wall surface (living tissue) of a lumen of a living tissue M. The biological adhesive tube 50 exhibits an adhesive force both in gas and in liquid, without application of any separate adhesive to an adhesion surface. Like in the first embodiment, the living tissue M to which the biological adhesive tube 50 is to be adhered is not specifically restricted.
As shown in
The thickness B of the base 52 is preferably designed appropriately according to the application site of the living tissue M and the use of the biological adhesive tube 50. For example, the thickness B is 3 to 3000 μm, more preferably 30 to 300 μm.
The axial length L of the base 52 is not particularly limited, and is preferably modified appropriately depending on the width of a lesion of the living tissue M to which the biological adhesive tube 50 is to be applied. For example, the axial length L is 5 to 50 mm.
The outside diameter G of the base 52 is not specifically restricted, and is preferably modified appropriately according to the width of the lesion of the living tissue M to which the biological adhesive tube 50 is to be applied. For example, the outside diameter G is 1 to 5 mm.
The axial length L and the outside diameter G of the base 52 can be selectively modified, for example, by preliminarily producing a plurality of biological adhesive tubes 50 differing in size, or can be modified as desired by cutting a large biological adhesive tube 50 to an arbitrary size. The material for the base 52 is the same as the material for the substrate 12 in the first embodiment, and, therefore, description thereof is omitted here for avoiding redundancy.
The projections 53 are formed in a columnar shape (in this embodiment, a cylindrical shape). The configuration of the projections 53 provided on the base 52 is the same as the projections 13 provided on the substrate 12 in the first embodiment, and, therefore, a detailed description of the projections 53 is not repeated.
In the biological adhesive tube 50 according to the second embodiment, adhesion is achieved by the van der Waals force generated when the plurality of projections 53 are put into contact with a living tissue, as above-mentioned. Therefore, another configuration for holding an adhered state is unnecessary, so that influence on the living tissue can be reduced and safety can be enhanced. Especially, in a therapy to the inside of a lumen wherein a stent (which is a strength supporting material) is ordinarily necessary, the influence on healthy parts of the tube can be reduced. Specifically, when a stent is used inside (indwelled in) a lumen, the lumen receives radial forces in a radial direction from the stent. When the biological adhesive tube 50 is used, on the other hand, adhesion can be achieved by the adhesive force of the adhesion surface 51 itself, without utilizing any radial forces, so that the influence on the lumen can be minimized as much as possible.
Depending on the part to which the biological adhesive tube 50 is adhered, the adhered biological adhesive tube 50 thus adhered, for example, to the inside wall of a blood vessel, is embedded by being covered with the living tissue M over time.
In addition, where the base 52 and the projections 53 are each formed of a biodegradable polymer, the adhered biological adhesive tube 50 disappears by being decomposed over the passage of time. In the case where the biological adhesive tube 50 is adhered to the inside wall of a blood vessel, therefore, the period of medication with an antiplatelet agent for restraining generation of a thrombus due to the presence of the foreign matter can be shortened.
When the base 52 and the projections 53 are both formed of biodegradable polymers such that the base 52 will disappear through decomposition (biodegrade) earlier than the projections 53, the base 52 can be restrained from peeling before the adhesive force is lost by disappearance of the projections 53 through decomposition. The decomposition of the base 52 earlier than the projections 53 in this way can be realized by, for example, applying biodegradable polymers differing in decomposition time to the base 52 and the projections 53, respectively. For example, a configuration may be adopted in which the projections 53 are formed of polycacrolactone and its derivative whereas the base 52 is formed of polylactic acid and its derivative.
In addition, in another example of the biological adhesive tube shown in
When at least one of the base 52 and the projections 53 contains a biologically active agent, it is possible to treat a lesion to which the biological adhesive tube 50 is applied, and to restrain obstruction or the like from occurring at the application site in the case where the biological adhesive tube 50 is disposed inside a body lumen.
A further example of the biological adhesive tube is shown in
Now, a procedure for delivering the biological adhesive tube 50 in a blood vessel and bonding it to body tissue at the site of a lesion A by use of the tube bonding device 20 described in the first embodiment, will be described below.
First, as shown in
Next, a blood vessel at the patient's leg or arm is minutely incised, an introducer sheath is set at the incision, and a guide wire W is precedingly advanced to a target position through a lumen of the introducer sheath under radioscopy. Then, the guide wire W is inserted and passed in a guide wire lumen L1 of the tube bonding device 20, and the tube bonding device 20 is moved along the guide wire W. In this instance, the biological adhesive tube 50 is delivered while being contained between the holding section 24 and the outer sheath 26. Then, after the biological adhesive tube 50 held on the holding section 24 is delivered to the vicinity of lesion A of a blood vessel, as shown in
Next, the inflation fluid is discharged from the inside of the balloon 25 through the medium lumen L2 by the fluid supply device 27, thereby deflating the balloon 25. Then, as shown in
In this embodiment, only one biological adhesive tube 50 is disposed on the holding section 24. However, a configuration may be adopted in which a plurality of biological adhesive tubes 50 are axially arrayed on the outer circumferential surface of the holding section 24, and are exposed to the blood vessel one by one by the outer sheath 26, whereby the plurality of biological adhesive tubes 50 are sequentially indwelled at a plurality of lesions A in the blood vessel.
An example of a method of manufacturing the biological adhesive tube 50 will be described below.
First, in the same manner as the procedure described in the first embodiment, a flat plate-shaped sheet formed by solidification of a material is prepared by use of a mold 30. Because this procedure for preparing the flat plate-shaped sheet is the same as described above with respect to the first embodiment, such description will not be repeated.
Thereafter, the sheet is cut to a predetermined size, after which the cut piece is curved into a tubular shape so that the projections 53 are located on the outside (project outwardly), and the overlapping portions are bonded to each other by crimping or by use of an adhesive composed of a biodegradable polymer (or a biocompatible material). In this manner, a biological adhesive tube 50 is obtained in which a plurality of projections 53 are formed on the outer circumferential surface of a base 52.
The invention here is not restricted to the above-described embodiments, as modifications can be made within the technical thought of the invention by those skilled in the art. For instance, the shape of the projections is not limited to the above-mentioned form insofar as the projections are able to adhere (bond) to living tissue by the van der Waals force. As shown in
In addition, the projections may be formed on both sides of the substrate (base). The substrate (base) may be formed in a tubular shape, and the projections may be formed on the inside surface or the outside surface of the substrate (base).
In addition, the biological adhesive sheet 10 according to the first embodiment may be provided with slits, like in the second embodiment disclosed by way of example and shown in
The detailed description above describes features and aspects of embodiments of a biological adhesive sheet and a device for bonding (adhering) the sheet, disclosed by way of example. The invention is not limited, however, to the precise embodiments and variations described and illustrated. Various changes, modifications and equivalents could be effected by one skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims. It is expressly intended that all such changes, modifications and equivalents which fall within the scope of the claims are embraced by the claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2010-212795 | Sep 2010 | JP | national |
| 2010-212797 | Sep 2010 | JP | national |
This application is a continuation of International Application No. PCT/JP2011/070493 filed on Sep. 8, 2011, and claims priority to Japanese Application No. 2010-212795 filed on Sep. 22, 2010 and Japanese Application No. 2010-212797 filed on Sep. 22, 2010, the entire content of all three of which is incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/JP2011/070493 | Sep 2011 | US |
| Child | 13755104 | US |
