Tissue regenerative composition
Abstract
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Expired 20 December 2020, 5.8 years ago.
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17 claims: 6 independent, 11 dependent
- 1組織移植片組成物を作製する方法であって、該方法は、以下:哺乳動物の上皮組織の少なくとも一部を高張生理食塩水に曝すことにより該組織を上皮分離して、上皮基底膜を含む失活した組織を形成する工程を包含する、方法。
- 2前記高張生理食塩水が、1.0Nの生理食塩水を含む、請求項1に記載の方法。
- 3前記組織が、約10分間~4時間の期間にわたり高張生理食塩水中に入れられる、請求項1に記載の方法。
- 4前記上皮基底膜に対して遠管腔側の組織層の少なくとも一部を除去する工程をさらに包含する、請求項1に記載の方法。
- 5前記組織層が、外膜を含む、請求項4に記載の方法。
- 6前記組織層が、筋層を含む、請求項4に記載の方法。
- 7前記組織層が、粘膜下組織を含む、請求項4に記載の方法。
- 8前記上皮組織が、膀胱である、請求項1に記載の方法。
- 9前記上皮組織が、腸である、請求項1に記載の方法。
- 10哺乳動物における欠損組織、病的組織、または損傷組織を修復(restore)、再構築、置換、または修復(repair)するための 医薬の製造における、請 求項1に記載の方法により製造された失活した組織移植片組成物 の使用 。
- 11前記欠損組織、病的組織、または損傷組織が、心臓組織、尿-生殖管の組織、胃腸管の組織、皮膚組織、神経組織、および結合組織からなる群より選択される、請求項10に記載の 使用 。
- 12前記尿-生殖管の組織が、尿括約筋および腎臓からなる群より選択される、請求項11に記載の 使用 。
- 13前記胃腸管の組織が、食道、胃、腸、および肝臓からなる群より選択される、請求項11に記載の 使用 。
- 14前記皮膚組織が、患者の頭部または頸部に位置する、請求項11に記載の 使用 。
- 15前記結合組織が、靱帯、腱、軟骨、骨、関節、および筋肉からなる群より選択される、請求項11に記載の 使用 。
- 16前記心臓組織が、心臓弁、心房中隔、心室中隔、および心筋層からなる群より選択される、請求項11に記載の 使用 。
- 17前記心臓弁が、肺動脈弁、大動脈弁、右房室弁および左房室弁からなる群より選択される、請求項16に記載の 使用 。
Independent claims17
51 paragraphs, as filed
(Cross-reference to related applications) The present application claims priority based on and to US Patent Provisional Application No. 60 / 171,733 filed December 22, 1999. (Description of research commissioned by the federal government) The present invention is also provided by the National Institutes of Health grants, 1-R43-HL85761-01, 1-R43-DC-04387-01, and 1-R43-DC-4387-02. Was supported by.
The present invention relates to devitalized cell-free tissue regeneration compositions, methods of production, and methods of use.
[Background of the Invention] Warm-blooded vertebrate submucosal tissue is useful in tissue transplantation materials. For example, submucosal tissue implant compositions derived from the small intestine are described in US Pat. No. 4,902,508 (hereafter, '508) and US Pat. No. 4,956,178 (hereafter, '178). ), And the bladder-derived submucosal tissue implant composition is described in US Pat. No. 5,554,389 (hereafter, '389 patent). All of these compositions consist essentially of the same panniculus and are prepared in the same way (the difference between them is that the starting material is the small intestine on the one hand and the bladder on the other). The procedures detailed in the '508 patent, the procedures referenced in the '389 patent, and the procedures detailed in the '178 patent are at least in the luminal portion of the mucosa of the intestine or bladder (ie, in the '178 patent). Includes a mechanical scraping step to remove the inner layer of tissue, including the thin epithelial mucosa (epithelial) and eigenlayer) as detailed. Detachment, exfoliation, or desquamation of the mucosa separates the epithelial cells and their associated basement membranes, as well as most of the lamina propria (at least to the level of a layer of organized dense connective tissue (dense layer)). Layer. Thus, tissue graft material already recognized as a replacement material for soft tissue lacks the epithelial basement membrane and consists of submucosal tissue and a dense layer.
[0004] The epithelial basement membrane is a thin sheet of extracellular material adjacent to the basal plane of epithelial cells. A sheet of similar aggregated epithelial cells forms the epithelium. Epithelial cells and their associated epithelial basement membranes are located in the luminal portion of the mucosa and constitute the inner surface of tubular and hollow organs and tissues of the body. Epithelial cells and their associated epithelial basement membranes are also located on the outer surface of the body (ie, skin). Examples of typical epithelial tissues with basement membranes include, but are not limited to: skin, intestine, bladder, esophagus, stomach, cornea, and liver epithelium.
[0005] Epithelial cells are located on the luminal side of the epithelial basement membrane, i.e., on the superficial side (opposite to connective tissue). Connective tissue (submucosal tissue) is located, for example, on the abluminal side of the basement membrane, that is, on the deep side. Examples of connective tissue located on the distant lumen side of the epithelial basement membrane include submucosa of the intestine and bladder, and submucosa of the dermis and skin.
[Abstract of Invention] The present invention provides an inactivated tissue regeneration composition comprising an epithelial basement membrane as part of a substrate or scaffold for tissue repair or regeneration. Inclusion of epithelial basement membranes in inactivated mammalian tissue regeneration compositions results in improved endogenous cell proliferation and tissue recovery in vivo as compared to the above submucosal substrates that do not contain epithelial basement membranes. For the purposes of the present invention, inactivation means cell-free or substantially cell-free. For the purposes of the present invention, epithelial basement membrane means at least a portion of the intact epithelial basement membrane.
[0007] According to the present invention, the preferred inactivating substrate for repair or regeneration of mammalian tissue is at least a portion, preferably all epithelial basement membranes of the mammalian epithelial basement membrane, and the lamina propria beneath the basement membrane. Includes layers. The inactivated substrate of the present invention restores or replaces diseased, defective, or missing tissue when placed in contact with host tissue. In a preferred embodiment, the invention comprises an inactivated substrate that is custom-shaped to fit diseased or defective tissue. In certain embodiments, the substrate includes a sheet of substrate from the bladder, intestine, or any other mammalian epithelial tissue. In another embodiment, the substrate becomes injectable by being converted into fine granules, emulsions, gels, or extracts. The substrates of the invention can act as carriers for pharmaceutical factors. A preferred application of the substrates of the invention is the repair or recovery of heart tissue. In particular, the substrates or compositions of the invention are useful for restoring or replacing at least a portion of a heart valve, atrial septum, interventricular septum, or myocardium. With respect to the intent of the invention, substrate and composition are interchangeable terms.
[0008] In one embodiment, the invention features an epithelial basement membrane and an inactivation composition comprising a lamina propria just below the basement membrane. The epithelial basement membrane and the lamina propria just below the basement membrane are delaminated from cells in the luminal region of the mammalian epithelium and lamina propria. The mammalian epithelial tissue used in this aspect of the invention is preferably derived from the bladder, intestine, or any other mammalian epithelial tissue. A further embodiment is a composition shaped to fit a pathological or defective heart valve (eg, a pulmonary valve, an aortic valve, a right or left atrioventricular valve, or at least a portion of the myocardium). It is characterized by.
[0009] In yet another embodiment, the present invention features a composition comprising an epithelial basement membrane, a lamina propria, and submucosa. The epithelial basement membrane and lamina propria are delaminated from epithelial cells and from the muscularis layer of mammalian epithelial tissue.
[0010] In yet another embodiment, the present invention features a composition comprising smooth muscle cells of the epithelial basement membrane, lamina propria, and muscularis. All of these cells are all delaminated from the epithelial cells of the mammalian epithelium.
[0011] Compositions according to the present invention are not limited to these embodiments that are included. Rather, a composition according to the invention comprises one or more layers of epithelial tissue combined with at least a portion, preferably the entire, intact epithelial basement membrane.
[0012] In another aspect, the invention provides a method for inducing recovery or repair of diseased or defective heart tissue. A preferred method of the present invention comprises contacting the host tissue with a mammalian-derived inactivated substrate. The inactivated substrate contains at least part of the epithelial basement membrane and the lamina propria just below the basement membrane. In a preferred embodiment, the method of the invention comprises inducing repair of the endogenous epithelium with the tissue regeneration composition of the invention.
[Detailed Description of the Invention] The inactivated tissue regeneration composition according to the present invention comprises at least a portion of the epithelial basement membrane or epithelial basement membrane collected from mammalian epithelial tissue, and at least the lower part of the lamina propria. Preferred epithelial tissues for use of the present invention include, but are not limited to: the bladder and other tissues of the urinary-genital tract, the small intestine, the esophagus and other tissues of the gastrointestinal tract, skin, liver, and so on. And arteries (eg, the aorta), as well as other tissues of the cardiovascular system. In a preferred embodiment, the present invention separates at least a portion of the epithelial basement membrane and the underlying layers (separated from the luminal epithelial cells, the epithelial epithelium, the serosa, and the smooth muscle layer). The technique of tissue separation or tissue delamination of the subserosal tissue layer according to the present invention provides a tissue implant composition comprising, at least a portion of the epithelial basement membrane or epithelial basement membrane, which is substantially cell-free. Provides a layer of inactivated extracellular substrate material containing. Any remaining cellular elements are then removed by further processing steps such as rinsing in hypertonic saline, peracetic acid or sterile water.
[0014] Therefore, with reference to FIGS. 1A and 1B, preferred embodiments of the present invention are the epithelial basement membrane B, and the epithelial basement membrane of the intestine illustrated in FIG. 1A or the bladder illustrated in FIG. 1B. Includes biointrospective connective tissue known as lamina propria C, or any other epithelial tissue, located just below B and above the distant lumen side of epithelial basement membrane B. This embodiment of the present invention features epithelial basement membrane B and a portion of lamina propria adjacent to epithelial basement membrane B. Epithelial basement membrane B and lamina propria are delaminated from epithelial cells A, submucosal tissue D, muscularis E, and serosa F. Thus, in this embodiment of the invention, the portion of the mucosa H adjacent to the lumen L (ie, the lumen portion of the mucosa) forms a preferred tissue substrate composition.
[0015] In another preferred embodiment, again referring to FIGS. 1A and 1B, the composition of the invention comprises epithelial basement membrane B, lamina propria C, and submucosal tissue D. Epithelial basement membrane B, lamina propria C, and submucosal tissue D are delaminated from epithelial cells A, muscularis E, and serosa F. In this embodiment, the epithelial basement membrane and a portion of mucosa H, including submucosal tissue, form a preferred tissue substrate composition.
[0016] In yet another composition, a preferred embodiment of the present invention is at least a portion of epithelial basement membrane B, lamina propria located adjacent to epithelial basement membrane B, submucosal tissue D, and muscular layer E. including.
(Source of Epithelial Tissue) Materials for the tissue regeneration compositions of the present invention typically include, but are not limited to, pigs, cattle, and sheep, animals raised for meat production. Prepared from tissue collected from. Other warm-blooded vertebrates are also useful as a source of tissue, but the greater utility of such animal-derived tissues used for meat production makes such tissues more desirable. To. Therefore, there are commercially available and inexpensive sources of tissue for use in the preparation of tissue compositions according to the present invention. There may be specially bred or genetically engineered strains of a particular species used as a tissue source. For example, pigs genetically engineered to be free of galacatosyl, α1,3 galactose (GAL epitope) can be used as a source of tissue for producing this composition. Alternatively, a herd of pigs kept free of specific pathogens can be used as a tissue source. Mammalian tissue used as a tissue source for the production of the compositions of the invention can be collected from animals of any age group, including embryonic tissue, market weight, gender, or stage of sexual maturation. ..
(Tissue Source of Epithelial Basement Membrane) (Bladder) A preferred source of epithelial basement membrane is the bladder illustrated in FIG. 1B of a warm-blooded vertebrate such as a pig. A good biological tissue that reconstructs properties is derived from a component of the epithelial basement membrane that supports and promotes cell proliferation without invasion, and enables adhesion, invasion, proliferation, and differentiation of endogenous cells. It is derived from the underlying propria substrate material that promotes these. Substrates subsequently referred to herein as bladder substrates (UBMs) include the basement membrane B of the bladder epithelium and the underlying lamina propria C. In this embodiment, the epithelial basement membrane B and the underlying lamina propria C are delaminated from the extracellular matrix, muscularis E, and serosa F of epithelial cells A and mucosal tissue D. UBMs are collected from any warm-blooded vertebrate, most preferably from pigs. UBM is a body tissue and organ (eg, musculoskeletal and cardiovascular structures, dermatological and gastrointestinal tissues, urogenital and reproductive tissues, neurological tissues, liver, kidneys, and head and neck tissues. Used as a biological skeleton for tissue) repair or recovery.
[0019] Preferred UBM tissue regeneration compositions include epithelial basement membranes, preferably bladder basement membranes, and biointrospective molecular structures located just below the epithelial basement membranes derived from warm-blooded vertebrate bladder tissue. In this embodiment, the epithelial basement membrane is delaminated from the epithelial cells of the lumen, the epithelial tissue, the serous tissue, and the smooth muscle tissue, and thus from the submucosa. Prior to being implanted or injected into a vertebrate host, the tissue graft compositions of the present invention are implanted in a vertebrate host to cause repair or replacement of injuring, missing or defective tissue or organ. It has the characteristic of proliferating significantly superior tissue as compared to the described submucosal graft compositions.
The methods of the present invention avoid complete loss of the epithelial basement membrane and yield a tissue regeneration composition comprising at least a portion of the epithelial basement membrane. In a preferred embodiment, the epithelial basement membrane as determined by conventional histochemical or immunohistochemical techniques and light microscopy or electron microscopy is largely intact. The resulting inactivated material obtained by the method of the present invention yields a graft material containing submucosal tissue excluding the epithelial basement membrane, the composition of tissue grafts derived from the small intestine and bladder described in the '508 and '389 patents. This is in contrast to the method for producing things. The steps for the preparation of UBM from bladder tissue are different from the steps described above for the preparation of submucosal tissue graft compositions as described in the '508 and '389 patents. In the methods for the preparation of submucosal tissue graft compositions described in the '508 and '389 patents, the mucosa is mechanically removed by scraping.
[0021] According to the present invention, UBM is performed by removing bladder tissue from a warm-blooded vertebrate (eg, pig) and in a deep ithelializing solution (eg, hypertonic saline, most preferably 1.0 N physiology). It is prepared by first immersing the tissue in saline) for a time range of 10 minutes to 4 hours to delaminate the tissue. Exposure to hypertonic saline effectively removes epithelial cells from the underlying basement membrane. The remaining tissue after the initial delamination procedure includes the epithelial basement membrane and the panniculus that is far from the epithelial basement membrane. This tissue is subjected to the next further procedure to remove the major luminal tissue other than the epithelial basement membrane. The outer subserosa, adventitial tissue, smooth muscle tissue, submucosal tissue, and the distant lumen of the lamina propria are left by mechanical scraping or by a combination of enzymatic treatment, hydration, and scraping. It is removed from the epithelially isolated tissue. Mechanical removal of these tissues, for example, removal of mesenteric tissue using Adson-Brown settler and Metzenbaum scissors, and vertical use of a scalpel handle or other hard material wrapped in moistened gauze. Achieved by wiping the muscularis and lamina propria with a directional wiping motion. After these tissues are removed, the resulting tissue skeleton consists of the epithelial basement membrane and the underlying lamina propria. This tissue differs from the already known tissue compositions derived from animal epithelial tissue in the content of the predominantly intact epithelial basement membrane in the present invention. This tissue can be further treated by rinsing with hypertonic saline, peracetic acid or sterile water. Other methods of removing the tissue layer (microtome) can also be used, for example, to obtain the tissue composition of the present invention.
[0022] The method for preparing a tissue regeneration composition according to the present invention is not limited to the use of bladder tissue as a starting material. The method according to the invention is also applicable to other starting tissues such as skin, esophagus, stomach, and intestinal tissue.
[0023] After the preparation of UBM according to the method of the present invention, the resulting tissue skeleton is approximately 10-120 micrometers consisting primarily (ie, more than about 90%) of extracellular matrix (ECM), including the epithelial basement membrane. Consists of a material of the same thickness. This material may or may not retain some of the cellular elements, including the original tissue (eg, capillary endothelial cells or fibrous cells). These cellular elements are removed by subsequent exposure to peracetic acid as part of the disinfection of the biomaterial. This material has a histological appearance and structure due to the smooth epithelial basement membrane that separates the luminal surface and the dense, partially organized collagen ECM that separates the luminal surface. , Different from the submucosal tissue implant composition. ECM material is dyed pink by H & E stain and blue by Masson trichrome stain.
[0024] (Skin, esophagus) Similarly, the step used in the preparation of tissue regeneration compositions from other epithelial organs (eg, skin, or esophagus) having a bladder-like tissue layer prepares UBM. Corresponds to the above steps for Materials remaining after removal of epithelial cells, serosa, muscularis, and lamina propria, such as the bladder matrix, include at least a portion of the epithelial basement membrane and adjacent lamina propria.
(Small intestine) The tissue regeneration composition of the present invention is also derived from the epithelial tissue of the gastrointestinal tract (eg, small intestine). The steps in the preparation of the tissue regeneration composition comprising at least a portion of the epithelial basement membrane of the small intestine and the underlying lamina propria named SIM are similar to the steps described above for the formation of UBM. Intestinal epithelial cells derived from the epithelial basement membrane can be removed using 1.0 N saline. An alternative method for removing epithelial cells is to use a detergent (eg, nonionic surfactant (eg, Triton X-100)) at a concentration of 0.025 to 1% for 5 minutes to several hours. It is a method of soaking.
[0026] In one embodiment, the delaminated tissue regeneration composition derived from epithelial tissue is either stored in a cryohydrate state or air-dried at room temperature before storage. is there. Alternatively, the tissue regeneration composition is lyophilized and stored in a dehydrated state either at room temperature or at freezing. In yet another embodiment, the tissue regeneration composition digests the material in a protease (eg, pepsin or trypsin) for a time sufficient to solubilize the tissue to form a substantially homogeneous solution. It can be finely divided and fluidized. The viscosity of the solubilizing material can be changed by adjusting the pH to a gel, gel-sol, or complete liquid state. The preparation of fluidized intestinal submucosa is described, for example, in US Pat. No. 5,275,826 (expressly incorporated herein by reference).
[0027] In yet another embodiment, the present invention considers the use of powdered forms of tissue regeneration compositions. In one embodiment, the powder form of the tissue regeneration composition is 0.005 mm.<sup>2</sup>~ 2.0mm<sup>2</sup>It is formed by finely chopping or grinding the delaminated material to produce particles in the size range of. The material delaminated from the undesired tissue layer is frozen in, for example, liquid nitrogen to carry out the grinding procedure. Alternatively, the material is dehydrated to carry out the grinding procedure. The milled form of the material is then lyophilized to form a substantially anhydrous particle structure regeneration composition.
[0028] The tissue composition of the present invention is suitable for a number of surgical and non-surgical applications for the purpose of inducing reconstructive wound healing and tissue regeneration. For example, these tissue compositions can be used to replace injurious, pathological, or defective heart valves, arteries, veins, bladder, liver, parts of the gastrointestinal tract, or these tissue compositions can be used in the head. It can be used as a template for repair or replacement of partial and cervical structures. The material, either in multiple solid or fluidized form, can be used as a scaffold for dermis repair or epidermal repair, or is injected into various body sphincters (eg, urinary or esophageal sphincter or gastric sphincter). It can be obtained, folded into a tube or part of a tube as a conduit for nerve tissue regeneration, or extruded or cast into any shape suitable for this application as a tissue regeneration composition. obtain. The tissue regeneration compositions of the present invention can be placed and sutured in solid sheet form, placed on a wound or body site in gel form, or injected in liquid or particle form. The tissue compositions of the invention are endogenous, including epithelial tissue and connective tissue when the target tissue in vivo is placed in contact with a mammalian-derived inactivated tissue composition comprising at least a portion of the epithelial basement membrane. Induces the growth of sexual tissue.
(Bladder Substrate (UBM)) The UBM composition comprises at least type I collagen and type IV collagen, glycosaminoglycans (including hyaluronic acid, chondroitin sulfate A and chondroitin sulfate B, heparin and heparin sulfate). In addition, one or more basic fibroblast growth factor, vascular endothelial growth factor, and TGFβ are present in UBM.
[0030] The physical properties of UBM are partially characterized. UBM has a uniaxial strength of approximately 0.1-2.0 lbs per 1.0 cm wide piece (measured using a system machine testing materials via American Standards for Testing Materials towed at 1 inch / min). The suture retention strength of this material is approximately 1.0-4.0 Newtons (N) per sheet layer, in particular 4-18N for 4-layer substrates and 30-120N for 30-layer substrates. The ball burst test failure force is about 4-10 lbs per layer, especially 32-80N for 8 layers, 16-40N for 4 layers, and 36-120N for 12 layers.
The perforation index is 1 cm at 120 mmHg pressure.<sup>2</sup>Defined as the amount of water flowing through the material per minute. The porosity of water differs between one side and the other side of UBM, depending on the direction of flow. Water flows from the epithelial basement membrane to the epithelial basement membrane at a rate of about 20% of the water flow from the far luminal side of the substrate to the epithelial basement membrane. UBM also has viscoelastic properties.
UBM can be sterilized by any of a number of standard methods without loss of ability to induce endogenous tissue growth. For example, after rinsing with saline and 0.05% to 1.0% peracetic acid, the material is treated with ethylene oxide, γ irradiation (0.5 to 2.5 mRad), gas plasma sterilized, or electron beam (e-beam). ) Can be sterilized by processing. The material can also be sterilized by treatment with glutaraldehyde, which causes cross-linking to the protein material, but this treatment substantially alters the material so that the material is slowly absorbed or completely absorbed. It does not and induces remodeling of different types of hosts that are more closely similar to scar tissue formation or encapsulation rather than constructive remodeling. Cross-linking of protein materials can also be induced using carbodimid, or using dehydrothermal or photooxidation methods.
[0033] The following examples will help to better demonstrate successful practice of the present invention.
[Examples] As an example of the usefulness of the methods and compositions of the present invention, UBM is applied to heart valve defects. As will be appreciated by those of skill in the art, the methods and compositions disclosed herein are from sources of epithelial tissue other than the bladder, from mammalian sources other than pigs, and tissue defects other than heart valves. It is applicable to other tissue regeneration compositions. In addition, the tissue regeneration compositions of the present invention can be applied in forms other than single-sheet or multi-layer sheet materials (eg, UBM as an extract, in gel form, in powdered form, in tubular form, in sheet form. Or as a small piece, cord or strut, or as a mixture with other pharmaceutical factors (eg, growth factors and gene products). The UBM can be extruded or cast in or on a form that fits a particular application of the body. Tissue preparations in fluid form are described in US Pat. No. 5,275,826, this disclosure is incorporated herein by reference, and preparations of solid sheets and pieces of tissue are described in US Pat. No. 5,711,969. , This disclosure is incorporated herein by reference.
(Application 1: Repair of Heart Tissue) According to the present invention, one embodiment is a tissue regeneration composition for repair or replacement of heart tissue. Cardiac tissue includes, but is not limited to, pathological heart tissue, injured heart tissue, or defective heart tissue, including, but not limited to: myocardial layer, epicardium, endocardium, epicardium, atrial septum, and. The ventricular septum, and all heart valves and associated leaflets (pulmonary arterial valve, aortic valve, right atrioventricular valve and left atrioventricular valve, and adjacent tubes of the heart (pulmonary artery, pulmonary vein, aorta, inferior aorta, and). Including part of the superior aneurysm)).
[0036] In this embodiment of the invention disclosed herein, UBM is prepared from the pig bladder as described above, and autologous and heterologous pulmonary valve valves in 5 pigs and 3 dogs. It was used as an anterior heart valve replacement leaf.
UBM (consisted as a single sheet material or twice as thick material) was cut with scissors or a scalpel during surgery to fit the anterior lobe of the pulmonary valve. The UBM was sutured directly to the annulus of the base of the valve. In a single-sheet embodiment, the epithelial basement membrane side of the UBM was placed on the luminal side of the right ventricle of its replacement valve lobe and sutured directly to the pulmonary valve annulus. In a two-fold thicker UBM embodiment, the UBM was folded so that the epithelial basement membrane was placed on both surfaces of the replacement pulmonary valve lobe (ie, the ventricular and arterial surfaces) and sutured directly to the pulmonary valve annulus. ..
[0038] Pulmonary valves in experimental dogs and pigs were tested 6 and 12 weeks after valve replacement. One dog was tested 5 months after leaflet replacement. Collected leaflets were tested using standard tissue fixation and histopathology techniques.
[0039] Six weeks after leaflet replacement, epithelialization of the replaced leaflet was present over all leaflet surfaces. Cells migrating across the leaflet surface were positively stained with von Bill Brandt factor, indicating that these cells were of endothelial origin. In some valve lobes, some of the endothelial cells had the properties of early progenitor cells. It was observed that neovascularization, endothelial cell infiltration, and extracellular matrix deposition originated from the host tissue of the pulmonary valve annulus and spread throughout this replacement valve lobe.
[0040] At 12 weeks and 5 months after leaflet replacement, no original UBM tissue composition was observed, and leaflet recovery was complete. Unexpected findings at all time points tested included lack of endothelial infiltration into the replacement leaflets, lack of thrombosis, and lack of calcium deposition or cell-mediated rejection of the replacement leaflets. Moreover, the shape of this replacement leaflet was unchanged from the original leaflet shape at all time points tested.
Ultrasound studies of the pulmonary valve in pigs at 8, 12, 16 and 20 weeks after valve replacement demonstrated a complete valve.
[0042] In another embodiment of this aspect of the invention, the fluidized, powdered or ground UBM is applied within or adjacent to pathological or defective heart tissue. Or inject to promote repair of endogenous tissue. For example, fluidized UBM may be injected into or adjacent to a congenital interventricular septal defect, a congenital intra-atrial septal defect, or injected into the lumen of the ductus arteriosus at these sites. Promotes the endogenous growth of tissues in.
[0043] The application of UBM to heart tissue is achieved by the application of several different surgical approaches. For example, a minimally invasive procedure is used to approach the surgical site of the heart with the assistance of a laproscope. Alternatively, perform a thoracotomy. UBM is introduced into the surgical site in any of its prepared forms (eg, sheets, loops, pieces, or injectable powdered or ground states). UBM sheets or pieces are custom-fit for specific cardiac applications prior to or during surgery. A sheet or piece of UBM is secured adjacent to or in the defective or pathological heart tissue using sutures, clasps, tissue adhesives, or any other means known to those of skill in the art. ..
(Application 2: Substrate for Cell Proliferation in Vitro) Human microvascular endothelial cells (HMVEC) are endothelium (a monolayer of cells organized on the basement membrane in vivo in a manner that mimics epithelium). To form. Studies were performed in vitro using an isolated HMV EC plated on: (i) the epithelial basement membrane side of the UBM sheet, (ii) the luminal surface of the UBM, (iii) '508 patent. And a small intestinal submucosal tissue implant composition (SIS) prepared according to the method disclosed in the '178 patent, and (iv) a bladder submucosal tissue composition (UBS) prepared according to the method disclosed in the '389 patent. ).
HMVEC proliferates within its substrate when plated on the surface of SIB or UBS, regardless of whether HMVEC is plated on the surface of the SIS or UBS, the surface of the lumen or the surface of the distant lumen. And, after 3 days of proliferation, it did not form a confluent cell layer.
HMVEC plated on the surface of the distant lumen of UBM proliferated into its substrate, proliferated into mature endothelial cells and differentiated. Similar to HMVEC plated on the surface of the SIS and UBM far lumen, a confluent layer of HMVEC was not formed on the surface of the UBM after 3 days of proliferation.
In contrast to other already known tissue regeneration compositions (eg, SIS and UBS in these studies), HMVEC plated on the epithelial basement membrane side (lumen) of a sheet of UBM is UBM. Adhered to, proliferated, differentiated, and formed a confluent monolayer 3 days after proliferation.
[0048] (Application 3:) It is intended that the tissue implant composition of the present invention can be used to induce repair or replacement of tissue in vivo, including: connective tissues (eg, ligaments, tendons, etc.). Cartilage, bones, joints, and muscles), epithelial tissue (eg, bladder), and other tissues of the urogenital tract, stomach, esophagus, and other tissues of the gastrointestinal tract, liver, nerve tissue, head tissue and neck. Department tissue, skin, and US patent 4,902,508; US patent 4,956,178; US patent 5,281,422; US patent 5,352,463; US patent 5,554,389; US patent 5,275,826; US patent 4,902,508; US Patent 5,372,821; US Patent 5,445,833; US Patent 5,516,533; US Patent 5,573,784; US Patent 5,641,518; US Patent 5,695,998; US Patent 5,711,969; US Patent 5,755,791; US Patent No. 5,762,966; and US Pat. No. 5,885,619 (this disclosure is incorporated herein by reference) to other organizations using the same procedure. The tissue graft compositions of the present invention can also be used with synthetic or non-synthetic polymers for tissue recovery.
BRIEF DESCRIPTION OF THE DRAWINGS This drawing is not at the same scale and instead is generally emphasized when illustrating the principles of the invention.
FIG. 1A is a cross-sectional view of the wall of the small intestine.
FIG. 1B is a cross-sectional view of the bladder wall.
Every citation, both waysCites: the store holds 4 of 5
| Document | Relation | Office |
|---|---|---|
| JP09122225A | Cites | Japan |
| US04776853A | Cites | United States of America |
| JP04501516A | Cites | Japan |
| JP10513388A | Cites | Japan |
| 生化学事典,1990年11月22日,第2版,pp 324-325 | Non-patent | – |
| 岩波講座 現代医学の基礎3 人体のなりたち,(株)岩波書店,1998年11月20日,pp 16-18 | Non-patent | – |
70 members in 10 offices
Priority claims19
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| 2000691345 | – | – | – |
| 2000691590 | – | – | – |
| 2000034938 | – | – | – |
| US19990171733P | – | – | – |
| US20000691345 | – | – | – |
| US20000691590 | – | – | – |
| WO2000US34938 | – | – | – |
Members70
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| US2003064112A1 | United States of America | A1 | |
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| JP2003252769A | Japan | A | |
| US2004043006A1 | United States of America | A1 | |
| EP1239897B1 | European Patent Office (EPO) | B1 | |
| AT262358T | Austria | T | |
| ATE262358T1 | Austria | T1 | |
| DE60009339D1 | Germany | D1 | |
| EP1428540A1 | European Patent Office (EPO) | A1 | |
| DE60009339T2 | Germany | T2 | |
| US6783776B2 | United States of America | B2 | |
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| JP3824537B2This record | Japan | B2 | |
| EP1428540B1 | European Patent Office (EPO) | B1 | |
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| ATE342742T1 | Austria | T1 | |
| DE60031461D1 | Germany | D1 | |
| EP1749543A1 | European Patent Office (EPO) | A1 | |
| DK1428540T3 | Denmark | T3 | |
| AU2005200350B2 | Australia | B2 | |
| ES2275147T3 | Spain | T3 | |
| DE60031461T2 | Germany | T2 | |
| EP1749543B1 | European Patent Office (EPO) | B1 | |
| US2009053279A1 | United States of America | A1 | |
| AT422908T | Austria | T | |
| ATE422908T1 | Austria | T1 | |
| DE60041611D1 | Germany | D1 | |
| EP2055325A2 | European Patent Office (EPO) | A2 | |
| DK1749543T3 | Denmark | T3 | |
| ES2322662T3 | Spain | T3 | |
| EP1749543B9 | European Patent Office (EPO) | B9 | |
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| EP2055325B1 | European Patent Office (EPO) | B1 | |
| DK2055325T3 | Denmark | T3 | |
| ES2749801T3 | Spain | T3 |
31 legal events, as the office reported them to INPADOC
Over the term
Point at a mark for the eventEvents
| Event | Code | |
|---|---|---|
| Cancellation because of completion of termEXPY | EXPY | |
| Receipt of annual feesJAPANESE INTERMEDIATE CODE: R250R250 | R250 | |
| Receipt of annual feesJAPANESE INTERMEDIATE CODE: R250R250 | R250 | |
| Receipt of annual feesJAPANESE INTERMEDIATE CODE: R250R250 | R250 | |
| Receipt of annual feesJAPANESE INTERMEDIATE CODE: R250R250 | R250 | |
| Receipt of annual feesJAPANESE INTERMEDIATE CODE: R250R250 | R250 | |
| Receipt of annual feesJAPANESE INTERMEDIATE CODE: R250R250 | R250 | |
| Receipt of annual feesJAPANESE INTERMEDIATE CODE: R250R250 | R250 | |
| Receipt of annual feesJAPANESE INTERMEDIATE CODE: R250R250 | R250 | |
| Renewal fee payment (event date is renewal date of database)FPAY | FPAY | |
| Receipt of annual feesJAPANESE INTERMEDIATE CODE: R250R250 | R250 | |
| Renewal fee payment (event date is renewal date of database)FPAY | FPAY | |
| Renewal fee payment (event date is renewal date of database)FPAY | FPAY | |
| Receipt of annual feesJAPANESE INTERMEDIATE CODE: R250R250 | R250 | |
| Renewal fee payment (event date is renewal date of database)FPAY | FPAY | |
| Receipt of annual feesJAPANESE INTERMEDIATE CODE: R250R250 | R250 | |
| Renewal fee payment (event date is renewal date of database)FPAY | FPAY | |
| Receipt of annual feesJAPANESE INTERMEDIATE CODE: R250R250 | R250 | |
| Renewal fee payment (event date is renewal date of database)FPAY | FPAY | |
| Certificate of patent or registration of utility modelJAPANESE INTERMEDIATE CODE: R150R150 | R150 | |
| Certificate of patent or registration of utility modelJAPANESE INTERMEDIATE CODE: R150R150 | R150 | |
| First payment of annual fees (during grant procedure)JAPANESE INTERMEDIATE CODE: A61A61 | A61 | |
| Written decision to grant a patent or to grant a registration (utility model)JAPANESE INTERMEDIATE CODE: A01A01 | A01 | |
| Decision of grant or rejection writtenTRDD | TRDD | |
| Written amendmentJAPANESE INTERMEDIATE CODE: A523A521 | A521 | |
| Written permission of extension of timeJAPANESE INTERMEDIATE CODE: A602A602 | A602 | |
| Written request for extension of timeJAPANESE INTERMEDIATE CODE: A601A601 | A601 | |
| Notification of reasons for refusalJAPANESE INTERMEDIATE CODE: A131A131 | A131 | |
| Written amendmentJAPANESE INTERMEDIATE CODE: A523A521 | A521 | |
| Written permission of extension of timeJAPANESE INTERMEDIATE CODE: A602A602 | A602 | |
| Written request for extension of timeJAPANESE INTERMEDIATE CODE: A601A601 | A601 |
Numbers
- Publication
- 3824537
- Publication, DOCDB
- 3824537
- Publication, EPODOC
- JP3824537B
- Application
- 2001546704
- Application, DOCDB
- 2001546704
- Application, EPODOC
- JP20010546704
Titles2
- Japanese
- 組織再生組成物
- English
- Tissue regeneration composition
Classification
- CPC, 14
- A61L27/3645
- A61K35/22
- A61K35/36
- A61K35/38
- A61L27/3604
- A61L27/3629
- A61L27/3666
- A61L27/3683
- A61L27/3813
- A61L27/3843
- A61L2430/22
- A61L2430/40
- A61L27/3641
- A61P43/00
- IPC, 9
- A61L27 00
- A61K35 12
- A61K35 22
- A61K35 34
- A61K35 36
- A61K35 37
- A61P43 00
- A61K35 38
- A61L27 36