CN1280411C - Tissue engineered peripheral nerve graft - Google Patents
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- CN1280411C CN1280411C CN 200410027222 CN200410027222A CN1280411C CN 1280411 C CN1280411 C CN 1280411C CN 200410027222 CN200410027222 CN 200410027222 CN 200410027222 A CN200410027222 A CN 200410027222A CN 1280411 C CN1280411 C CN 1280411C
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Abstract
本发明公开了一种组织工程化周围神经移植物，以提供适用范围更广和质量更好的修复神经缺损的外科移植物。本发明所述的组织工程化周围神经移植物，包括用于连接神经两断端的支架和具有促进神经再生功能的种子细胞，种子细胞附着于支架上，形成具有仿神经三维结构和生物活性的复合体。所述的支架为去细胞异体神经，所述的种子细胞是由成体干细胞经体外诱导而成的类许旺细胞。本发明是真正意义上的组织工程化周围神经移植物，不仅为再生的神经纤维通过神经缺损区提供了仿生化的通道，而且其内在的种子细胞对神经再生有促进作用，因此可用于修复更长距离的神经缺损，神经修复效果显著提高，临床应用范围更广。
The invention discloses a tissue engineered peripheral nerve graft to provide a surgical graft for repairing nerve defect with wider application range and better quality. The tissue engineered peripheral nerve graft of the present invention includes a scaffold used to connect the two stumps of the nerve and seed cells with the function of promoting nerve regeneration. The seed cells are attached to the scaffold to form a nerve-like three-dimensional structure and biological activity. Complex. The scaffold is decellularized allogeneic nerve, and the seed cells are Schwann-like cells induced from adult stem cells in vitro. The present invention is a tissue-engineered peripheral nerve graft in the true sense, which not only provides a bionic channel for the regenerated nerve fibers to pass through the nerve defect area, but also its internal seed cells can promote nerve regeneration, so it can be used to repair more For long-distance nerve defects, the effect of nerve repair is significantly improved, and the clinical application range is wider.
Description
Technical field
The present invention relates to a kind of surgical implant, especially for the nerve graft of repairing peripheral nerve defection.
Background technology
The neurologic defect that causes after peripheral nerve injury and the damage is clinical common disabling condition.For the Repair of Peripheral Nerve Injury that causes because of various mishaies, be a difficult problem of neurosurgical treatment always.Annual newly-increased nearly 1,000,000 examples of case of China wherein, need be repaired about 450,000 examples of injured nerve by the implantable neural graft.At present, the source of nerve graft is very deficient, is badly in need of the neural surrogate of research and development.
Development to nerve graft both at home and abroad rests on the conduit of imitative neuromechanism always, people's chemical product of being developed at present is the tubular medical material that two broken ends of fractured bone with nerve couple together, promptly so-called " artificial neural tube " or " artificial nerve graft ".(patent No.: disclosed a kind of biological duct of being made by chitosan material 01108208.9), biological duct is embedded with fibrous framework, and the fibrous framework material is polyglycolic acid or poly(lactic acid) at Chinese patent " medical artificial nerve graft and preparation method thereof "; 00810000.4), " artificial neural tube " (application number: 99807035.1), " artificial neural canal " (application number: decompose the pipe that absorbing material forms in all having disclosed by organism 97199928.7) at Chinese patent application " artificial neural canal " (application number:, have the microfibre collastromin in its inner chamber, be filled with laminine in its space.
Above-mentioned currently available products all is the conduit made from the degradable biological material, can be at back " bridge joint " the damaged nerve that implants, but, the said products only is that the growth for the regenerating nerve aixs cylinder provides one " bridge " or " passage ", itself does not have biological activity, can not provide nerve growth necessary interior environment, also not promote the effect of neurotization.
Modern medicine is verified, and schwann cell has very important effect in the human nerve process of growth, and they adhere to and surround aixs cylinder formation myelin, promote the extension and the maturation of aixs cylinder.Because above-mentioned currently available products does not provide necessary schwann cell of neurotization or the active cells with similar functions, when the nearly broken ends of fractured bone grows newborn aixs cylinder, can only rely on related long simultaneously the coming of schwann cell of body itself, this process is just not only very slow, and the migration of the schwann cell of body itself has certain limit, if schwann cell advances not go, perhaps advance seldom, neural growth just is greatly affected, if be applied to clinically, only can repair short-range neurologic defect, generally be no more than 15 millimeters, often can directly sew up short-range neurologic defect like this clinically, and need be by these nerve grafts.To the neurologic defect of longer distance, even " bridge joint " above-mentioned conduit, the regenerated neural axon can not arrive the broken ends of fractured bone far away, can not recover the function of injured nerve, thereby repairing effect is very undesirable.
In recent years, the reparation that appears as tissue injury of organizational engineering has brought new hope.Organizational engineering is the principle and the method for application engineering and life science, research normal and the mammalian tissues form of pathology and the mutual relationship of function, the science of the biological substitution thing of exploitation damaged tissue repair form and function is the important content of biological technical field.Be to utilize bionic principle specifically, preparation has specific three-dimensional structure and bioactive complex body, builds the tissue of normal physiological function, can be used for substituting the form and function of human body defective tissue.The appearance of organizational engineering indicates that medical science will enter the new stage with made tissue and organ transplantation repair deficiency and reconstruction function from existing pattern from body or allosome tissue and organ transplantation.
Above-mentioned currently available products does not have biological activity, is not tissue engineered peripheral nerve graft truly, and this is to cause currently available products unfavorable basic reason of effect in nerve is repaired.
Summary of the invention
The object of the present invention is to provide a kind of tissue engineered peripheral nerve graft, be used to repair the neurologic defect that occurs after the peripheral nerve injury.
Tissue engineered peripheral nerve graft of the present invention, comprise and be used to connect the support of neural two broken ends of fractured bone and have the seed cell that promotes the neurotization function, seed cell is attached on the support, forms to have imitative neural three-dimensional structure and bioactive complex body.
Described support is for going the cell allogeneic nerve, and that preferably adopts the chemical extraction method preparation goes the cell allogeneic nerve.
Be further to strengthen the adhesivity of support, and promote the vascularization process of neurotization and graft, describedly remove to add in the cell allogeneic nerve material that can promote cell adhesion, neurotization and graft vascularization seed cell.
The above-mentioned material that can promote cell adhesion, neurotization and graft vascularization can (extracellular matrix ECM), comprises collagen, aminoglycan, glycoprotein three major types for extracellular matrix; Also can be various somatomedins.
Described seed cell is that adult stem cell is through the external evoked class schwann cell that forms.Adult stem cell is preferably bone marrow interstital stem cell, perhaps fat stem cell.
Peripheral nerve is made up of neurocyte, schwann cell, reticular tissue, blood vessel, lymphatic vessel and special sustenticular cell.Neurocyte (neurone) is again that the cytoplasmic process by cell space part and projection constitutes, and the end of cytoplasmic process contacts with neurone after the branch repeatedly, and aixs cylinder is one of them the longest and most important cytoplasmic process, and is stretchable to effector.Schwann cell holds aixs cylinder and forms nerve fiber.Up to ten thousand fiber concentrates in together the formation nerve tract, and one or several nerve tracts are linked together by reticular tissue, have just formed peripheral nerve.When peripheral nerve fracture and occur damaged after, need come " bridge joint " damaged nerve segment with graft, newborn neural axon is from the nearly broken ends of fractured bone graft of growing into, under the guiding of schwann cell to broken ends of fractured bone growth far away.Modern medicine is verified, and schwann cell has important role in the human nerve process of growth, and they adhere to and surround aixs cylinder formation myelin, promote the extension and the maturation of aixs cylinder.The contriver successfully with adult stem cell in vitro culture by drug-induced for having the cell of schwann cell form and functional character, called after " class schwann cell ", these cells should be that human peripheral nerve injury is repaired one of cell the most suitable in the designed seed cell that engineered nerve adopted, and road has been paved in the regeneration that its propagation in vivo is neural axon.
Existing what is called " artificial neural tube " or " artificial nerve graft " only are " bridges " or " passage " that the growth for the regenerating nerve aixs cylinder provides, and tissue engineered peripheral nerve graft of the present invention has breakthrough advantage, promptly adopted the seed cell that " plantation " has biologic activity on the support that connects the neural broken ends of fractured bone, this seed cell is through external evoked " the class schwann cell " with schwann cell (Schwann ' s cells) form and functional character that forms by adult stem cell, cell has the characteristic of the growth of attaching, the class schwann cell can adhere at rack surface, migration, propagation, formation has the artificial nervous tissue of special three-dimensional structure and active cells.Support and seed cell all are the requisite integral parts of peripheral nerve graft of the present invention, have constituted tissue engineered peripheral nerve graft truly thus.
Still there are many parts that have much room for improvement in existing " artificial neural tube " or " artificial nerve graft " that utilizes the biodegradable material preparation.This class is artificial imitation by the support of biodegradable material preparation after all, compares with the structure of natural nerve fiber, and its three-dimensional structure is too simple, and it is very high to be processed into the technical costs of the support with complex construction.Therefore, the present invention adopts and goes the cell allogeneic nerve as support, can further overcome the defective of existing biodegradable material conduit.
Characteristics of the present invention are that allogeneic nerve is gone the cell processing and utilized its natural neural vessel of basilar membrane structure as support.The contriver successfully with the cell in chemicals destruction and the human peripheral nerve of wash-out, obtains " removing cell allogeneic nerve support ".Support is after treatment only removed the various cells in the nervous tissue and is kept matrix between neural vessel of basilar membrane and the pipe, and neural fiber reinforcement is still intact.
The present invention is when using, and with the neurologic defect position of described tissue engineered peripheral nerve graft implant into body, the newborn aixs cylinder that grows from the neural broken ends of fractured bone begins in the progress support and extension and ripe in support.In this process, the seed cell that is attached on the support is then constantly bred, is moved by the direction of growth of regeneration aixs cylinder, form the cell band of " class schwann cell ", waiting the arrival of newborn aixs cylinder, in the process of newborn neural axon growth, seed cell is equivalent to " guide " of " meeting " newborn aixs cylinder, and necessary trophism and inducing action is provided.Newborn peripheral nerve aixs cylinder just have one by one class schwann cell go " meeting " it, and surround aixs cylinder, form myelin, and make it to reach the maturation on the function.Simultaneously, absorbed by body gradually as the cell allogeneic nerve of going of support, and finally replaced by new life's nerve fiber.
Because the peripheral nerve growth necessarily needs schwann cell " escorting ".Existing nerve graft product only provides support and the active cells that schwann cell is not provided or has similar functions, when the nearly broken ends of fractured bone grows newborn aixs cylinder, can only rely on related long simultaneously the coming of schwann cell of body itself, this process is just not only very slow, and the migration of the schwann cell of body itself has certain limit, if schwann cell advances not go, perhaps advance seldom, neural growth just is greatly affected, if be applied to clinically, only can repair short-range neurologic defect, generally be no more than 15 millimeters, often can directly sew up short-range neurologic defect like this clinically, and need be by these nerve grafts.As the neurologic defect more than 3 centimetres, even " bridge joint " above-mentioned conduit, the regenerated neural axon can not arrive the broken ends of fractured bone far away, is difficult to recover the function of injured nerve, thereby repairing effect is very undesirable to longer distance.And the present invention adopts seed cell and support structure combining, the passage of imitation biochemistry not only is provided by the neurologic defect district for the regenerated nerve fiber, and its intrinsic seed cell has promoter action to neurotization, therefore can be used for repairing the neurologic defect of longer distance, neural repairing effect significantly improves, and clinical application range is wider.
Description of drawings
Fig. 1 is a structural representation of the present invention.
Fig. 2 is the local enlarged diagram of the A-A section of Fig. 1.
Fig. 3 is an application synoptic diagram of the present invention.
Embodiment
Tissue engineered peripheral nerve graft of the present invention, as depicted in figs. 1 and 2, comprise and be used to connect the support 1 of neural two broken ends of fractured bone and have the seed cell 2 that promotes the neurotization function, seed cell 2 is attached on the support 1, forms to have imitative neural three-dimensional structure and bioactive complex body.Support 1 is for going the cell allogeneic nerve.As shown in Figure 2, go the cell allogeneic nerve to be made up of many neural vessel of basilar membrane 11, the cell in the neural vessel of basilar membrane 11 is removed, remaining cavity, and seed cell 2 mainly is attached on the inwall of neural vessel of basilar membrane 11, also can be attached to outside the neural vessel of basilar membrane 11.As shown in Figure 3, when repairing neurologic defect, tissue engineered peripheral nerve graft of the present invention is implanted between the nearly broken ends of fractured bone 3 and the broken ends of fractured bone 4 far away.
In actual product, the neural vessel of basilar membrane of going the cell allogeneic nerve to be contained is minimum, and Fig. 1 to Fig. 3 is the microcosmic synoptic diagram, and its ratio is not represented the ratio of actual product.
Described seed cell is through the external evoked class schwann cell that forms by adult stem cell.Adult stem cell includes multiple stem cell, and as bone marrow interstital stem cell, fat stem cell etc., following examples are to be illustrated as seed cell respectively through external evoked bone marrow interstital stem cell and fat stem cell:
Embodiment one:
Cut complete nerve from donor's limbs, extract with the cell in chemicals (as trotyl and Sodium desoxycholate etc.) the destruction nervous tissue and with its cellular constituent, obtain the cell allogeneic nerve, the sterilization back is as support 1.In patient's body (as ilium, shin bone) extracts marrow, isolate bone marrow interstital stem cell, in the external cell cultures of carrying out, add inductor (as all-trans retinoic acid, mercaptoethanol, Prostatropin, platelet derived growth factor etc.) make it be divided into the class schwann cell, then above-mentioned cell is expelled to going on the cell allogeneic nerve support 1 after the sterilization as seed cell 2, promptly obtained of the present invention by bone marrow interstital stem cell through external evoked class schwann cell that forms and the tissue engineered peripheral nerve graft that removes cell allogeneic nerve structure.During clinical use, tissue engineered peripheral nerve graft of the present invention is implanted to the peripheral nerve defection place that to repair.As shown in Figure 3, after the peripheral nerve fracture, newborn aixs cylinder is longer from the nearly broken ends of fractured bone 3 of nerve, the class schwann cell near and surround aixs cylinder, provide nutrition to aixs cylinder, and the neurophilic far-end growth of guiding aixs cylinder, be connected with the broken ends of fractured bone far away 4 of nerve fiber.In this process, the function of class schwann cell performance schwann cell is then absorbed by body as the cell allogeneic nerve of going of support, and the nerve fiber that finally is reproduced replaces.
Be further to strengthen the adhesivity of support, and promote the vascularization process of neurotization and graft, in the present embodiment, remove the cell allogeneic nerve to add to promote the material of cell adhesion, neurotization and graft vascularization seed cell.This material can (extracellular matrix ECM), comprises collagen, aminoglycan, glycoprotein three major types for extracellular matrix; Also can be various somatomedins.
In the present embodiment, when 2 centimetres of patient's finger neurologic defects, the allosome of desirable respective length refers to that nerve goes cell to handle as support; When damaged 4 centimetres of patient's median nerve, the allosome median nerve of desirable respective length goes cell to handle as support; When damaged 6 centimetres of patient's sciatic nerve, the allosome sciatic nerve of desirable respective length goes cell to handle as support.
Embodiment two:
Cut complete nerve from donor's limbs, extract with the cell in chemicals (as trotyl and Sodium desoxycholate etc.) the destruction nervous tissue and with its cellular constituent, obtain the cell allogeneic nerve, the sterilization back is as support 1.Extract fatty tissue in abundant place (as stomach wall) at patient's body fat, isolate fat stem cell, in the external cell cultures of carrying out, adding inductor (as Prostatropin, nerve growth factor etc.) makes it be divided into the class schwann cell, then above-mentioned cell is expelled to going on the cell allogeneic nerve support 1 after the sterilization as seed cell 2, promptly obtained of the present invention by fat stem cell through external evoked class schwann cell that forms and the tissue engineered peripheral nerve graft that removes cell allogeneic nerve structure.During clinical use, tissue engineered peripheral nerve graft of the present invention is implanted to the peripheral nerve defection place that to repair.As shown in Figure 3, after the peripheral nerve fracture, newborn aixs cylinder is longer from the nearly broken ends of fractured bone 3 of nerve, the class schwann cell near and surround aixs cylinder, provide nutrition to aixs cylinder, and the neurophilic far-end growth of guiding aixs cylinder, be connected with the broken ends of fractured bone far away 4 of nerve fiber.In this process, the function of class schwann cell performance schwann cell is then absorbed by body as the cell allogeneic nerve of going of support, and the nerve fiber that finally is reproduced replaces.
Be further to strengthen the adhesivity of support, and promote the vascularization process of neurotization and graft, in the present embodiment, remove the cell allogeneic nerve to add to promote the material of cell adhesion, neurotization and graft vascularization seed cell.This material can (extracellular matrix ECM), comprises collagen, aminoglycan, glycoprotein three major types for extracellular matrix; Also can be various somatomedins.
In the present embodiment, when 2 centimetres of patient's finger neurologic defects, the allosome of desirable respective length refers to that nerve goes cell to handle as support; When damaged 4 centimetres of patient's median nerve, the allosome median nerve of desirable respective length goes cell to handle as support; When damaged 6 centimetres of patient's sciatic nerve, the allosome sciatic nerve of desirable respective length goes cell to handle as support.
Above-listed detailed description is at the specifying of possible embodiments of the present invention, but this embodiment is not in order to limiting claim of the present invention, does not allly break away from the equivalence that spirit of the present invention does and implements or change, all should be contained in the claim of the present invention.
Claims (4)
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| CN 200410027222 CN1280411C (en) | 2004-05-18 | 2004-05-18 | Tissue engineered peripheral nerve graft |
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| CN 200410027222 CN1280411C (en) | 2004-05-18 | 2004-05-18 | Tissue engineered peripheral nerve graft |
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| CN1280411C true CN1280411C (en) | 2006-10-18 |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100462105C (en) * | 2006-10-19 | 2009-02-18 | 中国人民解放军第四军医大学 | A kind of preparation method of recombinant nerve substitute |
| CN103751845B (en) * | 2014-01-30 | 2015-05-13 | 中国人民解放军海军总医院 | Tissue engineering biological material for transplanting and restoring peripheral nerve defect |
| CN106344965A (en) * | 2015-07-20 | 2017-01-25 | 中国人民解放军第二军医大学 | Decellularized epineurium catheter and preparation thereof as well as application to repairing of peripheral nerve injury |
| CN105169486B (en) * | 2015-10-11 | 2018-04-03 | 温州医科大学 | A kind of nerve repair material of combination Acellular nerve application |
| CN105288744B (en) * | 2015-10-29 | 2018-04-03 | 温州医科大学 | A kind of neural unit beaded support and its preparation |
| CN106421912A (en) * | 2016-10-13 | 2017-02-22 | 中山大学 | Preparation and application of matrix acellular nerve scaffold |
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