CN100569302C - A kind of photosensitive scaffold with control restenosis function - Google Patents
A kind of photosensitive scaffold with control restenosis function Download PDFInfo
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- CN100569302C CN100569302C CN 200610095066 CN200610095066A CN100569302C CN 100569302 C CN100569302 C CN 100569302C CN 200610095066 CN200610095066 CN 200610095066 CN 200610095066 A CN200610095066 A CN 200610095066A CN 100569302 C CN100569302 C CN 100569302C
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- photosensitizer
- photosensitive
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- support
- restenosis
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Abstract
The invention belongs to the biomedical engineering technology field, more particularly, the present invention relates to a kind of photosensitive scaffold with control restenosis function.Utilize photosensitizer that support is modified, obtain photosensitive scaffold, photosensitive scaffold is placed in the pathological lumen, through photoirradiation, the photosensitizer that activates on the support produces photochemical reaction generation reactive oxygen species, prevents neointimal hyperplasia, prevents the generation of stent restenosis.
Description
Technical field
The invention belongs to the biomedical engineering technology field, more particularly, the present invention relates to a kind of photosensitive scaffold with control restenosis function.
Background technology
The intracavity stent implantation is the interventional therapeutic technique that grows up on the intracavity forming operation basis, extensive use clinically now, only U.S.'s case 100,000 examples nearby of accepting the endovascular stent implantation in 1 year.Along with the accumulation of Clinical Follow-up data, the restenosis rate of postoperative is up to 30-50%.Reducing intracavity stent implantation postoperative restenosis is clinical problem demanding prompt solution.
In recent years, along with the fast development of Celluar and Molecular Biology, the mechanism research of intracavity forming postoperative restenosis has obtained some progress.Studies show that: early stage elastical retraction, blood vessel is reinvented and the new intima hypertrophy of stent-induced is the main cause of restenosis behind the Stent.From present research, support has been eliminated the tube wall elasticity retraction basically and the negativity blood vessel is reinvented, but neointimal hyperplasia is still unsolved so far subject matter.Studied multiple counter measure at the mechanism of stent-induced neointimal hyperplasia, comprise clinical systemic drug commonly used treatment and the multiple local therapeutic approaches such as gene therapy, topical remedy's embedding, local radiotherapy and multi-functional intravascular stent of carrying out recently, but do not have any can be really effectively lasting.We attempt the new method of preventing and treating this an urgent demand.
(photodynamic therapy is that the photosensitizer that utilizes selectivity to accumulate in tumor tissue cell that rises in recent years excites the novel method of treatment that issues the quick reaction of third contact of a total solar or lunar eclipse location killing tumor cell in suitable wavelength light PDT) to optical dynamic therapy.It is that photosensitizer selectivity in tumor tissue cell gathers the controllability with illumination dose, scope that tumor PDT has two outstanding advantages, and PDT is had can relative specificity ground killing tumor cell, to characteristics such as the health tissues infringement are little.Because laser penetration depth in tissue is limited, makes PDT have bigger limitation aspect oncotherapy.Optimum proliferative diseasees such as intracavity stent implantation postoperative restenosis have the class tumor characteristic and the characteristics (with regard to laser therapy) of " showing shallow " are all arranged comparatively on the histopathology structure, therefore PDT treats the advantage that this class disease had both been brought into play PDT selectivity and controllability, the problem of not having the laser penetration difference again, can fully maximize favourable factors and minimize unfavourable ones, the control of implanting restenosis for support provides a kind of new method of using future that has.
Summary of the invention
The objective of the invention is to provide a kind of photosensitive scaffold, under certain wavelength light irradiation, prevent neointimal hyperplasia, prevent the generation of stent restenosis with control restenosis function.
The technical scheme that realizes the object of the invention is to utilize photosensitizer to modify support to obtain photosensitive scaffold, lesion in the implant cavity, regular period is activated photosensitizer by this support of light source (or optical fiber) irradiation that is complementary with photosensitizer after implantation, photochemical reaction takes place produce active oxygen, because active oxygen life period short (lifetime＜0.04 μ s) and sphere of action little (10-20nm), photosensitizer on the photoactivation support produces photochemical damage and only is confined to the interior tissue of support periphery 10-20nm scope, directly prevent neointimal hyperplasia, prevent the generation of stent restenosis.
In the present invention, described as the photosensitizer of modifying support be safety non-toxic can selectivity very/neoplasm sex organization in retention and can be activated by certain wavelength light and produce the photosensitizer that photooxidation reaction generates reactive oxygen species, these materials are hydrophilic, lipophile, amphipathic photosensitizer.Described reactive oxygen species is a singlet oxygen.Physical behaviors such as the type of the photosensitizer that is used for photosensitive scaffold, particle size size are not had too much restriction,, under certain wavelength light effect, photochemical reaction can take place and get final product as long as this photosensitizer is after being applied on the support.Thereby the photosensitizer that is used for support of the present invention is selected from porphyrin and derivant such as hemoporphyrin, benzoporphyrin derivative list acid ring A etc., phthalocyanine and derivant thereof such as zinc phthalocyanine and aluminum phthalocyanine etc., chlorophyll and derivant thereof such as pheophytin and chlorin and C.I. Natural Red 8 18, anthraquinone and derivant thereof, the 5-amino-laevulic acid, rose-red, phycobniliprotein such as phycoerythrin and phycocyanin etc., quinones, fullerene, five nitrogen tooth analog derivatives such as lutecium III five nitrogen teeth, polyacetylene class such as benzene alkynes in heptan three, thiophenes such as α thiophene, inorganic sound sensitiser such as titanium oxide (TiO
2), a kind of and wantonly two kinds or multiple mixture in ruthenium compounds, zinc oxide, Chinese herbal medicine class photosensitizer such as hypocrellin derivant (hypocrellin A, hypocrellin B etc.), psoralen and curcumin, hypericin, pseudohypericin, emodin, riboflavin, aloe-emodin etc.At present widely used various photosensitizer and deutero-any photoactive substance thereof all can be used as photosensitizer on the photosensitive scaffold of the present invention in the photodynamic therapy field.Described light can derive from any light source that can reach the support implant site and can activate photosensitizer, can be laser or also ordinary light source.
Among the present invention photosensitizer be covered in rack surface can be carrier mediated by direct impregnation, spraying, polymer, protein carrier mediation or electrochemical treatments and ion beam depositing method finish.The carrier mediated photosensitizer of polymer is covered in the polymer described in the rack surface and can be (but being not limited only to) PLA (polylactic acid, PLA), glutin (gelatin), Polyethylene Glycol (polyethylene glycol, PEG), polysiloxanes (polysiloxane), polyethylene glycol oxide (polyethylene oxide, PEO), polyacrylamide (polyacrylamid), polyacrylic acid (ester) (polyacrylate), polyurethane (polyurethane, PU), poly phosphate (polyphosphate ester), polyglycolic acid (ester) (polyglycolide, PGA), poly butyric (ester) (polyhydroxylbutyrate, PHBT), poly-(acid) acid anhydride (polyanhydrides, PAN), polycaprolactam (polycaprolactone, PCL), polyamino acid (polyamine acid), copolymer (co-polymer) between poly-hydroxyethyl methacrylic acid (ester) (polyhydroxyethyl methacrylate) and above-mentioned polymer.The method that polymer or protein carrier mediation photosensitizer is covered in rack surface can be that directly application is flooded and made photosensitizer be covered in rack surface after using polymer or protein and photosensitizer combine; Also can application of radiation solidify or the photocuring effect makes photosensitizer be covered in rack surface.Ion beam depositing can directly carry out plated film on support.Described support can be prepare voluntarily or market on ready-made, can make by rustless steel or biodegradable material, manufacture method can be with reference to the preparation of the technology of patent EP132060 and U.S. Pat 5670161 patent disclosures.Biodegradable material comprises (being not limited only to this) Acetic acid, hydroxy-, bimol. cyclic ester (glycolic acid, GA), L-lactide (L-lactic acid, LLA), poly-(lactide) (PLA), 6-caprolactone (caprolactone, CL) a kind of in etc. homopolymer or the copolymer and with the copolymer of multifunctional amino acid as poly-(D, L-lactide-co-glycolide) (PLA or PLGA).This preparation methods is a prior art, and its preparation method can be consulted document (Makromol.Chem.1987,188:1809-1814) disclosed method.
All there is certain limitation in the support of existing control restenosis, though can obviously reduce the incidence rate of restenosis as the radiation support, later stage thrombosis and edge effect have limited its clinical practice; Existing common drug FirebirdTM effect is obvious, but these medicines all can suppress the endothelialization again of injury region, influences the agglutination of tube chamber damage, may make the blood vessel wall attenuation, even forms hemangioma.Compare with existing support, prevent neointimal hyperplasia with having the safety non-toxic effect and can under photoactivation, producing photochemistry mechanism generation active oxygen among the present invention, also may urge the reparation of tube chamber endothelium simultaneously, help its endothelialization again.This photosensitive scaffold can be applied to all tube chamber occlusive diseases such as esophagus, trachea, blood vessel, biliary tract, urethra, prevents that pathological tissues from growing to intracavity, restenosis behind the control Stent.Its prevention effect is that existing support is incomparable.It is more extensive in clinical practice to utilize photosensitizer will help interventional therapeutic technique as support dressing agent acquisition photosensitive scaffold.
Description of drawings
Fig. 1 is the sketch map that photoactivation photosensitizer generation photochemical reaction generates active oxygen:
Fig. 2 is that the photoactivation photosensitizer of implementing in 1 produces the active sketch map of photochemical reaction inhibition vascular smooth muscle cell proliferation
Fig. 3, photosensitizer are positioned at the sectional view of internal stent and tectal photosensitive scaffold
1 is support among the figure, and 2 for being wrapped in internal stent and the photosensitizer that is covered in rack surface, and 3 are a rack overlays.
Fig. 4, photosensitizer are positioned at the sectional view of tectal photosensitive scaffold
1 is support among the figure, and 2 for being covered in the photosensitizer of rack surface, and 3 are a rack overlays.
Fig. 5, photosensitizer are positioned at the sectional view of the photosensitive scaffold of internal stent
1 is support among the figure, and 2 for being wrapped in the photosensitizer in the support.
The specific embodiment
Below be non-limiting examples of the present invention:
Embodiment 1: the high intensity focused ultrasound enhancement effect of observing photosensitizer on the cultured cell in vitro: cultivate target cell: select vascular smooth muscle cell, be incubated in 37 ℃ of incubators that contain 5% carbon dioxide, saturation vapour with the DMEM culture fluid routine that contains 10% calf serum; Then, the take the logarithm target cell (2 * 10 of trophophase
4) individual cell, adding photosensitizer such as hemoporphyrin hatched 12～16 hours in 37 ℃ of incubators that contain 5% carbon dioxide, saturation vapour, owing to there is part photosensitizer hemoporphyrin not engulfed by target cell, also be free in the culture fluid, so before illumination, washing is removed hemoporphyrin remaining in the culture fluid for several times; Then, use laser (He-Ne laser, its wavelength 632.8nm, output are that 0mW-100mW is adjustable continuously, and optical fibers is exported continuously) irradiation target cell.Under the laser irradiation effect, photosensitizer hemoporphyrin generation photochemical reaction generates reactive oxygen species (as shown in Figure 1).Experiment adopts mtt assay to observe photosensitizer significantly reduces vascular smooth muscle cell under laser activation proliferation activity.As shown in Figure 2.
In present embodiment 1, the photosensitizer of selecting is a kind of safety non-toxic, the selective fixed photosensitizer that is positioned at the proliferative tissue cell of energy, except hemoporphyrin, also it can be aluminum phthalocyanine, 5-amino-laevulic acid, hypocrellin derivant, single asparagine chlorin, De Kesafei quinoline lutecium, rose-red or hematoporphyrin monomethyl ether etc.
Embodiment 2: the photosensitizer aloe-emodin is poured in the dehydrated alcohol, and fully mixing is made aloe-emodin solution through filtration, ultrasound wave aerofluxus again; Then, take out an individual lumen tube and prop up and be placed in the described aloe-emodin solution, dipping takes out after 10 seconds-4 hours; Dry up with nitrogen; Repeat above-mentioned steps 1-3 time again, dry up with nitrogen at last, obtain photosensitive scaffold as shown in Figure 4.
In present embodiment 2, the photosensitizer of selecting is a kind of safety non-toxic, the selective fixed photosensitizer that is positioned at the proliferative tissue cell of energy, except aloe-emodin, also it can be aluminum phthalocyanine, 5-amino-laevulic acid, hypocrellin derivant, single asparagine chlorin, De Kesafei quinoline lutecium, rose-red, hemoporphyrin or hematoporphyrin monomethyl ether etc.
Embodiment 3: will the photosensitizer aluminum phthalocyanine add in the polyamino acid (polyamine acid) and fully stir evenly, then, the liquid of gained is coated in the lumen tube rack surface; Naturally dry or dry up with nitrogen; Obtain photosensitive scaffold as shown in Figure 4.
Claims (9)
1. one kind has the photosensitive scaffold of preventing and treating the restenosis function, it is characterized in that photosensitive scaffold is a kind of support that contains photosensitizer, be to be covered in rack surface by photosensitizer, or in making the support process, add photosensitizer, make internal stent itself just contain photosensitizer, through photoirradiation, the photosensitizer generation photochemical reaction generation that activates on the support can be prevented neointimal hyperplasia, prevents the reactive oxygen species of the generation of stent restenosis.
2. a kind of photosensitive scaffold with control restenosis function according to claim 1 is characterized in that it is that, protein carrier mediation carrier mediated by direct impregnation, spraying, polymer or electrochemical treatments or ion beam depositing method are finished that this photosensitizer is covered in rack surface.
3. a kind of photosensitive scaffold with control restenosis function according to claim 2 is characterized in that it is copolymer between PLA, glutin, Polyethylene Glycol, polysiloxanes, polyethylene glycol oxide, polyacrylamide, polyacrylic acid, polyurethane, poly phosphate, polyglycolic acid, poly butyric, polyanhydride, polycaprolactam, polyamino acid or poly-hydroxyethyl methacrylic acid and above-mentioned polymer that the carrier mediated photosensitizer of polymer is covered in the polymer described in the rack surface.
4. a kind of photosensitive scaffold according to claim 2 with control restenosis function, it is characterized in that method that polymer or protein carrier mediation photosensitizer is covered in rack surface is that directly application is flooded and made photosensitizer be covered in rack surface after using polymer or protein and photosensitizer combine; Or application of radiation is solidified or the photocuring effect makes photosensitizer be covered in rack surface.
5. a kind of photosensitive scaffold according to claim 1 with control restenosis function, it is characterized in that described photosensitizer is by the photosensitizer of photoactivation, described photoactivation mode directly adopts light source light irradiation to activate for to transmit by optical fiber by laser active or by normal optical.
6. a kind of photosensitive scaffold with control restenosis function according to claim 1 and 2 is characterized in that described photosensitizer with photosensitive scaffold is the material that can be generated active oxygen by the photoactivation of certain wavelength generation oxidation reaction of safety non-toxic.
7. a kind of photosensitive scaffold according to claim 1 with control restenosis function, it is characterized in that the support as photosensitive scaffold is that rustless steel, memorial alloy or biodegradable material are made, wherein said Biodegradable material comprises Acetic acid, hydroxy-, bimol. cyclic ester (glycolicacid, GA), L-lactide (L-lactic acid, LLA), 6-caprolactone (caprolactone, a kind of and described Biodegradable material material monomer in homopolymer CL) or the copolymer and the copolymer of multifunctional amino acid.
8. a kind of photosensitive scaffold with control restenosis function according to claim 6 is characterized in that described reactive oxygen species is a singlet oxygen.
9. a kind of photosensitive scaffold with control restenosis function according to claim 1 prevents all tube chamber occlusive diseases in the human body being used for making, and prevents neointimal hyperplasia, prevents the application in the support of generation of restenosis.
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| CN 200610095066 CN100569302C (en) | 2006-08-25 | 2006-08-25 | A kind of photosensitive scaffold with control restenosis function |
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| CN100569302C true CN100569302C (en) | 2009-12-16 |
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0904907D0 (en) * | 2009-03-23 | 2009-05-06 | Univ Leeds | Scaffold |
| CN103239763A (en) * | 2012-02-02 | 2013-08-14 | 上海交通大学医学院附属第三人民医院 | Sutureless ureterostenosis restoration operation material and system thereof |
| US9259435B2 (en) * | 2012-08-31 | 2016-02-16 | W. L. Gore & Associates, Inc. | Reactive oxidative species generating materials and methods of use |
| CN106620893B (en) * | 2015-07-23 | 2021-07-30 | 爱博诺德(北京)医疗科技股份有限公司 | Materials for ocular disease phototherapy |
| CN106362215A (en) * | 2015-07-23 | 2017-02-01 | 爱博诺德（北京）医疗科技有限公司 | Intraocular lens for preventing and treating after cataract, and preparation method thereof |
| CN106901871B (en) * | 2015-12-23 | 2021-08-24 | 爱博诺德(北京)医疗科技股份有限公司 | Intraocular lens with one or more additional portions |
| CN105963770A (en) * | 2016-05-09 | 2016-09-28 | 中国人民解放军第三军医大学 | Photosensitive biogel and preparation method thereof |
| CN109663151B (en) * | 2018-12-19 | 2021-09-21 | 西南交通大学 | Preparation method and application of tetracarboxyphenylporphyrin copper modified amino-rich stent material, and vascular stent material and application |
| CN109999219B (en) * | 2019-04-29 | 2021-05-18 | 杨建安 | Artificial heart valve and preparation method thereof |
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