WO2010048757A1 - Procédé de préparation d'un matériel génétique porté par un support microporeux - Google Patents

Procédé de préparation d'un matériel génétique porté par un support microporeux Download PDF

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Publication number
WO2010048757A1
WO2010048757A1 PCT/CN2008/072887 CN2008072887W WO2010048757A1 WO 2010048757 A1 WO2010048757 A1 WO 2010048757A1 CN 2008072887 W CN2008072887 W CN 2008072887W WO 2010048757 A1 WO2010048757 A1 WO 2010048757A1
Authority
WO
WIPO (PCT)
Prior art keywords
micro
blind hole
gene
genetic material
stent
Prior art date
Application number
PCT/CN2008/072887
Other languages
English (en)
Chinese (zh)
Inventor
董何彦
李昕跃
李相宜
Original Assignee
Dong Heyan
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dong Heyan filed Critical Dong Heyan
Priority to PCT/CN2008/072887 priority Critical patent/WO2010048757A1/fr
Publication of WO2010048757A1 publication Critical patent/WO2010048757A1/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B17/00—Apparatus for spraying or atomising liquids or other fluent materials, not covered by the preceding groups
    • B05B17/04—Apparatus for spraying or atomising liquids or other fluent materials, not covered by the preceding groups operating with special methods
    • B05B17/06—Apparatus for spraying or atomising liquids or other fluent materials, not covered by the preceding groups operating with special methods using ultrasonic or other kinds of vibrations

Definitions

  • the present invention relates to a medical device device and a method for preparing the same for carrying a genetic material, and belongs to the fields of biomedical materials and biochemistry.
  • the preparation of the surface-coated genetic material-naked plasmid including genetic material
  • Cardiovascular stenting in medical devices has become an increasingly widely used method in the medical field.
  • simple cardiovascular stenting presents a serious challenge, namely postoperative biocompatibility and tissue regeneration.
  • the researchers tested carrying a drug, including bioactive substances, on the surface of the cardiovascular stent In order to make it more conducive to clinical therapeutic effects. Therefore, high-molecular polymers are used as a bearing transition layer, which is coated on the surface of the cardiovascular stent; then it is combined with a drug and the like, and released through the interface to achieve therapeutic effects.
  • the drug carrier of high molecular weight polymer as a carrier the adverse reaction of detachment after being implanted into the human body has occurred, especially the discrete movement of the polymer in the blood, which will cause a new distal end to the patient.
  • Thrombosis, etc. The cardiovascular stent with micro-blind holes on the surface can not only directly load particles such as drugs and genes, but also has good biocompatibility, so that vascular endothelial cells can quickly complete the endothelialization process, which can be very good. Therapeutic effect.
  • the genetically encoded gene containing a clinically meaningful active molecule is applied to the surface of the micro-blind vascular stent; after implantation into the human body, the genetic material carried by the human can enter the vascular endothelial cells at the implantation site and express corresponding The molecular activity is thus achieved for the intended therapeutic purpose.
  • the coating method currently applied is generally a soaking method; that is, the micro-blind-hole vascular stent is immersed in a solution of the genetic material to adhere the genetic material to the surface of the stent.
  • the solution cannot enter the micro-blind hole of the stent completely and effectively; the carrying amount of the genetic material on the surface of the single stent cannot be precisely controlled; the accuracy of the repeated repetition of the operation process cannot be scaled up.
  • the present invention provides a new method for solving the above problems.
  • the present invention provides a method for preparing a micro-blind hole scaffold carrying a genetic material, and the ultrasonic micro-atomizing pressurized jet coating is used.
  • the method enables the genetic material to smoothly enter the micro-blind hole and the surface of the stent, and precisely controls the amount of the genetic material carried by each micro-blind hole vascular stent.
  • the target gene substance is a naked plasmid, which is dissolved by ultrapure water or sugar which does not destroy its biological activity, and then added to the solution.
  • Vitamin 5 and vitamin C which are harmless to the human body, act as a protective agent; thus, the naked-plasmid coated stent of the genetic material can reach the target blood vessel smoothly.
  • the solution is atomized by ultrasonic wave, the ultrasonic intensity is 0.8, the drug flow rate is 0.025ml/min, the support speed of the support is 0.1cm/s, the rotation speed of the support is 250r/min, and the inert gas pressure lp sio is controlled by the auxiliary computer program after high-speed spraying.
  • the genetic material of a single scaffold can be carried within the range of 120-150 ⁇ ⁇ , which can be accurately adjusted, with high repeatability, and can realize large-scale processing.
  • a method for preparing a micro-blind-hole-supporting genetic material which is characterized in that a gene substance to be carried is dissolved at a normal temperature, and a gene-active protective agent is added in an appropriate amount; and ultrasonic micro-atomizing pressure spraying equipment is used for spraying to make a genetic substance Enter the inside of the micro-blind hole and apply it to the surface of the holder.
  • the material of the micro-blind hole bracket includes metal and non-metal; it can be medical stainless steel, titanium-nickel alloy, cobalt-chromium alloy and polymer material.
  • the micro-blind-aperture stent includes a balloon-expandable stent and a self-expanding stent, including metal and non-metallic stents that are otherwise delivered and expanded; the balloon catheter can be used for delivery and expansion of the stent.
  • Micro-blind hole supports include laser-engraved stents, braided stents, and other methods of implanting cardiovascular stents implanted into the human body.
  • the hosted genetic material is a naked plasmid; a naked plasmid derived from eukaryotic cells and prokaryotic cells, and a naked plasmid derived from a non-cell source; a naked plasmid DNA and a plasmid liposome which may be non-viral vectors.
  • the naked plasmid includes a resistance plasmid, a degradation plasmid, an invasive plasmid; it is an extrachromosomal exposure in a host cell. Double-stranded DNA.
  • the gene activity protective agent to be added may be a solution, a saccharide or a vitamin. They may be used singly or in combination, and the concentration is between 1.0% and 10%.
  • the solution may be ultrapure water; it may be any harmless liquid in which a sugar may be added or a plurality of sugars may be added.
  • the sugars include monosaccharides or polysaccharides; they may be glucose or sucrose. In the spraying of genetic material, it can be a single layer, or multiple layers.
  • micro-blind hole bracket is covered with micro-pores. If the stent is directly immersed in the solution of the genetic material, the surface of the micro-blind hole is immediately covered by the liquid, and the air in the micro-blind hole cannot be discharged due to the liquid tension, thereby causing The solution could not enter the micro-blind hole; as shown in Figure 7.
  • the genetic material has good water solubility, the surface of the stent that is simply coated, a considerable portion of the genetic material will be dissolved by the blood before reaching the target lesion.
  • a protective substance such as a solution, a saccharide or a vitamin which is harmless to the human body is added to the solution of the genetic substance, and after drying, a protective layer is provided for the genetic substance.
  • the protective agent can be dissolved in the blood, its dissolution rate is not so fast, and the genetic material carried on the stent can be safely reached to the diseased site.
  • the solution of the genetic material added with the solution or the saccharide or vitamin is ultrasonically oscillated to produce small droplets (range 18-48 ⁇ ) having a diameter of micrometers, and the droplets are in an inert gas (nitrogen or helium).
  • the applied pressure pushes the fast-moving micro-blind hole holder, and the front size can be quickly reduced when it enters the micro-blind hole smoothly.
  • the rotation of the stent is very important because during the rotation, there is a shearing force between the droplets and the surface of the stent, and this shearing force is an indispensable factor for the droplets to enter the micro-blind hole. .
  • the thickness of the liquid film on the surface of the stent is about 0.1 mm, and the thin liquid film forms spherical crown droplets as shown in Fig. 6 on each side of the stent rib.
  • the droplet radius r can be calculated by the Kalvin formula
  • the height of the spherical crown droplet that is, the liquid film thickness
  • the surface tension of the liquid is an important factor determining whether the liquid can spread on the surface of the metal. The smaller the surface tension, the smaller the contact angle, the easier it is to spread and contribute to the liquid. But the surface tension has passed Small, it will lead to the loss of liquid.
  • the ultrasonic sprayer atomizes the dissolved genetic material into small droplets with a diameter of 18 - 48 ⁇
  • Each droplet contains genetic material and solvent molecules. Each genetic material is surrounded by a plurality of solvent molecules. When the droplets are sprayed on the surface of the stent, the molecular material molecules can be dispersed into the micropores, as shown in FIG.
  • the main purpose of introducing micro-blind holes on the surface of the stent is to carry the cargo mainly by three aspects: 1.
  • the micro-blind hole itself directly loads a part of the genetic material; 2.
  • the roughness of the surface of the stent is increased; Free energy of the surface of the stent.
  • small droplets continuously land on the surface of the stent. Due to the large surface energy of the micro-blind hole holder, the genetic material is easily adsorbed, and a thin liquid film is formed on the surface of the stent, and the thickness of the thin liquid film depends on Surface tension of the liquid,
  • the droplet can overcome the surface tension into the micro-blind hole.
  • the beneficial effects of the present invention are that the genetic material can be effectively and accurately applied to the surface of the micro-blind hole holder by computer program control. High degree of automation, good repeatability, and large-scale processing.
  • Figure 1 and Figure 2 are schematic diagrams of the spraying machine (DES_2000);
  • Figure 3 Ultrasonic atomization particle size distribution;
  • Figure 4 Wet angle ⁇ ;
  • Figure 5 Small droplets of genetic material and solvent mixture;
  • micro blind hole bracket 4 micro blind hole bracket 4, bracket fixture 5, bracket thruster 6, coating solution pool joints 7, coating solution pool 8, solution high pressure propeller.
  • [25] Prepare a 2mg/ml solution of the genetic material in ultrapure water, dissolve it thoroughly, and add sucrose to make the sucrose concentration in the solution reach 1.1%. Put the prepared solution into the coating solution tank 8 and use a tetrafluoroethylene hose. Connecting the nozzle joint 2 and the coating solution pool joint 7; mounting the micro-blind hole blood vessel support 4 on the bracket clamp 5; starting the spraying system, the power of the ultrasonic generator 1, the advancement speed of the stent pusher 6, and the coating solution advancement The advancement speed of the device 9 is set such that the micro-blind hole holder 4 is reciprocated from the nozzle 3 multiple times to achieve the desired genetic material load. Repeated spraying should be performed after the micro-blind hole holder 4 is naturally dried.

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Abstract

L'invention concerne un procédé de préparation d'un matériel génétique porté par un support microporeux caractérisé en ce qu'il dissout le matériel génétique porté à température ambiante et qu'il ajoute une quantité adéquate de protecteur d'activité génétique; un équipement de micro-atomisation ultrasonique, de pressurisation et de pulvérisation est utilisé pour effectuer une pulvérisation afin de faire entrer le matériel génétique dans les micropores et de recouvrir la surface du support avec le matériel génétique. L'invention utilise un support microporeux pour porter un matériel génétique ce qui lui permet, sur le plan clinique, d'avoir un effet dans l'endothélialisation rapide de matériel génétique, et ainsi, d'améliorer un effet thérapeutique. D'une part, le matériel génétique porté est dissout à température ambiante et une quantité adéquate de protecteur d'activité génétique est ajoutée, ce qui garantit un effet normal du matériel génétique. D'autre part, l'utilisation d'une méthode de micro-atomisation par onde ultrasonique, de pressurisation et de pulvérisation permet de recouvrir le support microporeux de matériel génétique, ce qui permet de contrôler la quantité de matériel génétique sur la surface de chaque support, et ainsi, la reproductibilité est élevée.
PCT/CN2008/072887 2008-10-31 2008-10-31 Procédé de préparation d'un matériel génétique porté par un support microporeux WO2010048757A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2008/072887 WO2010048757A1 (fr) 2008-10-31 2008-10-31 Procédé de préparation d'un matériel génétique porté par un support microporeux

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2008/072887 WO2010048757A1 (fr) 2008-10-31 2008-10-31 Procédé de préparation d'un matériel génétique porté par un support microporeux

Publications (1)

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WO2010048757A1 true WO2010048757A1 (fr) 2010-05-06

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001074413A1 (fr) * 2000-04-04 2001-10-11 Boston Scientific Limited Dispositifs medicaux convenant a des schemas posologiques de therapie genique
CN1605366A (zh) * 2004-12-03 2005-04-13 北京美中双和医疗器械有限公司 一种开有非穿透性槽或盲孔的血管支架及其制作方法
US20050271696A1 (en) * 2004-05-27 2005-12-08 Dinh Thomas Q Medical device having a surface including a biologically active agent therein, and methods
CN1827178A (zh) * 2006-01-20 2006-09-06 重庆大学 药物洗脱性血管内支架喷涂方法及其喷涂装置
CN1919353A (zh) * 2006-08-14 2007-02-28 董何彦 金属支架表面微盲孔载药层的制作方法
CN101209360A (zh) * 2006-12-29 2008-07-02 微创医疗器械(上海)有限公司 一种生物支架的制备方法
CN101279111A (zh) * 2008-05-15 2008-10-08 哈尔滨工程大学 一种聚酯类药物洗脱性涂层血管支架的制备方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001074413A1 (fr) * 2000-04-04 2001-10-11 Boston Scientific Limited Dispositifs medicaux convenant a des schemas posologiques de therapie genique
US20050271696A1 (en) * 2004-05-27 2005-12-08 Dinh Thomas Q Medical device having a surface including a biologically active agent therein, and methods
CN1605366A (zh) * 2004-12-03 2005-04-13 北京美中双和医疗器械有限公司 一种开有非穿透性槽或盲孔的血管支架及其制作方法
CN1827178A (zh) * 2006-01-20 2006-09-06 重庆大学 药物洗脱性血管内支架喷涂方法及其喷涂装置
CN1919353A (zh) * 2006-08-14 2007-02-28 董何彦 金属支架表面微盲孔载药层的制作方法
CN101209360A (zh) * 2006-12-29 2008-07-02 微创医疗器械(上海)有限公司 一种生物支架的制备方法
CN101279111A (zh) * 2008-05-15 2008-10-08 哈尔滨工程大学 一种聚酯类药物洗脱性涂层血管支架的制备方法

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