WO2024031883A1 - 桂皮醛的应用及组织工程支架 - Google Patents

桂皮醛的应用及组织工程支架 Download PDF

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WO2024031883A1
WO2024031883A1 PCT/CN2022/136766 CN2022136766W WO2024031883A1 WO 2024031883 A1 WO2024031883 A1 WO 2024031883A1 CN 2022136766 W CN2022136766 W CN 2022136766W WO 2024031883 A1 WO2024031883 A1 WO 2024031883A1
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scaffold
bone
tissue engineering
cinnamaldehyde
osteosclerosis
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French (fr)
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王新峦
秦岭
孟祥波
曹会娟
李玲
黄翠珊
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Shenzhen Institute of Advanced Technology of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • This application belongs to the technical field of medical applications, and particularly relates to the application of cinnamic aldehyde and tissue engineering scaffolds.
  • osteosclerosis also known as hyperosteosclerosis
  • soft tissues such as cartilage, intervertebral discs, and ligaments that make up joints due to bone hyperplasia, the formation of bone spurs at the edges of joints, and synovial hypertrophy. Bone collapse occurs, followed by subchondral bone sclerosis.
  • osteosclerosis There are many causes of osteosclerosis. Current research shows that in addition to osteoarthritis, it may also be related to genetic factors.
  • Osteoarthritis also known as degenerative arthritis, is the most common joint disease. Its lesions mainly include cartilage degeneration, subchondral bone changes, and synovial inflammation. The pathogenesis of OA is currently unclear, but relevant studies have reported that subchondral bone sclerosis may be the initiating factor of OA. Subchondral bone serves as a structural beam and shock absorber for adjacent articular cartilage. Abnormal bone formation and sclerosis enhance the strength and stiffness of subchondral bone, but reduce elastic deformation and impact absorption capacity, resulting in uneven distribution of mechanical stress or in articular cartilage.
  • Overload causes the cartilage to undergo abnormal stress and damage, causing changes in the joint cartilage structure and progressive aggravation, accelerating the occurrence and development of OA.
  • Subchondral bone sclerosis as a cause of OA, causes cartilage degeneration, and cartilage degeneration reacts on the subchondral bone, further aggravating subchondral bone sclerosis, which in turn aggravates cartilage degeneration, and ultimately accelerates the progression of OA. Therefore, developing drugs that regulate subchondral bone metabolism and remodeling and improve subchondral bone sclerosis will open up a new way to prevent and treat OA.
  • Cinnamaldehyde also known as cinnamic aldehyde, phenylpropenal and cinnamic aldehyde
  • Cinnamaldehyde is the main component of the volatile oil of cassia twig or cinnamon. It is a light yellow oily liquid with a strong cinnamon smell.
  • cinnamic aldehyde at home and abroad have shown that it has various pharmacological activities such as anti-inflammatory, antipyretic and analgesic, anti-tumor, antibacterial, hypoglycemic, anti-obesity, etc.
  • the purpose of this application is to provide an application of cinnamic aldehyde and a tissue engineering scaffold, aiming to solve the technical problem of how to prevent and treat bone sclerosis in an inflammatory environment.
  • this application provides any of the following applications of cinnamic aldehyde:
  • bone sclerosis includes subchondral bone sclerosis.
  • bone sclerosis includes bone sclerosis caused by osteoarthritis or bone sclerosis caused by genetic factors.
  • osteosclerosis includes osteosclerosis of new bone or osteosclerosis of host bone.
  • the medical device product includes a tissue engineering scaffold containing cinnamic aldehyde.
  • the medical device product is a tissue engineering scaffold containing cinnamaldehyde.
  • the tissue engineering scaffold is a three-dimensional porous scaffold.
  • the three-dimensional porous scaffold includes a degradable organic and inorganic scaffold material and cinnamaldehyde loaded in the degradable organic and inorganic scaffold material.
  • the degradable organic-inorganic scaffold material includes polylactic acid-co-glycolic acid and ⁇ -tricalcium phosphate.
  • the mass ratio of the degradable organic-inorganic scaffold material to cinnamaldehyde is 1g: 4-6mg; and/or,
  • the porosity of tissue engineering scaffolds is 67 to 75%.
  • this application also provides a tissue engineering scaffold for treating, preventing, alleviating or resisting bone sclerosis in an inflammatory environment.
  • the tissue engineering scaffold is a three-dimensional porous scaffold.
  • the three-dimensional porous scaffold includes degradable organic and inorganic scaffold materials and a degradable load. Cinnamaldehyde in organic-inorganic scaffold materials.
  • the degradable organic-inorganic scaffold material includes polylactic acid-glycolic acid copolymer and ⁇ -tricalcium phosphate; and/or,
  • the mass ratio of the three-dimensional degradable polymer scaffold material to the cinnamic aldehyde is 1g: 4-6mg; and/or,
  • the porosity of tissue engineering scaffolds is 67 to 75%.
  • cinnamic aldehyde that is, pharmaceutical and device products made from cinnamic aldehyde can effectively treat, prevent, alleviate or resist bone sclerosis in an inflammatory environment. Therefore, cinnamic aldehyde can be used to prepare pharmaceutical and device products related to osteosclerosis. It has good clinical application prospects.
  • This application provides a tissue engineering scaffold, which includes a degradable organic and inorganic scaffold material and cinnamaldehyde loaded in the degradable organic and inorganic scaffold material.
  • the tissue engineering scaffold containing cinnamaldehyde provided by this application can effectively treat, prevent, alleviate or It resists bone sclerosis in an inflammatory environment and therefore has good clinical application prospects.
  • Figure 1 is a micro-CT image of a tissue engineering scaffold containing cinnamaldehyde provided by an embodiment of the present application
  • Figure 2 is a quantitative analysis area of interest of the tissue engineering scaffold containing cinnamic aldehyde provided by the embodiment of the present application;
  • Figure 3 is a diagram of the bone regeneration effect of the tissue engineering scaffold containing cinnamic aldehyde in an inflammatory environment and a non-inflammatory environment provided by the embodiment of the present application.
  • the size of the sequence numbers of the above-mentioned processes does not mean the order of execution. Some or all steps can be executed in parallel or one after another. The execution order of each process should be based on its function and order. The internal logic is determined and should not constitute any limitation on the implementation process of the embodiments of the present application.
  • weights of relevant components mentioned in the description of the embodiments of the present application may not only refer to the specific content of each component, but also represent the proportional relationship of weight between the components. Therefore, as long as the relevant components are combined according to the description of the embodiments of the present application, Any scaling up or down of the content is within the scope disclosed in the examples of this application.
  • the mass described in the description of the embodiments of this application may be mass units well known in the chemical industry such as ⁇ g, mg, g, kg, etc.
  • Cinnamaldehyde The English name of cinnamaldehyde is: Cinnamaldehyde, with a molecular formula of C 9 H 8 O. Cinnamaldehyde can be isolated from plants. Its chemical structure is as follows:
  • Pharmaceutical and device products refer to medical products that are composed of drugs and medical devices (such as tissue engineering materials) and are produced as a single entity.
  • a new use of cinnamic aldehyde was unexpectedly discovered. That is, cinnamic aldehyde can be made into medicinal and mechanical products that can effectively treat, prevent, alleviate or resist osteosclerosis in an inflammatory environment. Therefore, cinnamic aldehyde can be used to prepare osteosclerosis.
  • Related pharmaceutical and device products have good clinical application prospects.
  • osteosclerosis that is effectively treated, prevented, alleviated or counteracted may be osteosclerosis in an inflammatory environment.
  • osteosclerosis includes osteosclerosis caused by osteoarthritis or osteosclerosis caused by genetic factors.
  • factors that cause bone stress in an inflammatory environment such as osteoarthritis or genetic factors, and the present application
  • Related pharmaceutical and device products prepared from cinnamic aldehyde can treat, prevent, alleviate or resist bone sclerosis caused by various factors. It should be noted that osteosclerosis referred to in this application generally refers to bone sclerosis in mammals and humans.
  • osteosclerosis includes osteosclerosis of new bone or osteosclerosis of host bone.
  • This application finds for the first time that pharmaceutical and device products prepared from cinnamic aldehyde can promote subchondral bone regeneration in an inflammatory environment, and have the effect of treating, preventing, alleviating or resisting osteoarthritis or bone sclerosis caused by factors such as genetic factors. It can be used to treat osteosclerosis and subchondral bone regeneration caused by arthritis.
  • cinnamic aldehyde can promote subchondral bone regeneration in an inflammatory environment, and can be used to treat, prevent, alleviate or resist bone damage in an inflammatory environment. hardening.
  • the results show that cinnamic aldehyde can significantly increase the bone mass of new bone in the defect area in both inflammatory and non-inflammatory environments, and the bone density of new bone in the inflammatory environment is close to the bone density of new bone in the non-inflammatory environment. It can effectively alleviate or inhibit osteosclerosis of new bone; in addition, it can also effectively prevent, alleviate or resist osteosclerosis of host bone in osteoarthritis.
  • the pharmaceutical and device product related to osteoporosis includes a tissue engineering scaffold containing cinnamic aldehyde.
  • the medical device product may be a drug-loaded tissue engineering scaffold containing cinnamic aldehyde.
  • the tissue engineering scaffold is a three-dimensional porous scaffold, and the three-dimensional porous scaffold includes degradable organic and inorganic scaffold materials and cinnamic aldehyde loaded in the degradable organic and inorganic scaffold materials.
  • degradable organic and inorganic scaffold materials include polylactic acid-co-glycolic acid (PLGA) and ⁇ -tricalcium phosphate ( ⁇ -TCP).
  • PLGA polylactic acid-co-glycolic acid
  • ⁇ -TCP ⁇ -tricalcium phosphate
  • the preparation method of the drug-loaded tissue engineering scaffold containing cinnamic aldehyde includes: using 1,4-dioxane as the solvent, PLGA (75/25) and ⁇ -TCP as the materials, and preparing the load through low-temperature 3D printing technology Cinnamaldehyde tissue engineering scaffold (PLGA/ ⁇ -TCP/CIN scaffold).
  • the tissue engineering scaffold obtained in this way has uniform pore size, good scaffold connectivity, and high porosity.
  • the mass ratio of the three-dimensional degradable polymer scaffold material and cinnamaldehyde is 1g:4-6mg, and the porosity of the tissue engineering scaffold is 67-75%.
  • the tissue engineering scaffold obtained in this way can better release cinnamic aldehyde.
  • the PLGA/ ⁇ -TCP/CIN scaffold was implanted into a New Zealand white rabbit animal model with osteochondral defects of osteoarthritis. After 16 weeks of implantation, the knee joint was removed and fixed with formalin. , evaluate the bone mass and bone density of new bone in the defect area through micro-CT and histology. Studies have found that the PLGA/ ⁇ -TCP/CIN scaffold can effectively promote bone regeneration of subchondral bone in defective areas and effectively inhibit bone sclerosis caused by arthritis.
  • the second aspect of the embodiment of the present application provides a tissue engineering scaffold for treating, preventing, alleviating or resisting bone sclerosis in an inflammatory environment.
  • the tissue engineering scaffold is a three-dimensional porous scaffold.
  • the three-dimensional porous scaffold includes degradable organic and inorganic scaffold materials and a degradable load. Cinnamaldehyde in organic-inorganic scaffold materials.
  • the tissue engineering scaffold provided by the embodiments of the present application includes a degradable organic and inorganic scaffold material and cinnamaldehyde loaded in the degradable organic and inorganic scaffold material.
  • the cinnamaldehyde-containing tissue engineering scaffold can effectively treat, prevent, alleviate or resist inflammation. osteosclerosis in the environment and, therefore, has good clinical application prospects.
  • the degradable organic and inorganic scaffold material includes polylactic acid-glycolic acid copolymer and ⁇ -tricalcium phosphate; the mass ratio of the three-dimensional degradable polymer scaffold material and cinnamaldehyde is 1g:4-6mg; tissue engineering scaffold The porosity is 67-75%.
  • tissue engineering scaffold loaded with cinnamic aldehyde was prepared through low-temperature 3D printing technology.
  • the cinnamic aldehyde used in this example was purchased from Chengdu Refens Biotechnology Co., Ltd. It is a light yellow liquid with a molecular weight of 132.16, product number: 104-55-2, and purity: ⁇ 98%.
  • the cinnamic aldehyde used in this example was diluted with dimethyl sulfoxide (DMSO) to prepare a 75 mg/ml cinnamic aldehyde solution as a storage solution, which was stored in a refrigerator at 4°C until use.
  • DMSO dimethyl sulfoxide
  • Polylactic acid-glycolic acid copolymer (PLGA (75/25)) has a molecular weight of 150,000 Daltons and was purchased from Shandong Academy of Pharmaceutical Sciences; ⁇ -tricalcium phosphate ( ⁇ -TCP), biomedical grade, particle size ⁇ 30 ⁇ m, Purity >98%, purchased from Aladdin Reagent (Shanghai) Co., Ltd.
  • 3D printing After pre-cooling the temperature of the 3D printer to -30°C, pour the above-prepared ink into the silo, use a hose to connect the silo to the printer, and prepare the medicated tissue engineering scaffold according to the set parameters; the entire The printing process is carried out at -30°C to ensure the activity of the drug molecules in the slurry.
  • the biphasic scaffold After printing, the biphasic scaffold is placed in a freeze dryer and freeze-dried under vacuum conditions for 72 hours to remove the organic solvent in the material to obtain a tissue engineering scaffold containing cinnamic aldehyde (i.e., PLGA/ ⁇ -TCP/CIN scaffold) .
  • a cinnamaldehyde-free scaffold (PLGA/ ⁇ -TCP scaffold) can be prepared with the same parameters and methods.
  • the prepared tissue engineering scaffold containing cinnamic aldehyde (PLGA/ ⁇ -TCP/CIN scaffold) was scanned using micro-CT, and the results are shown in Figure 1.
  • the front and side pore diameter, porosity, and connectivity were quantitatively analyzed. The results are shown in Table 1 below.
  • the cinnamaldehyde-containing tissue engineering scaffold prepared in Example 1 was implanted into the osteochondral defect site with arthritis, and its ability to resist inflammation and promote osteochondral regeneration in vivo was evaluated.
  • the New Zealand white rabbits were euthanized, the femurs were removed, fixed in formalin for 48 hours, and stored in 75% alcohol for long-term storage.
  • the bone mass and bone density of the new bone in the defect site were evaluated by micro-CT.
  • Scanning equipment Skyscan1176, scanning parameters: voltage: 70kv, current: 114 ⁇ A, resolution: 16.4 ⁇ m, filter: Al 1.0mm; reconstruct the image after the scan is completed; use Data viewer software to adjust the analysis angle of the defective part; use CT-An The software selects the area of interest for analysis, and analyzes the bone volume and density of new bone in the defective area; use CT-vol software to color and save the analysis pictures; alternatively, the femoral trochlea (3.2 ⁇ 3.0mm) without defect area analyzes the host bone The bone mass and bone density are shown in Figure 2. Finally, the change data of bone mass of host bone and new bone in each group in non-inflammatory environment (Non-OA) and inflammatory environment (OA) are shown in Table 2.
  • Non-OA non-inflammatory environment
  • OA inflammatory environment
  • a vs Control, p ⁇ 0.05
  • b vs PLGA/ ⁇ -TCP, p ⁇ 0.05
  • OA inflammatory environment
  • Non-OA non-inflammatory environment
  • Table 3 shows the statistical data.
  • the results show that the inflammatory environment (OA) produced by papain can significantly increase the bone density of the host bone and new bone, leading to osteosclerosis; compared with the no-scaffold group (Control) and the drug-free scaffold group (PLGA/ ⁇ -TCP) Compared with the inflammatory environment, the bone density of the drug-containing scaffold group (PLGA/ ⁇ -TCP/CIN) was significantly reduced, and its value was close to the bone density in the non-inflammatory environment, which shows that: in the drug-loaded tissue engineering scaffold group Cinnamaldehyde works together with tissue engineering scaffold materials of polylactic acid-glycolic acid copolymer and ⁇ -tricalcium phosphate to effectively treat, prevent, alleviate or resist osteosclerosis of new bone and host bone in an inflammatory environment.
  • a vs Control, p ⁇ 0.05
  • b vs PLGA/ ⁇ -TCP, p ⁇ 0.05
  • # OA vs Non-OA, p ⁇ 0.05

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Abstract

本申请涉及医药用途技术领域，尤其涉及一种桂皮醛的应用及组织工程支架，具体是桂皮醛的下述任一应用：1)制备治疗炎症环境中骨硬化的药械产品中的应用；2)制备预防炎症环境中骨硬化的药械产品中的应用；3)制备缓解炎症环境中骨硬化的药械产品中的应用；4)制备抵抗炎症环境中骨硬化的药械产品中的应用。本申请发现了桂皮醛制成的药械产品可以有效治疗、预防、缓解和抵抗炎症环境中骨硬化，因此，桂皮醛可以用于制备炎症环境中骨硬化相关的药械产品，在临床上具有很好的应用前景。

Description

桂皮醛的应用及组织工程支架 技术领域
本申请属于医药用途技术领域，尤其涉及一种桂皮醛的应用及组织工程支架。
背景技术
在组织病理学中，骨硬化又称骨质增生硬化(Hyperosteosclerosis)，是指由于骨质增生构成关节的软骨、椎间盘、韧带等软组织变性、退化，关节边缘形成骨刺，滑膜肥厚等变化，而出现骨质塌陷，随后则出现软骨下骨硬化现象。骨硬化的原因有多种，目前研究可知除了骨性关节炎导致外，还可能与遗传因素导致有关。
骨关节炎(Osteoarthritis，OA)又称为退行性关节炎，是最常见的关节疾病，其病变主要包括软骨退变、软骨下骨的改变和滑膜的炎症。目前OA的发病机理尚不明确，相关研究报道软骨下骨硬化可能是OA的始发因素。软骨下骨作为结构梁和相邻关节软骨的减震器，异常的骨形成和硬化增强软骨下骨的强度和刚度，但减少弹性变形和冲击吸收能力，导致机械应力分布不均或在关节软骨过度负荷，使软骨承受异常应力并损伤，从而引起关节软骨结构发生改变并进行性加重，加速OA的发生与发展。软骨下骨硬化作为OA的一种病因导致软骨的退变，软骨退变又反作用于软骨下骨，致使软骨下骨硬化进一步加剧，进而又加重软骨的退化，最终加速OA的进程。因此，开发调控软骨下骨代谢和重塑的药物，改善软骨下骨硬化，将为OA防治开辟一条新途径。
桂皮醛又名肉桂醛、苯丙烯醛、桂醛，是桂枝或肉桂挥发油的主要成分，呈浅黄色油状液体，有强烈的肉桂气味。国内外对桂皮醛的大量研究表明，其具有抗炎、解热镇痛、抗肿瘤、抗菌、降糖、抗肥胖等多种药理活性，但其在 骨硬化方面的功效未见相关报道。
发明内容
本申请的目的在于提供一种桂皮醛的应用和组织工程支架，旨在解决如何防治炎症环境中骨硬化的技术问题。
为实现上述申请目的，本申请采用的技术方案如下：
第一方面，本申请提供一种桂皮醛的下述任一应用：
制备治疗炎症环境中骨硬化的药械产品中的应用；
制备预防炎症环境中骨硬化的药械产品中的应用；
制备缓解炎症环境中骨硬化的药械产品中的应用；
制备抵抗炎症环境中骨硬化的药械产品中的应用。
在一实施例中，骨硬化包括软骨下骨硬化。
在一实施例中，骨硬化包括骨性关节炎引起的骨硬化或遗传因素引起的骨硬化。
在一实施例中，骨硬化包括新生骨的骨硬化或宿主骨的骨硬化。
在一实施例中，药械产品包括含有桂皮醛的组织工程支架。
在一实施例中，药械产品为含有桂皮醛的组织工程支架，组织工程支架为三维多孔支架，三维多孔支架包括可降解有机无机支架材料和负载在可降解有机无机支架材料中的桂皮醛。
在一实施例中，可降解有机无机支架材料包括聚乳酸-羟基乙酸共聚物和β-磷酸三钙。
在一实施例中，可降解有机无机支架材料与桂皮醛的质量比为1g：4～6mg；和/或，
组织工程支架的孔隙率为67～75％。
第二方面，本申请还提供一种治疗、预防、缓解或抵抗炎症环境中骨硬化的组织工程支架，组织工程支架为三维多孔支架，三维多孔支架包括可降解有 机无机支架材料和负载在可降解有机无机支架材料中的桂皮醛。
在一实施例中，可降解有机无机支架材料包括聚乳酸-羟基乙酸共聚物和β-磷酸三钙；和/或，
三维可降解高分子支架材料与所述桂皮醛的质量比为1g：4～6mg；和/或，
组织工程支架的孔隙率为67～75％。
本申请发现了桂皮醛的新用途，即桂皮醛制成的药械产品可以有效治疗、预防、缓解或和抵抗炎症环境中的骨硬化，因此，桂皮醛可以用于制备骨硬化相关的药械产品，在临床上具有很好的应用前景。
本申请提供一种组织工程支架，包括可降解有机无机支架材料和负载在可降解有机无机支架材料中的桂皮醛，本申请提供的含桂皮醛的组织工程支架可以有效治疗、预防、缓解或和抵抗炎症环境中的骨硬化，因此，在临床上具有很好的应用前景。
附图说明
为了更清楚地说明本申请实施例中的技术方案，下面将对实施例描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本申请的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1是本申请实施例提供的含有桂皮醛的组织工程支架micro-CT图；
图2是本申请实施例提供的含有桂皮醛的组织工程支架的定量分析兴趣区；
图3是本申请实施例提供的含有桂皮醛的组织工程支架在炎性环境和非炎性环境中的骨再生效果图。
具体实施方式
为了使本申请要解决的技术问题、技术方案及有益效果更加清楚明白，以 下结合实施例，对本申请进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本申请，并不用于限定本申请。
应理解，在本申请的各种实施例中，上述各过程的序号的大小并不意味着执行顺序的先后，部分或全部步骤可以并行执行或先后执行，各过程的执行顺序应以其功能和内在逻辑确定，而不应对本申请实施例的实施过程构成任何限定。
在本申请实施例中使用的术语是仅仅出于描述特定实施例的目的，而非旨在限制本申请。在本申请实施例和所附权利要求书中所使用的单数形式的“一种”、“所述”和“该”也旨在包括多数形式，除非上下文清楚地表示其他含义。
本申请实施例说明书中所提到的相关成分的重量不仅仅可以指代各组分的具体含量，也可以表示各组分间重量的比例关系，因此，只要是按照本申请实施例说明书相关组分的含量按比例放大或缩小均在本申请实施例说明书公开的范围之内。具体地，本申请实施例说明书中所述的质量可以是μg、mg、g、kg等化工领域公知的质量单位。
本申请实施例第一方面提供桂皮醛的下述任一应用：
1)制备治疗炎症环境中骨硬化的药械产品中的应用；
2)制备预防炎症环境中骨硬化的药械产品中的应用；
3)制备缓解炎症环境中骨硬化的药械产品中的应用；
4)制备抵抗炎症环境中骨硬化的药械产品中的应用。
桂皮醛的英文名为：Cinnamaldehyde，分子式C 9H 8O，桂皮醛可以从植物中分离得到，化学结构如下：
Figure PCTCN2022136766-appb-000001
药械产品系指由药品与医疗器械(如组织工程材料)共同组成，并作为一 个单一实体生产的医疗产品。本申请实施例中，意外地发现了桂皮醛的新用途，即桂皮醛制成药械产品可以有效治疗、预防、缓解或和抵抗炎症环境中的骨硬化，因此，桂皮醛可以用于制备骨硬化相关的药械产品，在临床上具有很好的应用前景。
具体地，有效治疗、预防、缓解或和抵抗的骨硬化可以是炎症环境中的骨硬化。进一步地，骨硬化包括骨性关节炎引起的骨硬化或遗传因素引起的骨硬化，基于引起炎症环境中的骨应化的因素有多种，如骨性关节炎或者遗传因素，而本申请的桂皮醛制备的相关药械产品可以治疗、预防、缓解或和抵抗多种因素导致的骨硬化。需要说明的是，本申请中所指的骨应化一般是指哺乳动物和人中的骨硬化。
在一实施例中，骨硬化包括新生骨的骨硬化或宿主骨的骨硬化。
本申请首次发现桂皮醛制备的药械产品能够促进炎症环境中软骨下骨再生，具有治疗、预防、缓解或抵抗骨性关节炎或遗传因素等因素引起的骨硬化的作用。可用于治疗关节炎引起的骨硬化和软骨下骨再生。
本申请实施例采用患有骨性关节炎骨软骨缺损的新西兰大白兔动物模型来证明桂皮醛能够在炎症环境中促进软骨下骨再生，并且可用于治疗、预防、缓解或抵抗炎症环境中的骨硬化。结果显示，桂皮醛在炎性环境和非炎性环境中均能够显著增加缺损部位新生骨的骨量，并且炎性环境中新生骨的骨密度接近于非炎性环境中新生骨的骨密度，有效缓解或抑制新生骨的骨硬化；除此之外，还可以有效预防、缓解或和抵抗骨性关节炎中宿主骨的骨硬化。
在一实施例中，与骨应化相关的药械产品包括含有桂皮醛的组织工程支架。
具体地，该药械产品可以是含有桂皮醛的载药组织工程支架。该组织工程支架为三维多孔支架，三维多孔支架包括可降解有机无机支架材料和负载在可降解有机无机支架材料中的桂皮醛。
进一步地，可降解有机无机支架材料包括聚乳酸-羟基乙酸共聚物(PLGA)和β-磷酸三钙(β-Tricalcium phosphate，β-TCP)。
具体地，含有桂皮醛的载药组织工程支架的制备方法包括：以1,4-二氧六环为溶剂，以PLGA(75/25)和β-TCP为材料，通过低温3D打印技术制备负载桂皮醛的组织工程支架(PLGA/β-TCP/CIN支架)。这样得到的组织工程支架的孔径大小均匀、支架连通性好，孔隙率高。具体地，三维可降解高分子支架材料与桂皮醛的质量比为1g：4～6mg，组织工程支架的孔隙率为67～75％。这样得到的组织工程支架可以更好地释放桂皮醛。
本申请实施例中，将PLGA/β-TCP/CIN支架植入患有骨性关节炎的骨软骨缺损的新西兰大白兔动物模型，植入16周后，取出膝关节，使用福尔马林固定，通过micro-CT和组织学评价缺损部位新生骨的骨量和骨密度。研究发现，PLGA/β-TCP/CIN支架能够有效促进缺损部位软骨下骨的骨再生，并且有效抑制关节炎引起的骨硬化。
本申请实施例第二方面提供一种治疗、预防、缓解或抵抗炎症环境中骨硬化的组织工程支架，组织工程支架为三维多孔支架，三维多孔支架包括可降解有机无机支架材料和负载在可降解有机无机支架材料中的桂皮醛。
本申请实施例提供的组织工程支架，包括可降解有机无机支架材料和负载在可降解有机无机支架材料中的桂皮醛，该含桂皮醛的组织工程支架可以有效治疗、预防、缓解或和抵抗炎症环境中的骨硬化，因此，在临床上具有很好的应用前景。
在一实施例中，可降解有机无机支架材料包括聚乳酸-羟基乙酸共聚物和β-磷酸三钙；三维可降解高分子支架材料与桂皮醛的质量比为1g：4～6mg；组织工程支架的孔隙率为67～75％。具体地，本申请实施例通过低温3D打印技术制备负载桂皮醛的组织工程支架。
下面结合具体实施例进行说明。
实施例1
实验材料：
本实施例所用桂皮醛购买于成都瑞芬思生物科技有限公司，为淡黄色液体， 分子量为：132.16，产品货号：104-55-2，纯度：≥98％。本实施例用的桂皮醛用二甲基亚砜(DMSO)稀释，配成75mg/ml的桂皮醛溶液作为储存液，于4℃冰箱保存，待用。聚乳酸-羟基乙酸共聚物(PLGA(75/25))分子量为15万道尔顿，购买于山东省药学科学院；β-磷酸三钙(β-TCP)，生物医用级，粒径<30μm，纯度>98％，购买于阿拉丁试剂(上海)有限公司。
含桂皮醛的组织工程支架的制备：
配制PLGA/β-TCP/桂皮醛3D打印“墨水”：称取6.0g PLGA和1.5gβ-TCP置于100mL烧杯中，加入40mL1,4-二氧六环，室温(25～27℃)搅拌12小时，使其溶解。然后，加入500μL浓度为75mg/ml桂皮醛溶液，充分搅拌混合均匀，备用。
3D打印：将3D打印机的温度预冷至-30℃后，将上述配制的墨水倒入料仓，使用软管把料仓与打印机连接，按照设定好的参数制备含药组织工程支架；整个打印过程在-30℃条件下进行，以保证浆料中药物分子的活性。打印完毕后，将双相支架置于冷冻干燥机中，在真空条件下冷冻干燥72小时，去除材料中的有机溶剂，得到含桂皮醛的组织工程支架(即PLGA/β-TCP/CIN支架)。另外，可以相同参数和方法制备得到不含桂皮醛支架(PLGA/β-TCP支架)。
制备得到的含桂皮醛的组织工程支架(PLGA/β-TCP/CIN支架)使用micro-CT扫描，结果如图1所示。扫描设备skyscan1176，扫描参数：电压：40kv，电流：497μA，分辨率：9μm，No filter。扫描后对其正面和侧面孔径、孔隙率、连通性进行定量分析，结果如下表1所示。
表1.含桂皮醛的组织工程支架的正面和侧面孔径、孔隙率、连通性
  正面孔径/μm 侧面孔径/μm 孔隙率/％ 连通率/％
PLGA/β-TCP/CIN 473.17±13.19 265.28±25.51 71.02±3.80 100
实施例2
将实施例1制备得到的含桂皮醛的组织工程支架植入到患有关节炎的骨软骨缺损部位，评价其在体内抗炎和促进骨软骨再生的能力。
首先，24只新西兰大白兔右侧膝关节注射0.2mL浓度为12.5mg/mL的木瓜蛋白酶，构建关节炎动物模型，左侧膝关节注射相同体积的生理盐水，作对照组；然后，在股骨滑车中心建立3.2×3.0mm的骨缺损模型，随机分为3组(n＝8)：(1)无支架组(control)，(2)不含药的组织工程支架组(PLGA/β-TCP)，(3)载药的组织工程支架组(PLGA/β-TCP/CIN)。16周后，安乐死新西兰大白兔，取出股骨福尔马林固定48小时后，换75％酒精长期保存，通过micro-CT评价缺损部位新生骨的骨量和骨密度。扫描设备：Skyscan1176，扫描参数：电压：70kv，电流：114μA，分辨率：16.4μm，滤片：Al 1.0mm；扫描完成后重建生成图片；用Data viewer软件调整缺损部位分析角度；用CT-An软件选择兴趣区进行分析，分析缺损部位新生骨的骨量及新生骨密度；使用CT-vol软件对分析图片进行着色并保存；另选，股骨滑车(3.2×3.0mm)无缺损区域分析宿主骨的骨量及骨密度，如图2所示。最终，各组宿主骨和新生骨在非炎性环境(Non-OA)和炎性环境(OA)中骨量的变化数据如表2所示，各组宿主骨和新生骨在非炎性环境(Non-OA)和炎性环境(OA)中骨密度的变化数据如表3所示。结果显示：载药的组织工程支架组(PLGA/β-TCP/CIN)缺损部位新生骨的骨量均明显高于无支架组(Control)和不含药的组织工程支架组(PLGA/β-TCP)；各组间宿主骨的骨量无显著差异(p>0.05)。
表2.各组宿主骨和新生骨在非炎性环境和炎性环境中骨量的变化
Figure PCTCN2022136766-appb-000002
a:vs Control,p<0.05；b:vs PLGA/β-TCP,p<0.05；
在炎性环境(OA)和非炎性环境(Non-OA)中的骨密度的变化结果如图3所示，表3为统计数据。结果显示：木瓜蛋白酶产生的炎性环境(OA)可显著增加宿主骨和新生骨的骨密度，形成骨硬化；与无支架组(Control)和不含药支架组(PLGA/β-TCP)相比，炎性环境中含药支架组(PLGA/β-TCP/CIN)的骨密度显著降低，并且其数值接近于非炎性环境中的骨密度，这表明：载药的组织工程支架组中的桂皮醛与聚乳酸-羟基乙酸共聚物和β-磷酸三钙的组织工程支架材料共同作用，可有效治疗、预防、缓解或抵抗炎性环境中的新生骨和宿主骨的骨硬化。
表3.各组宿主骨和新生骨在非炎性环境和炎性环境中骨密度的变化
Figure PCTCN2022136766-appb-000003
a:vs Control,p<0.05；b:vs PLGA/β-TCP,p<0.05；#:OA vs Non-OA,p<0.05；
以上所述仅为本申请的较佳实施例而已，并不用以限制本申请，凡在本申请的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本申请的保护范围之内。

Claims (10)

  1. 桂皮醛的下述任一应用：
    制备治疗炎症环境中骨硬化的药械产品中的应用；
    制备预防炎症环境中骨硬化的药械产品中的应用；
    制备缓解炎症环境中骨硬化的药械产品中的应用；
    制备抵抗炎症环境中骨硬化的药械产品中的应用。
  2. 如权利要求1所述的应用，其特征在于，所述骨硬化包括软骨下骨硬化。
  3. 如权利要求1所述的应用，其特征在于，所述骨硬化包括骨性关节炎引起的骨硬化或遗传因素引起的骨硬化。
  4. 如权利要求1所述的应用，其特征在于，所述骨硬化包括新生骨的骨硬化或宿主骨的骨硬化。
  5. 如权利要求1-4任一项所述的应用，其特征在于，所述药械产品包括含有所述桂皮醛的组织工程支架。
  6. 如权利要求5所述的应用，其特征在于，所述药械产品为含有所述桂皮醛的组织工程支架，所述组织工程支架为三维多孔支架，所述三维多孔支架包括可降解有机无机支架材料和负载在所述可降解有机无机支架材料中的所述桂皮醛。
  7. 如权利要求6所述的应用，其特征在于，所述可降解有机无机支架材料包括聚乳酸-羟基乙酸共聚物和β-磷酸三钙。
  8. 如权利要求7所述的应用，其特征在于，所述可降解有机无机支架材料与所述桂皮醛的质量比为1g：4～6mg；和/或，
    所述组织工程支架的孔隙率为67～75％。
  9. 一种治疗、预防、缓解或抵抗炎症环境中骨硬化的组织工程支架，其特征在于，所述组织工程支架为三维多孔支架，所述三维多孔支架包括可降解有机无机支架材料和负载在所述可降解有机无机支架材料中的桂皮醛。
  10. 如权利要求9所述的组织工程支架，其特征在于，所述可降解有机无 机支架材料包括聚乳酸-羟基乙酸共聚物和β-磷酸三钙；和/或，
    所述三维可降解高分子支架材料与所述桂皮醛的质量比为1g：4～6mg；和/或，
    所述组织工程支架的孔隙率为67～75％。
PCT/CN2022/136766 2022-08-10 2022-12-06 桂皮醛的应用及组织工程支架 Ceased WO2024031883A1 (zh)

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