TWI587881B - Self-setting biodegradable bioactive bone graft putty material and application thereof - Google Patents

Self-setting biodegradable bioactive bone graft putty material and application thereof Download PDF

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TWI587881B
TWI587881B TW105123716A TW105123716A TWI587881B TW I587881 B TWI587881 B TW I587881B TW 105123716 A TW105123716 A TW 105123716A TW 105123716 A TW105123716 A TW 105123716A TW I587881 B TWI587881 B TW I587881B
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鐘吉品
常江
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鹽城倍爾生生物科技有限公司
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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
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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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
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • 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
    • A61L27/58—Materials at least partially resorbable by the body

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Description

自固化可降解的生物活性膏劑骨修復材料及應用Self-curing degradable bioactive paste bone repair material and application

本發明關於醫藥生物材料領域，特別是關於一種自固化可降解的生物活性膏劑骨修復材料及應用。 The invention relates to the field of medical biomaterials, in particular to a self-curing degradable bioactive paste bone repairing material and application.

隨著生物科技的發展，醫療器械產業特別是骨科醫療器械技術和產業發展興旺。目前，在骨科椎體成型手術、膝髖關節置換手術中，都需要用骨水泥來起到力學支撐或置換體的固定。椎體成型手術在中國從2010年前每年不到2萬台手術到2015年12萬台手術，預期每年會有15%的增長。椎體成型手術為受害病人椎體因各種原因骨折塌陷導，導致疼痛以及不能正常行動，必須通過手術將塌陷的椎體撐起，使脊椎慢慢恢復正常功能，減輕病人痛苦。在膝髖關節置換手術中，骨水泥用來固定人工膝蓋和髖柄，每年在中國有不低於百萬台的手術。在這些手術中，多年來在國內外填充到塌陷的椎體中，或填充在缺損中來固定人工膝蓋和髖柄用的是生物惰性骨水泥，化學名稱為聚甲基丙烯酸甲酯(polymethyl methacrylate)，代號PMMA。惰性骨水泥能在初期調配成膏體推注入椎體能迅速凝固，並具有強度起到支撐和固定作用。這些手術已很成熟。特別是椎體成型手術是比較典型的現代微創手術，不用開刀，一劑膏體推注到椎體骨折塌陷處，數小時內病人可離開醫院回家療養恢復。但最大問題是惰性骨水泥不降解， 與骨組織也不融合，幾年後，如同一塊硬石頭存在在病人體中，對周圍組織會有破壞作用，存在椎體再次塌陷破裂的可能。基於這一缺點，骨科大夫通常會對年輕或中年的椎體骨折的病人比較慎重，會儘量避免使用惰性骨水泥而採取其它複雜手術辦法來避免將來由惰性骨水泥帶來的問題。 With the development of biotechnology, the medical device industry, especially orthopedic medical device technology and industry, is booming. At present, in orthopedic vertebral body formation surgery and knee hip joint replacement surgery, bone cement is required to fix the mechanical support or the replacement body. Vertebroplasty surgery in China from less than 20,000 operations per year from 2010 to 120,000 operations in 2015, is expected to increase by 15% per year. Vertebral body formation surgery is a fracture of the vertebral body of the victim patient due to various reasons, resulting in pain and failure to operate normally. The collapsed vertebral body must be propped up by surgery to slowly restore the normal function of the spine and relieve the patient's pain. In knee and hip replacement surgery, bone cement is used to fix artificial knees and hip handles, and there are no less than one million operations in China each year. In these procedures, bio-inert bone cement is used to fill the collapsed vertebral body at home and abroad, or to fill the defect to fix the artificial knee and the hip handle. The chemical name is polymethyl methacrylate. ), codenamed PMMA. Inert bone cement can be quickly formulated into the vertebral body by initial blending into a paste, and has strength to support and fix. These operations are very mature. In particular, vertebral body shaping surgery is a typical modern minimally invasive surgery. Without a knife, a dose of paste is injected into the collapse of the vertebral body fracture. Within a few hours, the patient can leave the hospital and go home to recuperate. But the biggest problem is that the inert bone cement does not degrade, It does not fuse with bone tissue. After a few years, like a hard stone exists in the patient's body, it will have a destructive effect on the surrounding tissue, and there is a possibility that the vertebral body will collapse again. Based on this shortcoming, orthopedic doctors are usually more cautious about young or middle-aged patients with vertebral fractures. They will try to avoid using inert bone cement and other complicated surgical procedures to avoid future problems caused by inert bone cement.

目前，在大部分膝髖關節置換手術中需要用惰性骨水泥來固定人工膝和髖關節置換體。由於惰性骨水泥與骨組織不形成骨性結合，一般在十年左右固定會出現鬆動而置換的關節體需要再進行手術翻修，會產生更大缺損。 At present, inert knee cement is required to fix artificial knee and hip joint replacements in most knee arthroplasty operations. Since the inert bone cement does not form a bone bond with the bone tissue, the joint body that is loosened and replaced in a fixed manner for about ten years needs to be re-repaired, resulting in a larger defect.

理想的骨水泥修復材料應為膏體劑型，可推注為最佳；能在合理的時間內凝固逐漸建立起一定的力學強度；基於在骨科手術中的臨床應用，在10分鐘後20分鐘內凝固比較理想；這樣，給予手術醫生有一定時間進行手術準備和操作，又能在骨水泥修復材料被放置在所填充的缺損處後迅速凝固成形；骨水泥修復材料被放置在所填充的缺損處後能在一定時間內，如2星期內達到至少20MPa的抗壓強度；特別重要的是理想的骨水泥修復材料必須具有生物活性及骨傳導性，又能緩慢降解，如2到3年時間完全降解，不能降解太快，否則未能達到支撐作用；也不能不降解，否則會成為一塊硬石頭；緩慢降解的同時，材料由生物活性及骨傳導性會引導本體骨生長，最終，骨水泥修復材料完全降解時，由生長的本體骨完全取而代之。到目前為止，在椎體成型手術、膝髖關節置換手術中和其它骨科手術中還沒有這樣一個理想的材料和產品來取代傳統惰性骨水泥。 The ideal bone cement repair material should be a paste dosage form, which can be pushed to the best; it can establish a certain mechanical strength by solidification in a reasonable time; based on the clinical application in orthopedic surgery, within 20 minutes after 10 minutes Coagulation is ideal; thus, giving the surgeon a certain amount of time for surgical preparation and operation, and rapid solidification after the bone cement repair material is placed in the filled defect; the bone cement repair material is placed in the filled defect After a certain period of time, such as 2 weeks to achieve a compressive strength of at least 20MPa; it is particularly important that the ideal bone cement repair material must have biological activity and osteoconductivity, and can slowly degrade, such as 2 to 3 years completely Degradation, can not degrade too fast, otherwise it can not achieve the supporting effect; it can not be degraded, otherwise it will become a hard stone; while slowly degrading, the material will guide the growth of the body bone by biological activity and osteoconductivity, and finally, bone cement repair When the material is completely degraded, it is completely replaced by the growing body bone. So far, there is no such ideal material and product to replace traditional inert bone cement in vertebroplasty, knee and hip replacement surgery and other orthopedic surgery.

生物活性玻璃材料是目前人工合成的骨修復材料中生物活性最快的材料。生物活性玻璃材料開發出的人工骨修復產品已在全球以及中國在骨科臨床上成功應用20年多。是目前唯一被美國FDA認可的具有骨激發(Osteostmulation)特性的產品，即能促進骨細胞的繁衍和增長，活化骨細 胞的基因表達，這樣加速新骨的形成。目前在國際上生物活性玻璃產品形式為顆粒、塊體以及膏劑型，但都不會凝固來承受重力負荷。當小於50μm的生物活性玻璃與液體混合時，由其表面反應發生Si-O鍵以及水氫鍵的結合能發生凝固，但凝固強度十分微弱。 Bioactive glass materials are the most biologically active materials in synthetic bone repair materials. The artificial bone repair products developed by bioactive glass materials have been successfully applied in orthopedic clinics in the world and in China for more than 20 years. It is currently the only product approved by the US FDA with Osteostmulation, which promotes the proliferation and growth of bone cells and activates bones. The gene expression of the cell accelerates the formation of new bone. Currently, bioactive glass products are in the form of granules, blocks and pastes, but they do not solidify to withstand gravity loads. When the bioactive glass of less than 50 μm is mixed with the liquid, the binding energy of the Si—O bond and the water hydrogen bond is solidified by the surface reaction, but the solidification strength is very weak.

硫酸鈣也是作為骨修復常用的材料。硫酸鈣與液體混合在幾分鐘內凝固，但強度不太理想。最主要不足之處是硫酸鈣降解速度太快，可能在3個月內絕大部分降解而失去了在塌陷缺損處的支撐作用。 Calcium sulfate is also commonly used as a material for bone repair. Calcium sulphate is mixed with the liquid to solidify in a few minutes, but the strength is not ideal. The main disadvantage is that the degradation rate of calcium sulfate is too fast, and most of the degradation may be lost within 3 months and the support at the collapse defect is lost.

矽酸三鈣是著名的波特蘭水泥的主要化學成分。其特點是可凝固成具有較高強度的材料，能成為建築材料被使用。但缺點是凝固時間較長，一般需要1小時以上才能凝固。這在臨床上是不實用的。但在較長的時間結構穩定保持較高的力學強度是作為可負載負荷的骨修復材料如用於椎體成形手術、膝髖關節置換手術以及某些骨折修復是比較需要的。 Tricalcium citrate is the main chemical component of the famous Portland cement. It is characterized by its ability to solidify into a material with high strength and can be used as a building material. However, the disadvantage is that the solidification time is longer, and it usually takes more than 1 hour to solidify. This is not practical in the clinic. However, structural stability and high mechanical strength over a long period of time are required as load-bearing bone repair materials such as for vertebroplasty, knee and hip replacement surgery, and certain fracture repairs.

本發明主要解決的技術問題是提供一種生物活性膏劑骨修復材料及應用，採用生物活性玻璃-半水硫酸鈣-矽酸三鈣三元系統，具有更為理想的可推注自固化可吸收性，能作為骨修復替代材料用於椎體成型手術、膝髖關節置換手術以及其它一些骨折手術中的應用。 The technical problem mainly solved by the invention is to provide a bioactive paste bone repairing material and application thereof, and adopting a biologically active glass-calcium sulfate hemihydrate-tricalcium ternate system, which has better ideal self-curing absorbability. It can be used as an alternative material for bone repair in vertebral body shaping surgery, knee hip replacement surgery and other fracture operations.

為解決上述技術問題，本發明採用的一個技術方案是：提供一種自固化可降解的生物活性膏劑骨修復材料，包括混合固體材料和液相，所述混合固體材料包括生物活性玻璃、半水硫酸鈣和矽酸三鈣，所述液相包括調和液。 In order to solve the above technical problem, the present invention adopts a technical solution to provide a self-curing degradable bioactive paste bone repair material, including a mixed solid material and a liquid phase, the mixed solid material including bioactive glass, hemihydrate sulfuric acid. Calcium and tricalcium citrate, the liquid phase comprising a blending liquid.

在本發明一個較佳實施例中，所述混合固體材料的組成包括：以重量百分比計，生物活性玻璃15%-30%、半水硫酸鈣30%-45%、矽酸三 鈣30%-40%；所述混合固體材料與所述液相的調和比為1g：0.3ml-1g：0.8ml；所述生物活性玻璃的粒徑小於等於100μm，所述半水硫酸鈣的粒徑小於等於100μm，所述矽酸三鈣的粒徑小於等於100μm。 In a preferred embodiment of the present invention, the composition of the mixed solid material comprises: 15%-30% by weight of bioactive glass, 30%-45% of calcium sulfate hemihydrate, and citrate three Calcium 30%-40%; the mixing ratio of the mixed solid material to the liquid phase is 1g: 0.3ml-1g: 0.8ml; the particle diameter of the bioactive glass is 100μm or less, the calcium sulfate hemihydrate The particle diameter is 100 μm or less, and the particle size of the tricalcium citrate is 100 μm or less.

在本發明一個較佳實施例中，所述混合固體材料的組成包括：以重量百分比計，生物活性玻璃27%、半水硫酸鈣41.5%、矽酸三鈣31.5%；所述混合固體材料與所述液相的調和比為1g：0.5ml。 In a preferred embodiment of the present invention, the composition of the mixed solid material comprises: 27% of bioactive glass, 41.5% of calcium sulfate hemihydrate, and 31.5% of tricalcium citrate; and the mixed solid material and The blending ratio of the liquid phase was 1 g: 0.5 ml.

在本發明一個較佳實施例中，所述生物活性玻璃是組成為45S5的生物活性玻璃。 In a preferred embodiment of the invention, the bioactive glass is a bioactive glass having a composition of 45S5.

在本發明一個較佳實施例中，所述調和液為生理鹽水、去離子水、無機鹽溶液中的一種或多種。 In a preferred embodiment of the invention, the solution is one or more of physiological saline, deionized water, and inorganic salt solution.

在本發明一個較佳實施例中，所述無機鹽溶液為碳酸鹽溶液、氯化鈣溶液、磷酸鹽溶液中的一種或多種。 In a preferred embodiment of the invention, the inorganic salt solution is one or more of a carbonate solution, a calcium chloride solution, and a phosphate solution.

在本發明一個較佳實施例中，所述自固化可降解的生物活性膏劑骨修復材料的凝固時間為10-20分鐘；所述自固化可降解的生物活性膏劑骨修復材料在生物環境中的力學強度是逐漸增強的；所述自固化可降解的生物活性膏劑骨修復材料具有緩慢降解性。 In a preferred embodiment of the present invention, the self-cure degradable bioactive paste bone repair material has a setting time of 10-20 minutes; the self-cure degradable bioactive paste bone repair material is in a biological environment. The mechanical strength is gradually enhanced; the self-cure degradable bioactive plaster bone repair material has a slow degradability.

在本發明一個較佳實施例中，所述自固化可降解的生物活性膏劑骨修復材料在骨缺損填充手術中進行應用。 In a preferred embodiment of the invention, the self-cure degradable bioactive cream bone repair material is applied in a bone defect filling procedure.

在本發明一個較佳實施例中，所述自固化可降解的生物活性膏劑骨修復材料在骨科椎體成型手術、膝髖關節置換手術中進行應用。 In a preferred embodiment of the present invention, the self-cure degradable bioactive plaster bone repair material is applied in orthopedic vertebral body shaping surgery and knee hip joint replacement surgery.

在本發明一個較佳實施例中，所述自固化可降解的生物活性膏劑骨修復材料在使用時能直接與抗菌素調和，同時保持了藥效性又不影響凝固時間和強度；優選地，所述抗菌素為慶大黴素液體。 In a preferred embodiment of the present invention, the self-cure degradable bioactive paste bone repair material can be directly conditioned with the antibiotic when used, while maintaining the pharmacodynamic effect without affecting the setting time and strength; preferably, The antibiotic is a gentamicin liquid.

本發明的有益效果是： The beneficial effects of the invention are:

1、三元混合體組成由於生物活性玻璃的存在增加的生物活性即作為骨修復材料的成骨性。 1. Ternary Mixture Composition The increased biological activity due to the presence of bioactive glass is the osteogenicity of the bone repair material.

2、生物活性玻璃的引入加快了體系組成的凝固時間。 2. The introduction of bioactive glass accelerates the solidification time of the system composition.

3、由於體系組成中矽酸三鈣的存在，在液體環境中，矽酸三鈣會繼續反應至數月，並會使得凝固體的強度不斷增加。最後為負荷應用的骨修復材料，這一特性至關重要。 3. Due to the presence of tricalcium citrate in the system composition, in a liquid environment, tricalcium citrate will continue to react for several months and will increase the strength of the solidified body. This feature is critical to the final bone repair material for load applications.

4、本世紀初，大量臨床證明抗菌素引入骨水泥中能在手術初期起抗感染作用，手術後的翻修率顯著減少。由於習知惰性骨水泥用一種有機物溶液調和，抗菌素必須要預先加入粉體中，既影響其藥效性，又影響固化時間。而本發明使用水溶液調和三元混合體，可直接在使用時使用抗菌素水溶液調和，能較方便理想的儲存和保存藥物和藥性又不影響凝固反應時間和強度。 4. At the beginning of this century, a large number of clinically proven antibiotics were introduced into bone cement to prevent infection in the early stage of surgery, and the rate of revision after surgery was significantly reduced. Since the conventional inert bone cement is reconciled with an organic solution, the antibiotic must be added to the powder in advance, which affects both the efficacy and the curing time. The invention adopts the aqueous solution to adjust the ternary mixture, and can be directly used in the use of the antibiotic aqueous solution to be blended, which can conveniently store and preserve the drug and the drug without affecting the time and strength of the coagulation reaction.

為了更清楚地說明本發明實施例中的技術方案，下面將對實施例描述中所需要使用的附圖作簡單地介紹，顯而易見地，下面描述中的附圖僅僅是本發明的一些實施例，對於本領域普通技術人員來講，在不付出圖破性勞動的前提下，還可以根據這些附圖獲得其它的附圖，其中：圖1是本發明所述膏劑的可推注示意圖；圖2是本發明所述膏劑自固化後在擬人體溶液中反應1天、3天、7天後的紅外光譜圖；圖3是本發明所述膏劑的抗壓強度隨反應時間變化結果圖；圖4是本發明所述膏劑進行動物實驗的模型圖；圖5是本發明所述膏體植入兔髁骨缺損3個月後組織學情況圖；以及 圖6是本發明所述膏體植入兔髁骨缺損後骨結合率，即材料與骨組織形成骨性結合的面積百分比圖。 In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly described below. It is obvious that the drawings in the following description are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained according to the drawings without paying for the labor of the drawings. FIG. 1 is a schematic view of the paste of the present invention; FIG. Is the infrared spectrum of the paste of the present invention after reacting in the human body solution for 1 day, 3 days, and 7 days after self-curing; FIG. 3 is a graph showing the change of the compressive strength of the paste according to the present invention with the reaction time; FIG. Is a model diagram of the experiment of the present invention for animal experiments; FIG. 5 is a histological diagram of the paste of the present invention implanted into the rabbit tibia defect for 3 months; Figure 6 is a graph showing the osseointegration rate of the paste implanted into the rabbit's tibia defect, i.e., the area percentage of the material that forms a bone bond with the bone tissue.

下面將對本發明實施例中的技術方案進行清楚、完整地描述，顯然，所描述的實施例僅是本發明的一部分實施例，而不是全部的實施例。基於本發明中的實施例，本領域普通技術人員在沒有做出突破性勞動前提下所獲得的所有其它實施例，都屬於本發明保護的範圍。 The technical solutions in the embodiments of the present invention will be clearly and completely described below. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments obtained by a person of ordinary skill in the art based on the embodiments of the present invention without departing from the scope of the present invention are within the scope of the present invention.

提供一種自固化可降解的生物活性膏劑骨修復材料，包括生物活性玻璃、半水硫酸鈣、矽酸三鈣和調和液。 A self-curing degradable bioactive cream bone repair material is provided, including bioactive glass, calcium sulfate hemihydrate, tricalcium citrate, and a solution.

所述自固化可降解的生物活性膏劑骨修復材料，即生物活性玻璃-半水硫酸鈣-矽酸三鈣三元系統凝固反應機理如下。 The self-cure degradable bioactive paste bone repair material, that is, the bioactive glass-calcium sulfate hemihydrate-tricalcium citrate ternary system solidification reaction mechanism is as follows.

當三元混合物與水混合調勻成膏體後，將有以下三個反應進行： When the ternary mixture is mixed with water and mixed into a paste, the following three reactions will be carried out:

(1)生物活性玻璃顆粒表面遇水後迅速發生表面反應釋放出鈣和矽離子。 (1) The surface of the bioactive glass particles rapidly reacts with water to release calcium and barium ions.

(2)矽酸三鈣顆粒表面遇水後首先發生溶解。這時，顆粒空隙間的水中積聚鈣矽離子到飽和，出現新的相的沉積。沉積物為水合矽酸鈣凝膠(Calcium-Silicate-Hydrate gel,or C-S-H)，反應式為：2 Ca3SiO5+7 H2O→3 CaO．2 SiO2．4 H2O+3 Ca(OH)2。這一過程稱為水化-沉積反應過程。沉積後水中離子濃度降低使得水解繼續進行然後沉積後又水解出現，這樣水化-沉積反應反覆連續進行。 (2) The surface of the tricalcium citrate particles first dissolves when it encounters water. At this time, calcium strontium ions are accumulated in the water between the voids of the particles to saturation, and deposition of a new phase occurs. The sediment is Calcium-Silicate-Hydrate gel (or CSH), and the reaction formula is: 2 Ca 3 SiO 5 +7 H 2 O→3 CaO. 2 SiO 2 . 4 H 2 O+3 Ca(OH) 2 . This process is called the hydration-deposition reaction process. The concentration of ions in the water after deposition is lowered so that the hydrolysis proceeds and then hydrolyzed after deposition, so that the hydration-deposition reaction is continuously carried out repeatedly.

(3)半水硫酸鈣顆粒遇水後的反應與矽酸三鈣相似，只不過被認為反應更迅速。反應式為：CaSO4．1/2H2O+3/2H2O→CaSO4．2H2O。首先水化反應離子產物會迅速在周圍表面和顆粒空隙中沉澱析晶為穩定相-二水硫酸鈣。 (3) The reaction of calcium sulphate hemihydrate particles after water contact is similar to that of tricalcium citrate, but it is considered to be more rapid. The reaction formula is: CaSO 4 . 1/2H 2 O+3/2H 2 O→CaSO 4 . 2H 2 O. First, the hydration reaction ion product will rapidly precipitate and crystallize into the stable phase-calcium sulfate dihydrate in the surrounding surface and the voids of the particles.

反應(2)和(3)中的水化-沉積反應是一個動態連續過程，反應直至水分含量降低，新的沉積相填充顆粒間空隙使得密度增加強度增高以達到凝固，這是這兩個材料自固化凝固的基本反應原理。不同之處是半水硫酸鈣反應迅速，7分鐘能達到終凝狀態。而矽酸三鈣反應較慢，通常需要60分鐘以上達到終凝。 The hydration-deposition reaction in reactions (2) and (3) is a dynamic continuous process, the reaction is continued until the moisture content is reduced, and the new deposition phase fills the interparticle voids so that the density increases and the strength increases to achieve solidification. The basic reaction principle of self-curing solidification. The difference is that the calcium sulfate hemihydrate reacts quickly and reaches the final setting state in 7 minutes. The tricalcium citrate reaction is slower and usually takes more than 60 minutes to reach final setting.

當上述三個反應在這三元混合體系中同時發生時，反應(1)，即生物活性玻璃顆粒表面釋放出鈣和矽離子將會大大加快反應(2)和反應(3)的速度，即加快水合矽酸鈣凝膠相和二水硫酸鈣晶相的形成。這兩個新的相的形成，一方面佔據顆粒間隙提高材料密度，另一方面同時形成的新的相與原生物活性玻璃顆粒、矽酸三鈣顆粒以及半水硫酸鈣顆粒交織在一起增加了材料強度。這樣導致三元材料凝固加快，固化時間變短。這一特性使得三元系統具有更廣泛的實用性。 When the above three reactions occur simultaneously in the ternary mixed system, the reaction (1), that is, the release of calcium and barium ions on the surface of the bioactive glass particles will greatly accelerate the speed of the reaction (2) and the reaction (3), that is, Accelerate the formation of the hydrated calcium citrate gel phase and the calcium sulfate dihydrate crystal phase. The formation of these two new phases, on the one hand, occupies the particle gap to increase the density of the material, on the other hand, the new phase formed at the same time is intertwined with the original bioactive glass particles, the tricalcium citrate particles and the calcium sulfate hemihydrate particles. Material strength. This causes the ternary material to solidify faster and the curing time becomes shorter. This feature makes the ternary system more widely applicable.

本發明所用的生物活性玻璃是組成為45S5的生物活性玻璃，是目前國際常用的生物活性玻璃骨修復產品的組成。半水硫酸鈣和矽酸三鈣依照中國專利申請號為200610029067.3的方法製備。三個成分均為100μm以下的顆粒。 The bioactive glass used in the present invention is a bioactive glass having a composition of 45S5, and is a composition of a bioactive glass bone repair product commonly used in the world. Calcium hemihydrate hemihydrate and tricalcium citrate were prepared in accordance with the method of Chinese Patent Application No. 200610029067.3. The three components are all particles of 100 μm or less.

本發明的實驗方法為將三種材料按不同比例以及生物活性玻璃按不同的顆粒尺寸進行充分混合，各混合物與調和液依照液固質量比0.40-0.7ml/g的比例充分調和1分鐘，即得到我們所述的可推注的膏劑。本發明所用的調和液為去離子水、無機鹽(生理鹽水、碳酸鹽、氯化鈣、磷酸鹽等)溶液中的一種。 The experimental method of the present invention is to thoroughly mix the three materials in different proportions and the bioactive glass according to different particle sizes, and each mixture and the solution are fully conditioned for one minute according to the liquid-solid mass ratio of 0.40-0.7 ml/g, that is, The pushable paste we have described. The solution used in the present invention is one of a solution of deionized water or an inorganic salt (physiological saline, carbonate, calcium chloride, phosphate, etc.).

凝固時間是上述理想的骨水泥修復材料最關鍵的指標，在10分鐘後20分鐘內凝固最為理想。所以凝固實驗的測試是優化組成最重要的步驟。考慮到在實際臨床應用時，材料是在手術創傷傷口會有流血的存在， 作為對比，材料凝固實驗分別在空氣和水中進行。在水中凝固實驗時，混合物與調和液調好2分鐘後將調配物放入水中觀察測試凝固時間。水中的凝固更接近實際臨床應用有流血存在的環境。 The setting time is the most important indicator of the above-mentioned ideal bone cement repair material, and the solidification is ideal within 20 minutes after 10 minutes. Therefore, the test of the coagulation experiment is the most important step in optimizing the composition. Considering that in actual clinical applications, the material will have bleeding in the wound of the surgical wound, In contrast, material solidification experiments were carried out in air and water, respectively. In the water coagulation experiment, the mixture was adjusted to the conditioning solution for 2 minutes, and then the formulation was placed in water to observe the test setting time. The solidification in water is closer to the environment in which the actual clinical application has bleeding.

凝固時間實驗測試方法按ISO9597-1989E國際標準，採用維卡儀(Vicat)針對上述骨水泥糊狀膏劑物的初凝時間(I)和終凝時間(F)進行測試。初凝時間定義為維卡儀針(280g,1.13mm)垂直落下到裝在小管中的膏劑時穿透深度為5±1mm所需要的時間；終凝時間定義為維卡儀針(350g,2.0mm)垂直落下到裝在小管中的膏劑時在表面看不到明顯印記所需要的時間。 Coagulation time experimental test method According to the international standard of ISO9597-1989E, the initial setting time (I) and the final setting time (F) of the above-mentioned bone cement paste paste were tested by Vicat instrument. The initial setting time is defined as the time required for the Vicat instrument needle (280g, 1.13mm) to fall vertically to the paste contained in the small tube at a depth of 5 ± 1mm; the final setting time is defined as the Vicat needle (350g, 2.0) Mm) The time required for the mark to be placed in the small tube to be invisible on the surface.

(1)原材料單獨凝固特性測試。 (1) Test of individual solidification characteristics of raw materials.

調和液為去離子水，調和比為1g：0.5ml，凝固條件在空氣中： The blending solution is deionized water, the blending ratio is 1g: 0.5ml, and the solidification condition is in the air:

調和液為去離子水，凝固條件在水溶液中： The blending solution is deionized water and the solidification conditions are in an aqueous solution:

(2)三元系統的凝固時間測試。 (2) The solidification time test of the ternary system.

調和液為去離子水，凝固條件在空氣中： The blending solution is deionized water and the solidification conditions are in the air:

調和液為去離子水，凝固條件在水溶液中： The blending solution is deionized water and the solidification conditions are in an aqueous solution:

調和液為CaCl2無機鹽溶液，凝固條件在水溶液中： The blending solution is a CaCl 2 inorganic salt solution, and the solidification conditions are in an aqueous solution:

凝固實驗結果：實驗表明，半水硫酸鈣對減少凝固時間起到主要作用。生物活性玻璃大顆粒的加入對系統凝固時間沒有多大的改進，而小顆粒(<50μm)的加入對三元系統的凝固起到了促進作用。主要原因是小顆粒比表面積大，表面反應快，起到促進凝固的作用。根據上述結果可以發現序號18、19、21是同一組成，無論是用水或無機鹽溶液CaCl2調和還是在空氣中或者水中環境凝固，其凝固特性呈現出較理想的實用性。 Solidification test results: Experiments show that calcium sulfate hemihydrate plays a major role in reducing the setting time. The addition of large particles of bioactive glass did not improve the solidification time of the system, and the addition of small particles (<50 μm) promoted the solidification of the ternary system. The main reason is that the small particles have a large specific surface area and a fast surface reaction, which promotes solidification. According to the above results, it can be found that the serial numbers 18, 19, and 21 are the same composition, and the solidification characteristics thereof are more practical, whether it is blended with water or an inorganic salt solution of CaCl 2 or solidified in air or in water.

實施例一：序號為18號的自固化可降解的生物活性膏劑骨修復材料的推注和凝固實驗測試。 Example 1: The bolus and coagulation test of the self-curing degradable bioactive ointment bone repair material No. 18 was carried out.

稱取18號組成混合物3克，稱量1.5ml去離子水與混合物調拌混合60秒(調和比0.5ml/g)得到膏劑樣品。推注性實驗測試方法為將樣品灌入15mL容量的帶有噴嘴內徑(D)為2.0mm針頭的注射器，對其注射性進行試驗。膏劑可從針筒中推注出，如圖1所示。 3 g of the composition mixture No. 18 was weighed, and 1.5 ml of deionized water was weighed and mixed with the mixture for 60 seconds (harmonization ratio of 0.5 ml/g) to obtain a paste sample. The bolus experimental test method was to inject the sample into a 15 mL-capacity syringe with a nozzle inner diameter (D) of 2.0 mm and test its injectability. The paste can be pushed out of the syringe as shown in Figure 1.

推出膏劑到：6-mm直徑×6-mm高度的模具中進行凝固時間測試。凝固時間實驗測試方法按照ISO9597-1989E國際標準，採用維卡儀對上述膏劑物的初凝時間(I)和終凝時間(F)進行測試。測試3個樣品。下表為測試結果。 The paste was introduced into a mold of 6-mm diameter x 6-mm height for the setting time. Coagulation time experimental test method According to the international standard of ISO9597-1989E, the initial setting time (I) and the final setting time (F) of the above paste were tested by using a Vicat instrument. Test 3 samples. The table below shows the test results.

實施例二：序號為18號的自固化可降解的生物活性膏劑骨修復材料的生物活性測試。 Example 2: Bioactivity test of self-curing degradable bioactive paste bone repair material with serial number 18.

生物活性測試方法：自固化生物活性材料按配比調和，調和液為去離子水，調和比0.5ml/g，調和時間60秒。調成的膏劑再用模具：6-mm直徑×2-mm高度，凝固成圓片。樣品數量3個。浸泡SBF時按照樣品表面積/溶液體積=0.1cm-1將圓片分別懸掛在SBF中，在37℃的環境中反應。反應為1天、3天和7天。反應樣品進行FTIR紅外反射譜進行表面測試。反射峰574cm-1和608cm-1的出現將表示羥基磷灰石的形成，即表示材料具有生物活性。檢測結果見圖2。 Biological activity test method: self-curing bioactive material is blended according to the ratio, the blending solution is deionized water, the blending ratio is 0.5 ml/g, and the blending time is 60 seconds. The prepared paste is then used in a mold: 6-mm diameter x 2-mm height, and solidified into a wafer. The number of samples is 3. When the SBF was soaked, the wafers were suspended in SBF according to the sample surface area/solution volume = 0.1 cm -1 , and reacted in an environment of 37 ° C. The reaction was 1 day, 3 days and 7 days. The reaction samples were subjected to FTIR infrared reflectance spectroscopy for surface testing. The appearance of the reflection peaks of 574 cm -1 and 608 cm -1 will indicate the formation of hydroxyapatite, indicating that the material is biologically active. The test results are shown in Figure 2.

實施例三：序號為18號的自固化可降解的生物活性膏劑骨修復材料的抗壓強度測試。 Example 3: Compressive strength test of self-curing degradable bioactive paste bone repair material with serial number 18.

力學抗壓強度測試方法：新型自固化生物活性產品樣品通過SBF擬人體溶液浸泡反應不同時間來測定抗壓強度變化。自固化生物活性材料按照配比調和，調和液為去離子水，調和比0.5ml/g，調和時間60秒。調成的膏劑再用模具：6-mm直徑×12-mm高度，凝固成圓柱。樣品數量30個。浸泡SBF時，每天換液，按照樣品表面積/溶液體積=0.1cm-1將圓柱分別懸掛在SBF中，在37℃的環境中反應。反應為6個時間點，每個時間點為一組， 樣品分6組，每組測試5個樣品。6個時間點為：1小時、2小時、8小時、1天、3天和7天。將每組測試結果進行統計取平均值並計算出正負差，抗壓強度隨反應時間變化結果如下表和圖3所示。 Mechanical compressive strength test method: The new self-curing bioactive product sample is determined by SBF quasi-human solution soaking reaction for different time to determine the compressive strength change. The self-curing bioactive material is blended according to the ratio, the blending solution is deionized water, the blending ratio is 0.5 ml/g, and the blending time is 60 seconds. The prepared paste is then used in a mold: 6-mm diameter x 12-mm height, and solidified into a cylinder. The number of samples is 30. When soaking SBF, change the liquid every day, and suspend the cylinders in SBF according to the sample surface area/solution volume = 0.1 cm -1 , and react in an environment of 37 ° C. The reaction was at 6 time points, each time point was a group, the samples were divided into 6 groups, and each group was tested 5 samples. The six time points are: 1 hour, 2 hours, 8 hours, 1 day, 3 days, and 7 days. The statistical results of each set of test results were averaged and the positive and negative differences were calculated. The results of compressive strength as a function of reaction time are shown in the following table and in Figure 3.

實施例四：序號為18號的自固化可降解的生物活性膏劑骨修復材料的動物實驗。 Example 4: Animal experiment of self-curing degradable bioactive paste bone repair material with serial number 18.

動物實驗用新西蘭白兔2-3公斤。缺損模型為股骨遠端(distal femur condyle)髁骨，6mm×10mm，如圖4所示。植入3個月後的組織學觀察，如圖5所示。圖5顯示了18號膏體植入兔髁骨缺損3個月後的情況組織學情況。從圖片來看，材料大體上保持了其形狀特點(植入體為圓柱狀塊體)，材料內部未見明顯裂紋，材料表面未見明顯顆粒剝落，材料邊緣為白色，表面活性反應所致形成的多孔相表明溶解吸收反應開始。說明材料降解方式可 能主要是由外向內溶解吸收。在染色過程中發現材料內部會被染成藍色，乙醇未沖洗掉。對材料表面進行觀察可以發現明顯的新骨形成，圖6為材料植入後的骨結合率，即材料與骨組織形成骨性結合的面積百分比。這表明材料表面和骨組織呈現良好的骨性結合。通常的生物活性骨修復材料在3個月時會出現明顯降解。本發明的最佳組成18號在3個月時表面出現降解但材料基本上保持其形狀，表示非常緩慢的降解速度。這是本發明所需要的可凝固能承受負荷力又具有生物活性的膏劑，會緩慢降解，引導骨組織形成，最後由本體骨組織取代，為最理想骨修復產品。 New Zealand white rabbits used 2-3 kg for animal experiments. The defect model was the distal femur condyle tibia, 6 mm x 10 mm, as shown in Figure 4. Histological observations after 3 months of implantation are shown in Figure 5. Figure 5 shows the histology of the 18th paste implanted into the rabbit's tibia defect 3 months later. From the picture, the material generally retains its shape characteristics (the implant is a cylindrical block), there is no obvious crack inside the material, no obvious particle peeling on the surface of the material, the material edge is white, and the surface active reaction is formed. The porous phase indicates the start of the dissolution absorption reaction. Explain how the material is degraded Can be mainly absorbed from the outside to the inside. During the dyeing process, it was found that the inside of the material was dyed blue and the ethanol was not washed away. Observing the surface of the material revealed significant new bone formation. Figure 6 shows the osseointegration rate of the material after implantation, that is, the percentage of the area where the material forms a bone bond with the bone tissue. This indicates that the material surface and bone tissue exhibit a good bone bond. The usual bioactive bone repair materials show significant degradation at 3 months. The preferred composition of the present invention No. 18 exhibited degradation on the surface at 3 months but the material substantially retained its shape, indicating a very slow rate of degradation. This is a paste which can be solidified and can bear the load and is biologically active, which will slowly degrade, guide the formation of bone tissue, and finally be replaced by the body bone tissue, which is the most ideal bone repair product.

本發明公開的一種由生物活性玻璃-半水硫酸鈣-矽酸三鈣三元系統形成的可推注自固化可降解的生物活性膏劑骨修復材料，可代替目前常用的惰性骨水泥而用於骨科椎體成型手術、膝髖關節置換手術以及其它骨折缺損填充手術中。本發明提供的新一代骨水泥修復材料能在合理的時間內凝固，逐漸建立起一定的力學強度。特別重要的是這新一代骨水泥修復材料由於引入生物活性玻璃而加快了凝固時間，增強了生物活性及骨傳導性以及緩慢降解性。緩慢降解的同時，材料由生物活性及骨傳導性會引導本體骨生長，最終，在骨水泥修復材料完全降解時，由生長的本體骨完全取而代之。另一特別重要的是這新一代骨水泥修復材料與其它傳統的骨水泥不同，可直接與抗菌素(如慶大黴素)液體調和，且對凝固時間和力學強度無明顯影響。將抗菌素引入體系中而緩釋，以防止手術缺損傷口處的感染。 The invention discloses a pushable self-curing degradable bioactive paste bone repairing material formed by a bioactive glass-calcium sulfate hemihydrate-tricalcium ternate system, which can be used instead of the currently used inert bone cement. Orthopedic vertebral body surgery, knee and hip replacement surgery, and other fracture defect filling procedures. The new generation of bone cement repairing material provided by the invention can solidify in a reasonable time and gradually establish a certain mechanical strength. Of particular importance is the new generation of bone cement repair materials that accelerate the setting time due to the introduction of bioactive glass, enhancing bioactivity and osteoconductivity as well as slow degradation. At the same time of slow degradation, the material will guide the growth of the body bone by biological activity and osteoconductivity. Finally, when the bone cement repair material is completely degraded, the grown body bone is completely replaced. Another important point is that this new generation of bone cement repair material, unlike other traditional bone cements, can be directly blended with antibiotics (such as gentamicin) and has no significant effect on solidification time and mechanical strength. The antibiotic is introduced into the system for sustained release to prevent infection at the wound site.

本發明的發明人曾有專利，揭示了用半水硫酸鈣/矽酸三鈣兩元系統複合自固化生物活性材料、製備方法及其應用，具體的申請號為200610029067.3和200810204780.6。為了研製出更為理想的骨水泥修復材料，本發明引入生物活性最強、成骨性最快，且已在臨床上成功應用20多年的組成代號為45S5的生物活性玻璃，使之成為一個生物活性玻璃-半水硫 酸鈣-矽酸三鈣三元系統。由於微米生物活性玻璃顆粒的引入，將會使得新的材料凝固時間具有實用性，降解速率得到改善，生物相容性和成骨性得到提高。得到更理想的可推注自固化可吸收的膏劑骨水泥修復材料，作為骨修復替代材料能用於椎體成型手術、膝髖關節置換手術以及其它一些骨折手術中。 The inventors of the present invention have patented and disclosed a self-curing bioactive material composited with a calcium sulfate hemihydrate/tricalcium citrate system, a preparation method thereof and application thereof, and the specific application numbers are 200610029067.3 and 200810204780.6. In order to develop a more ideal bone cement repair material, the present invention introduces a biologically active glass with the most biological activity and the fastest osteogenicity and has been successfully applied clinically for more than 20 years, which is coded as 45S5, making it a biological activity. Glass-semi-sulfur Calcium acid-tricalcium ternate system. Due to the introduction of micron bioactive glass particles, the new material solidification time will be practical, the degradation rate will be improved, and the biocompatibility and osteogenic properties will be improved. A more desirable self-curing self-cure absorbable plaster cement repair material can be used as an alternative to bone repair for vertebral body shaping surgery, knee hip replacement surgery, and other fracture operations.

以上所述僅為本發明的實施例，並非因此限制本發明的專利範圍，凡是利用本發明說明書內容所作的等效結構或等效流程變換，或直接或間接運用在其它相關的技術領域，均同理包括在本發明的專利保護範圍內。 The above is only the embodiment of the present invention, and thus does not limit the scope of the patent of the present invention. Any equivalent structure or equivalent process transformation made by using the contents of the specification of the present invention, or directly or indirectly applied to other related technical fields, The same is included in the scope of patent protection of the present invention.

Claims (9)

一種自固化可降解的生物活性膏劑骨修復材料，包括：混合固體材料，包括生物活性玻璃、半水硫酸鈣和矽酸三鈣；以及液相，包括調和液，其中所述自固化可降解的生物活性膏劑骨修復材料在使用時能直接與一抗菌素液體調和，同時保持了藥效性又不影響凝固時間和強度。 A self-cure degradable bioactive paste bone repair material comprising: a mixed solid material comprising bioactive glass, calcium sulfate hemihydrate and tricalcium citrate; and a liquid phase comprising a blending liquid, wherein the self-cure degradable The bioactive plaster bone repair material can be directly conditioned with an antibiotic liquid while being used, while maintaining the efficacy without affecting the setting time and strength. 如請求項1所述的自固化可降解的生物活性膏劑骨修復材料，其中所述混合固體材料的組成包括：以重量百分比計，生物活性玻璃15%-30%、半水硫酸鈣30%-45%以及矽酸三鈣30%-40%；所述混合固體材料與所述液相的調和比為1g：0.3ml-1g：0.8ml；所述生物活性玻璃的粒徑小於等於100μm；所述半水硫酸鈣的粒徑小於等於100μm；以及所述矽酸三鈣的粒徑小於等於100μm。 The self-cure degradable bioactive cream bone repair material according to claim 1, wherein the composition of the mixed solid material comprises: 15%-30% by weight of bioactive glass, 30% calcium sulfate hemihydrate by weight percentage - 45% and tricalcium citrate 30%-40%; the mixing ratio of the mixed solid material to the liquid phase is 1g: 0.3ml-1g: 0.8ml; the particle size of the bioactive glass is less than or equal to 100μm; The particle size of the calcium sulfate hemihydrate is 100 μm or less; and the particle size of the tricalcium citrate is 100 μm or less. 如請求項2所述的自固化可降解的生物活性膏劑骨修復材料，其中，所述混合固體材料的組成包括：以重量百分比計，所述生物活性玻璃27%、所述半水硫酸鈣41.5%以及所述矽酸三鈣31.5%；以及所述混合固體材料與所述液相的調和比為1g：0.5ml。 The self-cure degradable bioactive paste bone repair material according to claim 2, wherein the composition of the mixed solid material comprises: 27% by weight of the bioactive glass, and 41.5% of the calcium sulfate hemihydrate by weight percentage. % and the tricalcium citrate 31.5%; and the blending ratio of the mixed solid material to the liquid phase is 1 g: 0.5 ml. 如請求項1-3中之任一項所述的自固化可降解的生物活性膏劑骨修復材料，其中，所述生物活性玻璃是組成為45S5的生物活性玻璃。 The self-curing degradable bioactive cream bone repair material according to any one of claims 1 to 3, wherein the bioactive glass is a bioactive glass having a composition of 45S5. 如請求項1-3中之任一所述的自固化可降解的生物活性膏劑骨修復材料，其中，所述調和液為去離子水、無機鹽溶液中的一種或多種。 The self-cure degradable bioactive cream bone repair material according to any one of claims 1 to 3, wherein the solution is one or more of deionized water and an inorganic salt solution. 如請求項5所述的自固化可降解的生物活性膏劑骨修復材料，其中，所述無機鹽溶液為碳酸鹽溶液、氯化鈣溶液、磷酸鹽溶液、生理鹽水中的一種或多種。 The self-curing biodegradable bioactive plaster bone repair material according to claim 5, wherein the inorganic salt solution is one or more of a carbonate solution, a calcium chloride solution, a phosphate solution, and a physiological saline. 如請求項1所述的自固化可降解的生物活性膏劑骨修復材料，其中，所述自固化可降解的生物活性膏劑骨修復材料的凝固時間為10-20分鐘；所述自固化可降解的生物活性膏劑骨修復材料在生物環境中的力學強度是逐漸增強的；以及所述自固化可降解的生物活性膏劑骨修復材料具有緩慢降解性。 The self-curing biodegradable bioactive paste bone repair material according to claim 1, wherein the self-curing biodegradable bioactive paste bone repair material has a setting time of 10-20 minutes; the self-cure degradable The mechanical strength of the bioactive plaster bone restorative material is gradually enhanced in a biological environment; and the self-curing degradable bioactive plaster bone repair material has a slow degradability. 如請求項1所述的自固化可降解的生物活性膏劑骨修復材料，其中，所述自固化可降解的生物活性膏劑骨修復材料在骨缺損填充手術中進行應用。 The self-curing biodegradable bioactive plaster bone repair material according to claim 1, wherein the self-curing degradable bioactive plaster bone repair material is applied in a bone defect filling operation. 如請求項8所述的自固化可降解的生物活性膏劑骨修復材料，其中，所述自固化可降解的生物活性膏劑骨修復材料在骨科椎體成型手術、膝髖關節置換手術中進行應用。 The self-cure degradable bioactive paste bone repair material according to claim 8, wherein the self-cure degradable bioactive paste bone repair material is applied in orthopedic vertebral body shaping surgery and knee hip joint replacement surgery.
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