TWI453174B

TWI453174B - Bone cement formula and bioresorbable hardened bone cement composites prepared with the same

Info

Publication number: TWI453174B
Application number: TW099135634A
Authority: TW
Inventors: Jiin-Huey Chern Lin; Chien-Ping Ju
Original assignee: Univ Nat Cheng Kung
Priority date: 2010-10-19
Filing date: 2010-10-19
Publication date: 2014-09-21
Also published as: TW201217296A

Description

骨水泥配方及由其製備的生物可吸收的硬化骨水泥複合材料Bone cement formula and bioabsorbable hardened bone cement composite prepared therefrom

本發明的示例性實施方式涉及用於藥物的骨修復物質。更具體地，本發明的示例性實施方式涉及一種骨水泥配方(bone cement formula)。An exemplary embodiment of the invention relates to a bone repair substance for a medicament. More specifically, an exemplary embodiment of the present invention relates to a bone cement formula.

骨水泥組合物廣泛用於粘結、填充和/或修復受損的天然骨。骨水泥通常用於矯形、牙齒程式(dental procedures)和/或其他醫學應用。儘管具有許多優點，例如優異的生物相容性、優良的骨傳導性(osteoconductivity)以及增強的機械強度或物理強度，但是大多數磷酸鈣表現出在臨床上的生物再吸收速率(bioresorption rate)低。另一方面，硫酸鈣的化合物還顯示較高的溶解速率，對於許多應用，為了使新的骨細胞在骨腔中快速生長，該溶解速率通常太高。含有硫酸鈣的複合材料通常具有比含有磷酸鈣的複合材料更低的機械強度和/或物理強度。Bone cement compositions are widely used to bond, fill and/or repair damaged natural bone. Bone cement is commonly used for orthopedics, dental procedures, and/or other medical applications. Despite many advantages, such as excellent biocompatibility, excellent osteoconductivity, and enhanced mechanical strength or physical strength, most calcium phosphates exhibit a low bioresorption rate in the clinic. . On the other hand, calcium sulphate compounds also show higher dissolution rates, which for many applications is typically too high in order for new bone cells to grow rapidly in the bone cavity. Composites containing calcium sulfate typically have lower mechanical strength and/or physical strength than composites containing calcium phosphate.

與傳統的骨水泥漿糊相關的另一個問題為延長固化時間，因而妨礙了對各種應用的適用性。例如，在美國專利No.4,612,053中所述的磷酸鈣(CPC)漿糊通常需要延長固化時間。Another problem associated with conventional bone cement pastes is the prolonged cure time, thus impeding applicability to a variety of applications. For example, the calcium phosphate (CPC) paste described in U.S. Patent No. 4,612,053 generally requires an extended cure time.

本發明的實施方式公開了一種提供磷酸鈣-硫酸鈣複合材料的方法，該複合材料表現出增強的強度、優異的生物相容性、優良的骨傳導性、適當且可調節的生物再吸收速率。Embodiments of the present invention disclose a method of providing a calcium phosphate-calcium sulfate composite exhibiting enhanced strength, excellent biocompatibility, excellent osteoconductivity, and a suitable and adjustable rate of bioresorption .

實施方式的目的是提供一種骨水泥配方、骨水泥漿糊、由所述漿糊形成的硬化骨水泥複合材料、通過對所述漿糊加壓同時從所述漿糊中漏出溶液而形成的具有增強的強度的硬化骨水泥複合材料、以及由所述漿糊形成的多孔硬化骨水泥複合材料。It is an object of an embodiment to provide a bone cement formulation, a bone cement paste, a hardened bone cement composite formed from the paste, formed by pressurizing the paste while leaking a solution from the paste An enhanced strength hardened bone cement composite, and a porous hardened bone cement composite formed from the paste.

本發明的實施方式提供了用於提供骨水泥配方、骨水泥漿糊、硬化骨水泥複合材料、具有增強的強度的硬化骨水泥複合材料、以及多孔硬化骨水泥複合材料的方法。Embodiments of the present invention provide methods for providing bone cement formulations, bone cement pastes, hardened bone cement composites, hardened bone cement composites having enhanced strength, and porous hardened bone cement composites.

本發明的一種實施方式提供了一種使用示例性實施方式的骨水泥漿糊填充骨中的孔或腔的方法，該骨水泥漿糊在需要處理的孔或腔中固化或硬化。本發明的另一種實施方式提供了一種在處理過程中植入硬化骨水泥複合材料的方法。One embodiment of the present invention provides a method of filling a hole or cavity in a bone using a bone cement paste of an exemplary embodiment that cures or hardens in a hole or cavity that requires treatment. Another embodiment of the present invention provides a method of implanting a hardened bone cement composite during processing.

本發明的一種實施方式提供了一種骨水泥配方，該骨水泥配方含有粉末組份和固化液體組份，其中液體與粉末的比率為0.20 cc/g至0.50 cc/g(cc為立方釐米，g為克)，優選0.25 cc/g至0.35 cc/g。在一個方面，所述粉末組份含有硫酸鈣源和磷酸鈣源，以所述硫酸鈣源和磷酸鈣源的總重量為基準，所述硫酸鈣源的重量比小於65%。在一個方面，所述固化液體組份含有濃度為約0.5 M至4 M的銨離子(NH₄ ⁺ )。在一個方面，所述磷酸鈣源包括磷酸四鈣(TTCP)和磷酸二鈣，其中TTCP與磷酸二鈣的摩爾比為約0.5至約2.5，優選為1.0，並且所述硫酸鈣源為半水合硫酸鈣(CSH)、脫水硫酸鈣(CSD)或無水硫酸鈣，並優選為CSH。One embodiment of the present invention provides a bone cement formulation comprising a powder component and a solidified liquid component, wherein the ratio of liquid to powder is from 0.20 cc/g to 0.50 cc/g (cc is cubic centimeters, g It is preferably 0.25 cc/g to 0.35 cc/g. In one aspect, the powder component comprises a source of calcium sulfate and a source of calcium phosphate based on the total weight of the source of calcium sulfate and calcium phosphate, the weight ratio of the source of calcium sulfate being less than 65%. In one aspect, the solidified liquid component contains ammonium ions (NH ₄ ⁺ ) at a concentration of from about 0.5 M to 4 M. In one aspect, the calcium phosphate source comprises tetracalcium phosphate (TTCP) and dicalcium phosphate, wherein the molar ratio of TTCP to dicalcium phosphate is from about 0.5 to about 2.5, preferably 1.0, and the source of calcium sulfate is hemihydrate Calcium sulfate (CSH), dehydrated calcium sulfate (CSD) or anhydrous calcium sulfate, and preferably CSH.

應注意到，對於不同的醫學跡象，所需的吸收速率可以不同。因此，更期望的水泥應能夠提供一定範圍的骨再吸收速率，而不會顯著改變其初級配方、性能和工作時間/固化時間。例如，由於硫酸鈣源和磷酸鈣源的共存，植入的硬化水泥複合材料的吸收速率是可調節的。動物研究表明，通過調節硫酸鹽/磷酸鹽的比率，可以調節硬化的硫酸鹽-磷酸鹽水泥複合材料的吸收速率。It should be noted that the rate of absorption required may vary for different medical indications. Therefore, more desirable cements should be able to provide a range of bone resorption rates without significantly altering their primary formulation, performance and working time/cure time. For example, due to the coexistence of a source of calcium sulfate and a source of calcium phosphate, the rate of absorption of the implanted hardened cementitious composite is adjustable. Animal studies have shown that by adjusting the ratio of sulfate to phosphate, the rate of absorption of the hardened sulfate-phosphate cement composite can be adjusted.

在一種實施方式中，以所述硫酸鈣源和磷酸鈣源粉末的總重量為基準，所述粉末組份的硫酸鈣源為大於5%，並優選為10%至55%。在一個方面，所述磷酸鈣源包括磷酸四鈣(TTCP)和磷酸二鈣，優選為DCPA，其中TTCP與磷酸二鈣的摩爾比為約0.5-2.5，優選為約1.0，並且所述硫酸鈣源為半水合硫酸鈣(CSH)、脫水硫酸鈣(CSD)或無水硫酸鈣，並優選為CSH。In one embodiment, the calcium component of the powder component is greater than 5%, and preferably from 10% to 55%, based on the total weight of the calcium sulfate source and the calcium phosphate source powder. In one aspect, the calcium phosphate source comprises tetracalcium phosphate (TTCP) and dicalcium phosphate, preferably DCPA, wherein the molar ratio of TTCP to dicalcium phosphate is from about 0.5 to 2.5, preferably about 1.0, and the calcium sulfate The source is calcium sulfate hemihydrate (CSH), dehydrated calcium sulfate (CSD) or anhydrous calcium sulfate, and is preferably CSH.

如在對照實施例1-4中說明或證明的，在以下的實驗程式部分中關於TTCP、DCPA與CSH的組合的詳細討論是必要的。由於TTCP、DCPA和CSH可在一定的重量比範圍內組合或混合，因此可得到各種獨特和不可替代的結果。另一方面，兩種化合物的混合物(例如TTCP/CSH和DCPA/CSH)的各種實驗產生了不令人滿意的結果。As explained or demonstrated in Comparative Examples 1-4, a detailed discussion of the combination of TTCP, DCPA and CSH in the experimental program section below is necessary. Since TTCP, DCPA, and CSH can be combined or mixed within a certain weight ratio range, various unique and irreplaceable results can be obtained. On the other hand, various experiments with a mixture of two compounds (e.g., TTCP/CSH and DCPA/CSH) produced unsatisfactory results.

雖然通常認為銨為一種較具毒性的組份，但是，以下所示的實驗說明，銨不僅提供了在細胞毒性上可接受的水泥配方，而且還提供了具有空前的性能的水泥配方。當銨離子的濃度太低時，水泥漿糊可在與液體例如水或體液(即，血液)接觸時分散，或者其初始機械強度太低以至於不能保持水泥漿糊的完整性，這樣可導致水泥漿糊過早破裂。另一方面，當銨離子濃度太高時，水泥漿糊變得毒性太大，以至於不能用作植入物。Although ammonium is generally considered to be a more toxic component, the experiments shown below demonstrate that ammonium not only provides a cytotoxic acceptable cement formulation, but also provides a cement formulation with unprecedented performance. When the concentration of ammonium ions is too low, the cement paste may be dispersed upon contact with a liquid such as water or body fluids (ie, blood), or its initial mechanical strength is too low to maintain the integrity of the cement paste, which may result in The cement paste broke prematurely. On the other hand, when the ammonium ion concentration is too high, the cement paste becomes too toxic to be used as an implant.

在一種實施方式中，所述固化液體組份含有銨離子(NH₄ ⁺ )，其濃度為約1.0 M至2.0 M，更優選為約1.2 M。In one embodiment, the solidified liquid component contains ammonium ions (NH ₄ ⁺ ) at a concentration of from about 1.0 M to 2.0 M, more preferably about 1.2 M.

在一個實例中，所述固化液體組份為NH₄ H₂ PO₄ 、(NH₄ )₂ HPO₄ 、(NH₄ )₃ PO₄ ‧3H₂ O的溶液或它們的混合物。優選情況下，所述固化液體組份為水溶液。選擇性地，所述固化液體組份還含有溶解於其中的檸檬酸或酒石酸。優選所述固化液體組份的pH值為約7.0至約9.0。In one example, the solidified liquid component is a solution of NH ₄ H ₂ PO ₄ , (NH ₄ ) ₂ HPO ₄ , (NH ₄ ) ₃ PO ₄ ‧3H ₂ O, or a mixture thereof. Preferably, the solidified liquid component is an aqueous solution. Optionally, the solidified liquid component further contains citric acid or tartaric acid dissolved therein. Preferably, the solidified liquid component has a pH of from about 7.0 to about 9.0.

在一種實施方式中，所述粉末組份含有造孔劑(pore-forming agent)，當將硬化骨水泥複合材料在溶液中浸漬時，該造孔劑在溶液中溶解。優選情況下，所述造孔劑選自由LiCl、KCl、NaCl、MgCl₂ 、CaCl₂ 、NaIO₃ 、KI、Na₃ PO₄ 、K₃ PO₄ 、Na₂ CO₃ 、胺基酸-鈉鹽、胺基酸-鉀鹽、葡萄糖、多糖、脂肪酸-鈉鹽、脂肪酸-鉀鹽、酒石酸氫鉀(KHC₄ H₄ O₆ )、碳酸鉀、葡萄糖酸鉀(KC₆ H₁₁ O₇ )、酒石酸鈉鉀(KNaC₄ H₄ O₆ ‧4H₂ O)、硫酸鉀(K₂ SO₄ )、硫酸鈉、乳酸鈉和甘露醇組成的組中。所用的造孔劑的量與硬化骨水泥複合材料期望得到的孔隙率成比例。In one embodiment, the powder component contains a pore-forming agent that dissolves in the solution when the hardened bone cement composite is impregnated in solution. Preferably, the pore former is selected from the group consisting of LiCl, KCl, NaCl, MgCl ₂ , CaCl ₂ , NaIO ₃ , KI, Na ₃ PO ₄ , K ₃ PO ₄ , Na ₂ CO ₃ , amino acid-sodium salt, Amino acid-potassium salt, glucose, polysaccharide, fatty acid-sodium salt, fatty acid-potassium salt, potassium hydrogen tartrate (KHC ₄ H ₄ O ₆ ), potassium carbonate, potassium gluconate (KC ₆ H ₁₁ O ₇ ), sodium tartrate In the group consisting of potassium (KNaC ₄ H ₄ O ₆ ‧4H ₂ O), potassium sulfate (K ₂ SO ₄ ), sodium sulfate, sodium lactate and mannitol. The amount of pore former used is proportional to the desired porosity of the hardened bone cement composite.

在一種實施方式中，所述磷酸鈣源為TTCP和DCPA的混合物。在一個方面，所述骨水泥配方使得骨水泥漿糊具有期望的工作時間和固化時間，從而使操作者在漿糊變硬之前有足夠的時間用所述漿糊來填充孔或腔。應注意到，已填充的漿糊將形成在可接受的短時間段內處理所需的最小強度。In one embodiment, the calcium phosphate source is a mixture of TTCP and DCPA. In one aspect, the bone cement formulation provides the bone cement paste with a desired working time and curing time such that the operator has sufficient time to fill the pores or cavities with the paste before the paste becomes hard. It should be noted that the filled paste will form the minimum strength required for processing in an acceptable short period of time.

在一種實施方式中，所述硬化骨水泥複合材料具有低毒性，因而，例如，在施用於患者時是安全的。注意到，硬化骨水泥具有提高的生物可再吸收的速率的、高初始強度的特性。In one embodiment, the hardened bone cement composite has low toxicity and is, for example, safe to administer to a patient. It is noted that the hardened bone cement has a high initial strength characteristic with an increased rate of bioresorbability.

由以下所述的詳細描述、圖表和申請專利範圍，本發明的另外的特徵和益處是顯而易見的。Further features and benefits of the present invention will be apparent from the detailed description, drawings and appended claims.

本文中在用於製備具有醫藥用增強的生物可再吸收的速率的硬化骨水泥複合材料的方法、配方、系統和/或過程的上下文中描述本發明的各實施方式。本領域普通技術人員認識到，具體實施方式的以下詳細描述僅用於舉例說明，而不是要以任何方式限制本發明。受益於本發明公開，專業人員容易提出本發明的其他實施方式。Embodiments of the invention are described herein in the context of methods, formulations, systems, and/or processes for preparing a hardened bone cement composite having a medically enhanced bioresorbable rate. It is to be understood by those skilled in the art that the following detailed description Other embodiments of the invention will be readily apparent to those skilled in the art from this disclosure.

涉及“一種實施方式”、“一個實施方式”、“實施例實施方式”、“各種實施方式”、“示例性實施方式”、“一方面”、“一個方面”、“示例性方面”、“各方面”等等時，說明這樣描述的本發明的具體實施方式可包括某一具體的特徵、結構或特性，但是不是每一個實施方式必然包括該具體的特徵、結構或特性。另外，重複使用的短語“在一種實施方式中”不必然指相同的實施方式，但是也可為相同的實施方式。References to "one embodiment", "one embodiment", "embodiment", "various embodiments", "exemplary embodiment", "one aspect", "one aspect", "exemplary aspect", The Detailed Description of the Invention The detailed description of the embodiments of the present invention may be construed as including a particular feature, structure, or characteristic. In addition, the phrase "in one embodiment" is not necessarily referring to the same embodiment, but may be the same embodiment.

為了清楚起見，不是對所有的實施和/或方法的傳統特徵都進行了說明和描述。當然，應理解的是，在開發任何這種實際的實施時，要進行眾多實施-特定性決定，以便達到開發者的特定目標，例如與應用和業務相關的限制一致，並且這些特定目標可以在不同的實施以及不同的開發者中變化。此外，應理解的是，這種開發計畫可能複雜且耗時，但是在受益於本發明公開的本領域普通技術人員常識性範圍內。For the sake of clarity, not all of the traditional features of the implementations and/or methods have been illustrated and described. Of course, it should be understood that in developing any such actual implementation, numerous implementation-specific decisions are made to achieve the developer's specific goals, such as application- and business-related restrictions, and these specific goals can be Different implementations and variations among different developers. Moreover, it should be understood that such development plans may be complex and time consuming, but are within the common knowledge of those of ordinary skill in the art having the benefit of the present disclosure.

本發明的具體實施方式為適用於各種醫學領域(例如矯形、脊柱和根管外科手術)的生物可再吸收的骨水泥。所述生物可再吸收的骨水泥或配方的特性或性能具有方便的工作環境和固化時間，以形成具有高強度、優異的生物相容性和優良的骨傳導性以及可調節的(或靈活的)生物再吸收速率的硬化塊。A specific embodiment of the invention is a bioresorbable bone cement suitable for use in various medical fields, such as orthopedic, spinal and root canal surgery. The properties or properties of the bioresorbable bone cement or formulation have a convenient working environment and curing time to form high strength, excellent biocompatibility and excellent osteoconductivity as well as adjustable (or flexible) a hardened block of bioresorption rate.

為了製備或製得生物可再吸收的骨水泥，該骨水泥具有靈活的(或方便的)工作環境(或時間)和固化時間的性能，以形成具有期望的強度和生物相容性的硬化骨水泥複合材料，本發明的一種實施方式公開了一種骨水泥配方，該骨水泥配方將在以下更詳細描述。在一個方面，用於製備硬化骨水泥複合材料的方法或過程包括產生骨水泥漿糊以及將所述漿糊放置在該漿糊可固化的環境中。To prepare or produce a bioresorbable bone cement, the bone cement has a flexible (or convenient) working environment (or time) and cure time performance to form a hardened bone having the desired strength and biocompatibility. Cement Composite, an embodiment of the present invention discloses a bone cement formulation, which will be described in more detail below. In one aspect, a method or process for preparing a hardened bone cement composite includes producing a bone cement paste and placing the paste in an environment in which the paste is curable.

在一種實施方式中，用於製備骨水泥漿糊的方法包括通過混合機器(例如攪拌)將粉末組份與固化液體組份混合。例如，所述粉末組份可包括硫酸鈣源和磷酸鈣源的混合物。或者，硫酸鈣源和磷酸鈣源可為分離的粉末。在這種情況下，在與固化液體組份混合之前，可首先將硫酸鈣源和磷酸鈣源組合，以形成粉末混合物。In one embodiment, a method for preparing a bone cement paste comprises mixing a powder component with a solidifying liquid component by a mixing machine (eg, agitation). For example, the powder component can include a mixture of a source of calcium sulfate and a source of calcium phosphate. Alternatively, the calcium sulfate source and the calcium phosphate source can be separate powders. In this case, the calcium sulfate source and the calcium phosphate source may first be combined to form a powder mixture prior to mixing with the solidified liquid component.

前述硫酸鈣源和磷酸鈣源可為磷酸四鈣(TTCP)和/或無水磷酸二鈣(DCPA)粉末。應注意到，可使用其他類型的來源，只要它們具有與TTCP和/或DCPA類似的化學性能或特性即可。The aforementioned calcium sulfate source and calcium phosphate source may be tetracalcium phosphate (TTCP) and/or anhydrous dicalcium phosphate (DCPA) powder. It should be noted that other types of sources may be used as long as they have similar chemical properties or characteristics as TTCP and/or DCPA.

在一種實施方式中，在大氣環境或體液(例如血液)圍繞的環境下，所述骨水泥漿糊在固化時間段內變硬或固化。在操作過程中，操作者或醫生通過切開術經由適當的工具將骨水泥漿糊放置在受損的骨的孔或腔中。例如，對於矯形、脊柱或根管處理，當骨水泥漿糊原位變成或固化成為硬化骨水泥複合材料時，根據預定的生物再吸收速率，該硬化骨水泥經過一定的時間可被受治療者再吸收。根據應用，在一種實施方式中，在將骨水泥漿糊植入到受治療者身體內以修復受損部位(例如骨或牙齒)之前，可將骨水泥漿糊成形為骨水泥複合材料的剛性塊或半剛性塊。In one embodiment, the bone cement paste hardens or solidifies during the curing period in an environment surrounded by the atmosphere or body fluids (eg, blood). During operation, the operator or physician places the bone cement paste in a hole or cavity of the damaged bone via an incision via a suitable tool. For example, for orthopedic, spinal or root canal treatment, when the cement paste becomes or solidifies in situ into a hardened bone cement composite, the hardened bone cement can be treated by the subject for a certain period of time according to a predetermined bioresorption rate. Reabsorb. Depending on the application, in one embodiment, the bone cement paste can be formed into the stiffness of the bone cement composite prior to implanting the bone cement paste into the body of the subject to repair the damaged site (eg, bone or teeth). Block or semi-rigid block.

在一種實施方式中，可使用矯形漿糊遞送工具(例如在US 7,325,702 B2中所述的傳統醫學儀器)將骨水泥漿糊注射至骨孔或腔中或通過模具成形，其中漿糊將形成硬化骨水泥複合材料塊。應注意到，矯形遞送工具能將漿糊連續遞送至骨腔中，直至骨腔被充滿。In one embodiment, the bone cement paste can be injected into a bone hole or cavity or formed by a mold using an orthopedic paste delivery tool (such as the conventional medical instrument described in US 7,325,702 B2), wherein the paste will form a hardening Bone cement composite block. It should be noted that the orthopedic delivery tool can deliver the paste continuously into the bone cavity until the bone cavity is filled.

根據應用，如果粉末組份不含適當的造孔劑，則可形成水泥的緻密塊。例如，為了從漿糊中排放或除去一部分液體，從而降低漿糊的液體/粉末比率，所述緻密塊可通過在漿糊固化之前對模具中的骨水泥漿糊加壓而形成。在一個方面，施用於模具中的所述漿糊的壓力為約1兆帕(“MPa”)至500 MPa，優選為100 MPa至500 MPa。注意到，該緻密塊具有優良的壓縮強度，其可用作醫學植入物。還應注意到，用浸漬液體將磷酸鈣水泥的剛性或實心的緻密塊浸漬預定的時間段，使得與未進行這種浸漬處理的塊相比，所得到的浸漬過的塊的總壓縮強度提高。在一種實施方式中，所述浸漬液體為含磷酸鹽的溶液。示例性水溶液可包括，但不限於，(NH₄ )₃ PO₄ 、(NH₄ )₂ HPO₄ 、NH₄ H₂ PO₄ 、K₃ PO₄ 、K₂ HPO₄ 、KH₂ PO₄ 、Na₃ PO₄ 、Na₂ HPO₄ 、NaH₂ PO₄ 或H₃ PO₄ 。在一個實例中，所述含磷酸鹽的溶液中磷酸鹽濃度為約0.1 M至約6 M，優選為約1 M至約3 M。Depending on the application, if the powder component does not contain a suitable pore former, a dense mass of cement can be formed. For example, to drain or remove a portion of the liquid from the paste to reduce the liquid/powder ratio of the paste, the dense mass can be formed by pressurizing the bone cement paste in the mold prior to curing of the paste. In one aspect, the paste applied to the mold has a pressure of from about 1 MPa ("MPa") to 500 MPa, preferably from 100 MPa to 500 MPa. It is noted that the dense block has excellent compressive strength and can be used as a medical implant. It should also be noted that the rigid or solid dense mass of calcium phosphate cement is impregnated with the impregnating liquid for a predetermined period of time such that the total compressive strength of the resulting impregnated block is increased compared to the block not subjected to such impregnation treatment. . In one embodiment, the impregnating liquid is a phosphate containing solution. Exemplary aqueous solutions can include, but are not limited to, (NH ₄ ) ₃ PO ₄ , (NH ₄ ) ₂ HPO ₄ , NH ₄ H ₂ PO ₄ , K ₃ PO ₄ , K ₂ HPO ₄ , KH ₂ PO ₄ , Na ₃ PO ₄ , Na ₂ HPO ₄ , NaH ₂ PO ₄ or H ₃ PO ₄ . In one example, the phosphate-containing solution has a phosphate concentration of from about 0.1 M to about 6 M, preferably from about 1 M to about 3 M.

當所述骨水泥配方的粉末組份含有造孔劑時，多孔塊可用作組織-工程支架(tissue-engineered scaffold)。通過將模塑塊在沉浸液體中浸漬，使得造孔劑溶解於沉浸液體中，可將造孔劑從模塑塊中除去。造孔劑可在粉末組份與固化液體組份的混合過程中加入，或者可在將其放置在模具中之前加入到所得到的漿糊中。所述沉浸液體例如可為酸性水溶液、鹼性水溶液、生理溶液、有機溶劑或基本上純水。在一種實施方式中，該沉浸液體與上述浸漬液體相同。在一種實施方式中，所述沉浸液體為水。在一個方面，所述多孔塊的孔隙率為50-90體積%。在一種實施方式中，根據所述骨水泥配方製備的緻密塊或多孔塊，通過將其浸漬於活體細胞的懸浮液或生長因數和/或藥物的溶液中，可在活體細胞、生長因數和/或藥物中沉積。在本發明中製備的緻密塊和多孔塊可被進一步破碎成粒料，用於其他醫學應用。When the powder component of the bone cement formulation contains a pore former, the porous block can be used as a tissue-engineered scaffold. The pore former can be removed from the molded block by immersing the molded block in an immersion liquid such that the pore former dissolves in the immersion liquid. The pore former may be added during the mixing of the powder component and the solidified liquid component, or may be added to the resulting paste before it is placed in the mold. The immersion liquid may be, for example, an acidic aqueous solution, an alkaline aqueous solution, a physiological solution, an organic solvent or substantially pure water. In one embodiment, the immersion liquid is the same as the impregnating liquid described above. In one embodiment, the immersion liquid is water. In one aspect, the porous block has a porosity of from 50 to 90% by volume. In one embodiment, the dense mass or porous mass prepared according to the bone cement formulation can be immersed in a suspension of living cells or a solution of growth factors and/or drugs in living cells, growth factors and/or Or deposition in drugs. The dense blocks and porous blocks prepared in the present invention can be further broken into pellets for other medical applications.

經由實驗程式的以下實施例為舉例說明，並且用於說明本發明的具體實施方式，但是，這些實施例不應看作是將本發明的實施方式局限於特定的實施方式，而是僅用於說明和理解，對於本領域技術人員來說，眾多修改和變化是顯而易見的。The following examples of the experimental examples are illustrative and are intended to illustrate the specific embodiments of the present invention. However, these embodiments should not be construed as limiting the embodiments of the present invention to the specific embodiments. Numerous modifications and changes will be apparent to those skilled in the art.

實驗程序Experimental procedure 縮寫abbreviation

TTCP：磷酸四鈣TTCP: tetracalcium phosphate

DCPA：無水磷酸二鈣DCPA: anhydrous dicalcium phosphate

CSH：半水合硫酸鈣CSH: calcium sulfate hemihydrate

WT：工作時間WT: Working hours

ST：固化時間ST: curing time

L/P比率：液體/粉末比率L/P ratio: liquid/powder ratio

CS：壓縮強度CS: compression strength

用於表格的符號Symbol for the form

#：將粉末與液體混合2分鐘，不能形成漿糊。#: The powder was mixed with the liquid for 2 minutes to form a paste.

*：從模具中移除(距將粉末與液體混合30分鐘)後，當在Hanks溶液中浸漬1天時，硬化水泥塊崩塌並破裂成粉末形式。*: After being removed from the mold (by mixing the powder with the liquid for 30 minutes), when immersed in the Hanks solution for 1 day, the hardened cement block collapsed and broke into a powder form.

※：在Hanks溶液中浸漬1天后，硬化水泥塊破碎(破裂/斷裂，但未分散成粉末形式)。*: After immersion in Hanks' solution for 1 day, the hardened cement block was broken (broken/broken, but not dispersed into a powder form).

TTCP粉末的製備Preparation of TTCP powder

TTCP粉末採用Brown和Epstein[Journal of Research of the National Bureau of Standards-A Physics and Chemistry 6 (1965) 69A 12]提出的方法、由焦磷酸二鈣(Ca₂ P₂ O₇ )(Sigma Chem. Co.，St. Louis，MO，USA)和碳酸鈣(CaCO₃ )(Katayama Chem. Co.，日本，東京)反應而自製得到。TTCP powder was prepared by the method proposed by Brown and Epstein [ Journal of Research of the National Bureau of Standards-A Physics and Chemistry 6 (1965) 69A 12], from calcium diphosphate (Ca ₂ P ₂ O ₇ ) (Sigma Chem. Co ., St. Louis, MO, USA) and calcium carbonate (CaCO ₃ ) (Katayama Chem. Co., Japan, Tokyo) were reacted and made.

TTCP粉末通過將Ca₂ P₂ O₇ 粉末與CaCO₃ 粉末均勻混合12小時而製得。Ca₂ P₂ O₇ 粉末與CaCO₃ 粉末的混合比率為1:1.27(重量比)，並將粉末混合物加熱至1400℃，使兩種粉末反應，以形成TTCP。The TTCP powder was prepared by uniformly mixing Ca ₂ P ₂ O ₇ powder with CaCO ₃ powder for 12 hours. The mixing ratio of the Ca ₂ P ₂ O ₇ powder to the CaCO ₃ powder was 1:1.27 (weight ratio), and the powder mixture was heated to 1400 ° C to react the two powders to form TTCP.

TTCP/DCPA/CSH複合漿糊的製備Preparation of TTCP/DCPA/CSH composite paste

將適量的TTCP與DCPA粉末在球磨機中均勻混合，接著與適量的CSH粉末均勻混合。將所得到的TTCP/DCPA/CSH混合粉末與期望的固化溶液(例如，0.6M(NH₄ )₂ HPO₄ )以期望的L/P比率(例如，0.28 cc/g)均勻混合，以形成TTCP/DCPA/CSH漿糊。An appropriate amount of TTCP and DCPA powder were uniformly mixed in a ball mill, followed by uniform mixing with an appropriate amount of CSH powder. The resulting TTCP/DCPA/CSH mixed powder is uniformly mixed with a desired curing solution (for example, 0.6 M (NH ₄ ) ₂ HPO ₄ ) at a desired L/P ratio (for example, 0.28 cc/g) to form TTCP. /DCPA/CSH paste.

用於研究的化學物質Chemicals used in research

複合水泥的壓縮強度測試Compressive strength test of composite cement

為了測定硬化水泥的CS，在混合1分鐘之後，在壓力為1.4 Mpa下，將水泥漿糊在直徑6 mm、深12 mm的圓柱形不銹鋼模具中填充30分鐘。從模具中移除後，將硬化水泥樣品在保持在37℃的Hanks生理溶液中浸漬，並且每天攪拌以助於保持離子濃度均勻。浸漬後，將樣品從溶液中移除，用於CS測試，此時樣品仍是濕的(“在濕條件下測試”)。使用臺式機械測定器(Shimadzu AG-10kNX，日本，東京)，以1.0 mm/min的試驗速度(crosshead speed)進行CS測試。測試方法根據ASTM 451-99a方法。To determine the CS of the hardened cement, the cement paste was filled in a cylindrical stainless steel mold having a diameter of 6 mm and a depth of 12 mm for 30 minutes at a pressure of 1.4 MPa after mixing for 1 minute. After removal from the mold, the hardened cement sample was dipped in a Hanks physiological solution maintained at 37 ° C and stirred daily to help maintain a uniform ion concentration. After immersion, the sample was removed from the solution for the CS test, at which time the sample was still wet ("tested under wet conditions"). The CS test was performed using a benchtop mechanical tester (Shimadzu AG-10kNX, Tokyo, Japan) at a crosshead speed of 1.0 mm/min. The test method is according to the ASTM 451-99a method.

工作時間/固化時間測定Working time / curing time determination

水泥漿糊的工作時間由在該水泥漿糊不再能工作之後的時間確定。水泥漿糊的固化時間根據在ISO 1566中所述的用於牙齒磷酸鋅水泥的標準方法來測定。當負載於具有直徑1 mm尖端的Vicat針上的400 g重物不能在水泥的表面上形成可察覺的圓形印記時，認為該水泥固化。The working time of the cement paste is determined by the time after the cement paste is no longer working. The curing time of the cement paste is determined according to the standard method for dental zinc phosphate cement described in ISO 1566. The cement was considered to cure when a 400 g weight loaded on a Vicat needle having a 1 mm diameter tip could not form a noticeable circular impression on the surface of the cement.

pH測定pH determination

使用pH計(Suntex Instruments SP2000，臺灣，臺北)確定早期階段(在固化過程中)的pH變化，在粉末與固化液體混合後，立即將該pH計浸入水泥漿糊中。在混合後1分鐘時，第一次讀數。繼續測定，直至漿糊幾乎變固化。每30秒進行讀數，直至混合後30分鐘。之後每60秒進行讀數。The pH change in the early stage (during curing) was determined using a pH meter (Suntex Instruments SP2000, Taipei, Taiwan), and the pH meter was immediately immersed in the cement paste after the powder was mixed with the solidified liquid. The first reading was taken 1 minute after mixing. Continue the measurement until the paste hardens. Readings were taken every 30 seconds until 30 minutes after mixing. The reading is then taken every 60 seconds.

使用相同的pH計監測在其中浸漬水泥漿糊樣品的Hanks溶液的pH值變化。在粉末與固化溶液混合5分鐘後，取出2 g水泥漿糊，並將其浸漬在20 ml pH值為7.05的Hanks溶液中，用於測試。在整個測試中溶液保持在37℃，並且連續攪拌以助於保持溶液的離子濃度均勻。The pH change of the Hanks solution in which the cement paste sample was impregnated was monitored using the same pH meter. After the powder was mixed with the solidification solution for 5 minutes, 2 g of the cement paste was taken out and immersed in 20 ml of Hanks' solution having a pH of 7.05 for testing. The solution was maintained at 37 ° C throughout the test and was continuously agitated to help maintain the ion concentration of the solution uniform.

細胞毒性測試Cytotoxicity test

根據ISO 10993-5進行細胞毒性測試。使用提取方法。將NIH/3T3成纖維細胞(播種密度5000/孔)在Dulbecco改性必需培養基(DMEM)中預先培養24小時，該培養基用牛血清(10%)和PSF(1%)補充。如下製備提取物：使硬化水泥漿糊以0.1(g/ml)的比率在37℃的培養基中浸漬24小時，接著通過離心作用收集液體。將提取物加入到96孔微板(100 μl/孔)中，該微板已在37℃的5% CO₂ 的潮濕大氣中溫育。24小時後，吸取提取物，隨後將培養基(100 μl)和WST-1(10 μl)的混合物加入到孔中，並於37℃下溫育1小時。使用WST-1試樣來測定細胞存活率。這是線粒體脫氫酶活性的比色測定，其中在450 nm下的吸光度與細胞中的脫氫酶活性成比例。孵化1小時後，將培養基與WST-1的混合物轉移至96孔微板，並使用ELISA讀數器來測定在450 nm下的吸光度。還檢測Al₂ O₃ 粉末作為對照物。對於每個樣品測試4次(n =4 )。Cytotoxicity tests were performed according to ISO 10993-5. Use the extraction method. NIH/3T3 fibroblasts (seeding density 5000/well) were pre-incubated for 24 hours in Dulbecco's modified essential medium (DMEM) supplemented with bovine serum (10%) and PSF (1%). The extract was prepared by immersing the hardened cement paste in a medium of 37 ° C for 24 hours at a ratio of 0.1 (g/ml), followed by collecting the liquid by centrifugation. The extract was added to a 96-well microplate (100 μl/well) which had been incubated in a humidified atmosphere of 5% CO ₂ at 37 °C. After 24 hours, the extract was aspirated, and then a mixture of the medium (100 μl) and WST-1 (10 μl) was added to the wells and incubated at 37 ° C for 1 hour. Cell viability was determined using a WST-1 sample. This is a colorimetric assay of mitochondrial dehydrogenase activity in which the absorbance at 450 nm is proportional to the dehydrogenase activity in the cell. One hour after incubation, the mixture of medium and WST-1 was transferred to a 96-well microplate and the absorbance at 450 nm was determined using an ELISA reader. Al ₂ O ₃ powder was also tested as a control. Test 4 times for each sample ( n = 4 ).

細胞株資訊Cell line information

對照1：TTCP/CSH水泥和(NH₄ )₂ HPO₄ 固化溶液Control 1: TTCP/CSH cement and (NH ₄ ) ₂ HPO ₄ curing solution 表1：與0.25-0.75M(NH₄ )₂ HPO₄ 混合的TTCP/CSHTable 1: TTCP/CSH mixed with 0.25-0.75M(NH ₄ ) ₂ HPO ₄

在使用0.25 M(NH₄ )₂ HPO₄ 製備漿糊的情況下，當在Hanks溶液中浸漬時模塑塊崩塌和破裂(*)，或者在Hanks溶液中浸漬1天后其壓縮強度無法測得(※)，如表1所示。至於使用較高濃度的(NH₄ )₂ HPO₄ 固化溶液製備的漿糊，在Hanks溶液中浸漬1天(1d-CS)後硬化水泥塊具有非常低的壓縮強度，如表1所示。顯然，僅具有TTCP和CSH相的粉末組份不能得到令人滿意的結果。In the case of preparing a paste using 0.25 M(NH ₄ ) ₂ HPO ₄ , the molded piece collapses and ruptures (*) when immersed in the Hanks solution, or the compressive strength cannot be measured after immersion in Hanks solution for 1 day ( ※),As shown in Table 1. As for the paste prepared using the higher concentration of the (NH ₄ ) ₂ HPO ₄ solid solution, the hardened cement block had a very low compressive strength after being immersed in the Hanks solution for 1 day (1d-CS), as shown in Table 1. Obviously, only powder components having TTCP and CSH phases did not give satisfactory results.

對照2：TTCP/CSH水泥和NH₄ H₂ PO₄ 固化溶液Control 2: TTCP/CSH cement and NH ₄ H ₂ PO ₄ curing solution 表2：與0.25-0.75M NH₄ H₂ PO₄ 混合的TTCP/CSHTable 2: TTCP/CSH mixed with 0.25-0.75M NH ₄ H ₂ PO ₄

表2表明，用於對照2的NH₄ H₂ PO₄ 固化溶液不能改進用於對照1的(NH₄ )₂ HPO₄ 固化溶液的工作時間/固化時間和1d-CS。顯然，僅具有TTCP和CSH相的粉末組份不能得到令人滿意的結果。Table 2 shows that the NH ₄ H ₂ PO ₄ curing solution for Control 2 did not improve the working time/cure time and 1d-CS of the (NH ₄ ) ₂ HPO ₄ curing solution for Control 1. Obviously, only powder components having TTCP and CSH phases did not give satisfactory results.

對照3：DCPA/CSH水泥和(NH₄ )₂ HPO₄ 固化溶液Control 3: DCPA/CSH cement and (NH ₄ ) ₂ HPO ₄ curing solution 表3：與0.25-0.75M(NH₄ )₂ HPO₄ 混合的DCPA/CSHTable 3: DCPA/CSH mixed with 0.25-0.75M(NH ₄ ) ₂ HPO ₄

由DCPA/CSH水泥製備的模塑塊，當將它們浸漬於Hanks溶液時崩塌和破裂(*)，或者在Hanks溶液中浸漬1天后它們的壓縮強度無法測得(※)，如表3所示。顯然，僅具有DCPA和CSH相的粉末組份不能得到令人滿意的結果。Molded blocks prepared from DCPA/CSH cement collapsed and ruptured (*) when immersed in Hanks' solution, or their compressive strength could not be measured after immersion in Hanks solution for 1 day, as shown in Table 3. . Obviously, only powder components having DCPA and CSH phases did not give satisfactory results.

對照4：DCPA/CSH水泥和NH₄ H₂ PO₄ 固化溶液Control 4: DCPA/CSH cement and NH ₄ H ₂ PO ₄ curing solution 表4：與0.25-0.75M NH₄ H₂ PO₄ 混合的DCPA/CSHTable 4: DCPA/CSH mixed with 0.25-0.75M NH ₄ H ₂ PO ₄

在Hanks溶液中浸漬1天后由DCPA/CSH水泥製備的模塑塊的壓縮強度無法測得(※)，如表4所示。顯然，僅具有DCPA和CSH相的粉末組份不能得到令人滿意的結果。The compressive strength of the molded piece prepared from DCPA/CSH cement after immersion for 1 day in the Hanks solution could not be measured (*), as shown in Table 4. Obviously, only powder components having DCPA and CSH phases did not give satisfactory results.

於表5-14中In Table 5-14

註：在所有條件下，TTCP與DCPA的摩爾比為1:1Note: The molar ratio of TTCP to DCPA is 1:1 under all conditions.

實施例1：(TTCP/DCPA)/CSH水泥和各種固化溶液Example 1: (TTCP/DCPA)/CSH cement and various curing solutions 表5：75重量%的磷酸鹽(TTCP/DCPA)/25重量%的CSH複合水泥Table 5: 75% by weight of phosphate (TTCP/DCPA) / 25% by weight of CSH composite cement

由表5中所示的資料可總結如下：The information shown in Table 5 can be summarized as follows:

1、K₂ HPO₄ -衍生的硬化水泥複合材料的WT/ST太短且CS低。1. The WT/ST of the K ₂ HPO ₄ -derived hardened cement composite is too short and CS is low.

2、(NH₄ )H₂ PO₄ -衍生的硬化水泥複合材料具有合理的WT/ST，但是在Hanks溶液中浸漬後分散。2. (NH ₄ )H ₂ PO ₄ - derived hardened cement composites have reasonable WT/ST, but are dispersed after immersion in Hanks' solution.

3、NaH₂ PO₄ ‧2H₂ O-衍生的硬化水泥複合材料具有合理的WT/ST，但是酸性太強且強度低。3. NaH ₂ PO ₄ ‧2H ₂ O-derived hardened cement composites have reasonable WT/ST, but are too acidic and low in strength.

4、在所有測試的固化溶液中，(NH₄ )₂ HPO₄ 產生最高的CS。4. (NH ₄ ) ₂ HPO ₄ produced the highest CS in all tested curing solutions.

5、在所有的(NH₄ )₂ HPO₄ 濃度中，0.6 M得到最高的CS(41 MPa)。5. Of all (NH ₄ ) ₂ HPO ₄ concentrations, 0.6 M gave the highest CS (41 MPa).

實施例2：與0.60M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSHExample 2: TTCP/DCPA/CSH mixed with 0.60 M (NH ₄ ) ₂ HPO ₄ 表6：與0.60M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSHTable 6: TTCP/DCPA/CSH mixed with 0.60 M (NH ₄ ) ₂ HPO ₄

在表6(與0.60M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSH)中所示的結果總結：The results shown in Table 6 (TTCP/DCPA/CSH mixed with 0.60M (NH ₄ ) ₂ HPO ₄ ) are summarized:

(1)　當在TTCP/DCPA/CSH水泥粉末中CSH含量高於約65 wt%時，其CS值變得太低(<15 MPa)。在測試條件下，適當的CSH含量應小於約65重量%。為了得到較高的強度(CS>30 MPa)，CSH含量應小於約35重量%。(1) When the CSH content in the TTCP/DCPA/CSH cement powder is higher than about 65 wt%, the CS value becomes too low (<15 MPa). Under the conditions of the test, the appropriate CSH content should be less than about 65% by weight. In order to obtain higher strength (CS > 30 MPa), the CSH content should be less than about 35% by weight.

(2)　當0.60 M(NH₄ )₂ HPO₄ 用作硬化溶液時，對於所有CSH含量(從約10重量%至約90重量%)，所有細胞毒性值可接受地大於80%。(2) When 0.60 M(NH ₄ ) ₂ HPO _{4 is} used as the hardening solution, all cytotoxicity values are acceptably greater than 80% for all CSH contents (from about 10% by weight to about 90% by weight).

實施例3：與0.20-3.0 M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSHExample 3: TTCP/DCPA/CSH mixed with 0.20-3.0 M(NH ₄ ) ₂ HPO ₄ 表7：與0.20-3.00M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSH(TTCP/DCPA:CSH=90:10)Table 7: TTCP/DCPA/CSH mixed with 0.20-3.00M(NH ₄ ) ₂ HPO ₄ (TTCP/DCPA: CSH=90:10)

在表7(與0.20-3.00M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSH(TTCP/DCPA:CSH=90:10))中所示的結果總結：The results shown in Table 7 (TTCP/DCPA/CSH (TTCP/DCPA: CSH=90:10) mixed with 0.20-3.00M(NH ₄ ) ₂ HPO ₄ ) are summarized:

(1)　當(NH₄ )₂ HPO₄ 濃度太低(在當前測試條件下，0.25 M或更低)時，硬化漿糊在Hanks溶液中浸漬時分散，並且其強度無法測得。(1) When the (NH ₄ ) ₂ HPO ₄ concentration is too low (0.25 M or less under the current test conditions), the hardened paste is dispersed in the Hanks solution, and its strength cannot be measured.

(2)　雖然銨為關鍵的壽命支撐元素，但是為了降低細胞毒性水準，(NH₄ )₂ HPO₄ 濃度也不能太高(在當前測試條件下，2 M或更高)。(2) Although ammonium is a key life support element, in order to reduce the cytotoxicity level, the (NH ₄ ) ₂ HPO ₄ concentration should not be too high (2 M or higher under current test conditions).

(3)　適當的(NH₄ )₂ HPO₄ 濃度應為0.25 M-2.0 M，優選為0.5 M-1.0 M。(或者NH₄ ⁺ 離子濃度為0.50 M-4.0 M，優選為1.0 M-2.0 M)。(3) The appropriate (NH ₄ ) ₂ HPO ₄ concentration should be 0.25 M-2.0 M, preferably 0.5 M-1.0 M. (Or NH ₄ ⁺ ion concentration is 0.50 M-4.0 M, preferably 1.0 M-2.0 M).

實施例4：與0.20-3.0 M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSHExample 4: TTCP/DCPA/CSH mixed with 0.20-3.0 M(NH ₄ ) ₂ HPO ₄ 表8：與0.20-3.00M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSH(TTCP/DCPA:CSH=75:25)Table 8: TTCP/DCPA/CSH mixed with 0.20-3.00M(NH ₄ ) ₂ HPO ₄ (TTCP/DCPA: CSH=75:25)

在表8(與0.20-3.00M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSH(TTCP/DCPA:CSH=75:25))中所示的結果總結：The results shown in Table 8 (TTCP/DCPA/CSH (TTCP/DCPA: CSH=75:25) mixed with 0.20-3.00M(NH ₄ ) ₂ HPO ₄ ) are summarized:

(2)　雖然銨為關鍵的壽命支撐元素，但是為了降低細胞毒性水準，(NH₄ )₂ HPO₄ 濃度也不能太高(在當前測試條件下，>2 M)。(2) Although ammonium is a key life support element, in order to reduce the cytotoxicity level, the (NH ₄ ) ₂ HPO ₄ concentration should not be too high (>2 M under current test conditions).

實施例5：與0.25-1.0 M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSHExample 5: TTCP/DCPA/CSH mixed with 0.25-1.0 M(NH ₄ ) ₂ HPO ₄ 表9：與0.25-1.0M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSH(TTCP/DCPA:CSH=65:35)Table 9: TTCP/DCPA/CSH mixed with 0.25-1.0 M (NH ₄ ) ₂ HPO ₄ (TTCP/DCPA: CSH=65:35)

在表9(與0.25-1.0M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSH(TTCP/DCPA:CSH=65:35))中所示的結果總結：The results shown in Table 9 (TTCP/DCPA/CSH (TTCP/DCPA: CSH=65:35) mixed with 0.25-1.0M(NH ₄ ) ₂ HPO ₄ ) are summarized:

(1)　當(NH₄ )₂ HPO₄ 濃度太低(在當前測試條件下，0.25M或更低)，硬化漿糊在Hanks溶液中浸漬時分散，並且其強度無法測得。(1) When the (NH ₄ ) ₂ HPO ₄ concentration is too low (0.25 M or less under the current test conditions), the hardened paste is dispersed in the Hanks solution, and its strength cannot be measured.

(2)　除了少數情況外，所有1-d CS值高於20 MPa，並且，在某些條件下，高於30 Mpa。(2) With the exception of a few cases, all 1-d CS values are above 20 MPa and, under certain conditions, above 30 Mpa.

實施例6：與0.40-1.0 M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSHExample 6: TTCP/DCPA/CSH mixed with 0.40-1.0 M(NH ₄ ) ₂ HPO ₄ 表10：與0.40-1.00M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSH(TTCP/DCPA:CSH=55:45)Table 10: TTCP/DCPA/CSH mixed with 0.40-1.00 M(NH ₄ ) ₂ HPO ₄ (TTCP/DCPA: CSH=55:45)

在表10(與0.40-1.00M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSH(TTCP/DCPA:CSH=55:45))中所示的結果總結：The results shown in Table 10 (TTCP/DCPA/CSH (TTCP/DCPA: CSH=55:45) mixed with 0.40-1.00 M(NH ₄ ) ₂ HPO ₄ ) are summarized:

(1)　所有1-d CS值高於20 MPa，並且，在某些條件下，高於30 MPa。(1) All 1-d CS values are higher than 20 MPa and, under certain conditions, above 30 MPa.

(2)　對於較高濃度(1.0M)和較低L/P值(低於0.33 cc/g)，WT/ST有點太短。(2) For higher concentrations (1.0M) and lower L/P values (less than 0.33 cc/g), WT/ST is a bit too short.

實施例7：與0.40-0.60 M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSHExample 7: TTCP/DCPA/CSH mixed with 0.40-0.60 M(NH ₄ ) ₂ HPO ₄ 表11：與0.40-0.60 M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSH(TTCP/DCPA:CSH=45:55)Table 11: TTCP/DCPA/CSH mixed with 0.40-0.60 M(NH ₄ ) ₂ HPO ₄ (TTCP/DCPA: CSH=45:55)

在表11(與0.40-0.60M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSH(TTCP/DCPA:CSH=45:55))中所示的結果總結：The results shown in Table 11 (TTCP/DCPA/CSH (TTCP/DCPA: CSH=45:55) mixed with 0.40-0.60M(NH ₄ ) ₂ HPO ₄ ) are summarized:

(1)　所有1-d CS值高於20 Mpa。(1) All 1-d CS values are higher than 20 Mpa.

(2)　在所有測試條件下，工作時間比5.5分鐘長，並且固化時間比7.5分鐘長。(2) Under all test conditions, the working time is longer than 5.5 minutes and the curing time is longer than 7.5 minutes.

表12在Hanks溶液中浸漬不同的天數後，TTCP/DCPA/CSH的CS(MPa)Table 12 CS (MPa) of TTCP/DCPA/CSH after immersion in Hanks solution for different days

在表12中所示的結果總結：The results summarized in Table 12 are summarized:

(1)　除了“55:45”複合材料外，所有42d-CS值高於20 MPa，這表明即使在Hanks溶液中浸漬42天后，強度也只溫和減小。但是，當CSH含量增至45重量%時，複合材料的CS值非常顯著地下降。(1) With the exception of the "55:45" composite, all 42d-CS values were higher than 20 MPa, indicating that the strength was only moderately reduced even after immersion in Hanks solution for 42 days. However, when the CSH content was increased to 45% by weight, the CS value of the composite material decreased very significantly.

實施例8：有機酸的加入對與1.0 M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSH的影響Example 8: Effect of addition of organic acid on TTCP/DCPA/CSH mixed with 1.0 M(NH ₄ ) ₂ HPO ₄ 表13：有機酸(酒石酸、檸檬酸和蘋果酸)的加入對與1 M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSH(TTCP/DCPA:CSH=75:25)的性能的影響Table 13: Effect of addition of organic acids (tartaric acid, citric acid and malic acid) on the properties of TTCP/DCPA/CSH (TTCP/DCPA: CSH=75:25) mixed with 1 M(NH ₄ ) ₂ HPO ₄

在表13中所示的結果總結：The results summarized in Table 13 are summarized:

(1)　在1 M(NH₄ )₂ HPO₄ 固化溶液中加入蘋果酸降低硬化複合水泥的CS值。(1) Adding malic acid to the 1 M(NH ₄ ) ₂ HPO ₄ solidified solution reduces the CS value of the hardened composite cement.

(2)　在1 M(NH₄ )₂ HPO₄ 固化溶液中加入檸檬酸提高硬化複合水泥的CS值(從約28 MPa至約32 MPa)。(2) Adding citric acid to the 1 M(NH ₄ ) ₂ HPO ₄ solidified solution increases the CS value of the hardened composite cement (from about 28 MPa to about 32 MPa).

(3)　在1 M(NH₄ )₂ HPO₄ 固化溶液中加入酒石酸提高硬化複合水泥的CS值(從約28 MPa至35 MPa)。(3) Adding tartaric acid to the 1 M(NH ₄ ) ₂ HPO ₄ solidified solution to increase the CS value of the hardened composite cement (from about 28 MPa to 35 MPa).

TTCP/DCPA/CSH複合材料緻密塊的製備Preparation of TTCP/DCPA/CSH composite dense block

在完全硬化之前，在期望的壓力(最大壓力為150、300或450 Kgf)下，將漿糊放置在模具中，以將一部分液體從漿糊中擠出。從模具中移除後，將一組硬化複合材料樣品在防潮容器中放置1天。將另一組樣品在保持在期望的溫度(37℃)下的浸漬溶液(1M(NH₄ )₂ HPO₄ 或1M K₂ HPO₄ )中再浸漬1天，接著在50℃的烘箱中乾燥1天。Prior to complete hardening, the paste is placed in a mold at a desired pressure (maximum pressure of 150, 300 or 450 Kgf) to squeeze a portion of the liquid out of the paste. After removal from the mold, a set of hardened composite samples were placed in a moisture barrier container for 1 day. Another set of samples was further immersed in an impregnation solution (1 M (NH ₄ ) ₂ HPO ₄ or 1 M K ₂ HPO ₄ ) maintained at the desired temperature (37 ° C) for 1 day, followed by drying in an oven at 50 ° C. day.

TTCP/DCPA/CSH複合材料多孔塊的製備Preparation of TTCP/DCPA/CSH composite porous block

將適量的TTCP與DCPA粉末在球磨機中均勻混合，接著與適量的CSH粉末均勻混合。將所得到的TTCP/DCPA/CSH混合粉末與期望的固化溶液(例如，0.6M(NH4)2HPO4)以期望的L/P比率(例如，0.28 cc/g)均勻混合，以形成TTCP/DCPA/CSH漿糊。An appropriate amount of TTCP and DCPA powder were uniformly mixed in a ball mill, followed by uniform mixing with an appropriate amount of CSH powder. The resulting TTCP/DCPA/CSH mixed powder is uniformly mixed with a desired curing solution (for example, 0.6 M (NH 4 ) 2 HPO 4 ) at a desired L/P ratio (for example, 0.28 cc/g) to form TTCP/DCPA/ CSH paste.

隨後將複合漿糊與造孔劑(例如，KCl顆粒)以期望的重量比(例如，TTCP/DCPA/CSH:KCl=1:1或1:2)均勻混合，以形成TTCP/DCPA/CSH/KCl漿糊。The composite paste is then uniformly mixed with a pore forming agent (for example, KCl particles) in a desired weight ratio (for example, TTCP/DCPA/CSH: KCl = 1:1 or 1:2) to form TTCP/DCPA/CSH/ KCl paste.

在完全硬化之前，在期望的壓力(最大壓力為450 Kgf)下，將複合漿糊放置在模具中，以將一部分液體從漿糊中擠出。從模具中移除後，將一組硬化複合材料塊在37℃的去離子水中沉浸3天，使得KCl顆粒溶解，形成多孔複合材料塊，接著在50℃的烘箱中乾燥1天。將另一組樣品在保持在期望的溫度(37℃)下的浸漬溶液(例如，1M(NH4)2HPO4或1M K2HPO4)中再浸漬1天，使得多孔塊的強度提高，接著在50℃的烘箱中乾燥1天。為了從孔內部除去殘餘的浸漬溶液，將浸漬過的多孔樣品在37℃的去離子水中進一步漂洗3天。Prior to complete hardening, the composite paste was placed in a mold at a desired pressure (maximum pressure of 450 Kgf) to squeeze a portion of the liquid out of the paste. After removal from the mold, a set of hardened composite blocks were immersed in deionized water at 37 ° C for 3 days to dissolve the KCl particles to form a porous composite block, which was then dried in an oven at 50 ° C for 1 day. Another set of samples was further immersed in an impregnation solution (for example, 1 M (NH4) 2HPO4 or 1 M K2HPO4) maintained at the desired temperature (37 ° C) for 1 day to increase the strength of the porous block, followed by an oven at 50 ° C. Dry for 1 day. In order to remove residual impregnation solution from the inside of the well, the impregnated porous sample was further rinsed for 3 days in deionized water at 37 °C.

孔隙率的測定Determination of porosity

根據ASTM C830-00(2006)方法“Standard Test Methods for Apparent Porosity,Liquid Absorption,Apparent Specific Gravity,and Bulk Density of Refractory Shapes by Vacuum Pressure(用於通過真空壓力的耐火型材的表觀孔隙率、液體吸收、表觀比重和體積密度的標準測試方法)”測定各樣品的孔隙率。According to ASTM C830-00 (2006) method "Standard Test Methods for Apparent Porosity, Liquid Absorption, Apparent Specific Gravity, and Bulk Density of Refractory Shapes by Vacuum Pressure" for apparent porosity and liquid absorption of refractory profiles by vacuum pressure , Standard Test Method for Apparent Specific Gravity and Bulk Density) "Measure the porosity of each sample.

實施例9：緻密的塊Example 9: Dense block 表14：由與0.6 M(NH₄ )₂ HPO₄ (L/P=0.28cc/g)混合的TTCP/DCPA/CSH混合粉末製備的TTCP/DCPA/CSH複合材料緻密塊的壓縮強度(MPa)Table 14: Compressive strength (MPa) of TTCP/DCPA/CSH composite dense blocks prepared from TTCP/DCPA/CSH mixed powder mixed with 0.6 M(NH ₄ ) ₂ HPO ₄ (L/P = 0.28 cc/g)

在表14(TTCP/DCPA/CSH複合材料緻密塊的壓縮強度)中所示的結果總結：The results shown in Table 14 (Compressive Strength of TTCP/DCPA/CSH Composite Dense Blocks) are summarized:

(1)　在所有條件下，經浸漬-處理過的樣品具有明顯較高的CS值。(1) The impregnated-treated sample has a significantly higher CS value under all conditions.

(2)　在所有條件下，隨著模塑壓力的升高，CS值顯著提高。(2) Under all conditions, the CS value increases significantly as the molding pressure increases.

實施例10：多孔塊Example 10: Porous block 表15：由與0.6 M(NH₄ )₂ HPO₄ (L/P=0.33cc/g)混合的TTCP/DCPA/CSH/KCl(造孔劑)混合粉末製備的TTCP/DCPA/CSH複合材料多孔塊的孔隙率值(體積%)Table 15: TTCP/DCPA/CSH composite porous material prepared from a mixed powder of TTCP/DCPA/CSH/KCl (porogen) mixed with 0.6 M(NH ₄ ) ₂ HPO ₄ (L/P=0.33 cc/g) Porosity value of the block (% by volume)

在表15(由與0.6 M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSH/KCl(造孔劑)混合粉末製備的TTCP/DCPA/CSH複合材料多孔塊)中所示的結果總結：The results shown in Table 15 (TTCP/DCPA/CSH composite porous blocks prepared from TTCP/DCPA/CSH/KCl (porogen) mixed powders mixed with 0.6 M(NH ₄ ) ₂ HPO ₄ ) are summarized:

(1)　在TTCP/DCPA/CSH:KC1=1:1時，孔隙率值為46-63%，並且在TTCP/DCPA/CSH:KCl=1:2時，孔隙率值為81-89%，其可理想地用作組織-工程支架。(1) When TTCP/DCPA/CSH: KC1=1:1, the porosity value is 46-63%, and when TTCP/DCPA/CSH:KCl=1:2, the porosity value is 81-89%. It is ideally used as a tissue-engineering scaffold.

(2)　隨著複合材料中CSH含量的提高，孔隙率值通常提高。(2) As the CSH content in the composite increases, the porosity value generally increases.

表16：由與0.6 M(NH₄ )₂ HPO₄ (L/P=0.33cc/g)混合的TTCP/DCPA/CSH/KCl(造孔劑)混合粉末製備的TTCP/DCPA/CSH複合材料多孔塊的壓縮強度(MPa)值Table 16: TTCP/DCPA/CSH composite porous material prepared from a mixed powder of TTCP/DCPA/CSH/KCl (porogen) mixed with 0.6 M(NH ₄ ) ₂ HPO ₄ (L/P = 0.33 cc/g) Block compressive strength (MPa) value

在表16(由與0.6M(NH₄ )₂ HPO₄ 混合的TTCP/DCPA/CSH/KCl(造孔劑)混合粉末製備的TTCP/DCPA/CSH複合材料多孔塊)中所示的結果總結：The results shown in Table 16 (TTCP/DCPA/CSH composite porous blocks prepared from TTCP/DCPA/CSH/KCl (porogen) mixed powders mixed with 0.6M (NH ₄ ) ₂ HPO ₄ ) are summarized:

(1)　在所有測試條件下，隨著複合材料中CSH含量的提高，多孔塊的CS強度下降。(1) Under all test conditions, as the CSH content in the composite increases, the CS strength of the porous block decreases.

(2)　在TTCP/DCPA/CSH:KCl=1:1時，由TTCP/DCPA/CSH/KCl製備的多孔塊(水/油浸漬處理)的CS值為約2-5 Mpa，並且在TTCP/DCPA/CSH:KCl=1:2時，CS值為約0.4-0.9 Mpa。(2) When TTCP/DCPA/CSH: KCl=1:1, the CS value of the porous block (water/oil immersion treatment) prepared by TTCP/DCPA/CSH/KCl is about 2-5 Mpa, and at TTCP/ When DCPA/CSH: KCl = 1:2, the CS value is about 0.4-0.9 Mpa.

(3)　浸漬處理顯著增強多孔塊的強度。在TTCP/DCPA/CSH:KCl=1:1時，經(NH₄ )₂ HPO₄ -浸漬過的多孔塊的CS值顯著增至4.8-8.9 MPa，並且在TTCP/DCPA/CSH:KCl=1:2時，CS值顯著增至約0.5-1.2 MPa。在TTCP/DCPA/CSH:KCl=1:1時，經K₂ HPO₄ -浸漬過的多孔塊的CS值顯著增至4.8-8.8 MPa，並且在TTCP/DCPA/CSH:KCl=1:2時，CS值顯著增至約0.5-1.2 MPa。(3) The immersion treatment significantly enhances the strength of the porous block. At TTCP/DCPA/CSH:KCl=1:1, the CS value of the (NH ₄ ) ₂ HPO ₄ -impregnated porous block was significantly increased to 4.8-8.9 MPa, and at TTCP/DCPA/CSH:KCl=1 At 2, the CS value is significantly increased to about 0.5-1.2 MPa. When TTCP/DCPA/CSH: KCl=1:1, the CS value of the K ₂ HPO ₄ -impregnated porous block is significantly increased to 4.8-8.8 MPa, and when TTCP/DCPA/CSH:KCl=1:2 The CS value is significantly increased to about 0.5-1.2 MPa.

實施例11：複合植入物吸收比率的動物研究和測定Example 11: Animal studies and determination of composite implant absorption ratio

在臺灣台南的國立成功大學醫學院動物中心進行動物研究。成年(體重2.8-3.5 kg)、健康的雄性新西蘭白兔用作實驗動物。將兔子單獨封裝在不銹鋼籠中，兔子可自由接近食物和水。在收到動物和開始研究之間允許最少7天的馴化週期。將注射部位剃毛，並用70%乙醇和Betadine^TM (聚維酮碘10%)清潔。所有動物在全身麻醉下操作。戊巴比妥鈉(0.1 ml/100 g，Tokyo Kasei Kogyo，日本，東京)用作全身麻醉劑，而利多卡因(Fujisawa Pharmaceutical CO.，日本，東京)用作局部麻醉劑。為了在股骨的內髁中植入水泥漿糊，在股骨的前表面上形成縱向切口。將兔子膝關節的內側切開，以暴露股骨。將股骨暴露之後，使骨膜反射，並鑽2 mm導向孔。使用具有增加尺寸的鑽使該孔逐漸變寬，直至達到最終的直徑為5 mm。使用專門的直徑5 mm的牙鑽(drill burr)，並且在深度為10mm處***環，以確保鑽孔的長度適當(10 mm)。Animal research was conducted at the Animal Center of the National Cheng Kung University School of Medicine in Tainan, Taiwan. Adult male (weight 2.8-3.5 kg), healthy male New Zealand white rabbits were used as experimental animals. The rabbits are individually packaged in stainless steel cages and the rabbits are free to access food and water. A minimum of 7 days of acclimation cycle is allowed between receipt of the animal and initiation of the study. The injection site was shaved, and washed with 70% ethanol and Betadine ^TM (10% povidone-iodine) cleaning. All animals were operated under general anesthesia. Sodium pentobarbital (0.1 ml/100 g, Tokyo Kasei Kogyo, Tokyo, Japan) was used as a general anesthetic, and lidocaine (Fujisawa Pharmaceutical CO., Tokyo, Japan) was used as a local anesthetic. In order to implant a cement paste in the medial malleolus of the femur, a longitudinal incision is made on the anterior surface of the femur. The inside of the rabbit knee was cut open to expose the femur. After exposing the femur, the periosteum was reflected and a 2 mm guide hole was drilled. The hole was gradually widened using a drill with an increased size until a final diameter of 5 mm was reached. Use a special 5 mm diameter drill burr and insert the ring at a depth of 10 mm to ensure the proper length of the hole (10 mm).

將兩種磷酸鈣/硫酸鈣複合水泥漿糊(90重量% TTCP/DCPA:10重量% CSH和55重量% TTCP/DCPA:45重量% CSH)植入準備好的骨腔中。填充漿糊後，將皮下組織和皮膚用絲線逐層封閉。為了降低手術期間感染的風險，以40 mg/kg的劑量對兔子進行皮下注射抗生素的處理。在手術後12周後，動物均死去。Two calcium phosphate/calcium sulfate composite cement pastes (90 wt% TTCP/DCPA: 10 wt% CSH and 55 wt% TTCP/DCPA: 45 wt% CSH) were implanted into the prepared bone cavity. After filling the paste, the subcutaneous tissue and the skin are closed layer by layer with a silk thread. In order to reduce the risk of infection during surgery, rabbits were treated with subcutaneous antibiotics at a dose of 40 mg/kg. The animals died after 12 weeks after surgery.

在動物死後，立即切除股骨部分，並除去多餘的組織。使用單透鏡反射照相機的切片照片和圖像分析系統來計算殘餘的植入物的面積。通過以下方程式確定植入物吸收比率：植入物吸收比率=(初始植入物的橫截面積-殘餘植入物的橫截面積)/初始植入物的橫截面積。Immediately after the animal dies, the femoral portion is removed and excess tissue is removed. A slice photo and image analysis system of a single lens reflex camera was used to calculate the area of the residual implant. The implant absorption ratio is determined by the following equation: implant absorption ratio = (cross-sectional area of the initial implant - cross-sectional area of the residual implant) / cross-sectional area of the initial implant.

總結：to sum up:

在以上提及的照片中看出，“90/10”和“55/45”樣品的平均殘餘植入物比率分別為81.1%(吸收比率：18.9%)和67.7%(吸收比率：32.3%)。這意味著，55/45植入物的愈合速度比90/10植入物的愈合速度快約70%。As seen in the photos mentioned above, the average residual implant ratios for the "90/10" and "55/45" samples were 81.1% (absorption ratio: 18.9%) and 67.7% (absorption ratio: 32.3%), respectively. . This means that the healing rate of the 55/45 implant is about 70% faster than the healing rate of the 90/10 implant.

Claims

一種骨水泥配方，該骨水泥配方含有粉末組份和固化液體組份，其中液體與粉末的比率為0.20cc/g至0.50cc/g，其中，所述粉末組份含有硫酸鈣源和磷酸鈣源，以所述硫酸鈣源和磷酸鈣源的總重量為基準，所述硫酸鈣源的重量比小於65%，並且所述固化液體組份含有濃度為0.5M至4M的銨離子，其中，所述磷酸鈣源包括磷酸四鈣和磷酸二鈣，其中磷酸四鈣與磷酸二鈣的摩爾比為0.5至2.5，並且所述硫酸鈣源為半水合硫酸鈣、脫水硫酸鈣或無水硫酸鈣，其中，以所述硫酸鈣源和磷酸鈣源的總重量為基準，所述粉末組份的硫酸鈣源大於5%。 A bone cement formulation comprising a powder component and a solidified liquid component, wherein a ratio of liquid to powder is from 0.20 cc/g to 0.50 cc/g, wherein the powder component comprises a calcium sulfate source and a calcium phosphate a source, the weight ratio of the calcium sulfate source is less than 65% based on the total weight of the calcium sulfate source and the calcium phosphate source, and the solidified liquid component contains ammonium ions having a concentration of 0.5 M to 4 M, wherein The calcium phosphate source comprises tetracalcium phosphate and dicalcium phosphate, wherein a molar ratio of tetracalcium phosphate to dicalcium phosphate is 0.5 to 2.5, and the calcium sulfate source is calcium sulfate hemihydrate, calcium sulfate dehydrate or anhydrous calcium sulfate. Wherein, the calcium component of the powder component is greater than 5% based on the total weight of the calcium sulfate source and the calcium phosphate source.

如申請專利範圍第1項所述的配方，其中所述液體與粉末的比率為0.25cc/g至0.35cc/g。 The formulation of claim 1, wherein the liquid to powder ratio is from 0.25 cc/g to 0.35 cc/g.

如申請專利範圍第1項所述的配方，其中所述磷酸四鈣與磷酸二鈣的摩爾比為1.0。 The formulation of claim 1, wherein the molar ratio of tetracalcium phosphate to dicalcium phosphate is 1.0.

如申請專利範圍第1項所述的配方，其中所述硫酸鈣源為半水合硫酸鈣。 The formulation of claim 1, wherein the calcium sulfate source is calcium sulfate hemihydrate.

如申請專利範圍第1項所述的配方，其中所述粉末組分的硫酸鈣源為10%-55%。 The formulation of claim 1, wherein the powder component has a calcium sulfate source of from 10% to 55%.

如申請專利範圍第1至5項中任一項所述的配方，其中，所述磷酸二鈣為無水磷酸二鈣。 The formulation of any one of claims 1 to 5 wherein the dicalcium phosphate is anhydrous dicalcium phosphate.

如申請專利範圍第1至5項中任一項所述的配方，其中，所述固化液體組份含有濃度為1.0M至2.0M的銨離子。 The formulation of any one of claims 1 to 5, wherein the solidified liquid component contains ammonium ions at a concentration of 1.0 M to 2.0 M.

如申請專利範圍第7項所述的配方，其中，所述固化液體組份為NH₄ H₂ PO₄ 、(NH₄ )₂ HPO₄ 、(NH₄ )₃ PO₄ ．3H₂ O或它們的混合物的溶液。The formulation of claim 7, wherein the solidified liquid component is NH ₄ H ₂ PO ₄ , (NH ₄ ) ₂ HPO ₄ , (NH ₄ ) ₃ PO ₄ . A solution of 3H ₂ O or a mixture thereof.

如申請專利範圍第8項所述的配方，其中，所述固化液體組份為(NH₄ )₂ HPO₄ 的水溶液。The formulation of claim 8, wherein the solidified liquid component is an aqueous solution of (NH ₄ ) ₂ HPO ₄ .

如申請專利範圍第6項所述的配方，其中，所述磷酸鈣源由磷酸四鈣和無水磷酸二鈣組成。 The formulation of claim 6, wherein the calcium phosphate source consists of tetracalcium phosphate and anhydrous dicalcium phosphate.

如申請專利範圍第1至5項中任一項所述的配方，其中，所述配方還包括造孔劑，當將由所述配方製備的硬化骨水泥複合材料浸漬於溶液中時，所述造孔劑溶解於該溶液中。 The formulation of any one of claims 1 to 5, wherein the formulation further comprises a pore forming agent, when the hardened bone cement composite prepared from the formulation is immersed in a solution, the making The porogen is dissolved in the solution.

一種製備硬化骨水泥複合材料的方法，該方法包括通過將申請專利範圍第1至5項中任一項中所述的骨水泥配方的粉末組份與固化液體組份混合，形成骨水泥漿糊；在模具中使所述漿糊成形；以及移除所述模具，以形成硬化骨水泥複合材料的塊。 A method of preparing a hardened bone cement composite, the method comprising the bone water described in any one of claims 1 to 5 The powder component of the mud formulation is mixed with the solidified liquid component to form a bone cement paste; the paste is shaped in a mold; and the mold is removed to form a block of the hardened bone cement composite.

如申請專利範圍第12項所述的方法，其中，該方法還包括在所述漿糊固化之前對所述模具中的所述漿糊加壓，以從所述漿糊中除去一部分液體，使得所述漿糊的液體與粉末的比率下降，其中，施用於所述模具中的所述漿糊的壓力為1MPa至500MPa。 The method of claim 12, wherein the method further comprises pressurizing the paste in the mold before the paste is cured to remove a portion of the liquid from the paste, such that The ratio of the liquid to the powder of the paste is lowered, wherein the pressure applied to the paste in the mold is from 1 MPa to 500 MPa.

如申請專利範圍第13項所述的方法，其中施用於所述模具中的所述漿糊的壓力為100MPa至500MPa。 The method of claim 13, wherein the pressure applied to the paste in the mold is from 100 MPa to 500 MPa.

如申請專利範圍第12項所述的方法，其中，該方法還包括用浸漬液體將所述塊浸漬一段時間，使得與未經所述浸漬處理的所述塊相比，從所述浸漬液體移除而得到的浸漬過的塊的壓縮強度提高了。 The method of claim 12, wherein the method further comprises immersing the block with an immersion liquid for a period of time such that it moves from the immersion liquid compared to the block that has not been subjected to the immersion treatment The resulting impregnated block has an increased compressive strength.

如申請專利範圍第15項所述的方法，其中，所述浸漬液體為含磷酸鹽的溶液，其中磷酸鹽的濃度為0.1M至6M。 The method of claim 15, wherein the impregnating liquid is a phosphate-containing solution, wherein the concentration of the phosphate is from 0.1 M to 6 M.

如申請專利範圍第16項所述的方法，其中，所述磷酸鹽的濃度為1M至3M。 The method of claim 16, wherein the phosphate has a concentration of from 1 M to 3 M.

如申請專利範圍第12項所述的方法，其中，所述骨水泥配方的粉末組份含有造孔劑，或者在混合過程中加入造孔劑，或者在使模具中的所述漿糊成形之前將造孔劑與漿糊混合，並且所述方法還包括將所述硬化骨水泥複合材料的塊浸漬於沉浸液體中，以將所述造孔劑溶解於所述沉浸液體，在所述塊中產生孔，從而形成多孔塊。 The method of claim 12, wherein the powder component of the bone cement formulation contains a pore former, or a pore former is added during the mixing, or before the paste in the mold is formed. The pore former is mixed with the paste, and the method further comprises immersing the block of the hardened bone cement composite in an immersion liquid to dissolve the pore former in the immersion liquid, in the block A hole is created to form a porous block.

如申請專利範圍第18項所述的方法，其中，所述多孔塊的孔隙率為50-90體積%。 The method of claim 18, wherein the porous block has a porosity of 50 to 90% by volume.

如申請專利範圍第18項所述的方法，其中，所述造孔劑為選自由LiCl、KCl、NaCl、MgCl₂ 、CaCl₂ 、NaIO₃ 、KI、Na₃ PO₄ 、K₃ PO₄ 、Na₂ CO₃ 、胺基酸-鈉鹽、胺基酸-鉀鹽、葡萄糖、多糖、脂肪酸-鈉鹽、脂肪酸-鉀鹽、酒石酸氫鉀、碳酸鉀、葡萄糖酸鉀、酒石酸鈉鉀、硫酸鉀、硫酸鈉、乳酸鈉和甘露醇組成的組中。The method of claim 18, wherein the pore former is selected from the group consisting of LiCl, KCl, NaCl, MgCl ₂ , CaCl ₂ , NaIO ₃ , KI, Na ₃ PO ₄ , K ₃ PO ₄ , Na ₂ CO ₃ , amino acid-sodium salt, amino acid-potassium salt, glucose, polysaccharide, fatty acid-sodium salt, fatty acid-potassium salt, potassium hydrogen tartrate, potassium carbonate, potassium gluconate, potassium sodium tartrate, potassium sulfate, In the group consisting of sodium sulfate, sodium lactate and mannitol.

如申請專利範圍第18項所述的方法，其中，所述沉浸液體為含磷酸鹽的溶液或水，所述磷酸鹽的溶液中磷酸鹽濃度為0.1M至6M。 The method of claim 18, wherein the immersion liquid is a phosphate-containing solution or water, and the phosphate solution has a phosphate concentration of 0.1 M to 6 M.

如申請專利範圍第21項所述的方法，其中，所述磷酸鹽濃度為1M至3M。 The method of claim 21, wherein the phosphate concentration is from 1 M to 3 M.

如申請專利範圍第18項所述的方法，其中，該方法還包括用浸漬液體將所述多孔塊浸漬一段時間，使得與未經所述浸漬處理的所述多孔塊相比，從所述浸漬液體移除而得到的浸漬過的多孔塊的壓縮強度提高了。 The method of claim 18, wherein the method further comprises impregnating the porous block with an impregnation liquid for a period of time such that the impregnation is compared to the porous block not subjected to the impregnation treatment. The compressive strength of the impregnated porous block obtained by liquid removal is improved.

如申請專利範圍第23項所述的方法，其中，所述浸漬液體為含磷酸鹽的溶液，其中磷酸鹽濃度為0.1M至6M。 The method of claim 23, wherein the impregnating liquid is a phosphate-containing solution, wherein the phosphate concentration is from 0.1 M to 6 M.

如申請專利範圍第24項所述的方法，其中，所述磷酸鹽濃度為1M至3M。 The method of claim 24, wherein the phosphate concentration is from 1 M to 3 M.

如申請專利範圍第12項所述的方法，其中，該方法還包括將所述塊破碎成粒料。 The method of claim 12, wherein the method further comprises breaking the block into pellets.

如申請專利範圍第18項所述的方法，其中，該方法還包括將所述多孔塊破碎成粒料。The method of claim 18, wherein the method further comprises breaking the porous block into pellets.