可降解速固化骨水泥的研制及相关基础研究
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摘要
骨缺损是现代战争中常见的战伤之一，其治疗一般采用骨移植术。由于战伤的特殊性，要求对战伤所致骨缺损的骨移植材料的选择，除要具有来源广泛，易于携带，使用方便，成骨活性良好的特点外，还必须适应各种各样的战伤骨缺损类型，具有可塑形和粘接功能，这点对于提高现代战争的战伤救治水平，显得尤为重要。目前，骨移植修复材料主要分两大类：生物材料和人工材料，具体材料多种多样，由于每种材料的性能和特点不同，实际应用中各有优缺点，因此联合采用两种以上的材料往往可以取长补短，达到理想效果。脱钙骨基质(DBM)具有成骨良好、易于大量获得、使用简单、便于保存和携带，且有较好的骨传导能力等优点，目前已成功应用于临床替代自体骨移植修复缺损，治疗骨折不连接；磷酸钙骨水泥(calcitun Phosphate cement，CPC)又称羟基磷灰石骨水泥(hydroxyapatite cement，HA)，是一种具有生物学活性的新型非陶瓷型羟基磷灰石类人工骨材料；氰基丙烯酸正丁酯(NBCA)是目前已用于临床的组织粘合剂。
本研究参考有关文献方法自行合成了脱钙骨基质(DBM)颗粒，并根据组织工程学原理，与新型人工骨材料磷酸钙骨水泥(CPC)复合，加入适量氰基丙烯酸正丁酯(NBCA)，研制成既具有骨诱导活性，又具有骨传导作用的可降解、速固化、
第四军医大学博士学位论文
强度高的复合骨水泥（DCN骨水泥）；为深讨真临床实际应用的可能性，对这一复
合材料进行了系列研究，包括理化特性、生物学相容性和成骨活性等，并进行
了动物节段性骨缺损的修复实验，以期为平、战时骨缺损的修复寻找一种新型、
理想的骨修复材料。
一、可降解速固化骨水泥结构特征及力学性能
扫描电镜观察发现，磷酸钙骨水泥均匀散在分布在脱钙骨基质骨粒间并呈
规则有序的蜂窝状被覆骨粒表面，上有大量 30飞0 p m孔洞；复合材料内骨粒间
形成多点状或多点面状结台，有较多不规则相互连通的自然孔隙存在，为新骨
长入填充，提供了很好的条件；生物力学测试发现，DCN骨水泥的抗压强度达
43．3MPa，稍低于PMMA骨水泥（P（．of），但明显高于CPC（P＜0．01），说明该材
料有较高的强度；DCN骨水泥的红外光谱，与单纯CPC、DBM、NBCA相比，末见
新的特征峰出现，表明CPC、DBM与NBCA之间虽发生了相互作用，但作用结果
井末改变单一材料的特征结构，因此对DBM的生物活性不会产生影晌。
二、可降解速固化骨水泥的生物相容性研究
通过体外溶m试验、凝血试验，动物体内毒性试验、热原试验、肌肉埋入
试验及皿清特异性抗体检测等方法观察DCN骨水泥的生物学相容性和生物学安
全性。结果表明材料无毒，不含致热原，体外不引起溶血反应，对凝血功能无
明显影晌。植入兔或小鼠肌袋内刘肌肉无刺激作用，可异伍诱导出新骨形成，
组织学检查末见组织变性、坏死和免疫排斥反应，血清中末检测出特异性抗体。
以上结果证明，DCN骨水泥有良好的生物学相容性和生物学安全性。
三、可降解速固化骨水泥骨诱导活性鉴定
将 DCN骨水泥和 DC骨水泥（不加 NBCA）分别植入兔背肌肌袋内，于不同时
间取材，通过组织学切片、ALP g手段观察异位诱导成骨倡况。结果表明：＊）
术后2周，DCN骨水泥组可见间充质细胞增殖、聚集并包绕DBM骨粒。u）术后
4固，DCN骨水泥组DBM己有部分吸收，并被由间充质细胞分化来的软骨样细胞
一3一
第四军医大学博士学位论文
和软骨样组织包裹。（3）木后6周，脱矿骨进一步吸收，软骨细胞和软骨组织
逐渐成熟，新骨形成，新骨骨细胞核明显，胞体大。新骨组织夫见连接成广。（4）
术后 12周，DBM吸收并被新骨组织部份或大部份代替且相互连接成片，可见毛
细血管居于其间。ALP测定结果与组织学观察的新骨形成情况基本一致，术后2
周后ALP显著升高，6 i达到最高值。以上均证明DCN骨水泥有较强的异位诱
导成骨能力，诱导新骨的形成伴随着材料的缓慢降解。
四、可降解速固化骨水泥修复兔挠骨节段性骨缺损
采用兔挠骨干 15rnTn阶段性骨／骨膜缺损摸型，实验组骨缺损处分别植入 DC＼
或DC骨水泥。术后4、8、16和24 ＄分别取材，通过组织切片、血清钙、磷和
ALP检测等方法观察新骨形成。清况，同时用X线检查、骨密度测量、生物力学、
计算机图像分析等测定手段综合评价材料的骨修复能力和降解谓况。研究发现，
DCN骨水泥植人4 i大量间充质细胞分化，在材料与骨端之间出现一层软骨细
胞，软骨细胞继续增生并向编织骨分化；SN材料降解的同时，小梁骨出
Bone defect is the most frequently encountered war injury cases under modern war situation. With respect to the special features of war injury, it's necessary to select the bone graft materials with care to satisfy its need. When meeting this goal, we should take into consideration of a few aspects pertinent to the graft materials, which include easy availability, portability, convenient for use, the best osteogenesis, besides, its suitability for different categories of war injury bone defect, and its plasticity and cohesiveness, the latter is very important for improving the level of war injury cure. Recently, bone graft materials can be roughly grouped into two categories, ie , biomaterials and artificial materials. In practice, many different materials are offered for our selection, which have their own respective advantage and disadvantage, so it is advisable for us to combine over two different materials to make up with some satisfied end-product. Decalcified bone matrix(DBM)boasts of good osteogenesis
, easily harvested in large quantity, convenient for preservation and portability,aand also the good bone transduction, all the above merits contribute to its successful clinical utilization in treating bone defect and nonunion as a substitute of former autograft practice; Calcium Phosphate cement(CPC), also called hydroxyapatite cement(HA), is a bioactive new-typed non-ceramic hydroxyapatite artificial material; N butyl cyanoacrylate (NBCA) is a bone adhesive current in
clinical use.
In this research, the DBM particles were synthesized by our own on the basis of referring to related published literature; besides, following the principle of tissue engineering, the DBM particles were integrated into Calcium Phosphate cement(CPC) with appropriate addition of NBCA. The end-product of this procedure is a compound bone cement(DCN), with the advantages of good bone induction and transduction, biodegradability, fast solidification and high intensity. For studying its feasibility in clinical practice, a series of research works were undergone , including chemical and physical features, biocompatibility, osteogenesis, and experiment of animal segmental bone defect repair; through the above endeavors, we hope to locate a new-typed and ideal bone repair material for both the peace and war-time bone defect repair.
1. Constructive and biomechenical properties of material of DCN bone cements
Under scanning electron microscope(SEM), the CPC was found to be well-distributed between DBM particles and covered the surface of DBM with honeycomb-like state where have a large quality of cave in 30-60 n m size. The DBM particles with irregular gaps existing within interspace were connected with CPC by the multipolar mode in the compound materials, this provide a good condition for newly formed bone fill in; The results of mechanical measurement show the ultimate compressive strengths of DCN bone cements were 43.3Mpa, slightly lower than PMMA (P<0.01) ,but obsviously higher than CPC (PO.01) ,this indicated that the DCN bone cement have a good strengths. Compared with CPC, DBM, NBCA, the FTIR results of DCN bone cements show that no new bond arise, it suggest that there are interaction among CPC, DBM and NBCA, but this did not change the special bond of each material, as a results, did not influence the osteoinduction of DBM.
2. Biocompatibility and biological safety evaluation of DCN bone cement
Biocompatibility and biological safety of DCN bone cement were evaluated
by a series of in vitro and in vivo studies including animal experiments, and histochemical detection to test the toxicity, pyrogen, coagulant, hemolysis and immunogen. The bone cement was found to have no toxicity and no pyrogen in animal test, no hemolytic activities and it couldn't influence the blood coagulation in vitro. Implanted the bone cement into the muscle pouches in the thigh of mice or rabbits, it was found no obvious specific antibodies produced in serum and no significant immune reaction of foreign body. All the results indicated tha
本研究参考有关文献方法自行合成了脱钙骨基质(DBM)颗粒，并根据组织工程学原理，与新型人工骨材料磷酸钙骨水泥(CPC)复合，加入适量氰基丙烯酸正丁酯(NBCA)，研制成既具有骨诱导活性，又具有骨传导作用的可降解、速固化、
第四军医大学博士学位论文
强度高的复合骨水泥（DCN骨水泥）；为深讨真临床实际应用的可能性，对这一复
合材料进行了系列研究，包括理化特性、生物学相容性和成骨活性等，并进行
了动物节段性骨缺损的修复实验，以期为平、战时骨缺损的修复寻找一种新型、
理想的骨修复材料。
一、可降解速固化骨水泥结构特征及力学性能
扫描电镜观察发现，磷酸钙骨水泥均匀散在分布在脱钙骨基质骨粒间并呈
规则有序的蜂窝状被覆骨粒表面，上有大量 30飞0 p m孔洞；复合材料内骨粒间
形成多点状或多点面状结台，有较多不规则相互连通的自然孔隙存在，为新骨
长入填充，提供了很好的条件；生物力学测试发现，DCN骨水泥的抗压强度达
43．3MPa，稍低于PMMA骨水泥（P（．of），但明显高于CPC（P＜0．01），说明该材
料有较高的强度；DCN骨水泥的红外光谱，与单纯CPC、DBM、NBCA相比，末见
新的特征峰出现，表明CPC、DBM与NBCA之间虽发生了相互作用，但作用结果
井末改变单一材料的特征结构，因此对DBM的生物活性不会产生影晌。
二、可降解速固化骨水泥的生物相容性研究
通过体外溶m试验、凝血试验，动物体内毒性试验、热原试验、肌肉埋入
试验及皿清特异性抗体检测等方法观察DCN骨水泥的生物学相容性和生物学安
全性。结果表明材料无毒，不含致热原，体外不引起溶血反应，对凝血功能无
明显影晌。植入兔或小鼠肌袋内刘肌肉无刺激作用，可异伍诱导出新骨形成，
组织学检查末见组织变性、坏死和免疫排斥反应，血清中末检测出特异性抗体。
以上结果证明，DCN骨水泥有良好的生物学相容性和生物学安全性。
三、可降解速固化骨水泥骨诱导活性鉴定
将 DCN骨水泥和 DC骨水泥（不加 NBCA）分别植入兔背肌肌袋内，于不同时
间取材，通过组织学切片、ALP g手段观察异位诱导成骨倡况。结果表明：＊）
术后2周，DCN骨水泥组可见间充质细胞增殖、聚集并包绕DBM骨粒。u）术后
4固，DCN骨水泥组DBM己有部分吸收，并被由间充质细胞分化来的软骨样细胞
一3一
第四军医大学博士学位论文
和软骨样组织包裹。（3）木后6周，脱矿骨进一步吸收，软骨细胞和软骨组织
逐渐成熟，新骨形成，新骨骨细胞核明显，胞体大。新骨组织夫见连接成广。（4）
术后 12周，DBM吸收并被新骨组织部份或大部份代替且相互连接成片，可见毛
细血管居于其间。ALP测定结果与组织学观察的新骨形成情况基本一致，术后2
周后ALP显著升高，6 i达到最高值。以上均证明DCN骨水泥有较强的异位诱
导成骨能力，诱导新骨的形成伴随着材料的缓慢降解。
四、可降解速固化骨水泥修复兔挠骨节段性骨缺损
采用兔挠骨干 15rnTn阶段性骨／骨膜缺损摸型，实验组骨缺损处分别植入 DC＼
或DC骨水泥。术后4、8、16和24 ＄分别取材，通过组织切片、血清钙、磷和
ALP检测等方法观察新骨形成。清况，同时用X线检查、骨密度测量、生物力学、
计算机图像分析等测定手段综合评价材料的骨修复能力和降解谓况。研究发现，
DCN骨水泥植人4 i大量间充质细胞分化，在材料与骨端之间出现一层软骨细
胞，软骨细胞继续增生并向编织骨分化；SN材料降解的同时，小梁骨出
Bone defect is the most frequently encountered war injury cases under modern war situation. With respect to the special features of war injury, it's necessary to select the bone graft materials with care to satisfy its need. When meeting this goal, we should take into consideration of a few aspects pertinent to the graft materials, which include easy availability, portability, convenient for use, the best osteogenesis, besides, its suitability for different categories of war injury bone defect, and its plasticity and cohesiveness, the latter is very important for improving the level of war injury cure. Recently, bone graft materials can be roughly grouped into two categories, ie , biomaterials and artificial materials. In practice, many different materials are offered for our selection, which have their own respective advantage and disadvantage, so it is advisable for us to combine over two different materials to make up with some satisfied end-product. Decalcified bone matrix(DBM)boasts of good osteogenesis
, easily harvested in large quantity, convenient for preservation and portability,aand also the good bone transduction, all the above merits contribute to its successful clinical utilization in treating bone defect and nonunion as a substitute of former autograft practice; Calcium Phosphate cement(CPC), also called hydroxyapatite cement(HA), is a bioactive new-typed non-ceramic hydroxyapatite artificial material; N butyl cyanoacrylate (NBCA) is a bone adhesive current in
clinical use.
In this research, the DBM particles were synthesized by our own on the basis of referring to related published literature; besides, following the principle of tissue engineering, the DBM particles were integrated into Calcium Phosphate cement(CPC) with appropriate addition of NBCA. The end-product of this procedure is a compound bone cement(DCN), with the advantages of good bone induction and transduction, biodegradability, fast solidification and high intensity. For studying its feasibility in clinical practice, a series of research works were undergone , including chemical and physical features, biocompatibility, osteogenesis, and experiment of animal segmental bone defect repair; through the above endeavors, we hope to locate a new-typed and ideal bone repair material for both the peace and war-time bone defect repair.
1. Constructive and biomechenical properties of material of DCN bone cements
Under scanning electron microscope(SEM), the CPC was found to be well-distributed between DBM particles and covered the surface of DBM with honeycomb-like state where have a large quality of cave in 30-60 n m size. The DBM particles with irregular gaps existing within interspace were connected with CPC by the multipolar mode in the compound materials, this provide a good condition for newly formed bone fill in; The results of mechanical measurement show the ultimate compressive strengths of DCN bone cements were 43.3Mpa, slightly lower than PMMA (P<0.01) ,but obsviously higher than CPC (PO.01) ,this indicated that the DCN bone cement have a good strengths. Compared with CPC, DBM, NBCA, the FTIR results of DCN bone cements show that no new bond arise, it suggest that there are interaction among CPC, DBM and NBCA, but this did not change the special bond of each material, as a results, did not influence the osteoinduction of DBM.
2. Biocompatibility and biological safety evaluation of DCN bone cement
Biocompatibility and biological safety of DCN bone cement were evaluated
by a series of in vitro and in vivo studies including animal experiments, and histochemical detection to test the toxicity, pyrogen, coagulant, hemolysis and immunogen. The bone cement was found to have no toxicity and no pyrogen in animal test, no hemolytic activities and it couldn't influence the blood coagulation in vitro. Implanted the bone cement into the muscle pouches in the thigh of mice or rabbits, it was found no obvious specific antibodies produced in serum and no significant immune reaction of foreign body. All the results indicated tha
引文
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