【作者】 彭维海；

【导师】 路来金；

【作者基本信息】 吉林大学 ， 外科学， 2009， 博士

【摘要】 骨折是骨科、颌面外科临床诊治中常见的疾病,目前常用的内固定系统金属固定系统,然而金属固定系统有许多弊端,因此许多学者致力于研究可吸收固定材料,以期得到最理想的内固定材料。羟基磷灰石(HA)/聚乳酸(PLA)复合材料作为新兴材料,具有良好的骨传导性、生物相容性、机械力学强度及适度的生物降解性而受到广泛关注。以往的合成HA/PLA的方法为物理方法,物理方法的原理是HA颗粒与PLA基质物理性结合,HA与PLA基体的界面结合力较差,一旦暴露在生理环境中, HA与聚合物基体的界面层首先遭到破坏,这样, HA粒子很快就从PLA基质中脱离下来,导致复合材料未等缺损完全修复而易于过早地失去其有效强度。因此探索一种能够提高HA与PLA之间黏附力的合成方法是当前研究热点。我们与中国科学院长春应用化学研究所合作,研制了一种制备新型PLLA/HA复合物的方法。PLLA在碘苯腈辛酸亚锡(Sn(Oct)2)催化下通过开环聚合将L-乳酸直接修饰在n-HA的羟基上,然后经修饰的羟基磷灰石(PLLA-gHA)进一步与PLLA基质混合制成新型PLLA/PLLA-gHA复合物。PLLA-gHA颗粒与非修饰的n-HA颗粒相比可以更均一的分散在氯仿溶液中,显示与PLLA基质更好的粘附性能。因此,PLLA/PLLA-gHA比简单PLLA/n-HA共混具有更好的力学性能。该合成方法国内、外尚未见报道,并已申请国家专利,具有独立知识产权。本实验在先期生物相容性及安全性实验取得预期结果基础上,重点从检测材料的生物降解性能、生物力学性能及促进骨折愈合等方面进行研究。新材料PLLA/PLLA-gHA与单纯PLLA材料做对比,进行体外、犬肌内种植、骨折固定等不同部位的材料大体外观观察,降解率和吸收率的测定,扫描电镜观察断面降解情况以评价材料的生物降解性能,通过大体观察骨折愈合情况,测试材料的弯曲强度,骨痂面积,X线成像,骨痂组织病理以评价新材料的生物力学性能和对骨折愈合的影响。结果表明,HA的加入使新材料PLLA/PLLA-gHA同单纯PLLA材料比较减缓了降解速度和吸收速度,有利于材料早期强度的保持,避免无菌性炎症的发生。PLLA/PLLA-gHA同PLLA材料比较具有更高的初始机械力学强度及适当的强度衰减速度,提供更加稳定的内环境,更加有利于骨折愈合。PLLA/PLLA-gHA接骨板完全可以满足犬下颌骨骨折固定的要求,并取得了预期的实验结果,为今后临床应用提供了实验基础。本实验证实新型PLLA/PLLA-gHA材料具备良好的机械性能及适当的降解性能,是一种理想的骨折固定材料。更多还原

【Abstract】 Fracture is a common desease in orthopedics and dentofacial surgery.The basic principle in treatment of fracture are reposition, fixation, functional exercise early and any one is necessary. Accurate reposition and stable fixation are basic factors which are important in healing course of bone fracture. Internal fixation of fractures is classically performed using metallic devices. Although these are claimed to be inert, complications may occur as a result of their permanent presence in the body, such as migration, growth disturbances, stress shielding, infection, osteoporosis and secondary removal operation. To resolve all these problems, absorbable devices have been developed. Polylactide acid (PLA) is most favorite materail in all kinds of absorbable materials, because it has such good properties. (1) excellent biocompatibility, non-toxicity, non-antigenicity. Polylactide acid was certifide as a safe material by FDA. (2) Mechanic power is decline gradually during degradation. Stress force transmits to fracture line slowly which can stimulate healing of bone fracture and avoid stress shielding. (3) Complete absorption. Degradation product can be absorbed or expeled by body without second operation to taking it out.Comercial products of PLA existed and were used in clinic more than twenty-year,especially were used in cancellous bone fracture and non-loading bone fracture fixation whicn obtain excellent results.Though obtained excellent results, the bioabsorbable devices are not yet an ideal internal fixation system and many problems should be resolved. (1) Mechanic power is not strong enough strong for cortical bone repairing and no compression, so just fit to cancellous bone repairing. (2) There is still some kind of inflammatory reaction during the degradation course of the polymers. In order to improve the PLA material’s properties, hydroxyapatite (HA) was mixed into PLA materiaLs to produce HA/PLA composite. HA either raise mechanic strength or buffer the acid of degradation product of PLA. Osteoinductive of HA provides proper circumstance of osteocyte growth.There are many methods that produce HA/PLA composite including chemical method and physical method.The strategy of physical method is physical mixture of HA particle and PLA matrix. Interfacial adhesion between the HP particles and the PLLA matrix is not strong enough.After transplanted to humanbody the interfacial layer between the filler and the polymer matrix was destroyedfirstly, thus HA particles may easily disengage from the organic matrix, resulting in a sharp decrease of mechanical properties in a short time,so its mechanical properties are low and its load-bearing applications are limited.To reshape the surface of HA particle is the key points of chemical method. Grafting polymerization of LLactide on the surface of hydroxyapatite nano-crystals change the properties of HA in order to increase interfacial adhesion between HA particles and the PLLA matrix.Because of chemical binding,so it needs stronger force whicn can depart the HA particles from PLLA matrix.It shows increasing of mechanical intensity.It is a optimal method.A new type PLLA/PLLA-gHA composite which is pocessing self- intellectual property rights wsa produces by Changchun institute of applied chemistry Chinese Academy of sciences.A noveL method to modify the surface of n-HA particles and grafting Poly-L-Lactic acid (PLLA) to synthesis composite which was then mixed with PLLA matrix to form HA/PLLA composite.The first stage we study the biocompatibility and the results indicates that PLLA /PLLA-gHA composite has excellent biocompatibility.The mechanical propeties and rate of degradation are unknown.Whether it can fixed fracture effectiveLy and whetther it can avoid stress shielding and osteoporosis unknown either.So we test the mechanical propeties and degradable propeties of the new composite by fixing the mandible fractures of beagle dogs using PLLA/PLLA-gHA composite plate and compare with PLLA plate.We hope to provide the effective data. The experiment was divided into three parts:1、An introduction of the preparation of PLLA/PLLA-gHA and their properties. PLLA was directly grafted onto the hydroxyl group of the surface of n-HA particles by ring-opening polymerization of L-Lactide in the presence of stannous octanoate (Sn (Oct) 2) as cataLyst.And the PLLA-gHA was further blended with PLLA matrix to form PLLA/PLLA-gHA.2、Test velocity of degradation of PLLA/PLLA-gHA and PLLA.Put the PLLA/ PLLA-gHA plate and PLLA plate into madible fracture area, muscle and PBS solution, Taking out them at corresponding time to test absorption rate and degrad- ation rate of two materials. Transection of material was scanning by electronm- icroscope. The date were compared with statistics method.3、Mechanical properties of PLLA/PLLA-gHA and PLLA were tested. To study the influence of fracture healing course by two plates. To establish animal modles of mandible fracture .They were fixed by PLLA/PLLA-gHA pLate and PLLA plate either and taken X-RAYS and then execute them at 1st, 2send, 3th, 6th and 12th month postoperatively.Taken the plates out from the mandible, the plates were tested on the CCS-44100 type of electron omnipotent mechanics apparatus to get bending strength of two kind plates and mandible bone. Bony callus were taken hematoxylin and eosin stain (HE stain) to make histological test. The date were compared with statistics method.Main Results are as follows:1、In the study, we synthesized a new bone repairing material PLLA/PLLA-gHA, grafting with PLLA successfully modified the surface of HA nano-particles. The PLLA-gHA particles could be more uniformly dispersed into chloroform than the non-grafted one. When they are blended with PLLA they can be uniformly dispersed in the PLLA matrix and show improved adhesion with PLLA matrix.The PLLA/PLLA-gHA composites exhibit better mechanical properties than simple PLLA/HA blend.2、The sequence of degradation rate was bone fracture>muscle>vitro situation, The pLates were not absorbed absolutely at 12th month. The degradation rate and absorption rate of PLLA/PLLA-gHA composite was slower than that of PLLA material.There was evident difference between two kinds in statistics after 6th month.3、Mechanical properties and ductility of PLLA/PLLA-gHA composite was stronger than that of PLLA material.The mechanical decLine rate of PLLA/PLLA-gHA composite was slower than that of PLLA material. The difference was evident. Observation of bone fracture healing, bony callus, X-rays and histological test showed that the cure of bone fractures which were fixed by PLLA/PLLA-gHA plate was better than that of PLLA plate, but the difference was not evident in statistics.ConcLusionThe PLLA/PLLA-gHA composite showed good mechanical properties and proper degradation rate and decrease the rate of inflammatory complication.It meets requirement of fixing mandible fracture. It is good substitute material of bone fracture fixtion system.更多还原