双磷酸盐及低频超声在骨水泥应用中的特殊作用研究
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摘要
随着我国正进入老龄化社会,膝关节炎的发病率不断上升,人工全膝关节置换技术的广泛开展,术后并发症逐年增加,以假体无菌性松动尤甚,一旦出现须行人工关节翻修术,不仅治疗难度大,术后并发症率显著提高,而且给病人带来身心毁灭性的打击。如何有效防治假体松动已成为骨科医生亟待解决的重要问题。无菌性松动与假体周围骨量丢失紧密相关。骨量丢失分为两类：一类为机械性,发生于术后早期,以应力遮挡机制最主要。主要集中于股骨远端和胫骨近端,在术后3个月内丢失最快,可持续长达8年,丢失量分别达44%、57%；另一类为生物性,发生于术后后期,指磨损颗粒作用于炎症细胞引起慢性炎症反应,促进破骨细胞吸收骨质,抑制成骨细胞形成新骨。该机制较机械性骨量丢失更为隐匿,持续时间更长。阿仑膦酸钠属第三代双磷酸盐,是目前抑制骨质吸收的最有效的药物之一,不仅能抑制巨噬细胞和破骨细胞,而且可促进诱导成骨细胞和骨髓间充质干细胞形成新骨。阿仑膦酸钠已获美国食品药品管理局批准广泛用于防治骨质疏松病、代谢性骨病和Paget病。口服阿仑膦酸钠可显著提高人工关节置换术后假体周围骨密度,缓解假体周围的骨量丢失,提高假体的稳定性。但口服给药存在生物利用度低、易致食道溃疡及胃肠道反应、需要长达数年服药、病人耐受性较差、一旦停药阿仑膦酸钠对假体周围骨量的保护作用消失等弊病。迫切需要寻找一种针对假体周围骨量丢失的有效、经济、方便且安全的给药途径。
体外研究证实,载双磷酸盐骨水泥能抑制骨水泥颗粒诱导巨噬细胞向破骨细胞分化和骨吸收作用。动物研究证实载双磷酸盐骨水泥能显著减少假体周围骨量丢失,增强假体的稳定性。尽管载阿仑膦酸钠骨水泥有着广阔的临床应用前景,但其药物缓释性能及机制的研究在国内外仍是空白。在以往力学性能的研究中,所载的阿仑膦酸钠基本为液剂,将不可避免地降低骨水泥的力学强度。
随着骨科技术的进展,近年来关节置换手术得到迅速发展,对一些终末性关节疾病进行关节功能的重建,取得了满意的疗效。但是人工关节存在着本身一些无法避免的并发症,其中假体术后感染是关节置换最严重的并发症,一旦发生,几乎每个患者都需要第二次、第三次乃至多次手术来进行翻修,不仅给病人带来身心和经济上多方打击,而且就医生而言,治疗难度大,且再次感染率远高于初次关节置换,就成熟的髋、膝关节置换而言,翻修后再感染率达5～34%。虽然随着无菌条件的改善,抗生素的发展,关节置换术后感染率出现了很大下降,但是随着置换手术的不断推广,人工关节感染的绝对例数仍然不断在上升,就美国统计而言,只人工髋关节术后深部感染的病例每年超过4000例。而返观国内,随着人口结构的老龄化发展,再加上庞大的人口基数,我国近几年来人工关节置换数量迅速上升,同时关节术后感染病例亦不断增加。因此,如何有效的进行人工关节感染后翻修是关节外科医生所必须面对的并亟待解决的重要问题。
尽管载抗生素骨水泥已广泛在防治人工关节感染上发挥了一定的作用,然而,不同国家地区对其作用所持观点、应用方法和疗效存在较大分歧,部分学者甚至对该项技术持否定态度。原因在于：(1)载抗生素骨水泥中药物难以溶出释放,不仅导致局部药物利用率低下,无法有效杀菌,而且局部无效抑菌浓度的释放可能引起选择性耐药的菌株出现；(2)骨水泥内载入抗生素会降低其力学性能,影响假体远期生存率；(3)长期载庆大霉素骨水泥的应用导致临床假体相关性感染的致病菌超过50%对庆大霉素耐药。低频超声已经成功的用于外科化脓性感染的治疗上,并迅速的推广到许多疾病的治疗,包括急慢性脓胸、各种妇科炎症等等。国外学者将其在体外作用于庆大霉素骨水泥后发现,低频超声能增强庆大霉素的释放,各样本中庆大霉素释放率提高了2.4～14.7%,但作者指出这仅仅是观察到的一个现象而已,许多机制尚不明了,参数和频率的优化组合尚需进一步研究。
本研究旨在分别研究双磷酸盐及低频超声在丙烯酸骨水泥中的特殊应用,分为四个部分：一、在磨损颗粒诱导骨溶解的动物模型中,通过骨密度检测及生物力学测试,比较载阿仑膦酸钠丙烯酸骨水泥与皮下注射阿仑膦酸钠抑制钛磨屑诱导的骨溶解疗效；二、制备不同载荷的阿仑膦酸钠纯粉复合骨水泥试件,通过检测抗压强度、压缩弹性模量、抗张强度、抗弯强度和疲劳寿命,威布尔频率函数分析疲劳性能,激光散射法测定纯粉的粒径,分析药物载荷和体液浸泡对其力学性能的影响和规律；三、对载万古霉素骨水泥试件进行不同参数的高功率密度低频超声辐照,通过药物释放观测及电镜扫描,研究高功率密度低频超声辐照模式对超声促进药物释放的影响,并探讨作用机制。四、制作万古霉素骨水泥-假体柄界面模型,通过电镜扫描、墨汁浸染、生物力学检测等手段,研究低频脉冲超声对载万古霉素丙烯酸骨水泥-假体柄界面孔隙率和剪切应力的影响。
第一章载阿仑膦酸钠骨水泥抑制钛磨屑诱导假体周围骨溶解
目的比较载阿仑膦酸钠丙烯酸骨水泥与皮下注射阿仑膦酸钠抑制钛磨屑诱导的骨溶解疗效。
方法48只成年雄性新西兰兔随机均分为无钛磨屑且无阿仑膦酸钠组(A组),有钛磨屑注射且无阿仑膦酸钠组(B组),钛磨屑分别注射0.1%、0.5%、1.0%且载阿仑膦酸钠丙烯酸骨水泥组(C、D、E组),钛磨屑注射且皮下注射阿仑膦酸钠组(F组),每组8只。将载阿仑膦酸钠骨水泥植入兔股骨远端。制备磨屑诱导骨溶解动物模型。术后8周对股骨行组织形态学分析、骨密度测定及界面力学测试。
结果B组假体周围可见明显的骨溶解,而C、D、E、F组骨溶解明显少于B组。B组假体周围骨密度(bone mineral density, BMD)和骨-骨水泥界面抗剪强度分别较A组下降17%和56%；D组假体周围BMD和界面抗剪强度较B组分别增加29%和62%；E组假体周围BMD和界面抗剪强度较B组分别增加37%和29%；F组假体周围BMD和界面抗剪强度较B组分别增加51%和69%；C组、D组、E组分别与F组比较,假体周围BMD和界面抗剪强度的差异均无统计学意义。
结论载阿仑膦酸钠丙烯酸骨水泥与皮下注射阿仑膦酸钠均可在一定程度上抑制磨损磨屑诱导的骨吸收,增强界面抗剪强度。
第二章载阿仑膦酸钠骨水泥的力学性能和显微结构
目的研究阿仑膦酸钠纯粉复合丙烯酸骨水泥的疲劳和静态力学性能,分析药物载荷和体液浸泡对其力学性能的影响和规律。
方法制备不同载荷的阿仑膦酸钠纯粉复合骨水泥试件,根据纯粉载荷及试件的贮存环境进行分组,检测抗压强度、压缩弹性模量、抗张强度、抗弯强度和疲劳寿命,威布尔频率函数分析疲劳性能,激光散射法测定纯粉的粒径。
结果增加纯粉载荷可提高试件的抗压强度极限、抗张强度极限,但降低疲劳寿命。体液浸泡可降低试件的抗压强度极限、压缩弹性模量、抗张强度极限及疲劳寿命。纯粉载入使骨水泥的疲劳性能下降16.7%-26.1%。纯粉的粒径为4.67Μm-44.21μgm。
结论阿仑膦酸钠纯粉的粒径及分布范围较小,载入后丙烯酸骨水泥的静态力学性能仍显著高于ASTM/ISO标准,但疲劳性能有一定程度下降。与以往采用双磷酸盐液剂或片剂磨粉相比,纯粉对丙烯酸骨水泥力学强度的影响最小
第三章高功率密度低频超声间断辐照对载万古霉素骨水泥药物释放的促进作用
目的研究高功率密度低频超声辐照模式对超声促进药物释放的影响,并探讨其作用机制。
方法制备质量分数为10%的载万古霉素骨水泥(vancomycin-loaded bone cement, VLBC)圆柱体试件,浸泡于40ml PBS中。将试件随机分为三组：空白对照组、超声连续辐照组、超声间断辐照组,后两组接受超声辐照14d。三组试件中部分样本(n=4)于浸泡28d内定时采样测定万古霉素浓度,计算T>MIC、14-28d亚抑菌浓度释药量、14d内累积释药量并行曲线拟合；部分样本(n=3)于浸泡14d后脱水、干燥、喷金,行扫描电镜观察表面形态。
结果(1)超声间断辐照组T>MIC较对照组及超声连续辐照组分别提高6.56d、7.09d,超声连续辐照组T>MIC较对照组下降0.53d。(2)超声间断辐照组亚抑菌浓度释药量较对照组及超声连续辐照组分别下降0.16mg.0.19mg;超声间断辐照组14d累积释药量较对照组及超声连续辐照组分别提高2.88mg、2.81mg。(3)三组采用指数增长至最大值模型拟合效果均理想,超声间断辐照组M0、 Mmax-M0、K均较对照组和超声连续辐照组提高,超声连续辐照组MO较对照组高,但Mmax-M0、K、N较对照组低。
结论高功率密度低频超声间断辐照不仅可显著提高VLBC药物的释放率,延长T>MIC还可抑制VLBC后期亚抑菌浓度释放。指数增长至最大值模型对超声辐照下VLBC药物释放的拟合度较理想。高功率密度低频超声间断辐照对VLBC的表面释放和内部弥散有明显的促进作用,连续辐照抑制VLBC的内部弥散。
第四章低频超声对载万古霉素骨水泥-假体柄界面的微观结构和力学特性的影响
目的研究低频脉冲超声对载万古霉素丙烯酸骨水泥-假体柄界面孔隙率和剪切应力的影响。
方法制备1%质量分数万古霉素骨水泥-假体柄界面模型,随机分为对照组、450mW/cm2超声组和1200mW/cm2超声组,每组10个样本。对照组于37℃PBS中浸泡30d,超声组于37℃PBS中超声辐照7d后再浸泡23d,试件空气中风干24h后万能力学试验机检测界面剪切应力,场发射扫描电子显微镜和Image-Pro Pus6.0图像处理软件观察和分析界面孔隙分布。每组另取两试样置于3℃PBS和印度墨汁混和溶液中如上行超声辐照和体液浸泡,观察界面墨汁渗透浸染程度。
结果450mW/cm2超声组界面剪切应力和孔隙率与对照组相比无显著差异；1200mW/cm2组界面剪切应力较对照组下降14%,界面孔隙率较对照组增加9%；1200mW/cm2组邻近超声探头的试件中上端孔隙率明显高于对照组相应区域,下部与对照组相比差异无统计学意义；1200mW/cm2组试件上端墨汁浸染较对照组和450mW/cm2超声组显著。
结论1200mW/cm2低频脉冲超声连续辐照一周可增加界面孔隙率和体液渗透界面,但可降低丙烯酸骨水泥-假体柄界面初始稳定性,450mW/cm2低频脉冲超声不会降低丙烯酸骨水泥-假体柄界面剪切应力。超声对界面远期稳定性的影响有待疲劳试验和动物体内试验进一步研究。
Particle-induced osteolysis is a major cause of aseptic loosening after total joint arthroplasty. Bisphosphonates are commonly used to treat conditions associated with bone loss, such as osteoporosis, Paget's disease and skeletal carcinomatosis. Recently, several studies have shown that bisphosphonates can inhibit wear debris-induced osteolysis and increase peri-implant bone mineral density (BMD). However, side effects like fever, throat and stomach ulcers, and low bioavailability were observed after systemic treatment. Thus, bisphosphonate-loaded acrylic bone cement was proposed as local delivery system to reduce the risk of osteolysis and resulting prosthetic loosening. This proposal is similar to the addition of antibiotic to bone cement against infection. However, studies showed that liquid form of bisphosphonate led to incomplete polymerization of bone cement and weaken its mechanical strength. Powdered bisphosphonates proved to be a superior choice. Lewis et al. found that given the addition of0.21g of alendronate powder into50g of cement powder, there was no significant reduction in the fatigue life.
Unfortunately, previous studies never focused on the effect of alendronate cement on wear debris-induced osteolysis in vivo. Also, it should be noted that bisphosphonates added to bone cement might reduce the mechanical properties of bone cement and led to the failure of the total joint replacement. Several studies have shown that liquid form of a bisphosphonate led to incomplete polymerization of acrylic bone cement and significantly reduced acrylic bone cement mechanical properties. Therefore, the aim of the present study is to comprehensively investigate the effect of drug load and fluid environment on the static mechanical properties, fatigue life, and micro structure of purified-alendronate-impregnated acrylic bone cement (PAIBC) in vitro and the related mechanism. In addition, the anti-resorptive efficacy of alendronate cement would be compared with systemic alendronate.
Implant-related infection has been a devastating disaster for patients undergoing joint arthroplasty. Antibiotic-loaded bone cement is proven a keystone against the infection since it can provide high local delivery of antibiotic. Two categories are included based on the purposes:the prophylactic cement refers to prophylaxis against the infection with a low antibiotic load during a primary arthroplasty or a revision arthroplasty, whereas the therapeutic cement means curing the infection by using beads or spacers with a high antibiotic load between implant removal and reimplantation. High susceptibility to staphylococci, rare resistant strains, and weak toxicity render vancomycin typically the last resort or the drug of choice to be combined with aminoglycosides for loading into the therapeutic cement. Unfortunately, the therapeutic cement has met with mixed results. The relapse rate of the infection was reported to9%～18%. Such problem was mainly attributed to the poor antibiotic release from cement, of which vancomycin was one of the poorest. The length of time when local drug level exceeded the MIC (T>MIC), a key indicator for the antimicrobial activity of vancomycin-loaded bone cement (VLBC), was far from the required time for effective killing of bacteria. Furthermore, the long-term subtherapeutic release of antibiotic from cement will definitely select resistant strains. Anagnostakos et al. have shown that after prolonged time periods bacteria can even colonize gentamicin-vancomycin-loaded bone cement.
Ultrasound, a popular medical device for sonoporation and bone healing, has been found to enhance antibiotic release from acrylic bone cement. However, the enhancement by previous milliwatt-level ultrasonication was confined in the early period of drug release. Then the burst release waned quickly to a sustained slow release, which did not contribute to adequately enhancing the drug release, extending the T>MIC, and avoiding drug-resistant strains. Furthermore, the mechanisms of improved drug release from cement are poorly understood. The nonthermal effect of ultrasound, mainly the stable cavitation and the radiation pressure, generates multidirectional acoustic microstreams which produces a high shear stress at drug-cement interfaces, allowing detachment of drug grains from the surface and pushing solution into acrylic matrix via craters and channels. Although it was reported that low-frequency pulsed wave ultrasound was found to be safe in vivo experiments, there were few reports on the effects of low-frequency pulsed wave ultrasound on the shear strength on at the cement-stem interface. Studies have suggested that the loosening failure of cemented stems was initiated by debonding of the stem-cement interface because of a lack of chemical bonding, and the debonding at the interface is was primarily dominated by shear failure as proven with Finite Element Analysis. In the present study the kinetics of vancomycin release and the surface microstructure of VLBC under the watt-level ultrasonication with and without the pause insertion were contrasted. The shear strength, porosity and the extent of penetration of fluid into the cement-stem interface were determined and contrasted among the control group and ultrasound groups. Finally, the involved mechanisms were discussed.
Part1Effects of local and systemic alendronate delivery on wear debris-induced osteolysis in vivo
Objective:To investigate the effects of locally and systemically administered alendronate on wear-debris induced osteolysis in vivo.
Methods:Endotoxin-free titanium particles were injected into rabbit femurs, prior to insertion of a non-weight-bearing polymethylmethacrylate plug into the distal femur canal. Then the particles were repeatedly injected into the knee2,4and6weeks after the implantation. Alendronate was incorporated at three different concentrations (0.1wt%,0.5wt%and1.0wt%) into bone cement for local delivery. For systemic delivery, alendronate was subcutaneously injected (1.0mg/kg/week) one week after the implantation and then once a week until sacrifice.
Results:Eight weeks postoperatively, there was significant evidence of osteolysis surrounding the plug in the control group compared with markedly-blocked osteolysis in the local0.5wt%, local1.0wt%, and the systemic group. There was a concentration-dependent effect of alendronate on the improvement of periprosthetic bone mineral density. Notably, no significant difference was found between local0.5wt%alendronate and systemic alendronate in bone mineral density and implant fixation.
Conclusions:Alendronate-loaded bone cement (0.5wt%) may be as effective as the systemic alendronate in inhibiting titanium particle-induced osteolysis.
Part2Mechanical properties and micro-architecture of an acrylic cement impregnated with purified alendronate powder
Objective:To investigate the static and fatigue properties of purified-alendronate-impregnated acrylic bone cement (PAIBC) in vitro, the effect of powder load and PBS immersion on biomechanics of PAIBC, and its related mechanism.
Methods:PAIBC specimens were successfully manufactured for in-vitro assay, and randomly assigned to eight groups based upon the aging condition and the mass ratio between drug and cement (n=31-37):the control air group, the control PBS group, the0.1%PAIBC air group, the0.1%PAIBC PBS group, the0.5%PAIBC air group, the0.5%PAIBC PBS group, the1%PAIBC air group, and the1%PAIBC PBS group. According to the corresponding ASTM/ISO standards, their ultimate compressive. strength, compressive elastic modulus, ultimate tensile strength, ultimate flexuous strength, and fatigue life were tested systematically. The particle size distribution of purified alendronate powder was analyzed with the laser light scattering method. The fatigue test results, given as number of cycles-to-failure, were analyzed using the linearized format of the two-parameter Weibull function. The parameters of Weibull slope, Weibull characteristic fatigue life, Weibull mean number of fatigue stress cycles, and fatigue performance index were all calculated.
Results:With drug load increased, there was an increase in ultimate compressive strength and ultimate tensile strength, and a decrease in fatigue life with statistical significance. When immersed in PBS for thirty days before the tests, the PAIBC specimens presented an overall significant decrease of ultimate compressive strength, compressive elastic modulus, ultimate tensile strength, and fatigue life. No effect of drug load or PBS immersion was noted on ultimate flexuous strength. The Weibull mean of fatigue life dropped by22.1%-26.1%after atmospheric aging and by 16.7%-18.9%after wet aging. The profile of particle size distribution presented a normal distribution. The diameter of drug particle ranged from4.67μm to44.21μm, with a mean diameter of20.77μm.
Conclusions:Purified alendronate was a more homogeneous powder than tablet-ground powder, which contained particles with a lower range of sizes. The impregnation of purified bisphosphonate exerted less negative effect on the static and fatigue strength of acrylic bone cement, compared with liquid bisphosphonate and the tablet-ground one in literatures. The static strength of PAIBC was maintained high above the ASTM/ISO standards. Our study laid a biomechanical foundation for the potential clinical use of PAIBC.
Part3Enhancement of intermittent insonation with low-frequency watt-level ultrasound on pharmacokinetics of vancomycin-loaded acrylic bone cement in vitro
Objective:To investigate the effect of intermittent insonation on pharmacokinetics and microstructure of vancomycin-loaded acrylic bone cement (VLBC) in vitro under low-frequency elevated-intensity ultrasound, and its related mechanism.
Methods:Twenty-one VLBC cylindrical specimens were successfully manufactured for in-vitro assay, and randomly assigned to three groups (n=7):the control group, the continuous-insonation group and the intermittent-insonation group. All specimens, from which both insonation groups were insonated for14d, were immersed in40-ml PBS. During28-d observation PBS from four specimens per group was extracted and analyzed with fluorescence polarization immunoassay at designated time intervals, respectively. Four pharmacokinetic parameters, the duration of time for which antimicrobial concentration exceed the minimum inhibitory concentration (T>MIC), the drug release during the first day, the drug release between14d and28d, the cumulative release during14d, were all calculated from plots of drug-release-versus-time curve. Exponential-rise-to-maximum model was adopted to fit the plots of drug cumulative release. After immersion of14d, three specimens were dehydrated, desiccated and coated with a thin layer of gold. Their surface microstructures were analyzed with scanning electron microscopy.
Results:T>LMIC of the intermittent-insonation group increased by6.56d and7.09d compared with the control group (P<0.05) and the continuous-insonation group (P<0.05), respectively. However, T>MIC of the continuous-insonation group was lower than the control group by0.53d (P<0.05). The total release of intermittent-insonation group at sub-inhibitory drug level decreased by0.16mg and0.19mg compared with the control group (P<0.01) and the continuous-insonation group (P<0.01), respectively. The cumulative release of intermittent-insonation group during14d increased by2.88mg and2.81mg compared with the control group (P<0.01) and the continuous-insonation group (P<0.01), respectively. The goodness of fit with exponential-rise-to-maximum model was satisfying for three groups (P<0.01). M0, Mmax-Mo and K in intermittent-insonation group significantly increased compared with the control group and the continuous-insonation group. K and N in intermittent-insonation group appeared lower compared with the control group despite increase in Mo.
Conclusions:Under the intermittent insonation with elevated-intensity low-frequency ultrasound, both the total drug release and T>MIC of VLBC will increase; in addition, the long-term release of sub-inhibitory drug release will almost cease. The exponential-rise-to-maximum model is suitable for predicting the drug release of VLBC with insonation. Our pharmacokinetic data and fitting curve confirmed the significant enhancement of intermittent insonation with low-frequency elevated-intensity ultrasound on surface liberation and internal diffusion of drug from VLBC.
Part4Effect of Low-Frequency Pulsed Wave Ultrasound on Micro-Architecture and Mechanics of Stem-Cement Interface
Objectives: Several studies have shown that low-frequency pulsed wave ultrasound can effectively enhance and accelerate antibiotic release from bone cement. The mechanisms may be associated with the effects of detaching forces and pushing forces by acoustic microstream. We hypothesized that low-frequency pulsed wave ultrasound improved interfacial porosity and penetration of fluid through the cement-stem interface.
Methods:The1%vancomycin-loaded acrylic bone cement-stem interface samples were successfully manufactured and randomly divided into three groups:the control group,450mW/cm2ultrasound group and1200mW/cm2ultrasound group. Two ultrasound groups were exposed to a local ultrasonic field for7days, then immersed in37℃PBS for23days, while the control group immersed in PBS for30days with no ultrasonication. After30-day immersion, the shear strength and the porosity of the stem-cement interface were determined. Two additional specimens from each group were investigated for the extent of penetration of fluid into the stem-cement surface.
Results:The450mW/cm2ultrasonication had no significant effect on the cement-stem interface (p<0.05). The mean shear strength decreased by14%and the interfacial porosity increased by9%in the1200mW/cm2ultrasound group compared with the control group; also, there was a higher porosity and much more penetration of fluid at the interface close to the ultrasound transducer in the1200mW/cm2group compared to the control group.
Conclusions:The1200mW/cm2low-frequency pulsed wave ultrasound significantly enhanced porosity and penetration of fluid at the interface which resulted in the lower interfacial initial stability. But the effect of low-frequency pulsed wave ultrasound on the fatigue strength of the stem-cement deserved further investigation with the cyclic loading tests in vivo.
体外研究证实,载双磷酸盐骨水泥能抑制骨水泥颗粒诱导巨噬细胞向破骨细胞分化和骨吸收作用。动物研究证实载双磷酸盐骨水泥能显著减少假体周围骨量丢失,增强假体的稳定性。尽管载阿仑膦酸钠骨水泥有着广阔的临床应用前景,但其药物缓释性能及机制的研究在国内外仍是空白。在以往力学性能的研究中,所载的阿仑膦酸钠基本为液剂,将不可避免地降低骨水泥的力学强度。
随着骨科技术的进展,近年来关节置换手术得到迅速发展,对一些终末性关节疾病进行关节功能的重建,取得了满意的疗效。但是人工关节存在着本身一些无法避免的并发症,其中假体术后感染是关节置换最严重的并发症,一旦发生,几乎每个患者都需要第二次、第三次乃至多次手术来进行翻修,不仅给病人带来身心和经济上多方打击,而且就医生而言,治疗难度大,且再次感染率远高于初次关节置换,就成熟的髋、膝关节置换而言,翻修后再感染率达5～34%。虽然随着无菌条件的改善,抗生素的发展,关节置换术后感染率出现了很大下降,但是随着置换手术的不断推广,人工关节感染的绝对例数仍然不断在上升,就美国统计而言,只人工髋关节术后深部感染的病例每年超过4000例。而返观国内,随着人口结构的老龄化发展,再加上庞大的人口基数,我国近几年来人工关节置换数量迅速上升,同时关节术后感染病例亦不断增加。因此,如何有效的进行人工关节感染后翻修是关节外科医生所必须面对的并亟待解决的重要问题。
尽管载抗生素骨水泥已广泛在防治人工关节感染上发挥了一定的作用,然而,不同国家地区对其作用所持观点、应用方法和疗效存在较大分歧,部分学者甚至对该项技术持否定态度。原因在于：(1)载抗生素骨水泥中药物难以溶出释放,不仅导致局部药物利用率低下,无法有效杀菌,而且局部无效抑菌浓度的释放可能引起选择性耐药的菌株出现；(2)骨水泥内载入抗生素会降低其力学性能,影响假体远期生存率；(3)长期载庆大霉素骨水泥的应用导致临床假体相关性感染的致病菌超过50%对庆大霉素耐药。低频超声已经成功的用于外科化脓性感染的治疗上,并迅速的推广到许多疾病的治疗,包括急慢性脓胸、各种妇科炎症等等。国外学者将其在体外作用于庆大霉素骨水泥后发现,低频超声能增强庆大霉素的释放,各样本中庆大霉素释放率提高了2.4～14.7%,但作者指出这仅仅是观察到的一个现象而已,许多机制尚不明了,参数和频率的优化组合尚需进一步研究。
本研究旨在分别研究双磷酸盐及低频超声在丙烯酸骨水泥中的特殊应用,分为四个部分：一、在磨损颗粒诱导骨溶解的动物模型中,通过骨密度检测及生物力学测试,比较载阿仑膦酸钠丙烯酸骨水泥与皮下注射阿仑膦酸钠抑制钛磨屑诱导的骨溶解疗效；二、制备不同载荷的阿仑膦酸钠纯粉复合骨水泥试件,通过检测抗压强度、压缩弹性模量、抗张强度、抗弯强度和疲劳寿命,威布尔频率函数分析疲劳性能,激光散射法测定纯粉的粒径,分析药物载荷和体液浸泡对其力学性能的影响和规律；三、对载万古霉素骨水泥试件进行不同参数的高功率密度低频超声辐照,通过药物释放观测及电镜扫描,研究高功率密度低频超声辐照模式对超声促进药物释放的影响,并探讨作用机制。四、制作万古霉素骨水泥-假体柄界面模型,通过电镜扫描、墨汁浸染、生物力学检测等手段,研究低频脉冲超声对载万古霉素丙烯酸骨水泥-假体柄界面孔隙率和剪切应力的影响。
第一章载阿仑膦酸钠骨水泥抑制钛磨屑诱导假体周围骨溶解
目的比较载阿仑膦酸钠丙烯酸骨水泥与皮下注射阿仑膦酸钠抑制钛磨屑诱导的骨溶解疗效。
方法48只成年雄性新西兰兔随机均分为无钛磨屑且无阿仑膦酸钠组(A组),有钛磨屑注射且无阿仑膦酸钠组(B组),钛磨屑分别注射0.1%、0.5%、1.0%且载阿仑膦酸钠丙烯酸骨水泥组(C、D、E组),钛磨屑注射且皮下注射阿仑膦酸钠组(F组),每组8只。将载阿仑膦酸钠骨水泥植入兔股骨远端。制备磨屑诱导骨溶解动物模型。术后8周对股骨行组织形态学分析、骨密度测定及界面力学测试。
结果B组假体周围可见明显的骨溶解,而C、D、E、F组骨溶解明显少于B组。B组假体周围骨密度(bone mineral density, BMD)和骨-骨水泥界面抗剪强度分别较A组下降17%和56%；D组假体周围BMD和界面抗剪强度较B组分别增加29%和62%；E组假体周围BMD和界面抗剪强度较B组分别增加37%和29%；F组假体周围BMD和界面抗剪强度较B组分别增加51%和69%；C组、D组、E组分别与F组比较,假体周围BMD和界面抗剪强度的差异均无统计学意义。
结论载阿仑膦酸钠丙烯酸骨水泥与皮下注射阿仑膦酸钠均可在一定程度上抑制磨损磨屑诱导的骨吸收,增强界面抗剪强度。
第二章载阿仑膦酸钠骨水泥的力学性能和显微结构
目的研究阿仑膦酸钠纯粉复合丙烯酸骨水泥的疲劳和静态力学性能,分析药物载荷和体液浸泡对其力学性能的影响和规律。
方法制备不同载荷的阿仑膦酸钠纯粉复合骨水泥试件,根据纯粉载荷及试件的贮存环境进行分组,检测抗压强度、压缩弹性模量、抗张强度、抗弯强度和疲劳寿命,威布尔频率函数分析疲劳性能,激光散射法测定纯粉的粒径。
结果增加纯粉载荷可提高试件的抗压强度极限、抗张强度极限,但降低疲劳寿命。体液浸泡可降低试件的抗压强度极限、压缩弹性模量、抗张强度极限及疲劳寿命。纯粉载入使骨水泥的疲劳性能下降16.7%-26.1%。纯粉的粒径为4.67Μm-44.21μgm。
结论阿仑膦酸钠纯粉的粒径及分布范围较小,载入后丙烯酸骨水泥的静态力学性能仍显著高于ASTM/ISO标准,但疲劳性能有一定程度下降。与以往采用双磷酸盐液剂或片剂磨粉相比,纯粉对丙烯酸骨水泥力学强度的影响最小
第三章高功率密度低频超声间断辐照对载万古霉素骨水泥药物释放的促进作用
目的研究高功率密度低频超声辐照模式对超声促进药物释放的影响,并探讨其作用机制。
方法制备质量分数为10%的载万古霉素骨水泥(vancomycin-loaded bone cement, VLBC)圆柱体试件,浸泡于40ml PBS中。将试件随机分为三组：空白对照组、超声连续辐照组、超声间断辐照组,后两组接受超声辐照14d。三组试件中部分样本(n=4)于浸泡28d内定时采样测定万古霉素浓度,计算T>MIC、14-28d亚抑菌浓度释药量、14d内累积释药量并行曲线拟合；部分样本(n=3)于浸泡14d后脱水、干燥、喷金,行扫描电镜观察表面形态。
结果(1)超声间断辐照组T>MIC较对照组及超声连续辐照组分别提高6.56d、7.09d,超声连续辐照组T>MIC较对照组下降0.53d。(2)超声间断辐照组亚抑菌浓度释药量较对照组及超声连续辐照组分别下降0.16mg.0.19mg;超声间断辐照组14d累积释药量较对照组及超声连续辐照组分别提高2.88mg、2.81mg。(3)三组采用指数增长至最大值模型拟合效果均理想,超声间断辐照组M0、 Mmax-M0、K均较对照组和超声连续辐照组提高,超声连续辐照组MO较对照组高,但Mmax-M0、K、N较对照组低。
结论高功率密度低频超声间断辐照不仅可显著提高VLBC药物的释放率,延长T>MIC还可抑制VLBC后期亚抑菌浓度释放。指数增长至最大值模型对超声辐照下VLBC药物释放的拟合度较理想。高功率密度低频超声间断辐照对VLBC的表面释放和内部弥散有明显的促进作用,连续辐照抑制VLBC的内部弥散。
第四章低频超声对载万古霉素骨水泥-假体柄界面的微观结构和力学特性的影响
目的研究低频脉冲超声对载万古霉素丙烯酸骨水泥-假体柄界面孔隙率和剪切应力的影响。
方法制备1%质量分数万古霉素骨水泥-假体柄界面模型,随机分为对照组、450mW/cm2超声组和1200mW/cm2超声组,每组10个样本。对照组于37℃PBS中浸泡30d,超声组于37℃PBS中超声辐照7d后再浸泡23d,试件空气中风干24h后万能力学试验机检测界面剪切应力,场发射扫描电子显微镜和Image-Pro Pus6.0图像处理软件观察和分析界面孔隙分布。每组另取两试样置于3℃PBS和印度墨汁混和溶液中如上行超声辐照和体液浸泡,观察界面墨汁渗透浸染程度。
结果450mW/cm2超声组界面剪切应力和孔隙率与对照组相比无显著差异；1200mW/cm2组界面剪切应力较对照组下降14%,界面孔隙率较对照组增加9%；1200mW/cm2组邻近超声探头的试件中上端孔隙率明显高于对照组相应区域,下部与对照组相比差异无统计学意义；1200mW/cm2组试件上端墨汁浸染较对照组和450mW/cm2超声组显著。
结论1200mW/cm2低频脉冲超声连续辐照一周可增加界面孔隙率和体液渗透界面,但可降低丙烯酸骨水泥-假体柄界面初始稳定性,450mW/cm2低频脉冲超声不会降低丙烯酸骨水泥-假体柄界面剪切应力。超声对界面远期稳定性的影响有待疲劳试验和动物体内试验进一步研究。
Particle-induced osteolysis is a major cause of aseptic loosening after total joint arthroplasty. Bisphosphonates are commonly used to treat conditions associated with bone loss, such as osteoporosis, Paget's disease and skeletal carcinomatosis. Recently, several studies have shown that bisphosphonates can inhibit wear debris-induced osteolysis and increase peri-implant bone mineral density (BMD). However, side effects like fever, throat and stomach ulcers, and low bioavailability were observed after systemic treatment. Thus, bisphosphonate-loaded acrylic bone cement was proposed as local delivery system to reduce the risk of osteolysis and resulting prosthetic loosening. This proposal is similar to the addition of antibiotic to bone cement against infection. However, studies showed that liquid form of bisphosphonate led to incomplete polymerization of bone cement and weaken its mechanical strength. Powdered bisphosphonates proved to be a superior choice. Lewis et al. found that given the addition of0.21g of alendronate powder into50g of cement powder, there was no significant reduction in the fatigue life.
Unfortunately, previous studies never focused on the effect of alendronate cement on wear debris-induced osteolysis in vivo. Also, it should be noted that bisphosphonates added to bone cement might reduce the mechanical properties of bone cement and led to the failure of the total joint replacement. Several studies have shown that liquid form of a bisphosphonate led to incomplete polymerization of acrylic bone cement and significantly reduced acrylic bone cement mechanical properties. Therefore, the aim of the present study is to comprehensively investigate the effect of drug load and fluid environment on the static mechanical properties, fatigue life, and micro structure of purified-alendronate-impregnated acrylic bone cement (PAIBC) in vitro and the related mechanism. In addition, the anti-resorptive efficacy of alendronate cement would be compared with systemic alendronate.
Implant-related infection has been a devastating disaster for patients undergoing joint arthroplasty. Antibiotic-loaded bone cement is proven a keystone against the infection since it can provide high local delivery of antibiotic. Two categories are included based on the purposes:the prophylactic cement refers to prophylaxis against the infection with a low antibiotic load during a primary arthroplasty or a revision arthroplasty, whereas the therapeutic cement means curing the infection by using beads or spacers with a high antibiotic load between implant removal and reimplantation. High susceptibility to staphylococci, rare resistant strains, and weak toxicity render vancomycin typically the last resort or the drug of choice to be combined with aminoglycosides for loading into the therapeutic cement. Unfortunately, the therapeutic cement has met with mixed results. The relapse rate of the infection was reported to9%～18%. Such problem was mainly attributed to the poor antibiotic release from cement, of which vancomycin was one of the poorest. The length of time when local drug level exceeded the MIC (T>MIC), a key indicator for the antimicrobial activity of vancomycin-loaded bone cement (VLBC), was far from the required time for effective killing of bacteria. Furthermore, the long-term subtherapeutic release of antibiotic from cement will definitely select resistant strains. Anagnostakos et al. have shown that after prolonged time periods bacteria can even colonize gentamicin-vancomycin-loaded bone cement.
Ultrasound, a popular medical device for sonoporation and bone healing, has been found to enhance antibiotic release from acrylic bone cement. However, the enhancement by previous milliwatt-level ultrasonication was confined in the early period of drug release. Then the burst release waned quickly to a sustained slow release, which did not contribute to adequately enhancing the drug release, extending the T>MIC, and avoiding drug-resistant strains. Furthermore, the mechanisms of improved drug release from cement are poorly understood. The nonthermal effect of ultrasound, mainly the stable cavitation and the radiation pressure, generates multidirectional acoustic microstreams which produces a high shear stress at drug-cement interfaces, allowing detachment of drug grains from the surface and pushing solution into acrylic matrix via craters and channels. Although it was reported that low-frequency pulsed wave ultrasound was found to be safe in vivo experiments, there were few reports on the effects of low-frequency pulsed wave ultrasound on the shear strength on at the cement-stem interface. Studies have suggested that the loosening failure of cemented stems was initiated by debonding of the stem-cement interface because of a lack of chemical bonding, and the debonding at the interface is was primarily dominated by shear failure as proven with Finite Element Analysis. In the present study the kinetics of vancomycin release and the surface microstructure of VLBC under the watt-level ultrasonication with and without the pause insertion were contrasted. The shear strength, porosity and the extent of penetration of fluid into the cement-stem interface were determined and contrasted among the control group and ultrasound groups. Finally, the involved mechanisms were discussed.
Part1Effects of local and systemic alendronate delivery on wear debris-induced osteolysis in vivo
Objective:To investigate the effects of locally and systemically administered alendronate on wear-debris induced osteolysis in vivo.
Methods:Endotoxin-free titanium particles were injected into rabbit femurs, prior to insertion of a non-weight-bearing polymethylmethacrylate plug into the distal femur canal. Then the particles were repeatedly injected into the knee2,4and6weeks after the implantation. Alendronate was incorporated at three different concentrations (0.1wt%,0.5wt%and1.0wt%) into bone cement for local delivery. For systemic delivery, alendronate was subcutaneously injected (1.0mg/kg/week) one week after the implantation and then once a week until sacrifice.
Results:Eight weeks postoperatively, there was significant evidence of osteolysis surrounding the plug in the control group compared with markedly-blocked osteolysis in the local0.5wt%, local1.0wt%, and the systemic group. There was a concentration-dependent effect of alendronate on the improvement of periprosthetic bone mineral density. Notably, no significant difference was found between local0.5wt%alendronate and systemic alendronate in bone mineral density and implant fixation.
Conclusions:Alendronate-loaded bone cement (0.5wt%) may be as effective as the systemic alendronate in inhibiting titanium particle-induced osteolysis.
Part2Mechanical properties and micro-architecture of an acrylic cement impregnated with purified alendronate powder
Objective:To investigate the static and fatigue properties of purified-alendronate-impregnated acrylic bone cement (PAIBC) in vitro, the effect of powder load and PBS immersion on biomechanics of PAIBC, and its related mechanism.
Methods:PAIBC specimens were successfully manufactured for in-vitro assay, and randomly assigned to eight groups based upon the aging condition and the mass ratio between drug and cement (n=31-37):the control air group, the control PBS group, the0.1%PAIBC air group, the0.1%PAIBC PBS group, the0.5%PAIBC air group, the0.5%PAIBC PBS group, the1%PAIBC air group, and the1%PAIBC PBS group. According to the corresponding ASTM/ISO standards, their ultimate compressive. strength, compressive elastic modulus, ultimate tensile strength, ultimate flexuous strength, and fatigue life were tested systematically. The particle size distribution of purified alendronate powder was analyzed with the laser light scattering method. The fatigue test results, given as number of cycles-to-failure, were analyzed using the linearized format of the two-parameter Weibull function. The parameters of Weibull slope, Weibull characteristic fatigue life, Weibull mean number of fatigue stress cycles, and fatigue performance index were all calculated.
Results:With drug load increased, there was an increase in ultimate compressive strength and ultimate tensile strength, and a decrease in fatigue life with statistical significance. When immersed in PBS for thirty days before the tests, the PAIBC specimens presented an overall significant decrease of ultimate compressive strength, compressive elastic modulus, ultimate tensile strength, and fatigue life. No effect of drug load or PBS immersion was noted on ultimate flexuous strength. The Weibull mean of fatigue life dropped by22.1%-26.1%after atmospheric aging and by 16.7%-18.9%after wet aging. The profile of particle size distribution presented a normal distribution. The diameter of drug particle ranged from4.67μm to44.21μm, with a mean diameter of20.77μm.
Conclusions:Purified alendronate was a more homogeneous powder than tablet-ground powder, which contained particles with a lower range of sizes. The impregnation of purified bisphosphonate exerted less negative effect on the static and fatigue strength of acrylic bone cement, compared with liquid bisphosphonate and the tablet-ground one in literatures. The static strength of PAIBC was maintained high above the ASTM/ISO standards. Our study laid a biomechanical foundation for the potential clinical use of PAIBC.
Part3Enhancement of intermittent insonation with low-frequency watt-level ultrasound on pharmacokinetics of vancomycin-loaded acrylic bone cement in vitro
Objective:To investigate the effect of intermittent insonation on pharmacokinetics and microstructure of vancomycin-loaded acrylic bone cement (VLBC) in vitro under low-frequency elevated-intensity ultrasound, and its related mechanism.
Methods:Twenty-one VLBC cylindrical specimens were successfully manufactured for in-vitro assay, and randomly assigned to three groups (n=7):the control group, the continuous-insonation group and the intermittent-insonation group. All specimens, from which both insonation groups were insonated for14d, were immersed in40-ml PBS. During28-d observation PBS from four specimens per group was extracted and analyzed with fluorescence polarization immunoassay at designated time intervals, respectively. Four pharmacokinetic parameters, the duration of time for which antimicrobial concentration exceed the minimum inhibitory concentration (T>MIC), the drug release during the first day, the drug release between14d and28d, the cumulative release during14d, were all calculated from plots of drug-release-versus-time curve. Exponential-rise-to-maximum model was adopted to fit the plots of drug cumulative release. After immersion of14d, three specimens were dehydrated, desiccated and coated with a thin layer of gold. Their surface microstructures were analyzed with scanning electron microscopy.
Results:T>LMIC of the intermittent-insonation group increased by6.56d and7.09d compared with the control group (P<0.05) and the continuous-insonation group (P<0.05), respectively. However, T>MIC of the continuous-insonation group was lower than the control group by0.53d (P<0.05). The total release of intermittent-insonation group at sub-inhibitory drug level decreased by0.16mg and0.19mg compared with the control group (P<0.01) and the continuous-insonation group (P<0.01), respectively. The cumulative release of intermittent-insonation group during14d increased by2.88mg and2.81mg compared with the control group (P<0.01) and the continuous-insonation group (P<0.01), respectively. The goodness of fit with exponential-rise-to-maximum model was satisfying for three groups (P<0.01). M0, Mmax-Mo and K in intermittent-insonation group significantly increased compared with the control group and the continuous-insonation group. K and N in intermittent-insonation group appeared lower compared with the control group despite increase in Mo.
Conclusions:Under the intermittent insonation with elevated-intensity low-frequency ultrasound, both the total drug release and T>MIC of VLBC will increase; in addition, the long-term release of sub-inhibitory drug release will almost cease. The exponential-rise-to-maximum model is suitable for predicting the drug release of VLBC with insonation. Our pharmacokinetic data and fitting curve confirmed the significant enhancement of intermittent insonation with low-frequency elevated-intensity ultrasound on surface liberation and internal diffusion of drug from VLBC.
Part4Effect of Low-Frequency Pulsed Wave Ultrasound on Micro-Architecture and Mechanics of Stem-Cement Interface
Objectives: Several studies have shown that low-frequency pulsed wave ultrasound can effectively enhance and accelerate antibiotic release from bone cement. The mechanisms may be associated with the effects of detaching forces and pushing forces by acoustic microstream. We hypothesized that low-frequency pulsed wave ultrasound improved interfacial porosity and penetration of fluid through the cement-stem interface.
Methods:The1%vancomycin-loaded acrylic bone cement-stem interface samples were successfully manufactured and randomly divided into three groups:the control group,450mW/cm2ultrasound group and1200mW/cm2ultrasound group. Two ultrasound groups were exposed to a local ultrasonic field for7days, then immersed in37℃PBS for23days, while the control group immersed in PBS for30days with no ultrasonication. After30-day immersion, the shear strength and the porosity of the stem-cement interface were determined. Two additional specimens from each group were investigated for the extent of penetration of fluid into the stem-cement surface.
Results:The450mW/cm2ultrasonication had no significant effect on the cement-stem interface (p<0.05). The mean shear strength decreased by14%and the interfacial porosity increased by9%in the1200mW/cm2ultrasound group compared with the control group; also, there was a higher porosity and much more penetration of fluid at the interface close to the ultrasound transducer in the1200mW/cm2group compared to the control group.
Conclusions:The1200mW/cm2low-frequency pulsed wave ultrasound significantly enhanced porosity and penetration of fluid at the interface which resulted in the lower interfacial initial stability. But the effect of low-frequency pulsed wave ultrasound on the fatigue strength of the stem-cement deserved further investigation with the cyclic loading tests in vivo.
引文
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