INTRODUCTION

Increasing human lifeexpectancyhasmeantthatgreater consideration needs to be given to oral implantation in patients with systemic diseases.Osteoporosis is known as one of the systemic risk factors for implant failure,1,2if without proper management,poor bone quality can result in the lack of primary stability,and impaired bone formation and healing can make achieving osseointegration difficult.

In the field of orthopedics and oral implantology,it is well known that bone adjust its mass and microstructure responding to mechanical loading.Low-magnitude,high-frequency(LMHF)loading,in which a low-magnitude is generally meant as＜1 g(1 g=9.98 m·s-2)and a high-frequency is generally meant as 20–90Hz,elicits a positive effect on the skeleton.3,4Numerous studies suggest that LMHF loading,applied by means of whole-body vibration (WBV),stimulates bone formation and fracture healing.5–8WBV loading has been used clinically as a nonpharmacological intervention in the treatment of osteoporosis.9–14

With regard to titanium implant osseointegration,which has similarities to bone fracture healing,previous studies have suggested that LMHF loading has an osteogenic effect on periimplant bone.15–17In particular,Ogawa et al.15,18confirmed that the specific parameters of a loading regimen,such as duration,session distribution,frequency,and amplitude ofloading,have important roles in the impact of LMHF loading on periimplant bone.In addition,LMHF loading reportedly increased bone–implantosseointegration in osteoporosis models.19–21 However,the combined effect of LMHF loading and antiosteoporosis medications,which are the most common treatment of osteoporosis,on peri-implant bone healing and implant osseointegration remains unclear.

Human parathyroid hormone(1-34)[hPTH(1-34)]is a new class of skeletal anabolic agents that stimulates osteoblastic bone formation and has already been approved for the treatment of osteoporotic patients who are at high risk for fractures or who have been intolerant of previous osteoporosis therapy.Intermittent systemic administration of PTH reportedly reduced the risk for fractures by improving bone microarchitecture and enhancing overall bone mass,22–25and exceeded bisphosphonates(BP),which are important antiresorptive agents,in increasing bone mineral density.26Therefore,PTH holds promise as an alternative to existing antiresorptive agents.27There has been growing interest in the use of PTH to accelerate fracture healing and increase bone formation in the early post-operative period after osteosynthesis and following joint replacement with orthopedic implants.28,29The effects of using PTH for maxillofacial bone formation and regeneration have also been investigated in recent years.30Intermittent PTH administration reportedly increased osseointegration of titanium oral implants in animal and clinical models.31–33

文献[19]显示，当模型的水平范围为8～10倍隧道直径时，即可获得较高的计算精度。本文建立了二维弹塑性动力有限元模型，模型水平方向为80 m，竖直方向为60 m，盾构隧道直径为6 m。

良好的课堂环境离不开师生的共同配合。教师的教学能够激发学生的学习兴趣，则课堂学习氛围好。要激发学生的学习兴趣，教师除了要有必备的学识，还要有良好的师德师风，具有人格魅力。而学生应多渠道加深对自己所学专业未来发展趋势的了解，挖掘所学专业的价值，发现学习的“有用性”，从而提升学习兴趣。[3]

5）并不热衷追求勘探热点。最近两年炙手可热的北大西洋塞内加尔和毛里塔尼亚以及南美近海圭亚那等热点区（包括巴西盐下深水），埃尼公司没有在其中或者近邻获取任何区块，这一点和埃克森美孚等国际大石油公司不同。埃尼的理念是通过自己的勘探发现来创造热点，已经成为热点的区域不符合埃尼公司前沿区的进入标准。这可以说是埃尼公司独特的一面。

Although both PTH and BP administration are effective for the management of osteoporotic condition,they have some limitations and side effects associated with the prolonged administration,36–38which are possible complications of oral implantation.Therefore,to treat osteoporotic patients with oral implants safely and successfully,it is necessary to reduce bone healing period and achieve early and strong osseointegration after implant surgery.LMHF loading may be a good consideration for a novel therapeutic option for efficient oral implantation in osteoporotic patients.

自动化和智能化技术在全球范围内蓬勃发展，但在装配式建筑智能建造领域却鲜有应用，采用的施工机械和现浇结构相差不大，无从体现其优势。构件吊装设备自动化和智能化程度低，精度差；灌浆设备由人工操作完成，过程质量不可保证；临时支撑调整困难，精度不高；大量工作仍依靠人工完成，还未形成标准化体系，效率低。导致装配式建筑施工周期长，成本高和市场接受程度较差。因此，装配式智能建造技术已经成为制约我国装配式建筑发展的关键因素。

RESULTS

Removal torque test

RT values were significantly differentiated by the loading and the drug administration (P＜0.01)(Fig.1).PTH administration significantly increased the biomechanicalstrength ofthe implant–bone interface compared with the saline-treated and alendronate(ALN)-treated groups(P＜0.01).

Micro-CT analysis

Figure 6a illustrates the experimental design.At 11-weeks-old rats were ovariectomized to induce osteoporosis.Two weeks after ovariectomy,rats were divided into six groups:saline(n=8),saline+WBV(n=8),alendronate(ALN)(n=7),ALN+WBV(n=7),PTH(n=7),and PTH+WBV(n=7).The ALN-treated groups(ALN and ALN+WBV)were injected subcutaneously twice per week with 15 μg·kg-1of ALN(Wako Pure Chemical Industries,Osaka,Japan).The PTH-treated groups(PTH and PTH+WBV)were injected subcutaneously 5 days per week with 40 μg·kg-1of PTH(hPTH(1-34);Peptide Institute,Osaka,Japan).Rats in the saline and saline+WBV groups were administered volume-matched subcutaneous injections of saline.Administration of drugs was continued until the rats were killed.The period from ovariectomy to the initiation of medication was set so that rats had reached the early stages of osteoporosis with the resultant abnormal conditions regulating bone metabolism.45The dosage of ALN was determined by reference to previous studies,46,47and was based on preclinical studies in OVX rats that demonstrated a significant increase in bone mass and strength.48The dosage is comparable with the 20 mg per day dosage prescribed to treat osteoporosis on a mg·kg-1basis.The dosage of PTH was determined by reference to a previous study,31and lies within the dose range investigated in a dose-dependency study.49These relatively high dosages were chosen to maximize the possibility of bone–implant osseointegration becoming established.

In the cortical bone surrounding the implant,RG values were significantly affected by the loading(P＜0.01)(Fig.2a).There were no significant differences according to the type of drug.In trabecular bone,RG values of the PTH-treated groups were significantly higher than those of the saline-treated and ALN-treated groups(P＜0.01)(Fig.2b).There were no significant differences according to the loading.

Histologic and histomorphometric analysis

Figure 3 shows representative images of the PTH+WBV and saline groups after 4 weeks of healing.In peri-implant trabecular bone of the drug-treated groups,specifically the PTH-treated groups,bone neoformation was observed.There was little mature bone around the implants in the saline group.In peri-implant cortical bone,the bone width seemed to have thickened by the loading and drug treatments.

Statistical analysis

DISCUSSION

This study investigated the osteogenic impact of LMHF loading and anti-osteoporosis medications on peri-implant bone healing and implant osseointegration in an osteoporosis model,and assessed their combined effects on these processes.The mainfindings of this study are as follows:(i)LMHF loading and PTH have additive effectson peri-implantbone healing and implant osseointegration in osteoporosis model.(ii)PTH administration is more effective than BP administration on preventing the OVX-induced impaired peri-implant bone response.(iii)LMHF loading and drug administration act locally on the bone healing process.

推荐理由:作者傅莹有深厚的学术功底，宝贵的外交经验，她曾任我国驻菲律宾、澳大利亚、英国大使，外交部副部长，十二届全国人大一至五次会议新闻发言人。本书集结傅莹大使数年文章和演讲精华，内容涉及世界秩序、全球格局与中国角色、中美关系、中俄关系、东亚问题、南海局势等，可帮助读者更好地了解和把握中国对外政策与国际关系的态势和趋势。

无独有偶，已连续亏损两年且今年前三季度依然亏损1.63亿元的*ST椰岛也寄希望于资产转让。11月6日晚间，*ST椰岛披露挂牌转让资产事项最新进展，西安天朗地产集团有限公司作为意向受让方，向海南产权交易所递交了《产权受让申请书》，并已缴纳保证金6000万元，拟以4亿元的挂牌价格，受让海南椰岛阳光置业有限公司60%股权及椰岛综合楼。

The assessed bone formation parameters in the PTH+WBV group tended to be highest after 4 weeks of healing,indicating that PTH and WBV additively facilitate implant osseointegration.Interestingly,no obvious positive effect was found in the ALN+WBV groups.Similarly,a comparable study reported that the combination of ALN and LMHF loading did not lead to an additive reaction influencing the bone healing response.21This might be because ALN inhibits osteoclastic bone activity,which is required in the process of bone adaptation and,therefore,implant osseointegration.Collectively,these results indicate that LMHF loading and PTH administration additively increase the osteogenic response in peri-implant bone,achieving early bone healing and strengthening implant osseointegration,and that PTH combined with LMHF loading has a bone-stimulating effect superior to that of ALN and LMHF loading.

Regarding anti-osteoporosis medications,the overall results of the post hoc analysis(Tukey’s HSD test)clearly showed that PTH was the medication that exhibited the most pronounced bonestimulating effect compared with ALN and control(saline),based on RT value,BIC,and BV/TV.This affirmed that PTH administration has potent osteogenic capability to stimulate implant osseointegration.Almagro et al.33reported that PTH administration improves implant osseointegration by increasing BIC and peri-implantbone mineraldensity in a rabbitmodelof ovariectomy and glucocorticoid-induced osteoporosis,findings that align with the present study.A clinical feasibility study also described the tendency for new bone formation around mini implants obtained from individuals on short-term treatment with teriparatide.32Furthermore,we observed that ALN did not have a positive effect on peri-implant bone formation compared with PTH.These results suggest that such a promotional effect on new bone formation depends on osteoblast activity around implants.39 However,

BP,on the other hand,are antiresorptive agents that reduce osteoclastic bone loss and are widely used for prevention and as the first-choice therapy for osteoporosis.BP administration suppress bone resorption and bone remodeling,resulting in a relative increase of bone formation and bone mineral density and subsequently lowing the fracture rate.34The current animal studies have reported its efficacy on implant osseointegration under osteoporotic conditions.35

some previous studies reported that BP stimulates implant osseointegration in comparable animal models,35which might be because of using the different osteoporosis animal model or dosing regimen of BP administration.There are still many controversial aspects regarding this point.Actually,the influence of BP administration on implant success has not been completely determined in clinical practice.40–44

Remarkably,micro-CT analysis revealed differences in effect profiles between LMHF loading and PTH.This means that the RG value of cortical bone was increased by the loading.In contrast,the RG value of trabecular bone was increased by the PTH administration.These results suggest that they act locally on the bone healing process.Zhang et al.17reported that only the cortical BIC significantly increased with high-frequency loading for 4 weeks compared with the unloaded control,suggesting that LMHF loading increased the degree of contact between cortical bone and the implant.Shirota et al.31reported that bone volume density and BIC around implants in the OVX group treated with PTH was almost the same as that of the sham-operated group throughout the observation period.The researchers suggested that intermittent PTH administration not only can prevent resorption of newly generated trabeculae around implants but also can recover bone volume lost because of ovariectomy.

The study was approved by the Institutional Animal Care and Use Committee of the Tohoku University Environmental&Safety Committee,and was carried out at the Institute for Animal Experimentation atTohoku University Graduate Schoolof Medicine.

Osteoporosis could potentially complicate oral implant treatment because of disease-specific characteristics such as abnormal bone conditions and poor bone healing ability.These problems must be resolved by proper management of osteoporotic condition to ensure that oral implant treatment is successful in osteoporotic patients.In summary,the findings of present study suggest that both LMHF loading and intermittent PTH administration have osteogenic potency on peri-implant bone.They also suggest that they act locally and additively on the bone healing process,improving the condition of implant osseointegration.This could be a new therapeutic option for oral implant treatment in osteoporotic patients,avoiding problems such as delayed bone healing and failure of osseointegration.

选取我院2017年6月～2018年6月47例行人工髋关节置换术患者的临床资料，男29例，女18例，年龄59～91岁，平均（73±3.5）岁，股骨颈骨折19例，老年性退行性骨关节炎11例；单股骨头置换术7例。

MATERIALS AND METHODS

Animals

Forty-four female Wistar rats(age,11 weeks;average weight,(171.9±8.7)g)were used in this study.The rats were kept under climate-controlled conditions(23.5°C,50%humidity,12-h light/dark cycle)and had free access to standard laboratory diet and tap water.

This study has some limitations.The study was planned as a basicstudytoexaminethefundamentalphenomenonin osteoporotic models,before progressing to an oral implant model using higher-level experimental animals.As long bones such as the tibia are different from craniofacial bones,further studies using jawbone models are necessary to optimize the performance of vibration devices for local application and explore the optimal timing and duration of PTH administration for peri-implant bone healing and implant osseointegration in osteoporosis.However,the rat tibia,which has been used successfully in previous experiments,15–18is considered a suitable and reliable location for implant surgery and can be maintained without unpredictable loading.Therefore,the findings of the current study will increase our understanding of the peri-implant bone response to loading and drugs,prior to subsequent studies using an oral implant model.

Experimental design

在典型地块内选定标准地块：乔木林20m×20 m、灌木林5 m×5 m、草地2 m×2 m。标准地的数量不得少于3块，主要测量每株立木在方格中的位置，用皮尺和罗盘测定每株树冠东西、南北方向的投影长度，再按实际形状在方格纸上按一定比例尺勾绘出树冠投影，在图上求出林冠投影面积和标准地面积，即可计算林地郁闭度。灌木盖度监测采用测绳法，草地覆盖度采用针刺法和目估法，调查标准地内树高、地径、林地郁闭度、灌木（草地）盖度等。

高校独立学院，是由国家公办本科院校结合社会资金举办的“二级学院”。独立学院作为我国高等教育改革的一种新型办学形式，已发展成为高等教育走向大众化的中坚力量和生力军。近年来随着我国高等教育领域的竞争日趋激烈，以及从2016年开始全国逐步推行新高考政策的改革，独立学院目前都面临着如何从量的扩张向质的提升的转型升级问题。高素质的教师是学校发展不可或缺的重要资源和核心能力，也是独立学院发展的关键瓶颈。如何提高师资管理水平，吸引、留住并有效激励教师员工，已成为独立学院未来发展的重中之重。

Three weeks following the onset of drug administration(5 weeks post ovariectomy),a custom-made titanium implant(2×13 mm2;cp-Titanium Grade 2,machine surface)was inserted into the proximal metaphysis of both tibiae in rats in all six groups(Fig.6b,c).Rats were anaesthetized with 2.5%isoflurane(Escain;Mylan,Pittsburgh,PA,USA).Both cortices of the tibia were perforated at a low rotational speed under constant saline cooling with a surgical drill,which was 0.2mm smaller than the implant’s diameter to achieve good primary stability.The implants were inserted by means of a custom-fit wrench with manual torque.After implant insertion,wounds were closed using 4-0 polyglycolic acid sutures(Matsuda Ika Kogyo,Tokyo,Japan).

In the three groups of rats that underwent WBV(saline+WBV,ALN+WBV,and PTH+WBV),LMHF loading was applied starting the day after implant installation via WBV at a frequency of 50 Hz and a magnitude of 0.5g for 15min per day,5 days per week.Big Wave G-Master(Asahi Seisakusyo,Tokyo,Japan)was used as the vibration device(Fig.6d,e).

Rats were killed 4 weeks following implantation by cervical displacement under isoflurane-induced anesthesia.The tibiae with the implants were then dissected.

Evaluation of implant osseointegration

Removal torque test:One implant per rat was used to perform the removal torque test.The tibiae were fixated with a jig that was perpendicular to the axis of the implant.A torque gauge(ATG1.5CN/ATG12CN;Tohnichi Mfg,Tokyo,Japan)was attached to the implant head.The peak loosening torque(i.e.,the removal torque(RT)value)was recorded.

Micro-CT analysis:Another implant per rat was used for micro-CT analysis.Each sample,positioned in a water-filled plastic cylinder(29×57mm2),was scanned using a micro-CT system(ScanXmate-D225RSS270;Comscantecno,Kanagawa,Japan),which was set to 200kV and 100μA.Three-dimensional sectional images were reconstructed with 928×736 pixel resolution,in which the pixel size was 0.254mm and the isotropic voxel size was 10.68μm(Fig.7a–c).From each 3D multiplanar reconstruction(MPR)images data set,a sagittal slice along the axis of the tibia and implant was selected at the center of the implant as 32-bit grayscale image data.A 32-bit gray value from 0 to 255 was measured using ImageJ software(U.S.National Institutes of Health,Bethesda,MA,USA;http://imagej.nih.gov/ij/,1997–2014).The region of interest(ROI)was set as a 0.37×0.37mm2(26-pixel)square in the cortical and trabecular bone adjacent to the implant surface(c-ROI and t-ROI).A relative gray(RG)value of the cortical and trabecular bone was calculated whereby the gray value of the water and implant was defined as the reference value(0 and 100,respectively)(Fig.7d).

Histologicand histomorphometricanalyses:Aftermicro-CT analysis,the bone–implant blocks were fixed in phosphatebuffered formalin solution and dehydrated in a series of increasing concentrations of alcohol.After dehydration,samples were embedded in poly(methyl methacrylate).Embedded samples were cut using a diamond saw(Exakt BS-300CP;Exakt Technologies,Norderstedt,Germany)along the axis of the tibia and implant.After polishing to a final sample thickness of 40μm(Exakt MG-400CS;Exakt Technologies),sections were stained with Villanueva–Goldner stain.

This study evaluated the hypothesis that LMHF loading and anti-osteoporosis medications have a beneficial effect on periimplant bone healing and implant osseointegration in osteoporosis model.More specifically,the aim of this study was to investigate the impact of LMHF loading on peri-implant bone response for ovariectomized(OVX)rats treated with PTH versus BP,to assess which combination is more effective in enhancing implant osseointegration.

Histologic and histomorphometric analyses were performed using a light microscope at a magnification of×100(Leica DM3000;LeicaLaborlux,Wetzlar,Germany).Sampleswere scanned with a high-sensitivity camera(Leica DFC295;Leica Laborlux)at an image resolution of 1.28 μm per pixel.Histomorphometric analysis was performed via digital imaging processing(Adobe Photoshop CS6;Adobe Systems,San Jose,CA,USA and ImageJ,U.S.National Institutes of Health).The following analyses were performed:(i)Bone-to-implant contact(BIC;%):(summation of the length of contact between the bone and implant(μm)/implant length extending from the most medial to most lateral BIC point(μm))× 100;and(ii)Peri-implant bone volume relative to tissue volume(BV/TV;%):(area occupied by bone(μm2)/reference area(μm2))× 100.Two regions of interest(ROI)were defined:0–100 μm(BV/TV ROI1)and 100–500μm(BV/TV ROI2)zones extending from the implant surface.The areas encompassed the peri-implant tissues from the medial to lateral cortex(Fig.8).BIC and BV/TV measurements were performed on both the proximal and distal implant sides.

各中高层领了军令状，也都玩了命。不管风吹日晒，不计工作界面，天天蹲守古城，与各方势力斗智斗勇，大有不破楼兰终不还的气魄。

In the histomorphometric analysis,BIC wassignificantly increased by the loading and the PTH administration(P＜0.01)(Fig.4).BV/TV ROI1 and ROI2 were significantly enhanced by the PTH administration(P＜0.01)(Fig.5a,b).

Statistical analyses were conducted using SPSS(ver.13.0;SPSS Inc.,Chicago,IL,USA).Two-way analysisofvariance was performed to evaluate differences among the drug administration(ALN,PTH,or saline)and the loading(with or without WBV).The Tukey’s honest significant difference(HSD)test was performed to compare differences between groups.A P-value＜0.05 was considered statistically significant.

ACKNOWLEDGEMENTS

This study was partially supported by a Grant-in-Aid for Scientific Research(C)(15K11147),a Grant-in-Aid for Challenging Exploratory Research(26670830),and a Grant-in-Aid for Young Scientists(B)(26861620)from the Ministry of Education,Culture,Sports,Science and Technology,Japan.We thank Dr.Masahiro Iikubo,Department of Oral Diagnosis,Tohoku University Graduate School of Dentistry,for providing assistance with the micro-CT analysis.

结合实际的改扩建施工方案，对交通量和现有的通行现状进行调差，充分考虑施工单位的实际需求以及道路使用者的实际需求，确定最终的交通组织总方案。根据交通组织原则，在对施工过程进行管理的过程中，应综合考虑实际交通量大小及项目工程的具体情况，以降低对交通安全影响为目标，确定最为合理的改扩建施工方案。

ADDITIONAL INFORMATION

Competing interests:The authors declare no competing interests.

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