Intra-articular delivery of tetramethylpyrazine microspheres with enhanced articular cavity retention for treating osteoarthritis

Tetramethylpyrazine(TMP) is a traditional Chinese herbal medicine with strong antiinflammatory and cartilage protection activities, and thus a promising candidate for treating osteoarthritis. However, TMP is rapidly cleared from the joint cavity after intra-articular injection and requires multiple injections to maintain efficacy. The aim of this study was to encapsulate TMP into poly(lactic-co-glycolic acid)(PLGA) microspheres to enhance the TMP retention in the joint, reducing injection frequencies and decreasing dosage. TMP microspheres were prepared by emulsion/solvent evaporation method. The intra-articular retention of the drug was assessed by detecting the drug concentration distributed in the joint tissue at different time points. The therapeutic effect of TMP microspheres was evaluated by the swelling of knee joints and histologic analysis in papain-induced OA rat model. The prepared freezedried microspheres with a particle size of about 10 μm can effectively prolong the retention time of the drug in the articular cavity to 30 d, which is 4.7 times that of the TMP solution.Intra-articular injection of TMP microspheres efficiently relieved inflammatory symptoms,improved joint lesions and decreased the depletion of proteoglycan. In conclusion, intraarticular injection of TMP loaded microspheres was a promising therapeutic method in the treatment of OA.

Direct in vivo injection of ^(131)I-GMS and its distribution and excretion in rabbit

AIM: To explore the distribution and metabolism of 131 I-gelatin microspheres ( 131 I-GMSs) in rabbits after direct injection into rabbits’ livers.METHODS: Twenty-eight healthy New Zealand rabbits were divided into seven groups,with four rabbits per group.Each rabbit’s hepatic lobes were directly injected with 41.336 ± 5.106 MBq 131 I-GMSs.Each day after 131 I-GMSs administration,4 rabbits were randomly selected,and 250 μL of serum was collected for γ count.Hepatic and thyroid functions were tested on days 1,4,8,16,24,32,48 and 64 after 131 I-GMSs administration.Single-photon emission computed tomography (SPECT) was taken for each group on days 0,1,4,8,16,24,32,48,64 after 131 I-GMSs administration.A group of rabbits were sacrificed respectively on days 1,4,16,24,32,48,64 after 131 I-GMSs administration.Their livers were taken out for histological examination.RESULTS: After 131 I-GMSs administration,the nuclide was collected in the hepatic area with microspheres.The radiation could be detected on day 48 after 131 IGMSs administration,and radiography could be seen in thyroid areas in SPECT on days 4,8,16 and 24.One day after 131 I-GMSs administration,the liver function was damaged but recovered 4 d later.Eight days after 131 I-GMSs administration,the levels of free triiodothyronine and free thyroxin were reduced,which restored to normal levels on day 16.Histological examination showed that the microspheres were degraded to different degrees at 24,32 and 48 d after 131 I-GMSs administration.The surrounding parts of injection points were in fibrous sheathing.No microspheres were detected in histological examination on day 64 after 131 I-GMSs administration.CONCLUSION: Direct in vivo injection of 131 I-GMSs is safe in rabbits.It may be a promising method for treatment of malignant tumors.

注射用醋酸亮丙瑞林微球联合腹腔镜手术对子宫内膜异位症患者的影响

目的:探讨注射用醋酸亮丙瑞林微球联合腹腔镜手术对子宫内膜异位症(EMS)患者的影响。方法:选取2021年1月—2023年9月北京怀柔医院收治的86例EMS患者。根据随机数表法将其分为研究组(n=43)与对照组(n=43)。两组均接受腹腔镜手术,对照组术后给予去氧孕烯炔雌醇片,研究组术后给予注射用醋酸亮丙瑞林微球。比较两组临床疗效,治疗前后血清学指标、卵巢功能、疼痛程度,不良反应。结果:研究组治疗总有效率高于对照组,差异有统计学意义(P<0.05)。治疗后,两组基质蛋白酶-2(MMP-2)、血管内皮生长因子(VEGF)水平均降低,研究组MMP-2、VEGF水平均低于对照组,差异有统计学意义(P<0.05)。治疗后,两组卵巢中窦卵泡数量降低,卵巢体积减小,研究组卵巢中窦卵泡数量多于对照组,卵巢体积大于对照组,差异有统计学意义(P<0.05)。治疗后,两组痛经、性交痛视觉模拟评分法(VAS)评分均降低,研究组痛经、性交痛VAS评分均低于对照组,差异有统计学意义(P<0.05)。两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论:注射用醋酸亮丙瑞林微球联合腹腔镜手术应用于EMS患者中,能够提高临床疗效,改善血清学指标、卵巢功能,降低疼痛程度,具有较高安全性。

Polymeric microsphere injection in large pore-size porous media

High water-cut has become a worldwide challenge for oil production.It requires extensive efforts to process and dispose.This entails expanding water handling facilities and incurring high power consumption costs.Polymeric microsphere injection is a cost-effective way to deal with excessive water production from subterranean formations.This study reports a laboratory investigation on polymeric microsphere injection in a large volume to identify its in-depth fluid diversion capacity in a porous media with large pore/particle size ratio.The performance of polymeric microsphere injection was evaluated using etched glass micromodels based on the pore network of a natural carbonate rock,which were treated as water-wet or oil-wet micromodels.Waterflooding was conducted to displace oil at reservoir temperature of 95°C,followed by one pore volume of polymeric microsphere injection.Three polymeric microsphere samples with median particle size of 0.05,0.3,and 20μm were used to investigate the impact of particle size of the polymeric microspheres on incremental oil production capacity.Although the polymeric microspheres were much smaller than the pores,additional oil production was observed.The incremental oil production increased with increasing polymeric microsphere concentration and particle size.As a comparison,polymeric microsphere solutions were injected into oil-wet and water-wet micromodels after waterflooding.It was observed that the oil production in oil-wet micromodel was much higher than that in water-wet micromodel.The wettability of micromodels affected the distribution patterns of the remaining oil after waterflooding and further dominated the performance of the microsphere injection.The study supports the applicability of microsphere injection in oil-wet heterogeneous carbonates.

聚合物微球堵塞物的解堵技术

针对油气田注水井注入聚合物微球后堵塞致使压力升高欠注的问题,开展了解除聚合物微球堵塞物的研究,考察了解堵剂加量、反应温度、反应时间等对微球溶液黏度和粒径的影响,优化了解堵剂的最优作用条件同时进行了现场试验。结果表明:解堵剂(30%JT-1+35%HRJ+22%APG0814+10%H_(2)O+3%NaCl)可显著降低微球粒径和黏度。在同一解堵剂浓度下,反应时间越长,反应温度越高,解堵剂对微球堵塞物的作用效果越好;在同一盐浓度下,不同盐对解堵剂解堵效果的影响次序为:NaCl≥KCl>NH_4Cl。在室温下,2%微球+5%解堵剂的解堵液在反应4 h时黏度为1.46 m Pa·s,微球平均粒径为203.6 nm,与未加解堵剂的空白样(解堵液黏度为2.17mPa·s,平均粒径为3243.74 nm)比较,解堵液黏度下降了33%,微球粒径下降了94%,解堵液中的固体物含量由675 mg/L降至70 mg/L,下降近90%,解堵液的表面张力为24.89 mN/m、界面张力为1.849×10^(-2)mN/m,具有较高的表界面活性。采用该解堵剂在长庆现场进行了4口井的现场试验,取得良好解堵增注效果,较好解决了注水井长期注纳米微球后堵塞欠注问题。

红金消结胶囊联合醋酸亮丙瑞林治疗子宫内膜异位症临床研究

目的:观察红金消结胶囊联合醋酸亮丙瑞林治疗子宫内膜异位症的临床疗效。方法:选取82例子宫内膜异位症患者,按随机数字表法分为对照组与治疗组各41例。对照组给予注射用醋酸亮丙瑞林缓释微球治疗,治疗组在对照组基础上联合红金消结胶囊联合治疗。比较2组临床疗效与不良反应发生率,以及2组治疗前后中医证候评分、血清糖类抗原125 (CA125)、抗子宫内膜抗体(EMAb)、脂联素(APN)、肝细胞生长因子(HGF)水平、子宫体积、子宫内膜厚度、包块直径。结果:治疗组总有效率为95.12%,对照组为78.05%,2组比较,差异有统计学意义(P<0.05)。治疗后,2组中医证候评分均较治疗前降低(P<0.05),且治疗组中医证候评分低于对照组(P<0.05)。治疗后,2组子宫内膜厚度、子宫体积、包块直径均较治疗前缩小(P<0.05),且治疗组上述3项指标均小于对照组(P<0.05)。治疗后,2组血清CA125、EMAb、HGF水平均较治疗前降低(P<0.05),APN水平较治疗前升高(P<0.05);且治疗组CA125、EMAb、HGF水平低于对照组(P<0.05),APN水平高于对照组(P<0.05)。对照组不良反应发生率为9.76%,治疗组为4.88%,2组比较,差异无统计学意义(P>0.05)。结论:红金消结胶囊联合注射用醋酸亮丙瑞林缓释微球治疗子宫内膜异位症疗效显著,能改善患者临床症状和体征,调节相关血清细胞因子水平,且没有增加药物治疗的不良反应。

五里湾X1油藏如何提高采收率

靖安油田五里湾油藏以开发三叠系X1油藏为主,储层为湖成三角洲沉积,属于低渗透油藏,油藏平面、剖面非均质性较强。开发以注水为主,X1油藏目前综合含水率72.5%、采出程度25.4%,处于双高开发阶段,随着注入、采出程度的增大,油藏的平面单向突进、剖面上层内、层间矛盾日益突出,水驱油效率逐渐下降,从而影响着油田的稳产和开发效果,如何提高最终采收率是油藏开发永恒的主体。本文重点总结了X1油藏实施空泡驱、微球驱、注采井网调整、不稳定注水、精准堵水等措施后提高最终采收率,为后期整个X1油藏提高采收率提供方向。

微球/聚合物复配体系性能评价及机理分析

为探究聚合物和微球之间相互作用规律,利用扫描电镜对微球和“微球+聚合物”复配体系进行了微观结构观测,利用布氏黏度计对微球溶液、聚合物溶液和“微球+聚合物”复配体系增黏性能进行了评价。在此基础上,对比了聚合物溶液与“聚合物、微球段塞注入”方式的封堵性能。实验结果表明:15天后的“微球+聚合物”复配体系具有致密线网状微观结构。在微球质量分数不变时,“微球+聚合物”复配体系黏度增幅随聚合物质量分数增加而增加;在2000×10^(-3)μm^(2)、3000×10^(-3)μm^(2)和5000×10^(-3)μm^(2),渗透率条件下,与单独注入聚合物相比,“微球+聚合物”复配体系段塞注入方式阻力系数更低,可有效控制注入压力;“微球+聚合物”复配体系在具备良好注入性能的同时,封堵率与单独注入聚合物方式接近,分别为98.82%、98.40%和72.50%。

微球调驱技术在深部堵塞特征油藏的应用研究

随着油藏注水开发时间延长,水驱状况变差,含水率逐年上升,水驱效率下降,严重影响油藏的采收率。一般认为注水开发过程中会发生孔喉被注水冲刷变化、微裂缝开启等导致的注水突进,往往忽略深部堵塞对水驱的影响。针对油层深部堵塞缺乏研究认识,治理过程中缺乏有效措施,影响此类油藏的开发效果。本文通过对典型的低渗透注水开发油藏分析深部堵塞特征,在此基础上开展微球调驱矿场试验。从效果来看,微球调驱技术与这种深部堵塞油藏适应性较好,通过微球吸水膨胀封堵深部水驱通道,表面活性剂疏通堵塞通道,有效改善水驱,取得了较好的控水稳油效果,为同类型油藏的稳产工作提供科学依据。

基于示卓安超声造影Kupffer期的深度学习预测肝细胞癌微血管侵犯的研究

目的:评估基于注射用全氟丁烷微球[商品名示卓安(Sonazoid)]超声造影Kupffer期的深度学习模型预测肝细胞癌(hepatocellular carcinoma,HCC)微血管侵犯(microvascular invasion,MVI)的效能,并将其与影像组学模型及临床模型进行比较。方法:回顾并纳入2020年7月—2022年9月于广西医科大学第一附属医院接受Sonazoid超声造影检查的146例原发性HCC患者,以7∶3随机划分为训练集102例和验证集44例。基于肿瘤感兴趣区,使用ResNet101模型通过迁移学习提取深度学习特征,使用PyRadiomics提取影像组学特征。采用Mann-Whitney U检验、最小绝对收缩和选择算子(least absolute shrinkage and selection operator,LASSO)算法进行特征降维。LASSO回归用于构建深度学习模型和影像组学模型,同时还基于临床特征构建一个临床模型。采用受试者工作特征曲线的曲线下面积(area under the curve,AUC)、灵敏度、特异度和准确度评估模型的诊断效能。DeLong检验用于比较模型间的诊断效能。结果:在训练集中,深度学习模型、影像组学模型、临床模型的AUC(95%CI)分别为0.931(0.880~0.981)、0.823(0.744~0.903)、0.719(0.614~0.824)。在验证集中,深度学习模型、影像组学模型、临床模型的AUC(95%CI)分别为0.895(0.757~1.000)、0.711(0.514~0.909)、0.606(0.390~0.822)。DeLong检验表明在训练集和验证集中,深度学习模型的诊断效能均优于影像组学模型及临床模型(P<0.05)。单因素及多因素logistic回归分析示甲胎蛋白和巴塞罗那临床肝癌分期可作为HCC患者MVI的独立预测因子(P<0.01)。结论:基于Sonazoid超声造影Kupffer期的深度学习模型在预测HCC患者MVI方面表现出优异的性能,有望成为预测MVI的无创影像学生物标志物。

Exhausted local lactate accumulation via injectable nanozyme-functionalized hydrogel microsphere for inflammation relief and tissue regeneration

Local lactate accumulation greatly hinders tissue repair and regeneration under ischemic condition.Herein,an injectable microsphere(MS@MCL)for local lactate exhaustion was constructed by grafting manganese dioxide(MnO_(2))-lactate oxidase(LOX)composite nanozyme on microfluidic hyaluronic acid methacrylate(HAMA)microspheres via chemical bonds,achieving a long-term oxygen-promoted lactate exhaustion effect and a long half-life in vivo.The uniform and porous microspheres synthesized by microfluidic technology is beneficial to in situ injection therapy and improving encapsulation efficiency.Furthermore,chemical grafting into HAMA microspheres through amide reactions promoted local enzymatic concentration and activity enhancement.It was showed that the MS@MCL eliminated oxidative and inflammatory stress and promoted extracellular matrix metabolism and cell survival when co-cultured with nucleus pulposus cells(NPCs)in vitro.In the rat degenerative intervertebral disc model caused by lactate injection,MS@MCL showed a long-term therapeutic effect in reducing intervertebral height narrowing and preventing extracellular matrix(ECM)degradation as well as inflammatory damage in vivo.Altogether,this study confirms that this nanozyme-functionalized injectable MS@MCL effectively improves the regenerative and reparative effect in ischemic tissues by disposing of enriched lactate in local microenvironment.

Injectable bone cement with magnesium-containing microspheres enhances osteogenesis via anti-inflammatory immunoregulation

Injectable bone cement is especially useful in minimally invasive surgeries to repair small and irregular bone defects.Amongst different kinds of injectable bone cements,bioactive calcium phosphate bone cement(CPC)has been widely studied due to its biological activity.However,its dense structure and poor biodegradability prevent the ingrowth of living tissue,which leads to undesirable bone regeneration and clinical translation.To address this issue,we prepared bone cement based on Magnesium-containing microspheres(MMSs)that can not only be cured into a 3D porous scaffold but also have controllable biodegradability that continuously provides space for desired tissue ingrowth.Interestingly,magnesium ions released from MMSs cement(MMSC)trigger positive immunomodulation via upregulation of the anti-inflammatory genes IL-10 and M2 macrophage polarization with increased expression of CD206,which is beneficial to osteogenesis.Moreover,the physicochemical properties of MMSC,including heat release,rheology and setting time,can be tuned to meet the requirements of injectable bone cement for clinical application.Using a rat model,we have demonstrated that MMSC promoted osteogenesis via mediation of tissue ingrowth and anti-inflammatory immunomodulation.The study provides a paradigm for the design and preparation of injectable bone cements with 3D porous structures,biodegradability and anti-inflammatory immunoregulation to efficiently promote osteogenesis.

低渗透油藏聚合物微球深部调驱适应性研究

聚合物微球是目前低渗透油田广泛应用的一种能够提高水驱采收率的深部调剖剂。以长庆X46试验区块为研究对象,预测增油量与可采储量,结合关键注入参数,对低渗透油藏聚合物微球深部调驱适应性进行分析,绘制了聚合物微球调剖效果影响因素图版,明确最佳调剖参数,并结合流线模拟软件验证试验X46区块结论的正确性。结果表明,试验区推荐采用微球浓度为0.50%,将注入量控制在1500~2000 m^(3)的范围内。微球的粒径应设定为100 nm,最佳注入时机应确保含水率维持在40%~70%之间。该研究可为该油田深部调剖措施以及类似油田高含水后期的开发调整提供一定的指导和借鉴意义。

核磁共振氢谱法测定注射用微球专用溶剂中硅油的含量

目的:建立测定注射用微球专用溶剂中硅油含量的定量核磁共振氢谱(qHNMR)法。方法:采用Bruker Avance NEO 600型核磁共振波谱仪测定核磁共振氢谱(^(1)H NMR),脉冲序列zg30,弛豫延迟时间15 s,采样次数16,测定温度25℃,以咖啡因为内标,不加四甲基硅烷(TMS)的氘代氯仿为溶剂,对注射用微球专用溶剂中的硅油进行定量研究,以硅油定量峰与内标定量峰面积之比对其含量(μg)绘制标准曲线,计算注射用微球专用溶剂中硅油含量。结果:硅油含量在6~100μg范围内线性关系良好,r=0.9999,低、中、高浓度的平均回收率为97.8%(n=9),重复性RSD为9.8%。结论:该方法操作简单快捷、灵敏度高、结果准确,可用于注射用微球专用溶剂中硅油含量的测定。

注射用醋酸亮丙瑞林缓释微球联合甲地孕酮治疗小儿性早熟的临床疗效及不良反应

目的观察注射用醋酸亮丙瑞林缓释微球联合甲地孕酮治疗小儿性早熟的临床疗效及不良反应。方法选择2021年3月—2022年3月于大连市妇女儿童医疗中心(集团)接受治疗的性早熟患儿82例为研究对象,采用随机数字表法分为试验组和对照组,每组41例。对照组采用甲地孕酮治疗,试验组在对照组基础上联合注射用醋酸亮丙瑞林缓释微球治疗,2组均持续治疗1年。比较2组患儿治疗前后性激素水平、影像学指标、生长情况及不良反应。结果治疗1年后,2组卵泡刺激素、雌二醇、黄体生成素水平、卵泡直径、子宫容积、卵巢容积及骨龄均较治疗前下降,身高及体质量均较治疗前升高,且试验组变化幅度大于对照组(P<0.01);试验组与对照组不良反应总发生率比较差异无统计学意义(7.32%vs.9.76%,χ^(2)=0.156,P=0.692)。结论注射用醋酸亮丙瑞林缓释微球联合甲地孕酮治疗小儿性早熟可取得显著的临床疗效,可有效改善患儿性激素水平,促进身体生长发育,抑制第二性征,且安全性高。

注射用醋酸亮丙瑞林微球治疗子宫内膜异位症腹腔镜术后患者的效果

目的:观察注射用醋酸亮丙瑞林微球治疗子宫内膜异位症腹腔镜术后患者的效果。方法:选取2021年1月至2022年12月该院收治的124例子宫内膜异位症腹腔镜术后患者进行前瞻性研究,按照随机数字表法将其分为对照组和观察组各62例。两组均行腹腔镜手术治疗,术后对照组予以孕三烯酮胶囊治疗,观察组予以注射用醋酸亮丙瑞林微球治疗,两组均治疗6个月。比较两组临床疗效,治疗前后性激素指标[抗苗勒管激素(AMH)、雌二醇(E_(2))、卵泡刺激素(FSH)]水平、窦状卵泡数、卵巢体积,以及不良反应发生率。结果:观察组治疗总有效率为96.77%(60/62),高于对照组的72.58%(45/62),差异有统计学意义(P<0.05);治疗后,两组AMH水平均高于治疗前,且观察组高于对照组,两组E_(2)、FSH水平均低于治疗前,且观察组低于对照组,差异有统计学意义(P<0.05);治疗后,两组窦状卵泡数均少于治疗前,但观察组多于对照组,两组卵巢体积均小于治疗前,但观察组大于对照组,差异有统计学意义(P<0.05);两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论:注射用醋酸亮丙瑞林微球治疗子宫内膜异位症腹腔镜术后患者可提高治疗总有效率,增加窦状卵泡数,增大卵巢体积,改善性激素指标水平,效果优于孕三烯酮胶囊治疗。

前列地尔注射液临床用药分析

目的：调查本院前列地尔注射液的使用情况,分析其临床使用的适宜性。方法：对2013年8月-2014年8月的3681例使用前列地尔注射液成人患者的分布情况、原患疾病及用法用量、疗程、药液使用时间、溶媒使用量、药物利用指数（DUI）进行统计分析。结果：前列地尔注射液在各科室使用广泛,3 681例患者使用中49.8%存在超说明书适应证、10.3%的患者超剂量、13.6%的患者药液使用时间过长、1%患者使用疗程过长、67.7%的患者使用溶媒量超说明书推荐等情况。结论：前列地尔注射液不规范使用情况需引起重视。对于前列地尔注射液存在的用药情况,医院应该制定前列地尔注射液使用规范,使前列地尔注射液的适应证、用法用量、疗程、药液使用时间、溶媒使用量等方面进一步优化。

聚合物微球调驱工艺优化设计

聚合物微球具有进行深部调驱的性能,选用纳米聚合物微球与核壳自胶结微球进行室内实验,对注入段塞工艺、不同类型微球组合注入次序与比例以及注入方式进行了系统的优化。结果表明,相比高质量浓度短段塞及低质量浓度长段塞,中等质量浓度中等段塞注入聚合物纳米球工艺综合了以上两种注入工艺的优点,可以在适当的时间内获得相对稳定的采收率;先注入核壳自胶结微球后注入纳米球对于中低渗地层进行深部调驱具有更高的微球利用率及开发效果,实验条件下两者的最佳PV数比为1∶1;间隔注入工艺,使得微球分布于更为广泛的地层中,对于前期形成的新的渗水通道可以进行及时的微球补充,从而使得采收率持续增长。

不同渗透率级差下化学驱油体系优选

针对聚合物驱过程中出现的剖面返转现象,选取不同驱油体系(聚合物、微球、凝胶、泡沫),开展了渗透率级差为3、6、10时不同驱油体系单一或交替注入的驱油效果实验对比,结果表明:渗透率级差为3时,浓度为1 400 mg/L和800 mg/L的聚合物交替注入较浓度为1 100 mg/L的聚合物连续注入可提高采出程度3.5个百分点;渗透率级差为6或10时,凝胶和聚合物交替注入效果最好,采出程度较聚合物连续注入可分别提高14.6个百分点或20.3个百分点。对于渗透率级差较小的储层,推荐采用高低浓度聚合物交替注入;对于渗透率级差较大的储层,高低浓度聚合物交替注入失效,采用高黏体系封堵高渗层再注入聚合物的方式能够显著改善吸液剖面。

深部调剖剂YG聚合物微球性能评价与应用

为考查深部调剖剂YG型聚合物微球在中原油田高温高矿化度油藏中的性能,通过透射电镜显微照相、吸水膨胀实验、岩心驱替实验和现场先导试验对其进行了性能评价与矿场应用。性能评价结果表明:该聚合物微球体积微小,可均匀分散在溶液中,与地层水表现出良好的配伍性;在95℃文留油田回注污水中,吸水膨胀倍数达40倍以上,具有较好的耐温抗盐和吸水膨胀性能;向中、低渗透率岩心注入微球体系过程中,呈现开始压力迅速上升、然后趋于稳定、压力略有下降的波动过程,具有较好的注入性;向中、高渗透率岩心注入微球体系过程中,随溶胀时间的延长,封堵率逐步增加,第10天达到最大,为17.14%。采用YG型微球在文留油田文10东块进行了深部调剖先导试验,取得了较好的开发效果。