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Bone microenvironment regulative hydrogels with ROS scavenging and prolonged oxygen-generating for enhancing bone repair

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Bioactive Materials 2023年第6期24卷 477-496页

作者： Han Sun Juan xu Yangyufan Wang Siyu Shen Xingquan Xu Lei Zhang Qing Jiang State Key Laboratory of Pharmaceutical Biotechnology Division of Sports Medicine and Adult Reconstructive SurgeryDepartment of Orthopedic SurgeryNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical School321 Zhongshan RoadNanjing210008JiangsuPR China Branch of National Clinical Research Center for Orthopedics Sports Medicine and RehabilitationPR China Co-innovation Center of Neuroregeneration Nantong University9 Seyuan RoadNantong226019JiangsuPR China Articular Orthopaedics The Third Affiliated Hospital of Soochow University185 Juqian RoadChangzhou213003JiangsuPR China

Large bone defects resulting from fractures and disease are a major clinical challenge,being often unable to heal spontaneously by the body’s repair mechanisms.Lines of evidence have shown that hypoxia-induced overproduction of ROS in bone defect region has a major impact on delaying bone regeneration.However,replenishing excess oxygen in a short time cause high oxygen tension that affect the activity of osteoblast precursor cells.Therefore,reasonably restoring the hypoxic condition of bone microenvironment is essential for facilitating bone repair.Herein,we designed ROS scavenging and responsive prolonged oxygen-generating hydrogels(CPP-L/GelMA)as a“bone microenvironment regulative hydrogel”to reverse the hypoxic microenvironment in bone defects region.CPP-L/GelMA hydrogels comprises an antioxidant enzyme catalase(CAT)and ROS-responsive oxygen-releasing nanoparticles(PFC@PLGA/PPS)co-loaded liposome(CCP-L)and GelMA hydrogels.Under hypoxic condition,CPP-L/GelMA can release CAT for degrading hydrogen peroxide to generate oxygen and be triggered by superfluous ROS to continuously release the oxygen for more than 2 weeks.The prolonged oxygen enriched microenvironment generated by CPP-L/GelMA hydrogel significantly enhanced angiogenesis and osteogenesis while inhibited osteoclastogenesis.Finally,CPP-L/GelMA showed excellent bone regeneration effect in a mice skull defect model through the Nrf2-BMAL1-autophagy pathway.Hence,CPP-L/GelMA,as a bone microenvironment regulative hydrogel for bone tissue respiration,can effectively scavenge ROS and provide prolonged oxygen supply according to the demand in bone defect region,possessing of great clinical therapeutic potential.

关键词： Bone defect Hypoxic microenvironment Reactive oxygen species responsiveness Prolonged oxygen generation Brain and muscle arnt-like protein 1

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Platelet-rich plasma combined with injectable hyaluronic acid hydrogel for porcine cartilage regeneration: a 6-month follow-up

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Regenerative Biomaterials 2020年第1期7卷 77-90页

作者： Wenqiang Yan Xingquan Xu Qian xu Ziying Sun Qing Jiang Dongquan Shi State Key Laboratory of Pharmaceutical Biotechnology Department of Sports Medicine and Adult Reconstructive SurgeryNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical School321 Zhongshan RoadNanjing 210008JiangsuChina Laboratory for Bone and Joint Disease Model Animal Research Center(MARC)Nanjing UniversityNanjing 210093JiangsuChina

Based on our previous study,the utilization of an ultraviolet light photo-cross-linkable hyaluronic acid(HA)hydrogel integrated with a small molecule kartogenin-encapsulated nanoparticles obtained good reconstruction of osteochondral defects in a rabbit model,indicating the superiority of injectable hydrogel-based scaffolds in cartilage tissue engineering.Platelet-rich plasma(PRP),rich in various growth factors,proteins and cytokines,is considered to facilitate cartilage healing by stimulating cell proliferation and inducing chondrogenesis in cartilage defect site.The aim of this study was to test the therapeutic feasibility of autologous PRP combined with injectable HA hydrogel on cartilage repair.The focal cartilage defects with different critical sizes in the medial femoral condyle of a porcine model were used.At 6 months,the minipigs were sacrificed for assessment of macroscopic appearance,magnetic resonance imaging,micro-computed tomography,histology staining and biomechanics.The HA hydrogel combined with PRP-treated group showed more hyaline-like cartilage exhibited by macroscopic appearance and histological staining in terms of extracellular matrix and type II collagen without formation of hypertrophic cartilage,indicating its capacity to improve cartilage healing in the minipig model evaluated at 6 months,with full-thickness cartilage defect of 8.5mm diameter and osteochondral defect of 6.5mm diameter,5mm depth exhibiting apparent regeneration.

关键词： platelet-rich plasma hyaluronic acid hydrogel cartilage repair regenerative medicine

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Analysis of the Lost Circulation Problem

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Fluid Dynamics & Materials Processing 2023年第6期19卷 1721-1733页

作者： xingquan Zhang Renjun Xie Kuan Liu Yating Li Yuqiang xu CNOOC Research Institute Beijing100101China College of Petroleum Engineering China University of PetroleumQingdao266580China

The well-known“lost circulation”problem refers to the uncontrolled flow of whole mud into a formation.In order to address the problem related to the paucity of available data,in the present study,a model is introduced for the lost-circulation risk sample profile of a drilled well.The model is built taking into account effective data(the Block L).Then,using a three-dimensional geological modeling software,relying on the variation function and sequential Gaussian simulation method,a three-dimensional block lost-circulation risk model is introduced able to provide relevant information for regional analyses.

关键词： Geostatistics risk assessment variation function sequential gaussian simulation drilling risk lost circulation evaluation method

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Power Minimization for the IRS-Aided SWIPT Secure Communication System with Imperfect Cascaded Channel

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Journal of Communications and Information Networks 2023年第2期8卷 133-140页

作者： Chunlong He Shuqiong xu Gongbin Qian xingquan Li Chiya Zhang Guangdong Key Laboratory of Intelligent Information Processing Shenzhen UniversityShenzhen 518060China School of Microelectronics Shenzhen Institute of Information TechnologyShenzhen 518000China School of Electronic and Information Engineering Harbin Institute of TechnologyShenzhen 518055China National Mobile Communications Research Laboratory Southeast UniversityNanjing 210096China Peng Cheng Laboratory(PCL) Shenzhen 5180523China

Intelligent reflecting surface(IRS)-assisted simultaneous wireless information and power transfer(SWIPT)is a promising technology for prolonging the lifetime of the users and improving system performance.However,it is challenging to obtain the perfect channel state information(CSI)at the base station(BS)due to the lack of radio frequency(RF)chains at the IRS,which becomes even harder when eavesdroppers(Eves)exist.In this paper,we study the power issues in the IRS-aided SWIPT system under the imperfect CSI of BS-IRS-Eves links.We aim to minimize the transmitting power at the BS by jointly designing transmit beamforming and reflective beamforming with subject to the rate outage probability constraints of the Eves,the energy harvesting constraints of the energy receivers(ERs),and the minimum rate constraints of the information receivers(IRs).We use Bernstein-type inequality to solve the rate outage probability constraints.Afterward,the formulated nonconvex problem can be efficiently tackled by employing alternating optimization(AO)combined with semidefinite relaxation(SDR)and penalty convex-concave procedure(CCP).Numerical results demonstrate the effectiveness of the proposed scheme.

关键词： IRS SWIPT secure communication AO

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Analysis of the Applicability of a Risk Quantitative Evaluation Method to High Temperature-Pressure Drilling Engineering

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Fluid Dynamics & Materials Processing 2023年第6期19卷 1385-1395页

作者： Renjun Xie xingquan Zhang Baolun He Ningyu Zheng Yuqiang xu CNOOC Research Institute Beijing100101China College of Petroleum Engineering China University of PetroleumQingdao266580China

The optimization of methods for the quantitative evaluation of risks in drilling engineering is an effective means to ensure safety in situations where high temperature and high pressure blocks are considered.In such a context,this study analyzes the complexity of the drilled wells in such blocks.It is shown that phenomena such as well kick,loss,circulation,and sticking,are related to the imbalance of wellbore pressure.A method for risk quantitative evaluation is proposed accordingly.The method is used to evaluate the risk for 9 drilled wells.By comparing the predictions of the method with actual historical data related to these wells,it is found that the coincidence rate is about 95%.

关键词： Risk assessment applicability formation pressure

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Advances of injectable hydrogel-based scaffolds for cartilage regeneration

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Regenerative Biomaterials 2019年第3期6卷 129-140页

作者： Jiawei Li Guojun Chen Xingquan Xu Peter Abdou Qing Jiang Dongquan Shi Zhen Gu Department of Sports Medicine and Adult Reconstructive Surgery Drum Tower HospitalSchool of MedicineNanjing University321 Zhongshan RoadNanjing 210008JiangsuP.R.China Department of Bioengineering University of CaliforniaLos Angeles410 Westwood PlazaLos AngelesCA 90095USA California NanoSystems Institute University of CaliforniaLos Angeles570 Westwood PlazaLos AngelesCA 90095USA Jonsson Comprehensive Cancer Center University of CaliforniaLos Angeles8-684 Factor BuildingLos AngelesCA 90095USA Center for Minimally Invasive Therapeutics University of CaliforniaLos Angeles570 Westwood PlazaLos AngelesCA 90095USA

Articular cartilage is an important load-bearing tissue distributed on the surface of diarthrodial joints.Due to its avascular,aneural and non-lymphatic features,cartilage has limited self-regenerative properties.To date,the utilization of biomaterials to aid in cartilage regeneration,especially through the use of injectable scaffolds,has attracted considerable attention.Various materials,therapeutics and fabrication approaches have emerged with a focus on manipulating the cartilage microenvironment to induce the formation of cartilaginous structures that have similar properties to the native tissues.In particular,the design and fabrication of injectable hydrogel-based scaffolds have advanced in recent years with the aim of enhancing its therapeutic efficacy and improving its ease of administration.This review summarizes recent progress in these efforts,including the structural improvement of scaffolds,network cross-linking techniques and strategies for controlled release,which present new opportunities for the development of injectable scaffolds for cartilage regeneration.

关键词： drug delivery tissue engineering injectable hydrogel cartilage regeneration

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Night-time diastolic blood pressure variability relates to stroke recurrence in patients who had ischaemic stroke with small artery occlusion

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Stroke & Vascular Neurology 2022年第3期7卷 237-244页

作者： Tingting Wang Jie xu Anxin Wang Ying Liu xingquan Zhao Yongjun Wang Yilong Wang Department of Neurology Beijing Tiantan HospitalCapital Medical UniversityBeijingChina China National Clinical Research Center for Neurological Diseases BeijingChina

Background and purpose The association between blood pressure variability(BPV)and stroke recurrence among patients who had ischaemic stroke(IS)remains unclear.This study aimed to investigate the association between BPV and stroke recurrence in patients who had IS of large artery atherosclerosis(LAA)subtype and small artery occlusion(SAO)subtype.Methods Data from the BOSS(Blood Pressure and Clinical Outcome in Transient Ischemic Attack or Ischemic Stroke)study were examined.IS subtypes were diagnosed according to the Trial of Org 10172 in Acute Stroke Treatment criteria.BPV was performed by 24-hour ambulatory blood pressure monitoring and defined through SD of blood pressure.The primary outcome was stroke recurrence within 90 days after discharge.Multivariable Cox regression model was used to assess the association between BPV and stroke recurrence in patients who had IS of LAA subtype and SAO subtype.Results A total of 1390 patients who had IS from the BOSS study were included in the present study.Multivariable analysis suggests that 24-hour systolic BPV(SBPV)and night-time diastolic BPV(DBPV)were significantly associated with stroke recurrence among all patients who had IS(HR,2.50,95%CI 1.07 to 5.84;HR,1.85,95%CI 1.07 to 3.21,respectively).Night-time SBPV and night-time DBPV were significantly associated with stroke recurrence in patients with SAO subtype(HR,2.77,95%CI 1.07 to 7.15;HR,3.60,95%CI 1.39 to 9.29,respectively).However,in the adjusted model,only night-time DBPV remained significant in patients with SAO subtype(HR,3.87,95%CI 1.40 to 10.71).Similar results were not found in patients who had IS of LAA subtype.Conclusions High night-time DBPV was associated with increased risk of stroke recurrence among patients who had IS of SAO subtype.The results of this study have implications for the secondary prevention management and future research of patients who had IS of SAO subtype.The association between BPV and stroke recurrence in patients who had IS of LAA subtype and SAO subtype should be investigated in

关键词： patients diastolic Blood

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Association between cumulative exposure to different lipid parameters and risk of newly developed carotid plaque

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Stroke & Vascular Neurology 2021年第3期6卷 359-365页

作者： Jianwei Wu Yu Wang Kaijiang Kang Anxin Wang Jie xu xingquan Zhao Department of Neurology Beijing Tiantan HospitalCapital Medical UniversityBeijingChina China National Clinical Research Center for Neurological Diseases BeijingChina Center of Stroke Beijing Institute for Brain DisordersBeijingChina Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease BeijingChina Department of Epidemiology and Health Statistics School of Public HealthCapital Medical UniversityBeijingChina Beijing Municipal Key Laboratory of Clinical Epidemiology BeijingChina

Background and purpose Both the magnitude and cumulative exposure of atherogenic lipoproteins have an impact on the atherosclerosis risk,and the exploration focus has shifted from one single lipoprotein assessment to the cumulative exposure of lipoproteins.We aim to investigate the relationship between cumulative exposure to different lipid parameters and the risk of newly developed carotid plaque in this study.Methods In the Asymptomatic Polyvascular Abnormalities Community study,2947 participants were included with follow-up every 2 years from 2006 to 2012.Lipid parameters including total cholesterol(TC),triglycerides(TGs),low-density lipoprotein cholesterol(LDLC),high-density lipoprotein cholesterol(HDLC)and non-HDLC were measured.Cumulative exposure was calculated by adding the weighted sum of the difference between the measured value and the cut-off value of each parameter.Newly developed carotid plaques were identified by carotid ultrasound performed at the third and fourth follow-ups.Results In the univariate analysis,non-HDLC burden had the highest ORs among the five lipid parameters for newly developed carotid plaque in each quartile,as 1.0(reference),1.35(1.09-1.67),1.68(1.36-2.08)and 2.74(2.22-3.38)from the lowest to the highest quartile.In the multivariate analysis and sensitivity analysis,we obtained similar results.Conclusions TC burden,TG burden,LDLC burden and non-HDLC burden are all independent risk factors for newly developed carotid plaque,especially for the vulnerable plaques.Among lipid parameters,non-HDLC burden is an optimal predictor.Moreover,the predictive value remained significant for participants under the age of 65 years old or free of hypertension,diabetes mellitus and hyperlipidaemia.

关键词： carotid Lipid cholesterol

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Cerium oxide nanozymes alleviate oxidative stress in tenocytes for Achilles tendinopathy healing

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Nano Research 2023年第5期16卷 7364-7372页

作者： Xingquan Xu Rongliang Wang Yixuan Li Rui Wu Wenjin Yan Sheng Zhao Quanyi Liu Yan Du Wenli Gong Weitong Li Hui Wei Dongquan Shi State Key Laboratory of Pharmaceutical Biotechnology Division of Sports Medicine and Adult Reconstructive SurgeryDepartment of Orthopedic SurgeryNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing 210008China Department of Biomedical Engineering College of Engineering and Applied SciencesNanjing National Laboratory of MicrostructuresJiangsu Key Laboratory of Artificial Functional MaterialsNanjing UniversityNanjing 210023China State Key Laboratory of Electroanalytical Chemistry Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchun 130022China University of Science and Technology of China Hefei 230026China State Key Laboratory of Analytical Chemistry for Life Science School of Chemistry and Chemical EngineeringChemistry and Biomedicine Innovation Center(ChemBIC)Nanjing UniversityNanjing 210023China

Background:Reactive oxygen species(ROS)is considered as ubiquitous and highly active chemicals that influence tendon integrity and orchestrate tendon repair.With significant recent advances in nanomaterials,cerium oxide nanoparticles(CeO_(2)NPs)exhibit superoxide dismutase-and catalase-like activities.Herein,we introduced a therapeutic approach of CeO_(2)NPs for Achilles tendinopathy(AT)healing.Methods:CeO_(2)NPs were synthesized to examine their effect as ROS scavengers on AT healing in vitro and in vivo.The mRNA levels of inflammatory factors were evaluated in AT after CeO_(2)NPs treatment in vitro.The mechanisms underlying CeO_(2)NPs-mediated stimulation of NRF2 translocation and ERK signaling were verified through immunofluorescence and Western blot analysis.The efficacy of CeO_(2)NPs was tested in an AT rat model in comparison with the control.Results:CeO_(2)NPs not only significantly scavenged multiple ROS and suppressed ROS-induced inflammatory reactions but also protected cell proliferation under oxidative stress induced by tert-butyl hydroperoxide(TBHP).Moreover,CeO_(2)NPs could promote NRF_(2)nuclear translocation for anti-oxidation and anti-inflammation through the ERK signaling pathway.In a rat model of collagenase-induced tendon injuries,CeO_(2)NPs showed significant therapeutic efficacy by ameliorating tendon damage.Conclusion:The present study provides valuable insights into the molecular mechanism of CeO_(2)NPs to ameliorate ROS in tenocytes via the ERK/NRF_(2)signaling pathway,which underscores the potential of CeO_(2)NPs for application in the treatment of enthesopathy healing.

关键词： CeO_(2)nanozymes enthesiopathy NRF2 translocation ERK signaling

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Targeting macrophagic SHP2 for ameliorating osteoarthritis via TLR signaling

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Acta Pharmaceutica Sinica B 2022年第7期12卷 3073-3084页

作者： Ziying Sun Qianqian Liu Zhongyang Lv Jiawei Li Xingquan Xu Heng Sun Maochun Wang Kuoyang Sun Tianshu Shi Zizheng Liu Guihua Tan Wenqiang Yan Rui Wu Yannick Xiaofan Yang Shiro Ikegawa Qing Jiang Yang Sun Dongquan Shi State Key Laboratory of Pharmaceutical Biotechnology Department of Sports Medicine and Adult Reconstructive SurgeryNanjing Drum Tower Hospitalthe Affiliated Hospital of Nanjing University Medical SchoolNanjing 210008China Laboratory for Bone and Joint Disease Model Animal Research Center(MARC)Nanjing UniversityNanjing 210093China State Key Laboratory of Pharmaceutical Biotechnology Department of Biotechnology and Pharmaceutical SciencesSchool of Life ScienceNanjing UniversityNanjing 210023China Drum Tower of Clinical Medicine Nanjing Medical UniversityNanjing 210008China Laboratory for Bone and Joint Diseases RIKEN Center for Integrative Medical Science(IMSRIKEN)Tokyo 108-8639Japan

Osteoarthritis(OA),in which M1 macrophage polarization in the synovium exacerbates disease progression,is a major cause of cartilage degeneration and functional disabilities.Therapeutic strategies of OA designed to interfere with the polarization of macrophages have rarely been reported.Here,we report that SHP099,as an allosteric inhibitor of src-homology 2-containing protein tyrosine phosphatase 2(SHP2),attenuated osteoarthritis progression by inhibiting M1 macrophage polarization.We demonstrated that M1 macrophage polarization was accompanied by the overexpression of SHP2 in the synovial tissues of OA patients and OA model mice.Compared to wild-type(WT)mice,myeloid lineage conditional Shp2 knockout(c KO)mice showed decreased M1 macrophage polarization and attenuated severity of synovitis,an elevated expression of cartilage phenotype protein collagen II(COL2),and a decreased expression of cartilage degradation markers collagen X(COL10)and matrix metalloproteinase3(MMP3)in OA cartilage.Further mechanistic analysis showed that SHP099 inhibited lipopolysaccharide(LPS)-induced Toll-like receptor(TLR)signaling mediated by nuclear factor kappa B(NF-κB)and PI3K—AKT signaling.Moreover,intra-articular injection of SHP099 also significantly attenuated OA progression,including joint synovitis and cartilage damage.These results indicated that allosteric inhibition of SHP2 might be a promising therapeutic strategy for the treatment of OA.

关键词： SHP2 SHP099 Osteoarthritis Synovitis Toll-like receptor signaling Macrophage Cartilage degradation M1 macrophage polarization

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