Physiological supporting systems,such as the vascular network and excretion system,are crucial for the effective functioning of organs.This study demonstrates that when a body-on-a-chip microdevice is coupled with min...Physiological supporting systems,such as the vascular network and excretion system,are crucial for the effective functioning of organs.This study demonstrates that when a body-on-a-chip microdevice is coupled with miniaturized physiological support systems,it can create a multi-organ microphysiological system capable of more accurately mimicking the physiological complexity of a body,thereby offering potential for preclinical drug testing.To exemplify this concept,we have developed a model system comprising 18 types of microtissues interconnected by a vascular network that replicates the in vivo blood distribution among the organs.Furthermore,this system includes an excretory system with a micro-stirrer that ensures elimination efficiency akin to in vivo conditions.Our findings indicate that this system can:(1)survive and function for almost two months;(2)achieve two-compartment pharmacokinetics of a drug;(3)investigate the dynamic relationship between the tissue distribution and toxicity of a drug;(4)establish the multimorbidity model and evaluate the effectiveness of polypharmacy,challenging tasks with traditional animal models;(5)reduce animal usage in drug evaluations.Notably,features from points(2)to(4)are capabilities not achievable by other in vitro models.The strategy proposed in this study can also be applied to the development of multi-organ microphysiological systems that mimic the physiological complexity of human organs or the entire body.展开更多
Combining with entransy theory,constructal designs of the X-shaped vascular networks(XSVNs)are implemented with fixed total tube volumes of the XSVNs.The entransy dissipation rates(EDRs)of the XSVNs are minimized,and ...Combining with entransy theory,constructal designs of the X-shaped vascular networks(XSVNs)are implemented with fixed total tube volumes of the XSVNs.The entransy dissipation rates(EDRs)of the XSVNs are minimized,and the optimal constructs of the XSVNs are derived.Comparison of the optimal constructs of the XSVNs with two optimization objectives(EDR minimization and entropy generation rate(EGR)minimization)is conducted.It is found that when the dimensionless mass flow rate(DMFR)is small,the optimal diameter ratio of the elemental XSVN derived by EDR minimization is different from that derived by EGR minimization.For the multilevel XSVN,when the DMFR is 100,compared the XSVN with the corresponding H-shaped vascular network(HSVN),the dimensionless EDRs of the elemental,second and fourth order XSVNs are reduced by 26.39%,15.34%and 9.81%,respectively.Compared with the entransy dissipation number(EDN)of the second order XSVN before angle optimization,the EDN after optimization is reduced by 26.15%,which illustrates that it is significant to conduct angle optimization of the XSVN.Entransy theory is applied into the constructal design of the vasculature with heat transfer and fluid flow in this paper,which provides new directions for the vasculature designs.展开更多
Artificial organs are devices implanted into the living body as a substitute for damaged or diseased organs.Current efforts focus on the construction of fully functionalized artificial tissues/organs with vascular net...Artificial organs are devices implanted into the living body as a substitute for damaged or diseased organs.Current efforts focus on the construction of fully functionalized artificial tissues/organs with vascular networks.Although engineering efforts have been made in creating artificial vessels with simple or complex configurations,building vascular networks with hierarchical architectures approximating native counterparts remains challenging.Herein,we give a perspective of cellular fluidics-based construction of vascular networks for tissue engineering,with inspirations drawn from a novel concept of 3D fluidic control platform based on unit-cell constructs.Through architected design of the unit cells,it enables programmed control over gas-liquid-solid interfaces and fluid flow processes in open-cell structures.This cellular-fluidics concept and the associated platform provide lots of inspirations for constructing artificial vascular networks.We believe that cellular fluidics opens a new avenue for fluid control and deterministic delivery,and would find vast opportunities in tissue engineering.展开更多
OBJECTIVE Numerous references made clear that triphala is revered as a multiuse therapeutic and perhaps even panacea historically.Nevertheless,the protective mechanism of triphala on cardio-cerebral vascular diseases(...OBJECTIVE Numerous references made clear that triphala is revered as a multiuse therapeutic and perhaps even panacea historically.Nevertheless,the protective mechanism of triphala on cardio-cerebral vascular diseases(CCVDs)remains not comprehensive understanding.Hence,a network pharmacology-based method was suggested in this study to address this problem.METHODS This study was based on network pharmacology and bioinformatics analysis.Information on compounds in herbal medicines of triphala formula was acquired from public databases.Oral bioavailability as well as drug-likeness were screened by using absorption,distribution,metabolism,and excretion(ADME)criteria.Then,components of triphala,candidate targets of each component and known therapeutic targets of CCVDs were collected.Compound-target gene and compounds-CCVDs target networks were created through network pharmacology data sources.In addition,key targets and pathway enrichment were analyzed by STRING database and DAVID database.Moreover,we verified three of the key targets(PTGS2,MMP9 and IL-6)predicted by using Western blotting analysis.RESULTS Network analysis determined 132 compounds in three herbal medicines that were subjected to ADME screening,and 23 compounds as well as 65 genes formed the principal pathways linked to CCVDs.And 10 compounds,which actually linked to more than three genes,are determined as crucial chemicals.Core genes in this network were IL-6,TNF,VEGFA,PTGS2,CXCL8,TP53,CCL2,IL-10,MMP9 and SERPINE1.And pathways in cancer,TNF signaling path⁃way,neuroactive ligand-receptor interaction,etc.related to CCVDs were identified.In vitro experiments,the results indi⁃cated that compared with the control group(no treatment),PTGS2,MMP9 and IL-6 were up-regulated by treatment of 10μg·L^-1 TNF-α,while pretreatment with 20-80 mg·L^-1 triphala could significantly inhibit the expression of PTGS2,MMP9 and IL-6.With increasing Triphala concentration,the expression of PTGS2,MMP9 and IL-6 decreased.CON⁃CLUSION Complex components and pharmacological mechanism of triphala,and obtained some potential therapeutic targets of CCVDs,which could provide theoretical basis for the research and development of new drugs for treating CCVDs.展开更多
The cerebral vasculature plays a significant role in the development of Alzheimer's disease(AD),however,the specific association between them remains unclear.In this paper,based on the benefits of photoacoustic im...The cerebral vasculature plays a significant role in the development of Alzheimer's disease(AD),however,the specific association between them remains unclear.In this paper,based on the benefits of photoacoustic imaging(PAI),including label-free,high-resolution,in vivo imaging of vessels,we investigated the structural changes of cerebral vascular in wild-type(WT)mice and AD mice at different ages,analyzed the characteristics of the vascular in different brain regions,and correlated vascular characteristics with cognitive behaviors.The results showed that vascular density and vascular branching index in the cortical and frontal regions of both WT and AD mice decreased with age.Meanwhile,vascular lacunarity increased with age,and the changes in vascular structure were more pronounced in AD mice.The trend of vascular dysfunction aligns with the worsening cognitive dysfunction as the disease progresses.Here,we utilized in vivo PAI to analyze the changes in vascular structure during the progression of AD,elucidating the spatial and temporal correlation with cognitive impairment,which will provide more intuitive data for the study of the correlation between cerebrovascular and the development of AD.展开更多
Tissue engineering is an interdisciplinary field promising new therapeutic means for replacing lost or severely damaged tissues or organs. However, the fabrication of complex engineered tissues has been hampered due t...Tissue engineering is an interdisciplinary field promising new therapeutic means for replacing lost or severely damaged tissues or organs. However, the fabrication of complex engineered tissues has been hampered due to the lack of vascularization to provide sufficient blood supply after implantation. In this article, we propose using rapid prototyping technology to prefabricate a scaffold with an inside hollowed vascular system including an arterial end, a venous end and capillary networks between them. The scaffold will be ''printed'' layer by layer. When printing every layer, a ''low-melting point'' material will be used to form a blood vessel network and a tissue-specific material will be used outside it. Hereafter the ‘low-melting point’ material will be evacuated by vaporization to ensure a hollowed vessel network. Then the inside hollowed capillary network can be endothelialized by using autologous endothelial cells in a cycling bioreactor while the outside material can be embedded with tissue-special cells. In the end, the new vascularized autologous grafts could be transferred to the defect site by using microsurgical techniques to connect the grafts with the host artery and vein. The strategy would facilitate construction of complex tissue engineering if the hypothesis proved to be practical.展开更多
The fields of tissue engineering and regenerative medicine have made astounding progress in recent years,evidenced by cutting-edge 4D printing technologies,precise gene editing tools,and sustained long-term functional...The fields of tissue engineering and regenerative medicine have made astounding progress in recent years,evidenced by cutting-edge 4D printing technologies,precise gene editing tools,and sustained long-term functionality of engineered tissue grafts.Despite these fantastic feats,the clinical success of tissue-engineered constructs so far remains limited to only those relatively simple types of tissues such as thin bilayer skin equivalents or avascular cartilage.On the other hand,volumetric tissues(larger than a few millimeters in all dimensions),which are highly desirable for clinical utility,suffer from poor oxygen supply due to limited dimensional diffusion.Notably,large,complex tissues typically require a vascular network to supply the growing cells with nutrients for metabolic demands to prolong viability and support tissue formation.In recognition,extensive efforts have been made to create vascular-like networks in order to facilitate mass exchange through volumetric scaffolds.This review underlines the urgent need for continued research to create more complex and functional vascular networks,which is crucial for generating viable volumetric tissues,and highlights the recent advances in sacrificial template-enabled formation of vascular-like networks.展开更多
目的比较3种抗血管内皮生长因子(VEGF)药物治疗新生血管性年龄相关性黄斑变性(nAMD)的有效性和安全性。方法检索PubMed、Web of Science、Cochrane Library、中国知网(CNKI)、万方(WanFang)和维普(VIP)数据库,纳入自建库起至2023年5月3...目的比较3种抗血管内皮生长因子(VEGF)药物治疗新生血管性年龄相关性黄斑变性(nAMD)的有效性和安全性。方法检索PubMed、Web of Science、Cochrane Library、中国知网(CNKI)、万方(WanFang)和维普(VIP)数据库,纳入自建库起至2023年5月31日发表的有关雷珠单抗(IVR)、康柏西普(IVC)和阿柏西普(IVA)单药治疗nAMD的随机对照试验(RCT),提取、整理数据。以Cochrane 2.0版偏倚风险评估工具评价文献质量,采用Stata 17.0软件对各结局指标进行网状Meta分析。结果最终纳入30项RCT,共涉及2901例患者。网状Meta分析结果显示,3种药物的整体有效性相似,但在不同治疗时间点改善最佳矫正视力(BCVA)和降低黄斑中央视网膜厚度(CRT)方面结果有一定差异;治疗3个月后,BCVA和CRT改善效果为IVA>IVR>IVC;治疗12个月后,CRT改善效果为IVC>IVA>IVR;BCVA改善效果为IVA>IVC>IVR。安全性方面,总不良事件发生率、眼部不良事件发生率和结膜出血发生率均为IVC<IVR<IVA,其余安全性指标3种药物结果相似且良好。结论IVR、IVC和IVA治疗nAMD均有效且各有优势。但由于可纳入的研究文献数量少,研究质量一般,不同治疗时间内3种药物的有效性指标结果存在差异,上述结果仍需大样本、高质量的RCT佐证。展开更多
基金National Natural Science Foundation of China(Grant No.82373840)Jiangsu Key Laboratory of Neuropsychiatric Diseases(Grants BM2013003 and ZZ2009).
文摘Physiological supporting systems,such as the vascular network and excretion system,are crucial for the effective functioning of organs.This study demonstrates that when a body-on-a-chip microdevice is coupled with miniaturized physiological support systems,it can create a multi-organ microphysiological system capable of more accurately mimicking the physiological complexity of a body,thereby offering potential for preclinical drug testing.To exemplify this concept,we have developed a model system comprising 18 types of microtissues interconnected by a vascular network that replicates the in vivo blood distribution among the organs.Furthermore,this system includes an excretory system with a micro-stirrer that ensures elimination efficiency akin to in vivo conditions.Our findings indicate that this system can:(1)survive and function for almost two months;(2)achieve two-compartment pharmacokinetics of a drug;(3)investigate the dynamic relationship between the tissue distribution and toxicity of a drug;(4)establish the multimorbidity model and evaluate the effectiveness of polypharmacy,challenging tasks with traditional animal models;(5)reduce animal usage in drug evaluations.Notably,features from points(2)to(4)are capabilities not achievable by other in vitro models.The strategy proposed in this study can also be applied to the development of multi-organ microphysiological systems that mimic the physiological complexity of human organs or the entire body.
基金supported by the National Natural Science Foundation of China(Grant Nos.51506220,51579244)the Natural Science Foundation of Hubei Province(Grant No.2016CFB504)the Independent Project of Naval University of Engineering(Grant No.425317Q017)
文摘Combining with entransy theory,constructal designs of the X-shaped vascular networks(XSVNs)are implemented with fixed total tube volumes of the XSVNs.The entransy dissipation rates(EDRs)of the XSVNs are minimized,and the optimal constructs of the XSVNs are derived.Comparison of the optimal constructs of the XSVNs with two optimization objectives(EDR minimization and entropy generation rate(EGR)minimization)is conducted.It is found that when the dimensionless mass flow rate(DMFR)is small,the optimal diameter ratio of the elemental XSVN derived by EDR minimization is different from that derived by EGR minimization.For the multilevel XSVN,when the DMFR is 100,compared the XSVN with the corresponding H-shaped vascular network(HSVN),the dimensionless EDRs of the elemental,second and fourth order XSVNs are reduced by 26.39%,15.34%and 9.81%,respectively.Compared with the entransy dissipation number(EDN)of the second order XSVN before angle optimization,the EDN after optimization is reduced by 26.15%,which illustrates that it is significant to conduct angle optimization of the XSVN.Entransy theory is applied into the constructal design of the vasculature with heat transfer and fluid flow in this paper,which provides new directions for the vasculature designs.
基金supported by the National Key Research and Development Program of China(2020YFB1313100)the National Natural Science Foundation of China(22002018)the Innovative Research Team of High-level Local University in Shanghai,and the Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learning(SSH1340011).
文摘Artificial organs are devices implanted into the living body as a substitute for damaged or diseased organs.Current efforts focus on the construction of fully functionalized artificial tissues/organs with vascular networks.Although engineering efforts have been made in creating artificial vessels with simple or complex configurations,building vascular networks with hierarchical architectures approximating native counterparts remains challenging.Herein,we give a perspective of cellular fluidics-based construction of vascular networks for tissue engineering,with inspirations drawn from a novel concept of 3D fluidic control platform based on unit-cell constructs.Through architected design of the unit cells,it enables programmed control over gas-liquid-solid interfaces and fluid flow processes in open-cell structures.This cellular-fluidics concept and the associated platform provide lots of inspirations for constructing artificial vascular networks.We believe that cellular fluidics opens a new avenue for fluid control and deterministic delivery,and would find vast opportunities in tissue engineering.
基金National Natural Science Foundation of China(81603385)China Postdoctoral Science Foundation(2018M643843)+1 种基金Natural Science Foundation of Shaanxi Province(2017JM8056)Key Research and Development Foundation of Shaanxi province(2018SF-241)
文摘OBJECTIVE Numerous references made clear that triphala is revered as a multiuse therapeutic and perhaps even panacea historically.Nevertheless,the protective mechanism of triphala on cardio-cerebral vascular diseases(CCVDs)remains not comprehensive understanding.Hence,a network pharmacology-based method was suggested in this study to address this problem.METHODS This study was based on network pharmacology and bioinformatics analysis.Information on compounds in herbal medicines of triphala formula was acquired from public databases.Oral bioavailability as well as drug-likeness were screened by using absorption,distribution,metabolism,and excretion(ADME)criteria.Then,components of triphala,candidate targets of each component and known therapeutic targets of CCVDs were collected.Compound-target gene and compounds-CCVDs target networks were created through network pharmacology data sources.In addition,key targets and pathway enrichment were analyzed by STRING database and DAVID database.Moreover,we verified three of the key targets(PTGS2,MMP9 and IL-6)predicted by using Western blotting analysis.RESULTS Network analysis determined 132 compounds in three herbal medicines that were subjected to ADME screening,and 23 compounds as well as 65 genes formed the principal pathways linked to CCVDs.And 10 compounds,which actually linked to more than three genes,are determined as crucial chemicals.Core genes in this network were IL-6,TNF,VEGFA,PTGS2,CXCL8,TP53,CCL2,IL-10,MMP9 and SERPINE1.And pathways in cancer,TNF signaling path⁃way,neuroactive ligand-receptor interaction,etc.related to CCVDs were identified.In vitro experiments,the results indi⁃cated that compared with the control group(no treatment),PTGS2,MMP9 and IL-6 were up-regulated by treatment of 10μg·L^-1 TNF-α,while pretreatment with 20-80 mg·L^-1 triphala could significantly inhibit the expression of PTGS2,MMP9 and IL-6.With increasing Triphala concentration,the expression of PTGS2,MMP9 and IL-6 decreased.CON⁃CLUSION Complex components and pharmacological mechanism of triphala,and obtained some potential therapeutic targets of CCVDs,which could provide theoretical basis for the research and development of new drugs for treating CCVDs.
基金supported by STI2030-Major Projects 2022ZD0212200,Hainan Province Key Area R&D Program(KJRC2023C30,ZDYF2021SHFZ094)Project of Collaborative Innovation Center of One Health(XTCX2022JKB02).
文摘The cerebral vasculature plays a significant role in the development of Alzheimer's disease(AD),however,the specific association between them remains unclear.In this paper,based on the benefits of photoacoustic imaging(PAI),including label-free,high-resolution,in vivo imaging of vessels,we investigated the structural changes of cerebral vascular in wild-type(WT)mice and AD mice at different ages,analyzed the characteristics of the vascular in different brain regions,and correlated vascular characteristics with cognitive behaviors.The results showed that vascular density and vascular branching index in the cortical and frontal regions of both WT and AD mice decreased with age.Meanwhile,vascular lacunarity increased with age,and the changes in vascular structure were more pronounced in AD mice.The trend of vascular dysfunction aligns with the worsening cognitive dysfunction as the disease progresses.Here,we utilized in vivo PAI to analyze the changes in vascular structure during the progression of AD,elucidating the spatial and temporal correlation with cognitive impairment,which will provide more intuitive data for the study of the correlation between cerebrovascular and the development of AD.
文摘Tissue engineering is an interdisciplinary field promising new therapeutic means for replacing lost or severely damaged tissues or organs. However, the fabrication of complex engineered tissues has been hampered due to the lack of vascularization to provide sufficient blood supply after implantation. In this article, we propose using rapid prototyping technology to prefabricate a scaffold with an inside hollowed vascular system including an arterial end, a venous end and capillary networks between them. The scaffold will be ''printed'' layer by layer. When printing every layer, a ''low-melting point'' material will be used to form a blood vessel network and a tissue-specific material will be used outside it. Hereafter the ‘low-melting point’ material will be evacuated by vaporization to ensure a hollowed vessel network. Then the inside hollowed capillary network can be endothelialized by using autologous endothelial cells in a cycling bioreactor while the outside material can be embedded with tissue-special cells. In the end, the new vascularized autologous grafts could be transferred to the defect site by using microsurgical techniques to connect the grafts with the host artery and vein. The strategy would facilitate construction of complex tissue engineering if the hypothesis proved to be practical.
基金National ScienceFoundation,Grant/Award Number:NSF-GCR award number 2219014U.S.Army Medical Research and Development Command,Grant/Award Number:W81XWH2211044Established Investigator Grant award from MTF Biologics。
文摘The fields of tissue engineering and regenerative medicine have made astounding progress in recent years,evidenced by cutting-edge 4D printing technologies,precise gene editing tools,and sustained long-term functionality of engineered tissue grafts.Despite these fantastic feats,the clinical success of tissue-engineered constructs so far remains limited to only those relatively simple types of tissues such as thin bilayer skin equivalents or avascular cartilage.On the other hand,volumetric tissues(larger than a few millimeters in all dimensions),which are highly desirable for clinical utility,suffer from poor oxygen supply due to limited dimensional diffusion.Notably,large,complex tissues typically require a vascular network to supply the growing cells with nutrients for metabolic demands to prolong viability and support tissue formation.In recognition,extensive efforts have been made to create vascular-like networks in order to facilitate mass exchange through volumetric scaffolds.This review underlines the urgent need for continued research to create more complex and functional vascular networks,which is crucial for generating viable volumetric tissues,and highlights the recent advances in sacrificial template-enabled formation of vascular-like networks.
文摘目的 基于网络药理学及动物实验探讨天丝饮治疗血管性痴呆(vascular dementia,VD)的作用机制。方法 通过TCMSP数据库检索天丝饮的有效成分及相关靶点;采用OMIM和GeneCards数据库搜集VD靶点,通过String在线数据库构建靶蛋白相互作用网络,采用R语言对关键靶点进行基因本体(gene ontology,GO)和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)富集分析。采用改良双侧颈总动脉结扎法制备VD模型。苏木素-伊红染色观察海马区病理形态学变化;透射电镜观察海马组织线粒体超微结构;流式细胞术检测线粒体膜电位变化以及活性氧(reactive oxygen species,ROS)水平;生化比色法检测海马组织中Fe^(2+)、丙二醛(malondialdehyde,MDA)和谷胱甘肽(glutathione,GSH)含量;借助Western blotting及RT-qPCR试验明确相关靶点蛋白表达及基因转录情况。结果 共获得天丝饮有效成分13个,与VD相关靶点共103个,KEGG相关信号通路前20条,GO分析前20个生物学过程。动物实验发现,天丝饮能够提高模型大鼠的学习、空间记忆能力(P<0.05或P<0.01),减轻海马组织的病理形态学及线粒体损伤,提升GSH和线粒体膜电位,降低Fe^(2+)、MDA和ROS水平(P<0.05或P<0.01),上调线粒体融合素1(mitofusion 1,Mfn1)、线粒体融合素2(mitofusion 2,Mfn2)、谷胱甘肽过氧化物酶4(glutathione peroxidase 4,GPX4)、溶质载体家族7成员11(solute carrier family 7 member 11, SLC7A11)、铁蛋白重链1(ferritin heavy chain 1, FTH1)蛋白及m RNA的表达(P<0.05或P<0.01),下调动力相关蛋白1(dynamics related protein 1,Drp1)、裂变蛋白1(fission protein 1,Fis1)、酰基辅酶A合成酶长链家族4(acyl-CoA synthetase long-chain family member 4,ACSL4)、环氧合酶2(cyclooxygenase-2,COX-2)蛋白及m RNA的表达(P<0.05或P<0.01)。天丝饮处理后提升了海马组织中AMPK磷酸化水平,上调了核因子E2相关因子2(nuclear factor erythroid 2-related factor 2,Nrf2)、血红素加氧酶1(Heme oxygenase 1,HO-1)蛋白及mRNA的表达,促进了AMPK/Nrf2途径的活化(P<0.05或P<0.01)。然而,Compound C的使用可部分逆转天丝饮对于铁死亡的治疗效果。结论天丝饮通过激活AMPK/Nrf2通路改善线粒体动力学失衡状态,抑制铁死亡,从而提高VD大鼠的认知功能。
