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Efficacy and safety of PD-1 blockade plus long-course chemoradiotherapy in locally advanced rectal cancer(NECTAR):a multi-center phase 2 study

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1721-1729页

作者： Zhengyang Yang Jiale Gao Jianyong Zheng Jiagang Han Ang Li Gang Liu Yi Sun Jie Zhang Guangyong Chen Rui Xu Xiao Zhang Yishan Liu Zhigang Bai Wei Deng Wei He Hongwei Yao Zhongtao Zhang department of General surgery Beijing Friendship HospitalCapital Medical UniversityState Key Lab of Digestive HealthNational Clinical Research Center for Digestive DiseasesBeijingChina department of Gastrointestinal surgery The First Affiliated Hospital of Air Force Medical UniversityXi'anChina department of General surgery Beijing Chaoyang HospitalCapital Medical UniversityBeijingChina department of General surgery Beijing Xuanwu HospitalCapital Medical UniversityBeijingChina department of General surgery Tianjin Medical University General HospitalTianjinChina department of Anorectal Tianjin People's HospitalTianjinChina department of Radiology Beijing Friendship Hospital Capital Medical UniversityBeijingChina department of Pathology Beijing Friendship HospitalCapital Medical UniversityBeijingChina department of Thoracic surgery/institute of Thoracic Oncology West China HospitalSichuan UniversityChengduChina

Adding PD-1 blockade in the neoadjuvant regimens for locally advanced rectal cancer(LARC)patients with microsatellite stable(MsS)/mismatch repair-proficient(pMMR)tumors is an attractive,but debatable strategy.This phase 2,multicenter,prospective,single-arm study enrolled patients from 6 centers from June 2021 to November 2022.Locally advanced rectal cancer(LARC,cT_(3-4a)N_(0)M_(0) and cT_(1-4a)N_(1-2)M_(0))patients aged≥18 years with the distance from distal border of tumor to anal verge≤10 cm(identified by Magnetic Resonance Imaging)were qualifed for inclusion.The patients received long-course radiotherapy(50 Gy/25 fractions,2 Gy/fraction,5 days/week)and three 21-day cycles capecitabine(850-1000 mg/m2,bid,po,day1-14)and three 21-day cycles tislelizumab(200 mg,iv.gtt,day8)as neoadjuvant.Total mesorectal excision(TME)was 6-12 weeks after the end of radiotherapy to achieve radical resection.A total of 50 patients were enrolled in this study.The pathological complete response rate was 40.0%[20/50,95%confidence interval(CI):27.61-53.82%],while 15(30.0%,95%CI:19.1-43.75%),9(18.0%,95%CI:9.77-30.8%),2(4.0%,95%CI:1.10-13.46%)patients respectively achieved grade 1,2,and 3 tumor regression.Treatment-related adverse events(TRAEs)occurred in 28(56.0%)LARC patients,including 26(52.0%)with grade I-II and 2(4.0%)with grade II(1 with grade 3 immune-related colitis and 1 with grade 3 rash).PD-1 blockade plus long-course chemoradiotherapy(CRT)showed promising therapeutic effects according to pathological complete response rate and is well-tolerated in LARC patients.A larger randomized controlled study is desired to further validate the above findings.

关键词： rectal cancer phase

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Laparoscopic left hemihepatectomy guided by indocyanine green fluorescence: A cranial-dorsal approach

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World Journal of Gastrointestinal surgery 2024年第2期16卷 409-418页

作者： Xing-Ru Wang Xiao-Ju Li Dan-Dan Wan Qian Zhang Tian-Xi Liu Zong-Wen Shen Hong-Xing Tong Yan Li Jian-Wei Li institute of Hepatobiliary surgery First Affiliated HospitalArmy Medical UniversityChongqing 400038China department of Hepatobiliary surgery Qujing Central Hospital of Yunnan Regional Medical CenterQujing 655000Yunnan ProvinceChina School of clinical Medicine Qujing Medical CollegeQujing 655000Yunnan ProvinceChina

BACKGROUND Advancements in laparoscopic technology and a deeper understanding of intra-hepatic anatomy have led to the establishment of more precise laparoscopic hepatectomy(LH)techniques.The indocyanine green(ICG)fluorescence navi-gation technique has emerged as the most effective method for identifying hepatic regions,potentially overcoming the limitations of LH.While laparoscopic left hemihepatectomy(LLH)is a standardized procedure,there is a need for innova-tive strategies to enhance its outcomes.important anatomical markers,surgical skills,and ICG staining methods.METHODS Thirty-seven patients who underwent ICG fluorescence-guided LLH at Qujing Second People's Hospital between January 2019 and February 2022 were retrospectively analyzed.The cranial-dorsal approach was performed which involves dissecting the left hepatic vein cephalad,isolating the Arantius ligament,exposing the middle hepatic vein,and dissecting the parenchyma from the dorsal to the foot in order to complete the anatomical LLH.The surgical methods,as well as intra-and post-surgical data,were recorded and analyzed.Our hospital’s Medical Ethics Committee approved this study(Ethical review:2022-019-01).RESULTS Intraoperative blood loss during LLH was 335.68±99.869 mL and the rates of transfusion and conversion to laparotomy were 13.5%and 0%,respectively.The overall incidence of complications throughout the follow-up(median of 18 months;range 1-36 months)was 21.6%.No mortality or severe complications(level iv)were reported.CONCLUSION LLH has the potential to become a novel,standardized approach that can effectively,safely,and simply expose the middle hepatic vein and meet the requirements of precision surgery.

关键词： Laparoscopic left hemihepatectomy Indocyanine green Cranial-dorsal approach Laparoscopic hepatectomy Arantius ligament Glissonean pedicle

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Pathologically successful conversion hepatectomy for advanced giant hepatocellular carcinoma after multidisciplinary therapy:A case report and review of literature

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World Journal of Gastrointestinal Oncology 2024年第4期16卷 1647-1659页

作者： Ju-Hang Chu Lu-Yao Huang Ya-Ru Wang Jun Li Shi-Long Han Hao Xi Wen-Xue Gao Ying-Yu Cui Ming-Ping Qian department of General surgery Shanghai Tenth People's HospitalSchool of MedicineTongji UniversityShanghai 200072China department of Interventional and Vascular surgery Shanghai Tenth People's HospitalSchool of MedicineTongji UniversityShanghai 200072China department of Pathology Shanghai Tenth People's HospitalSchool of MedicineTongji UniversityShanghai 200072China clinical research Management Office Shanghai Tenth People’s HospitalShanghai 200072China department of Cell Biology Institute of Medical GeneticsState Key Laboratory of CardiologyTongji University School of MedicineShanghai 200331China

BACKGROUND Hepatocellular carcinoma(HCC)is one of the leading causes of death due to its complexity,heterogeneity,rapid metastasis and easy recurrence after surgical resection.We demonstrated that combination therapy with transcatheter arterial chemoembolization(TACE),hepatic arterial infusion chemotherapy(HAIC),Epclusa,Lenvatinib and Sintilimab is useful for patients with advanced HCC.CASE SUMMARY A 69-year-old man who was infected with hepatitis C virus(HCV)30 years previously was admitted to the hospital with abdominal pain.Enhanced computed tomography(CT)revealed a low-density mass in the right lobe of the liver,with a volume of 12.9 cm×9.4 cm×15 cm,and the mass exhibited a“fast-in/fast-out”pattern,with extensive filling defect areas in the right branch of the portal vein and an alpha-fetoprotein level as high as 657 ng/mL.Therefore,he was judged to have advanced HCC.During treatment,the patient received three months of Epclusa,three TACE treatments,two HAIC treatments,three courses of sintilimab,and twenty-one months of lenvatinib.In the third month of treatment,the patient developed severe side effects and had to stop immunotherapy,and the Lenvatinib dose had to be halved.Postoperative pathological diagnosis indicated a complete response.The patient recovered well after the operation,and no tumor recurrence was found.CONCLUSION Multidisciplinary conversion therapy for advanced enormous HCC caused by HCV infection has a significant effect.Individualized drug adjustments should be made during any treatment according to the patient's tolerance to treatment.

关键词： Hepatocellular therapy Conversion hepatectomy Interventional therapy Epclusa Lenvatinib Sintilimab Case report

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中国胃癌肝转移患者临床诊疗特征及预后分析:全国多中心队列研究(RECORD研究)

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Science Bulletin 2024年第3期69卷 303-307页

作者：高云鹤郗洪庆商亮唐兆庆卫勃乔治唐云王鑫鑫周静汪学非黄昌明陆俊李国新余江梁延锐季加孚李子禹薛侃梁寒柯彬臧潞何子锐谢少华黄华徐泽宽田艳涛熊建平李佶阳崔秋霞李力卢婷婷宋奇嬴刘诗贺孙益红李乐平陈凛 RECORD研究协作组 Section of Gastric surgery Senior Department of General SurgeryThe First Medical CenterChinese PLA General HospitalBeijing 100853China Section of Abdominal Trauma surgery Senior Department of General SurgeryThe First Medical CenterChinese PLA General HospitalBeijing 100853China institute of General surgery The First Medical CenterChinese PLA General HospitalBeijing 100853China department of Gastrointestinal surgery Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinan 250021China department of General surgery Fudan University Zhongshan HospitalShanghai 200032China department of General surgery Fujian Medical University Union HospitalFuzhou 350001China department of General surgery Nanfang Hospital Affiliated to Southern Medical UniversityGuangzhou 510515China Key Laboratory of Carcinogenesis and Translational research(Ministry of Education) Gastrointestinal Cancer CenterPeking University Cancer Hospital&InstituteBeijing 100142China department of Gastric Cancer surgery Tianjin Medical University Cancer Institute and HospitalTianjin 300060China department of General surgery Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China institute of Population Medicine and School of Public Health Fujian Medical UniversityFuzhou 350122China department of Gastric surgery Fudan University Shanghai Cancer CenterShanghai 200032China department of General surgery Jiangsu Province HospitalNanjing Medical UniversityNanjing 210029China department of Pancreatic and Gastric surgery National Cancer CenterNational Clinical Research Center for CancerCancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100029China

Despite surgical improvements and pharmacological advances,management of late-stage gastric cancer patients,especially those with hepatic metastasis remains challenging[1–3].Although nationwide registry data from SEER(Surveillance,Epidemiology,and End Results)[4]and the Nordic database[5]in Western countries have provided epidemiological information for patients with gastric cancer liver metastasis(GCLM),little is known about the detailed clinical characteristics.

关键词：胃癌肝转移 metastasis cancer

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Mitochondrial dysfunction affects hepatic immune and metabolic remodeling in patients with hepatitis B virus-related acute-onchronic liver failure

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World Journal of Gastroenterology 2024年第8期30卷 881-900页

作者： Yu Zhang Xiao-Ling Tian Jie-Qun Li Dong-Sheng Wu Qiang Li Bin Chen department of Hepatology Institute of HepatologyThe First Affiliated Hospital of Hunan University of Chinese MedicineChangsha 410021Hunan ProvinceChina department of Liver Transplant Transplant Medical Research CenterThe Second Xiangya Hospital of Central South UniversityChangsha 410011Hunan ProvinceChina department of surgery The First Affiliated Hospital of Hunan University of Chinese MedicineChangsha 410021Hunan ProvinceChina

BACKGROUND Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF).However,the mechanisms underlying immune and metabolic derangement in patients with advanced HBV-ACLF are unclear.AIM To identify the bioenergetic alterations in the liver of patients with HBV-ACLF causing hepatic immune dysregulation and metabolic disorders.METHODS Liver samples were collected from 16 healthy donors(HDs)and 17 advanced HBV-ACLF patients who were eligible for liver transplantation.The mitochondrial ultrastructure,metabolic characteristics,and immune microenvironment of the liver were assessed.More focus was given to organic acid metabolism as well as the function and subpopulations of macrophages in patients with HBV-ACLF.RESULTS Compared with HDs,there was extensive hepatocyte necrosis,immune cell infiltration,and ductular reaction in patients with ACLF.In patients,the liver suffered severe hypoxia,as evidenced by increased expression of hypoxia-inducible factor-1α.Swollen mitochondria and cristae were observed in the liver of patients.The number,length,width,and area of mitochondria were adaptively increased in hepatocytes.Targeted metabolomics analysis revealed that mitochondrial oxidative phosphorylation decreased,while anaerobic glycolysis was enhanced in patients with HBV-ACLF.These findings suggested that,to a greater extent,hepa-tocytes used the extra-mitochondrial glycolytic pathway as an energy source.Patients with HBV-ACLF had elevated levels of chemokine C-C motif ligand 2 in the liver homogenate,which stimulates peripheral monocyte infiltration into the liver.Characterization and functional analysis of macrophage subsets revealed that patients with ACLF had a high abundance of CD68^(+)HLA-DR^(+)macrophages and elevated levels of both interleukin-1βand transforming growth factor-β1 in their livers.The abundance of CD206^(+)CD163^(+)macrophages and expression of interleukin-10 decreased.Th

关键词： Acute-on-chronic liver failure Hypoxia-inducible factor-1α Mitochondria Metabolic phenotype Immune cells

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A multidimensional platform of patient-derived tumors identifies drug susceptibilities for clinical lenvatinib resistance

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Acta Pharmaceutica Sinica B 2024年第1期14卷 223-240页

作者： Lei Sun Arabella H.Wan Shijia Yan Ruonian Liu Jiarui Li Zhuolong Zhou Ruirui Wu Dongshi Chen Xianzhang Bu Jingxing Ou Kai Li Xiongbin Lu Guohui Wan Zunfu Ke department of Pathology the First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation National Engineering Research Center for New Drug and Druggability(Cultivation)Guangdong Province Key Laboratory of New Drug Design and EvaluationSchool of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China department of Medical and Molecular Genetics Indiana University School of MedicineIndianapolisIN 46202USA department of Medicine Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90033USA department of hepatic surgery and Liver Transplantation Center Third Affiliated HospitalOrgan Transplantation InstituteSun Yat-sen UniversityOrgan Transplantation Research Center of Guangdong ProvinceGuangdong Province Engineering Laboratory for Transplantation MedicineGuangzhou 510630China Guangdong Provincial Key Laboratory of Liver Disease research Guangzhou 510630China department of Ultrasound Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510630China Melvin and Bren Simon Comprehensive Cancer Center Indiana UniversityIndianapolisIN 46202USA

Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug resistance.Here,we applied a multidimensional,high-throughput screening platform comprising patient-derived resistant liver tumor cells(PDCs),organoids(PDOs),and xenografts(PDXs)to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings.Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment,expediting drug repurposing screens.Pharmacological screening identified romidepsin,YM155,apitolisib,NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models.Notably,romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway.A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models.Collectively,our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer,providing a feasible multidimensional platform for personalized medicine.

关键词： Lenvatinib Drug resistance High-throughput screening Drug discovery Patient-derived model Romidepsin EGFR Liver cancer

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Goji berry-derived phenylpropionyl phenylethylamine derivatives protect against ethanol-induced hepatic damage

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Food Science and Human Wellness 2024年

作者： Zhengqun Zhou Zhaodi Che Jiancong Mai Rui Zhang Zhihui Luo Yifang Li Kwokfai So Jia Xiao Xinsheng Yao Hao Gao GMH institute of CNS Regeneration Guangdong Medical Key Laboratory of Brain Function and Diseases Jinan University clinical Medicine research institute and department of Metabolic and Bariatric surgery the First Affiliated Hospital of Jinan University institute of Traditional Chinese Medicine and Natural Products College of Pharmacy/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs research/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China Jinan University

Goji berry is a famous edible and medicinal substance around the world. In this research， 15 phenylpropionyl phenylethylamine derivatives (1-15)， including one new compound (1)， were separated and identified from goji berry. All isolates were elucidated via extensive NMR spectral analyses and chemical techniques. Six known isolates were first obtained from Lycium genus. Six isolates were effectively split into double chromatographic peaks accompanied by the basically identical areas， indicating they belong to racemates. The ORAC experiment indicated that all isolates displayed a capacity of scavenging free radicals， and most of them exhibited higher ORAC values than EGCG. In ethanol/palmitic acid (PA)-established in vitro hepatocyte injury model， four phenylpropionyl phenylethylamine derivatives (1， 2， 9， and 15) significantly alleviated hepatocyte injury， among which compound 1 exerted the strongest protective activity. Notably， the hepatoprotective effect of compound 1 was further confirmed in ethanol-established liver damage mouse model， reflected by the reduction of lipid accumulation and the attenuation of pathological alteration. Combined with the in vitro results， the in vivo observations suggested that compound 1 suppressed cell apoptosis and the outburst of inflammation. Our findings provided first-hand evidence proving that goji berry-derived phenylpropionyl phenylethylamine derivatives hold a potential in treating alcoholic liver disease.

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Decitabine induces IRF7-mediated immune responses in p53-mutated triple-negative breast cancer:a clinical and translational study

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Frontiers of Medicine 2024年第2期18卷 357-374页

作者： Haoyu Wang Zhengyuan Wang Zheng Wang Xiaoyang Li Yuntong Li Ni Yan Lili Wu Ying Liang Jiale Wu Huaxin Song Qing Qu Jiahui Huang Chunkang Chang Kunwei Shen Xiaosong Chen Min Lu department of General surgery Comprehensive Breast Health CenterRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200025China Shanghai institute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine(Shanghai)Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200025China department of Hematology Shanghai Institute of HematologyRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200025China department of Hematology Shanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghai200025China

p53 is mutated in half of cancer cases.However,no p53-targeting drugs have been approved.Here,we reposition decitabine for triple-negative breast cancer(TNBC),a subtype with frequent p53 mutations and extremely poor prognosis.In a retrospective study on tissue microarrays with 132 TNBC cases,DNMT1 overexpression was associated with p53 mutations(P=0.037)and poor overall survival(OS)(P=0.010).In a prospective DEciTabinE and Carboplatin in TNBC(DETECT)trial(NCT03295552),decitabine with carboplatin produced an objective response rate(ORR)of 42%in 12 patients with stage iv TNBC.Among the 9 trialed patients with available TP53 sequencing results,the 6 patients with p53 mutations had higher ORR(3/6 vs.0/3)and better OS(16.0 vs.4.0 months)than the patients with wild-type p53.In a mechanistic study,isogenic TNBC cell lines harboring DETECT-derived p53 mutations exhibited higher DNMT1 expression and decitabine sensitivity than the cell line with wild-type p53.In the DETECT trial,decitabine induced strong immune responses featuring the striking upregulation of the innate immune player IRF7 in the p53-mutated TNBC cell line(upregulation by 16-fold)and the most responsive patient with TNBC.Our integrative studies reveal the potential of repurposing decitabine for the treatment of p53-mutated TNBC and suggest IRF7 as a potential biomarker for decitabine-based treatments.

关键词： p53 mutation triple-negative breast cancer decitabine DNMT1 IRF7 innate immune response

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Protective effects of cyclosporine and its analog NIM-811 in a murine model of hepatic ischemia-reperfusion injury

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Liver research 2024年第1期8卷 46-53页

作者： Joshua Hefler Rena Pawlick Braulio A.Marfil-Garza Aducio Thiesen Nerea Cuesta-Gomez Sanaz Hatami Darren H.Freed Constantine Karvellas David L.Bigam A.M.James Shapiro department of surgery Faculty of Medicine&DentistryUniversity of AlbertaEdmontonABCanada department of Medicine Faculty of Medicine&DentistryUniversity of AlbertaEdmontonABCanada CHRISTUS-LatAm Hub Excellence&Innovation Center MonterreyMexico Alberta Diabetes institute University of AlbertaEdmontonABCanada clinical Islet Transplant Program University of AlbertaEdmontonABCanada department of Laboratory Medicine&Pathology Faculty of Medicine&DentistryUniversity of AlbertaEdmontonABCanada

Background and aim:The liver is susceptible to ischemia-reperfusion injury(IRI)during hepatic surgery,when the vessels are compressed to control bleeding,or liver transplantation,when there is an obligate period of ischemia.The hallmark of IRI comprises mitochondrial dysfunction,which generates reactive oxygen species,and cell death through necrosis or apoptosis.Cyclosporine(CsA),which is a well-known immunosuppressive agent that inhibits calcineurin,has the additional effect of inhibiting the mito-chondrial permeability transition pore(mPTP),thereby,preventing mitochondrial swelling and injury.NIM-811,which is the nonimmunosuppressive analog of CsA,has a similar effect on the mPTP.In this study,we tested the effect of both agents on mitigating warm hepatic IRI in a murine model.Materials and methods:Before ischemic insult,the mice were administered with intraperitoneal normal saline(control);CsA at 2.5,10,or 25 mg/kg;or NIM-811 at 10 mg/kg.Thereafter,the mice were subjected to partial warm hepatic ischemia by selective pedicle clamping for 60 min,followed by 6 h of recovery after reperfusion.Serum alanine transaminase(ALT)was measured,and the liver tissue was examined histologically for the presence of apoptosis and the levels of inflammatory cytokines.Results:Compared with the control mice,the mice treated with 10 and 25 mg/kg of CsA and NIM-811 had significantly lower ALT levels(Pively).Moreover,the liver tissue showed reduced histological injury scores after treatment with CsA at 2.5,10,and 25 mg/kg and NIM-811(P=0.041,ively)and significant decrease in apoptosis after treatment with CsA at all doses(P=0.012,0.007,andively).Levels of the pro-inflammatory cyto-kines,particularly interleukin(IL)-1β,IL-2,IL-4,IL-10,and keratinocyte chemoattractant/human growth-regulated oncogene significantly decreased in the mice treated with the highest dose of CsA(25 mg/kg)than those in the control mice.Conclusions:Premedication with CsA or NIM-811 mitig

关键词： Cyclosporine(CsA) Cyclosporine analogue Liver surgery Ischemia-reperfusion injury(IRI) Animal model NIM-811

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基于压印细胞片组装的仿生肝小叶

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Science Bulletin 2024年第10期69卷 1448-1457页

作者：王经琳黄丹青陈涵旭赵远锦 department of Hepatobiliary surgery Hepatobiliary InstituteNanjing Drum Tower HospitalMedical SchoolNanjing UniversityNanjing 210008China State Key Laboratory of Bioelectronics School of Biological Science and Medical EngineeringSoutheast UniversityNanjing 210096China

Liver-tissue engineering has proven valuable in treating liver diseases,but the construction of liver tissues with high fidelity remains challenging.Here,we present a novel three-dimensional(3D)-imprinted cell-sheet strategy for the synchronous construction of biomimetic hepatic microtissues with high accuracy in terms of cell type,density,and distribution.To achieve this,the specific composition of hepatic cells in a normal human liver was determined using a spatial proteogenomics dataset.The data and biomimetic hepatic micro-tissues with hexagonal hollow cross-sections indicate that cell information was successfully generated using a homemade 3D-imprinted device for layer-by-layer imprinting and assembling the hepatic cell sheets.By infiltrating vascular endothelial cells into the hollow section of the assembly,biomimetic hepatic microtissues with vascularized channels for nutrient diffusion and drug perfusion can be obtained.We demonstrate that the resultant vascularized biomimetic hepatic micro-tissues can not only be integrated into a microfluidic drug-screening liver-on-a-chip but also assembled into an enlarged physiological structure to promote liver regeneration.We believe that our 3D-imprinted cell sheets strategy will open new avenues for biomimetic microtissue construction.

关键词： Biomimetic hepatic lobules Cell sheets 3D imprinting Tissue engineering Artificial liver

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