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Bioactive extracellular matrix scaffolds engineered with proangiogenic proteoglycan mimetics and loaded with endothelial progenitor cells promote neovascularization and diabetic wound healing

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Bioactive Materials 2022年第4期7卷 460-473页

作者： Siqi He Tanaya Walimbe Hongyuan Chen Kewa Gao Priyadarsini Kumar Yifan Wei Dake Hao Ruiwu Liu Diana L.Farmer Kit S.Lam Jianda Zhou Alyssa Panitch Aijun Wang Department of burns and Plastic Surgery The Third Xiangya Hospital of Central South UniversityChina Department of Surgery UC DavisUnited States Department of Biomedical Engineering UC DavisUnited States Department of Biochemistry and Molecular Medicine UC DavisUnited States Institute for Pediatric Regenerative Medicine Shriners Hospitals for Children Northern CaliforniaUnited States

Diabetic ischemic wound treatment remains a critical clinical *** plays a significant role in wound healing during all stages of the tissue repair *** that enhance angiogenesis and neovascularization and improve ischemic pathology may promote the healing of poor wounds,particularly diabetic wounds in highly ischemic *** previously identified a cyclic peptide LXW7 that specifically binds to integrinαvβ3 on endothelial progenitor cells(EPCs)and endothelial cells(ECs),activates vascular endothelial growth factor(VEGF)receptors,and promotes EC growth and *** this study,we designed and synthesized a multi-functional pro-angiogenic molecule by grafting LXW7 and collagen-binding peptides(SILY)to a dermatan sulfate(DS)glycosaminoglycan backbone,named LXW7-DS-SILY,and further employed this multi-functional molecule to functionalize collagen-based extracellular matrix(ECM)*** confirmed that LXW7-DS-SILY modification significantly promoted EPC attachment and growth on the ECM scaffolds in vitro and supported EPC survival in vivo in the ischemic *** applied in an established Zucker Diabetic Fatty(ZDF)rat ischemic skin flap model,LXW7-DS-SILY-functionalized ECM scaffolds loaded with EPCs significantly improved wound healing,enhanced neovascularization and modulated collagen fibrillogenesis in the ischemic ***,this study provides a promising novel treatment to accelerate diabetic ischemic wound healing,thereby reducing limb amputation and mortality of diabetic patients.

关键词： Diabetic ischemic wound ECM scaffold Endothelial progenitor cells Neovascularization Wound healing

Hydrogels for the management of second-degree burns:currently available options and future promise

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burns & Trauma 2022年第1期10卷 71-87页

作者： Katherine A.Cook Edith Martinez-Lozano Robert Sheridan Edward K.Rodriguez Ara Nazarian Mark W.Grinstaff Department of Chemistry Biomedical Engineeringand MedicineBoston UniversityBostonMA02215USA Musculoskeletal Translational Innovation Initiative Carl J.ShapiroDepartment of Orthopaedic SurgeryBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonMA02215USA shriners hospitals for children and burns service Department of SurgeryMassachusetts General HospitalBostonMA02214USA Department of Orthopaedic Surgery Yerevan State Medical UniversityYerevanArmenia

Burn wounds result from exposure to hot liquids,chemicals,fire,electric discharge or *** severity ranges from first-degree injury,which is superficial,to fourth-degree injury,which exposes bone,tendons and *** assessment of burn depth and accurate wound management in the outpatient setting is critical to prevent injury progression into deeper layers of the *** progression is of particular pertinence to second-degree burns,which are the most common form of thermal *** our understanding of wound healing advances,treatment options and technologies for second-degree burn management also *** hydrogels are a class of burn wound dressings that adhere to tissue,absorb wound exudate,protect from the environment,can be transparent facilitating serial wound evaluation and,in some cases,enable facile removal for dressing *** review briefly describes the burn level classification and common,commercially available dressings used to treat second-degree burns,and then focuses on new polymeric hydrogel burn dressings under preclinical development analyzing their design,structure and *** review presents the follow key learning points:(1)introduction to the integument system and the wound-healing process;(2)classification of burns according to severity and clinical appearance;(3)available dressings currently used for second-degree burns;(4)introduction to hydrogels and their preparation and characterization techniques;and(5)pre-clinical hydrogel burn wound dressings currently being developed.

关键词： Burn Wound Hydrogel Dressing Second-degree

Oligodendrocyte pathology in fetal alcohol spectrum disorders

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Neural Regeneration Research 2022年第3期17卷 497-502页

作者： Nune Darbinian Michael E.Selzer Center for Neural Repair and Rehabilitation(shriners hospitals Pediatric Research Center) Lewis Katz School of Medicine at Temple UniversityPhiladelphiaPAUSA

The pathology of fetal alcohol syndrome and the less severe fetal alcohol spectrum disorders includes brain *** studies have shed light on the molecular mechanisms underlying these white matter *** models of fetal alcohol syndrome and human studies have shown suppressed oligodendrocyte differentiation and apoptosis of oligodendrocyte precursor *** exposure led to reduced expression of myelin basic protein and delayed myelin basic protein expression in rat and mouse models of fetal alcohol syndrome and in human histopathological *** studies have reported increased expression of many chemokines in dysmyelinating disorders in central nervous system,including multiple sclerosis and fetal alcohol *** ethanol exposure reduced levels of the neuroprotective insulin-like growth factor-1 in fetal and maternal sheep and in human fetal brain tissues,while ethanol increased the expression of tumor necrosis factor α in mouse and human *** matter lesions have been induced in the developing sheep brain by alcohol exposure in early *** fetal alcohol syndrome models have shown reduced axon diameters,with thinner myelin sheaths,as well as reduced numbers of oligodendrocytes,which were also morphologically aberrant *** of markers for mature myelination,including myelin basic protein,also were *** accumulating knowledge concerning the mechanisms of ethanol-induced dysmyelination could lead to the development of strategies to prevent dysmyelination in children exposed to ethanol during fetal *** studies using fetal oligodendrocyte-and oligodendrocyte precursor cell-derived exosomes isolated from the mother's blood may identify biomarkers for fetal alcohol syndrome and even implicate epigenetic changes in early development that affect oligodendrocyte precursor cell and oligodendrocyte function in *** combining various imaging modalities with mo

关键词： alcohol development dysmyelination ethanol fetal alcohol syndrome fetal brain myelin basic protein neurodegeneration oligodendrocyte injury oligodendrocyte precursor cells

In utero delivery of mRNA to the heart,diaphragm and muscle with lipid nanoparticles

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Bioactive Materials 2023年第7期25卷 387-398页

作者： Kewa Gao Jie Li Hengyue Song Hesong Han Yongheng Wang Boyan Yin Diana L.Farmer Niren Murthy Aijun Wang Department of Surgery School of MedicineUniversity of CaliforniaDavisSacramentoCA95817United States Department of Bioengineering University of CaliforniaBerkeleyCA94704United States Institute for Pediatric Regenerative Medicine Shriners Hospitals for ChildrenSacramentoCA95817United States Department of Biomedical Engineering University of CaliforniaDavisCA95616United States Department of burns and Plastic Surgery The Third Xiangya Hospital of Central South UniversityHunan410013China

Nanoparticle-based drug delivery systems have the potential to revolutionize medicine,but their low vascular permeability and rapid clearance by phagocytic cells have limited their medical *** delivered at the in utero stage can overcome these key limitations due to the high rate of angiogenesis and cell division in fetal tissue and the under-developed immune ***,very little is known about nanoparticle drug delivery at the fetal stage of *** this report,using Ai9 CRE reporter mice,we demonstrate that lipid nanoparticle(LNP)mRNA complexes can deliver mRNA in utero,and can access and transfect major organs,such as the heart,the liver,kidneys,lungs and the gastrointestinal tract with remarkable efficiency and low *** addition,at 4 weeks after birth,we demonstrate that 50.99±5.05%,36.62±3.42%and 23.7±3.21%of myofiber in the diaphragm,heart and skeletal muscle,respectively,were ***,we show here that Cas9 mRNA and sgRNA complexed to LNPs were able to edit the fetal organs in *** experiments demonstrate the possibility of non-viral delivery of mRNA to organs outside of the liver in utero,which provides a promising strategy for treating a wide variety of devastating diseases before birth.

关键词： In utero mRNA delivery Nanoparticles Gene editing CRISPR/Cas9

Disruption of bone and skeletal muscle in severe burns

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Bone Research 2015年第1期3卷 6-10页

作者： Gordon L Klein Department of Orthopaedic Surgery and Rehabilitation University of Texas Medical Branch and Shriners Hospitals for Children

Severe burn injury triggers the body＇s nonspecific adaptive responses to acute insult, including the systemic inflammatory and stress responses, as well as the sympathetic response to immobilization. These responses trigger inflammatory bone resorption followed by glucocorticoid-induced apoptosis of osteoblasts and probably osteocytes. Because these patients are catabolic, they suffer concomitant muscle wasting and negative nitrogen balance. The use of anabolic agents such as recombinant human growth hormone and oxandrolone results in improved bone mineral content and muscle strength after approximately I year. Use of bisphosphonates within the first 10 days of a severe burn completely blocks the resorptive bone loss and has the added advantage of appearing to preserve muscle protein from excessive breakdown. The mechanism for the protective effect on muscle is not currently known. However, if the effect of bisphosphonates on muscle can be confirmed, it raises the possibility that bone communicates with muscle.

关键词： bone Disruption of bone and skeletal muscle in severe burns

Partial epithelial-mesenchymal transition in keloid scars: regulation of keloid keratinocyte gene expression by transforming growth factor-β1

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burns & Trauma 2016年第3期4卷 199-215页

作者： Jennifer M.Hahn Kevin L.McFarland Kelly A.Combs Dorothy M.Supp Research Department Shriners Hospitals for Children-CincinnatiCincinnatiOHUSA Research Department Shriners Hospitals for Children-CincinnatiCincinnatiOHUSA Department of Surgery University of Cincinnati College of MedicineCincinnatiOHUSA

Background:Keloids are an extreme form of abnormal scarring that result from a pathological fibroproliferative wound healing *** molecular mechanisms driving keloid pathology remain incompletely understood,hindering development of targeted,effective *** studies in our laboratory demonstrated that keloid keratinocytes exhibit adhesion abnormalities and display a transcriptional signature reminiscent of cells undergoing epithelial-mesenchymal transition(EMT),suggesting a role for EMT in keloid *** the current study,we further define the EMT-like phenotype of keloid scars and investigate regulation of EMT-related genes in ***:Primary keratinocytes from keloid scar and normal skin were cultured in the presence or absence of transforming growth factor beta 1(TGF-β1)+/-inhibitors of TGF-β1 and downstream signaling *** expression was measured using quantitative polymerase chain *** was analyzed using an in vitro wound healing *** in keloid scar and normal skin sections were localized by *** analyses utilized SigmaPlot(SyStat Software,San Jose,CA)or SAS?(SAS Institute,Cary,NC).Results:In keloid and normal keratinocytes,TGF-β1 regulated expression of EMT-related genes,including hyaluronan synthase 2,vimentin,cadherin-11,wingless-type MMTV integration site family,member 5A,frizzled 7,ADAM metallopeptidase domain 19,and *** of canonical TGF-β1 signaling in keloid keratinocytes significantly inhibited expression of these genes,and TGF-β1 stimulation of normal keratinocytes increased their *** inhibition of the extracellular signal-regulated kinase 1/2(ERK1/2)signaling pathway or the p38 mitogen-activated protein kinase pathway attenuated TGF-β1-induced expression of subsets of these *** of keloid keratinocytes,previously shown to be increased compared with normal keratinocytes,was significantly reduced by inhibition of TGF-β1 or E

关键词： Keloid Keratinocyte Epithelial-mesenchymal transition Wound healing Scar Fibrosis

Empowering sonic hedgehog to rescue brain cells after ischemic stroke

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Neural Regeneration Research 2015年第3期10卷 360-362页

作者： Olga V.Chechneva Wenbin Deng Department of Biochemistry and Molecular Medicine University of California Institute for Pediatric Regenerative Medicine Shriners Hospitals for Children

Ischemic stroke occurs when blood supply to the brain is interrupted. This can cause irreversible injury to the cen- tral nervous system （CNS） tissue. Each year in the United States almost 800,000 people experience a new or recur- rent stroke. 15% of stroke patients die shortly after insult and only 10% recover completely, leaving the majority of surviving stroke patients with disabilities. Tissue-type plasminogen activator （tPA） is the only available therapy for stroke but its clinical use is limited because of associ- ated danger of intracranial hemorrhage. Therefore, there is an emergent need for stroke therapeutics that are safe and effective when administered at a later time point after insult.

关键词： Shh Empowering sonic hedgehog to rescue brain cells after ischemic stroke PUR MCAO BBB

Clinical and Bacteriological Profile of Infections in Sickle Cell children in Two Referral hospitals in Niamey, Niger

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Open Journal of Pediatrics 2024年第1期14卷 36-42页

作者： Kamaye Moumouni Samaila Aboubacar Garba Moumouni Georges Thomas Ibrahim Mamoudou Abdou Djafar Mamane Halima Hamadou Ibrahim Hamani Issaka Djibrilla Almoustapha Amadou Yacouba Abdourahamane Marou Soumana Boubacar Moussa Saley Sahada Bade Malam Abdou Soumana Alido service de Pédiatrie A H&#244pital National de Niamey Niamey Niger Faculté des Sciences de la Santé Université Abdou Moumouni de Niamey Niamey Niger service de Pédiatrie H&#244pital national Amirou Boubacar Diallo Niamey Niger service d’Onco-Hématologie H&#244pital national de Niamey Niamey Niger service de Biologie Médicale H&#244pital national Amirou Boubacar Diallo Niamey Niger

Introduction: Infections are significant causes of mortality in sickle cell children in resource-limited countries. This study aimed to determine the clinical profile and bacterial ecology of infections in children with sickle-cell disease in two referral hospitals in Niamey. Patients and methods: A retrospective descriptive study was conducted from January 2018 to July 2020 in two referral hospitals in Niamey. All children aged one (1) to 15 years with sickle cell disease admitted for suspected infection, including at least one bacterial culture, were studied. Bacteriological analysis was performed using the appropriate culture media, using BactAlert (Reference 4700003 BTA3D60 BioMérieux). Results: Over 36-months, 350 children with a mean age of 10.9 months were admitted. The sex ratio was 1.2. The SS electrophoretic profile was the most common (93.4%). Immunization status was up to date in 66% of patients. Fever was the common reason for consultation (55.1%). Infection was confirmed in 62 patients (17.7%). The primary diagnoses were bacterial gastroenteritis (24.2%) and urinary tract infection (19.4%). Blood cultures were isolated from Salmonella typhi (13.0%) and Escherichia coli (8.7%). Klebsiella spp (7.1%) and Escherichia coli (5.0%) were detected in cytobacteriological examination of urine. Salmonella typhi (23.5%) and Escherichia coli (5.9%) were isolated on coproculture. Conclusion: Bacterial ecology appears not different from that usually observed in sickle-cell children. Salmonella and Escherichia coli were predominant.

关键词： Sickle Cell Disease Child Infection Niger

[^(18)F]MAGL-4-11 positron emission tomography molecular imaging of monoacylglycerol lipase changes in preclinical liver fibrosis models

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Acta Pharmaceutica Sinica B 2022年第1期12卷 308-315页

作者： Tuo Shao Zhen Chen Jian Rong Vasily Belov Jiahui Chen Andre Jeyarajan Xiaoyun Deng Hualong Fu Qingzhen Yu Steve H.Rwema Wenyu Lin Mikhail Papisov Lee Josephson Raymond T.Chung Steven H.Liang Division of Nuclear Medicine and Molecular Imaging Department of RadiologyMassachusetts General Hospital and Harvard Medical SchoolBostonmA 02114USA Liver Center and Gastrointestinal Division Department of MedicineMassachusetts General HospitalHarvard Medical SchoolBostonA 02114USA shriners hospitals for children-Boston Boston BostonMA 02114USA

Monoacylglycerol lipase(MAGL) is a pivotal enzyme in the endocannabinoid system, which metabolizes 2-arachidonoylglycerol(2-AG) into the proinflammatory eicosanoid precursor arachidonic acid(AA). MAGL and other endogenous cannabinoid(EC) degrading enzymes are involved in the fibrogenic signaling pathways that induce hepatic stellate cell(HSC) activation and ECM accumulation during chronic liver disease. Our group recently developed an;F-labeled MAGL inhibitor([18F]MAGL-4-11)for PET imaging and demonstrated highly specific binding in vitro and in vivo. In this study, we determined [18F]MAGL-4-11 PET enabled imaging MAGL levels in the bile duct ligation(BDL) and carbon tetrachloride(CCl_(4)) models of liver cirrhosis;we also assessed the hepatic gene expression of the enzymes involved with EC system including MAGL, NAPE-PLD, FAAH and DAGL that as a function of disease severity in these models;[18F]MAGL-4-11 autoradiography was performed to assess tracer binding in frozen liver sections both in animal and human. [18F]MAGL-4-11 demonstrated reduced PET signals in early stages of fibrosis and further significantly decreased with disease progression compared with control mice. We confirmed MAGL and FAAH expression decreases with fibrosisseverity, while its levels in normal liver tissue are high;in contrast, the EC synthetic enzymes NAPE-PLD and DAGL are enhanced in these different fibrosis models. In vitro autoradiography further supported that[18F]MAGL-4-11 bound specifically to MAGL in both animal and human fibrotic liver tissues. Our PET ligand [18F]MAGL-4-11 shows excellent sensitivity and specificity for MAGL visualization in vivo and accurately reflects the histological stages of liver fibrosis in preclinical models and human liver tissues.

关键词： [18F]MAGL-4-11 PET imaging Liver fibrosis MAGL