Autograft or metal implants are routinely used in skeletal repair.However,they fail to provide long-term clinical resolution,necessitating a functional biomimetic tissue engineering alternative.The use of native human...Autograft or metal implants are routinely used in skeletal repair.However,they fail to provide long-term clinical resolution,necessitating a functional biomimetic tissue engineering alternative.The use of native human bone tissue for synthesizing a biomimeticmaterial inkfor three-dimensional(3D)bioprintingof skeletal tissueis anattractivestrategyfor tissueregeneration.Thus,human bone extracellular matrix(bone-ECM)offers an exciting potential for the development of an appropriate microenvironment for human bone marrow stromal cells(HBMSCs)to proliferate and differentiate along the osteogenic lineage.In this study,we engineered a novel material ink(LAB)by blending human bone-ECM(B)with nanoclay(L,Laponite®)and alginate(A)polymers using extrusion-based deposition.The inclusion of the nanofiller and polymeric material increased the rheology,printability,and drug retention properties and,critically,the preservation of HBMSCs viability upon printing.The composite of human bone-ECM-based 3D constructs containing vascular endothelial growth factor(VEGF)enhanced vascularization after implantation in an ex vivo chick chorioallantoic membrane(CAM)model.The inclusion of bone morphogenetic protein-2(BMP-2)with the HBMSCs further enhanced vascularization and mineralization after only seven days.This study demonstrates the synergistic combination of nanoclay with biomimetic materials(alginate and bone-ECM)to support the formation of osteogenic tissue both in vitro and ex vivo and offers a promising novel 3D bioprinting approach to personalized skeletal tissue repair.展开更多
Objectives:‘OMICs encapsulates study of scaled data acquisition,at the levels of DNA,RNA,protein,and metabolite species.The broad objectives of OMICs in biomedical exercise research are multifarious,but commonly rela...Objectives:‘OMICs encapsulates study of scaled data acquisition,at the levels of DNA,RNA,protein,and metabolite species.The broad objectives of OMICs in biomedical exercise research are multifarious,but commonly relate to biomarker development and understanding features of exercise adaptation in health,ageing and metabolic diseases.Methods:Thisfield is one of exponential technical(i.e.,depth of feature coverage)and scientific(i.e.,in health,metabolic conditions and ageing,multi-OMICs)progress adopting targeted and untargeted approaches.Results:Keyfindings in exercise biomedicine have led to the identificationofOMIC featureslinking toheritability or adaptive responses to exercise e.g.,the forging of GWAS/proteome/metabolome links to cardiovascularfitness and metabolic health adaptations.The recent addition of stable isotope tracing to proteomics(‘dynamic proteomics’)and metabolomics(‘fluxomics’)represents the next phase of state-of-the-art in‘OMICS.Conclusions:These methods overcome limitations associated with point-in-time‘OMICs and can be achieved using substrate-specific tracers or deuterium oxide(D2O),depending on the question;these methods could help identify how individual protein turnover and metaboliteflux may explain exercise responses.We contend application of these methods will shed new light in translational exercise biomedicine.展开更多
Our recent breakthrough discovery demonstrated that the anticancer drug FL118 tightly binds to and then dephosphorylates and degrades the oncogenic protein DEAD-box helicase 5(DDX5),leading to the inhibition of DDX5 d...Our recent breakthrough discovery demonstrated that the anticancer drug FL118 tightly binds to and then dephosphorylates and degrades the oncogenic protein DEAD-box helicase 5(DDX5),leading to the inhibition of DDX5 downstream targets(e.g.,survivin,myeloid cell leukemia 1(Mcl-1),X-linked inhibitor of apoptosis(XIAP),c-Myc,mutant Kras,etc.)[1].FL118 is a molecular glue(MG)that can alter the interactomes of two or more non-interacting proteins[2].Thus,FL118 exhibits high efficacy against colorectal and pancreatic cancer xenograft tumors[1,3].However,moving FL118 into clinical trials requires a clinically compatible FL118 drug product(DP)that possesses high antitumor efficacy and low toxicity via oral(ideal)or intravenous(iv)administration.Here,we report the development and characterization of a clinically and orally compatible FL118 DP.We show that(1)FL118 drug substances(DS)exhibit high chemical stability under various test conditions;(2)a clinically and orally compatible FL118 DP can be manufactured through the formulation of FL118 DS with 2-hydroxypropyl-bcyclodextrin(HPbCD)using mixed solvents of glacial acetic acid(GAA)with ethanol through microfluidizer-mediated spray dried dispersion(M-SDD).展开更多
基金supported by grants from the Biotechnology and Biological Sciences Research Council(Nos.BBSRC LO21071/and BB/L00609X/1)UK Regenerative Medicine Platform Hub Acellular Approaches for Therapeutic Delivery(No.MR/K026682/1)+3 种基金Acellular Hub,SMART Materials 3D Architecture(No.MR/R015651/1)the UK Regenerative Medicine Platform(No.MR/L012626/1 Southampton Imaging)to ROCOMRCAMED Regenerative Medicine and Stem Cell Research Initiative(No.MR/V00543X/1)to JID,ROCO and YHKGC acknowledges funding from AIRC Aldi Fellowship under grant agreement No.25412.
文摘Autograft or metal implants are routinely used in skeletal repair.However,they fail to provide long-term clinical resolution,necessitating a functional biomimetic tissue engineering alternative.The use of native human bone tissue for synthesizing a biomimeticmaterial inkfor three-dimensional(3D)bioprintingof skeletal tissueis anattractivestrategyfor tissueregeneration.Thus,human bone extracellular matrix(bone-ECM)offers an exciting potential for the development of an appropriate microenvironment for human bone marrow stromal cells(HBMSCs)to proliferate and differentiate along the osteogenic lineage.In this study,we engineered a novel material ink(LAB)by blending human bone-ECM(B)with nanoclay(L,Laponite®)and alginate(A)polymers using extrusion-based deposition.The inclusion of the nanofiller and polymeric material increased the rheology,printability,and drug retention properties and,critically,the preservation of HBMSCs viability upon printing.The composite of human bone-ECM-based 3D constructs containing vascular endothelial growth factor(VEGF)enhanced vascularization after implantation in an ex vivo chick chorioallantoic membrane(CAM)model.The inclusion of bone morphogenetic protein-2(BMP-2)with the HBMSCs further enhanced vascularization and mineralization after only seven days.This study demonstrates the synergistic combination of nanoclay with biomimetic materials(alginate and bone-ECM)to support the formation of osteogenic tissue both in vitro and ex vivo and offers a promising novel 3D bioprinting approach to personalized skeletal tissue repair.
文摘Objectives:‘OMICs encapsulates study of scaled data acquisition,at the levels of DNA,RNA,protein,and metabolite species.The broad objectives of OMICs in biomedical exercise research are multifarious,but commonly relate to biomarker development and understanding features of exercise adaptation in health,ageing and metabolic diseases.Methods:Thisfield is one of exponential technical(i.e.,depth of feature coverage)and scientific(i.e.,in health,metabolic conditions and ageing,multi-OMICs)progress adopting targeted and untargeted approaches.Results:Keyfindings in exercise biomedicine have led to the identificationofOMIC featureslinking toheritability or adaptive responses to exercise e.g.,the forging of GWAS/proteome/metabolome links to cardiovascularfitness and metabolic health adaptations.The recent addition of stable isotope tracing to proteomics(‘dynamic proteomics’)and metabolomics(‘fluxomics’)represents the next phase of state-of-the-art in‘OMICS.Conclusions:These methods overcome limitations associated with point-in-time‘OMICs and can be achieved using substrate-specific tracers or deuterium oxide(D2O),depending on the question;these methods could help identify how individual protein turnover and metaboliteflux may explain exercise responses.We contend application of these methods will shed new light in translational exercise biomedicine.
文摘Our recent breakthrough discovery demonstrated that the anticancer drug FL118 tightly binds to and then dephosphorylates and degrades the oncogenic protein DEAD-box helicase 5(DDX5),leading to the inhibition of DDX5 downstream targets(e.g.,survivin,myeloid cell leukemia 1(Mcl-1),X-linked inhibitor of apoptosis(XIAP),c-Myc,mutant Kras,etc.)[1].FL118 is a molecular glue(MG)that can alter the interactomes of two or more non-interacting proteins[2].Thus,FL118 exhibits high efficacy against colorectal and pancreatic cancer xenograft tumors[1,3].However,moving FL118 into clinical trials requires a clinically compatible FL118 drug product(DP)that possesses high antitumor efficacy and low toxicity via oral(ideal)or intravenous(iv)administration.Here,we report the development and characterization of a clinically and orally compatible FL118 DP.We show that(1)FL118 drug substances(DS)exhibit high chemical stability under various test conditions;(2)a clinically and orally compatible FL118 DP can be manufactured through the formulation of FL118 DS with 2-hydroxypropyl-bcyclodextrin(HPbCD)using mixed solvents of glacial acetic acid(GAA)with ethanol through microfluidizer-mediated spray dried dispersion(M-SDD).
