The therapeutic interventions of human hypertrophic scars(HHS)remain puzzle largely due to the lack of accepted models.Current HHS models are limited by their inability to mimic native scar architecture and associated...The therapeutic interventions of human hypertrophic scars(HHS)remain puzzle largely due to the lack of accepted models.Current HHS models are limited by their inability to mimic native scar architecture and associated pathological microenvironments.Here,we create a 3D functional HHS model by preformed cellular aggregates(PCA)bioprinting,firstly developing bioink from scar decellularized extracellular matrix(ECM)and alginate-gelatin(Alg-Gel)hydrogel with suitable physical properties to mimic the microenvironmental factors,then pre-culturing patient-derived fibroblasts in this bioink to preform the topographic cellular aggregates for sequent printing.We confirm the cell aggregates preformed in bioink displayed well defined aligned structure and formed functional scar tissue self-organization after bioprinting,hence showing the potential of creating HHS models.Notably,these HHS models exhibit characteristics of early-stage HHS in gene and protein expression,which significantly activated signaling pathway related to inflammation and cell proliferation,and recapitulate in vivo tissue dynamics of scar forming.We also use the in vitro and in vivo models to define the clinically observed effects to treatment with concurrent anti-scarring drugs,and the data show that it can be used to evaluate the potential therapeutic target for drug testing.The ideal humanized scar models we present should prove useful for studying critical mechanisms underlying HHS and to rapidly test new drug targets and develop patient-specific optimal therapeutic strategies in the future.展开更多
基金supported in part by the National Nature Science Foundation of China(81830064,81721092,32000969,82002056)Key Support Program for Growth Factor Research(SZYZ-TR-03)+3 种基金Chinese PLA General Hospital for Military Medical Innovation Research Project(CX-19026)the CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-059)the Military Medical Research and Development Projects(AWS17J005)National Key Research and Development Program of China(2018YFA0108700,2017YFA0105602).
文摘The therapeutic interventions of human hypertrophic scars(HHS)remain puzzle largely due to the lack of accepted models.Current HHS models are limited by their inability to mimic native scar architecture and associated pathological microenvironments.Here,we create a 3D functional HHS model by preformed cellular aggregates(PCA)bioprinting,firstly developing bioink from scar decellularized extracellular matrix(ECM)and alginate-gelatin(Alg-Gel)hydrogel with suitable physical properties to mimic the microenvironmental factors,then pre-culturing patient-derived fibroblasts in this bioink to preform the topographic cellular aggregates for sequent printing.We confirm the cell aggregates preformed in bioink displayed well defined aligned structure and formed functional scar tissue self-organization after bioprinting,hence showing the potential of creating HHS models.Notably,these HHS models exhibit characteristics of early-stage HHS in gene and protein expression,which significantly activated signaling pathway related to inflammation and cell proliferation,and recapitulate in vivo tissue dynamics of scar forming.We also use the in vitro and in vivo models to define the clinically observed effects to treatment with concurrent anti-scarring drugs,and the data show that it can be used to evaluate the potential therapeutic target for drug testing.The ideal humanized scar models we present should prove useful for studying critical mechanisms underlying HHS and to rapidly test new drug targets and develop patient-specific optimal therapeutic strategies in the future.
