Multicellular microtissues of primary human hepatocytes(PHHs)co-cultured with other supporting cell types are a promis-ing model for drug screening and toxicological studies.However,these liver microtissues(LMs)rapidl...Multicellular microtissues of primary human hepatocytes(PHHs)co-cultured with other supporting cell types are a promis-ing model for drug screening and toxicological studies.However,these liver microtissues(LMs)rapidly lose their functions during ex vivo culture.Here,in order to mimic the cellular and structural hepatic microenvironment,we co-cultured PHHs with human mesenchymal stromal cells(MSCs)and human umbilical vein endothelial cells(HUVECs)in the presence of cell-sized microparticles(MPs)derived from liver extracellular matrix(LEMPs).The microwell culture platform enabled biofabrication of size-controlled multicellular microtissues(PHH:HUVEC:MSC=3:2:1)with efficient LEMP incorporation(about 70%at a 2:1 ratio of cells:MP).The biofabricated liver microtissues(BLMs)were cultured ex vivo for 14 days and compared to the cell-only LM in terms of gene and protein expression,functional activity,cytochrome P450(CYP450)enzyme inducibility,and drug sensitivity.The results supported superior hepatic-related gene expression,functional activity,and polarity for PHH in BLM compared to LM.CYP450 enzyme inducibility and dose-responsive sensitivity to toxic drugs were significantly higher in the BLM group.In conclusion,microtissue engineering by incorporation of tissue-specific microparticles within a multicellular microtissue can offer some advantages for drug discovery studies and cell transplantation applications.In the near future,this approach could generate a scalable platform of several functional biofabricated microtissues representing different organs.展开更多
Andrographolide (AG) is the characteristic constituent of Andrographis paniculata, of the Acanthaceae family. This plant is a well-known Asian medicinal plant that is widely used in India, China, and Thailand. A monog...Andrographolide (AG) is the characteristic constituent of Andrographis paniculata, of the Acanthaceae family. This plant is a well-known Asian medicinal plant that is widely used in India, China, and Thailand. A monograph of Herba Andrographidis (Chuanxinlian) is included in the Chinese Pharmacopoeia, which reports that this decoction can “remove heat, counteract toxicity, and reduce swellings.” The numerous potential activities of AG range from anti-inflammatory to anti-diabetic action, from neuroprotection to antitumor activity, and from hepatoprotective to anti-obesity properties. However, AG has low bioavailability and poor water solubility, which can limit its distribution and accumulation in the body after administration. In addition, AG is not stable in gastrointestinal alkaline and acidic environments, and has been reported to have a very short half-life. Among the diverse strategies that have been adopted to increase AG water solubility and permeability, the technological approach is the most useful way to develop appropriate delivery systems. This review reports on published studies related to microparticles (MPs) and nanoparticles (NPs) loaded with AG. MPs based on polylactic-glycolic acid (PLGA), alginic acid, and glucan derivatives have been developed for parenteral oral and pulmonary administration, respectively. NPs include vesicles (both liposomes and niosomes);polymeric NPs (based on polyvinyl alcohol, polymerized phenylboronic acid, PLGA, human serum albumin, poly ethylcyanoacrylate, and polymeric micelles);solid lipid NPs;microemulsions and nanoemulsions;gold NPs;nanocrystals;and nanosuspensions. Improved bioavailability, target-tissue distribution, and efficacy of AG loaded in the described drug delivery systems have been reported.展开更多
The field of biomaterials has advanced significantly in the past decade.With the growing need for high-throughput manufacturing and screening,the need for modular materials that enable streamlined fabrication and anal...The field of biomaterials has advanced significantly in the past decade.With the growing need for high-throughput manufacturing and screening,the need for modular materials that enable streamlined fabrication and analysis of tissue engineering and drug delivery schema has emerged.Microparticles are a powerful platform that have demonstrated promise in enabling these technologies without the need to modify a bulk scaffold.This building block paradigm of using microparticles within larger scaffolds to control cell ratios,growth factors and drug release holds promise.Gelatin microparticles(GMPs)are a well-established platform for cell,drug and growth factor delivery.One of the challenges in using GMPs though is the limited ability to modify the gelatin post-fabrication.In the present work,we hypothesized that by thiolating gelatin before microparticle formation,a versatile platform would be created that preserves the cytocompatibility of gelatin,while enabling post-fabrication modification.The thiols were not found to significantly impact the physicochemical properties of the microparticles.Moreover,the thiolated GMPs were demonstrated to be a biocompatible and robust platform for mesenchymal stem cell attachment.Additionally,the thiolated particles were able to be covalently modified with a maleimide-bearing fluorescent dye and a peptide,demonstrating their promise as a modular platform for tissue engineering and drug delivery applications.展开更多
基金supported by Grants from Royan Institute(No.96000165)to MV and HBBahar Tashkhis Teb Co.(Nos.BTT,9702,and 9802)+1 种基金Iran National Science Foundation(No.97014445)to MVthe Ministry of Health and Medical Education(No.56700/147)to HB.
文摘Multicellular microtissues of primary human hepatocytes(PHHs)co-cultured with other supporting cell types are a promis-ing model for drug screening and toxicological studies.However,these liver microtissues(LMs)rapidly lose their functions during ex vivo culture.Here,in order to mimic the cellular and structural hepatic microenvironment,we co-cultured PHHs with human mesenchymal stromal cells(MSCs)and human umbilical vein endothelial cells(HUVECs)in the presence of cell-sized microparticles(MPs)derived from liver extracellular matrix(LEMPs).The microwell culture platform enabled biofabrication of size-controlled multicellular microtissues(PHH:HUVEC:MSC=3:2:1)with efficient LEMP incorporation(about 70%at a 2:1 ratio of cells:MP).The biofabricated liver microtissues(BLMs)were cultured ex vivo for 14 days and compared to the cell-only LM in terms of gene and protein expression,functional activity,cytochrome P450(CYP450)enzyme inducibility,and drug sensitivity.The results supported superior hepatic-related gene expression,functional activity,and polarity for PHH in BLM compared to LM.CYP450 enzyme inducibility and dose-responsive sensitivity to toxic drugs were significantly higher in the BLM group.In conclusion,microtissue engineering by incorporation of tissue-specific microparticles within a multicellular microtissue can offer some advantages for drug discovery studies and cell transplantation applications.In the near future,this approach could generate a scalable platform of several functional biofabricated microtissues representing different organs.
基金the Fondazione Cassa Risparmio di Firenze for kindly supporting this review study
文摘Andrographolide (AG) is the characteristic constituent of Andrographis paniculata, of the Acanthaceae family. This plant is a well-known Asian medicinal plant that is widely used in India, China, and Thailand. A monograph of Herba Andrographidis (Chuanxinlian) is included in the Chinese Pharmacopoeia, which reports that this decoction can “remove heat, counteract toxicity, and reduce swellings.” The numerous potential activities of AG range from anti-inflammatory to anti-diabetic action, from neuroprotection to antitumor activity, and from hepatoprotective to anti-obesity properties. However, AG has low bioavailability and poor water solubility, which can limit its distribution and accumulation in the body after administration. In addition, AG is not stable in gastrointestinal alkaline and acidic environments, and has been reported to have a very short half-life. Among the diverse strategies that have been adopted to increase AG water solubility and permeability, the technological approach is the most useful way to develop appropriate delivery systems. This review reports on published studies related to microparticles (MPs) and nanoparticles (NPs) loaded with AG. MPs based on polylactic-glycolic acid (PLGA), alginic acid, and glucan derivatives have been developed for parenteral oral and pulmonary administration, respectively. NPs include vesicles (both liposomes and niosomes);polymeric NPs (based on polyvinyl alcohol, polymerized phenylboronic acid, PLGA, human serum albumin, poly ethylcyanoacrylate, and polymeric micelles);solid lipid NPs;microemulsions and nanoemulsions;gold NPs;nanocrystals;and nanosuspensions. Improved bioavailability, target-tissue distribution, and efficacy of AG loaded in the described drug delivery systems have been reported.
基金This work was supported by the National Institutes of Health(R01 AR068073 and P41 EB023833)H.A.P.,M.M.S.and E.Y.J.acknowledge support from the National Science Foundation Graduate Research Fellowship Program.M.M.S.also acknowledges support from the Ford Doctoral Fellowship Program.E.W.received support from Ruth L.Kirschstein Fellowship and the National Institute of Dental and Craniofacial Research(F31 DE027586).
文摘The field of biomaterials has advanced significantly in the past decade.With the growing need for high-throughput manufacturing and screening,the need for modular materials that enable streamlined fabrication and analysis of tissue engineering and drug delivery schema has emerged.Microparticles are a powerful platform that have demonstrated promise in enabling these technologies without the need to modify a bulk scaffold.This building block paradigm of using microparticles within larger scaffolds to control cell ratios,growth factors and drug release holds promise.Gelatin microparticles(GMPs)are a well-established platform for cell,drug and growth factor delivery.One of the challenges in using GMPs though is the limited ability to modify the gelatin post-fabrication.In the present work,we hypothesized that by thiolating gelatin before microparticle formation,a versatile platform would be created that preserves the cytocompatibility of gelatin,while enabling post-fabrication modification.The thiols were not found to significantly impact the physicochemical properties of the microparticles.Moreover,the thiolated GMPs were demonstrated to be a biocompatible and robust platform for mesenchymal stem cell attachment.Additionally,the thiolated particles were able to be covalently modified with a maleimide-bearing fluorescent dye and a peptide,demonstrating their promise as a modular platform for tissue engineering and drug delivery applications.
