Hiroaki Hatano, Fanlu Meng, Momoko Sakata, A. Matsumoto, K. Ishihara, Y. Miyahara, T. Goda
Epithelial barriers that seal cell gaps by forming tight junctions to prevent the free permeation of nutrients, electrolytes, and drugs, are essential for maintaining homeostasis in multicellular organisms. The development of nanocarriers that can permeate epithelial tissues without compromising barrier function is key for establishing a safe and efficient drug delivery system (DDS). Previously, we have demonstrated that a water-soluble phospholipid-mimicking random copolymer, poly(2-methacryloyloxyethyl phosphorylcholine30-random-n-butyl methacrylate70) (PMB30W), enters the cytoplasm of live cells by passive diffusion mechanisms, without damaging the cell membranes. The internalization mechanism was confirmed to be amphiphilicity-induced membrane fusion. In the present study, we demonstrated energy-independent permeation of PMB30W through the model epithelial barriers of Madin-Darby canine kidney (MDCK) cell monolayers in vitro. The polymer penetrated epithelial MDCK monolayers via transcellular pathways without breaching the barrier functions. This was confirmed by our unique assay that can monitor the leakage of the proton as the smallest indicator across the epithelial barriers. Moreover, energy-independent transepithelial permeation was achieved when insulin was chemically conjugated with the phospholipid-mimicking nanocarrier. The bioactivity of insulin as a growth factor was found to be maintained even after translocation. These fundamental findings may aid the establishment of transepithelial DDS with advanced drug efficiency and safety. STATEMENT OF SIGNIFICANCE: A nanocarrier that can freely permeate epithelial tissues without compromising barrier function is key for successful drug delivery system (DDS). Existing strategies mainly rely on paracellular transport associated with tight junction breakdown or transcellular transport via transporter recognition-mediated active uptake. These approaches raise concerns about efficiency and safety. In this study, we performed non-endocytic permeation of phospholipid-mimicking polymers through the model epithelial barriers in vitro. The polymer penetrated via transcytotic pathways without breaching the barriers of biomembrane and tight junction. Moreover, transepithelial permeation occurred when insulin was covalently attached to the nanocarrier. The bioactivity of insulin as a growth factor was maintained even after translocation. The biomimetic design of nanocarrier may realize safe and efficient transepithelial DDS.
{"title":"Transepithelial Delivery of Insulin Conjugated with Phospholipid-Mimicking Polymers via Biomembrane Fusion-Mediated Transcellular Pathways","authors":"Hiroaki Hatano, Fanlu Meng, Momoko Sakata, A. Matsumoto, K. Ishihara, Y. Miyahara, T. Goda","doi":"10.2139/ssrn.3890358","DOIUrl":"https://doi.org/10.2139/ssrn.3890358","url":null,"abstract":"Epithelial barriers that seal cell gaps by forming tight junctions to prevent the free permeation of nutrients, electrolytes, and drugs, are essential for maintaining homeostasis in multicellular organisms. The development of nanocarriers that can permeate epithelial tissues without compromising barrier function is key for establishing a safe and efficient drug delivery system (DDS). Previously, we have demonstrated that a water-soluble phospholipid-mimicking random copolymer, poly(2-methacryloyloxyethyl phosphorylcholine30-random-n-butyl methacrylate70) (PMB30W), enters the cytoplasm of live cells by passive diffusion mechanisms, without damaging the cell membranes. The internalization mechanism was confirmed to be amphiphilicity-induced membrane fusion. In the present study, we demonstrated energy-independent permeation of PMB30W through the model epithelial barriers of Madin-Darby canine kidney (MDCK) cell monolayers in vitro. The polymer penetrated epithelial MDCK monolayers via transcellular pathways without breaching the barrier functions. This was confirmed by our unique assay that can monitor the leakage of the proton as the smallest indicator across the epithelial barriers. Moreover, energy-independent transepithelial permeation was achieved when insulin was chemically conjugated with the phospholipid-mimicking nanocarrier. The bioactivity of insulin as a growth factor was found to be maintained even after translocation. These fundamental findings may aid the establishment of transepithelial DDS with advanced drug efficiency and safety. STATEMENT OF SIGNIFICANCE: A nanocarrier that can freely permeate epithelial tissues without compromising barrier function is key for successful drug delivery system (DDS). Existing strategies mainly rely on paracellular transport associated with tight junction breakdown or transcellular transport via transporter recognition-mediated active uptake. These approaches raise concerns about efficiency and safety. In this study, we performed non-endocytic permeation of phospholipid-mimicking polymers through the model epithelial barriers in vitro. The polymer penetrated via transcytotic pathways without breaching the barriers of biomembrane and tight junction. Moreover, transepithelial permeation occurred when insulin was covalently attached to the nanocarrier. The bioactivity of insulin as a growth factor was maintained even after translocation. The biomimetic design of nanocarrier may realize safe and efficient transepithelial DDS.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125591747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tianhao Yan, D. Rao, Ye Chen, Yu Wang, Qingchuan Zhang, Shangquan Wu
As cells have the capacity to respond to their mechanical environment, cellular biological behaviors can be regulated by the stiffness of extracellular matrix. Moreover, biological processes are dynamic and accompanied by matrix stiffening. Herein, we developed a stiffening cell culture platform based on polyacrylamide-Fe3O4 magnetic nanocomposite hydrogel with tunable stiffness under the application of magnetic field. This platform provided a wide range of tunable stiffness (∼0.3-20 kPa) covering most of human tissue elasticity with a high biocompatibility. Overall, the increased magnetic interactions between magnetic nanoparticles reduced the pore size of the hydrogel and enhanced the hydrogel stiffness, thereby facilitating the adhesion and spreading of stem cells, which was attributed to the F-actin assembly and vinculin recruitment. Such stiffening cell culture platform provides dynamic mechanical environments for probing the cellular response to matrix stiffening, and benefits studies of dynamic biological processes. STATEMENT OF SIGNIFICANCE: : Cellular biological behaviors can be regulated by the stiffness of extracellular matrix. Moreover, biological processes are dynamic and accompanied by matrix stiffening. Herein, we developed a stiffening cell culture platform based on polyacrylamide/Fe3O4 magnetic nanocomposite hydrogels with a wide tunable range of stiffness under the application of magnetic field, without adversely affecting cellular behaviors. Such matrix stiffening caused by enhanced magnetic interaction between magnetic nanoparticles under the application of the magnetic field could induce the morphological variations of stem cells cultured on the hydrogels. Overall, our stiffening cell culture platform can be used not only to probe the cellular response to matrix stiffening but also to benefit various biomedical studies.
{"title":"Magnetic Nanocomposite Hydrogel with Tunable Stiffness for Probing Cellular Responses to Matrix Stiffening","authors":"Tianhao Yan, D. Rao, Ye Chen, Yu Wang, Qingchuan Zhang, Shangquan Wu","doi":"10.2139/ssrn.3897769","DOIUrl":"https://doi.org/10.2139/ssrn.3897769","url":null,"abstract":"As cells have the capacity to respond to their mechanical environment, cellular biological behaviors can be regulated by the stiffness of extracellular matrix. Moreover, biological processes are dynamic and accompanied by matrix stiffening. Herein, we developed a stiffening cell culture platform based on polyacrylamide-Fe3O4 magnetic nanocomposite hydrogel with tunable stiffness under the application of magnetic field. This platform provided a wide range of tunable stiffness (∼0.3-20 kPa) covering most of human tissue elasticity with a high biocompatibility. Overall, the increased magnetic interactions between magnetic nanoparticles reduced the pore size of the hydrogel and enhanced the hydrogel stiffness, thereby facilitating the adhesion and spreading of stem cells, which was attributed to the F-actin assembly and vinculin recruitment. Such stiffening cell culture platform provides dynamic mechanical environments for probing the cellular response to matrix stiffening, and benefits studies of dynamic biological processes. STATEMENT OF SIGNIFICANCE: : Cellular biological behaviors can be regulated by the stiffness of extracellular matrix. Moreover, biological processes are dynamic and accompanied by matrix stiffening. Herein, we developed a stiffening cell culture platform based on polyacrylamide/Fe3O4 magnetic nanocomposite hydrogels with a wide tunable range of stiffness under the application of magnetic field, without adversely affecting cellular behaviors. Such matrix stiffening caused by enhanced magnetic interaction between magnetic nanoparticles under the application of the magnetic field could induce the morphological variations of stem cells cultured on the hydrogels. Overall, our stiffening cell culture platform can be used not only to probe the cellular response to matrix stiffening but also to benefit various biomedical studies.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115465887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
B. Labat, N. Buchbinder, S. Morin-Grognet, G. Ladam, Hassan Atmani, J. Vannier
Neuroblastoma is the third most common pediatric cancer composed of malignant immature cells that are usually treated pharmacologically by all trans-retinoic acid (ATRA) but sometimes, they can spontaneously differentiate into benign forms. In that context, biomimetic cell culture models are warranted tools as they can recapitulate many of the biochemical and biophysical cues of normal or pathological microenvironments. Inspired by that challenge, we developed a neuroblastoma culture system based on biomimetic LbL films of physiological biochemical composition and mechanical properties. For that, we used chondroitin sulfate A (CSA) and poly-L-lysine (PLL) that were assembled and mechanically tuned by crosslinking with genipin (GnP), a natural biocompatible crosslinker, in a relevant range of stiffness (30-160 kPa). We then assessed the adhesion, survival, motility, and differentiation of LAN-1 neuroblastoma cells. Remarkably, increasing the stiffness of the LbL films induced neuritogenesis that was strengthened by the combination with ATRA. These results highlight the crucial role of the mechanical cues of the neuroblastoma microenvironment since it can dramatically modulate the effect of pharmacologic drugs. In conclusion, our biomimetic platform offers a promising tool to help fundamental understanding and pharmacological screening of neuroblastoma differentiation and may assist the design of translational biomaterials to support neuronal regeneration. Statement of significance: Neuroblastoma is one of the most common pediatric tumor commonly treated by the administration of all-trans-retinoic acid (ATRA). Unfortunately, advanced neuroblastoma often develop ATRA resistance. Accordingly, in the field of pharmacological investigations on neuroblastoma, there is a tremendous need of physiologically relevant cell culture systems that can mimic normal or pathological extracellular matrices. In that context, we developed a promising matrix-like cell culture model that provides new insights on the crucial role of mechanical properties of the microenvironment upon the success of ATRA treatment on the neuroblastoma maturation. We were able to control adhesion, survival, motility, and differentiation of neuroblastoma cells. More broadly, we believe that our system will help the design of in vitro pharmacological screening strategy.
{"title":"Biomimetic Matrix for the Study of Neuroblastoma Cells: A Promising Combination of Stiffness and Retinoic Acid","authors":"B. Labat, N. Buchbinder, S. Morin-Grognet, G. Ladam, Hassan Atmani, J. Vannier","doi":"10.2139/ssrn.3849028","DOIUrl":"https://doi.org/10.2139/ssrn.3849028","url":null,"abstract":"Neuroblastoma is the third most common pediatric cancer composed of malignant immature cells that are usually treated pharmacologically by all trans-retinoic acid (ATRA) but sometimes, they can spontaneously differentiate into benign forms. In that context, biomimetic cell culture models are warranted tools as they can recapitulate many of the biochemical and biophysical cues of normal or pathological microenvironments. Inspired by that challenge, we developed a neuroblastoma culture system based on biomimetic LbL films of physiological biochemical composition and mechanical properties. For that, we used chondroitin sulfate A (CSA) and poly-L-lysine (PLL) that were assembled and mechanically tuned by crosslinking with genipin (GnP), a natural biocompatible crosslinker, in a relevant range of stiffness (30-160 kPa). We then assessed the adhesion, survival, motility, and differentiation of LAN-1 neuroblastoma cells. Remarkably, increasing the stiffness of the LbL films induced neuritogenesis that was strengthened by the combination with ATRA. These results highlight the crucial role of the mechanical cues of the neuroblastoma microenvironment since it can dramatically modulate the effect of pharmacologic drugs. In conclusion, our biomimetic platform offers a promising tool to help fundamental understanding and pharmacological screening of neuroblastoma differentiation and may assist the design of translational biomaterials to support neuronal regeneration. Statement of significance: Neuroblastoma is one of the most common pediatric tumor commonly treated by the administration of all-trans-retinoic acid (ATRA). Unfortunately, advanced neuroblastoma often develop ATRA resistance. Accordingly, in the field of pharmacological investigations on neuroblastoma, there is a tremendous need of physiologically relevant cell culture systems that can mimic normal or pathological extracellular matrices. In that context, we developed a promising matrix-like cell culture model that provides new insights on the crucial role of mechanical properties of the microenvironment upon the success of ATRA treatment on the neuroblastoma maturation. We were able to control adhesion, survival, motility, and differentiation of neuroblastoma cells. More broadly, we believe that our system will help the design of in vitro pharmacological screening strategy.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126472054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mesoporous silica-based materials, especially mesoporous bioactive glasses (MBGs), are widely used in biomedical applications including tissue engineering and drug delivery, not only because of their excellent bioactivity and biocompatibility but also due to their tunable composition and potential use as drug delivery carriers owing to their controllable nanoporous structure. Numerous researches have reported that MBGs can be doped with various therapeutic ions (strontium, copper, magnesium, zinc, lithium, silver, etc.) and loaded with specific biomolecules (e.g., therapeutic drugs, antibiotics, growth factors) achieving controllable loading and release kinetics. Therefore, co-delivery of ions and biomolecules using a single MBG carrier is highly interesting as this approach provides synergistic effects toward improved therapeutic outcomes in comparison to the strategy of sole drug or ion delivery. In this review, we discuss the state-of-the-art in the field of mesoporous silica-based materials used for co-delivery of ions and therapeutic drugs with osteogenesis/cementogenesis, angiogenesis, antibacterial and anticancer properties. The analysis of the literature reveals that specially designed mesoporous nanocarriers could controllably release multiple ions and drugs at therapeutically safe and relevant levels, achieving the desired biological effects (in vivo, in vitro) for specific biomedical applications. It is expected that this review on the ion/drug co-delivery concept using MBG carriers will shed light on the advantages of such co-delivery systems for clinical use. Areas for future research directions are identified and discussed.
{"title":"Multi-Functional Silica-Based Mesoporous Materials as Co-Delivery Systems for Biologically Active Ions and Therapeutic Biomolecules","authors":"Hui Zhu, K. Zheng, A. Boccaccini","doi":"10.2139/ssrn.3770987","DOIUrl":"https://doi.org/10.2139/ssrn.3770987","url":null,"abstract":"Mesoporous silica-based materials, especially mesoporous bioactive glasses (MBGs), are widely used in biomedical applications including tissue engineering and drug delivery, not only because of their excellent bioactivity and biocompatibility but also due to their tunable composition and potential use as drug delivery carriers owing to their controllable nanoporous structure. Numerous researches have reported that MBGs can be doped with various therapeutic ions (strontium, copper, magnesium, zinc, lithium, silver, etc.) and loaded with specific biomolecules (e.g., therapeutic drugs, antibiotics, growth factors) achieving controllable loading and release kinetics. Therefore, co-delivery of ions and biomolecules using a single MBG carrier is highly interesting as this approach provides synergistic effects toward improved therapeutic outcomes in comparison to the strategy of sole drug or ion delivery. In this review, we discuss the state-of-the-art in the field of mesoporous silica-based materials used for co-delivery of ions and therapeutic drugs with osteogenesis/cementogenesis, angiogenesis, antibacterial and anticancer properties. The analysis of the literature reveals that specially designed mesoporous nanocarriers could controllably release multiple ions and drugs at therapeutically safe and relevant levels, achieving the desired biological effects (in vivo, in vitro) for specific biomedical applications. It is expected that this review on the ion/drug co-delivery concept using MBG carriers will shed light on the advantages of such co-delivery systems for clinical use. Areas for future research directions are identified and discussed.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125386439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ruiyi Zhou, Lihong Zhu, Zhaohao Zeng, Rixin Luo, Jiawei Zhang, Li Deng, R. Guo, Lei Zhang, Qunying Zhang, Wei Bi
Alzheimer's disease (AD) is a neurodegenerative disease related to age. The main pathological features of AD are β-amyloid protein (Aβ) deposition and tau protein hyperphosphorylation. Currently, there are not an effective drug for the etiological treatment of AD. Rifampicin (RIF) is a semi-synthetic broad-spectrum antibiotic with anti-β-amyloid deposition, anti-inflammatory, anti-apoptosis and neuroprotective effects, but its application in AD treatment has been limited by its strong hydrophobicity, high toxicity, short half-life, low bioavailability and blood-brain barrier (BBB) hindrance. We designed a novel brain-targeted and MRI-characteristic nanomedicine through loading rabies virus protein 29 (RVG29), rifampicin and Gd on poly(L-lactide) nanoparticles (RIF@PLA-PEG-Gd/Mal-RVG29). The cytotoxicity assay demonstrated that RIF@PLA-PEG-Gd/Mal-RVG29 had good biocompatibility and security. The results of cellular uptake and fluorescence in vivo imaging showed that PLA-PEG-Gd/Mal-RVG29 could deliver rifampicin into brain by enhancing cellular uptake and brain targeting performance, so that improving the bioavailability of rifampicin. In vivo study, compared with rifampicin, RIF@PLA-PEG-Gd/Mal-RVG29 improved the spatial learning and memory capability of APP/PS1 mice in the Morris water maze. Immunofluorescence, TEM, immunoblotting and HE test showed that RIF@PLA-PEG-Gd/Mal-RVG29 could reduce Aβ deposition in hippocampal and cortex of APP/PS1 mice, improve the damage of synaptic ultrastructure, increase the expression level of PSD95 and SYP, as well as reduce the necrosis of neurons. These findings suggest that RIF@PLA-PEG-Gd/Mal-RVG29 may be an effective strategy for the treatment and diagnosis of AD.
{"title":"Targeted Brain Delivery of RVG29-Modified Rifampicin-Loaded Nanoparticles for Treatment and Diagnosis of Alzheimer Disease","authors":"Ruiyi Zhou, Lihong Zhu, Zhaohao Zeng, Rixin Luo, Jiawei Zhang, Li Deng, R. Guo, Lei Zhang, Qunying Zhang, Wei Bi","doi":"10.2139/ssrn.3762216","DOIUrl":"https://doi.org/10.2139/ssrn.3762216","url":null,"abstract":"Alzheimer's disease (AD) is a neurodegenerative disease related to age. The main pathological features of AD are β-amyloid protein (Aβ) deposition and tau protein hyperphosphorylation. Currently, there are not an effective drug for the etiological treatment of AD. Rifampicin (RIF) is a semi-synthetic broad-spectrum antibiotic with anti-β-amyloid deposition, anti-inflammatory, anti-apoptosis and neuroprotective effects, but its application in AD treatment has been limited by its strong hydrophobicity, high toxicity, short half-life, low bioavailability and blood-brain barrier (BBB) hindrance. We designed a novel brain-targeted and MRI-characteristic nanomedicine through loading rabies virus protein 29 (RVG29), rifampicin and Gd on poly(L-lactide) nanoparticles (RIF@PLA-PEG-Gd/Mal-RVG29). The cytotoxicity assay demonstrated that RIF@PLA-PEG-Gd/Mal-RVG29 had good biocompatibility and security. The results of cellular uptake and fluorescence in vivo imaging showed that PLA-PEG-Gd/Mal-RVG29 could deliver rifampicin into brain by enhancing cellular uptake and brain targeting performance, so that improving the bioavailability of rifampicin. In vivo study, compared with rifampicin, RIF@PLA-PEG-Gd/Mal-RVG29 improved the spatial learning and memory capability of APP/PS1 mice in the Morris water maze. Immunofluorescence, TEM, immunoblotting and HE test showed that RIF@PLA-PEG-Gd/Mal-RVG29 could reduce Aβ deposition in hippocampal and cortex of APP/PS1 mice, improve the damage of synaptic ultrastructure, increase the expression level of PSD95 and SYP, as well as reduce the necrosis of neurons. These findings suggest that RIF@PLA-PEG-Gd/Mal-RVG29 may be an effective strategy for the treatment and diagnosis of AD.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131042740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem cells demonstrate considerable promise for various preclinical and clinical applications, including drug screening, disease treatments, and regenerative medicine. Producing high-quality and large amounts of stem cells is in demand for these applications. Despite challenges, as hydrogel-based cell culture technology has developed, tremendous progress has been made in stem cell expansion and directed differentiation. Hydrogels are soft materials with abundant water. Many hydrogel properties, including biodegradability, mechanical strength, and porosity, have been shown to play essential roles in regulating stem cell proliferation and differentiation. The biochemical and physical properties of hydrogels can be specifically tailored to mimic the native microenvironment that various stem cells reside in vivo. A few hydrogel-based systems have been developed for successful stem cell cultures and expansion in vitro. In this review, we summarize various types of hydrogels that have been designed to effectively enhance the proliferation of hematopoietic stem cells (HSCs), mesenchymal stem/stromal cells (MSCs), and pluripotent stem cells (PSCs), respectively. According to each stem cell type's preference, we also discuss strategies for fabricating hydrogels with biochemical and mechanical cues and other characteristics representing microenvironments of stem cells in vivo. STATEMENT OF SIGNIFICANCE: In this review article we summary current progress on the construction of hydrogel systems for the culture and expansion of various stem cells, including hematopoietic stem cells (HSCs), mesenchymal stem/stromal cells (MSCs), and pluripotent stem cells (PSCs). The Significance includes: (1) Provide detailed discussion on the stem cell niches that should be considered for stem cell in vitro expansion. (2) Summarize various strategies to construct hydrogels that can largely recapture the microenvironment of native stem cells. (3) Suggest a few future directions that can be implemented to improve current in vitro stem cell expansion systems.
{"title":"Hydrogels for Large-Scale Expansion of Stem Cells","authors":"Sheng Yin, Yi Cao","doi":"10.2139/ssrn.3762193","DOIUrl":"https://doi.org/10.2139/ssrn.3762193","url":null,"abstract":"Stem cells demonstrate considerable promise for various preclinical and clinical applications, including drug screening, disease treatments, and regenerative medicine. Producing high-quality and large amounts of stem cells is in demand for these applications. Despite challenges, as hydrogel-based cell culture technology has developed, tremendous progress has been made in stem cell expansion and directed differentiation. Hydrogels are soft materials with abundant water. Many hydrogel properties, including biodegradability, mechanical strength, and porosity, have been shown to play essential roles in regulating stem cell proliferation and differentiation. The biochemical and physical properties of hydrogels can be specifically tailored to mimic the native microenvironment that various stem cells reside in vivo. A few hydrogel-based systems have been developed for successful stem cell cultures and expansion in vitro. In this review, we summarize various types of hydrogels that have been designed to effectively enhance the proliferation of hematopoietic stem cells (HSCs), mesenchymal stem/stromal cells (MSCs), and pluripotent stem cells (PSCs), respectively. According to each stem cell type's preference, we also discuss strategies for fabricating hydrogels with biochemical and mechanical cues and other characteristics representing microenvironments of stem cells in vivo. STATEMENT OF SIGNIFICANCE: In this review article we summary current progress on the construction of hydrogel systems for the culture and expansion of various stem cells, including hematopoietic stem cells (HSCs), mesenchymal stem/stromal cells (MSCs), and pluripotent stem cells (PSCs). The Significance includes: (1) Provide detailed discussion on the stem cell niches that should be considered for stem cell in vitro expansion. (2) Summarize various strategies to construct hydrogels that can largely recapture the microenvironment of native stem cells. (3) Suggest a few future directions that can be implemented to improve current in vitro stem cell expansion systems.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126085469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The lymphatic system plays an integral part in regulating immune cells trafficking and the transport of macromolecules. However, its influence on disease progression and drug uptake is understood less than the vascular system. To bridge the knowledge gap, biomaterials can be used to investigate the lymphatic system and to provide novel understanding into complex disease states, including cancer metastasis and inflammatory diseases. Insight gained from these mechanistic studies, can be further used to design innovative biomaterials to modulate the immune system, improve drug delivery, and promote tissue regeneration. This review article focuses on recent progresses in (i) biomaterials used for lymphatic vessel formation, (ii) lymphatic models for studying lymphatic-immune cells interactions, (iii) pharmaceuticals and their interactions with the lymphatic system, (iv) drug screening, and (v) disease prediction. Finally, a number of challenges in adopting biomaterials for immunomodulation and future perspectives are discussed.
{"title":"Harnessing Biomaterials and the Lymphatic System for Immunomodulation","authors":"Laura Alderfer, Eva Hall, Donny Hanjaya-Putra","doi":"10.2139/ssrn.3751564","DOIUrl":"https://doi.org/10.2139/ssrn.3751564","url":null,"abstract":"The lymphatic system plays an integral part in regulating immune cells trafficking and the transport of macromolecules. However, its influence on disease progression and drug uptake is understood less than the vascular system. To bridge the knowledge gap, biomaterials can be used to investigate the lymphatic system and to provide novel understanding into complex disease states, including cancer metastasis and inflammatory diseases. Insight gained from these mechanistic studies, can be further used to design innovative biomaterials to modulate the immune system, improve drug delivery, and promote tissue regeneration. This review article focuses on recent progresses in (i) biomaterials used for lymphatic vessel formation, (ii) lymphatic models for studying lymphatic-immune cells interactions, (iii) pharmaceuticals and their interactions with the lymphatic system, (iv) drug screening, and (v) disease prediction. Finally, a number of challenges in adopting biomaterials for immunomodulation and future perspectives are discussed.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131836523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diana Silva, Hermínio C. de Sousa, Maria Helena Gil, Luís F. Santos, R. Amaral, Jorge A. Saraiva, M. Oom, C. Alvarez‐Lorenzo, A. P. Serro, B. Saramago
A combined strategy to control the release of two drugs, one anti-inflammatory (diclofenac sodium, DCF) and one antibiotic (moxifloxacin hydrochloride, MXF), from a soft contact lens (SCL) material, was assessed. The material was a silicone-based hydrogel, which was modified by molecular imprinting with MXF and coated by the layer-by-layer (LbL) method using natural polyelectrolytes: alginate (ALG), poly-l-lysine (PLL) and hyaluronate (HA), crosslinked with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC). Imprinting was used to increase the amount of MXF loaded and to sustain its release, while the LbL coating acted as a diffusion barrier for DCF and improved the surface properties. The drugs were loaded by soaking in a DCF + MXF dual solution. High hydrostatic pressure (HHP) was successfully applied in the sterilization of the drug-loaded hydrogels. The transmittance, refractive index, wettability and ionic permeability of the hydrogels remained within the required levels for SCLs application. The concentrations of the released DCF and MXF stayed above the IC50 and the MIC (for S. aureus and S. epidermidis) values, for 9 and 10 days, respectively. No ocular irritancy was detected by the HET-CAM test. NIH/3T3 cell viability demonstrated that the drug-loaded hydrogels were not toxic, and cell adhesion was reduced.
{"title":"Imprinted Hydrogels with LbL Coating for Dual Drug Release from Soft Contact Lenses Materials","authors":"Diana Silva, Hermínio C. de Sousa, Maria Helena Gil, Luís F. Santos, R. Amaral, Jorge A. Saraiva, M. Oom, C. Alvarez‐Lorenzo, A. P. Serro, B. Saramago","doi":"10.2139/ssrn.3606830","DOIUrl":"https://doi.org/10.2139/ssrn.3606830","url":null,"abstract":"A combined strategy to control the release of two drugs, one anti-inflammatory (diclofenac sodium, DCF) and one antibiotic (moxifloxacin hydrochloride, MXF), from a soft contact lens (SCL) material, was assessed. The material was a silicone-based hydrogel, which was modified by molecular imprinting with MXF and coated by the layer-by-layer (LbL) method using natural polyelectrolytes: alginate (ALG), poly-l-lysine (PLL) and hyaluronate (HA), crosslinked with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC). Imprinting was used to increase the amount of MXF loaded and to sustain its release, while the LbL coating acted as a diffusion barrier for DCF and improved the surface properties. The drugs were loaded by soaking in a DCF + MXF dual solution. High hydrostatic pressure (HHP) was successfully applied in the sterilization of the drug-loaded hydrogels. The transmittance, refractive index, wettability and ionic permeability of the hydrogels remained within the required levels for SCLs application. The concentrations of the released DCF and MXF stayed above the IC50 and the MIC (for S. aureus and S. epidermidis) values, for 9 and 10 days, respectively. No ocular irritancy was detected by the HET-CAM test. NIH/3T3 cell viability demonstrated that the drug-loaded hydrogels were not toxic, and cell adhesion was reduced.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122736485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In view of the fact that titanium (Ti)-based implants still face the problem of loosening and failure of the implants caused by the slow biological response, the low osseointegration rate and the implant bacterial infection in clinical application, we designed a cancellous bone-like biomimetic Ti scaffold via using the template accumulated by sugar spheres as pore-forming agent. And based on a modified surface mineralization process and mussel-like adhesion mechanism, a silicon-doped calcium phosphate composite coating (Van-pBNPs/pep@pSiCaP) with Vancomycin (Van)-loaded polydopamine (pDA)-modified albumin nanoparticles (Van-pBNPs) and cell adhesion peptides (GFOGER) was constructed on the surface of Ti scaffold for mimicking the extracellular matrix (ECM) microenvironment of natural bone matrix to induce greater tissue regeneration. The in vitro study demonstrated that this porous Ti scaffold with functional bio-surface could distinctly facilitate cell early adhesion and spreading, and activate the expression of α2β1 integrin receptor on the cell membrane through promoting the formation of focal adhesions (FAs) in bone marrow stromal cells (BMSCs), thus mediating greater osteogenic cell differentiation. And it could also effectively inhibit the adhesion and growth of Staphylococcus epidermidis, exhibiting excellent antibacterial properties. Moreover, the Van-pBNPs/pep@pSiCaP-Ti scaffolds showed enhanced in vivo bone-forming ability due to the contributions of bioactive chemical components and the natural cancellous bone-like macrostructure. This work offers a promising structural and functional bio-inspired strategy for designing metal implants with desirable ability of osteoinduction synergistically with antibacterial efficacy for promoting bone regeneration and infection prevention simultaneously.
{"title":"Bifunctional Bio-Surface Decorated Bone-Grafting Titanium Material with Cancellous Bone-Like Biomimetic Structure for Enhanced Bone Tissue Regeneration","authors":"Bingjun Zhang, J. Li, Lei He, Hao Huang, J. Weng","doi":"10.2139/ssrn.3577287","DOIUrl":"https://doi.org/10.2139/ssrn.3577287","url":null,"abstract":"In view of the fact that titanium (Ti)-based implants still face the problem of loosening and failure of the implants caused by the slow biological response, the low osseointegration rate and the implant bacterial infection in clinical application, we designed a cancellous bone-like biomimetic Ti scaffold via using the template accumulated by sugar spheres as pore-forming agent. And based on a modified surface mineralization process and mussel-like adhesion mechanism, a silicon-doped calcium phosphate composite coating (Van-pBNPs/pep@pSiCaP) with Vancomycin (Van)-loaded polydopamine (pDA)-modified albumin nanoparticles (Van-pBNPs) and cell adhesion peptides (GFOGER) was constructed on the surface of Ti scaffold for mimicking the extracellular matrix (ECM) microenvironment of natural bone matrix to induce greater tissue regeneration. The in vitro study demonstrated that this porous Ti scaffold with functional bio-surface could distinctly facilitate cell early adhesion and spreading, and activate the expression of α2β1 integrin receptor on the cell membrane through promoting the formation of focal adhesions (FAs) in bone marrow stromal cells (BMSCs), thus mediating greater osteogenic cell differentiation. And it could also effectively inhibit the adhesion and growth of Staphylococcus epidermidis, exhibiting excellent antibacterial properties. Moreover, the Van-pBNPs/pep@pSiCaP-Ti scaffolds showed enhanced in vivo bone-forming ability due to the contributions of bioactive chemical components and the natural cancellous bone-like macrostructure. This work offers a promising structural and functional bio-inspired strategy for designing metal implants with desirable ability of osteoinduction synergistically with antibacterial efficacy for promoting bone regeneration and infection prevention simultaneously.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123894380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L. Vong, Yuna Sato, Pennapa Chonpathompikunlert, Supita Tanasawet, P. Hutamekalin, Y. Nagasaki
Although Levodopa (L-DOPA), a dopamine precursor, exhibits a high risk of dyskinesia, it remains the primary treatment in Parkinson's disease (PD), a progressive neurodegenerative disorder. In this study, we designed poly(L-DOPA)-based self-assembled nanodrug (NanoDOPA) from amphiphilic block copolymer possessing poly(L-DOPA(OAc)2), which is a precursor of L-DOPA as a hydrophobic segment, for treatment in a PD model mouse. Under physiological enzyme treatment, the poly(L-DOPA(OAc)2) in the block copolymer was hydrolyzed to liberate L-DOPA gradually. Using the MPTP-induced PD mouse model, we observed that mice treated with NanoDOPA demonstrated a significant improvement of PD symptoms compared to the L-DOPA treatment. Interestingly, the NanoDOPA treatment did not cause the dyskinesia symptoms, which was clearly observed in the L-DOPA-treated mice. Furthermore, NanoDOPA exhibited remarkably lower toxicity in vitro compared to L-DOPA, in addition with no noticeable NanoDOPA toxicity observed in the treated mice. These results suggested that self-assembled NanoDOPA is a promising therapeutic in the treatment of PD. Statement of significance In this study, we proposed a therapeutic approach for the effective treatment of Parkinson disease (PD) using newly designed poly(L-DOPA)-based self-assembled nanodrug (NanoDOPA) prepared from amphiphilic block copolymers possessing poly(L-DOPA(OAc)2), which is a precursor of L-DOPA as a hydrophobic segment, for treatment in a PD model mouse. Under physiological enzyme treatments, NanoDOPA was hydrolyzed to liberate L-DOPA gradually, improving the pharmacokinetic value of L-DOPA. The mice treated with NanoDOPA significantly improved PD symptoms compared to the L-DOPA treatment in a neurotoxin-induced PD mouse model. Interestingly, NanoDOPA treatment did not cause dyskinesia symptoms, which was observed in the L-DOPA-treated mice. The obtained results in this study suggested that self-assembly NanoDOPA is a promising therapeutic in the treatment of PD.
{"title":"Self-Assembled Polydopamine Nanoparticles Improve Treatment in Parkinson's Disease Model Mice and Suppress Dopamine-Induced Dyskinesia","authors":"L. Vong, Yuna Sato, Pennapa Chonpathompikunlert, Supita Tanasawet, P. Hutamekalin, Y. Nagasaki","doi":"10.2139/ssrn.3539216","DOIUrl":"https://doi.org/10.2139/ssrn.3539216","url":null,"abstract":"Although Levodopa (L-DOPA), a dopamine precursor, exhibits a high risk of dyskinesia, it remains the primary treatment in Parkinson's disease (PD), a progressive neurodegenerative disorder. In this study, we designed poly(L-DOPA)-based self-assembled nanodrug (NanoDOPA) from amphiphilic block copolymer possessing poly(L-DOPA(OAc)2), which is a precursor of L-DOPA as a hydrophobic segment, for treatment in a PD model mouse. Under physiological enzyme treatment, the poly(L-DOPA(OAc)2) in the block copolymer was hydrolyzed to liberate L-DOPA gradually. Using the MPTP-induced PD mouse model, we observed that mice treated with NanoDOPA demonstrated a significant improvement of PD symptoms compared to the L-DOPA treatment. Interestingly, the NanoDOPA treatment did not cause the dyskinesia symptoms, which was clearly observed in the L-DOPA-treated mice. Furthermore, NanoDOPA exhibited remarkably lower toxicity in vitro compared to L-DOPA, in addition with no noticeable NanoDOPA toxicity observed in the treated mice. These results suggested that self-assembled NanoDOPA is a promising therapeutic in the treatment of PD. Statement of significance In this study, we proposed a therapeutic approach for the effective treatment of Parkinson disease (PD) using newly designed poly(L-DOPA)-based self-assembled nanodrug (NanoDOPA) prepared from amphiphilic block copolymers possessing poly(L-DOPA(OAc)2), which is a precursor of L-DOPA as a hydrophobic segment, for treatment in a PD model mouse. Under physiological enzyme treatments, NanoDOPA was hydrolyzed to liberate L-DOPA gradually, improving the pharmacokinetic value of L-DOPA. The mice treated with NanoDOPA significantly improved PD symptoms compared to the L-DOPA treatment in a neurotoxin-induced PD mouse model. Interestingly, NanoDOPA treatment did not cause dyskinesia symptoms, which was observed in the L-DOPA-treated mice. The obtained results in this study suggested that self-assembly NanoDOPA is a promising therapeutic in the treatment of PD.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129224660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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