Dong Wang, Wenzhen Liu, Le Wang, Yu Wang, C. Liao, Jincan Chen, Ping Hu, W. Hong, Mingdong Huang, Zhuo Chen, Peng Xu
Cancer therapeutics are varied and target diverse processes in cancer progression. Photodynamic therapy (PDT), photothermal therapy (PTT), and the inhibition of pro-cancer proteases are novel non-invasive anticancer therapeutics that attract increasing attentions for their enhanced specificities and milder systemic toxicities compared to traditional therapeutics (surgery, radio- or chemo-therapies). These modalities offer advantages to compensate for the shortcomings of their counterparts. For instance, PDT or PTT efficiently eliminates locally confined tumor cells while exhibiting no effect on metastatic tumor cells. In contrast, the inhibition of pro-cancer proteases systemically suppresses the proliferation and metastasis of cancer cells but does not eradicate existing cancer cells. To synergize these therapeutics, we hereby report a versatile nanoparticle that integrates the anticancer effects of PDT, PTT, and enzyme-inhibition. This nanoparticle (CIKP-NP) was synthesized by covalently or non-covalently modifying a photothermal nanoparticle with a photosensitizer, a pro-cancer protease inhibitor, and an albumin-binding molecule. After confirming that CIKP-NP encompasses the properties of PDT, PTT, albumin-binding, and enzyme-inhibition at the molecular level, we evaluated the anti-tumor and anti-metastatic effects of CIKP-NP at the cellular level. In addition, through a human breast cancer xenograft mouse model, we demonstrated that CIKP-NP suppressed tumor growth by PDT or PTT effect. Notably, the synergism of PDT and PTT significantly enhanced its anticancer effect. Furthermore, CIKP-NP significantly suppressed cancer metastasis in a lung metastatic mouse model. Beyond demonstrating the anti-tumor and anti-metastatic efficacy of CIKP-NP, our study also suggests a new strategy to synergize multiple anticancer therapeutics.
{"title":"Suppression of Cancer Proliferation and Metastasis by a Versatile Nanomedicine Integrating Multiple Therapeutic Mechanisms","authors":"Dong Wang, Wenzhen Liu, Le Wang, Yu Wang, C. Liao, Jincan Chen, Ping Hu, W. Hong, Mingdong Huang, Zhuo Chen, Peng Xu","doi":"10.2139/ssrn.3531318","DOIUrl":"https://doi.org/10.2139/ssrn.3531318","url":null,"abstract":"Cancer therapeutics are varied and target diverse processes in cancer progression. Photodynamic therapy (PDT), photothermal therapy (PTT), and the inhibition of pro-cancer proteases are novel non-invasive anticancer therapeutics that attract increasing attentions for their enhanced specificities and milder systemic toxicities compared to traditional therapeutics (surgery, radio- or chemo-therapies). These modalities offer advantages to compensate for the shortcomings of their counterparts. For instance, PDT or PTT efficiently eliminates locally confined tumor cells while exhibiting no effect on metastatic tumor cells. In contrast, the inhibition of pro-cancer proteases systemically suppresses the proliferation and metastasis of cancer cells but does not eradicate existing cancer cells. To synergize these therapeutics, we hereby report a versatile nanoparticle that integrates the anticancer effects of PDT, PTT, and enzyme-inhibition. This nanoparticle (CIKP-NP) was synthesized by covalently or non-covalently modifying a photothermal nanoparticle with a photosensitizer, a pro-cancer protease inhibitor, and an albumin-binding molecule. After confirming that CIKP-NP encompasses the properties of PDT, PTT, albumin-binding, and enzyme-inhibition at the molecular level, we evaluated the anti-tumor and anti-metastatic effects of CIKP-NP at the cellular level. In addition, through a human breast cancer xenograft mouse model, we demonstrated that CIKP-NP suppressed tumor growth by PDT or PTT effect. Notably, the synergism of PDT and PTT significantly enhanced its anticancer effect. Furthermore, CIKP-NP significantly suppressed cancer metastasis in a lung metastatic mouse model. Beyond demonstrating the anti-tumor and anti-metastatic efficacy of CIKP-NP, our study also suggests a new strategy to synergize multiple anticancer therapeutics.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125553085","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}
Xiaowei Zhou, Yitian Gao, Yuanxing Wang, Q. Xia, Ruimin Zhong, Yue Liu, Chengbang Ma, Mei Zhou, Xinping Xi, Chris Shaw, Di Wu, Tianbao Chen, Lei Wang, H. Kwok
Antimicrobial peptides (AMPs) are promising therapeutic alternatives to conventional antibiotics for the treatment of drug-resistant bacterial infections. However, the application of AMPs is limited because of moderate antimicrobial activity, high toxicity and high manufacturing costs. Conformation, net charge and amphipathicity are considered key factors in AMPs. In order to generate short AMPs with enhanced therapeutic efficacy, six peptides were designed based on the active motifs of natural AMPs followed by evaluating their biological activity, stability and cytotoxicity. Brevinin-OSd, OSe and OSf exhibited broad-spectrum antibacterial effects, especially OSf, which presented the highest therapeutic index for the tested bacteria. Also, these peptides displayed good stability. The results from CLSM, SEM and TEM studies, indicated that brevinin-OS, OSd, OSe and OSf possessed rapid bactericidal ability by disturbing membrane permeability and causing release of cytoplasm. In addition, OSd, OSe and OSf dramatically decreased the mortality of MRSA acutely-infected waxworms. Taken together, these data suggested that a balance between positive charge, degrees of α-helicity and hydrophobicity, is necessary for maintaining antimicrobial activity, and these data successfully contributed to the design of short AMPs with significant bactericidal activity and cell selectivity.
{"title":"Rational Design of Novel Brevinin Analogues with Broad Antimicrobial Spectrum and Less Cytotoxicity","authors":"Xiaowei Zhou, Yitian Gao, Yuanxing Wang, Q. Xia, Ruimin Zhong, Yue Liu, Chengbang Ma, Mei Zhou, Xinping Xi, Chris Shaw, Di Wu, Tianbao Chen, Lei Wang, H. Kwok","doi":"10.2139/ssrn.3507481","DOIUrl":"https://doi.org/10.2139/ssrn.3507481","url":null,"abstract":"Antimicrobial peptides (AMPs) are promising therapeutic alternatives to conventional antibiotics for the treatment of drug-resistant bacterial infections. However, the application of AMPs is limited because of moderate antimicrobial activity, high toxicity and high manufacturing costs. Conformation, net charge and amphipathicity are considered key factors in AMPs. In order to generate short AMPs with enhanced therapeutic efficacy, six peptides were designed based on the active motifs of natural AMPs followed by evaluating their biological activity, stability and cytotoxicity. Brevinin-OSd, OSe and OSf exhibited broad-spectrum antibacterial effects, especially OSf, which presented the highest therapeutic index for the tested bacteria. Also, these peptides displayed good stability. The results from CLSM, SEM and TEM studies, indicated that brevinin-OS, OSd, OSe and OSf possessed rapid bactericidal ability by disturbing membrane permeability and causing release of cytoplasm. In addition, OSd, OSe and OSf dramatically decreased the mortality of MRSA acutely-infected waxworms. Taken together, these data suggested that a balance between positive charge, degrees of α-helicity and hydrophobicity, is necessary for maintaining antimicrobial activity, and these data successfully contributed to the design of short AMPs with significant bactericidal activity and cell selectivity.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133692821","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}
Ya-nan Wang, T. Jia, Yao Feng, Shiyue Liu, Wenjing Zhang, Dongjiao Zhang, Xin Xu
The influence of hyperlipidemia on titanium implant osseointegration and the underlying mechanisms remain elusive. Here, we studied the effects of hyperlipidemia on osseointegration and the related mechanisms. In vivo, specialized titanium implants were implanted in the femurs of diet-induced or genetic hyperlipidemia mice. In vitro, primary murine osteoblasts were cultured on titanium surface. Results showed that hyperlipidemia led to poor bone formation on bone-implant interface in two types of mice in vivo. In vitro, high-fat medium caused significant overproduction of reactive oxygen species (ROS) and inhibiting of Wnt/β-catenin pathway in osteoblasts on titanium surface, inducing obvious cell dysfunction. Both N-acetyl-L-cysteine(NAC, a ROS antagonist) and Wnt3a(an activator of Wnt/β-catenin pathway) could effectively attenuated the poor osteogenic ability of osteoblasts. Besides, NAC reactivated the Wnt/β-catenin pathway in osteoblasts under high-fat stimulation. Our results suggested that the cellular oxidative stress leads to osteoblasts dysfunction via the Wnt/β-catenin pathway, which plays a critical role in the compromised implant osseointegration under hyperlipidemia conditions. These results demonstrated new insights into the negative effect of hyperlipidemia on osseointegration and also provided ROS or Wnt/β-catenin pathway as promising therapeutic targets for developing novel implant materials to accelerate the osseointegration of implants in hyperlipidemia patients.
{"title":"Osteogenesis Impairment by Oxidative Stress Via Wnt/β-Catenin Pathway at the Bone-Implant Interface: Critical Mechanisms and Potential Therapeutic Targets for Poor Osseointegration Under Hyperlipidemia Conditions","authors":"Ya-nan Wang, T. Jia, Yao Feng, Shiyue Liu, Wenjing Zhang, Dongjiao Zhang, Xin Xu","doi":"10.2139/ssrn.3677520","DOIUrl":"https://doi.org/10.2139/ssrn.3677520","url":null,"abstract":"The influence of hyperlipidemia on titanium implant osseointegration and the underlying mechanisms remain elusive. Here, we studied the effects of hyperlipidemia on osseointegration and the related mechanisms. In vivo, specialized titanium implants were implanted in the femurs of diet-induced or genetic hyperlipidemia mice. In vitro, primary murine osteoblasts were cultured on titanium surface. Results showed that hyperlipidemia led to poor bone formation on bone-implant interface in two types of mice in vivo. In vitro, high-fat medium caused significant overproduction of reactive oxygen species (ROS) and inhibiting of Wnt/β-catenin pathway in osteoblasts on titanium surface, inducing obvious cell dysfunction. Both N-acetyl-L-cysteine(NAC, a ROS antagonist) and Wnt3a(an activator of Wnt/β-catenin pathway) could effectively attenuated the poor osteogenic ability of osteoblasts. Besides, NAC reactivated the Wnt/β-catenin pathway in osteoblasts under high-fat stimulation. Our results suggested that the cellular oxidative stress leads to osteoblasts dysfunction via the Wnt/β-catenin pathway, which plays a critical role in the compromised implant osseointegration under hyperlipidemia conditions. These results demonstrated new insights into the negative effect of hyperlipidemia on osseointegration and also provided ROS or Wnt/β-catenin pathway as promising therapeutic targets for developing novel implant materials to accelerate the osseointegration of implants in hyperlipidemia patients.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133683412","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}
Hanan Moussa, MSc, Wenge Jiang, Ammar A. Alsheghri, A. Mansour, A. E. Hadad, H. Pan, R. Tang, Jun Song, J. Vargas, M. McKee, F. Tamimi
In biomineralization, biological molecules guide the formation and organization of inorganic crystals to construct materials that have exceptional mechanical properties. In Nature, these biomolecules are homochiral, composed exclusively of L-amino acids. Here, we show that chiral tartaric acid can improve the mechanical properties of a calcium-phosphate bioceramic by regulating its crystal structure. The mechanical properties of brushite bioceramic were improved by the addition of L-(+)-tartaric acid, which decreased crystal size, with this relationship following the classic Hall-Petch strengthening effect; D-(-)-tartaric acid had the opposite effect. Characterization of brushite crystals from the macro- to the atomic-level revealed that this regulation is attributable to a stereochemical matching between L-(+)-tartaric acid and chiral steps of brushite crystals, which results in inhibition of brushite crystallization. These findings provide insight into understanding the role of chiral L-biomolecules in biomineralization, and how bioceramics can be fabricated with a controlled crystallographic structure that defines high-performance mechanical properties.
{"title":"High Strength Brushite Bioceramics by Selective Regulation with Chiral Biomolecules","authors":"Hanan Moussa, MSc, Wenge Jiang, Ammar A. Alsheghri, A. Mansour, A. E. Hadad, H. Pan, R. Tang, Jun Song, J. Vargas, M. McKee, F. Tamimi","doi":"10.2139/ssrn.3455086","DOIUrl":"https://doi.org/10.2139/ssrn.3455086","url":null,"abstract":"In biomineralization, biological molecules guide the formation and organization of inorganic crystals to construct materials that have exceptional mechanical properties. In Nature, these biomolecules are homochiral, composed exclusively of L-amino acids. Here, we show that chiral tartaric acid can improve the mechanical properties of a calcium-phosphate bioceramic by regulating its crystal structure. The mechanical properties of brushite bioceramic were improved by the addition of L-(+)-tartaric acid, which decreased crystal size, with this relationship following the classic Hall-Petch strengthening effect; D-(-)-tartaric acid had the opposite effect. Characterization of brushite crystals from the macro- to the atomic-level revealed that this regulation is attributable to a stereochemical matching between L-(+)-tartaric acid and chiral steps of brushite crystals, which results in inhibition of brushite crystallization. These findings provide insight into understanding the role of chiral L-biomolecules in biomineralization, and how bioceramics can be fabricated with a controlled crystallographic structure that defines high-performance mechanical properties.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131652345","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}
Recent findings suggest that the cellular and extracellular materials surrounding the cancerous cells from an atypical tumor microenvironment (TM) plays a pivotal role in the process of tumor initiation and progression. It comprises an intricate system involving diverse cell types embracing endothelial cells, pericytes, smooth muscle cells, fibroblasts, various inflammatory cells, dendritic cells, and cancer stem cells (CSCs). The TM forming cells dynamically interacts with the cancerous cells via various signaling mechanisms and pathways. The existence of this dynamic cellular communication is responsible for creating an environment which is suitable for sustaining a reasonably high cellular proliferation. Nowadays, researchers are paying interest to utilize these TM conditions to mediate effective targeting measures for cancer therapy. The use of Nanotherapeutics-based combination therapy, stimuli-responsive nanotherapeutics targeting acidic pH, hypoxic environment, and nanoparticles induced hyperthermia are some of the upright approaches which are under vibrant exploration for cancer therapy. This review discusses TM and its role in cancer progression; and cross-talk understanding, opportunities and epigenetic modifications involved therein to materialize the capability of Nanotherapeutics to target cancer by availing TM.
{"title":"A Cross-Talk on Tumor Microenvironment Targeted Nanotherapeutics for Cancer Therapy and Diagnosis","authors":"S. Thakkar, D. Sharma, K. Kalia, R. Tekade","doi":"10.2139/ssrn.3396277","DOIUrl":"https://doi.org/10.2139/ssrn.3396277","url":null,"abstract":"Recent findings suggest that the cellular and extracellular materials surrounding the cancerous cells from an atypical tumor microenvironment (TM) plays a pivotal role in the process of tumor initiation and progression. It comprises an intricate system involving diverse cell types embracing endothelial cells, pericytes, smooth muscle cells, fibroblasts, various inflammatory cells, dendritic cells, and cancer stem cells (CSCs). The TM forming cells dynamically interacts with the cancerous cells via various signaling mechanisms and pathways. The existence of this dynamic cellular communication is responsible for creating an environment which is suitable for sustaining a reasonably high cellular proliferation. Nowadays, researchers are paying interest to utilize these TM conditions to mediate effective targeting measures for cancer therapy. The use of Nanotherapeutics-based combination therapy, stimuli-responsive nanotherapeutics targeting acidic pH, hypoxic environment, and nanoparticles induced hyperthermia are some of the upright approaches which are under vibrant exploration for cancer therapy. This review discusses TM and its role in cancer progression; and cross-talk understanding, opportunities and epigenetic modifications involved therein to materialize the capability of Nanotherapeutics to target cancer by availing TM.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121995260","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}
O. Syed, Joong-Hyun Kim, Z. Erdogan, Richard M. Day, A. El-Fiqi, H. Kim, Jonathan C. Knowles
With donor organs not readily available, the need for a tissue-engineered oesophagus remains high, particularly for congenital childhood conditions such as atresia. Previous attempts have not been successful, and challenges remain. Small intestine submucosa (SIS) is an acellular matrix material with good biological properties; however, as is common with these types of materials, they demonstrate poor mechanical properties. In this work, electrospinning was performed to mechanically reinforce tubular SIS with polylactic-co-glycolic acid (PLGA) nanofibers. It was hypothesised that if attachment could be achieved between the two materials, then this would (i) improve the SIS mechanical properties, (ii) facilitate smooth muscle cell alignment to support directional growth of muscle cells and (iii) allow for the delivery of bioactive molecules (VEGF in this instance). Through a relatively simple multistage process, adhesion between the layers was achieved without chemically altering the SIS. It was also found that altering mandrel rotation speed affected the alignment of the PLGA nanofibers. SIS-PLGA scaffolds performed mechanically better than SIS alone; yield stress improvement was 200% and 400% along the longitudinal and circumferential directions, respectively. Smooth muscle cells cultured on the aligned fibres showed resultant unidirectional alignment. In vivo the SIS-PLGA scaffolds demonstrated limited foreign body reaction judged by the type and proportion of immune cells present and lack of fibrous encapsulation. The scaffolds remained intact at 4 weeks in vivo, and good cellular infiltration was observed. The incorporation of VEGF within SIS-PLGA scaffolds increased the blood vessel density of the surrounding tissues, highlighting the possible stimulation of endothelialisation by angiogenic factor delivery. Overall, the designed SIS-PLGA-VEGF hybrid scaffolds might be used as a potential matrix platform for oesophageal tissue engineering. In addition to this, achieving improved attachment between layers of acellular matrix materials and electrospun fibre layers offers the potential utility in other applications. STATEMENT OF SIGNIFICANCE: Because of its multi-layered nature and complex structure, the oesophagus tissue poses several challenges for successful clinical grafting. Therefore, it is promising to utilise tissue engineering strategies to mimic and form structural compartments for its recovery. In this context, we investigated the use of tubular small intestine submucosa (SIS) reinforced with polylactic-co-glycolic acid (PLGA) nanofibres by using electrospinning and also, amongst other parameters, the integrity of the bilayered structure created. This was carried out to facilitate smooth muscle cell alignment, support directional growth of muscle cells and allow the delivery of bioactive molecules (VEGF in this study). We evaluated this approach by using in vitro and in vivo models to determine the efficacy of this new system.
{"title":"SIS/Aligned Fibre Scaffold Designed to Meet Layered Oesophageal Tissue Complexity and Properties","authors":"O. Syed, Joong-Hyun Kim, Z. Erdogan, Richard M. Day, A. El-Fiqi, H. Kim, Jonathan C. Knowles","doi":"10.2139/ssrn.3385802","DOIUrl":"https://doi.org/10.2139/ssrn.3385802","url":null,"abstract":"With donor organs not readily available, the need for a tissue-engineered oesophagus remains high, particularly for congenital childhood conditions such as atresia. Previous attempts have not been successful, and challenges remain. Small intestine submucosa (SIS) is an acellular matrix material with good biological properties; however, as is common with these types of materials, they demonstrate poor mechanical properties. In this work, electrospinning was performed to mechanically reinforce tubular SIS with polylactic-co-glycolic acid (PLGA) nanofibers. It was hypothesised that if attachment could be achieved between the two materials, then this would (i) improve the SIS mechanical properties, (ii) facilitate smooth muscle cell alignment to support directional growth of muscle cells and (iii) allow for the delivery of bioactive molecules (VEGF in this instance). Through a relatively simple multistage process, adhesion between the layers was achieved without chemically altering the SIS. It was also found that altering mandrel rotation speed affected the alignment of the PLGA nanofibers. SIS-PLGA scaffolds performed mechanically better than SIS alone; yield stress improvement was 200% and 400% along the longitudinal and circumferential directions, respectively. Smooth muscle cells cultured on the aligned fibres showed resultant unidirectional alignment. In vivo the SIS-PLGA scaffolds demonstrated limited foreign body reaction judged by the type and proportion of immune cells present and lack of fibrous encapsulation. The scaffolds remained intact at 4 weeks in vivo, and good cellular infiltration was observed. The incorporation of VEGF within SIS-PLGA scaffolds increased the blood vessel density of the surrounding tissues, highlighting the possible stimulation of endothelialisation by angiogenic factor delivery. Overall, the designed SIS-PLGA-VEGF hybrid scaffolds might be used as a potential matrix platform for oesophageal tissue engineering. In addition to this, achieving improved attachment between layers of acellular matrix materials and electrospun fibre layers offers the potential utility in other applications. STATEMENT OF SIGNIFICANCE: Because of its multi-layered nature and complex structure, the oesophagus tissue poses several challenges for successful clinical grafting. Therefore, it is promising to utilise tissue engineering strategies to mimic and form structural compartments for its recovery. In this context, we investigated the use of tubular small intestine submucosa (SIS) reinforced with polylactic-co-glycolic acid (PLGA) nanofibres by using electrospinning and also, amongst other parameters, the integrity of the bilayered structure created. This was carried out to facilitate smooth muscle cell alignment, support directional growth of muscle cells and allow the delivery of bioactive molecules (VEGF in this study). We evaluated this approach by using in vitro and in vivo models to determine the efficacy of this new system.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122580180","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}
Chaoqi Xie, Qing Gao, Peng Wang, Lei Shao, Huipu Yuan, Jianzhong Fu, Wei Chen, Yong He
As a fundamental issue, cell-scaffold interaction has drawn increased attention in tissue engineering. The ability of tendril-climbers to perceive position and climb up toward the trellis in an ingenious manner induces interest. Thus, the question arises whether the cell can also grow as ingenious as the plant. Prompted by the climbing mechanism of tendril climbers, we proposed a novel method for inducing cell growth by using specially designed scaffolds with heterogeneous structures. A high-resolution 3D printing method via melt direct writing for fabricating these scaffolds was developed. By melting biodegradable polymers in the nozzle and high-voltage attraction, scaffolds with fiber diameters measuring 3μm can be printed layer by layer. Heterogeneous structures, such as various fiber diameters and pore sizes, can be freely printed in one scaffold at the different locations by adjusting correlated parameters. Owing to these properties of the scaffold, interesting phenomena of cell growth were observed. Human umbilical vein endothelial cells (HUVECs) exhibited different growth rates on the scaffold with different pore sizes. And bone marrow stem cell (BMSCs) showed several morphological characteristics on the scaffold consisting of fibers with specific diameters. Therefore, we can regulate and control cell growth to different status in one scaffold by merely designing structures. This study generally provides a structure-induced cell growth strategy for better simulating in-vivo like environment.
{"title":"Tendril Climber Inspired Structure-Induced Cell Growth by Direct Writing Heterogeneous Scaffold","authors":"Chaoqi Xie, Qing Gao, Peng Wang, Lei Shao, Huipu Yuan, Jianzhong Fu, Wei Chen, Yong He","doi":"10.2139/ssrn.3321957","DOIUrl":"https://doi.org/10.2139/ssrn.3321957","url":null,"abstract":"As a fundamental issue, cell-scaffold interaction has drawn increased attention in tissue engineering. The ability of tendril-climbers to perceive position and climb up toward the trellis in an ingenious manner induces interest. Thus, the question arises whether the cell can also grow as ingenious as the plant. Prompted by the climbing mechanism of tendril climbers, we proposed a novel method for inducing cell growth by using specially designed scaffolds with heterogeneous structures. A high-resolution 3D printing method via melt direct writing for fabricating these scaffolds was developed. By melting biodegradable polymers in the nozzle and high-voltage attraction, scaffolds with fiber diameters measuring 3μm can be printed layer by layer. Heterogeneous structures, such as various fiber diameters and pore sizes, can be freely printed in one scaffold at the different locations by adjusting correlated parameters. Owing to these properties of the scaffold, interesting phenomena of cell growth were observed. Human umbilical vein endothelial cells (HUVECs) exhibited different growth rates on the scaffold with different pore sizes. And bone marrow stem cell (BMSCs) showed several morphological characteristics on the scaffold consisting of fibers with specific diameters. Therefore, we can regulate and control cell growth to different status in one scaffold by merely designing structures. This study generally provides a structure-induced cell growth strategy for better simulating in-vivo like environment.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115532580","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}
Reid L Wilson, Ganesh Swaminathan, K. Ettayebi, Carolyn Bomidi, Xi-Lei Zeng, S. Blutt, M. Estes, K. J. Grande-Allen
The recent development of stem cell-derived, organotypic in vitro models, known as organoids, has revolutionized our ability to study important biological processes in vitro. However, their continued development is limited by the failure of the hydrogel matrices in which they are grown to adequately replicate the tissue-specific ECM cues they experience in their native in vivo environment. Here, we present a highly customizable, modular hydrogel scaffold that can incorporate tissue-specific cues from the extracellular matrix. We demonstrate that these scaffolds can be functionalized with a wide variety of cell adhesion molecules, including peptides and full-length proteins, and can support the attachment and growth of intestinal epithelials organoids, a model organoid system. We also found that these scaffolds can be patterned with large, high-aspect ratio topographical features that mimic anatomical structures (such as intestinal villi) found in vivo. Finally, we show that organoids cultured on these hydrogel scaffolds retain their capacity for multi-lineage differentiation and their ability to model enteric infections. Together, these findings are an excellent proof-of-concept that such hydrogel scaffolds can facilitate the development of organoid models of many organ systems and improve our ability to study a variety of important developmental and pathological processes.
{"title":"Modular, Topographically Patterned, Biomimetic Poly(Ethylene Glycol) Hydrogels as Customized Scaffolds for Organoid Culture","authors":"Reid L Wilson, Ganesh Swaminathan, K. Ettayebi, Carolyn Bomidi, Xi-Lei Zeng, S. Blutt, M. Estes, K. J. Grande-Allen","doi":"10.2139/ssrn.3582163","DOIUrl":"https://doi.org/10.2139/ssrn.3582163","url":null,"abstract":"The recent development of stem cell-derived, organotypic <i>in vitro</i> models, known as organoids, has revolutionized our ability to study important biological processes <i>in vitro</i>. However, their continued development is limited by the failure of the hydrogel matrices in which they are grown to adequately replicate the tissue-specific ECM cues they experience in their native <i>in vivo</i> environment. Here, we present a highly customizable, modular hydrogel scaffold that can incorporate tissue-specific cues from the extracellular matrix. We demonstrate that these scaffolds can be functionalized with a wide variety of cell adhesion molecules, including peptides and full-length proteins, and can support the attachment and growth of intestinal epithelials organoids, a model organoid system. We also found that these scaffolds can be patterned with large, high-aspect ratio topographical features that mimic anatomical structures (such as intestinal villi) found <i>in vivo</i>. Finally, we show that organoids cultured on these hydrogel scaffolds retain their capacity for multi-lineage differentiation and their ability to model enteric infections. Together, these findings are an excellent proof-of-concept that such hydrogel scaffolds can facilitate the development of organoid models of many organ systems and improve our ability to study a variety of important developmental and pathological processes.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116780374","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}
Yuya Mizukami, Yuki Takahashi, K. Shimizu, S. Konishi, Y. Takakura, M. Nishikawa
Multicellular spheroids are expected to be used for in vivo-like tissue models and cell transplantation. Microwell devices are useful for the fabrication of multicellular spheroids to improve productivity and regulate their size. However, the high cell density in microwell devices and densely packed cells in the spheroids limit oxygen supply to the core region of the spheroids, which leads to accelerated cell death. In this study, we developed O2-generating microwells by incorporating calcium peroxide (CaO2) into polydimethylsiloxane (PDMS)-based microwells. The CaO2-containing PDMS was shown to react with water and generate O2 for 3 days. Then, CaO2-containing PDMS was used to fabricate O2-generating microwells using a micro-molding technique. HepG2 spheroids were then prepared using either conventional PDMS microwells or O2-generating microwells. Using the conventional PDMS microwells, the O2 concentration in the culture medium reduced to ~67% of the cell-free level. In contrast, the O2-generating microwells maintained O2 at constant levels. The HepG2 spheroids prepared using the O2-generating microwells were greater in size and had a larger number of live cells than those prepared using the conventional microwells. In addition, the O2-generating microwells rescued hypoxia in the HepG2 spheroids and increased cell viability in the core region of the spheroids. Lastly, the O2-generating microwells were also useful for the preparation of multicellular spheroids of other cell types (i.e., MIN6, B16-BL6, and adipose-derived stem cells) with high cell viability. These results showed that the O2-generating microwells are useful for preparing multicellular spheroids with high functional activity.
{"title":"Calcium Peroxide-Containing Polydimethylsiloxane-Based Microwells for Inhibiting Cell Death in Multicellular Spheroids Through Improved Oxygen Supply","authors":"Yuya Mizukami, Yuki Takahashi, K. Shimizu, S. Konishi, Y. Takakura, M. Nishikawa","doi":"10.2139/ssrn.3729642","DOIUrl":"https://doi.org/10.2139/ssrn.3729642","url":null,"abstract":"Multicellular spheroids are expected to be used for <i>in vivo</i>-like tissue models and cell transplantation. Microwell devices are useful for the fabrication of multicellular spheroids to improve productivity and regulate their size. However, the high cell density in microwell devices and densely packed cells in the spheroids limit oxygen supply to the core region of the spheroids, which leads to accelerated cell death. In this study, we developed O<sub>2</sub>-generating microwells by incorporating calcium peroxide (CaO<sub>2</sub>) into polydimethylsiloxane (PDMS)-based microwells. The CaO<sub>2</sub>-containing PDMS was shown to react with water and generate O<sub>2</sub> for 3 days. Then, CaO<sub>2</sub>-containing PDMS was used to fabricate O<sub>2</sub>-generating microwells using a micro-molding technique. HepG2 spheroids were then prepared using either conventional PDMS microwells or O<sub>2</sub>-generating microwells. Using the conventional PDMS microwells, the O<sub>2</sub> concentration in the culture medium reduced to ~67% of the cell-free level. In contrast, the O<sub>2</sub>-generating microwells maintained O<sub>2</sub> at constant levels. The HepG2 spheroids prepared using the O<sub>2</sub>-generating microwells were greater in size and had a larger number of live cells than those prepared using the conventional microwells. In addition, the O<sub>2</sub>-generating microwells rescued hypoxia in the HepG2 spheroids and increased cell viability in the core region of the spheroids. Lastly, the O<sub>2</sub>-generating microwells were also useful for the preparation of multicellular spheroids of other cell types (i.e., MIN6, B16-BL6, and adipose-derived stem cells) with high cell viability. These results showed that the O<sub>2</sub>-generating microwells are useful for preparing multicellular spheroids with high functional activity.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131276426","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}
Sofia Ribeiro, E. Fernandes, M. Gomes, R. Reis, Y. Bayon, D. Zeugolis
Although it has been repeatedly indicated the importance to develop implantable devices and cell culture substrates with tissue-specific rigidity, current commercially available products, in particular cell culture substrates, have rigidity values well above most tissues in the body. Herein, six resorbable polyester films were synthesised and fabricated using compression moulding with a thermal presser into films with tailored stiffness by appropriately selecting the ratio of their building up monomers (e.g. lactic acid, glycolic acid, trimethylene carbonate, dioxanone, ε-caprolactone). Typical NMR and FTIR spectra were obtained, suggesting that the fabrication process did not have a negative effect on the conformation of the monomers. Surface roughness analysis revealed no apparent differences between the films as a function of monomer ratio or polymer composition. Subject to monomer ratio / polymer composition, polymeric films were obtained with glass transition temperatures from -52 ºC to 61 ºC; contact angles in water from 81 º to 94 º; storage modulus from 108 MPa to 2,756 MPa and loss modulus from 8 MPa to 507 MPa (both in wet state, at 1 Hz frequency and at 37 ºC); ultimate tensile strength from 8 MPa to 62 MPa, toughness from 23 MJ/m 3 to 287 MJ/m 3 , strain at break from 3 % to 278 %, macro-scale Young’s modulus from 110 MPa to 2,184 MPa (all in wet state); and nano-scale Young’s modulus from 6 kPa to 15,019 kPa (in wet state). With respect to in vitro degradation in phosphate buffered saline at 37 ºC, some monomer combinations resulted in polymeric films that started degrading from day 7, whilst for other polymeric films no significant degradation was observed up to 21 days of degradation. In vitro biological analysis using human dermal fibroblasts and a human monocyte cell line (THP-1) showed the potential of the polymeric films to support cell growth and controlled immune response. Evidently, the selected polymers exhibited properties suitable for a range of clinical indications.
{"title":"Design and Characterisation of Cytocompatible Polyester Substrates with Tunable Mechanical Properties and Degradation Rate","authors":"Sofia Ribeiro, E. Fernandes, M. Gomes, R. Reis, Y. Bayon, D. Zeugolis","doi":"10.2139/ssrn.3676748","DOIUrl":"https://doi.org/10.2139/ssrn.3676748","url":null,"abstract":"Although it has been repeatedly indicated the importance to develop implantable devices and cell culture substrates with tissue-specific rigidity, current commercially available products, in particular cell culture substrates, have rigidity values well above most tissues in the body. Herein, six resorbable polyester films were synthesised and fabricated using compression moulding with a thermal presser into films with tailored stiffness by appropriately selecting the ratio of their building up monomers (e.g. lactic acid, glycolic acid, trimethylene carbonate, dioxanone, ε-caprolactone). Typical NMR and FTIR spectra were obtained, suggesting that the fabrication process did not have a negative effect on the conformation of the monomers. Surface roughness analysis revealed no apparent differences between the films as a function of monomer ratio or polymer composition. Subject to monomer ratio / polymer composition, polymeric films were obtained with glass transition temperatures from -52 ºC to 61 ºC; contact angles in water from 81 º to 94 º; storage modulus from 108 MPa to 2,756 MPa and loss modulus from 8 MPa to 507 MPa (both in wet state, at 1 Hz frequency and at 37 ºC); ultimate tensile strength from 8 MPa to 62 MPa, toughness from 23 MJ/m 3 to 287 MJ/m 3 , strain at break from 3 % to 278 %, macro-scale Young’s modulus from 110 MPa to 2,184 MPa (all in wet state); and nano-scale Young’s modulus from 6 kPa to 15,019 kPa (in wet state). With respect to <i>in vitro</i> degradation in phosphate buffered saline at 37 ºC, some monomer combinations resulted in polymeric films that started degrading from day 7, whilst for other polymeric films no significant degradation was observed up to 21 days of degradation. <i>In vitro</i> biological analysis using human dermal fibroblasts and a human monocyte cell line (THP-1) showed the potential of the polymeric films to support cell growth and controlled immune response. Evidently, the selected polymers exhibited properties suitable for a range of clinical indications.","PeriodicalId":105746,"journal":{"name":"AMI: Acta Biomaterialia","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130317497","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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