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1.
Proc Natl Acad Sci U S A ; 116(36): 18060-18067, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31427534

RESUMO

Translational control plays a key role in regulation of neuronal activity and behavior. Deletion of the translational repressor 4E-BP2 in mice alters excitatory and inhibitory synaptic functions, engendering autistic-like behaviors. The contribution of 4E-BP2-dependent translational control in excitatory and inhibitory neurons and astrocytic cells to these behaviors remains unknown. To investigate this, we generated cell-type-specific conditional 4E-BP2 knockout mice and tested them for the salient features of autism, including repetitive stereotyped behaviors (self-grooming and marble burying), sociability (3-chamber social and direct social interaction tests), and communication (ultrasonic vocalizations in pups). We found that deletion of 4E-BP2 in GABAergic inhibitory neurons, defined by Gad2, resulted in impairments in social interaction and vocal communication. In contrast, deletion of 4E-BP2 in forebrain glutamatergic excitatory neurons, defined by Camk2a, or in astrocytes, defined by Gfap, failed to cause autistic-like behavioral abnormalities. Taken together, we provide evidence for an inhibitory-cell-specific role of 4E-BP2 in engendering autism-related behaviors.

2.
Int J Gynaecol Obstet ; 144(1): 21-26, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30353543

RESUMO

OBJECTIVES: To determine the relationship between maternal serum uric acid levels and fetal/neonatal complications in women with pre-eclampsia/eclampsia, and to establish a predictive threshold value. METHODS: A diagnostic test and historical cohort study conducted by prospective cross-sectional data collection on pregnant women with pre-eclampsia/eclampsia at Hue University Hospital, Vietnam, between March 2015 and July 2017. Pre-eclampsia was diagnosed based on ACOG criteria. Serum uric acid levels were measured by enzymatic colorimetric testing using a Cobas c 501 analyzer (Roche Diagnostics, Mannheim, Germany). Fetal complications included intrauterine growth restriction, preterm delivery, fetal death, and neonatal death. RESULTS: There were 205 women enrolled. Serum uric acid at a cutoff of 393 µmol/L is a good predictor of fetal/neonatal complications (AUC 0.752), with 64.4% sensitivity and 79.5% specificity. High uric acid level (≥393 µmol/L) resulted in increased risk of preterm birth (OR 6.367, 95% CI 3.009-13.084), low Apgar scores (OR 5.514, 95% CI 1.877-16.198), intrauterine growth restriction (OR 7.188, 95% CI 3.592-14.382), and neonatal death (OR 7.818, 95% CI 1.614-37.867). There was no relationship between uric acid level and fetal death (OR 1.803, 95% CI 0.355-9.168). CONCLUSIONS: Maternal serum uric acid concentration is a good predictor of fetal/neonatal outcomes in women with pre-eclampsia/eclampsia.


Assuntos
Eclampsia/sangue , Retardo do Crescimento Fetal/sangue , Pré-Eclâmpsia/sangue , Nascimento Prematuro/sangue , Ácido Úrico/sangue , Adulto , Índice de Apgar , Estudos Transversais , Feminino , Retardo do Crescimento Fetal/etiologia , Humanos , Recém-Nascido , Valor Preditivo dos Testes , Gravidez , Resultado da Gravidez , Nascimento Prematuro/etiologia , Estudos Prospectivos , Índice de Gravidade de Doença , Vietnã
3.
Biomacromolecules ; 19(11): 4277-4285, 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30226977

RESUMO

On-demand photo-uncaging of reactive thiols have been employed in engineering biomaterial scaffolds for regulation of cellular activities. A drawback of the current photo-uncaging chemistry is the utilization of high energy UV light or 2-photon laser light, which may be harmful to cells and cause undesired side reactions within the biological environment. We introduce an effective approach for the caging of thiol using monobromobimane, which can be removed under irradiation of light at λ = 420 nm and in the presence of electrophiles, such as acrylate, propiolate and maleimide, for trapping of the newly release thiol. This chemical approach can be used in visible light-induced polymer coupling and cross-linking for the preparation of cell-laden hydrogels.

4.
PLoS Pathog ; 14(8): e1007264, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30138450

RESUMO

Herpes Simplex Virus 1 (HSV1) is amongst the most clinically advanced oncolytic virus platforms. However, efficient and sustained viral replication within tumours is limiting. Rapamycin can stimulate HSV1 replication in cancer cells, but active-site dual mTORC1 and mTORC2 (mammalian target of rapamycin complex 1 and 2) inhibitors (asTORi) were shown to suppress the virus in normal cells. Surprisingly, using the infected cell protein 0 (ICP0)-deleted HSV1 (HSV1-dICP0), we found that asTORi markedly augment infection in cancer cells and a mouse mammary cancer xenograft. Mechanistically, asTORi repressed mRNA translation in normal cells, resulting in defective antiviral response but also inhibition of HSV1-dICP0 replication. asTORi also reduced antiviral response in cancer cells, however in contrast to normal cells, transformed cells and cells transduced to elevate the expression of eukaryotic initiation factor 4E (eIF4E) or to silence the repressors eIF4E binding proteins (4E-BPs), selectively maintained HSV1-dICP0 protein synthesis during asTORi treatment, ultimately supporting increased viral replication. Our data show that altered eIF4E/4E-BPs expression can act to promote HSV1-dICP0 infection under prolonged mTOR inhibition. Thus, pharmacoviral combination of asTORi and HSV1 can target cancer cells displaying dysregulated eIF4E/4E-BPs axis.

5.
Blood ; 132(17): 1842-1850, 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30042098

RESUMO

Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry-specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P = 6.6 × 10-5) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

6.
Acta Biomater ; 77: 48-62, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30006317

RESUMO

Current clinical approaches to treat articular cartilage degeneration provide only a limited ability to regenerate tissue with long-term durability and functionality. In this application, injectable bulk hydrogels and microgels containing stem cells can provide a suitable environment for tissue regeneration. However insufficient cell-cell interactions, low differentiation efficiency and poor tissue adhesion hinder the formation of high-quality hyaline type cartilage. Here, we have designed a higher order tissue-like structure using injectable cell-laden microgels as the building blocks to achieve human bone marrow-derived mesenchymal stem cell (hBMSC) long-term maintenance and chondrogenesis. We have demonstrated that a 4-arm poly(ethylene glycol)-N-hydroxysuccinimide (NHS) crosslinker induces covalent bonding between the microgel building blocks as well as the surrounding tissue mimic. The crosslinking process assembles the microgels into a 3D construct and preserves the viability and cellular functions of the encapsulated hBMSCs. This assembled microgel construct encourages upregulation of chondrogenic markers in both gene and glycosaminoglycan (GAG) expression levels. In addition, the regenerated tissue in the assembled microgels stained positively with Alcian blue and Safranin O exhibiting unique hyaline-like cartilage features. Furthermore, the immunostaining showed a favourable distribution and significantly higher content of type II collagen in the assembled microgels when compared to both the bulk hydrogel and pellet cultures. Collectively, this tissue adhesive hBMSC-laden microgel construct provides potential clinical opportunities for articular cartilage repair and other applications in regenerative medicine. STATEMENT OF SIGNIFICANCE: A reliable approach to reconstruct durable and fully functional articular cartilage tissue is required for effective clinical therapies. Here, injectable hydrogels together with cell-based therapies offer new treatment strategies in cartilage repair. For effective cartilage regeneration, the injectable hydrogel system needs to be bonded to the surrounding tissue and at the same time needs to be sufficiently stable for prolonged chondrogenesis. In this work, we utilised injectable hBMSC-laden microgels as the building blocks to create an assembled construct via N-hydroxysuccinimide-amine coupling. This crosslinking process also allows for rapid bonding between the assembled microgels and a surrounding tissue mimic. The resultant assembled microgel-construct provides both a physically stable and biologically dynamic environment for hBMSC chondrogenesis, leading to the production of a mature hyaline type cartilage structure.

7.
PLoS One ; 12(10): e0182472, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29084233

RESUMO

BACKGROUND: DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation. METHODS: Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive MTHFR 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation. RESULTS: Meta-analysis revealed that the MTHFR 677C>T variant was associated with 35 CpG sites in cis, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5. CONCLUSIONS: Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes.


Assuntos
Metilação de DNA , Homocisteína/metabolismo , Leucócitos/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Adulto , Cromossomos Humanos Par 6 , Estudos de Coortes , Ilhas de CpG , Humanos , Polimorfismo de Nucleotídeo Único
8.
Chem Commun (Camb) ; 53(89): 12076-12079, 2017 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-29035405

RESUMO

We introduce a click and visible-light triggered unclick approach via thio-bromo reaction and hydroquinone photoreduction/trimethyl lock cleavage for polymer modifications. Both reactions can be carried out in water and at ambient temperature, enabling preparation of bioorthogonal hydrogels for encapsulation and controlled release of various cells.

9.
Epigenomics ; 9(11): 1403-1422, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28990796

RESUMO

AIM: Homocysteine (Hcy) is a sensitive marker of one-carbon metabolism. Higher Hcy levels have been associated with global DNA hypomethylation. We investigated the association between plasma Hcy and epigenome-wide DNA methylation in leukocytes. METHODS: Methylation was measured using Illumina 450 k arrays in 2035 individuals from six cohorts. Hcy-associated differentially methylated positions and regions were identified using meta-analysis. RESULTS: Three differentially methylated positions cg21607669 (SLC27A1), cg26382848 (AJUBA) and cg10701000 (KCNMA1) at chromosome 19, 14 and 10, respectively, were significantly associated with Hcy. In addition, we identified 68 Hcy-associated differentially methylated regions, the most significant of which was a 1.8-kb spanning domain (TNXB/ATF6B) at chromosome 6. CONCLUSION: We identified novel epigenetic loci associated with Hcy levels, of which specific role needs to be further validated.


Assuntos
Metilação de DNA , Epigênese Genética , Homocisteína/sangue , Leucócitos/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Masculino , Tenascina/genética , Tenascina/metabolismo
10.
ACS Appl Mater Interfaces ; 9(38): 32441-32445, 2017 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-28892355

RESUMO

We introduce an efficient method for the preparation of photolabile polymer linkers to be used in the fabrication of bioorthogonal and photodegradable hydrogels. The versatility of this synthesis strategy allows for incorporation of a series of chromophores responsive to addressable wavelengths of UV and broad spectrum visible light. Consequently, selective release of different cell types from composite hydrogels by user-defined timing can be achieved by irradiating the materials with different wavelengths of light.

11.
Sci Rep ; 7(1): 11207, 2017 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-28894120

RESUMO

Efficient interventions to reduce blood triglycerides are few; newer and more tolerable intervention targets are needed. Understanding the molecular mechanisms underlying blood triglyceride levels variation is key to identifying new therapies. To explore the role of epigenetic mechanisms on triglyceride levels, a blood methylome scan was conducted in 199 individuals from 5 French-Canadian families ascertained on venous thromboembolism, and findings were replicated in 324 French unrelated patients with venous thromboembolism. Genetic context and functional relevance were investigated. Two DNA methylation sites associated with triglyceride levels were identified. The first one, located in the ABCG1 gene, was recently reported, whereas the second one, located in the promoter of the PHGDH gene, is novel. The PHGDH methylation site, cg14476101, was found to be associated with variation in triglyceride levels in a threshold manner: cg14476101 was inversely associated with triglyceride levels only when triglyceride levels were above 1.12 mmol/L (discovery P-value = 8.4 × 10-6; replication P-value = 0.0091). Public databases findings supported a functional role of cg14476101 on PHGDH expression. PHGDH catalyses the first step in the serine biosynthesis pathway. These findings highlight the role of epigenetic regulation of the PHGDH gene in triglyceride metabolism, providing novel insights on putative intervention targets.

12.
Nat Med ; 23(6): 674-677, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28504725

RESUMO

Fragile X syndrome (FXS) is the leading monogenic cause of autism spectrum disorders (ASD). Trinucleotide repeat expansions in FMR1 abolish FMRP expression, leading to hyperactivation of ERK and mTOR signaling upstream of mRNA translation. Here we show that metformin, the most widely used drug for type 2 diabetes, rescues core phenotypes in Fmr1-/y mice and selectively normalizes ERK signaling, eIF4E phosphorylation and the expression of MMP-9. Thus, metformin is a potential FXS therapeutic.


Assuntos
Comportamento Animal/efeitos dos fármacos , Fator de Iniciação 4E em Eucariotos/efeitos dos fármacos , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Hipoglicemiantes/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metformina/farmacologia , Comportamento Social , Animais , Modelos Animais de Doenças , Fator de Iniciação 4E em Eucariotos/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Síndrome do Cromossomo X Frágil/fisiopatologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Fosforilação/efeitos dos fármacos , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Expansão das Repetições de Trinucleotídeos
13.
Genet Epidemiol ; 41(5): 455-466, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28421636

RESUMO

Tissue factor pathway inhibitor (TFPI) regulates the formation of intravascular blood clots, which manifest clinically as ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). TFPI plasma levels are heritable, but the genetics underlying TFPI plasma level variability are poorly understood. Herein we report the first genome-wide association scan (GWAS) of TFPI plasma levels, conducted in 251 individuals from five extended French-Canadian Families ascertained on VTE. To improve discovery, we also applied a hypothesis-driven (HD) GWAS approach that prioritized single nucleotide polymorphisms (SNPs) in (1) hemostasis pathway genes, and (2) vascular endothelial cell (EC) regulatory regions, which are among the highest expressers of TFPI. Our GWAS identified 131 SNPs with suggestive evidence of association (P-value < 5 × 10-8 ), but no SNPs reached the genome-wide threshold for statistical significance. Hemostasis pathway genes were not enriched for TFPI plasma level associated SNPs (global hypothesis test P-value = 0.147), but EC regulatory regions contained more TFPI plasma level associated SNPs than expected by chance (global hypothesis test P-value = 0.046). We therefore stratified our genome-wide SNPs, prioritizing those in EC regulatory regions via stratified false discovery rate (sFDR) control, and reranked the SNPs by q-value. The minimum q-value was 0.27, and the top-ranked SNPs did not show association evidence in the MARTHA replication sample of 1,033 unrelated VTE cases. Although this study did not result in new loci for TFPI, our work lays out a strategy to utilize epigenomic data in prioritization schemes for future GWAS studies.


Assuntos
Biomarcadores/sangue , Lipoproteínas/sangue , Lipoproteínas/genética , Polimorfismo de Nucleotídeo Único/genética , Sequências Reguladoras de Ácido Nucleico/genética , Tromboembolia Venosa/sangue , Tromboembolia Venosa/genética , Adulto , Canadá , Células Cultivadas , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Epigenômica , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Tromboembolia Venosa/diagnóstico
14.
ACS Appl Mater Interfaces ; 9(10): 8589-8601, 2017 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-28225583

RESUMO

Stem cell injections for the treatment of articular cartilage damage are a promising approach to achieve tissue regeneration. However, this method is encumbered by high cell apoptosis rates, low retention in the cartilage lesion, and inefficient chondrogenesis. Here, we have used a facile, very low cost-based microfluidic technique to create visible light-cured microgels composed of gelatin norbornene (GelNB) and a poly(ethylene glycol) (PEG) cross-linker. In addition, we have demonstrated that the process enables the rapid in situ microencapsulation of human bone marrow-derived mesenchymal stem cells (hBMSCs) under biocompatible microfluidic-processing conditions for long-term maintenance. The hBMSCs exhibited an unusually high degree of chondrogenesis in the GelNB microgels with chondro-inductive media, specifically toward the hyaline cartilage structure, with significant upregulation in type II collagen expression compared to the bulk hydrogel and "gold standard" pellet culture. Overall, we have demonstrated that these protein-based microgels can be engineered as promising therapeutic candidates for articular cartilage regeneration, with additional potential to be used in a variety of other applications in regenerative medicine.

15.
Biomacromolecules ; 18(3): 757-766, 2017 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-28195689

RESUMO

Swelling of hydrogels leads to a decrease in mechanical performance coupled with complications in solute diffusion. In addition, hydrogel swelling affects patient safety in biomedical applications such as compression of tissue and fluid blockage. A conventional strategy for suppressing swelling is to introduce a thermoresponsive polymer with a lower critical solution temperature (LCST) within the network structure to counter the water uptake at elevated temperature. However, altering the gel's mechanical strength via modification of the network structure often affects the water uptake behavior and thus a nonswelling platform with tunable mechanical properties suitable for various biomedical applications is desirable. In this study we applied the commercially available triblock PEG-PPG-PEG (Pluronic) as a cross-linker for the preparation of nucleophilic thiol-yne click cross-linked hydrogels with suppressed swelling at physiologically relevant temperature. The mechanical properties and degradation rate of these nonswelling hydrogels can be tuned by judicious combinations of the available linkers. The Pluronic linkers can be applied to prepare biologically relevant gelatin based hydrogels with suppressed swelling under physiological conditions that support attachment of fibroblast cells in 2D culture and controlled release of albumin, paving the way for the development of reliable and better performing soft biomaterials.


Assuntos
Materiais Biocompatíveis/química , Gelatina/química , Hidrogéis/química , Poloxâmero/química , Polietilenoglicóis/química , Propilenoglicóis/química , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Água/química
16.
Hum Mol Genet ; 26(3): 637-649, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28053049

RESUMO

Coagulation factor XI (FXI) has become increasingly interesting for its role in pathogenesis of thrombosis. While elevated plasma levels of FXI have been associated with venous thromboembolism and ischemic stroke, its deficiency is associated with mild bleeding. We aimed to determine novel genetic and post-transcriptional plasma FXI regulators.We performed a genome-wide association study (GWAS) for plasma FXI levels, using novel data imputed to the 1000 Genomes reference panel. Individual GWAS analyses, including a total of 16,169 European individuals from the ARIC, GHS, MARTHA and PROCARDIS studies, were meta-analysed and further replicated in 2,045 individuals from the F5L family, GAIT2 and MEGA studies. Additional association with activated partial thromboplastin time (aPTT) was tested for the top SNPs. In addition, a study on the effect of miRNA on FXI regulation was performed using in silico prediction tools and in vitro luciferase assays.Three loci showed robust, replicating association with circulating FXI levels: KNG1 (rs710446, P-value = 2.07 × 10-302), F11 (rs4253417, P-value = 2.86 × 10-193), and a novel association in GCKR (rs780094, P-value = 3.56 ×10-09), here for the first time implicated in FXI regulation. The two first SNPs (rs710446 and rs4253417) also associated with aPTT. Conditional and haplotype analyses demonstrated a complex association signal, with additional novel SNPs modulating plasma FXI levels in both the F11 and KNG1 loci. Finally, eight miRNAs were predicted to bind F11 mRNA. Over-expression of either miR-145 or miR-181 significantly reduced the luciferase activity in cells transfected with a plasmid containing FXI-3'UTR.These results should open the door to new therapeutic targets for thrombosis prevention.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Moléculas de Adesão Celular/sangue , Cininogênios/genética , Receptores de Superfície Celular/sangue , Trombose/genética , Moléculas de Adesão Celular/genética , Simulação por Computador , Feminino , Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Tempo de Tromboplastina Parcial , Polimorfismo de Nucleotídeo Único , Processamento de Proteína Pós-Traducional/genética , Receptores de Superfície Celular/genética , Trombose/sangue , Trombose/fisiopatologia
17.
Angew Chem Int Ed Engl ; 55(42): 13076-13080, 2016 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-27654023

RESUMO

In most synthetic elastomers, changing the physical properties by monomer choice also results in a change to the crystallinity of the material, which manifests through alteration of its mechanical performance. Using organocatalyzed stereospecific additions of thiols to activated alkynes, high-molar-mass elastomers were isolated via step-growth polymerization. The resulting controllable double-bond stereochemistry defines the crystallinity and the concomitant mechanical properties as well as enabling the synthesis of materials that retain their excellent mechanical properties through changing monomer composition. Using this approach to elastomer synthesis, further end group modification and toughening through vulcanization strategies are also possible. The organocatalytic control of stereochemistry opens the realm to a new and easily scalable class of elastomers that will have unique chemical handles for functionalization and post synthetic processing.

18.
Biomater Sci ; 4(7): 1123-31, 2016 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-27217071

RESUMO

Hydrogels prepared from naturally derived gelatin can provide a suitable environment for cell attachment and growth, making them favourable materials in tissue engineering. However, physically crosslinked gelatin hydrogels are not stable under physiological conditions while chemical crosslinking of gelatin by radical polymerization may be harmful to cells. In this study, we attached the norbornene functional group to gelatin, which was subsequently crosslinked with a polyethylene glycol (PEG) linker via the nitrile oxide-norbornene click reaction. The rapid crosslinking process allows the hydrogel to be formed within minutes of mixing the polymer solutions under physiological conditions, allowing the gels to be used as injectable materials. The hydrogels properties including mechanical strength, swelling and degradation, can be tuned by changing either the ratio of the reacting groups or the total concentration of the polymer precursors. Murine embryonic fibroblastic cells cultured in soft gels (2 wt% of gelatin and 1 wt% of PEG linker) demonstrated high cell viability as well as similar phenotypic profiles (PDGFRα and MTS15) to Matrigel cultures over 5 days. Thymic epithelial cell and fibroblast co-cultures produced epithelial colonies in these gels following 7 days incubation. These studies demonstrate that gelatin based hydrogels, prepared using "click" crosslinking, provide a robust cell culture platform with retained benefits of the gelatin material, and are therefore suitable for use in various tissue engineering applications.


Assuntos
Técnicas de Cultura de Células , Química Click , Células Epiteliais/citologia , Gelatina/química , Hidrogéis/química , Animais , Sobrevivência Celular , Técnicas de Cocultura , Colágeno/química , Combinação de Medicamentos , Fibroblastos/citologia , Laminina/química , Camundongos , Camundongos Endogâmicos C57BL , Polietilenoglicóis/química , Proteoglicanas/química , Reologia , Engenharia Tecidual/métodos
19.
Macromol Rapid Commun ; 36(19): 1729-34, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26250120

RESUMO

This communication describes the first application of cycloaddition between an in situ generated nitrile oxide with norbornene leading to a polymer crosslinking reaction for the preparation of poly(ethylene glycol) hydrogels under physiological conditions. Hydrogels with high water content and robust physical strength are readily formed within 2-5 min by a simple two-solution mixing method which allows 3D encapsulation of neuronal cells. This bioorthogonal crosslinking reaction provides a simple yet highly effective method for preparation of hydrogels to be used in bioengineering.


Assuntos
Hidrogéis/química , Nitrilos/química , Norbornanos/química , Animais , Linhagem Celular , Reação de Cicloadição , Hidrogéis/síntese química , Camundongos , Microscopia de Fluorescência , Óxidos/química , Reologia
20.
Biomacromolecules ; 16(7): 2246-53, 2015 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-26056855

RESUMO

In this study, we present a method for the fabrication of in situ forming gelatin and poly(ethylene glycol)-based hydrogels utilizing bioorthogonal, strain-promoted alkyne-azide cycloaddition as the cross-linking reaction. By incorporating nitrobenzyl moieties within the network structure, these hydrogels can be designed to be degradable upon irradiation with low intensity UV light, allowing precise photopatterning. Fibroblast cells encapsulated within these hydrogels were viable at 14 days and could be readily harvested using a light trigger. Potential applications of this new class of injectable hydrogel include its use as a 3D culturing platform that allows the capture and release of cells, as well as light-triggered cell delivery in regenerative medicine.


Assuntos
Técnicas de Cultura de Células/métodos , Fibroblastos/citologia , Gelatina/química , Hidrogéis/síntese química , Animais , Engenharia Celular , Células Cultivadas , Química Click/métodos , Reação de Cicloadição/métodos , Hidrogéis/química , Camundongos , Fotólise
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