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1.
Nat Biomed Eng ; 5(8): 880-896, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34426676

RESUMO

Fibroblasts can be directly reprogrammed into cardiomyocytes, endothelial cells or smooth muscle cells. Here we report the reprogramming of mouse tail-tip fibroblasts simultaneously into cells resembling these three cell types using the microRNA mimic miR-208b-3p, ascorbic acid and bone morphogenetic protein 4, as well as the formation of tissue-like structures formed by the directly reprogrammed cells. Implantation of the formed cardiovascular tissue into the infarcted hearts of mice led to the migration of reprogrammed cells to the injured tissue, reducing regional cardiac strain and improving cardiac function. The migrated endothelial cells and smooth muscle cells contributed to vessel formation, and the migrated cardiomyocytes, which initially displayed immature characteristics, became mature over time and formed gap junctions with host cardiomyocytes. Direct reprogramming of somatic cells to make cardiac tissue may aid the development of applications in cell therapy, disease modelling and drug discovery for cardiovascular diseases.


Assuntos
Células Endoteliais/transplante , Coração/fisiologia , Infarto do Miocárdio/terapia , Miócitos de Músculo Liso/transplante , Regeneração , Animais , Ácido Ascórbico/farmacologia , Proteína Morfogenética Óssea 4/farmacologia , Reprogramação Celular/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Junções Comunicantes/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Miocárdio/citologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Neovascularização Fisiológica , Transcriptoma
2.
Adv Drug Deliv Rev ; 170: 142-199, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33428994

RESUMO

Atherosclerosis is a chronic inflammatory disease driven by lipid accumulation in arteries, leading to narrowing and thrombosis. It affects the heart, brain, and peripheral vessels and is the leading cause of mortality in the United States. Researchers have strived to design nanomaterials of various functions, ranging from non-invasive imaging contrast agents, targeted therapeutic delivery systems to multifunctional nanoagents able to target, diagnose, and treat atherosclerosis. Therefore, this review aims to summarize recent progress (2017-now) in the development of nanomaterials and their applications to improve atherosclerosis diagnosis and therapy during the preclinical and clinical stages of the disease.


Assuntos
Aterosclerose , Nanoestruturas , Animais , Aterosclerose/diagnóstico , Aterosclerose/tratamento farmacológico , Humanos , Nanoestruturas/química , Nanoestruturas/uso terapêutico
3.
Nanomedicine (Lond) ; 15(11): 1113-1126, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32292108

RESUMO

Aims: We investigated whether miRNA (miR) 146a-5p-loaded nanoparticles (NPs) can attenuate neuropathic pain behaviors in the rat spinal nerve ligation-induced neuropathic pain model by inhibiting activation of the NF-κB and p38 MAPK pathways in spinal microglia. Materials & methods: After NP preparation, miR NPs were assessed for their physical characteristics and then injected intrathecally into the spinal cords of rat spinal nerve ligation rats to test their analgesic effects. Results: miR NPs reduced pain behaviors for 11 days by negatively regulating the inflammatory response in spinal microglia. Conclusion: The anti-inflammatory effects of miR 146a-5p along with nanoparticle-based materials make miR NPs promising tools for treating neuropathic pain.

4.
J Mater Chem B ; 8(14): 2814-2825, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32163093

RESUMO

We report a novel and facile organosilane plasma polymerization method designed to improve the surface characteristics of poly(tetrafluoroethylene) (PTFE). We hypothesized that the polymerized silane coating would provide an adhesive surface for endothelial cell proliferation due to a large number of surface hydroxyl groups, while the large polymer networks on the surface of PTFE would hinder platelet attachment. The plasma polymerized PTFE surfaces were then systematically characterized via different analytical techniques such as FTIR, XPS, XRD, Contact angle, and SEM. The key finding of the characterization is the time-dependent deposition of an organosilane layer on the surface of PTFE. This layer was found to provide favorable surface properties to PTFE such as a very high surface oxygen content, high hydrophilicity and improved surface mechanics. Additionally, in vitro cellular studies were conducted to determine the bio-interface properties of the plasma-treated and untreated PTFE. The important results of these experiments were rapid endothelial cell growth and decreased platelet attachment on the plasma-treated PTFE compared to untreated PTFE. Thus, this new surface modification technique could potentially address the current challenges associated with PTFE for blood contact applications, specifically poor endothelial cell growth and risk of thrombosis.


Assuntos
Materiais Biocompatíveis/farmacologia , Compostos de Organossilício/farmacologia , Politetrafluoretileno/química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Plaquetas/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Humanos , Estrutura Molecular , Compostos de Organossilício/síntese química , Compostos de Organossilício/química , Tamanho da Partícula , Adesividade Plaquetária/efeitos dos fármacos , Polimerização , Propriedades de Superfície
5.
J Clin Med ; 9(2)2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32033375

RESUMO

Dental pulp tissue exposed to mechanical trauma or cariogenic process results in root canal and/or periapical infections, and conventionally treated with root canal procedures. The more recent regenerative endodontic procedure intends to achieve effective root canal disinfection and adequate pulp-dentin tissue regeneration; however, numerous limitations are reported. Because tooth is composed of vital soft pulp enclosed by the mineralized hard tissue in a highly organized structure, complete pulp-dentin tissue regeneration has been challenging to achieve. In consideration of the limitations and unique dental anatomy, it is important to understand the healing and repair processes through inflammatory-proliferative-remodeling phase transformations of pulp-dentin tissue. Upon cause by infectious and mechanical stimuli, the innate defense mechanism is initiated by resident pulp cells including immune cells through chemical signaling. After the expansion of infection and damage to resident pulp-dentin cells, consequent chemical signaling induces pluripotent mesenchymal stem cells (MSCs) to migrate to the injury site to perform the tissue regeneration process. Additionally, innovative biomaterials are necessary to facilitate the immune response and pulp-dentin tissue regeneration roles of MSCs. This review highlights current approaches of pulp-dentin tissue healing process and suggests potential biomedical perspective of the pulp-dentin tissue regeneration.

6.
Nano Converg ; 7(1): 6, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31984429

RESUMO

Atherosclerosis is a major contributor to many cardiovascular events, including myocardial infarction, ischemic stroke, and peripheral arterial disease, making it the leading cause of death worldwide. High-density lipoproteins (HDL), also known as "good cholesterol", have been shown to demonstrate anti-atherosclerotic efficacy through the removal of cholesterol from foam cells in atherosclerotic plaques. Because of the excellent anti-atherosclerotic properties of HDL, in the past several years, there has been tremendous attention in designing HDL mimicking nanoparticles (NPs) of varying functions to image, target, and treat atherosclerosis. In this review, we are summarizing the recent progress in the development of HDL mimicking NPs and their applications for atherosclerosis.

7.
Adv Mater ; 31(41): e1904476, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31454108

RESUMO

Inserting a graft into vessels with different diameters frequently causes severe damage to the host vessels. Poor flow patency is an unresolved issue in grafts, particularly those with diameters less than 6 mm, because of vessel occlusion caused by disturbed blood flow following fast clotting. Herein, successful patency in the deployment of an ≈2 mm diameter graft into a porcine vessel is reported. A new library of property-tunable shape-memory polymers that prevent vessel damage by expanding the graft diameter circumferentially upon implantation is presented. The polymers undergo seven consecutive cycles of strain energy-preserved shape programming. Moreover, the new graft tube, which features a diffuser shape, minimizes disturbed flow formation and prevents thrombosis because its surface is coated with nitric-oxide-releasing peptides. Improved patency in a porcine vessel for 18 d is demonstrated while occlusive vascular remodeling occurs. These insights will help advance vascular graft design.


Assuntos
Oclusão de Enxerto Vascular/prevenção & controle , Fenômenos Mecânicos , Polímeros/farmacologia , Animais , Polímeros/química , Estresse Mecânico , Suínos
8.
Adv Exp Med Biol ; 1064: 123-144, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30471030

RESUMO

Cardiovascular disease is the number one cause of death in the U.S and results in the loss of approximately one million lives and more than 400 billion U.S. dollars for treatments every year. Recently, tissue engineered blood vessels have been studied and developed as promising replacements for treatment with autologous veins. Here, we summarize the cell sources and methods to make tissue-engineered blood vessels (TEBVs), the recent progress in TEBV related research, and also the recent progress in TEBV related clinical studies.


Assuntos
Vasos Sanguíneos , Doenças Cardiovasculares/terapia , Engenharia Tecidual , Humanos
9.
PLoS One ; 13(10): e0205534, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30308037

RESUMO

Successful disinfection alongside complete endodontic tissue regeneration and revascularization are the most desired clinical outcomes of regenerative endodontics. Despite reported clinical successes, significant limitations to the current regenerative endodontic procedure (REP) have been elucidated. To improve the current REP, an antibiotics and nitric oxide (NO) releasing biomimetic nanomatrix gel was developed. The study evaluates antibacterial effects of an antibiotics and NO releasing biomimetic nanomatrix gel on multispecies endodontic bacteria. Antibiotics, ciprofloxacin (CF) and metronidazole (MN) were mixed and encapsulated within the NO releasing biomimetic nanomatrix gel. The gel was synthesized and self-assembled from peptide amphiphiles containing various functional groups. Antibacterial effects of the antibiotics and NO releasing biomimetic nanomatrix gel were evaluated using bacterial viability assays involving endodontic microorganisms including clinical samples. Pulp-dentin regeneration was evaluated via animal-model experiments. The antibiotics and NO releasing biomimetic nanomatrix gel demonstrated a concentration dependent antibacterial effect. In addition, NO alone demonstrated a concentration dependent antibacterial effect on endodontic microorganism. An in vivo analysis demonstrated the antibiotics and NO releasing biomimetic nanomatrix gel promoted tooth revascularization with maturation of root canals. An optimal concentration of and NO releasing nanomatrix gel is suggested for its potential as a root treatment material for REP and an appropriate protocol for human trials. Further investigation is required to obtain a larger sample size and decide upon ideal growth factor incorporation.


Assuntos
Antibacterianos/administração & dosagem , Polpa Dentária/efeitos dos fármacos , Dentina/efeitos dos fármacos , Géis , Óxido Nítrico/administração & dosagem , Regeneração/efeitos dos fármacos , Animais , Biofilmes/efeitos dos fármacos , Materiais Biomiméticos/síntese química , Polpa Dentária/diagnóstico por imagem , Polpa Dentária/patologia , Polpa Dentária/fisiopatologia , Dentina/diagnóstico por imagem , Dentina/patologia , Dentina/fisiopatologia , Cães , Sistemas de Liberação de Medicamentos , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/fisiologia , Géis/síntese química , Infecções por Bactérias Gram-Positivas/diagnóstico por imagem , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/patologia , Infecções por Bactérias Gram-Positivas/fisiopatologia , Humanos , Nanoestruturas , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Projetos Piloto , Pulpite/diagnóstico por imagem , Pulpite/tratamento farmacológico , Pulpite/patologia , Pulpite/fisiopatologia , Regeneração/fisiologia , Treponema denticola/efeitos dos fármacos , Treponema denticola/fisiologia
10.
Sci Rep ; 8(1): 15749, 2018 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-30356078

RESUMO

To date, bone tissue regeneration strategies lack an approach that effectively provides an osteogenic and angiogenic environment conducive to bone growth. In the current study, we evaluated the osteogenic and angiogenic response of human mesenchymal stem cells (hMSCs) and green fluorescent protein-expressing human umbilical vein endothelial cells (GFP-HUVECs) cocultured on a self-assembled, peptide amphiphile nanomatrix functionalized with the cell adhesive ligand RGDS (PA-RGDS). Analysis of alkaline phosphatase activity, von Kossa staining, Alizarin Red quantification, and osteogenic gene expression, indicates a significant synergistic effect between the PA-RGDS nanomatrix and coculture that promoted hMSC osteogenesis. In addition, coculturing on PA-RGDS resulted in enhanced HUVEC network formation and upregulated vascular endothelial growth factor gene and protein expression. Though PA-RGDS and coculturing hMSCs with HUVECs were each previously reported to individually enhance hMSC osteogenesis, this study is the first to demonstrate a synergistic promotion of HUVEC angiogenesis and hMSC osteogenesis by integrating coculturing with the PA-RGDS nanomatrix. We believe that using the combination of hMSC/HUVEC coculture and PA-RGDS substrate is an efficient method for promoting osteogenesis and angiogenesis, which has immense potential as an efficacious, engineered platform for bone tissue regeneration.


Assuntos
Técnicas de Cocultura/métodos , Células Endoteliais da Veia Umbilical Humana/citologia , Células-Tronco Mesenquimais/citologia , Neovascularização Fisiológica , Osteogênese , Medicina Regenerativa/métodos , Regeneração Óssea , Células Cultivadas , Humanos , Oligopeptídeos/farmacologia
11.
ACS Biomater Sci Eng ; 4(7): 2435-2442, 2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-33435107

RESUMO

Peptides with proper sequences are capable of self-assembling into well-defined nanostructures, which can subsequently grow and entangle into three-dimensional nanomatrices. In this study, hemopressin, a cannabinoid receptor-modulating peptide derived from the α-chain of hemoglobin known to self-assemble into nanofibrils, was examined for its potential applicability as a gelator. The results indicated that hemopressin's gel formation was dependent on pH and salt concentration. Although hemopressin's macroscopic states showed differences, its microscopic structure remained largely unchanged in which it consisted mainly of the antiparallel ß-sheet conformation as confirmed by FTIR (C=O stretch peaks at 1630 and 1695 cm-1) and CD (ß-sheet peak at 195 nm). The major difference between the gel and sol states was displayed in the fibril length in which the gelation at pH 7.4 resulted in 4 µm fibrils, whereas the solution at pH 5.0 showed 800 nm fibrils. The pH-dependent sol-gel phase transition property was then utilized for the investigation of the pH-responsive release of FITC-dextran (4-40 kDa) from hemopressin fibrillary gel. Finally, the biocompatibility of the peptide was demonstrated by proliferation assay of cultured bone marrow mesenchymal stem cells. Altogether, the results suggested that hemopressin is a potentially promising candidate as a therapeutically active platform for drug delivery.

12.
Circulation ; 136(20): 1939-1954, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-28972000

RESUMO

BACKGROUND: Human pluripotent stem cell (hPSC)-derived endothelial cells (ECs) have limited clinical utility because of undefined components in the differentiation system and poor cell survival in vivo. Here, we aimed to develop a fully defined and clinically compatible system to differentiate hPSCs into ECs. Furthermore, we aimed to enhance cell survival, vessel formation, and therapeutic potential by encapsulating hPSC-ECs with a peptide amphiphile (PA) nanomatrix gel. METHODS: We induced differentiation of hPSCs into the mesodermal lineage by culturing on collagen-coated plates with a glycogen synthase kinase 3ß inhibitor. Next, vascular endothelial growth factor, endothelial growth factor, and basic fibroblast growth factor were added for endothelial lineage differentiation, followed by sorting for CDH5 (VE-cadherin). We constructed an extracellular matrix-mimicking PA nanomatrix gel (PA-RGDS) by incorporating the cell adhesive ligand Arg-Gly-Asp-Ser (RGDS) and a matrix metalloproteinase-2-degradable sequence. We then evaluated whether the encapsulation of hPSC-CDH5+ cells in PA-RGDS could enhance long-term cell survival and vascular regenerative effects in a hind-limb ischemia model with laser Doppler perfusion imaging, bioluminescence imaging, real-time reverse transcription-polymerase chain reaction, and histological analysis. RESULTS: The resultant hPSC-derived CDH5+ cells (hPSC-ECs) showed highly enriched and genuine EC characteristics and proangiogenic activities. When injected into ischemic hind limbs, hPSC-ECs showed better perfusion recovery and higher vessel-forming capacity compared with media-, PA-RGDS-, or human umbilical vein EC-injected groups. However, the group receiving the PA-RGDS-encapsulated hPSC-ECs showed better perfusion recovery, more robust and longer cell survival (> 10 months), and higher and prolonged angiogenic and vascular incorporation capabilities than the bare hPSC-EC-injected group. Surprisingly, the engrafted hPSC-ECs demonstrated previously unknown sustained and dynamic vessel-forming behavior: initial perivascular concentration, a guiding role for new vessel formation, and progressive incorporation into the vessels over 10 months. CONCLUSIONS: We generated highly enriched hPSC-ECs via a clinically compatible system. Furthermore, this study demonstrated that a biocompatible PA-RGDS nanomatrix gel substantially improved long-term survival of hPSC-ECs in an ischemic environment and improved neovascularization effects of hPSC-ECs via prolonged and unique angiogenic and vessel-forming properties. This PA-RGDS-mediated transplantation of hPSC-ECs can serve as a novel platform for cell-based therapy and investigation of long-term behavior of hPSC-ECs.


Assuntos
Células Endoteliais da Veia Umbilical Humana/transplante , Isquemia/terapia , Metaloproteinase 2 da Matriz/administração & dosagem , Nanoestruturas/administração & dosagem , Oligopeptídeos/administração & dosagem , Células-Tronco Pluripotentes/transplante , Animais , Diferenciação Celular/fisiologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células Cultivadas , Células Endoteliais/fisiologia , Células Endoteliais/transplante , Membro Posterior/irrigação sanguínea , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Isquemia/fisiopatologia , Masculino , Camundongos , Camundongos Nus , Células-Tronco Pluripotentes/fisiologia , Distribuição Aleatória , Resultado do Tratamento
13.
J Am Coll Cardiol ; 70(6): 766-775, 2017 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-28774384

RESUMO

Transplantations of various stem cells or their progeny have repeatedly improved cardiac performance in animal models of myocardial injury; however, the benefits observed in clinical trials have been generally less consistent. Some of the recognized challenges are poor engraftment of implanted cells and, in the case of human cardiomyocytes, functional immaturity and lack of electrical integration, leading to limited contribution to the heart's contractile activity and increased arrhythmogenic risks. Advances in tissue and genetic engineering techniques are expected to improve the survival and integration of transplanted cells, and to support structural, functional, and bioenergetic recovery of the recipient hearts. Specifically, application of a prefabricated cardiac tissue patch to prevent dilation and to improve pumping efficiency of the infarcted heart offers a promising strategy for making stem cell therapy a clinical reality.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Cardiopatias/terapia , Engenharia Tecidual/métodos , Humanos
14.
Macromol Rapid Commun ; 38(19)2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28833950

RESUMO

In the past decade, the self-immolative biodegradable polymer arose as a novel paradigm for its efficient degradation mechanism and vast potential for advanced biomedical applications. This study reports successful synthesis of a novel biodegradable polymer capable of self-immolative backbone cleavage. The monomer is designed by covalent conjugations of both pendant redox-trigger (p-nitrobenzyl alcohol) and self-immolative linker (p-hydroxybenzyl alcohol) to the cyclization spacer (n-2-(hydroxyethyl)ethylene diamine), which serves as the structural backbone. The polymerization of the monomer with hexamethylene diisocyanate yields a linear redox-sensitive polymer that can systemically degrade via sequential 1,6-elimination and 1,5-cyclization reactions within an effective timeframe. Ultimately, the polymer's potential for biomedical application is simulated through in vitro redox-triggered release of paclitaxel from polymeric nanoparticles.


Assuntos
Plásticos Biodegradáveis/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Polímeros/química , Plásticos Biodegradáveis/uso terapêutico , Ciclização , Humanos , Isocianatos/química , Nanopartículas/uso terapêutico , Oxirredução , Paclitaxel/química , Paclitaxel/uso terapêutico , Polimerização , Polímeros/uso terapêutico
15.
Int Forum Allergy Rhinol ; 7(4): 352-358, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27992118

RESUMO

BACKGROUND: Chronic rhinosinusitis (CRS) is often associated with persistent bacterial infection despite the use of systemic antibiotics. Topically administered antibiotics are an alternative strategy, but require effective local concentrations, prolonged mucosal contact time, minor systemic absorption, and minimal depletion. The objectives of the current study were to analyze the in vitro release rate and in vivo drug delivery tolerance and pharmacokinetics of a ciprofloxacin-coated sinus stent (CSS). METHODS: The CSS (2 mg) was created from biodegradable poly-D/L-lactic acid. After analyzing in vitro release profile, CSSs were placed unilaterally in maxillary sinuses of 16 rabbits via dorsal sinusotomy. Animals were euthanized between 1 and 3 weeks postoperatively. Ciprofloxacin concentrations in the sinus tissue and plasmas were assessed using high-performance liquid chromatography. Radiological and histological evaluations were performed. RESULTS: In the in vitro release profile, an initial burst release was observed over the first 24 hours, followed by sustained release through the 14-day time point. In the rabbit model, ciprofloxacin was continuously released from the stent up to 3 weeks at doses >50 ng/mL. Histologic examination found no evidence of inflammation, epithelial ulceration, or bony reaction upon euthanization of the animals at 21 days. Computed tomography also demonstrated no signs of mucosal edema or opacification in the sinus. CONCLUSION: The CSS was safe in this preclinical model and sustained release was observed in both the in vitro and in vivo analyses. The innovative stent design coated with ciprofloxacin may provide a unique therapeutic strategy for chronic rhinosinusitis (CRS).


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Ciprofloxacina/administração & dosagem , Ciprofloxacina/farmacocinética , Stents Farmacológicos , Seio Maxilar/metabolismo , Animais , Antibacterianos/sangue , Ciprofloxacina/sangue , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Seio Maxilar/anatomia & histologia , Seio Maxilar/diagnóstico por imagem , Coelhos , Mucosa Respiratória/anatomia & histologia , Mucosa Respiratória/diagnóstico por imagem , Mucosa Respiratória/metabolismo , Tomografia Computadorizada por Raios X
16.
ACS Biomater Sci Eng ; 3(9): 2110-2119, 2017 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31289747

RESUMO

The major concern of pancreatic islet transplantation is that the implanted islets are exposed to the immune system of the recipient. To overcome this challenge, the peptide amphiphile (PA) nanomatrix gel was used for immunoisolation of islets through microencapsulation. The PA can self-assemble to form a nanomatrix gel with an extracellular matrix-mimicking, islet nurturing microenvironment and a semipermeable immune barrier. In this study, the islet protective effect of the PA nanomatrix gel was evaluated by coculture of PA-encapsulated human islets with differentiated U937 cells (human monocyte cell-line) for 3 and 7 days. The coculture of the bare islets with the differentiated U937 cells stimulated proinflammatory cytokine (IL-1ß and TNF-α) secretion and caused islet death after 7 days, which simulated an early inflammatory response environment after islet transplantation. The PA-encapsulated islets, however, did not stimulate proinflammatory cytokine secretion and maintained islet viability up to 7 days. More insulin-producing ß cells were observed when islets were PA-encapsulated than control islets with the differentiated U937 cells for 7 days compared to the bare islets. This result was also confirmed by dithizone staining analysis. Further evaluation of islet functionality was assessed by a glucose-stimulated insulin secretion test. The PA-encapsulated islets showed greater insulin secretion response to glucose stimulation than the bare islets with the differentiated U937 cells after 3 and 7 days. These results demonstrated that islet encapsulation with the PA nanomatrix gel was able to improve islet survival and function in the presence of inflammatory responses, which will increase the success rate of islet engraftment and the efficacy of islet transplantation.

17.
Acta Biomater ; 41: 224-34, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27286678

RESUMO

UNLABELLED: For three-dimensional tissue engineering scaffolds, the major challenges of hydrogels are poor mechanical integrity and difficulty in handling during implantation. In contrast, electrospun scaffolds provide tunable mechanical properties and high porosity; but, are limited in cell encapsulation. To overcome these limitations, we developed a "hybrid nanosack" by combination of a peptide amphiphile (PA) nanomatrix gel and an electrospun poly (ε-caprolactone) (ePCL) nanofiber sheet with porous crater-like structures. This hybrid nanosack design synergistically possessed the characteristics of both approaches. In this study, the hybrid nanosack was applied to enhance local angiogenesis in the omentum, which is required of tissue engineering scaffolds for graft survival. The ePCL sheet with porous crater-like structures improved cell and blood vessel penetration through the hybrid nanosack. The hybrid nanosack also provided multi-stage fibroblast growth factor-2 (FGF-2) release kinetics for stimulating local angiogenesis. The hybrid nanosack was implanted into rat omentum for 14days and vascularization was analyzed by micro-CT and immunohistochemistry; the data clearly demonstrated that both FGF-2 delivery and porous crater-like structures work synergistically to enhance blood vessel formation within the hybrid nanosack. Therefore, the hybrid nanosack will provide a new strategy for engineering scaffolds to achieve graft survival in the omentum by stimulating local vascularization, thus overcoming the limitations of current strategies. STATEMENT OF SIGNIFICANCE: For three-dimensional tissue engineering scaffolds, the major challenges of hydrogels are poor mechanical integrity and difficulty in handling during implantation. In contrast, electrospun scaffolds provide tunable mechanical properties and high porosity; but, are limited in cell encapsulation. To overcome these limitations, we developed a "hybrid nanosack" by combination of a peptide amphiphile (PA) nanomatrix gel and an electrospun poly (ε-caprolactone) (ePCL) nanofiber sheet with porous crater-like structures. This design synergistically possessed the characteristics of both approaches. In this study, the hybrid nanosack was applied to enhance local angiogenesis in the omentum, which is required of tissue engineering scaffolds for graft survival. The hybrid nanosack was implanted into rat omentum for 14days and vascularization was analyzed by micro-CT and immunohistochemistry. We demonstrate that both FGF-2 delivery and porous crater-like structures work synergistically to enhance blood vessel formation within the hybrid nanosack. Therefore, the hybrid nanosack will provide a new strategy for engineering scaffolds to achieve graft survival in the omentum by stimulating local vascularization, thus overcoming the limitations of current strategies.


Assuntos
Materiais Biocompatíveis/farmacologia , Nanofibras/química , Neovascularização Fisiológica/efeitos dos fármacos , Omento/irrigação sanguínea , Tecidos Suporte/química , Animais , Ensaio de Imunoadsorção Enzimática , Fator 2 de Crescimento de Fibroblastos/farmacologia , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Cinética , Omento/efeitos dos fármacos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Poliésteres/farmacologia , Porosidade , Ratos , Microtomografia por Raio-X
18.
Biomater Res ; 20: 14, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27257508

RESUMO

Regenerative endodontics has been proposed to replace damaged and underdeveloped tooth structures with normal pulp-dentin tissue by providing a natural extracellular matrix (ECM) mimicking environment; stem cells, signaling molecules, and scaffolds. In addition, clinical success of the regenerative endodontic treatments can be evidenced by absence of signs and symptoms; no bony pathology, a disinfected pulp, and the maturation of root dentin in length and thickness. In spite of the various approaches of regenerative endodontics, there are several major challenges that remain to be improved: a) the endodontic root canal is a strong harbor of the endodontic bacterial biofilm and the fundamental etiologic factors of recurrent endodontic diseases, (b) tooth discolorations are caused by antibiotics and filling materials, (c) cervical root fractures are caused by endodontic medicaments, (d) pulp tissue is not vascularized nor innervated, and (e) the dentin matrix is not developed with adequate root thickness and length. Generally, current clinical protocols and recent studies have shown a limited success of the pulp-dentin tissue regeneration. Throughout the various approaches, the construction of biomimetic microenvironments of pulp-dentin tissue is a key concept of the tissue engineering based regenerative endodontics. The biomimetic microenvironments are composed of a synthetic nano-scaled polymeric fiber structure that mimics native pulp ECM and functions as a scaffold of the pulp-dentin tissue complex. They will provide a framework of the pulp ECM, can deliver selective bioactive molecules, and may recruit pluripotent stem cells from the vicinity of the pulp apex. The polymeric nanofibers are produced by methods of self-assembly, electrospinning, and phase separation. In order to be applied to biomedical use, the polymeric nanofibers require biocompatibility, stability, and biodegradability. Therefore, this review focuses on the development and application of the biomimetic microenvironments of pulp-dentin tissue among the current regenerative endodontics.

19.
ACS Appl Mater Interfaces ; 8(8): 5178-87, 2016 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-26849167

RESUMO

Inflammatory responses play a critical role in tissue-implant interactions, often limiting current implant utility. This is particularly true for cardiovascular devices. Existing stent technology does little to avoid or mitigate inflammation or to influence the vasomotion of the artery after implantation. We have developed a novel endothelium-mimicking nanomatrix composed of peptide amphiphiles that enhances endothelialization while decreasing both smooth muscle cell proliferation and platelet adhesion. Here, we evaluated whether the nanomatrix could prevent inflammatory responses under static and physiological flow conditions. We found that the nanomatrix reduced monocyte adhesion to endothelial cells and expression of monocyte inflammatory genes (TNF-α, MCP-1, IL-1ß, and IL-6). Furthermore, the nitric-oxide releasing nanomatrix dramatically attenuated TNF-α-stimulated inflammatory responses as demonstrated by significantly reduced monocyte adhesion and inflammatory gene expression in both static and physiological flow conditions. These effects were abolished by addition of a nitric oxide scavenger. Finally, the nanomatrix stimulated vasodilation in intact rat mesenteric arterioles after constriction with phenylephrine, demonstrating the bioavailability and bioactivity of the nanomatrix, as well as exhibiting highly desired release kinetics. These results demonstrate the clinical potential of this nanomatrix by both preventing inflammatory responses and promoting vasodilation, critical improvements in stent and cardiovascular device technology.


Assuntos
Inflamação/prevenção & controle , Nanocompostos/uso terapêutico , Stents/efeitos adversos , Vasodilatação/efeitos dos fármacos , Animais , Artérias/efeitos dos fármacos , Artérias/patologia , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Humanos , Inflamação/patologia , Monócitos/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Nanocompostos/química , Óxido Nítrico/metabolismo , Peptídeos/química , Adesividade Plaquetária/efeitos dos fármacos , Ratos
20.
Nano Converg ; 3(1): 28, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28191438

RESUMO

Pancreatic islet transplantation has been validated as a treatment for type 1 diabetes since it maintains consistent and sustained type 1 diabetes reversal. However, one of the major challenges in pancreatic islet transplantation is the body's natural immune response to the implanted islets. Immunosuppressive drug treatment is the most popular immunomodulatory approach for islet graft survival. However, administration of immunosuppressive drugs gives rise to negative side effects, and long-term effects are not clearly understood. A bioartificial pancreas is a therapeutic approach to enable pancreatic islet transplantation without or with minimal immune suppression. The bioartificial pancreas encapsulates the pancreatic islets in a semi-permeable environment which protects islets from the body's immune responses, while allowing the permeation of insulin, oxygen, nutrients, and waste. Many groups have developed various types of the bioartificial pancreas and tested their efficacy in animal models. However, the clinical application of the bioartificial pancreas still requires further investigation. In this review, we discuss several types of bioartificial pancreases and address their advantages and limitations. We also discuss recent advances in bioartificial pancreas applications with microfluidic or micropatterning technology.

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