MICRO-/NANOTECHNOLOGIES TO ENGINEER MICROENVIRONMENTAL CUES FOR REGENERATIVE HEART VALVE THERAPIES

Scaffold-based regenerative heart valve therapy represents a promising and innovative approach to address the unmet clinical need in treating valvular heart diseases. However, current tissue-engineered heart valve scaffolds often suffer from issues such as architectural and mechanical mismatch to native valve leaflet, thrombogenicity, and calcification tendency. Our overall goal is to provide effective strategies to improve the design of regenerative heart valve therapies by alleviating these common issues. This dissertation summarizes our efforts to develop micro-/nanotechnology-based strategies in mimicking the fibrous architecture and mechanical properties of the native valves while improving the biocompatibility of tissue-engineered scaffolds. We first synthesized a novel series of polyethylene glycol (PEG) functionalized biodegradable elastomers. With different molar ratios and molecular weights of PEG in the polymer backbone, these biodegradable and biocompatible elastomers possessed widely tunable mechanical properties and desirable degradation mechanism. We then fabricated PEGylated biodegradable elastomers into fibrous scaffolds by electrospinning. The introduction of PEG into the polymer backbone led to reduced thrombogenicity of the fibrous scaffolds. Moreover, the uniaxial and cyclic mechanical properties of fibrous scaffolds could be tuned to mimic those of the native valve leaflets. The electrospinning process was further modified to fabricate anisotropic fibrous scaffolds. By modulating polymer formulation, fibrous scaffolds were produced to possess anisotropic biaxial mechanical properties. The anisotropic nature of scaffold also guided the alignment of human valvular interstitial cells (hVICs) seeded on the scaffolds. To address the calcification tendency of heart valve substitutes, we developed shape-specific cerium oxide nanoparticles (CNPs), which have unique properties to mitigate oxidative stress. We demonstrated that the oxidative stress exacerbated the calcification in hVICs. We then demonstrated the effectiveness of CNPs in alleviating oxidative stress and preventing calcification in hVICs. Finally, we combined antioxidant CNPs with anisotropic fibrous scaffolds to obtain nanocomposite scaffolds. These scaffolds possessed antioxidant properties and supported hVIC attachment and proliferation. In an oxidative stress-induced calcification model, hVICs cultured on CNP encapsulated scaffolds displayed reduced calcification tendency. Collectively, using micro-/nanotechnology-based strategies, we developed novel tissue-engineered heart valve scaffolds with anisotropic mechanical properties and the potential to mitigate the thrombogenicity and calcification frequently observed in current valve replacement therapies

The effect of resolvin D1 on bone regeneration in a rat calvarial defect model

Resolvin D1 (RvD1) is a pro-resolving lipid mediator of inflammation, endogenously synthesized from omega-3 docosahexaenoic acid. The purpose of this study was to investigate the effect of RvD1 on bone regeneration using a rat calvarial defect model. Collagen 3D nanopore scaffold (COL) and Pluronic F127 hydrogel (F127) incorporated with RvD1 (RvD1-COL-F127 group) or COL and F127 (COL-F127 group) were implanted in symmetrical calvarial defects. After implantation, RvD1 was administrated subcutaneously every 7 days for 4 weeks. The rats were sacrificed at weeks 1 and 8 post-implantation. Tissue samples were analyzed by real-time reverse transcriptase-polymerase chain reaction and histology at week 1. Radiographical and histological analyses were done at week 8. At week 1, calvarial defects treated with RvD1 exhibited decreased numbers of inflammatory cells and tartrate-resistant acid phosphatase (TRAP) positive cells, greater numbers of newly formed blood vessels, upregulated gene expression of vascular endothelial growth factor and alkaline phosphatase, and downregulated gene expression of receptor activator of nuclear factor-κB ligand, interleukin-1β and tumor necrosis factor-α. At week 8, the radiographical results showed that osteoid area fraction of the RvD1-COL-F127 group was higher than that of the COL-F127 group, and histological examination exhibited enhanced osteoid formation and newly formed blood vessels in the RvD1-COL-F127 group. In conclusion, this study showed that RvD1 enhanced bone formation and vascularization in rat calvarial defects

Design and Fabrication of Flexible Naked-Eye 3D Display Film Element Based on Microstructure

The naked-eye three-dimensional (3D) display technology without wearing equipment is an inevitable future development trend. In this paper, the design and fabrication of a flexible naked-eye 3D display film element based on a microstructure have been proposed to achieve a high-resolution 3D display effect. The film element consists of two sets of key microstructures, namely, a microimage array (MIA) and microlens array (MLA). By establishing the basic structural model, the matching relationship between the two groups of microstructures has been studied. Based on 3D graphics software, a 3D object information acquisition model has been proposed to achieve a high-resolution MIA from different viewpoints, recording without crosstalk. In addition, lithography technology has been used to realize the fabrications of the MLA and MIA. Based on nanoimprint technology, a complete integration technology on a flexible film substrate has been formed. Finally, a flexible 3D display film element has been fabricated, which has a light weight and can be curled

CD36-mediated podocyte lipotoxicity promotes foot process effacement

Lipid metabolism disorders lead to lipotoxicity. The hyperlipidemia-induced early stage of renal injury mainly manifests as podocyte damage. CD36 mediates fatty acid uptake and the subsequent accumulation of toxic lipid metabolites, resulting in podocyte lipotoxicity

The effect of resolvin D1 on bone regeneration in a rat calvarial defect model

Resolvin D1 (RvD1) is a pro-resolving lipid mediator of inflammation, endogenously synthesized from omega-3 docosahexaenoic acid. The purpose of this study was to investigate the effect of RvD1 on bone regeneration using a rat calvarial defect model. Collagen 3D nanopore scaffold (COL) and Pluronic F127 hydrogel (F127) incorporated with RvD1 (RvD1-COL-F127 group) or COL and F127 (COL-F127 group) were implanted in symmetrical calvarial defects. After implantation, RvD1 was administrated subcutaneously every 7 days for 4 weeks. The rats were sacrificed at weeks 1 and 8 post-implantation. Tissue samples were analyzed by real-time reverse transcriptase-polymerase chain reaction and histology at week 1. Radiographical and histological analyses were done at week 8. At week 1, calvarial defects treated with RvD1 exhibited decreased numbers of inflammatory cells and tartrate-resistant acid phosphatase (TRAP) positive cells, greater numbers of newly formed blood vessels, upregulated gene expression of vascular endothelial growth factor and alkaline phosphatase, and downregulated gene expression of receptor activator of nuclear factor-κB ligand, interleukin-1β and tumor necrosis factor-α. At week 8, the radiographical results showed that osteoid area fraction of the RvD1-COL-F127 group was higher than that of the COL-F127 group, and histological examination exhibited enhanced osteoid formation and newly formed blood vessels in the RvD1-COL-F127 group. In conclusion, this study showed that RvD1 enhanced bone formation and vascularization in rat calvarial defects.publishedVersio

Pretreatment with an antibiotics cocktail enhances the protective effect of probiotics by regulating SCFA metabolism and Th1/Th2/Th17 cell immune responses

Abstract Background Probiotics are a potentially effective therapy for inflammatory bowel disease (IBD); IBD is linked to impaired gut microbiota and intestinal immunity. However, the utilization of an antibiotic cocktail (Abx) prior to the probiotic intervention remains controversial. This study aims to identify the effect of Abx pretreatment from dextran sulfate sodium (DSS)-induced colitis and to evaluate whether Abx pretreatment has an enhanced effect on the protection of Clostridium butyricum Miyairi588 (CBM) from colitis. Results The inflammation, dysbiosis, and dysfunction of gut microbiota as well as T cell response were both enhanced by Abx pretreatment. Additionally, CBM significantly alleviated the DSS-induced colitis and impaired gut epithelial barrier, and Abx pretreatment could enhance these protective effects. Furthermore, CBM increased the benefit bacteria abundance and short-chain fatty acids (SCFAs) level with Abx pretreatment. CBM intervention after Abx pretreatment regulated the imbalance of cytokines and transcription factors, which corresponded to lower infiltration of Th1 and Th17 cells, and increased Th2 cells. Conclusions Abx pretreatment reinforced the function of CBM in ameliorating inflammation and barrier damage by increasing beneficial taxa, eliminating pathogens, and inducing a protective Th2 cell response. This study reveals a link between Abx pretreatment, microbiota, and immune response changes in colitis, which provides a reference for the further application of Abx pretreatment before microbiota-based intervention