Intraocular pressure control efficacy and safety of HA-Mg glaucoma drainage plate implantation in the anterior chamber of rabbit eyes.

The current clinical application of glaucoma drainage devices is made of non-degradable materials. These non-degradable drainage devices often trigger inflammatory responses and scar proliferation, possibly leading to surgical failure. We developed a biodegradable material hydroxyapatite-coated magnesium (HA-Mg) as a glaucoma drainage device. Twelve New Zealand white rabbits were randomly assigned to three groups: HA-Mg drainage plate group (6 right eyes), trabeculectomy group (6 right eyes), and control group (12 left eyes). Results showed that all HA-Mg drainage plates were completely degraded ~4 months postoperatively. At the 5th month postoperatively, there was no statistical difference in the corneal endothelium density between the HA-Mg drainage plate group and the control group (p = 0.857). The intraocular pressure (IOP) level in the HA-Mg drainage plate implantation group was lower than in the other two groups. The trypan blue dye still drained from the anterior chamber to the subconjunctiva 5 months after HA-Mg drainage plate implantation. HE staining revealed the scleral linear aqueous humor drainage channel and anterior synechia were observed after drainage plate completely degraded, with no obvious infiltration with the inflammatory cells. This study showed the safety and efficacy of HA-Mg glaucoma drainage plate in controlling IOP after implantation into the anterior chamber of rabbit eyes.

Prospective association between perceived stress and anxiety among nursing college students: the moderating roles of career adaptability and professional commitment.

BACKGROUND: Anxiety may stay with nursing students throughout their internship and even persist afterwards. Although many studies have explored the effects of perceived stress on anxiety, the relationship between pre-internship perceived stress and post-internship anxiety levels has not been clarified. In addition, none had focused on the moderating roles of career adaptability and professional commitment between perceived stress and anxiety. This study aims to investigate the influence of pre-internship perceived stress on the post-internship anxiety level of nursing college students, and to analyze the moderating effects of career adaptability and professional commitment on their relationships. METHODS: A longitudinal study design was employed. Full-time nursing college students from a Chinese medical university were recruited by convenient sampling. All surveys were conducted via Wen Juan Xing ( www.wjx.cn ), a widely used web-based survey platform in China. Two waves of surveys were collected in the pre-internship and post-internship periods, with an interval of one year. Among 823 nursing students recruited, 692 students completed all two waves of the survey (response rate: 84.08%). Participants completed a series of questionnaires examining general demographic characteristics, perceived stress, anxiety, career adaptability, and professional commitment both before and after the internship. The bias-corrected bootstrap technique of the Hayes PROCESS macro (Model 2) was used to test the moderation effect. RESULTS: Pre-internship perceived stress was positively associated with post-internship anxiety (ß = 0.474, p < 0.001). Career adaptability would mitigate the effect of perceived stress on anxiety (ß = -0.009, p < 0.01, 95% CI = [-0.013, -0.004]), and this influence became stronger for nursing college students with higher levels of career adaptability. Instead, the professional commitment would enhance the effect of perceived stress on anxiety (ß = 0.004, p < 0.05, 95% CI = [0.001, 0.009]). CONCLUSIONS: Adequate career adaptability was key to alleviating anxiety among nursing interns. Nursing educators and clinical nursing managers should pay attention to cultivating the career adaptability of nursing college students in order to help them successfully achieve identity transformation and career development. Meanwhile, it is crucial to guide them to develop appropriate professional commitment.

Percutaneous Mechanical Atherothrombectomy Using the Rotarex Device in Acute Ischemic Disease of Lower Limbs: A China Retrospective Multicenter Study on 186 Patients.

BACKGROUND: To evaluate the efficacy and safety of the Rotarex mechanical thrombectomy device in treating acute lower extremity arterial ischemia and to explore the appropriate indication of the Rotarex device. METHODS: A retrospective analysis was performed in 186 patients with acute lower extremity arterial ischemia treated with the Rotarex mechanical thrombectomy device from April 2015 to March 2020 in three vascular surgery centers of Tianjin. As per the comprehensive judgment of the etiology, onset time, imaging of ultrasonography (US) and angiography, and findings during treatment, the patients were divided into the embolization group (69 cases), thrombosis group (primary artery stenosis with thrombosis; 86 cases), and restenosis group (stent restenosis with thrombosis; 31 cases). The primary study outcomes included the success rate of Rotarex mechanical thrombectomy device alone, percutaneous transluminal angioplasty (PTA), stent, catheter-directed thrombolysis (CDT) auxiliary rate, target vessel patency rate, and freedom from clinically driven target lesion revascularization rate (f-CD-TLR). The secondary study outcomes included intraoperative distal arterial embolization, postoperative 30-day bleeding, and deterioration of renal function, amputation, and mortality. RESULTS: The success rate of Rotarex mechanical thrombectomy device alone in the embolization group (44.93%) was significantly higher than that in the thrombosis group (13.95%) and restenosis group (0%) (P < 0.01). The PTA auxiliary rate in the embolization group (26.09%) was significantly lower than that in the thrombosis group (72.09%) and restenosis group (100%) (P < 0.01). The stent implantation rates in the embolization group and restenosis group (11.60% and 33.30%, respectively) were significantly lower than that in the thrombosis group (72.09%) (P < 0.01). There were no significant differences in the CDT auxiliary rate, distal arterial embolization, hemorrhage, renal function deterioration, amputation rate, and mortality among the three groups (P > 0.05). The primary patency at 3 months, 6 months, and 12 months postoperatively was 98.6%, 98.6%, and 84.3% in the embolization group, 96.4%, 89.5%, and 74.9% in the thrombosis group, and 93.2%, 84.7%, and 67.5% in the restenosis group, respectively (P < 0.01). The f-CD-TLR at 12 months postoperatively was 88.9% in the embolization group, which was higher than 77.8% in the thrombosis group and 67.5% in the restenosis group (P < 0.01). CONCLUSIONS: The Rotarex mechanical thrombectomy device is a minimally invasive, safe, and effective treatment option for acute lower extremity arterial ischemia, particularly acute arterial embolization. For acute thrombosis secondary to primary artery stenosis and in-stent restenosis, Rotarex device can effectively reduce the thrombus burden and create favorable conditions for other concurrent interventions.

Excimer laser atherectomy combined with drug-coated balloon versus drug-eluting balloon angioplasty for the treatment of infrapopliteal arterial revascularization in ischemic diabetic foot: 24-month outcomes.

There are few studies on excimer laser (308 nm) atherectomy in the treatment of infrapopliteal artery disease. The purpose of this retrospective clinical study was to assess the efficacy and safety of excimer laser atherectomy (ELA) in combination with adjuvant drug-coated balloon angioplasty (DCB) compared to DCB for infrapopliteal arterial revascularization in patients with ischemic diabetic foot. From September 2018 to February 2019, a total of 79 patients with diabetic foot were treated for infrapopliteal arterial revascularization at Tianjin First Central Hospital (Tianjin, China). In this project, 35 patients were treated with ELA combined with DCB angioplasty, and 44 patients were treated with DCB angioplasty. The patients' baseline characteristics were similar between the 2 groups. The primary efficacy endpoints through 24 months were clinically driven target lesion revascularization (CD-TLR), wound healing rate, major amputation rate, and target vessel patency rate. The primary safety endpoint through 24 months was all-cause mortality. The primary efficacy results at 24 months of ELA + DCB versus DCB were CD-TLR of 14.3% versus 34.1% (p = 0.044), wound healing rate of 88.6% versus 65.9% (p = 0.019), target vessel patency rate of 80.0% versus 52.3% (p = 0.010), and major amputations rate of 5.7% versus 22.7% (p = 0.036). The safety signal at 24 months of all-cause mortality rate was 2.9% for ELA + DCB group and 4.5% for DCB group (p = 0.957). ELA combined with DCB angioplasty is more effective than DCB in the treatment of infrapopliteal artery disease in patients with ischemic diabetic foot, which can improve the wound healing rate and target vessel patency rate. There was no statistical difference in the safety results between the two groups.

Identify Candidate Genes in the Interaction between Abdominal Aortic Aneurysm and Type 2 Diabetes Mellitus by Using Biomedical Discovery Support System.

Objective To explore the candidate genes that play significant roles in the interconnection between abdominal aortic aneurysm (AAA) and type 2 diabetes mellitus (DM). Methods We used the Biomedical Discovery Support System (BITOLA) to screen out the candidate intermediate molecular (CIM) "Gene or Gene Product" that are related to AAA and DM. The dataset of GSE13760, GSE7084, GSE57691, GSE47472 were used to analyze the differentially expressed genes (DEGs) of AAA and DM compared to the healthy status. We used the online tool of Venny 2.1 assisted by manual checking to identify the overlapped DEGs with the CIMs. The Human eFP Browser was applied to examine the tissue specific expression levels of the detected genes in order to recognize strong expressed genes in both human artery and pancreatic tissue. Results There were 86 CIMs suggested by the closed BITOLA system. Among all the DEGs of AAA and DM, 8 genes in GSE7084 (ISG20, ITGAX, DSTN, CCL5, CCR5, AGTR1, CD19, CD44) and 2 genes in GSE13760 (PSMD12, FAS) were found to be overlapped with the 86 CIMs. By manual checking and comparing with tissue-specific gene data through Human eFP Browser, the gene PSMD12 (proteasome 26S subunit, non-ATPase 12) was recognized to be strongly expressed in both the aorta and pancreatic tissue. Conclusion We proposed a hypothesis through text mining that PSMD12 might be involved or potentially involved in the interconnection between AAA and DM, which may provide a new clue for studies on novel therapeutic strategies for the two diseases.

Identifying essential proteins in dynamic protein networks based on an improved h-index algorithm.

BACKGROUND: The essential proteins in protein networks play an important role in complex cellular functions and in protein evolution. Therefore, the identification of essential proteins in a network can help to explain the structure, function, and dynamics of basic cellular networks. The existing dynamic protein networks regard the protein components as the same at all time points; however, the role of proteins can vary over time. METHODS: To improve the accuracy of identifying essential proteins, an improved h-index algorithm based on the attenuation coefficient method is proposed in this paper. This method incorporates previously neglected node information to improve the accuracy of the essential protein search. Based on choosing the appropriate attenuation coefficient, the values, such as monotonicity, SN, SP, PPV and NPV of different essential protein search algorithms are tested. RESULTS: The experimental results show that, the algorithm proposed in this paper can ensure the accuracy of the found proteins while identifying more essential proteins. CONCLUSIONS: The described experiments show that this method is more effective than other similar methods in identifying essential proteins in dynamic protein networks. This study can better explain the mechanism of life activities and provide theoretical basis for the research and development of targeted drugs.

Dietary values of macroalgae Porphyra haitanensis in Litopenaeus vannamei under normal rearing and WSSV challenge conditions: Effect on growth, immune response and intestinal microbiota.

Two trials were conducted to determine the effects of dietary macroalgae Porphyra haitanensis on growth, immunity and intestinal microbiota of Litopenaeus vannamei. In trial 1, shrimp (mean initial wet weight about 0.64 g) were fed with seven diets (P0, P1, P2, P3, P4, P5 and P6) containing 0% (basal diet), 1%, 2%, 3%, 4%, 5% and 6% P. haitanensis in triplicate for 60 days. Growth performance (weight gain, WG; specific growth rate, SGR) of shrimp fed the P4 diet were significantly higher than that of shrimp fed P0, P5 and P6 diets (P < 0.05) but without significant differences with shrimp fed P1-P3 diets (P > 0.05). Hepatopancreas phenoloxidase (PO) activity of shrimp fed the P. haitanensis containing diets was significantly higher than that of shrimp fed the basal diet (P0) (P < 0.05). Total haemocyte count (THC) of shrimp fed basal diet (P0) was significantly lower than that of shrimp fed diets containing P. haitanensis. Our results declared that dietary P. haitanensis supplementation increases the abundance of beneficial bacterials such as Nitrosopumilus, Marinobacter or Bifidobacterium and reduces the abundance of harmful bacterias such as Vibrio, and especially pronounced in P4 diet treatment. In trial 2, a WSSV injection challenge test was conducted for 7-day after the rearing trial and shrimp survival was also compared among treatments. A sudden shrimp death was found from the 4th day, and values of survival of shrimp fed the P3-P4 diets were higher than that of shrimp fed other diets during 4-7 days challenge test. The immune response in trial 2 were characterized by higher superoxide dismutase activity (SOD) and PO activities, lower THC and higher HCT compared to levels found in trial 1. In conclusion, suitable dietary P. haitanensis could enhance the growth performance, antioxidant capacity and alter total bacterial numbers or microbial diversity of L. vannamei and furthermore reduce oxidative stress and immune depression challenged by WSSV injection stress, and the level of P. haitanensis supplemented in the diet should be between 2.51% and 3.14%.

Localized surface plasmon enhanced deep UV-emitting of AlGaN based multi-quantum wells by Al nanoparticles on SiO2 dielectric interlayer.

In this paper, we report a 2.6-fold deep ultraviolet emission enhancement of integrated photoluminescence (PL) intensity in AlGaN-based multi-quantum wells (MQWs) by introducing the coupling of local surface plasmons from Al nanoparticles (NPs) on a SiO2 dielectric interlayer with excitons and photons in MQWs at room temperature. In comparison to bare AlGaN MQWs, a significant 2.3-fold enhancement of the internal quantum efficiency, from 16% to 37%, as well as a 13% enhancement of photon extraction efficiency have been observed in the MQWs decorated with Al NPs on SiO2 dielectric interlayer. Polarization-dependent PL measurement showed that both the transverse electric and transverse magnetic mode were stronger than the original intensity in bare AlGaN MQWs, indicating a strong LSPs coupling process and vigorous scattering ability of the Al/SiO2 composite structure. These results were confirmed by the activation energy of non-radiative recombination from temperature-dependent PL measurement and the theoretical three dimensional finite difference time domain calculations.

Induced core-shell structure and the electric properties of (K0.48Na0.52)0.95Li0.05Nb0.95Sb0.05O3 ceramics.

The relationship among dielectric anomaly, ferroelectric response, defects, and microstructures was established for (K0.48(1+x)Na0.52)0.95Li0.05Nb0.95Sb0.05O3 (x = 0.04, 0.00, -0.02, -0.04 and -0.08) ceramics. For x = -0.02 and -0.04, larger coercive fields and lower remnant polarizations were obtained; besides, an additional dielectric relaxation behavior was observed with the activation energy Ea being about 2.19 eV and 1.92 eV, respectively. Furthermore, the grain and grain boundary contributions to the capacitance were separated using impedance spectroscopy, which, combined with back-scattering characterization, firmly indicates the core-shell structure of K-deficient samples (x = -0.02 and -0.04). Unlike the cores, the shells possess a large amount of K+ vacancies (). This work paves a way for regulating the fine structure and more on the electrical properties of KNN-based materials.

Effects of dietary Bacillus licheniformis on growth performance, immunological parameters, intestinal morphology and resistance of juvenile Nile tilapia (Oreochromis niloticus) to challenge infections.

The effects of oral administration of Bacillus licheniformis on growth performance, immunity, intestinal morphology and disease resistance of juvenile tilapia were investigated. Six experimental diets supplemented with different concentrations of B. licheniformis (0%, 0.02%, 0.04%, 0.06%, 0.08% and 0.1% of AlCare(®), containing live germ 2 × 10(10) CFU/g) were formulated, viz. control, T1, T2, T3, T4 and T5. Each diet was randomly assigned to triplicate groups of 30 fishes (3.83 ± 0.03 g). After 10 weeks of feeding trial, weight gain (WG), final body wet weight (FBW) and specific growth rate (SGR) increased significantly in groups T2, T3, T4 and T5 compared with control and T1 (p < 0.05). However, survival rate and feed conversion ratio (FCR) were not found to be significantly affected (P > 0.05). Compared with control, dietary B. licheniformis supplementation increased the content of complement C3 in serum significantly (P < 0.05). The lysozyme activity was observed to be highest in T2 (P < 0.05) without differences among other groups. However, SOD activity was not affected by B. licheniformis supplementation (P > 0.05). When tilapia were challenged against Streptococcus iniae, survival rate improved significantly when tilapia fed with T2, T3, T4 and T5 (P < 0.05). Although there was no significant differences in villi length and muscular layer thickness of anterior intestinal among the treatments, intestinal villi of fish fed with higher concentrations of B. licheniformis (T2, T3, T4, T5) tended to be regularly arranged and exhibited less exfoliation, twist and fusion. These results indicated that dietary supplementation of B. licheniformis not only increased the growth, immune response and disease resistance of juvenile tilapia, but also influenced anterior intestinal development and integrity. Furthermore, in our study, the optimal concentration of B. licheniformis in diets for tilapia was greater than or equal to 4.4 × 10(6) CFU/g.

Dysregulated miR1254 and miR579 for cardiotoxicity in patients treated with bevacizumab in colorectal cancer.

Methods for detecting circulating microRNAs (miRNAs), small RNAs that control gene expression, at high sensitivity and specificity in the blood have been reported in recent studies. The goal of this study was to determine if detectable levels of specific miRNAs are released into the circulation for bevacizumab-induced cardiotoxicity. A miRNA array analysis was performed using RNA isolated from 10 control patients in bevacizumab treatment, and n=10 patients have been confirmed to have bevacizumab-induced cardiotoxicity. From the array, we selected 19 candidate miRNA for a second validation study in 90 controls and 88 patients with bevacizumab-induced cardiotoxicity. Consistent with the data obtained from the microRNA array, circulating levels of five miRNAs were significantly increased in patients with bevacizumab-induced cardiotoxicity compared with controls. To confirm these data, we compared selected miRNAs in the plasma of patients with bevacizumab-induced cardiotoxicity with those of 66 patients with acute myocardial infarction (AMI). Moreover, we went on to analyze what factors may influence the levels of potential biomarker miRNAs. Consistent with the data obtained from the microRNA array, circulating levels of five miRNAs were significantly increased in patients with bevacizumab-induced cardiotoxicity compared with those of healthy bevacizumab treatment controls. However, only miRNA1254 and miRNA579 showed high specificity in the validation experiments. Moreover, we went on to analyze what factors may influence the levels of potential biomarker miRNAs. We identify two miRNAs that are specifically elevated in patients with bevacizumab-induced cardiotoxicity, miR1254 and miRNA579, and miRNA1254 shows the strongest correlation to the clinical diagnosis of bevacizumab-induced cardiotoxicity.

Inhibition of the function of class IIa HDACs by blocking their interaction with MEF2.

Enzymes that modify the epigenetic status of cells provide attractive targets for therapy in various diseases. The therapeutic development of epigenetic modulators, however, has been largely limited to direct targeting of catalytic active site conserved across multiple members of an enzyme family, which complicates mechanistic studies and drug development. Class IIa histone deacetylases (HDACs) are a group of epigenetic enzymes that depends on interaction with Myocyte Enhancer Factor-2 (MEF2) for their recruitment to specific genomic loci. Targeting this interaction presents an alternative approach to inhibiting this class of HDACs. We have used structural and functional approaches to identify and characterize a group of small molecules that indirectly target class IIa HDACs by blocking their interaction with MEF2 on DNA.Weused X-ray crystallography and (19)F NMRto show that these compounds directly bind to MEF2. We have also shown that the small molecules blocked the recruitment of class IIa HDACs to MEF2-targeted genes to enhance the expression of those targets. These compounds can be used as tools to study MEF2 and class IIa HDACs in vivo and as leads for drug development.

[Qianlongtong capsule elevates the Smad4 gene expression in prostate stromal cells].

OBJECTIVE: To investigate the effects of the plasma containing Qianlongtong Capsule (QLT)-containing plasma on the expression of the Smad4 gene in prostate stromal cells in vitro and provide some experimental evidence for the treatment of benign prostatic hyperplasia (BPH) with Chinese medicinal compound. METHODS: Fifteen cases of BPH were equally randomized to three groups to be treated with QLT at a high dose (6 capsules once), a medium dose (3 capsules once), and a low dose (1.5 capsules once), tid, for 7 days consecutively. QLT-containing plasma was collected from the patients. Prostate stromal cells were identified by immunofluorescence when they became monolayered and cultured in the QLT-containing plasma for 24 hours, followed by detection of the expression of the Smad4 gene by real-time quantitative PCR and that of the Smad4 protein by Western blot. RESULTS: After treatment with the QLT-containing plasma, the expression of the Smad4 gene in the stromal cells was significantly increased in a dose-dependent manner as compared with the blank control and no-QLT groups (P < 0.01). The expression of the Smad4 protein was also markedly elevated after treatment. The differences were statistically significant between the blank control and medium-dose groups (P < 0.01), low-dose and medium-dose groups (P < 0.05), and high-dose and the other groups (P < 0.01), but not between the blank control and low-dose groups (P > 0.05). CONCLUSION: QLT-containing plasma could inhibit the proliferation and improve the apoptotic index of prostate stromal cells in vitro, which was related to the elevation of the mRNA and protein expressions of Smad4.

Baicalein 6-O-ß-D-glucopyranuronoside is a main metabolite in the plasma after oral administration of baicalin, a flavone glucuronide of scutellariae radix, to rats.

Baicalin (BG) and its aglycone, baicalein (B) are strong antioxidants that exert various pharmacological actions and show unique metabolic fates in the rat. The aim of the present study was to identify major metabolite(s) besides BG in rat plasma after oral administration of BG or B. The main metabolite was detected by HPLC equipped with an electrochemical detector at a potential of +500 mV and identified as baicalein 6-O-ß-D-glucopyranuronoside (B6G) by HPLC/MS/MS. When BG at a dose of 20 mg/kg was administered orally to Wistar rats, the level of B6G in plasma was higher than that of BG. Cmax and the area under the concentration-curve from 0 to 24 h (AUC0-24 h) values of the plasma B6G were 1.66 ± 0.34 µM and 19.8 3.9 ± µM · h, respectively, whereas those of BG were 0.853 ± 0.065 µM and 10.0 ± 3.1 µM · h, respectively. When B was administered, similar results were also obtained. B6G-producing activities from B were found in microsomes of both rat jejunum and liver, in spite of the low activity. Rat everted jejunal sacs formed B6G after application of B, but only in a small amount that was excreted into the mucosal side, and not the serosal side, indicating little contribution to the appearance of B6G in plasma. On the other hand, when B was injected into the rat portal vein, B6G was detected at a higher level than BG in the systemic circulation, demonstrating the hepatic contribution to the appearance of plasma B6G.

Structure of p300 bound to MEF2 on DNA reveals a mechanism of enhanceosome assembly.

Transcription co-activators CBP and p300 are recruited by sequence-specific transcription factors to specific genomic loci to control gene expression. A highly conserved domain in CBP/p300, the TAZ2 domain, mediates direct interaction with a variety of transcription factors including the myocyte enhancer factor 2 (MEF2). Here we report the crystal structure of a ternary complex of the p300 TAZ2 domain bound to MEF2 on DNA at 2.2Å resolution. The structure reveals three MEF2:DNA complexes binding to different sites of the TAZ2 domain. Using structure-guided mutations and a mammalian two-hybrid assay, we show that all three interfaces contribute to the binding of MEF2 to p300, suggesting that p300 may use one of the three interfaces to interact with MEF2 in different cellular contexts and that one p300 can bind three MEF2:DNA complexes simultaneously. These studies, together with previously characterized TAZ2 complexes bound to different transcription factors, demonstrate the potency and versatility of TAZ2 in protein-protein interactions. Our results also support a model wherein p300 promotes the assembly of a higher-order enhanceosome by simultaneous interactions with multiple DNA-bound transcription factors.

Construction of Rapid Extracellular Matrix-Deposited Small-Diameter Vascular Grafts Induced by Hypoxia in a Bioreactor.

Cardiovascular disease has become one of the most globally prevalent diseases, and autologous or vascular graft transplantation has been the main treatment for the end stage of the disease. However, there are no commercialized small-diameter vascular graft (SDVG) products available. The design of SDVGs is promising in the future, and SDVG preparation using an in vitro bioreactor is a favorable method, but it faces the problem of long-term culture of >8 weeks. Herein, we used different oxygen (O2) concentrations and mechanical stimulation to induce greater secretion of extracellular matrix (ECM) from cells in vitro to rapidly prepare SDVGs. Culturing with 2% O2 significantly increased the production of the ECM components and growth factors of human dermal fibroblasts (hDFs). To accelerate the formation of ECM, hDFs were seeded on a polycaprolactone (PCL) scaffold and cultured in a flow culture bioreactor with 2% O2 for only 3 weeks. After orthotopic transplantation in rat abdominal aorta, the cultured SDVGs (PCL-decellularized ECM) showed excellent endothelialization and smooth muscle regeneration. The vascular grafts cultured with hypoxia and mechanical stimulation could accelerate the reconstruction speed and obtain an improved therapeutic effect and thereby provide a new research direction for improving the production and supply of SDVGs.

Functionalization of in vivo tissue-engineered living biotubes enhance patency and endothelization without the requirement of systemic anticoagulant administration.

Vascular regeneration and patency maintenance, without anticoagulant administration, represent key developmental trends to enhance small-diameter vascular grafts (SDVG) performance. In vivo engineered autologous biotubes have emerged as SDVG candidates with pro-regenerative properties. However, mechanical failure coupled with thrombus formation hinder translational prospects of biotubes as SDVGs. Previously fabricated poly(ε-caprolactone) skeleton-reinforced biotubes (PBs) circumvented mechanical issues and achieved vascular regeneration, but orally administered anticoagulants were required. Here, highly efficient and biocompatible functional modifications were introduced to living cells on PB lumens. The 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-methoxy (DMPE)-PEG-conjugated anti-coagulant bivalirudin (DPB) and DMPE-PEG-conjugated endothelial progenitor cell (EPC)-binding TPS-peptide (DPT) modifications possessed functionality conducive to promoting vascular graft patency. Co-modification of DPB and DPT swiftly attained luminal saturation without influencing cell viability. DPB repellent of non-specific proteins, DPB inhibition of thrombus formation, and DPB protection against functional masking of DPT's EPC-capture by blood components, which promoted patency and rapid endothelialization in rat and canine artery implantation models without anticoagulant administration. This strategy offers a safe, facile, and fast technical approach to convey additional functionalization to living cells within tissue-engineered constructs.

Biomimetic tri-layered small-diameter vascular grafts with decellularized extracellular matrix promoting vascular regeneration and inhibiting thrombosis with the salidroside.

Small-diameter vascular grafts (SDVGs) are urgently required for clinical applications. Constructing vascular grafts mimicking the defining features of native arteries is a promising strategy. Here, we constructed a tri-layered vascular graft with a native artery decellularized extracellular matrix (dECM) mimicking the component of arteries. The porcine thoracic aorta was decellularized and milled into dECM powders from the differential layers. The intima and media dECM powders were blended with poly (L-lactide-co-caprolactone) (PLCL) as the inner and middle layers of electrospun vascular grafts, respectively. Pure PLCL was electrospun as a strengthening sheath for the outer layer. Salidroside was loaded into the inner layer of vascular grafts to inhibit thrombus formation. In vitro studies demonstrated that dECM provided a bioactive milieu for human umbilical vein endothelial cell (HUVEC) extension adhesion, proliferation, migration, and tube-forming. The in vivo studies showed that the addition of dECM could promote endothelialization, smooth muscle regeneration, and extracellular matrix deposition. The salidroside could inhibit thrombosis. Our study mimicked the component of the native artery and combined it with the advantages of synthetic polymer and dECM which provided a promising strategy for the design and construction of SDVGs.

Endothelium-Mimetic Surface Modification Improves Antithrombogenicity and Enhances Patency of Vascular Grafts in Rats and Pigs.

We first identified thrombomodulin (TM) and endothelial nitric oxide (NO) synthase as key factors for the antithrombogenic function of the endothelium in human atherosclerotic carotid arteries. Then, recombinant TM and an engineered galactosidase responsible for the conversion of an exogenous NO prodrug were immobilized on the surface of the vascular grafts. Surface modification by TM and NO cooperatively enhanced the antithrombogenicity and patency of vascular grafts. Importantly, we found that the combination of TM and NO also promoted endothelialization, whereas it reduced adverse intimal hyperplasia, which is critical for the maintenance of vascular homeostasis, as confirmed in rat and pig models.

Intracellular delivery of nitric oxide enhances the therapeutic efficacy of mesenchymal stem cells for myocardial infarction.

Cell therapy by autologous mesenchymal stem cells (MSCs) is a clinically acceptable strategy for treating various diseases. Unfortunately, the therapeutic efficacy is largely affected by the low quality of MSCs collected from patients. Here, we showed that the gene expression of MSCs from patients with diabetes was differentially regulated compared to that of MSCs from healthy controls. Then, MSCs were genetically engineered to catalyze an NO prodrug to release NO intracellularly. Compared to extracellular NO conversion, intracellular NO delivery effectively prolonged survival and enhanced the paracrine function of MSCs, as demonstrated by in vitro and in vivo assays. The enhanced therapeutic efficacy of engineered MSCs combined with intracellular NO delivery was further confirmed in mouse and rat models of myocardial infarction, and a clinically relevant cell administration paradigm through secondary thoracotomy has been attempted.