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Supplemental Material, sj-pdf-1-sri-10.1177_15533506211046100 for Hemostatic Efficacy and Biocompatibility Evaluation of a Novel Absorbable Porous Starch Hemostat by Jianjun Zhu, Zhuona Wu, Wenzhong Sun, Zhiyun Meng, Xiaoxia Zhu, Hui Gan, Ruolan Gu, Xuan Guo and Guifang Dou in Surgical Innovation

In the process of decomposing the original signal, Doppler sodar used to measure the wind speed can effectively strip the high frequency, intermediate frequency and low frequency signals from each other by the empirical mode decomposition in wind power prediction. The prediction process of the model used in this paper and the evaluation index of the results. In order to verify the effect of the model, the measured data of an offshore wind farm in the coastal area of East Asia from January to April 2019 were selected for strict and standardized verification. The collected raw data are input into the empirical mode decomposition of the collection accurately and normatively, thereby obtaining accurate and complete modal components. At the same time, they are divided into three categories of intermediate frequency, low frequency and high frequency according to their fluctuation characteristics. Through the selected indicators for a comprehensive and objective evaluation, it is understood by testing that the model created in this paper has good feasibility and effectiveness, not only high prediction accuracy, but also fast calculation speed.

A novel strategy was proposed for the construction of photoelectrochemical (PEC) sensing platform based on multifunctional photosensitizer which can simultaneously achieve photo-sensitization, target-recognition and interface conjugation. Herein, N3 dye, bis(4,4′-dicarboxy-2,2′-bipyrid ine) dithiocyanato ruthenium (II), was employed as a model multifunctional molecule and covalently tethered on amino-functionalized TiO2 nanowires. The obtained photoanode can produce a sensitive photocurrent response towards Hg2+ under visible illumination (∼540 nm). The decrease in photocurrent can be attributed the larger HOMO-LUMO gap, the higher LUMO energy level and the reduced electron cloud density of N3–Hg2+ complex compared with the free N3 dye, which is demonstrated by DFT calculations. Under optimized conditions, the PEC assay displayed a linear dynamic range of 0.5–50 μM for Hg2+ with a detection limit of 0.13 nM. Moreover, the long-term stability of the PEC sensor was achieved due to the covalent conjugation of the photosensitizer to the TiO2 nanowire. The proposed sensing strategy, by utilizing the multifunctional molecule photosensitizers for direct responding to targets, presents a novel methodology for the development of high performance PEC sensors in future.

In the present study genipin crosslinked chitosan (CHI) hydrogels, which had been constructed and reported in our previous studies (Gao et al., 2014 [22]), were further evaluated for their advantage as a carrier for silver sulfadiazine (AgSD) nanocrystal systems. Firstly, AgSD nanocrystals with a mean particle size of 289 nm were prepared by wet milling method and encapsulated into genipin crosslinked CHI hydrogels. AgSD nanocrystals displayed a uniform distribution and very good physical stability in the hydrogel network. Swelling-dependent release pattern was found for AgSD nanocrystals from hydrogels and the release profile could be well fitted with Peppas equation. When AgSD nanocrystals were encapsulated in hydrogels their fibroblast cytotoxicity decreased markedly, and their antibacterial effects against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa were still comparable to unencapsulated AgSD nanocrystals. In vivo evaluation in excision and burn cutaneous wound models in mice showed that AgSD nanocrystal hydrogels markedly decreased the expression of inflammatory cytokine IL-6, but increased the levels of growth factors VEGF-A and TGF-β1. Histopathologically, the wounds treated by hydrogels containing AgSD nanocrystals showed the best healing state compared with commercial AgSD cream, hydrogels containing AgSD bulk powders and blank hydrogels. The wounds treated by AgSD nanocrystal hydrogels were dominated by marked fibroblast proliferation, new blood vessels and thick regenerated epithelial layer. Sirius Red staining assay indicated that AgSD nanocrystal hydrogels resulted in more collagen deposition characterized by a large proportion of type I fibers. Our study suggested that genipin-crosslinked CHI hydrogel was a potential carrier for local antibacterial nanomedicines.

Starch hemostatic agents have been clinically used in surgical hemostasis in recent years. Calcium ion (Ca2+)-exchange cross-linked porous starch microparticles (Ca2+CPSMs) were prepared as a new hemostatic agent to enhance the hemostatic efficacy. A series of Ca2+CPSMs with varying Ca2+ contents were prepared and characterized by Fourier-transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), scanning electron microscope (SEM), and ion content analysis. The XPS and FT-IR results indicated that the surface of Ca2+CPSMs was modified by Ca2+, which might form coordination bonds with oxygen atoms of starch molecules. Ca2+CPSMs revealed a porous surface structure and a lower crystallinity degree according to SEM and XRD, which facilitated the phosphate buffer saline (PBS) uptake rate and enzymatic degradation in vitro. The fast release of Ca2+ from Ca2+CPSMs accelerated the whole blood clotting rate, shortened the activated partial thromboplastin time, and promoted platelet adhesion. The physical hemostatic mechanism benefited from the rapid PBS uptake capacity and porous surface structure of Ca2+CPSMs, in addition to the chemical activation of coagulation process by Ca2+, thus achieving a significant hemorrhage control in the mouse tail amputation model.

Xiaoya Liu, Hui Gan, Chaoran Hu, Wenzhong Sun, Xiaoxia Zhu, Zhiyun Meng, Ruolan Gu, Zhuona Wu, Guifang Dou Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, People’s Republic of China Background: Silver sulfadiazine (AgSD) is widely employed as an antibacterial agent for surface burn management. However, the antibacterial activity of AgSD was restrained because of the lower drug solubility and possible cytotoxicity. Objective: This study aimed to formulate stable silver sulfadiazine/nanosuspensions (AgSD/NSs) with improved AgSD solubility and prepare a suitable carrier for AgSD/NS delivery. Nanotechnology was used to overcome the low drug dissolution rate of AgSD, while the new carrier loaded with AgSD/NS was assumed to decrease the possible cytotoxicity, enhance antibacterial activity, and promote wound healing. Methods: AgSD/NSs were prepared by high pressure homogenization method. Poloxamer 407-based thermoresponsive hydrogels were prepared by cold method as carriers of AgSD/NS to obtain AgSD/NS-loaded thermoresponsive hydrogel. Scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) were used to measure the physicalchemical properties of AgSD/NSs and AgSD/NS-loaded gel. The cytotoxicity of the AgSD/NS-loaded gel was evaluated using methyl thiazolyltetrazolium assay with L929 mouse fibroblast cell lines. In vitro antibacterial activities of AgSD/NSs and AgSD/NS loaded gel were also measured. Results: Stable AgSD/NSs with an average particle size of 369 nm were formulated while 1.5% P407 was selected as a stabilizer. The optimized AgSD/NS thermoresponsive hydrogel exhibited the gelation temperature of approximately 30°C. A significant improvement in solubility was observed for AgSD nanoparticles (96.7%) compared with AgSD coarse powders (12.5%). The results of FTIR and XRD revealed that the physicochemical properties of AgSD/NS were reserved after incorporating into the hydrogel. The cell viability after incubation with AgSD/NS-loaded thermoresponsive hydrogel improved from 60.7% to 90.6% compared with incubation with AgSD/NS directly. Drug release profiles from the thermoresponsive hydrogel increased compared with the commercial AgSD cream, implying less application frequency of AgSD cream clinically. In vitro antibacterial studies manifested that AgSD nanocrystallization significantly enhanced the antibacterial activity compared with the AgSD coarse powder. Conclusion: The combination of AgSD nanosuspensions and thermoresponsive hydrogel effectively improved the AgSD antibacterial activity and decreased the cytotoxicity. This study also suggested that a poloxamer thermoresponsive hydrogel could be used as a delivery system for other nanocrystals to decrease possible nanotoxicity. Keywords: cytotoxicity, wound healing infection, nanotechnology

Porous starch (PS) is a multifunctional biomaterial and has been widely applied in both pharmaceutical and food industry. This study was carried out to develop a new type of porous starch microspheres (PSM) through the dual-modification of the alcohol-alkaline treatment and inverse crosslinking-emulsion method, which could rapidly uptake water. The chemical and physical characteristics of the PSMs were determined by FTIR, SEM, XRD, DSC, ESD (equilibrium swelling ratio) and WS (water solubility). The results showed that PSMs could reach its saturated water uptake volume (about 1 mL/100 mg) in 60 s. The PSMs also revealed rough surface with observable pores and lower crystallinity degree after the dual-modification according to SEM and XRD. The use of epichlorohydrin (ECH) as a crosslinking agent could introduce crosslinks between starch molecular chains, which was determined by ESD, WS and the thermal properties. These results indicated that the dual-modification could be successfully used for preparation of rapid water uptake PSMs with enhanced structure stability.

Icaritin is one of the Epimedium products with various biological activities. In the present study, we developed a rapid, reliable and robust UHPLC–MS/MS method to simultaneously determine unconjugated icaritin and its multiple glucuronides (icaritin-3-glucuronide, icaritin-7-glucuronide and icaritin-3,7-diglucuronide) in microsomal incubation systems, and applied it to study icaritin regioselective glucuronidation in vitro. We identified the involvement of human UDP-glucuronosyltransferase (UGT) isoforms in icaritin metabolism and further studied the kinetic profiles of icaritin glucuronidation using pooled human liver microsomes (HLMs), pooled rat liver microsomes (RLMs), pooled human intestine microsomes (HIMs) and UGTs, respectively. We also evaluated regioselective glucuronidation of icaritin by UGT isoforms and conducted time-dependent experiment to elucidate the metabolic pathways for icaritin clearance. Catalytic efficiency of microsomes is determined according to rank orders of total intrinsic clearance (CLint): CLint,HLM (24.19 mL/mg/min) > CLint,RLM (13.15 mL/mg/min) > CLint,HIM (6.43 mL/mg/min). Besides, icaritin glucuronidation is mediated by multiple enzymes, with UGT1A1 the principal metabolizing enzyme (total CLint,UGT1A1 = 6.38 mL/mg/min). As for the regioselectivity, except for UGT1A8 and UGT2B7, most UGT isoforms exhibit preference for the position of 3-OH on icaritin structure. Moreover, time-dependent conversion from monoglucuronides to diglucuronide indicate that icaritin-3,7-diglucuronide may be the final metabolite from icaritin elimination.

Purpose The aim of the present study was to investigate the effects of genipin (Gp) cross-linking of chitosan (CHI) hydrogels on the cell adhesion and viability. Method Series of Gp crosslinked CHI hydrogels were prepared by incubation of solutions containing a mixture of Gp and CHI in different ratios. The resulting hydrogels were characterized by scanning electron microscopy (SEM), parallel plate rheometer, contact angle and swelling ratio measurement. The in vitro cytocompatibility of hydrogels was evaluated with L929 fibroblasts by MTT method. The cell adhesion morphology on gel surface was characterized by SEM, and the cell viability was assessed through cell count and flow cytometry analysis. Results It was found that macroporous structure of the CHI hydrogels could be tailored by varying Gp or CHI amount. Gp cross-linking of hydrogels enhanced their storage modulus significantly, and also altered their hydrophilicity and swell properties. The MTT results revealed that the cross-linked hydrogels did not induce cytotoxic effects. Cell count and flow cytometry analysis demonstrated that denser surface milieu of hydrogels could facilitate better cell adhesion and viability. Conclusions It could be concluded that increased cross-linking density significantly improved the cell adhesion and viability on hydrogel surface. This research provides prospective biocompatible approaches by making gel stiffness modifications to hydrogel scaffolds for the purpose of different tissue engineering.

Glucagon-like peptide-1 (GLP-1) has attracted considerable research interest in terms of the treatment of type 2 diabetes due to their multiple glucoregulatory functions. However, the short half-life, rapid inactivation by dipeptidyl peptidase-IV (DPP-IV) and excretion, limits the therapeutic potential of the native incretin hormone. Therefore, efforts are being made to develop the long-acting incretin mimetics via modifying its structure. Here we report a novel recombinant exendin-4 human serum albumin fusion protein E2HSA with HSA molecule extends their circulatory half-life in vivo while still retaining exendin-4 biological activity and therapeutic properties. In vitro comparisons of E2HSA and exendin-4 showed similar insulinotropic activity on rat pancreatic islets and GLP-1R-dependent biological activity on RIN-m5F cells, although E2HSA was less potent than exendin-4. E2HSA had a terminal elimation half-life of approximate 54 h in healthy rhesus monkeys. Furthermore, E2HSA could reduce postprandial glucose excursion and control fasting glucose level, dose-dependent suppress food intake. Improvement in glucose-dependent insulin secretion and control serum glucose excursions were observed during hyperglycemic clamp test (18 h) and oral glucose tolerance test (42 h) respectively. Thus the improved physiological characterization of E2HSA make it a new potent anti-diabetic drug for type 2 diabetes therapy.

Chitosan is a versatile biomaterial lately used as a new generation of local hemostatic agent approved to date for external use only. Here we introduced a fly-larva shell-derived chitosan sponge (CS) and its feasibility for internal use as an absorbable surgical hemostatic agent was evaluated in a rat hepatic hemorrhage model. CS was a better implantable hemostatic material than gelatin sponge (GS) or oxidized cellulose (OC) in both the acute and chronic bleeding models. The better efficacy of CS may be due to its greater ability to enhance platelet activation, erythrocyte aggregation and morphological alteration, and thrombin generation at sites it is applied than GS or OC. Moreover, preliminary safety evaluations have demonstrated excellent blood and cell compatibility in hemorheological measurements, blood coagulation analysis, histological evaluations and hepatocytes culture experiments. None of CS, GS, or OC induced acute inflammation or other adverse effects while normal tissue growth and vascularization were observed in each case 4 weeks after each hemostatic agent had been implanted. Thus, CS has promising properties as an absorbable, implantable agent for promoting perioperative hemostasis and this material warrants further study.