[Preparation and in vitro evaluation of FDM 3D printed theophylline tablets with personalized dosage].

OBJECTIVE: To explore the feasibility of preparing different doses of tablets for personalized treatment by fused deposition modeling (FDM) 3D printing technology, and to evaluate the in vitro quality of the FDM 3D printed tablets. METHODS: Three different sizes of hollow tablets were prepared by fused deposition modeling 3D printing technology with polyvinyl alcohol (PVA) filaments. Theophylline was chosen as the model drug. In the study, 20 mg, 50 mg and 100 mg of theophylline was filled into the cavity of the tablets, respectively. The microscopic morphology of the tablets was observed by scanning electron microscopy (SEM). The weight variation of the tablets was investigated by weighing method. The hardness of the tablets was measured by tablet hardness tester. The contents of the drugs in the tablets were determined by ultraviolet and visible spectrophotometry (UV-Vis), and the dissolution apparatus was used to assay the in vitro drug release of the tablets. RESULTS: The prepared FDM 3D printed tablets were all in good shape without printing defects. And there was no leakage phenomenon. The diameter and thickness of the tablets were consistent with the design. The layers were tightly connected, and the fine structure of the formulation could be clearly observed without printing defects by scanning electron microscopy. The average weight of the three sizes of tablets was (150.5±2.3) mg, (293.6±2.6) mg and (456.2±5.6) mg, respectively. The weight variation of the three sizes of tablets were boss less than 5%, which met the requirements; The hardness of the tablets all exceeded 200 N; The contents of theophylline in the three tablets were 98.0%, 97.2% and 97.9% of the dosage (20 mg, 50 mg and 100 mg), and the relative standard deviation (RSD) was 1.06%, 1.15% and 0.63% respectively; The time for 80% drug released from the three dosage of tablets was within 30 min. CONCLUSION: Three different dosages of theophylline tablets were successfully prepared by FDM 3D printing technology in this study. The exploration may bring beneficial for the preparation of personalized dose preparations. We expect that with the development of 3D printing technology, FDM 3D printed personalized tablets can be used in the clinic as soon as possible to provide personalized treatment for patients.

Crystal orientation mapping and microindentation reveal anisotropy in Porites skeletons.

Structures made by scleractinian corals support diverse ocean ecosystems. Despite the importance of coral skeletons and their predicted vulnerability to climate change, few studies have examined the mechanical and crystallographic properties of coral skeletons at the micro- and nano-scales. Here, we investigated the interplay of crystallographic and microarchitectural organization with mechanical anisotropy within Porites skeletons by measuring Young's modulus and hardness along surfaces transverse and longitudinal to the primary coral growth direction. We observed micro-scale anisotropy, where the transverse surface had greater Young's modulus and hardness by ∼ 6 GPa and 0.2 GPa, respectively. Electron backscatter diffraction (EBSD) revealed that this surface also had a higher percentage of crystals oriented with the a-axis between ± 30-60∘, relative to the longitudinal surface, and a broader grain size distribution. Within a region containing a sharp microscale gradient in Young's modulus, nanoscale indentation mapping, energy dispersive spectroscopy (EDS), EBSD, and Raman crystallography were performed. A correlative trend showed higher Young's modulus and hardness in regions with individual crystal bases (c-axis) facing upward, and in crystal fibers relative to centers of calcification. These relationships highlight the difference in mechanical properties between scales (i.e. crystals, crystal bundles, grains). Observations of crystal orientation and mechanical properties suggest that anisotropy is driven by microscale organization and crystal packing rather than intrinsic crystal anisotropy. In comparison with previous observations of nanoscale isotropy in corals, our results illustrate the role of hierarchical architecture in coral skeletons and the influence of biotic and abiotic factors on mechanical properties at different scales. STATEMENT OF SIGNIFICANCE: Coral biomineralization and the ability of corals' skeletal structure to withstand biotic and abiotic forces underpins the success of reef ecosystems. At the microscale, we show increased skeletal stiffness and hardness perpendicular to the coral growth direction. By comparing nano- and micro-scale indentation results, we also reveal an effect of hierarchical architecture on the mechanical properties of coral skeletons and hypothesize that crystal packing and orientation result in microscale anisotropy. In contrast to previous findings, we demonstrate that mechanical and crystallographic properties of coral skeletons can vary between surface planes, within surface planes, and at different analytical scales. These results improve our understanding of biomineralization and the effects of scale and direction on how biomineral structures respond to environmental stimuli.

[Preparation and in vitro evaluation of fused deposition modeling 3D printed compound tablets of captopril and hydrochlorothiazide].

OBJECTIVE: To explore the feasibility of preparing compound tablets for the treatment of hypertension by fused deposition modeling (FDM) 3D printing technology and to evaluate the quality of the printed compound tablets in vitro. METHODS: Polyvinyl alcohol (PVA) filaments were used as the exci-pient to prepare the shell of tablet. The ellipse-shaped tablets (the length of major axes of ellipse was 20 mm, the length of the minor axes of ellipse was 10 mm, the height of tablet was 5 mm) with two separate compartments were designed and printed using FDM 3D printer. The height of layer was 0.2 mm, and the thickness of roof or floor was 0.6 mm. The thickness of shell was 1.2 mm, and the thickness of the partition wall between the two compartments was 0.6 mm. Two cardiovascular drugs, captopril (CTP) and hydrochlorothiazide (HCT), were selected as model drugs for the printed compound tablet and filled in the two compartments of the tablet, respectively. The microscopic morphology of the tablets was observed by scanning electron microscopy (SEM). The weight variation of the tablets was investigated by electronic scale. The hardness of the tablets was measured by a single-column mechanical test system. The contents of the drugs in the tablets were determined by high performance liquid chromatography (HPLC), and the dissolution apparatus was used to measure the in vitro drug release of the tablets. RESULTS: The prepared FDM 3D printed compound tablets were all in good shape without printing defects. The average weight of the tablets was (644.3±6.55) mg. The content of CTP and HCT was separately (52.3±0.26) mg and (49.6±0.74) mg. A delayed in vitro release profile was observed for CTP and HCT, and the delayed release time for CTP and HCT in vitro was 20 min and 40 min, respectively. The time for 70% of CTP and HCT released was separately 30 min and 60 min. CONCLUSION: CTP and HCT compound tablets were successfully prepared by FDM 3D printing technology, and the printed tablets were of good qualities.

[Preparation and in vitro evaluation of fused deposition modeling 3D printed verapa-mil hydrochloride gastric floating formulations].

OBJECTIVE: To explore the feasibility of preparing gastric floating formulations by fused de-position modeling (FDM) 3D printing technology, to evaluate the in vitro properties of the prepared FDM 3D printed gastric floating formulations, and to compare the influence of different external shapes of the formulation with their in vitro properties. METHODS: Verapamil hydrochloride and polyvinyl alcohol (PVA) were used as the model drug and the excipient, respectively. The capsule-shaped and hemisphere-shaped gastric floating formulations were then prepared by FDM 3D printing. The infill percentages were 15%, the layer heights were 0.2 mm, and the roof or floor thicknesses were 0.8 mm for both the 3D printed formulations, while the number of shells was 3 and 4 for capsule-shaped and hemisphere-shaped formulation, respectively. Scanning electron microscopy (SEM) was used to observe the morpho-logy of the surface and cross section of the formulations. Gravimetric method was adopted to measure the weights of the formulations. Texture analyzer was employed to evaluate the hardness of the formulations. High performance liquid chromatography method was used to determine the drug contents of the formulations. The in vitro floating and drug release behavior of the formulations were also characterized. RESULTS: SEM showed that the appearance of the FDM 3D printed gastric floating formulations were both intact and free from defects with the filling structure which was consistent with the design. The weight variations of the two formulations were relatively low, indicating a high reproducibility of the 3D printing fabrication. Above 800.0 N of hardness was obtained in two mutually perpendicular directions for the two formulations. The drug contents of the two formulations approached to 100%, showing no drug loss during the 3D printing process. The two formulations floated in vitro without any lag time, and the in vitro floating time of the capsule-shaped and hemisphere-shaped formulation were (3.97±0.41) h and (4.48±0.21) h, respectively. The in vitro release of the two formulations was significantly slower than that of the commercially available immediate-release tablets. CONCLUSION: The capsule-shaped and hemisphere-shaped verapamil hydrochloride gastric floating formulations were prepared by FDM 3D printing technology successfully. Only the floating time was found to be influenced by the external shape of the 3D printed formulations in this study.

[Preparation and evaluation of blank and doxorubicin loaded poly (acrylic acid) microspheres for embolization].

OBJECTIVE: To prepare ion exchange doxorubicin-loaded poly (acrylic acid) microspheres (DPMs) and evaluate the properties of these chemoembolic agents. METHODS: Poly (acrylic acid) microspheres (PMs) without drug were prepared by inverse suspension polymerization method and then doxorubicin was loaded by ion exchange mechanism to prepare DPMs. Optical microscope was used to investigate the morphology and particle size distribution of PMs and DPMs; fluorescence microscope and confocal microscope were used to observe the distribution of doxorubicin after drug loading. Elasticities of both the microspheres were evaluated by texture analyzer. High performance liquid chromatography (HPLC) method was established to determine the drug loading behavior of PMs and releasing behavior of DPMs. The in vivo embolic property was evaluated by embolizing the hepatic artery of a rabbit with 0.1 mL of DPMs. RESULTS: PMs and DPMs were both spherical in shape, smooth in surface and dispersed well. Doxorubicin was mainly in the outer area inside of DPMs and distributed evenly. The average particle size of PMs and DPMs were (283±136) µm and (248±149) µm, respectively. PMs and DPMs both had good compression ability with the Young's modulus of (62.63±1.65) kPa and (93.94±1.10) kPa separately. PMs reached the drug loading balance at 12 h, and the entrapment efficiency was greater than 99%. Drug loading of PMs in doxorubicin solution at the concentration of 5.0 g/L and 12.5 g/L was (19.78±0.27) g/L and (49.45±0.37) g/L, respectively. Doxorubicin released slowly from DPMs in PBS and the accumulative release percentages of DPMs with corresponding drug loading were 6.82%±0.02% and 2.83%±0.10% after 24 h, respectively. Arterial angiograms showed that the hepatic artery of the rabbit was successfully embolized with DPMs. CONCLUSION: DPMs with good performance of loading doxorubicin could be a potential embolic agent for transcatheter arterial chemoembolization.

[Clinical analysis of de novo HBV infection after liver transplantation in non-HBV- related liver disease].

Objective: The aim of this study was to summarize and analyze the clinical features and characteristics of de novo HBV infection after liver transplantation in non-HBV-related liver disease. Methods: We retrospectively analyzed the clinical data of 13 patients with new HBV infection in 376 cases of liver transplantation patients with non-HBV related liver diseases from April 2002 to December 2013 in our hospital. Results: Among 376 patients with non-HBV-related liver disease after liver transplantation, 13 patients developed new HBV infection, and the rate of new HBV infection was 3.46%. Of the 13 cases, 5 were males and 8 were females. The follow-up time was 14.7 -128.7 months, and the average time from surgery to new HBV infection was 19.06 months. The primary diseases were as follows: 5 cases of primary biliary cholangitis, 3 cases of alcoholic liver disease, 2 cases of drug-induced liver damage, 1 cases of post-hepatitis C cirrhosis, congenital biliary atresia and congenital liver fibrosis. All patients were positive for HBsAg, HBeAg, anti-HBc, 11 were positive for HBV DNA, and 2 were negative for HBV DNA. 6 cases had abnormal liver function and 7 cases had normal liver function. All patients were treated with antiviral therapy with nucleoside (acid) analogues. HBsAg was negative in 6 patients; HBsAg remained positive in 7 cases, including HBsAg, HBeAg, anti-HBc positive in 6 cases, HBsAg, anti-HBe, anti- HBc was positive in 1 case, HBV DNA was still positive in 1 patient, and HBV DNA was negative in 6 patients; liver function was normal in all patients. Conclusion: Non-HBV- related liver transplantation are high-risk group of new HBV infection, with the highest incidence of autoimmune liver disease. It is speculated that it may be related to the long-term use of hormones after the transplantation. The prognosis of newly diagnosed HBV infection after liver transplantation is fine as long as it can be found and treated early.

[Preparation and characterization of citric acid-modified superparamagnetic iron oxide nanoparticles].

OBJECTIVE: To prepare and characterize citric acid (CA)-modified super paramagnetic iron oxide nanoparticles (SPIONs) for magnetic targeting, hyperthermia and magnetic resonance imaging (MRI). METHODS: CA-modified SPIONs (CA-SPIONs) were prepared by co-precipitation method and then the magnetic responsiveness, morphology, particle size, infrared feature, weight percentage of CA, magnetic property and X-ray diffraction pattern of CA-SPIONs were respectively characterized by magnet, transmission electron microscope, laser particle size analyzer, Fourier transform infrared (FT-IR) spectroscopy, thermogravimetry-differential thermal analyzer, vibrating sample magnetometer and X-ray diffractometer (XRD). The heating efficiency of the CA-SPIONs was investigated by a high frequency induction heater. The transverse relaxivity (r2) of the CA-SPIONs was evaluated by a 3.0 T MRI scanner. RESULTS: The CA-SPIONs prepared were dispersed well in water with a dark black color and had good magnetic responsiveness. The CA-SPIONs were spherical in shape and uniform in size with an average size around 12 nm. The hydrodynamic average size of the CA-SPIONs was (72.35±4.47) nm with a polydispersity index of 0.231 ± 0.029. The result of infrared spectrum indicated that CA was successfully modified to the surface of SPIONs. The result of thermogravimetric analysis showed that the weight percentage of CA modified on the CA-SPIONs was 9.0%. The result of magnetic property evaluation demonstrated that the CA-SPIONs exhibited excellent superparamagetism with a saturation magnetism of 63.58 emu/g. The XRD result indicated that the CA-SPIONs were in inverse spinel structure. The crystallite size of the CA-SPIONs was calculated to be 12.4 nm by Debye-Scherrer equation. Under the high frequency alternating electromagnetic field with electric current of 9 A and frequency ranging from 45 to 50 kHz, the CA-SPIONs exhibited excellent heating efficiency and the specific absorption rate (SAR) value was calculated to be 26 W/g. The r2 of the CA-SPIONs was assessed to be 338 (mmol/L)-1×s-1 by a 3.0 T MRI scanner, which suggested the excellent negative contrast enhancement effect of the CA-SPIONs. CONCLUSION: The CA-SPIONs are expected to be used as a promising agent for magnetic targeting, hyperthermia and MRI detection.

Photonic lantern kW-class fiber amplifier.

Pump-limited kW-class operation in a multimode fiber amplifier using adaptive mode control and a photonic lantern front end was achieved. An array of three single-mode fiber inputs was used to adaptively inject the appropriate superposition of input modes in a three-mode gain fiber to achieve the desired mode at the output. Mode fluctuations at high power were compensated by adjusting the relative phase, amplitude, and polarization of the single-mode fiber inputs. The outlook for further power scaling and adaptive-optic compensation is described.

Picosecond kilohertz-class cryogenically cooled multistage Yb-doped chirped pulse amplifier.

A multistage cryogenic chirped pulse amplifier has been developed, utilizing two different Yb-doped gain materials in subsequent amplifier stages. A Yb:GSAG regenerative amplifier followed by a Yb:YAG power amplifier is able to deliver pulses with a broader bandwidth than a system using only one of these two gain media throughout. We demonstrate 90 mJ of pulse energy (113 W of average power) uncompressed and 67 mJ (84 W of average power) compressed at 1.25 kHz pulse repetition frequency, 3.0 ps FWHM Gaussian pulse width, and near-diffraction-limited (M2<1.3) beam quality.

Diode-pumped narrow linewidth multi-kilowatt metalized Yb fiber amplifier.

We investigate high brightness pumping of a multi-kilowatt Yb fiber amplifier in a bi-directional pumping configuration. Each pump outputs 2 kW in a 200 µm, 0.2 NA multimode fiber. Gold-coated specialty gain fibers, with a 17 µm mode field diameter and a 5 dB/m pump absorption, have been developed. The maximum fiber amplifier output power is 3.1 kW, limited by multimode instability, with 90% O-O efficiency and M2<1.15. The fiber amplifier linewidth is 12 GHz.

[Risk factors for hepatitis B recurrence after liver transplantation for HBV-related liver disease].

Objective: To investigate the risk factors for hepatitis B recurrence after liver transplantation for HBV-related liver disease, and to provide a basis for effective preventive measures. Methods: A retrospective analysis was performed for the clinical data of 907 patients with HBV-related liver disease who underwent liver transplantation from April 2002 to December 2013. The chi-square test was used to determine the risk factors for hepatitis B recurrence, and multivariate Cox regression analysis was used for identifying the independent risk factors. Results: There were 907 patients with HBV-related liver disease who underwent liver transplantation. The patients were followed up for 1-144 months, with a median follow-up time of 50.9 months. Among them, 56 experienced hepatitis B recurrence, yielding a recurrence rate of 6.17%. The univariate analysis showed that positive HBeAg before surgery, positive HBV DNA before surgery, positive anti-HBc in liver donor, postoperative tumor recurrence, and postoperative regimen for the prevention of hepatitis B recurrence were significantly correlated with hepatitis B recurrence after liver transplantation (P < 0.05). The multivariate Cox regression analysis showed that positive HBeAg before surgery (OR = 1.891, 95% CI 1.064-3.360, P < 0.05), positive anti-HBc in liver donor (OR = 3.128, 95% CI 1.591-6.151, P < 0.01), and postoperative tumor recurrence (OR = 4.365, 95% CI 2.152-8.857, P < 0.01) were independent risk factors for hepatitis B recurrence. Conclusion: Positive HBeAg before surgery, postoperative tumor recurrence, and positive anti-HBc in liver donor are independent risk factors for hepatitis B recurrence after liver transplantation. For the patients who plan to undergo liver transplantation, antiviral therapy should be given before surgery to reduce HBV viral load, and effective preventive measures after surgery are the key to the prevention and reduction of postoperative hepatitis B recurrence.

[Cone beam CT-derived adaptive radiotherapy for setup error assessment and correction in whole breast intensity modulated radiotherapy].

OBJECTIVE: To quantify the setup error (SE) in breast cancer patients treated with intensity modulated radiotherapy (IMRT) based on cone beam CT (CBCT), and to explore the feasibility of using several CBCT scans to presume and correct SE in the treatment for breast cancer patients. METHODS: Eighteen breast cancer patients after breast conserving surgery who underwent whole breast IMRT were included in this study. Three dimensional interfraction motion before and after on-line CBCT-based corrections were quantified. The on-line CBCT-based corrections were performed using automated greyscale match. The system SE (Σ) and random error (σ) were calculated for each patient based on the consecutive multiple online scanning based on CBCT (≥5). The trends in magnitudes of Σ and σwere assessed during the treatment. RESULTS: The magnitude variation of Σ was less than 1 mm before and after on-line CBCT-based corrections. As the CBCT scanning times increase (before 10 times), the Σ in anteroposterior (AP) direction was increased significantly, and σin three dimensional directions was also increased after 7 times of CBCT scanning. After on-line CBCT-based corrections, the Σ showed a steady trend by variation near zero for the first 20 times irradiation; but after 20 times, the Σ in AP and superoinferior (SI) directions was increased slightly (less than 0.5 mm), and σdecreased in three-dimensional directions. There were no significant differences for Σ, σand setup margin (SM) before and after on-line CBCT-based corrections in all three directions (P>0.05). CONCLUSIONS: For breast cancer patients who underwent IMRT after breast conserving surgery, the setup error is relatively stable during the whole irradiation. The first 5 CBCT scans are suitable to presume and correct SE, and also can be used as the right time for adaptive radiotherapy planning revision.

Photonic lantern adaptive spatial mode control in LMA fiber amplifiers.

We demonstrate adaptive-spatial mode control (ASMC) in few-moded double-clad large mode area (LMA) fiber amplifiers by using an all-fiber-based photonic lantern. Three single-mode fiber inputs are used to adaptively inject the appropriate superposition of input modes in a multimode gain fiber to achieve the desired mode at the output. By actively adjusting the relative phase of the single-mode inputs, near-unity coherent combination resulting in a single fundamental mode at the output is achieved.

Coherent combining of a 4 kW, eight-element fiber amplifier array.

Commercial 0.5 kW Yb-doped fiber amplifiers have been characterized and found to be suitable for coherent beam combining. Eight such fiber amplifiers have been coherently combined in a tiled-aperture configuration with 78% combining efficiency and total output power of 4 kW. The power-in-the-bucket vertical beam quality of the combined output is 1.25 times diffraction limited at full power. The beam-combining performance is independent of output power.

1450-nm high-brightness wavelength-beam combined diode laser array.

We have demonstrated wavelength beam combining of a 1450-nm diode laser array with a novel smile compensation method. We have achieved 20-W cw from a 25-element single bar with an M(2) of 1.9 (fast axis) x 10 (wavelength-beam-combined dimension).

Efficient, high-brightness wavelength-beam-combined commercial off-the-shelf diode stacks achieved by use of a wavelength-chirped volume Bragg grating.

We report a method of scaling the spatial brightness from commercial off-the-shelf diode laser stacks through wavelength beam combining, by use of a linearly wavelength-chirped volume Bragg grating (VBG). Using a three-bar commercial stack of broad-area lasers and a VBG, we demonstrate 89.5 W cw of beam-combined output with a beam-combining efficiency of 75%. The output beam has a propagation factor M2 approximately 26 on the slow axis and M2 approximately 21 on the fast axis. This corresponds to a brightness of approximately 20 MW/cm2 sr. To our knowledge, this is the highest brightness broad-area diode laser system. We achieve 81% coupling efficiency into a 100 microm, 0.22 N.A. fiber.

Near-diffraction-limited diode laser arrays by wavelength beam combining.

We demonstrate 35 W output peak power with M2 approximately 1.35 in both dimensions from a 100 element, 100 microm pitch slab-coupled optical waveguide laser diode array using wavelength beam combining.