Outcome of Chinese patients with hepatitis B at 96 weeks after functional cure with IFN versus combination regimens.

BACKGROUND & AIMS: Nucleotides with add-on interferon treatment (NUC-IFN) provide significantly higher rates of hepatitis B surface antigen (HBsAg) loss in patients with chronic hepatitis B (CHB). This study aimed to investigate the sustainability of HBsAg loss and the prevention of clinical relapse. METHODS: Patients with CHB who achieved HBsAg loss and HBV DNA levels <20 IU/ml after IFN or NUC-IFN therapy were enrolled and followed up for 96 weeks. The primary outcome was HBsAg negativity without viremia at week 96. Secondary outcomes included virological or clinical relapse and predictors of relapse. RESULTS: 420 patients were included in intention-to-treat analysis with 290 and 130 in the IFN and NUC-IFN groups respectively. At week 96, the intention-to-treat analysis revealed similar outcomes between groups, including HBsAg seroreversion (24.83% vs. 23.08%, P = .70), viremia (16.90% vs 13.08%, P = .32) and clinical relapse (11.38% vs 10.00%, P = .68); the per-protocol analyses also showed HBsAg seroreversion, viremia and clinical relapse in IFN group (15.50%, 6.59% and 0.39%) did not differ from those in NUC-IFN group (15.25%, 4.24% and 0.85%, P > .05). These outcomes were similar between patients who received entecavir and those who received telbivudine/lamivudine/adefovir before the combination therapy. In NUC-IFN-treated patients, fibrosis regression was observed at week 96. Baseline HBsAb negativity was independent predictors of HBsAg sero-reversion and recurrence of viremia in IFN treated group. CONCLUSION: NUC-IFN and IFN therapies are equally effective in achieving sustained functional cure and fibrosis regression. (ClinicalTrials.gov, Number NCT02336399).

The reduction in CD8+PD-1+ T cells in liver histological tissue is related to Pegylated IFN-α therapy outcomes in chronic hepatitis B patients.

BACKGROUND: Antiviral therapy is recommended for patients with immune-active chronic hepatitis B (CHB) to decrease the risk of liver-related complications. However, the outcomes of the pegylated IFN-α (PEG-IFN-α) therapy vary among CHB patients. We aimed to identify factors that can influence the outcomes in CHB patients who received antiviral PEG-IFN-α monotherapy. METHODS: Thirty-two CHB patients who received PEG-IFN-α monotherapy were enrolled in this study. All of the patients underwent two liver biopsies at baseline and 6 months after the initiation of the therapy. CD8+ T cells, CD4+ T cells, CD68+ mononuclear cells, and PD-1 levels in the 64 liver biopsy specimens were examined via immunofluorescence. RESULTS: The overall median frequency of CD8+ T cells in the liver tissues of 32 CHB patients significantly decreased at 6 months after the therapy initiation (p < 0.01). In the FIER (fibrosis and inflammation response with HBeAg seroconversion) group, CD8+PD-1+ T cells significantly decreased at 6 months (p < 0.05), while CD8+PD-1- T cells had no significant difference. On the contrary, in the FIENR (no fibrosis and inflammation response and HBeAg seroconversion) group, CD8+PD-1- T cells significantly decreased after 6 months of PEG-IFN-α treatment (p < 0.05), while CD8+PD-1+ T cells had no significant difference. In addition, the levels of CD68+ mononuclear cells in the FIER group showed an overall increasing trend after treatment (p < 0.05). CONCLUSIONS: The changes in the levels of CD8+PD-1+ T cells and CD68+ mononuclear cells may be related to the response to PEG-IFN-α therapy.

[Efficacy of pegylated-interferon alpha-2a treatment in patients with HBeAg-positive chronic hepatitis B and partial viral response to nucleoside analogue therapy].

OBJECTIVE: To investigate the efficacy and related factors of pegylated-interferon alpha-2a (PEG-IFN-2a) treatment in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) who achieved partial viral response with nucleoside analogue (NA) therapy. METHODS: Patients with HBeAg-positive CHB and partial viral response to NA treatment were administered a PEG-IFN-2a therapy regimen of 180 g subcutaneous injection once weekly for a personlized duration of time. The existing NA therapy was continued in combination with the new PEG-IFN-2a treatment for 12 weeks. Measurements of serum HBV DNA load, hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), HBeAg and hepatitis B e antibody (anti-HBe) were taken at baseline (prior to addition of the PEG-IFN-2a therapy) and every 3 months afterwards.For determining response to treatment, primary efficacy was defined as undetectable HBsAg and seroconversion, and secondary efficacy was defined as HBsAg less than 10 IU/mL and HBeAg seroconversion.Statistical analysis was carried out using SPSS statistical software. RESULTS: A total of 81 consecutive patients with an average of 12.0 months (range: 6.0-24.0 months) of NA therapy were included in the study and received an average of 19.6 months (range: 15.5-33.3 months) of PEG-IFN-2a treatment. At the end of PEG-IFN-2a therapy, 7 (8.6%) of the patients achieved undetectable HBsAg and seroconversion, and 14 (17.3%) showed HBsAg less than 10IU/mL. In addition, 40.7% achieved undetectable HBeAg and seroconversion, a rate that was slightly higher than that (38.3%) seen in treatment-naive patients who received PEG-IFN-2a. Statistical analyses suggest that baseline level of HBsAg at less than 1500 IU/mL may predict end of PEG-IFN-2a treatment response for HBsAg less than 10 IU/mL, as evidenced by the area under the curve measure of 0.747, sensitivity measure of 87.3%, specificity measure of 33.3%, positive predictive value of 82.1% and negative predictive value of 42.8%. CONCLUSION: Patients with HBeAg-positive CHB and partial viral response to NA therapy can achieve undetectable HBsAg and HBeAg seroconversion after switching to PEG-IFN-2a treatment. Baseline HBsAg level may be predictive of response to this therapeutic strategy.

Expression of Functional Molecule on Plasmacytoid Dendritic Cells Is Associated With HBsAg Loss in HBeAg-Positive Patients During PEG-IFN α-2a Treatment.

Objective: The ideal endpoint of antiviral therapy in chronic hepatitis B (CHB) patients is to clear hepatitis B surface antigen (HBsAg). This study aimed to evaluate whether the expression of functional molecules on plasmacytoid dendritic cells (pDCs) is associated with HBsAg loss in HBeAg-positive patients during peginterferon alpha-2a (PEG IFN α-2a) therapy. Methods: A single-center prospective cohort study was performed in HBeAg-positive CHB patients who were treated with PEG-IFN α-2a and followed up for 4 years. HBsAg clearance, HBeAg loss and undetectable HBV DNA achieved by PEG-IFN α-2a therapy was considered as functional cure. The frequencies of pDC and CD86+ pDC in peripheral blood, and the mean fluorescence intensity of CD86 (CD86MFI) on the surface of pDC were measured at starting therapy, after 12 and 24 weeks of therapy. Results: Of 63 patients enrolled, 17 patients achieved HBsAg loss. The baseline HBV DNA load in Non-functional-cure group was significantly higher than that in Functional cure group, and the CD86+ pDC% was significantly lower in patients without functional cure. HBV DNA load (OR=0.146, P = 0.002) and CD86+ pDC% (OR=1.183, P = 0.025) were independent factors associated with functional cure confirmed by binary logistic regression analysis. In the Functional cure group, HBsAg, HBeAg, and HBV DNA loads decreased remarkably after 12 weeks and 24 weeks of treatment compared to baseline. In Non-functional-cure group, CD86+ pDC% and CD86MFI increased significantly from baseline after 12 weeks of treatment. In the Functional cure group, compared with baseline, pDC% increased significantly at 24 weeks, while CD86MFI increased significantly after 24 weeks of treatment. Conclusion: The lower the baseline HBV DNA load and the more the baseline CD86+ pDC%, the easier it is for patients to obtain functional cure.

Dynamic Changes of Cytokine Profiles and Virological Markers Associated With HBsAg Loss During Peginterferon Alpha-2a Treatment in HBeAg-Positive Chronic Hepatitis B Patients.

Objective: To explore dynamic changes of cytokines and virological markers associated with hepatitis B surface antigen (HBsAg) loss during peginterferon alpha-2a (PEG-IFN α-2a) treatment in hepatitis B e antigen (HBeAg) positive chronic hepatitis B (CHB) patients. Methods: It was a single-center prospective cohort study. HBeAg-positive CHB patients were prospectively and consecutively enrolled. Cytokines were detected at baseline, week 12 and 24 of PEG-IFN treatment. HBsAg disappearance rate was the primary evaluation index at 48 weeks of PEG-IFN treatment. Results: Among 100 patients who completed the 48-week PEG-IFN α-2a treatment, 38 patients achieved serum HBeAg disappearance, 25 patients achieved HBeAg seroconversion, 9 patients achieved functional cure, 37 patients had HBsAg decline of ≥1 log IU/ml, and 8 patients produced hepatitis B surface antibody (HBsAb). Albumin (ALB), fms-like tyrosine kinase 3 ligand (FLT3-L) and interferon-alpha2 (IFN-α2) in the clinical cure group were significantly lower than those in the non-clinical-cure group at baseline. After 12 weeks of treatment, HBsAg in the clinical cure group was significantly lower than that in the non-clinical-cure group (median 1.14 vs. 3.45 log10IU/ml, Z=-4.355, P < 0.001). The decrease of HBsAg and hepatitis B virus desoxyribose nucleic acid (HBV DNA) in the clinical cure group was significantly higher than that in non-clinical-cure group (median: HBsAg 1.96 vs. 0.33 log10IU/ml, Z=-4.703, P< 0.001; HBV DNA 4.49 vs.3.13 log10IU/ml, Z=-3.053, P=0.002). The increase of IFN-α2 in the cure group was significantly higher than that in the non-clinical-cure group (497.89 vs. 344.74, Z=-2.126, P=0.034). After 24 weeks of treatment, HBsAg, HBeAg, Flt3-L, and IL-10 in the clinical cure group were significantly lower than those in the non-clinical-cure group (median: HBsAg 0.70 vs. 3.15 log10IU/ml, Z=-4.535, P< 0.001; HBeAg 1.48 vs. 13.72 S/CO, Z = 2.512, P = 0.012; Flt3-l 0.00 vs 2.24 pg/ml, Z = 3.137, P=0.002; IL-10 0.70 vs. 2.71 pg/ml, Z=-4.067, P < 0.001). HBsAg decreased significantly in the clinical cure group compared with non-clinical-cure group (median 3.27 vs. 0.45, Z=-4.463, P < 0.001). Conclusion: Dynamic changes of cytokines and virology markers during early PEG IFN α-2a treatment were associated with HBsAg loss in HBeAg-positive CHB patients.

The Characteristics of Natural Killer Cells in Chronic Hepatitis B Patients Who Received PEGylated-Interferon versus Entecavir Therapy.

BACKGROUND: To explore the role of natural killer (NK) cells in the process of hepatitis B virus (HBV) clearance and whether their phenotype is related to antiviral treatment outcome in chronic hepatitis B (CHB) patients. METHOD: We performed a single-center prospective cohort study to analyze changes of NK cells at weeks 12 and 24 from baseline in CHB patients who received PEGylated-interferon- (PEG-IFN-) α-2a versus entecavir. The frequencies of NK, CD56bright, CD56dim, IFNAR2+, NKp46+, NKp46bright, and NKp46dim NK cells and mean fluorescence intensity (MFI) of receptors NKp46 and IFNAR2 on the surface of NK cells were measured. Subgroup analyses were performed by comparing treatment responders versus nonresponders with aforementioned parameters in each group. RESULTS: In PEG-IFN-α-treated patients, posttreatment CD56bright NK cell frequency increased, but CD56dim NK cell frequency decreased. Additionally, receptor NKp46 and IFNAR2 expression enhanced. In entecavir-treated patients, although NK cell frequency increased, CD56bright and CD56dim NK cell frequencies and IFNAR2 expression did not differ between baseline and posttreatment. In subgroup analyses, posttreatment CD56bright NK cell frequency and IFNAR2 expression significantly increased in PEG-IFN-α responders from baseline, while changes were absent in PEG-IFN-α nonresponders and entecavir treatment responders. Among patients with HBV viremia after entecavir therapy, NK cell frequency significantly increased, whereas NKp46bright and IFNAR2+ NK frequency and IFNAR2 MFI significantly decreased at 12 and 24 weeks from baseline. CONCLUSIONS: In CHB patients, PEG-IFN-α treatment significantly enhanced NK cell frequency and function when compared to entacavir. Positive treatment responses to either interferon or entecavir were associated with NK cell function improvement. This trial is registered with clinical trial registration no. NCT03208998.

Fabrication and evaluation of Zn containing fluoridated hydroxyapatite layer with Zn release ability.

A biphasic layer with a Zn-containing beta-tricalcium phosphate (ZnTCP) phase and a fluoridated hydroxyapatite (FHA) phase on titanium alloy substrate was prepared by the sol-gel technique. Scanning electron microscopy and energy-dispersive X-ray analysis results showed the ZnTCP/FHA layer to have a heterogeneous surface with microscaled gibbous structures originating from ZnTCP particle agglomeration. This layer had a slow and sustained Zn release behavior. The scratch test result of the ZnTCP/FHA layer was 489+/-4mN, indicating good interface bonding between the layer and substrate. The ZnTCP/FHA layer supported cell growth, and showed a statistically significant increase in cell viability in comparison with another biphasic layer (TCP/FHA) without Zn. This work demonstrates that the present biphasic ZnTCP/FHA layer has the potential to play a significant role in enhancing bone growth when used as the outermost part of bioactive coatings on metallic implants.

Quantitation of Plasmacytoid Dendritic Cells in Chronic Hepatitis B Patients with HBeAg Positivity During PEG-IFN and Entecavir Therapy.

Plasmacytoid dendritic cells (pDCs) are crucial for control of chronic hepatitis B (CHB) virus infection. In this study, we evaluated the frequencies of pDCs and expression of functional molecules on pDCs in patients treated with PEG-IFN-α-2a or entecavir (ETV) and investigated changes during treatment. The mean fluorescence intensity of CD86 (CD86MFI) on the surface of pDCs and frequencies of pDCs and CD86+ pDCs in peripheral blood were measured. Compared with baseline, CD86+ pDC% and CD86MFI increased obviously after PEG-IFN-α-2a treatment for 12 and 24 weeks. For patients treated with ETV, only pDC% increased observably after treatment weeks 12 and 24 (P < 0.001) compared with baseline. Hepatitis B surface antigen (HBsAg) decline was significantly associated with elevated CD86+ pDC% (r = 0.348, P = 0.015) during PEG-IFN-α-2a treatment. In the HBsAg response group, CD86+ pDC% and CD86MFI (P < 0.001) increased observably after PEG-IFN-α-2a therapy, whereas only CD86MFI had a statistically significant difference after therapy compared with baseline (12 weeks versus 0 weeks, P = 0.022; 24 weeks versus 0 weeks, P = 0.015) in the HBsAg nonresponse group. CD86+ pDC% between the 2 groups had statistically significant differences at baseline (P = 0.001) and at the treatment time points of 12 and 24 weeks (P < 0.001), respectively. For patients receiving ETV therapy, pDC% increased observably, but CD86+ pDC% decreased significantly (P < 0.001) in the HBV DNA nonresponse group during early treatment with ETV. In CHB patients, HBsAg response in PEG-IFN-α-2a therapy correlated with the increase of CD86+ pDC% and HBV DNA nonresponse in ETV treatment correlated with the decrease of CD86+ pDC%.

Kinetics of Hepatitis B Surface Antigen Level in Chronic Hepatitis B Patients who Achieved Hepatitis B Surface Antigen Loss during Pegylated Interferon Alpha-2a Treatment.

BACKGROUND: Hepatitis B surface antigen (HBsAg) loss/seroconversion is considered to be the ideal endpoint of antiviral therapy and the ultimate treatment goal in chronic hepatitis B (CHB). This study aimed to assess the patterns of HBsAg kinetics in CHB patients who achieved HBsAg loss during the treatment of pegylated interferon (PEG-IFN) α-2a. METHODS: A total of 150 patients were enrolled, composing of 83 hepatitis B envelope antigen (HBeAg)-positive and 67 HBeAg-negative patients. Patients were treated with PEG-IFN α-2a180 µg/week until HBsAg loss/seroconversion was achieved, which occurred within 96 weeks. Serum hepatitis B virus deoxyribonucleic acid and serological indicators (HBsAg, anti-HBs, HBeAg, and anti-HBe) were determined before and every 3 months during PEG-IFN α-2a treatment. Biochemical markers and peripheral blood neutrophil and platelet counts were tested every 1-3 months. RESULTS: Baseline HBsAg levels were 2.5 ± 1.3 log IU/ml, and decreased rapidly at 12 and 24 weeks by 48.3% and 88.3%, respectively. The mean time to HBsAg loss was 54.2 ± 30.4 weeks, though most patients needed extended treatment and 30.0% of HBsAg loss occurred during 72-96 weeks. Baseline HBsAg levels were significantly higher in HBeAg-positive patients (2.9 ± 1.1 log IU/ml) compared with HBeAg-negative patients (2.0 ± 1.3 log IU/ml; t = 4.733, P < 0.001), but the HBsAg kinetics were similar. Patients who achieved HBsAg loss within 48 weeks had significantly lower baseline HBsAg levels and had more rapid decline of HBsAg at 12 weeks compared to patients who needed extended treatment to achieve HBsAg loss. CONCLUSIONS: Patients with lower baseline HBsAg levels and more rapid decline during early treatment with PEG-IFN are more likely to achieve HBsAg loss during 96 weeks of treatment, and extended therapy longer than 48 weeks may be required to achieve HBsAg loss.

Preparation, characterization and cytocompatibility of porous ACP/PLLA composites.

The purpose of this work was to incorporate amorphous calcium phosphate (ACP) into porous poly(L-lactic acid) (PLLA), because ACP is capable of fast phase transformation and morphological change in body fluid, such, a desired pore wall surface within bone tissue engineering scaffolds can be created. A highly porous ACP/PLLA composite was prepared by a thermally induced phase separation technique. The results showed that the composite had an interconnected pore structure with 100 mum macropores and 10 mum micropores, and 91% porosity; 40 nm primary particles of ACP were agglomerated to 3 mum aggregates, and the aggregates were homogeneously distributed in pore walls; These aggregates showed to be in situ transformed into bone-like apatite after 1 h soaking in phosphate buffered saline solution. Human osteoblast-like cell culture showed that the ACP/PLLA composite had better cell adhesion and alkaline phosphotase activity than pure PLLA. This study demonstrates that the ACP/PLLA composite can enhance cytocompatibility and could act as a promising scaffold for bone tissue engineering.

Preparation and characterization of porous beta-tricalcium phosphate/collagen composites with an integrated structure.

Porous beta-tricalcium phosphate (TCP)/collagen composites with different beta-TCP/collagen weight ratio were prepared. The influences of the preparation conditions on the microstructure of porous composite and the joint status of beta-TCP particles with collagen fibrils were characterized by X-ray diffractometer, scanning electron microscopy and transmission electron microscopy. The results showed: (1) an acid treatment could effectively disassemble collagen fibrils; (2) in the resulting porous composites, beta-TCP particles homogenously existed on the skeleton of the collagen fibril network and bonded tightly to both the fibrils and themselves. The tight bonding formation could be due to the reaction between Ca ions in the particles and carboxyl groups in collagen polypeptide chains and due to the reprecipitation of partially dissolved beta-TCP during synthesis. The tight bonding between beta-TCP particles and collagen fibrils in the composites demonstrated an integrated structure, which was reproducible when beta-TCP/collagen ratio ranged from 2 to 4. Such integrated structure would make significant contributions in reliably tailoring properties of the porous composites by varying beta-TCP content. In addition, the porous composites had large porosity (approximately 95%) and appropriate pore size (approximately 100 microm), showed no negative impact in cytotoxicity assay and complete bone tissue regeneration after 12 weeks in animal test.

Sol-gel preparation and in vitro test of fluorapatite/hydroxyapatite films.

Fluorapatite/hydroxyapatite (FA/HA) films have been demonstrated to be a good alternative to pure hydroxyapatite (HA) ones in medical applications because of their bioactivity and relatively low solubility. In this study, Ca(NO(3))(2), P(2)O(5), and HPF(6) were used to prepare FA/HA films on Ti6Al4V substrate with the use of a sol-gel method. The F contents in the films could be tailored by adjusting the amount of HPF(6) added. The in vitro evaluation of the films was carried out in both SBF9# solution and TRIS buffer solution. The films with appropriate F contents showed a better ability to induce calcium phosphate deposition on their surfaces than either pure HA film and FA/HA films with even higher F content, as well as smaller dissolution amounts than HA film in TRIS buffer solution. Hence, the FA/HA films obtained in this work integrate both good bioactivity and stability, and could be a better choice for bioactive film on titanium alloys to produce high-quality implants.

[Bone tissue engineering scaffolds].

Bone tissue engineering may provide an alternative to the repairs to skeletal defects resulting from disease, trauma or surgery. Scaffold has played an important role in bone tissue engineering, which functions as the architecture for bone in growth. In this paper, the authors gave a brief introduction about the requirement of bone tissue engineering scaffold, the key of the design of scaffolds and the current research on this subject.

Mesoporous silica nanoparticles with manipulated microstructures for drug delivery.

A range of mesoporous silica nanoparticles (MSNs) with controlled microstructural characteristics were successfully prepared via the binary surfactant templated synthesis approach with varied concentration of triblock copolymer Pluronic F127. The relationship between the MSNs structural evolution and the surfactant concentration was extensively discussed. Ibuprofen (IBU) was loaded as drug model to uncover the in vitro drug releasing kinetics. It was found that the quantity of the drug loaded mainly depended on the specific surface area, while the drug releasing rate was dominantly determined by the length and curvature of the mesopores. This study has uncovered the core influential factors of MSNs system on its drug releasing properties, and thus demonstrated a facile approach to prepare MSNs with manipulated structural characteristics for drug delivery applications.

[Study on retreatment of CHC patients with initial treatment failure].

OBJECTIVE: To explore the retreatment of CHC patients with initial treatment failure and how to achieve SVR. METHODS: 54 patients who had experienced treatment failure were enrolled and retreated with standard treatment of pegylated interferon and ribavirin or intensive treatment, respectively. Their SVR rates were statistically compared, to decide two therapies' application. RESULTS: 54 patients had been retreated, and total SVR rate was up to 75.92%, with 88.46% in relapsed patients and 64.29% in non-responders. After retreatment with pegylated interferon and ribavirin, SVR rate was 95.45% in patients with prior interferon monotherapy, and 64.71% in patients with prior interferon and ribavirin, and 60% in patients with prior pegylated interferon alpha-2a monotherapy. SVR rate of relapsed patients was significantly higher than that of non-responders. CONCLUSIONS: In CHC patients with treatment failure, SVR rate of retreatment with standard treatment or intensive treatment still can be up to 60%-90%. Retreatment with standard therapy can be applied to patients who had received interferon monotherapy or interferon plus ribavirin. Three types of patients who need intensive retreatment were as following: patients nonresponsive to interferon plus ribavirin or pegylated interferon alpha-2a monotherapy, and patients with treatment failure who had received prior standard treatment.

[Study on effect of intensive treatment for refractory chronic hepatitis C patients].

OBJECTIVE: To explore the effect of intensive treatment for refractory chronic hepatitis C, and to improve the sustained viral response (SVR) rate of treatment with interferon plus ribavirin by optimizing therapeutic dose and course. METHODS: Patients who did not acquire response or partial response by standard therapy (PEG-IFN alpha subcutaneous injection weekly plus Ribavirin 10.5 mg/kg) every day were enrolled and retreated with intensive treatment of 10 MU interferon every other day or 360 microg pegylated interferon alpha-2a weekly according to patients' wishes, and ribavirin 15 mg/kg every day. Serum HCV RNA was detected at baseline,treatment week 4, 12 and every 12 weeks succedent and 24 weeks after treatment end. Course of treatment was 72 to 96 weeks according to viral response. SVR was the mark of therapeutic effect. RESULTS: 18 patients completed whole range therapy and follow-up, in which 12 patients acquired SVR, 5 patients treatment failure and 1 relapse. 3 patients acquired rapid viral response (RVR), and they all got complete Early Viral Response (cEVR) and SVR. RVR Patients' viral loads were significantly lower than that of patients who did not acquire RVR (t = 4. 687, P < 0.001). In 15 patients who did not acquire RVR, 8 patients acquired cEVR, and 9 acquired SVR. SVR rate of patients who were administered PEG-IFN alpha-2a was 4/5, 11 patients who acquired cEVR all acquired SVR, while in 7 patients who did not acquire cEVR, only 1 patient acquired SVR. CONCLUSIONS: High percent patients, who did not acquire response or partial response by previous standard antiviral therapy, could gain SVR by intensive dose interferon plus Ribavirin. In intensive treatment procedure, adjusting and prolonging course according to viral response after HCV RNA turned negative were important measures to improve refractory Chronic Hepatitis C SVR rate.

Electrolytic deposition of octacalcium phosphate/collagen composite coating on titanium alloy.

Osteointegration of titanium or its alloy with bone can be greatly improved by calcium phosphate coatings, and further enhanced by an extracellular matrix protein layer such as collagen. In this study, an octacalcium phosphate (OCP)/collagen composite coating layer on Ti6Al4V substrate was prepared using electrolytic deposition method. A layer of OCP mineral consisting of flake-like crystals was first formed on the Ti6Al4V substrate. Subsequently, mineralized collagen fibrils were deposited on the former OCP layer. These collagen fibrils were interconnected and well adhered on the OCP layer so that they were immobilized. The microstructure of the composite coating varied with collagen concentration in the electrolyte. This study could offer a possibility of fabricating a desired surface matrix on orthopedic implants to enhance bone formation and fixation of implants.

Effect of PEG amount in amorphous calcium phosphate on its crystallized products.

Biphasic alpha-tricalcium phosphate/beta-tricalcium phosphate (alpha/beta-TCP) with a designed phase ratio is thought to have controllable dissolution-reprecipitation behavior that is significant in the repair and regeneration of bone. Amorphous calcium phosphate (ACP) was selected as a precursor to prepare biphasic alpha/beta-TCP. The influence of polyethylene glycol (PEG) content in ACP on its crystallization, or on the phase ratio of the resulting biphasic TCP, was investigated. ACP was synthesized by the reaction of Ca(NO(3))(2) with (NH(4))(2)HPO(4) using PEG as an additive. Depending on the amount of PEG addition, resulting ACP could be crystallized to alpha-TCP, beta-TCP or biphasic alpha/beta-TCP after heat-treatment at 800 degrees C, showing that PEG addition is a critical factor to tailor the phase ratio of biphasic alpha/beta-TCP. One reason for the influence of PEG is that ACP with different PEG content could have two types of unit structures that tend to form alpha-TCP and beta-TCP after crystallization.

Porous beta-tricalcium phosphate/collagen composites prepared in an alkaline condition.

Bone substitute materials with natural bone-like structure are considered to be favorable for bone regeneration. In this work, porous beta-tricalcium phosphate (beta-TCP)/collagen composite consisting of bone-like microstructural units was prepared using nanosized beta-TCP particles and alkaline-disassembled collagen. The resulting composite showed a good interconnecting porous structure with approximately 90% porosity and 100 approximately 300 microm pore size. The pore walls were dense, and the combination status of collagen and nanosized beta-TCP particles demonstrated that nanosized beta-TCP particles tightly connected collagen microfibrils as a bone-like microstructural unit. MTT and alkaline phosphatase (ALP) assays showed that the porous composite had enhanced effects on cellular proliferation and activity of osteoblast compared with a control of pure collagen. It is suggested that the adoption of nanosized beta-TCP particles is a main contribution to the formation of the composite with a bone-like microstructural unit, and the unique microstructure could be a main role for the composite to have the positive influence on osteoblast cell proliferation.

In vitro bioactivity and osteoblast-like cell test of zinc containing fluoridated hydroxyapatite films.

Zinc containing fluoridated hydroxyapatite (ZnFHA) films on Ti6Al4V substrates was prepared using sol-gel dip-coating method. The release of zinc ions from ZnFHA film was controlled mainly by the zinc content in the film. The release behavior showed an initial rapid increase release followed by a tapering-off and directed to a constant value at longer time. After soaking in SBF for 8 days, a layer was deposited and completely covered the original surface of the ZnFHA film, indicating good in vitro "bioactivity." The osteoblast-like MG63 cells were seeded on the ZnFHA films; FHA film and Ti6Al4V substrate were used as control. The cell culture result showed that cell adhesion and proliferation on ZnFHA films were significantly increased compared with the controls. The results in this work suggest that ZnFHA films on Ti6Al4V substrates can function as an implant with good bioactivity and cytocompatibility.