Site-specific and hydrophilic ADCs through disulfide-bridged linker and branched PEG.

Kadcyla® (T-DM1), an antibody-drug conjugates (ADCs) for HER2+ breast cancer treatment, has been approved by the Food and Drug Administration (FDA) in 2013. An ADC of random lysine conjugation, it has difficulties in DAR control and unsatisfactory PK due to uneven DAR distribution. It also gives rise to aggregation during conjugation because of the hydrophobicity nature of the cytotoxin, DM1. The linker-drug in T-DM1, SMCC-DM1 is hydrophobic and requires certain percentage of organic solvent such as DMA in the conjugation solution, limiting the manufacturing process in an organic-solvent-compatible device and adding extra costs. To address these problems, a site-specific conjugation method was developed involving full reduction of antibody and full conjugation with the bridge-like conjugator-drug, based on the work of Caddick and co-workers, to obtain a site-directed antibody-drug conjugate with DAR 4. The bridge-like conjugator was assembled with SMCC-DM1 and different lengths of hydrophilic polyethylene glycol (PEG) moiety. By applying PEG moiety in the side chain of the linker-drug, the organic solvent used in the conjugation can be reduced. When the PEG length is about 26 units, organic solvent is no longer needed in the conjugation. Reducing the amount of organic solvent in conjugation could also diminish the aggregation occurrence during the conjugation. Moreover, the conjugation configuration with the designed conjugator was also discussed in the article. The binding affinity of the resulting ADCs did not show significant decrease and the cell based assay and animal study have shown the comparable results with T-DM1.

Study on short-term clinical observation of the effect of apically repositioned flap combined with free gingival graft to widen keratinized tissue in implant area.

Objective: To analyse the short-term clinical results of the effect of apically repositioned flap combined with free gingival graft to widen keratinized tissue in implant area, so as to provide a basis for its clinical application. Methods: Fifteen patients with intraoral single or multiple missing teeth, who did not undergo implant restoration or who re-examined after implant restoration completed were included, along with KW less than 1-2 mm on the buccal side of the median line of the alveolar ridge crest in the implant area, or KW less than 1-2 mm on the buccal side of the abutments and dental crown margins. All underwent apically repositioned flap combined with free gingival graft, which were reviewed. Results: Fifteen patients with missing keratinized gingivae underwent free gingival flap graft, survived with all grafted gingival flaps. Compared with before implantation, significant keratinized tissue widening and area gain were obtained at 1 and 3 months postoperatively. Conclusion: The free gingival flap graft can significantly widen the buccal keratinized mucosa of the implant, and to some extent maintains the health status of the implant, which is worthy of clinical promotion and application.

Salivary chromogranin A and myeloid-related protein-8/14 from periodontitis patients with type 2 diabetes.

OBJECTIVES: The bidirectional relationship between diabetes mellitus and chronic periodontitis is well known from clinical trials. Periodontitis in diabetic patients is characterized by severe inflammation and tissue destruction. The purpose of this study was to investigate the levels of chromogranin A (CgA), a stress marker, and myeloid-related protein (MRP)-8/14, an inflammatory marker, in saliva from patients with periodontitis and diabetes mellitus, and to investigate the relationship between CgA and MRP-8/14 in all individuals and in the three groups separately. METHOD AND MATERIALS: Stimulated saliva was collected from 20 diabetic patients with chronic periodontitis, 16 patients with chronic periodontitis, and 21 healthy individuals. Salivary CgA and MRP-8/14 were determined with enzyme-linked immunosorbent assay. Salivary CgA and MRP-8/14 levels were assessed in the saliva of diabetic periodontitis and periodontitis patients, and the relationship with periodontal disease severity was investigated. RESULTS: CgA values in saliva samples from chronic periodontitis patients and diabetic patients with chronic periodontitis were significantly higher than those of the control group. MRP-8/14 values in saliva from chronic periodontitis patients and diabetic patients with chronic periodontitis was significantly higher than that in the control group. Salivary CgA level was positively correlated to MRP-8/14 in all individuals, but there was no significant correlation within the chronic periodontitis patient group, diabetic patients with chronic periodontitis group, and the healthy patient group. No significant correlation between salivary CgA/MRP-8/14 and clinical parameters of periodontitis was found in the three groups. CONCLUSIONS: The results suggest that salivary CgA and MRP-8/14 could be related to the pathogenesis of periodontitis and diabetes. CgA concentration in saliva was positively associated with increased MRP-8/14 in all individuals.

Effect of Plasma Oxidation-Treated TiOx Film on Early Osseointegration.

PURPOSE: To develop a TiOx film with high wettability using plasma oxidation methodology and to evaluate the effect of such surface modification on new bone formation and early osseointegration. MATERIALS AND METHODS: Twenty sandblasted and acid-etched (SLA) titanium implants layered with a TiOx film layer were modified by plasma oxidation using a Radio Frequency Plasma Enhanced Chemical Vapor Deposition (RFPECVD) system. Twenty SLA implants without any treatment were employed as the control group. Scanning electron microscopy was used to evaluate surface morphology of the coating. X-ray photoelectron spectroscopy (XPS) was utilized to identify the chemical composition of the implant surface, and the wettability was tested with the help of the contact angle calculation. All implants were randomly inserted into the proximal tibia of 20 rats with a split-plot design. Four weeks after implantation, early osseointegration of the two groups was analyzed by a removal torque test and histologic analysis. RESULTS: The surface characteristics showed that both SLA and plasma oxidization-treated SLA (PO-SLA) surfaces displayed similar typical isotropic irregular indentations. As revealed by the XPS analyses, both TiO2 and Ti2O3 were coexistent in the PO-SLA surface. The contact angle measurement revealed that the super-hydrophilic surface was created out in the PO-SLA surface. Four weeks after implantation, a higher removal torque value was observed in the group of implants with the PO-SLA surface compared with the control group (12.68 ± 1.07 vs 9.95 ± 1.42 Ncm, P < .05), and a higher rate of bone-to-implant contact was also detected in the same group of implants with the PO-SLA surface (47.79% ± 9.59% vs 39.41% ± 9.00%, P < .05). The bone area ratio was also higher in the PO-SLA surface group than the control group (39.10% ± 10.01% vs 29.01% ± 7.24%, P < .05). CONCLUSION: It was indicated that the PO-SLA surface has combined the effect of high wettability and micro/nano-structures to notably increase early bone apposition.

[Clinical evaluation of short implants in atrophic posterior region].

PURPOSE: To evaluate the clinical effect of short implants in atrophic posterior region. METHODS: A total of 38 Bicon short implants (≤8 mm) were placed in 30 patients with 3-10 mm of bone height in the posterior region from January to December 2012. The follow-up period was 4 years, radiographic, clinical examination(improved plaque index, improved bleeding index, probing depth)were conducted and patient satisfactions were investigated with Oral Health Impact Profile (OHIP-I). Statistical analysis was performed using SPSS17.0 software package. RESULES: Implant survival rate of short implants was 100% and implant success rate was 94.7%. The mean peri-implant bone resorption value was (0.25±0.65) mm，the change of mesial and distal marginal bone was (-0.23±0.74) mm and (-0.27±0.59) mm, respectively. Crown to implant ratio (C/I)= 1.77±0.34, the implants were divided into 3 groups according to C/I≤1,12,there was no significant difference in marginal bone changes and no correlation between C/I and bone resorption. Through clinical examination，improved plaque index was 1.08±0.88，improved bleeding index was 1.11±0.83 and the average probing depth was (3.08±1.19) mm. OHIP-I score was 2.66±0.88, there was significant difference compared with preoperative OHIP-I score. CONCLUSIONS: Short implants are feasible and the success rate is high in the posterior region with insufficient bone height. The soft tissue around the short implants is in good health.While avoiding complex surgical procedures, reducing trauma, shortening the duration of treatment,short implants have a high degree of acceptance and the patient satisfactions are excellent.At the same time, regular preventive maintenance is important to maintain the long-term stability of implant dentures.

[Animal study of sensory function of nerve fibers surrounding dental implant].

PURPOSE: To investigate the distribution of sensory nerve fibers in the tissue of peri-implant bone and to study the reconstruction procedure of somatosensory evoked potentials of unloaded dental implant. METHODS: The bilateral 2nd, 3rd and 4th mandibular premolars and the 1st molars were extracted from 3 beagle dogs. Three months later, 4 screw-type implants were inserted. Then 1, 6 and 12 weeks later, the sensory nerve action potential(SNAP) tests were performed. The stimulating electrode was connected to the implant, and the recording electrodes were fixed on the inferior alveolar nerve stem to record the amplitude of SNAP. Then the dogs were sacrificed, and the specimens were prepared for immunohistochemical examination. The SNAP results were statistically analyzed using SPSS17.0 software package. RESULTS: SNAP of the inferior alveolar nerve stem could be recorded following stimulations to each implant. The difference in SNAP amplitudes between the 1-week group and the other two groups was significant (P<0.05) But there was no significant difference between the 6-week and 12-week group. Some NFP-positive nerve fibers were found in the tissues of peri-implant bone. These fibers localized in both the bone marrow space and in the peri-implant fibrous tissues. CONCLUSIONS: Neuroreceptors do exist in the tissue of peri-implant bone, but much less than the periodontal ligament. These neuroreceptors could receive electrical stimulus then evoke SNAP of the inferior alveolar nerve stem. In unloaded condition, the reconstruction of never endings in the peri-implant bone tissue is apparently time-dependent.