BACKGROUND:Titanium alloy, a commonly used bone biomaterial, holds good biocompatibility and proper mechanical properties, but without osteointegration ability. Surface bioactive coating of titanium alloy can overcome such problems. OBJECTIVE:To review the application progress of surface bioactive coating on titanium alloys, and to explore the mechanism underlying its osteogenic induction. METHODS:PubMed and CNKI databases were searched for literatures concerning surface bioactive coating on titanium alloys published from January 2000 to March 2016, using the keywords oftitanium, titanium alloys, coating, surface modification, bonein English and Chinese, respectively. Through preliminary analysis, 42 eligible articles were selected. RESULTS AND CONCLUSION:The surface modification method has undergone the transition from surface roughening, oxidation, acidification treatment to the most widely used biomimetic coating technology. The surface biomimetic coatings of titanium alloys mainly include hydroxyapatite, bioactive glass, zeolite, which have been developed from a single coating to the composite coatings and gradient coatings. What's more, the bioactive factor or/and metal ions in the coating can improve the osteointegration of surface coating. Surface modification for titanium alloys is a complex process, during which, both the osteogenesis ability and the bonding strength between the coating and its substrate cannot be ignored. Improving the fabrication method of existing coatings and exploring new materials of biomimetic coatings are critical to achieve a high-quality surface coating modification.

BACKGROUND: Porosity has been proven to improve the stability of orthopedic implants, and the architecture of pores is considered as a significant factor to improve the osseointegration of implants. OBJECTIVE: To introduce the research advance in porous architecture. METHODS: WOS database was searched for the articles addressing the porous structure of the implants published from January 2000 to April 2016 using the keywords of scaffold, pore size, porosity, osteogenesis. The literatures were screened according to the inclusion and exclusion criteria.RESULTS AND CONCLUSION: (1) The stability of traditional implants cannot meet the requirements in some specific circumstances, while the implants with porosity can improve the stability due to its osteogenesis ability. (2) Porous structure is a hotspot, and the osseointegration of porous implants in vivo is explored through series of in vitro and in vivo experiments. (3) It has been shown that higher porosity, proper pore size, microporous morphology and microstructure of the pore wall may contribute to the growth and differentiation of bone tissue under enough mechanical support. (4) However, most studies on the porous implants are still on the in vivo and animal experimental stage, and its promoting effects on the osteogenesis and bone in-growth are needed to be investigated in depth.

BACKGROUND:Surface modification of titanium surface to improve its biological activity is the research hotspot. Strontium-doped coating is considered to be an effective approach to promote the implant osseointegration. OBJECTIVE:To introduce the research progress of strontium-modified biomedical titanium al oys.METHODS:Articles related to the medical titanium al oys modified with strontium published from January 2000 to April 2016 were retrieved from CNKI and PubMed databases. The keywords were“titanium (Ti), strontium (Sr), bone, osteogenic”in Chinese and English, respectively. RESULTS AND CONCLUSION:Titanium al oys have been widely used in bone implantation because of their good biocompatibility and similar elasticity modulus with human bones. However, pure titanium al oys have poor bioactivity which leads to weak bone-implant contact. Surface modification is a good approach to enhance implant osseointegration. Sr-doped surface treatment can promote new bone formation and osseointegration. Most of the studies about Sr-doped modification are ongoing at the extracorporeal and animal experiment stage;therefore, further investigation is required to seek rapid, stable, available, safe and effective methods.

Objective To introduce a new spinal surgery navigation system based on structured light scanning(structured light navigation system,SLNS),and to compare accuracy of pedicle screw placement using SLNS,CT based navigation system and free hand technique.Methods Thirty-two calf vertebral pedicles,40 and 32 were placed with pedicle screws using SLNS,CT navigation system,and free hand technique,respectively.The pedicle breakage ratio,transverse section angle (TSA),sagittal section angle (SSA),screw offset deviation of each screw were detected according to CT images.Results The pedicle breakage ratio of pedicle screws in SLNS group,CT navigation group and free hand group were 6%(2./32),5%(2/40),25%(8/32),respectively.The difference between each of the two navigation groups and free hand group were statistically significant regarding frequency of screw misplacement.The difference between the two navigation systems was not obvious.The average SSA error and TSA error in SLNS group were 2.58°±2.74° and 4.26°±5.20°.For CT navigation group,they were 2.95°±2.61° and 3.13°±-2.75°.There was no statistical difference between the two navigation methods for the SSA or TSA error.There was no statistical difference in offset deviation among SLNS group,CT navigation group and free hand group.Conclusion The SLNS is a new and practical navigation system,which has similar accuracy with CT navigation system.

Objective To investigate the added value of CTAC for improving image quality and diagnostic efficiency of bone imaging in SPECT/CT.Methods Seventy-five patients (47 males,28 females,(56.6± 12.8) years) with abnormal uptake in planar whole-body bone scintigraphy underwent SPECT/CTfor differentiation of malignant from benign spinal lesions.NAC and CTAC SPECT images were classified based on 5-point scale (5:excellent,4:good,3:adequate,2:suboptimal,1:inadequate).The diagnostic confidence for both NAC and CTAC SPECT images were classified based on 4-point scale (4:definite,3:certain,2:equivocal,1:uninterpretable).The pathological results after surgery were used as gold standard to evaluate the added diagnostic value of CTAC for spinal lesions.Wilcoxon-signed rank sum test was used for data analysis.Results CTAC improved the image quality in 37.3％ (28/75) of patients,and downgraded in 2.7％ (2/75) of patients.The remaining 45 patients were unchanged (60.0％,45/75).SPECT with CTAC could significantly improve the image quality (z=-4.747,P＜0.001),but the overall diagnostic confidence was not increased (z=-1.000,P＞0.05).Conclusion CTAC can improve the image quality of spinal SPECT,especially useful in imaging with poorer quality,but it has no significant incremental value in diagnostic confidence.

Objective To compare the effects of oxygen therapy and local pressurization in alleviating plateau hypoxia at high altitude.Methods Forty-five healthy male soldiers were investigated at an altitude of 3992 meters.The subjects were randomly divided into three groups, ie.an oxygen inhalation group, a single-soldier oxygen increasing respirator (SOIR) group and a BiPAP group.The oxygen inhalation group was treated with oxygen inhalation via nasal catheter at 2 L/min.SOIR was used to assist breath in the SOIR group.The BiPAP group were treated with bi-level positive airway pressure ventilation, with IPAP of 10 cm H20 and EPAP of 4 cm H2O.PaO2、PaCO2、SpO2 and heart rate were measured before and 30 minutes after the treatment.Results There were continuous increase of PaO2 from (53.30±4.88) mm Hg to (58.58±5.05) mm Hg and (54.43±3.01) mm Hg to (91.36±10.99) mm Hg after BiPAP ventilation and oxygen inhalation, respectively (both P < 0.01).However, the PaO2、of the SOIR group was decreased from (56.00±5.75) mm Hg to (50.82±5.40) mm Hg (P < 0.05).In the other hand, the PaCO2、 was increased from (30.41±1.51) mm Hg to (32.5±2.98) mm Hg in the oxygen inhalation group (P< 0.05), declined from (28.74±2.91) mm Hg to (25.82±4.35) mm Hg in the BiPAP group (P < 0.05), and didn't change significantly from (28.65±2.78)mm Hg to (29.75±3.89) nun Hg in the SOIR group (P > 0.05).Conclusions Both BiPAP ventilation and oxygen inhalation can alleviate plateau hypoxia by improving PaO2 at 3992 meter altitude while SOIR has no significant effect.

Objective To evaluate a model for axillary lymph node involvement combining CK19 mRNA with contrast enhanced ultrasound sonography (CEUS) score in operable breast cancer.Methods Operable breast cancer patients planned for sentinel lymph node (SLN) biopsy were enrolled.Preoperative CK19mRNA expressions in peripheral blood and CEUS score of axillary lymph nodes were tested before surgery.In the training set,postoperative sentinel lymph node (SLN) and non-sentinel lymph node (nSLN) pathological results were taken as the gold standard,effective modeling variables were screened,logistic regression was used to establish the prediction model.Parallel control studies were conducted between the validation set and the MSKCC model to evaluate the prediction accuracy and prediction efficiency.Results From Oct 2015 to Nov 2016,359 cases (training set) were enrolled and mathematical formulas for predicting SLN and nSLN were established,respectively.The sensitivity,specificity and AUC of predicting SLN involvement were 91.36％,94.92％ and 0.979 respectively.The sensitivity,specificity and AUC of predicting nSLN metastasis were 91.04％,90.53％ and 0.932 respectively.From Dec 2016 to Jul 2017,219 cases (verification set) were included.The sensitivity of SLN metastasis predicted by the model was 91.84％,the specificity was 96.69％,and the AUC was 0.979,significantly superior to the MSKCC model (0.739).The sensitivity,specificity and AUC of predicting nSLN metastasis were 95.35％,92.73％ and 0.945 respectively,significantly superior to the MSKCC model (0.873).Concolusions Combined with peripheral blood CK19 mRNA and CEUS score,the prediction model for axillary lymph node involvement for operable breast cancer,SLN/nSLN involvement probability can be calculated and qualitative judgment can be made.The overall accuracy and AUC of this model are better than the prediction model of MSKCC.

Objective:To develop a novel α vβ 3-targeted theranostic agent 177Lu-Evans blue (EB)-Arg-Gly-Asp (RGD) and evaluate its value for SPECT imaging and targeted radionuclide therapy in the non-small cell lung cancer (NSCLC)-patient-derived xenografts (PDX). Methods:The α vβ 3-targeted molecule RGD was conjugated with the albumin binding moiety EB to obtain EB-RGD, and EB-RGD was further conjugated with the chelator 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA) for 177Lu radiolabeling. NSCLC-PDX mice models ( n=68) were established. 177Lu-EB-RGD SPECT imaging, biodistribution study were performed in 28 PDX mice models after being injected with 177Lu-EB-RGD or 177Lu-RGD. Targeted radionuclide therapy were subsequently performed in NSCLC-PDX mice models, saline group (group A), 18.5 MBq 177Lu-RGD group (group B), 18.5 MBq 177Lu-EB-RGD group (group C), 29.6 MBq 177Lu-EB-RGD group (group D), n=10 in each group; tumor volumes of PDX mice models in each group were observed within 50 d. Differences between 2 groups were compared using independent-sample t test. Results:177Lu-EB-RGD was radiolabeled at a specific activity of (55±14) GBq/μmol, with a radiochemical yield of more than 95% and a radiochemical purity of more than 95%. Regarding the SPECT imaging, tumors in NSCLC-PDX mice were clearly observed from 4 to 96 h post-injection and the tumor to muscle ratio (T/M) reached 7.34±0.67, 14.63±3.82, 15.69±3.58 and 15.99±5.42 at 4, 24, 72, 96 h post-injection, respectively. Biodistribution study further confirmed the findings from SPECT imaging, and the tumor uptake of 177Lu-EB-RGD were markedly increased compared to 177Lu-RGD 4 h post-injection ((10.15±1.17) vs (3.30±1.47) percent injection dose per gram (%ID/g); t=18.60, P<0.05). Regarding targeted radiotherapy, the tumor volumes were quickly increased within 50 d after treatment in group A and B, while the tumor volumes were decreased in group C and D, until the tumors in group C and D disappeared at the 28th day after initial treatment with no sign of recurrence during the observation period. Conclusions:177Lu-EB-RGD can target α vβ 3-positive NSCLC-PDX with intense tumor to background ratio and strong tumor inhibition efficacy. The preclinical data suggests that 177Lu-EB-RGD may be an effective new treatment option for advanced NSCLC patients with resistance or ineffective results for targeted therapy.

Objective:To investigate the therapeutic efficacy and potential mechanisms of integrin α vβ 3-targeted radionuclide therapy (TRT) in combination with anti-programmed cell death protein ligand 1 (PD-L1) immunotherapy. Methods:Integrin α vβ 3-targeted molecule Arg-Gly-Asp (RGD) was conjugated with Evans blue (EB) and then labeled with 177Lu to obtain 177Lu-EB-RGD. The radioactivity and radiochemical purity were determined. MicroSPECT imaging, biodistribution, and in vivo therapeutic efficacy were subsequently performed in MC38 murine colon cancer models. Volume of tumor and body mass of mice were observed to assess the therapeutic efficacy and safety ( n=9 in each group). Flow cytometry was used to evaluate therapy response of saline-treated (control, group A), 18.5 MBq 177Lu-EB-RGD-treated (group B), 10 mg/kg PD-L1 antibody-treated (group C), TRT combined with immunotherapy-treated (group D, 18.5 MBq 177Lu-EB-RGD and 10 mg/kg PD-L1 antibody) mice and alterations in tumor microenvironment (PD-L1 + immune cells, CD8 + T cells and regulatory T cells). Independent-sample t test and repeated measures analysis of variance were used for data analysis. Results:The radioactivity of 177Lu-EB-RGD was (55.85±14.00) GBq/μmol. SPECT imaging clearly visualized the MC38 tumors in mice models with high uptake and long retention time, the tumor/muscle ratio reached 14.87±0.88 at 24 h postinjection, while less uptake and retention in normal tissues. Tumor uptake of 177Lu-EB-RGD was significantly higher than that of 177Lu-RGD 4 h post-injection ((12.00±1.60) vs (3.69±0.37) %ID/g; t=8.63, P<0.01). The efficacy results between each treatment group was significantly different ( F=7.32, P=0.03) at day 6 post-treatment. The combination therapy showed the most outstanding anti-tumor efficacy with 7/9 mice showed complete response. Flow cytometry results showed that TRT up-regulated the PD-L1 expression significantly, namely, PD-L1 + immune cells in group B and group A were significantly different (CD45 + /PD-L1: 2.34% vs 0.95%, CD11b + /PD-L1: 2.41% vs 0.66%; t values: 11.17 and 8.70, both P<0.01); immunotherapy and combination therapy dramatically stimulated the infiltration of CD8 + T cells (2.07% vs 0.26%, 2.71% vs 0.26%; t values: 4.10 and 6.03, both P<0.05). Conclusion:TRT in combination with immunotherapy synergistically enhance anti-tumor efficacy, which is expected to play a role in the treatment of patients with advanced tumor where TRT can be applied.

Objective:To develop a tetramer probe targeting fibroblast activation protein (FAP), named 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA)-4P(FAP inhibitor (FAPI)) 4, evaluate its biodistribution and PET image in FAP-positive-tumor bearing nude mice, and explore its feasibility as a novel radio-regent for treatment of FAP-positive tumor. Methods:FAP tetramer probe was constructed on the FAPI-46 motif with four mini-polyethylene glycol (PEG)(PEG 3) spacers between the four FAPI motifs, denoted as 4P(FAPI) 4. DOTA was used as the chelator for radiolabeling with 68Ga and 177Lu. The FAP binding characteristics were test by in vitro cell competitive binding experiment. Small-animal PET, in vivo biodistribution, and radionuclide targeting therapy were performed in HT-1080-FAP tumor bearing nude mice ( n=39). Independent-sample t test was performed to analyze tumor uptake data, and two-factor repeated measures analysis of variance was utilized to compare tumor volume data in radioactive isotope therapy. Results:Cell experiment showed that FAPI-tetramer and FAPI-monomer had similar half maximal inhibitory concentration values (3.29 and 2.15 nmol/L). 68Ga/ 177Lu radiolabeled FAPI-tetramer had better tumor uptake and retention than FAPI-monomer in small-animal PET and in vivo biodistribution experiment, with the tumor uptake for 177Lu-DOTA-4P(FAPI) 4 and 177Lu-FAPI-46 at 48 h of (18.72±1.32) vs (2.72±1.20) percentage activity of injection dose per gram of tissue (%ID/g) ( t=15.55, P<0.001). 177Lu-DOTA-4P(FAPI) 4 group showed best anti-tumor efficacy compared with 177Lu-FAPI-46 and control group in radionuclide targeting therapy. On the 2nd day after the start of treatment, the tumor volume in the tetramer treatment group was significantly smaller than that in the control group (mean difference 67.19 mm 3, P=0.049); on the 14th day after the start of treatment, the tumor volume in the tetramer treatment group was significantly smaller than that in the monomer treatment group (mean difference 414.33 mm 3, P=0.005). Conclusion:FAPI-tetramer can improve tumor uptake and retention ability compared with FAPI-46, and 177Lu-DOTA-4P(FAPI) 4 can be a promising radio-agent for FAP-positive tumor therapy.