BACKGROUND:Exosomes are nanoscale extracellular vesicles secreted by various types of cells,with advantages such as high bioavailability,low toxicity,low immunogenicity,and good biocompatibility.However,natural exosomes have certain limitations in clinical therapy.By using bioengineering techniques to modify and engineer exosomes,the engineered exosomes not only improve their original therapeutic effects but also exhibit excellent biostability and targeting specificity,showing great potential for application in the field of tissue repair.OBJECTIVE:To summarize the various strategies for engineering exosomes,including functional loading and surface modification,outline the research progress of engineered exosomes in different tissue repairs,and explore the therapeutic potential of engineered exosomes in tissue repair.METHODS:PubMed database was searched for relevant literature published between 2010 and 2024 using the search terms"engineered exosomes,tissue repair,biomaterials,tissue engineering,wound healing,parenchyma,bone regeneration,cartilage,neural,myocardial,hepatic."Studies that were not closely related to the article's theme,of poor quality,repetitive,or outdated were excluded.A total of 115 articles met the inclusion criteria.RESULTS AND CONCLUSION:(1)Functional loading is used to combine therapeutic molecules with exosomes to obtain additional properties or to enhance the original physiological function of the exosome,among which ultrasonication and extrusion are simple to operate and can obtain higher drug loading capacity at the same time.(2)Surface modification can make exosomes express desired proteins or enhance their targeting,including genetic engineering and chemical modification.Genetic engineering is complicated,poorly reproducible,and the end product is poorly controllable.Chemical modification,on the other hand,is relatively simple and versatile,and is more suitable for designing highly targeted and functionally specific engineered exosomes.(3)Among the techniques for pre-treating cells to obtain engineered exosomes,hypoxic pre-treatment is more widely used because of its simplicity and clearer mechanism,which can activate glycolysis to promote cell proliferation,and regulate the vascular endothelial growth factor receptor signaling pathway through the generation of hypoxia-inducible factors to promote angiogenesis.(4)The function of exosomes is affected by various factors such as cell source,cell state,synthesis process,and extracellular environment.If the engineering strategy is complicated,it is more difficult to ensure the functional consistency of the final engineered exosomes,so the relatively simple and reliable engineering strategy is more suitable for its clinical application.(5)Engineered exosomes combined with biomaterials or scaffolds can be used to treat complex wounds of skin soft tissue,such as infected wounds and diabetic ulcers.This approach enhances exosome delivery and controls their release,promotes tissue repair,controls infection,and regulates the local microenvironment of the wound.(6)A single mechanism of engineered exosomes is often ineffective due to the specificity of the bone tissue fracture,so dual or even multi-functional engineered exosomes are needed to promote fracture repair while anti-inflammatory or remodeling the vascular system.(7)The source of exosomes has a significant impact on neural tissue repair.Exosomes derived from different neural cells promote neural repair through different effects.In addition,the combination of stents and engineered exosomes for traumatic brain injury has obvious advantages,the stent itself provides hemostasis and support,combined with the engineered exosomes itself to promote the repair effect,can obtain better therapeutic effect.(8)In cardiac and hepatic tissue repair,it is needed to develop anti-fibrotic engineered exosomes to resist the abnormal repair of cardiac and hepatic tissues themselves,which will require further research in the future.

BACKGROUND:Exosomes are nanoscale extracellular vesicles secreted by various types of cells,with advantages such as high bioavailability,low toxicity,low immunogenicity,and good biocompatibility.However,natural exosomes have certain limitations in clinical therapy.By using bioengineering techniques to modify and engineer exosomes,the engineered exosomes not only improve their original therapeutic effects but also exhibit excellent biostability and targeting specificity,showing great potential for application in the field of tissue repair.OBJECTIVE:To summarize the various strategies for engineering exosomes,including functional loading and surface modification,outline the research progress of engineered exosomes in different tissue repairs,and explore the therapeutic potential of engineered exosomes in tissue repair.METHODS:PubMed database was searched for relevant literature published between 2010 and 2024 using the search terms"engineered exosomes,tissue repair,biomaterials,tissue engineering,wound healing,parenchyma,bone regeneration,cartilage,neural,myocardial,hepatic."Studies that were not closely related to the article's theme,of poor quality,repetitive,or outdated were excluded.A total of 115 articles met the inclusion criteria.RESULTS AND CONCLUSION:(1)Functional loading is used to combine therapeutic molecules with exosomes to obtain additional properties or to enhance the original physiological function of the exosome,among which ultrasonication and extrusion are simple to operate and can obtain higher drug loading capacity at the same time.(2)Surface modification can make exosomes express desired proteins or enhance their targeting,including genetic engineering and chemical modification.Genetic engineering is complicated,poorly reproducible,and the end product is poorly controllable.Chemical modification,on the other hand,is relatively simple and versatile,and is more suitable for designing highly targeted and functionally specific engineered exosomes.(3)Among the techniques for pre-treating cells to obtain engineered exosomes,hypoxic pre-treatment is more widely used because of its simplicity and clearer mechanism,which can activate glycolysis to promote cell proliferation,and regulate the vascular endothelial growth factor receptor signaling pathway through the generation of hypoxia-inducible factors to promote angiogenesis.(4)The function of exosomes is affected by various factors such as cell source,cell state,synthesis process,and extracellular environment.If the engineering strategy is complicated,it is more difficult to ensure the functional consistency of the final engineered exosomes,so the relatively simple and reliable engineering strategy is more suitable for its clinical application.(5)Engineered exosomes combined with biomaterials or scaffolds can be used to treat complex wounds of skin soft tissue,such as infected wounds and diabetic ulcers.This approach enhances exosome delivery and controls their release,promotes tissue repair,controls infection,and regulates the local microenvironment of the wound.(6)A single mechanism of engineered exosomes is often ineffective due to the specificity of the bone tissue fracture,so dual or even multi-functional engineered exosomes are needed to promote fracture repair while anti-inflammatory or remodeling the vascular system.(7)The source of exosomes has a significant impact on neural tissue repair.Exosomes derived from different neural cells promote neural repair through different effects.In addition,the combination of stents and engineered exosomes for traumatic brain injury has obvious advantages,the stent itself provides hemostasis and support,combined with the engineered exosomes itself to promote the repair effect,can obtain better therapeutic effect.(8)In cardiac and hepatic tissue repair,it is needed to develop anti-fibrotic engineered exosomes to resist the abnormal repair of cardiac and hepatic tissues themselves,which will require further research in the future.

Objective To explore the application value of intravoxel incoherent motion(IVIM)imaging parameters in the differential diagnosis of benign and malignant breast nodules and their correlation with the expression of Ki-67 receptor in breast cancer.Methods The data of 41 female patients who completed 3.0 T breast magnetic resonance imaging(MRI)with complete surgical pathology results in the Second Hospital of Jiaxing City from October 2022 to January 2025 were analysed and evaluated.Conventional images and diffusion-weighted images with 11 b values were collected.The IVIM imaging parameters of real diffusion coefficient(D),perfusion related diffusion coefficient(D*)and perfusion fraction(f)were measured and calculated in the region of interest of each lesion.The receiver operating characteristic curve were plotted to quantify the differential diagnostic efficacy of each parameter of IVIM imaging in benign and malignant breast nodules.The differences of parameters between benign and malignant breast nodules and between the groups with different expression levels of Ki-67 receptor in breast cancer were analysed,and the correlation between each parameter and the expression level of Ki-67 in breast cancer was counted.Results The D value of benign breast nodules group(benign groups)was significantly higher than that of malignant breast nodules group(malignant groups),and the D*value was significantly lower than that of malignant group,and the differences between benign group and malignant group were statistically significant(t=-4.773,t=2.063,P＜0.05);Thefvalue of benign group was slightly lower than that of malignant group,and the differences between two groups were not statistically significant(t=0.035,P＞0.05).Among the parameters of IVIM imaging,D value had the best differential diagnostic efficacy for benign and malignant breast nodules,with area under the curve(AUC)of 0.870(95％CI:0.755-0.985)and a specificity of 75.0％;D*value had the second best differential diagnostic efficacy after D value,with an AUC of 0.789(95％CI:0.658-0.920),but it had the highest sensitivity of 88.2％;And the differential diagnosis efficiency off value was the worst,much less than D and D*values.The D value in the high Ki-67 expression group of breast cancer was lower than that in the low expression group,while the D* and f values in the high expression group were higher than that in the low expression group,and the differences of each imaging parameter of IVIM were not statistically significant between two groups(t=-2.617,t=2.169,t=0.647,P＞0.05).There was a significant negative correlation between the expression of the Ki-67 receptor and the D value(r=-0.615,P＜0.05),and no significant correlation was seen with either D *or f value(r=0.223,r-0.031,P＞0.05).Conclusion The D and D*values of IVIM imaging parameters have great clinical value in the differential diagnosis of benign and malignant breast nodules.

Objective To conduct a scoping review of the application of gamification programs in exercise rehabilitation for knee osteoarthritis,examining the application carriers,game content,outcome indicators,measurement tools,and application effects of gamification programs,to provide references for future practice and related research in this field.Methods The search was conducted in PubMed,Web of Science,Cochrane Library,Scopus,CIN AHL,China National Knowledge Infrastructure,CNKI,and Wanfang Data from their inception to December 28,2024.The included studies were summarized and analyzed.Results A total of 28 studies were included in the review.The game carriers encompassed virtual reality technology,sensor devices,and mobile applications.The game content covered interactive motion games,aerobic exercises,and goal-motivated games.Outcome indicators included functional performance,physical activity,pain,psychological and health status,and user experience.Gamification programs were found to effectively enhance user engagement,improve physical function,reduce negative emotions,and improve quality of life.However,there remains controversy regarding their efficacy in pain relief.Conclusion Gamification programs have shown positive effects in exercise rehabilitation for knee osteoarthritis.Future efforts should focus on developing gamification programs that are culturally appropriate for China,creating"digital therapeutics",continuously updating systems,conducting economic evaluations,and ensuring digital equity to enhance patients'rehabilitation experiences and improve health outcomes.

Hemoglobin A1c (HbA1c) has a unique structure that makes monoclonal antibody (mAb) preparation challenging. This study aims to develop a method for preparing HbA1c mAbs and establish a fluorescent immunochromatographic assay (FICA) for rapid detection of HbA1c. Three glycosylated peptides were synthesized and used to prepare complete antigens, which were identified by dot enzyme-linked immunosorbent assay (Dot-ELISA) and ultraviolet absorption spectroscopy. The complete antigens and natural HbA1c were used for cross-immunization of mice, and the optimal complete antigen was selected. The mouse with the highest serum titer was chosen for mAb preparation. The purity and specificity of the mAbs were verified, and a FICA method was developed. The optimal complete antigen, with a titer of 1:512 000, was successfully prepared and selected. Fusion with splenocytes resulted in four specific HbA1c antibodies (purity > 90%). The best antibody exhibited a binding constant (Ka) of 1.67×10¹⁰ L/mol with the antigen. Based on this antibody, a FICA method was successfully established, capable of producing results within 15 min. The method demonstrated a good linear range (3%-13% HbA1c, y=0.071 3x+0.005 6, R²=0.993 7), recovery rates of 98%-102%, precision < 10.00%, and no nonspecific reactions. Clinical testing of 210 samples showed positive agreement of 96.36%, negative agreement of 97.00%, and overall agreement of 96.68%. The receiver operating characteristic (ROC) curve analysis yielded an area under curve (AUC) of 0.980 9 [95% confidence interval (CI): 0.961 0-1.000 0], with high consistency verified in multicenter studies. We successfully developed a key technique for preparing HbA1c monoclonal antibodies and established a FICA method for rapid detection of HbA1c. It will provide an efficient and convenient detection method for the early diagnosis and long-term management of diabetes and its complications.
Antibodies, Monoclonal/biosynthesis* ; Animals ; Mice ; Glycated Hemoglobin/immunology* ; Mice, Inbred BALB C ; Humans ; Antibody Specificity ; Chromatography, Affinity/methods* ; Enzyme-Linked Immunosorbent Assay/methods* ; Female

Psoriatic arthritis(PsA),an inflammatory articular disease closely associated with psoriasis,is characterized by a wide range of symptoms including skin lesion,peripheral and axial joint involvement,en-thesitis,and dactylitis.In recent years,significant advancements have been made in the treatment of PsA,pro-moting continuous improvement in patient outcomes.This article aims to comprehensively review the current sta-tus of drug treatment for PsA,encompassing not only new clinical evidence for conventional synthetic disease-modifying antirheumatic drugs(csDMARDs)but also an in-depth exploration of biologics or targeted synthetic disease-modifying antirheumatic drugs(tsDMARDs)against various targets in recent years.The objective of this study is to enhance clinicians'understanding of treatment strategies for PsA and provide more precise and effective treatment options for patients.

Objective To observe the expression levels of base excision repair(BER)pathway-related proteins in small cell lung cancer(SCLC)tissues,and analyze their relationship with the prognosis and tumor immune microenvironment.Methods A retrospective cohort study was conducted on 74 patients with limited-stage SCLC undergoing surgical treatment in our medical center from December 2018 to June 2023.Immunohistochemical staining was performed to analyze the protein expression of BER pathway components,apurinic/apyrimidinic endonuclease 1(APE1),8-oxoguanine DNA glycosylase 1(OGG1),DNA polymerase β(POLβ),X-ray repair cross-complementing protein 1(XRCC1),ATP-dependent DNA ligase I(LIGⅠ),and immune cell infiltration markers of CD3? T cells,CD8? T cells,CD68? macrophages in SCLC tissues.Chi-square test was applied to analyze the relationship of BER protein expression and clinicopathological features;Kaplan-Meier survival curve was plotted to evaluate the impacts of BER protein expression and immune cells on disease-free survival(DFS)and overall survival(OS),multivariate Cox regression analysis was utilized to identify DFS prognostic factors,and Spearman correlation analysis was performed to analyze the correlation of BER-immune cell infiltration.In in vitro experiments,transient transfection was applied in H196 cells to overexpress APE1/POLβ/LIGⅠ,respectively.Thus,the cells were divided into negative control(NC,empty vector)and overexpression(OE,target plasmids)groups.CCK-8 and TUNEL assays were employed to determine the effects of OEAPE1,OEPOLβ and OELIGⅠon cell sensitivity to cisplatin.In in vivo experiments,nude mice bearing xenograft tumors were grouped into WT,E3330(APE1 inhibitor),cisplatin,and cisplatin+E3330 groups to determine the effects of the combination therapy on tumor growth.Results There were no significant correlations of the expression levels of key BER pathway proteins with clinicopathological characteristics,including gender,age,smoking history,tumor location,Ki67 index,or TNM stage(all P>0.05).The patients with low expression of APE1,POLβ,and LIGⅠ had obviously higher DFS rates than those with high expression(P<0.05),and the patients with larger proportion of CD3+T cells also had higher DFS rates than those with smaller proportion(P=0.043).Multivariate Cox regression analysis indicated that tumor TNM stage(HR=2.465)and APE1 expression(HR=2.730)were independent risk factors for the prognosis of SCLC patients(P<0.05).Spearman correlation analysis demonstrated a positive correlation between APE1 and CD8+T cell proportion in the SCLC patients(r=0.27,P<0.05).In vitro experiments showed that the overexpression(OE)cells(OEAPE1 and OELIGⅠ)exhibited reduced sensitivity to cisplatin than the NC group(P<0.05).Animal experiments indicated that cisplatin+E3330 significant inhibited xenograft tumor growth,indicating enhanced therapeutic efficacy(P<0.01).Conclusion High expression of APE1,POLβ,and LIGⅠ in the BER pathway indicates poor prognosis and low DFS rate in SCLC patients.High expression of APE1 is positively correlated with CD8+T cells,and can be used as an auxiliary marker for SCLC immunotherapy.

Objective: This study aims to investigate the anatomical relationship among the nerve roots, intervertebral space, pedicles, and intradural rootlets of the cervical spine for improving operative outcomes and exploring neuroventral decompression approach in posterior endoscopic cervical discectomy (PECD). Methods: Cervical computed tomography myelography imaging data from January 2021 to May 2023 were collected, and the RadiAnt DICOM Viewer Software was employed to conduct multiplane reconstruction. The following parameters were recorded: width of nerve root (WN), nerve root-superior pedicle distance (NSPD), nerve root-inferior pedicle distance (NIPD), and the relationship between the intervertebral space and the nerve root (shoulder, anterior, and axillary). Additionally, the descending angles between the spinal cord and the ventral (VRA) and dorsal (DRA) rootlets were measured. Results: The WN showed a gradual increase from C4 to C7, with measurements notably larger in men compared to women. The NSPD decreased gradually from the C2–3 to the C5–6 levels. However, the NIPD showed an opposite level-related change, notably larger than the NSPD at the C4–5, C5–6, and C7–T1 levels. Furthermore, significant differences in NIPD were observed between different age groups and genders. The incidence of the anterior type exhibited a gradual decrease from the C2–3 to the C5–6 levels. Conversely, the axillary type exhibited an opposite level-related change. Additionally, the VRA and DRA decreased as the level descended, with measurements significantly larger in females. Conclusion A prediction of the positional relationship between the intervertebral space and the nerve root is essential for the direct neuroventral decompression in PECD to avoid damaging the neural structures. The axillary route of the nerve root offers a safer and more effective pathway for performing direct neuroventral decompression compared to the shoulder approach.

AIM:To compare the efficacy and safety of early combination therapy with ranibizumab and dexamethasone intravitreal implants versus ranibizumab monotherapy for the treatment of macular edema secondary to retinal vein occlusion(RVO-ME).METHODS: A retrospective cohort study was conducted on a total of 62 cases(64 eyes)of patients who were first diagnosed with RVO-ME at the Eye Centre of the Affiliated Hospital of Shandong Second Medical University between February 2022 and February 2023. The subjects were divided into two groups according to the different treatment regimens: 32 cases(34 eyes)in the monotherapy group received only ranibizumab [3+pro re nata(PRN)regimen], and 30 cases(30 eyes)in the combination therapy group were injected with ranibizumab once first, followed by dexamethasone intravitreal implant 3 wk later(1+DEX regimen). The best corrected visual acuity(BCVA), central retina thickness(CRT), foveal avascular zone(FAZ)area, macular vascular density(MVD)at the level of the deep vascular complex(DVC)of the retina, the incidence of ocular adverse effects, the number of drug injections, and the total cost between the two groups were compared before and after treatment.RESULTS: At 3 wk, 3 and 6 mo, and at the final follow-up of the two groups of patients, the improvement in BCVA, CRT, and MVD in the DVC layer was significantly better than that before treatment(all P<0.05); there were differences in the comparisons of BCVA and CRT between the two groups at 6 mo and the final follow-up(all P<0.05), and the increase in the number of letters of BCVA was the most pronounced in the combination therapy group at 6 mo of treatment. Statistical significant difference was observed in the comparison of MVD in the DVC layer between the two groups at 3 and 6 mo after treatment and at the final follow-up(all P<0.05). However, no significant change in FAZ area was evident before and after treatment in both groups(P>0.05). The combination therapy group exhibited a reduced number of injections and total cost in comparison to the monotherapy group. The combination therapy group exhibited a slightly higher incidence of high intraocular pressure and cataract progression compared to the monotherapy group, with no statistical significant difference(all P>0.05). Furthermore, no serious adverse events were observed in either group following treatment.CONCLUSION:Compared with ranibizumab alone, ranibizumab combined with dexamethasone intravitreal implant significantly improved vision, reduced macular edema, and lowered the frequency of injections and total treatment cost in patients with RVO-ME. CRT and MVD in the DVC layer are reliable prognostic indicators for patients with RVO-ME.

Objective: This study aims to investigate the anatomical relationship among the nerve roots, intervertebral space, pedicles, and intradural rootlets of the cervical spine for improving operative outcomes and exploring neuroventral decompression approach in posterior endoscopic cervical discectomy (PECD). Methods: Cervical computed tomography myelography imaging data from January 2021 to May 2023 were collected, and the RadiAnt DICOM Viewer Software was employed to conduct multiplane reconstruction. The following parameters were recorded: width of nerve root (WN), nerve root-superior pedicle distance (NSPD), nerve root-inferior pedicle distance (NIPD), and the relationship between the intervertebral space and the nerve root (shoulder, anterior, and axillary). Additionally, the descending angles between the spinal cord and the ventral (VRA) and dorsal (DRA) rootlets were measured. Results: The WN showed a gradual increase from C4 to C7, with measurements notably larger in men compared to women. The NSPD decreased gradually from the C2–3 to the C5–6 levels. However, the NIPD showed an opposite level-related change, notably larger than the NSPD at the C4–5, C5–6, and C7–T1 levels. Furthermore, significant differences in NIPD were observed between different age groups and genders. The incidence of the anterior type exhibited a gradual decrease from the C2–3 to the C5–6 levels. Conversely, the axillary type exhibited an opposite level-related change. Additionally, the VRA and DRA decreased as the level descended, with measurements significantly larger in females. Conclusion A prediction of the positional relationship between the intervertebral space and the nerve root is essential for the direct neuroventral decompression in PECD to avoid damaging the neural structures. The axillary route of the nerve root offers a safer and more effective pathway for performing direct neuroventral decompression compared to the shoulder approach.