| Ovarian cancer is the most lethal gynecologic malignancy,and 70% of patients are already in the advanced clinical stage when they are diagnosed,posing a serious threat to women’s health worldwide.Studies show that the cure rate for stage I patients is 90%,while the 5-year survival rate for stage III-IV patients is only 20% to 30%.Therefore,early detection,early diagnosis,and early treatment are of great significance to the survival of patients.At present,clinical diagnosis of ovarian cancer mainly includes imaging,histopathology,and serological examination,but there are shortcomings such as difficulty in detecting early tumors,complicated operation,and high invasiveness.Therefore,a minimally invasive,painless,and highly sensitive method for early ovarian cancer diagnosis is urgently needed.In this paper,we combined porous polymer microneedle technology with an enzyme-linked immunoassay to construct a minimally invasive,convenient,and highly sensitive combined detection system for early ovarian cancer biomarkers.The details are as follows:1.In this paper,the predatory behavior of coral with hierarchical porous structure in flowing seawater was used as an inspiration source to prepare a bionic coral polymer microneedle system with a through-going multistage pore structure based on thermogenic phase separation method to substantially increase the binding sites of antibodies on microneedles and improve the extraction ability of tumor markers in interstitial fluid.The porous structure of microneedles was characterized by optical/fluorescence microscopy and scanning electron microscopy,and the results of multistation specific surface area and pore size analyzer and mercury piezometer tests further demonstrated the high specific surface area and high permeation flux of microneedles.In addition,several mechanical properties tests confirmed that the microneedles have the sufficient mechanical strength to ensure penetration into the skin.The safety of microneedles was also confirmed by cytotoxicity tests,hemolysis tests,and transdermal water loss tests.2.To avoid false-positive interference,the structural design of the multiwell microneedles was further optimized,and a dual-module integrated microneedle system was constructed by introducing a groove structure to achieve the combined detection of two ovarian cancer biomarkers,epithelial protein 4(HE4)and glycoconjugate antigen 125(CA125),to improve the detection accuracy.The hydrophilicity of microneedles was improved by oxygen plasma treatment and the optimal detection protocol was determined by in vitro detection of HE4.A nude mouse model of ovarian cancer was established by subcutaneous injection of SKOV3 cells to further validate that the porous biomimetic microneedle has a similar detection capability as the ELISA kit.And the concentration of HE4 in ovarian cancer nude mice increased with the growth of tumor volume,and it was determined that the microneedle could basically replace the serological assay.And it was verified that the microneedle could achieve the in vitro and in vivo detection of CA125.In conclusion,the integrated biomimetic microneedle patch with a hierarchical porous structure established in this study can realize the combined detection of tumor biomarkers with high sensitivity and accuracy,which provides a new way for the early detection of ovarian cancer. |
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