BACKGROUND:Bone tissue defects are one of the most common diseases in orthopedics,and the current treatments for this disease are inadequate.The development of tissue engineering brings new hope for bone defect repair:by regulating the release of bioactive substances and the process of vascularization and neurogenesis at the defect site,it can effectively improve the microenvironment of bone tissue and promote osseointegration,which is the most promising research idea for large-size bone defect repair. OBJECTIVE:To explore the research progress of regulating bone microenvironment changes in bone defect repair in recent years from the effects of bioactive substances,vascularization and neurotization on three aspects of bone microenvironment changes,and to provide new ideas and strategies for the treatment of large-size bone defects. METHODS:The search terms"bone tissue engineering,angiogenesis,neurotization,cytokines,bone morphogenetic protein,vascular endothelial growth factor,neuropeptides,bone microenvironment"in Chinese and English were used to search for articles on the influence of changes in the bone microenvironment and their application in bone tissue engineering published from January 1,2001 to December 31,2022 on CNKI,WanFang,Web of Science,Science Direct,and PubMed.Finally,109 articles were included for review. RESULTS AND CONCLUSION:(1)The bone microenvironment is essential for the induction of bone tissue stem cell growth and differentiation,and mainly consists of the extracellular matrix of the bone tissue seeds and the biochemical factors required for intercellular interactions,the local blood circulation network and the surrounding nerve tissue.(2)Bone defect repair is a continuous process divided into multiple phases that overlap and are mediated by multiple cytokines,and the same cytokine can have mutually synergistic or antagonistic effects in one or more healing phases.(3)Neovascular regeneration is key to initiating bone repair,as neovascularisation not only provides essential nutrients,osteoblasts and growth factors for bone repair,but is also a gateway for repair cells to enter the injury zone.(4)In addition to regulating the type,dose and timeliness of vascular-inducing factor release to achieve blood transport reconstruction.The study of differential release delivery systems of multiple factors and the application of gene transfer technology will be the future research direction to solve large bone defects.(5)Neuropeptides can bind to relevant receptors and act on specific signaling pathways to guide vascular growth and influence bone healing,bone regeneration and the balance between osteogenesis and osteolysis through a variety of pathways.(6)In the establishment of neuralized tissue-engineered bone,the role of changes in the bone tissue microenvironment and neuromodulation is bidirectional.Cytokines in the bone matrix can participate in neuronal signaling pathways through the blood-nerve barrier.Neuropeptides secreted by glial cells act on the bone microenvironment,affecting bone healing,bone regeneration and the balance between osteogenesis and osteolysis.(7)There are still many questions regarding the regulation of the bone microenvironment by bioactive substances and the processes of vascularization and neurogenesis,such as the rapid diffusion and degradation of cytokines in the body and their loss of activity,the temporal and spatial distribution of angiogenesis-related growth factors,and the establishment of neurogenesis through the body's feedback regulatory mechanism,which need to be improved by subsequent studies.

ObjectiveTo identify the relationship between tumor tissue interleukins （ILs） and non-small cell lung cancer （NSCLC） patients with poor response to immune checkpoint blockade （ICB） therapy， and to investigate the differential expression of ILs in tumor of NSCLC patients as well as its effect on ICB response and prognosis. MethodsA total of 61 patients diagnosed with NSCLC and treated with ICB were retrospectively collected from the data of a previous study. We obtained transcriptome sequencing data from tumor tissues and survival data of the patients before ICB treatment. Using bioinformatics methods， we screened for ILs that significantly affected the efficacy and prognosis of ICB treatment. We evaluated the efficacy of ICB treatment using progressive-free survival （PFS） and assessed the prognosis using overall survival （OS）. The Kaplan-Meier survival curve and ROC curve were used to analyze the predictive effect and efficacy of ILs on the efficacy and prognosis of ICB in NSCLC patients. ResultsThe results of the univariate Cox regression analysis in our study showed that nine ILs were found to be associated with OS of NSCLC patients treated with ICB at a significance level of P < 0.1. Further multivariate analysis revealed that high expression of IL-11， IL-17D， and IL-36A was significantly associated with poor prognosis in these patients （P < 0.05）. The results from the Kaplan-Meier survival curve analysis revealed a significant negative correlation between the high expression of IL-17D and both PFS and OS in NSCLC patients. Specifically， patients with IL-17D high expression had a median PFS of 3.1 months compared with 6.5 months in low expression patients ［95% confidence interval （CI） （1.178， 3.655）， P = 0.009］. Similarly， the median OS was 9.8 months in the high expression group versus 21.8 months in the low expression group ［95%CI （1.116， 4.392）， P = 0.018］. ROC curve showed that the prediction performance was favorable ［AUC_PFS = 0.702，95%CI （0.562， 0.842）， P = 0.027； AUC_OS = 0.684， 95%CI （0.550， 0.818）， P = 0.014］. Although IL-11 and IL-36A alone were not significant predictors of PFS and OS in NSCLC patients， the median PFS and OS were notably shortened to 2.2 months （P = 0.003） and 3.0 months （P < 0.001）， respectively， when high expression of IL-11 and IL-36A was combined with high expression of IL-17D. The ROC curve analysis demonstrated an improvement in prediction efficiency for both PFS and OS in NSCLC patients ［AUC_PFS = 0.748， 95%CI （0.615， 0.880）， P = 0.007； AUC_OS = 0.703， 95%CI （0.573， 0.833）， P = 0.007］. ConclusionThe results suggest that high expression of IL-11， IL-17D， and IL-36A is associated with a higher risk of disease progression which correlates to poor PFS and OS in NSCLC patients.