Intervertebral disc degeneration (IVDD) is a globally prevalent disease, yet achieving dual repair of tissue and function presents significant challenges. Considering reactive oxygen species (ROS) is a primary cause of IVDD, and given the decrease of nucleus pulposus cells (NPCs) and extensive degradation of extracellular matrix (ECM) during IVDD development, the present study, inspired by the seeds-and-soil strategy, has developed NPCsloaded TBA@Gel&Chs hydrogel microspheres. These microspheres serve as exogenous supplements of NPCs and ECM analogs, replenishing seeds and soil for nucleus pulposus repair, and incorporating polyphenol antioxidant components to interrupt the oxidative stress-IVDD cycle, thereby constructing a microsphere system where NPCs and ECM support each other. Experiments proved that TBA@Gel&Chs exhibited significant extra-cellular ROS-scavenging antioxidant capabilities while effectively upregulating intracellular antioxidant proteins expression (Sirt3 and Sod2). This dual-action antioxidant capability effectively protects the vitality and physiological functions of NPCs. The therapeutic effects of microspheres on IVDD were also confirmed in rat models, which was found significantly restore histological structure and mechanical properties of degenerated discs. Additionally, RNA-seq results have provided evidences of antioxidant mechanism by which TBA@Gel&Chs protected NPCs from oxidative stress. Therefore, the NPCs-loaded TBA@Gel&Chs microspheres developed in this study have achieved excellent therapeutic effects, offering a paradigm using antioxidant biomaterials combined with cellular therapy for IVDD treatment.

BACKGROUND Chemotherapy-associated ovarian damage (CAOD) is one of the most feared short- and long-term side effects of anticancer treatment in premenopausal women. Accumulating detailed data show that different chemotherapy regimens can lead to disturbance of ovarian hormone levels, reduced or lost fertility, and an increased risk of early menopause. Previous studies have often focused on the direct effects of chemotherapeutic drugs on ovarian follicles, such as direct DNA damage-mediated apoptotic death and primordial follicle burnout. Emerging evidence has revealed an imbalance in the ovarian microenvironment during chemotherapy. The ovarian microenvironment provides nutritional support and transportation of signals that stimulate the growth and development of follicles, ovulation, and corpus luteum formation. The close interaction between the ovarian microenvironment and follicles can determine ovarian function. Therefore, designing novel and precise strategies to manipulate the ovarian microenvironment may be a new strategy to protect ovarian function during chemotherapy.OBJECTIVE AND RATIONALE This review details the changes that occur in the ovarian microenvironment during chemotherapy and emphasizes the importance of developing new therapeutics that protect ovarian function by targeting the ovarian microenvironment during chemotherapy.SEARCH METHODS A comprehensive review of the literature was performed by searching PubMed up to April 2024. Search terms included 'ovarian microenvironment' (ovarian extracellular matrix, ovarian stromal cells, ovarian interstitial, ovarian blood vessels, ovarian lymphatic vessels, ovarian macrophages, ovarian lymphocytes, ovarian immune cytokines, ovarian oxidative stress, ovarian reactive oxygen species, ovarian senescence cells, ovarian senescence-associated secretory phenotypes, ovarian oogonial stem cells, ovarian stem cells), terms related to ovarian function (reproductive health, fertility, infertility, fecundity, ovarian reserve, ovarian function, menopause, decreased ovarian reserve, premature ovarian insufficiency/failure), and terms related to chemotherapy (cyclophosphamide, lfosfamide, chlormethine, chlorambucil, busulfan, melphalan, procarbazine, cisplatin, doxorubicin, carboplatin, taxane, paclitaxel, docetaxel, 5-fluorouraci, vincristine, methotrexate, dactinomycin, bleomycin, mercaptopurine).OUTCOMES The ovarian microenvironment shows great changes during chemotherapy, inducing extracellular matrix deposition and stromal fibrosis, angiogenesis disorders, immune microenvironment disturbance, oxidative stress imbalances, ovarian stem cell exhaustion, and cell senescence, thereby lowering the quantity and quality of ovarian follicles. Several methods targeting the ovarian microenvironment have been adopted to prevent and treat CAOD, such as stem cell therapy and the use of free radical scavengers, senolytherapies, immunomodulators, and proangiogenic factors.WIDER IMPLICATIONS Ovarian function is determined by its 'seeds' (follicles) and 'soil' (ovarian microenvironment). The ovarian microenvironment has been reported to play a vital role in CAOD and targeting the ovarian microenvironment may present potential therapeutic approaches for CAOD. However, the relation between the ovarian microenvironment, its regulatory networks, and CAOD needs to be further studied. A better understanding of these issues could be helpful in explaining the pathogenesis of CAOD and creating innovative strategies for counteracting the effects exerted on ovarian function. Our aim is that this narrative review of CAOD will stimulate more research in this important field.REGISTRATION NUMBER Not applicable. Graphical Abstract Chemotherapy causes an imbalance of the ovarian microenvironment leading to chemotherapy-associated ovarian damage and dysfunction, and further research is needed to explore the possible protective treatments. Created with BioRender.com, with permission.