The formation and progression of CSDH are driven by multiple molecular signaling pathways, with inflammation amplification, abnormal angiogenesis, and coagulation–fibrinolysis imbalance forming the core regulatory axes supporting hematoma chronicity.

First, regarding inflammatory signaling, NF-κB and its upstream TLR4 pathway are persistently activated in the outer membrane, resulting in high-level expression of pro-inflammatory cytokines such as IL-6, IL-8, and TNF-α, thereby establishing a typical chronic inflammation amplification loop (Osuka et al., 2020; Holl et al., 2018). Simultaneously, concurrent activation of the IL-6/STAT3 pathway not only promotes continuous thickening of the outer membrane but also closely interacts with abnormal angiogenesis, representing a key molecular basis for the high recurrence propensity of CSDH (Osuka et al., 2017; Osuka et al., 2013). Evidence supporting activation of this inflammatory–angiogenic positive feedback loop is derived primarily from immunohistochemical analyses of CSDH outer membranes, which demonstrate increased NF-κB nuclear translocation and STAT3 phosphorylation, as well as from experimental animal models showing attenuation of membrane growth following pathway inhibition.

In terms of angiogenic regulation, dual upregulation of VEGF and Ang-2 constitutes the molecular basis for the “leaky angiogenesis” phenotype observed in CSDH (Kim and Lee, 2023). Elevated VEGF drives the formation of numerous structurally immature neovessels, while Ang-2 antagonizes Tie2-mediated stabilization signals, further compromising vascular integrity and increasing susceptibility to rupture and leakage. Additionally, overexpression of matrix metalloproteinases such as MMP-9 accelerates degradation of the vascular basement membrane, maintaining long-term vascular instability and serving as a critical source of repeated microbleeds and hematoma expansion (Su et al., 2022a; Su et al., 2022b) (Figure 5).

At the coagulation–fibrinolysis level, the hematoma cavity exhibits a characteristic “hyperfibrinolytic and hypocoagulable” state. Tissue plasminogen activator (tPA) is significantly elevated, while abnormal fluctuations in PAI-1 further exacerbate uncontrolled fibrinolytic activity (Brazdzioni et al., 2019; Neils et al., 2012; Doan et al., 2018). Repeated local microbleeds generate degradation products under persistent fibrinolysis, which in turn enhance inflammatory responses and promote extracellular matrix destruction, forming a bidirectional pathological cycle between inflammation and fibrinolysis, and creating the unique “hemorrhagic microenvironment” of CSDH.

Overall, inflammation amplification, abnormal angiogenesis, and coagulation–fibrinolysis dysregulation collectively establish a self-sustaining and difficult-to-terminate pathological signaling network, representing the key mechanisms driving the persistence and recurrence of CSDH.

The extracellular matrix (ECM) and biophysical factors play critical regulatory roles in the CSDH microenvironment, influencing not only cellular behaviors but also the tissue’s ability to restore homeostasis from the ongoing inflammatory and hemorrhagic cycles (Huang et al., 2024; Huang et al., 2024). The ECM of the CSDH outer membrane exhibits marked structural remodeling, characterized by disorganized collagen fibers, abundant deposition of fibronectin and fibrin degradation products, and overexpression of MMP-2 and MMP-9, leading to continuous ECM degradation and reconstruction (Hua et al., 2015). This abnormal dynamic imbalance places local tissue in a state resembling a “chronic wound,” affecting fibroblast proliferation, migration, and secretory activity, while also promoting immune cell infiltration and compromising vascular stability, thus forming a key structural basis for sustaining the pathological CSDH cycle.

Beyond the chemical and structural properties of the ECM, various biophysical factors within the hematoma cavity also profoundly influence microenvironmental evolution. As the hematoma enlarges, increased intracavitary pressure directly compresses neovessels in the outer membrane, further enhancing vascular permeability and promoting the influx of exudates and inflammatory mediators, thereby creating a vicious cycle (Mehta et al., 2018). Concurrently, mechanical stretching of local tissue can induce fibroblasts to adopt a more secretory phenotype, releasing large amounts of pro-angiogenic factors and further driving the formation of unstable neovessels (Mehmandoost et al., 2025). Recent studies also suggest that changes in shear stress and osmotic pressure may affect endothelial junctional structures and barrier function, providing a biological basis for repeated leakage and recurrence in CSDH.

Overall, abnormal ECM remodeling and biophysical mechanical stimuli together constitute key factors regulating cellular behavior in the CSDH microenvironment. They maintain local tissue in a persistent state of inflammation, leakage, and failed repair, representing important targets for future microenvironmental remodeling and regenerative therapies.

The pathological progression of CSDH is closely linked to persistent inflammatory activation and abnormal immune cell polarization. Long-term activation of signaling pathways such as NF-κB and IL-6/STAT3 in the membrane tissue increases pro-inflammatory cytokine release, enhances angiogenesis, and drives continuous membrane thickening (Osuka et al., 2017; Osuka et al., 2016). Therefore, inhibiting these key pathways has emerged as an important strategy to regulate the local microenvironment. Corticosteroids, atorvastatin, and other drugs have been shown to downregulate these pathways, attenuating the inflammatory cascade in membrane tissue and reducing the risk of hematoma recurrence. Recently, precise regulation of the immune microenvironment has become a research focus. Strategies that promote macrophage polarization from the pro-inflammatory M1 phenotype to the reparative M2 phenotype show significant potential. Various miRNAs, including miR-21 and miR-146a, can regulate macrophage polarization and suppress pro-inflammatory signaling, reducing local inflammation and promoting tissue repair in animal models, providing a feasible direction for future immune-targeted therapies (Wang et al., 2018; Olivieri et al., 2021; Böttcher et al., 2023).

The persistent growth and recurrence of CSDH are closely associated with fragile and abnormal neovasculature. Pathological vessels often exhibit high VEGF expression, basement membrane defects, and reduced endothelial junction integrity, leading to increased vascular permeability and accumulation of fluid within the hematoma cavity. Anti-VEGF or multi-target anti-angiogenic therapies have been shown in animal models to reduce fragile vessel density, inhibit leakage, and attenuate inflammatory cascades (Verma et al., 2024). Additionally, restoring the Tie2/Ang signaling axis enhances endothelial barrier integrity, reducing the formation of leaky vessels (Isaji et al., 2020). Small molecules or protease inhibitors targeting basement membrane degradation can further stabilize vascular structures and interrupt the “inflammation–leakage–re-inflammation” cycle. Integrated strategies that modulate angiogenesis and vascular barrier function hold promise for fundamentally reducing CSDH recurrence rates.

Advances in nanomedicine have opened new avenues for extracellular vesicles (EV) - and nucleic acid-based strategies to modulate the CSDH microenvironment. EVs can carry miRNAs, siRNAs, and proteins, playing important roles in intercellular communication and inflammation regulation. By delivering specific miRNAs or siRNAs to target pro-inflammatory pathways, inhibit vascular leakage, or modulate matrix-degrading factors, multidimensional molecular-level interventions can be achieved in membrane pathology (Gao et al., 2019). Concurrently, nanocarrier technologies have greatly enhanced the stability and targeting of these biomolecules. DNA nanostructures such as tetrahedral framework nucleic acids (tFNA) exhibit high biocompatibility, efficient cellular uptake, and the ability to cross the blood-brain barrier, and have demonstrated anti-inflammatory and repair-promoting effects in neural disorders (Fu et al., 2021). Applying tFNA platforms to deliver anti-inflammatory, anti-leakage, or repair-related RNAs could enable precise and synergistic regulation of the CSDH microenvironment, providing a foundation for highly controllable regenerative medicine therapies in the future.

Despite the promising potential of regenerative medicine–based strategies for modulating the chronic subdural hematoma microenvironment, several limitations and risks should be acknowledged. Therapeutic responses may be heterogeneous among patients due to differences in age, comorbidities, hematoma stage, and underlying microenvironmental profiles. In addition, the efficiency and precision of local or targeted delivery—particularly for extracellular vesicles, nucleic acid–based therapeutics, and biomaterials—remain technically challenging, potentially limiting their reproducibility and translational applicability. Safety considerations, including immunogenicity, off-target effects, long-term biocompatibility, and dose control, also require careful evaluation before widespread clinical adoption. Addressing these challenges through optimized delivery systems, rigorous preclinical validation, and well-designed clinical studies will be essential for translating regenerative microenvironmental regulation from concept to clinical reality.

Surgical drainage can rapidly reduce hematoma volume, relieve local pressure, and provide a foundation for rebalancing the microenvironment (Uno, 2023). However, residual inflammatory cells, abnormal vessels, and actively degrading extracellular matrix (ECM) in the outer membrane may still drive postoperative recurrence (Hamou et al., 2022). Accordingly, middle meningeal artery (MMA) embolization has emerged as a therapeutic approach. By occluding the abnormal neovasculature that supplies the pathological membranes of the subdural space, it reduces vascular leakage and inflammatory drive, thereby effectively lowering the recurrence rate of chronic subdural hematoma (Schmolling et al., 2024; Catapano et al., 2020). On the other hand, perioperative interventions using targeted drugs or regenerative materials—such as anti-inflammatory molecules, biologics that inhibit vascular leakage, or hydrogels capable of sustained release of reparative factors—can further suppress inflammatory cascades, improve vascular stability, and promote orderly remodeling of membrane tissue, potentially lowering recurrence rates. Experimental studies have shown that delivering anti-inflammatory or anti-fibrinolytic agents directly into the drainage cavity or applying them to the outer membrane surface can significantly enhance tissue repair, supporting the concept of continuous intra- and postoperative microenvironmental regulation.

With advances in regenerative medicine and nanomaterials, non-surgical regenerative therapies are gradually emerging. This approach aims to precisely modulate core pathological elements of the microenvironment, promoting spontaneous hematoma absorption and preventing expansion without surgical intervention (Yun and Ding, 2020; Scerrati et al., 2020). Its theoretical basis includes: reducing exudate formation by inhibiting central inflammatory pathways, decreasing rebleeding by stabilizing fragile neovessels, and restoring tissue homeostasis by reconstructing ECM architecture and balancing protease activity. Injectable hydrogels, targeted RNA nanomedicines, MSC-derived extracellular vesicles, and multifunctional biomaterials may all serve as non-invasive or minimally invasive delivery modalities, offering particular value for elderly patients or those with comorbidities who cannot tolerate surgery (Varderidou-Minasian and Lorenowicz, 2020). Preclinical models have shown that combined interventions targeting inflammation, vascular stabilization, and ECM reconstruction can significantly reduce hematoma volume without surgical drainage, providing a scientific basis for non-surgical regenerative therapy.

Advances in precision regenerative medicine offer a higher-level theoretical framework for integrated CSDH treatment. Multi-dimensional analyses—including hematoma fluid omics, outer membrane transcriptomics, proteomics, and single-cell sequencing—can reveal patient-specific heterogeneity in inflammation, angiogenesis, ECM degradation, and immune responses (Zhang et al., 2024). This heterogeneity suggests that CSDH is not a single disease entity but may comprise multiple microenvironment-driven subtypes, such as inflammation-dominant, vascular leakage-dominant, or fibrosis/ECM imbalance-dominant types (Edlmann et al., 2017). Subtype-based therapeutic models enable more precise interventions: inflammation-dominant patients may benefit from NF-κB or IL-6/STAT3 inhibitors; vascular leakage-dominant patients may be better suited for Tie2 activators, anti-VEGF therapy, or protease inhibitors; ECM imbalance-dominant patients may benefit more from MSCs or biomaterials with matrix-reconstructive capabilities (Osuka et al., 2020; Osuka et al., 2017; Jensen et al., 2024). In the future, integrating clinical imaging, omics data, and AI-based predictive models may facilitate individualized treatment pathways, achieving true precision management of the CSDH microenvironment—from lesion clearance to functional reconstruction.