Background: Bone marrow-derived mesenchymal stromal cell (BM-MSC) secretome is a promising cell-free therapeutic approach for tissue regeneration. However, clinical translation requires scalable manufacturing processes, rigorous quality control, and evidence of biological potency. Here, we established a GMP-compliant manufacturing workflow for BM-MSC secretome and evaluated its safety and biological activity in corneal epithelial cells. Methods: Allogeneic human BM-MSCs were expanded under controlled GMP-compliant conditions and conditioned for 72 h in protein- and phenol red-free MEM-α medium. The resulting secretome underwent predefined lot-release and quality-control testing, including protein-associated content analysis and nanoparticle tracking analysis (NTA). Cytocompatibility was evaluated using cell viability and LDH assays, while biological activity was assessed using cell proliferation and in vitro scratch-wound assays. Results: The manufacturing process consistently generated a high-quality BM-MSC secretome that met predefined microbiological, product-integrity, and release criteria. Secretome conditioning resulted in increased protein-associated content and measurable nanoparticle particle population compared with unconditioned medium, providing quantitative product-characterization attributes for the manufactured secretome. The product demonstrated favorable cytocompatibility, maintaining high corneal epithelial cell viability without substantial membrane damage. Functionally, BM-MSC secretome promoted epithelial cell proliferation and enhanced wound closure compared with control medium, with the most pronounced biological effect observed during the early stages of wound repair. Conclusions: We established a scalable, quality-controlled, GMP-compliant framework for the manufacture and characterization of BM-MSC secretome. The resulting product demonstrated favorable safety characteristics and biological activity in corneal epithelial cells, supporting its potential as a cell-free regenerative therapy for ocular surface repair. This integrated manufacturing and potency-testing strategy provides a translational foundation for further development and preclinical evaluation of BM-MSC secretome-based therapeutics.
Neuroendovascular medicine is moving beyond purely mechanical treatment toward catheter-based systems that also deliver biologic therapies. In this narrative review, “biologic-enabled neurointervention” denotes three groups, distinguished throughout and grouped by route rather than regulatory class: true biologic products (recombinant proteins, monoclonal antibodies, cell therapies, extracellular vesicles and gene-transfer vectors); adjunctive small-molecule pharmacotherapy; and bioengineered device and nanocarrier platforms. We synthesize clinical, translational and preclinical evidence on periprocedural pharmacotherapy, bioactive devices, biologics for delayed cerebral ischemia, genotype-guided and anti-angiogenic therapies for arteriovenous malformations (AVMs), endovascular stem cell delivery, intra-arterial gene therapy and nanoscale delivery platforms. Superselective intra-arterial delivery may achieve higher target-site concentrations, lower systemic exposure and access to difficult-to-reach territories, although these advantages are not universal and depend on cerebral blood flow, first-pass extraction, molecular size and barrier integrity. Limitations include immunogenicity, off-target distribution, procedure-related risk, small and heterogeneous clinical datasets, and unresolved regulatory and manufacturing pathways for living and gene-based products. With the exception of adjunctive intra-arterial thrombolysis, which is supported by randomized evidence, the approaches reviewed here remain predominantly investigational, and each is assigned an explicit evidence tier. Whether biologic-enabled neurointervention becomes an integrated component of standard cerebrovascular care will depend on adequately powered multicenter trials.
Background/Objectives: Difficult-to-treat rheumatoid arthritis (D2T-RA) affects approximately 11.7% of patients. Real-world data on treatment trajectories, biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), and adverse events (AEs) remain limited. This study evaluated treatment patterns, line survival, and AEs in D2T-RA. Methods: This retrospective study included 97 D2T-RA patients. Treatment-line survival was assessed using Kaplan–Meier analysis with log-rank tests and a cluster-robust Cox proportional hazards model. Generalized estimating equation models (GEE) identified factors associated with AEs. Cluster analysis (K-modes, MCA followed by K-means, and hierarchical clustering) was performed to identify treatment patterns. Results: A median time to first prescription of b/tsDMARDs was 1369 days (IQR 852–2557). Inefficacy was the most common reason for switching (65.8%); csDMARD/GCs were discontinued for inefficacy more frequently than b/tsDMARD (70.1% vs. 61.3%). Among 470 b/tsDMARD-containing treatment lines, interleukin-6 (IL-6) inhibitors were most common (127 lines, 27.0%), followed by tumor necrosis factor-α (TNF-α) inhibitors (109 lines, 23.2%), Janus kinase (JAK) inhibitors (89 lines, 18.9%), rituximab (82 lines, 17.4%), and abatacept (61 lines, 13.0%). The agents used included tocilizumab, levilimab, sarilumab, and olokizumab; adalimumab, etanercept, infliximab, golimumab, and certolizumab pegol; and tofacitinib, baricitinib, and upadacitinib. In adjusted GEE models, treatment type was not a significant predictor of AE occurrence (OR 0.93, 95% CI 0.63–1.36); line number and female sex were independently associated with AEs, and a previous AE increased the risk of AE on the current line (OR 1.72, 95% CI 1.13–2.60; p = 0.011). TNF-α inhibitors were prescribed without concomitant methotrexate in 59 of 109 treatment lines (54.1%). At the final treatment line, lower disease activity was observed with abatacept, levilimab, and olokizumab, whereas higher values were observed with rituximab and etanercept; between-treatment differences were significant for DAS28-ESR (p = 0.0269), but not for CDAI, SDAI, or DAS28-CRP. Cluster analysis identified three exploratory treatment patterns, differing primarily in the use of tsDMARDs and hydroxychloroquine. Conclusions: D2T-RA is characterized by multiple treatment lines and frequent switching due to inefficacy, particularly for csDMARD/GC therapy. Among the targeted therapies evaluated, IL-6 inhibitors and abatacept were associated with lower disease activity at the final treatment line, whereas rituximab and etanercept were associated with higher values; these exploratory observations do not establish comparative effectiveness. The frequent use of TNF-α inhibitors without concomitant methotrexate highlights a potential target for treatment optimization. A history of AEs may help identify patients requiring closer safety monitoring.
Background/Objectives: The role of intravenous immunoglobulins (eIg) in septic shock remains controversial, and the identification of patients most likely to benefit from therapy is still uncertain. Emerging evidence suggests that dynamic parameters may outperform static baseline measurements in predicting outcomes and guiding treatment decisions. This study aimed to evaluate the prognostic value of baseline variables and their temporal changes in septic shock patients treated with eIgs. Methods: We analyzed data from the SORRISO prospective observational registry including 248 septic shock patients treated with eIgs. Baseline clinical and biochemical variables were recorded at treatment initiation (D0), and their changes were evaluated over the D0–D4 interval. Multivariable logistic regression models were used to assess predictors of outcome, focusing on both static and dynamic parameters. Results: Overall ICU mortality was 38.3%. Several baseline variables showed associations with outcome in univariable analyses; however, norepinephrine trajectory emerged as the most consistent independent predictor across multivariable models. Patients with increasing NE requirements (NE-UP) had significantly higher mortality than those with decreasing doses (NE-DOWN) (66.7% vs. 23.0%, p < 0.0001). The association remained significant across all adjustment strategies (OR range 4.31–8.12, all p < 0.05), whereas no baseline or post-treatment immunological variables retained independent statistical significance. Conclusions: In septic shock patients treated with eIgs, early changes in vasopressor support may represent a key prognostic indicator and a potentially useful tool for patient monitoring, outperforming static baseline variables. Monitoring norepinephrine trajectory may support a more personalized approach to eIg therapy and guide clinical decision-making.
Extracellular vesicles (EVs) are increasingly recognized as mediators of intercellular communication and as potential therapeutic and diagnostic platforms. In the ocular surface and anterior segment, EVs are released by epithelial, stromal, endothelial, immune, and aqueous outflow-related cells and are also detectable in tears and aqueous humor. Experimental studies suggest that EVs may promote corneal epithelial repair, modulate local immune responses, reduce stromal fibrosis, and participate in extracellular matrix regulation within the trabecular meshwork. In parallel, mesenchymal stromal cell-derived EVs are being investigated as cell-free therapeutics, while engineered EVs and EV–lipid hybrid systems may facilitate the delivery of nucleic acids and other therapeutic cargo to anterior segment tissues. Tear- and aqueous humor-derived EV preparations have also yielded candidate molecular signatures for ocular surface disease, glaucoma, and selected systemic disorders. However, much of the current evidence remains preclinical or exploratory. Reported effects are frequently based on conditioned medium, EV-enriched fractions, or incompletely characterized preparations, making it difficult to distinguish EV-specific activity from that of the broader secretome. Biomarker studies are additionally limited by small cohorts, low sample volumes, non-vesicular contaminants, and methodological heterogeneity. This review summarizes the biological roles, therapeutic applications, drug-delivery potential, and diagnostic use of EVs in anterior segment medicine. Particular emphasis is placed on the strength of EV-specific evidence, the limitations of extrapolating from non-ocular models, and the methodological, manufacturing, and regulatory requirements for clinical translation. EVs represent a promising interface between anterior segment biology, precision diagnosis, and targeted therapy, but rigorous characterization and comparative validation remain essential.
