Lotus-Inspired Microspheres Tackle Periodontitis on Three Fronts Simultaneously
Bioinspired hydrogel microspheres co-delivering berberine and bone-promoting stem cells eradicate resistant bacteria, quell inflammation, and rebuild bone.
Summary
Researchers engineered nano/micron hydrogel microspheres inspired by the lotus seedpod to treat periodontitis. The microspheres encapsulate polydopamine nanoparticles loaded with berberine (a natural antimicrobial) inside a GelMA hydrogel core, with BMP9-infected periodontal ligament stem cells (PDLSCs) seeded on the surface. This tri-functional system simultaneously combats antibiotic-resistant Fusobacterium nucleatum, suppresses periodontal inflammation, and promotes alveolar bone regeneration. In vitro and in vivo studies showed superior antibacterial, anti-inflammatory, and osteogenic outcomes compared to controls. RNA sequencing revealed synergistic regulation of TNF, TGF-β, and PPAR signaling pathways by berberine and BMP9 together, explaining the enhanced therapeutic effects. No organ toxicity was observed, suggesting a safe, comprehensive alternative to current periodontitis treatments.
Detailed Summary
Periodontitis affects hundreds of millions globally and remains notoriously difficult to treat because deep, irregular periodontal pockets harbor antibiotic-resistant pathogens—especially Fusobacterium nucleatum—while current therapies cannot simultaneously control infection, resolve inflammation, and regenerate destroyed alveolar bone. This study addresses all three challenges with a single bioinspired delivery system.
Drawing inspiration from the lotus seedpod—which shelters seeds within protective petals in a symbiotic relationship—the team constructed PDA/BBR@Gel@BMP9-PDLSC microspheres. Polydopamine (PDA) nanoparticles, chosen for their strong drug-loading capacity and tissue adhesion, were used to carry berberine (BBR), a traditional Chinese medicine compound with broad antimicrobial and anti-inflammatory properties. These PDA/BBR nanoparticles were embedded into gelatin methacrylate (GelMA) hydrogel microspheres fabricated via microfluidics, yielding uniformly sized, injectable particles. BMP9-overexpressing PDLSCs—known to outperform other dental stem cells in osteogenesis—were then seeded onto the microsphere surface, creating a nano/micron hybrid system capable of sustained, localized co-delivery of BBR and BMP9.
In vitro characterization confirmed successful BBR loading (verified by FTIR), appropriate zeta potentials, mechanical integrity, and pH-responsive sustained release mimicking both physiological (pH 7.4) and inflammatory (pH 6.3) periodontal conditions. Biocompatibility was demonstrated through live/dead staining, CCK-8 proliferation assays, and cytoskeletal imaging. Antibacterial efficacy against F. nucleatum was confirmed, and the system robustly inhibited LPS-induced inflammatory markers while promoting alkaline phosphatase activity, calcium nodule formation, and osteogenic gene expression in PDLSCs.
In vivo, the microspheres were tested in two rat models: a calvaria bone defect model and a ligature-induced periodontitis model with persistent F. nucleatum infection. Micro-CT and histological analyses revealed markedly greater new bone volume, improved bone mineral density, and reduced inflammatory infiltrate in the PDA/BBR@Gel@BMP9-PDLSC group compared to all controls. No systemic organ toxicity was detected in histopathological evaluation.
RNA sequencing and Western blot analyses illuminated the mechanistic basis for the synergistic effects: BBR and BMP9 together downregulated TNF signaling pathway components (reducing pro-inflammatory cytokine cascades), upregulated TGF-β pathway genes (promoting osteogenic differentiation), and activated PPAR signaling (known to modulate both inflammation and bone metabolism). Neither BBR nor BMP9 alone produced the same magnitude of transcriptional reprogramming, underscoring the importance of their combination. The lotus-inspired design thus provided not just a clever aesthetic parallel but a functionally optimized architecture for periodontal microenvironment remodeling.
Key Findings
- PDA/BBR@Gel@BMP9-PDLSC microspheres effectively killed antibiotic-resistant F. nucleatum while sustaining BBR release over weeks.
- The system promoted significantly greater alveolar bone regeneration than monotherapy controls in rat periodontitis models.
- BBR and BMP9 synergistically regulated TNF, TGF-β, and PPAR pathways, identified by RNA sequencing and Western blot.
- No systemic organ toxicity was observed, supporting the biocompatibility and safety profile of the platform.
- Microfluidic fabrication yielded uniformly sized, injectable microspheres with pH-responsive drug release matching inflammatory periodontal conditions.
Methodology
Injectable GelMA microspheres co-encapsulating PDA/BBR nanoparticles and BMP9-infected PDLSCs were fabricated via microfluidics and characterized physicochemically. Efficacy was evaluated in vitro using LPS-stimulated PDLSC models and in vivo in rat calvaria defect and ligature-induced periodontitis models with F. nucleatum infection. Mechanistic studies used RNA sequencing and Western blotting.
Study Limitations
Findings are based on rodent models, which may not fully replicate the complex human periodontal environment or long-term disease chronicity. The use of adenoviral BMP9 delivery raises translational concerns regarding immune response and regulatory approval. Long-term in vivo safety and degradation kinetics beyond the study period were not assessed.
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