Fluffy hybrid nanoadjuvants for reversing the imbalance of osteoclastic andosteogenic niches in osteoporosis

Osteoporosis is majorly caused by an imbalance between osteoclastic and osteogenic niches. Despite thedevelopment of nationally recognized first-line anti-osteoporosis drugs, including alendronate (AL), their lowbioavailability, poor uptake rate, and dose-related side effects present significant challenges in treatment. Thiscalls for an urgent need for more effective bone-affinity drug delivery systems. In this study, we produced hybridstructures with bioactive components and stable fluffy topological morphology by cross-linking calcium andphosphorus precursors based on mesoporous silica to fabricate nanoadjuvants for AL delivery. The subsequentgrafting of -PEG-DAsp8 ensured superior biocompatibility and bone targeting capacity. RNA sequencing revealedthat these fluffy nanoadjuvants effectively activated adhesion pathways through CARD11 and CD34 molecularmechanisms, hence promoting cellular uptake and intracellular delivery of AL. Experiments showed that smalldoseAL nanoadjuvants effectively suppress osteoclast formation and potentially promote osteogenesis. In vivoresults restored the balance between osteogenic and osteoclastic niches against osteoporosis as well as theconsequent significant recovery of bone mass. Therefore, this study constructed a drug nanoadjuvant withpeculiar topological structures and high bone targeting capacities, efficient intracellular drug delivery as well asbone bioactivity. This provides a novel perspective on drug delivery for osteoporosis and treatment strategies forother bone diseases.

Durable immunomodulatory hierarchical patch for rotator cuff repairing

Degradable rotator cuff patches,followed over five years,have been observed to exhibit high re-tear rates exceeding 50%,which is attributed to the inability of degradable polymers alone to restore the post-rotator cuff tear(RCT)inflammatory niche.Herein,poly(ester-ferulic acid-urethane)urea(PEFUU)was developed,featuring prolonged anti-inflammatory functionality,achieved by the integration of ferulic acid(FA)into the polyurethane repeating units.PEFUU stably releases FA in vitro,reversing the inflammatory niche produced by M1 macrophages and restoring the directed differentiation of stem cells.Utilizing PEFUU,hierarchical composite nanofiber patch(HCNP)was fabricated,simulating the natural microstructure of the tendon-to-bone interface with an aligned-random alignment.The incorporation of enzymatic hydrolysate derived from decellularized Wharton jelly tissue into the random layer could further enhance cartilage regeneration at the tendon-to-bone interface.Via rat RCT repairing model,HCNP possessing prolonged anti-inflammatory properties uniquely facilitated physiological healing at the tendon-to-bone interface’s microstructure.The alignment of fibers was restored,and histologically,the characteristic tripartite distribution of collagen I-collagen II-collagen I was achieved.This study offers a universal approach to the functionalization of degradable polymers and provides a foundational reference for their future applications in promoting the in vivo regeneration of musculoskeletal tissues.

Multifunctional bioactive core-shell electrospun membrane capable to terminate inflammatory cycle and promote angiogenesis in diabetic wound

Diabetic wound(DW)healing is a major clinical challenge due to multifactorial complications leading to prolonged inflammation.Electrospun nanofibrous(NF)membranes,due to special structural features,are promising biomaterials capable to promote DW healing through the delivery of active agents in a controlled manner.Herein,we report a multifunctional composite NF membrane loaded with ZnO nanoparticles(NP)and oregano essential oil(OEO),employing a new loading strategy,capable to sustainedly co-deliver bioactive agents.Physicochemical characterization revealed the successful fabrication of loaded nanofibers with strong in vitro anti-bacterial and anti-oxidant activities.Furthermore,in vivo wound healing confirmed the potential of bioactive NF membranes in epithelialization and granulation tissue formation.The angiogenesis was greatly prompted by the bioactive NF membranes through expression of vascular endothelial growth factor(VEGF).Moreover,the proposed NF membrane successfully terminated the inflammatory cycle by downregulating the pro-inflammatory cytokines interleukin6(IL-6)and matrix metalloproteinases-9(MMP-9).In vitro and in vivo studies revealed the proposed NF membrane is a promising dressing material for the healing of DW.