Bisphosphonate conjugation enhances the bone-specificity of NELL-1-based systemic therapy for spaceflight-induced bone loss in mice.

Microgravity-induced bone loss results in a 1% bone mineral density loss monthly and can be a mission critical factor in long-duration spaceflight. Biomolecular therapies with dual osteogenic and anti-resorptive functions are promising for treating extreme osteoporosis. We previously confirmed that NELL-like molecule-1 (NELL-1) is crucial for bone density maintenance. We further PEGylated NELL-1 (NELL-polyethylene glycol, or NELL-PEG) to increase systemic delivery half-life from 5.5 to 15.5 h. In this study, we used a bio-inert bisphosphonate (BP) moiety to chemically engineer NELL-PEG into BP-NELL-PEG and specifically target bone tissues. We found conjugation with BP improved hydroxyapatite (HA) binding and protein stability of NELL-PEG while preserving NELL-1's osteogenicity in vitro. Furthermore, BP-NELL-PEG showed superior in vivo bone specificity without observable pathology in liver, spleen, lungs, brain, heart, muscles, or ovaries of mice. Finally, we tested BP-NELL-PEG through spaceflight exposure onboard the International Space Station (ISS) at maximal animal capacity (n = 40) in a long-term (9 week) osteoporosis therapeutic study and found that BP-NELL-PEG significantly increased bone formation in flight and ground control mice without obvious adverse health effects. Our results highlight BP-NELL-PEG as a promising therapeutic to mitigate extreme bone loss from long-duration microgravity exposure and musculoskeletal degeneration on Earth, especially when resistance training is not possible due to incapacity (e.g., bone fracture, stroke).

Neural EGFL like 1 as a potential pro-chondrogenic, anti-inflammatory dual-functional disease-modifying osteoarthritis drug.

Arthritis, an inflammatory condition that causes pain and cartilage destruction in joints, affects over 54.4 million people in the US alone. Here, for the first time, we demonstrated the emerging role of neural EGFL like 1 (NELL-1) in arthritis pathogenesis by showing that Nell-1-haploinsufficient (Nell-1+/6R) mice had accelerated and aggravated osteoarthritis (OA) progression with elevated inflammatory markers in both spontaneous primary OA and chemical-induced secondary OA models. In the chemical-induced OA model, intra-articular injection of interleukin (IL)1ß induced more severe inflammation and cartilage degradation in the knee joints of Nell-1+/6R mice than in wildtype animals. Mechanistically, in addition to its pro-chondrogenic potency, NELL-1 also effectively suppressed the expression of inflammatory cytokines and their downstream cartilage catabolic enzymes by upregulating runt-related transcription factor (RUNX)1 in mouse and human articular cartilage chondrocytes. Notably, NELL-1 significantly reduced IL1ß-stimulated inflammation and damage to articular cartilage in vivo. In particular, NELL-1 administration markedly reduced the symptoms of antalgic gait observed in IL1ß-challenged Nell-1+/6R mice. Therefore, NELL-1 is a promising pro-chondrogenic, anti-inflammatory dual-functional disease-modifying osteoarthritis drug (DMOAD) candidate for preventing and suppressing arthritis-related cartilage damage.

Using an Engineered Galvanic Redox System to Generate Positive Surface Potentials that Promote Osteogenic Functions.

Successful osseointegration of orthopaedic and orthodontic implants is dependent on a competition between osteogenesis and bacterial contamination on the implant-tissue interface. Previously, by taking advantage of the highly interactive capabilities of silver nanoparticles (AgNPs), we effectively introduced an antimicrobial effect to metal implant materials using an AgNP/poly(dl-lactic- co-glycolic acid) (PLGA) coating. Although electrical forces have been shown to promote osteogenesis, creating practical materials and devices capable of harnessing these forces to induce bone regeneration remains challenging. Here, we applied galvanic reduction-oxidation (redox) principles to engineer a nanoscale galvanic redox system between AgNPs and 316L stainless steel alloy (316L-SA). Characterized by scanning electron microscopy , energy-dispersive X-ray spectroscopy, atomic force microscopy, Kelvin probe force microscopy, and contact angle measurement, the surface properties of the yield AgNP/PLGA-coated 316L-SA (SNPSA) material presented a significantly increased positive surface potential, hydrophilicity, surface fractional polarity, and surface electron accepting/donating index. Importantly, in addition to its bactericidal property, SNPSA's surface demonstrated a novel osteogenic bioactivity by promoting peri-implant bone growth. This is the first report describing the conversion of a normally deleterious galvanic redox reaction into a biologically beneficial function on a biomedical metal material. Overall, this study details an innovative strategy to design multifunctional biomaterials using a controlled galvanic redox reaction, which has broad applications in material development and clinical practice.