Growing evidence suggests that versican is important in the innate immune response to lung infection. Our goal was to understand the regulation of macrophage-derived versican and the role it plays in innate immunity. We first defined the signaling events that regulate versican expression, using bone marrow-derived macrophages (BMDMs) from mice lacking specific Toll-like receptors (TLRs), TLR adaptor molecules, or the type I interferon receptor (IFNAR1). We show that LPS and polyinosinic-polycytidylic acid [poly(I:C)] trigger a signaling cascade involving TLR3 or TLR4, the Trif adaptor, type I interferons, and IFNAR1, leading to increased expression of versican by macrophages and implicating versican as an interferon-stimulated gene. The signaling events regulating versican are distinct from those for hyaluronan synthase 1 (HAS1) and syndecan-4 in macrophages. HAS1 expression requires TLR2 and MyD88. Syndecan-4 requires TLR2, TLR3, or TLR4 and both MyD88 and Trif. Neither HAS1 nor syndecan-4 is dependent on type I interferons. The importance of macrophage-derived versican in lungs was determined with LysM/ mice. These studies show increased recovery of inflammatory cells in the bronchoalveolar lavage fluid of poly(I:C)-treated LysM/ mice compared with control mice. IFN-β and IL-10, two important anti-inflammatory molecules, are significantly decreased in both poly(I:C)-treated BMDMs from LysM/ mice and bronchoalveolar lavage fluid from poly(I:C)-treated LysM/ mice compared with control mice. In short, type I interferon signaling regulates versican expression, and versican is necessary for type I interferon production. These findings suggest that macrophage-derived versican is an immunomodulatory molecule with anti-inflammatory properties in acute pulmonary inflammation.

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Incomplete osseointegration is primary cause of failure for orthopedic implants. New biomaterials that present stable signals promoting osteogenesis could reduce failure rates of orthopedic implants. In this study bone morphogenetic protein‐2 (BMP‐2) was delivered from titania nanotubes (Nt) modified with chitosan/heparin polyelectrolyte multilayers (PEMs). The surfaces were characterized by scanning electron microscopy and X‐ray photoelectron spectroscopy. BMP‐2 release from the surfaces was measured in vitro for up to 28 days. After an initial burst release of BMP‐2 during the first 2 days, most of the BMP‐2 remained on the surface. To determine the osteogenic properties of these surfaces, they were seeded with rat bone marrow cells; alkaline phosphatase (ALP) activity, total protein, calcium deposition, and osteocalcin were measured up to 4 weeks in vitro. When compared to Nt surfaces, the surfaces with BMP‐2 induce greater osteocalcin and calcium deposition. PEMs provide sustained presentation of BMP‐2, from a biomimetic surface. This enhances the osteogenic properties of the surface without requiring supraphysiologic growth factor dose. This growth factor delivery strategy could be used to improve bone healing outcomes and reduce complications for recipients of orthopedic implants.

Infection is the second leading cause of failure of orthopedic implants following incomplete osseointegration. Materials that increase the antimicrobial properties of surfaces while maintaining the ability for bone cells to attach and proliferate could reduce the failure rates of orthopedic implants. In this study, titania nanotubes (Nts) were modified with chitosan/heparin polyelectrolyte multilayers (PEMs) for gentamicin delivery. The antimicrobial activity of the surfaces was tested by coculturing bacteria with mammalian cells. Over 60% of gentamicin remained on the surface after an initial burst release on the first day. Antimicrobial activity of these surfaces was determined by exposure to Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli) for up to 24 h. Gentamicin surfaces had less live E. coli and S. aureus by 6 h and less E. coli by 24 h compared to Nt surfaces. S. aureus and human adiposederived stem cells (hADSCs) were cocultured on surfaces for up to 7 days to characterize the so-called "race to the surface" between bacteria and mammalian cells, which is hypothesized to ultimately determine the outcome of orthopedic implants. By day 7, there was no significant difference in bacteria between surfaces with gentamicin adsorbed on the surface and surfaces with gentamicin in solution. However, gentamicin delivered in solution is toxic to hADSCs. Alternatively, gentamicin presented from PEMs enhances the antimicrobial properties of the surfaces without inhibiting hADSC attachment and cell growth. Delivering gentamicin from the surfaces is therefore superior to delivering gentamicin in solution and represents a strategy that could improve the antimicrobial activity of orthopedic implants and reduce risk of failure due to infection, without reducing mammalian cell attachment.