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Osteochondral defect repair in osteoarthritis (OA) remains an unsolved clinical problem due to the lack of enough seed cells in the defect and chronic inflammation in the joint. To address this clinical need, we designed a bone marrow-derived mesenchymal stem cell (BMSC)-laden 3D-bioprinted multilayer scaffold with methacrylated hyaluronic acid (MeHA)/polycaprolactone incorporating kartogenin and β-TCP for osteochondral defect repair within each region. BMSC-laden MeHA was designed to actively introduce BMSCs in situ, and diclofenac sodium (DC)-incorporated matrix metalloproteinase-sensitive peptide-modified MeHA was induced on the BMSC-laden scaffold as an anti-inflammatory strategy. BMSCs in the scaffolds survived, proliferated, and produced large amounts of cartilage-specific extracellular matrix in vitro . The effect of BMSC-laden scaffolds on osteochondral defect repair was investigated in an animal model of medial meniscectomy-induced OA. BMSC-laden scaffolds facilitated chondrogenesis by promoting collagen II and suppressed interleukin 1β in osteochondral defects of the femoral trochlea. Congruently, BMSC-laden scaffolds significantly improved joint function of the injured leg with respect to the ground support force, paw grip force, and walk gait parameters. Therefore, this research demonstrates the potential of 3D-bioprinted BMSC-laden scaffolds to simultaneously inhibit joint inflammation and promote cartilage defect repair in OA joints.

The adverse macrophage-mediated immune response elicited by the surface of polyetheretherketone (PEEK) is responsible for the formation of fibrous encapsulation and resulting inferior osseointegration of PEEK implants in the dental and orthopedic fields. Therefore, endowing the PEEK surface with immunomodulatory ability is an appealing strategy to enhance implant-bone integration. Herein, a reliable and cost-effective method to construct adherent films with tunable nanoporous structures on PEEK is described. The functionalized surface not only suppresses the acute inflammatory response of macrophages, but also provides a favorable milieu for osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs). Whole genome expression analysis reveals that the suppression effect arises from synergistic inhibition of focal adhesion, Toll-like receptor, and NOD-like receptor signaling pathways, as well as the attenuating loop through the JAK-STAT and TNF signaling pathways in macrophages. Further in vivo studies confirm that the functionalized surface induces less fibrous capsule formation and an improved bone regeneration. The nanoporous films fabricated on PEEK harmonize the early macrophage-mediated inflammatory response and subsequent hBMSCs-centered osteogenic functions consequently yielding superior osseointegration.

Preserving the bioactivity of growth factors (GFs) and mimicking their in vivo supply patterns are challenging in the development of GFs-based bone grafts. In this study, we develop a 2-N, 6-O-sulfated chitosan (26SCS) functionalized dual-modular scaffold composed of mesoporous bioactive glass (MBG) with hierarchical porous structures (module I) and GelMA hydrogel columns (module II) in situ fixed in hollowed channels of the module I, which is capable of realizing differentiated delivery modes for osteogenic rhBMP-2 and angiogenic VEGF. A combinational release profile consisting of a high concentration of VEGF initially followed by a decreasing concentration over time, and a slower/sustainable release of rhBMP-2 is realized by immobilizing rhBMP-2 in module I and embedding VEGF in module II. Systematic in vitro and in vivo studies prove that the two coupled processes of osteogenesis and angiogenesis are well-orchestrated and both enhanced ascribed to the specific GFs delivery modes and 26SCS decoration. 26SCS not only enhances the GFs' bioactivity but also decreases antagonism effects of noggin. This study highlights the importance of differentiating the delivery pattern of different GFs and likely sheds light on the future design of growth factor-based bone grafts.

Rapid corrosion of biodegradable magnesium alloys under in vivo condition is a major concern for clinical applications. Inspired by the stability and biocompatibility of titanium oxide (TiO

Most commercial dental implants are made of titanium (Ti) because Ti possesses excellent properties such as osseointegration. However, many types of Ti products still suffer from insufficient antibacterial capability and bacterial infection after surgery remains one of the most common and intractable complications. In this study, a dual process encompassing anodization and silver plasma immersion ion implantation (Ag PIII) is utilized to produce titania nanotubes (TiO₂-NTs) containing Ag at different sites and depths. The concentration and depth of the incorporated Ag can be tailored readily by changing the PIII parameters. The Ag-embedded TiO₂-NTs which retain the nanotubular morphology are capable of sterilizing oral pathogens as opposed to pure Ti plates and pristine TiO₂-NTs. Biological assays indicate that the in vitro and in vivo biocompatibility of the sample plasma-implanted at a lower voltage of 0.5 kV (NT-Ag-0.5) is significantly compromised due to the large amount of surface Ag. On the other hand, the sample implanted at 1 kV (NT-Ag-1.0) exhibits unimpaired effects due to the smaller surface Ag accumulation. Sample NT-Ag-1.0 is further demonstrated to possess sustained antibacterial properties due to the large embedded depth of Ag and the technique and resulting materials have large potential in dental implants.

Rapid corrosion of biodegradable magnesium alloys under in vivo condition is a major concern for clinical applications. Inspired by the stability and biocompatibility of titanium oxide (TiO2) passive layer, a functionalized TiO2/Mg2TiO4 nano-layer has been constructed on the surface of WE43 magnesium implant by using plasma ion immersion implantation (PIII) technique. The customized nano-layer not only enhances corrosion resistance of Mg substrates significantly, but also elevates the osteoblastic differentiation capability in vitro due to the controlled release of magnesium ions. In the animal study, the increase of new bone formation adjacent to the PIII-treated magnesium substrate is 175% higher at post-operation 12 weeks, whereas the growth of new bone on titanium control and untreated magnesium substrate are only 97% and 29%, respectively. In addition, its Young's modulus can be restored to about 82% as compared with the surrounding matured bone. Furthermore, this specific TiO2/Mg2TiO4 layer even exhibits photoactive bacteria disinfection capability when irradiated by ultraviolet light which is attributed to the intracellular reactive oxygen species (ROS) production. With all these constructive observations, it is believed that the TiO2/Mg2TiO4 nano-layer on magnesium implants can significantly promote new bone formation and suppress bacterial infection, while the degradation behavior can be controlled simultaneously.

The regeneration capacity of the osteoporotic bones is generally lower than that of the normal bones. Current methods of bone defect treatment for osteoporosis are not always satisfactory. Recent studies have shown that the silicate based biomaterials can stimulate osteogenesis and angiogenesis due to the silicon (Si) ions released from the materials, and enhance bone regeneration in vivo. Other studies showed that strontium (Sr) plays a distinct role on inhibiting bone resorption. Based on the hypothesis that the combination of Si and Sr may have synergetic effects on osteoporotic bone regeneration, the porous Sr-substituted calcium silicate (SrCS) ceramic scaffolds combining the functions of Sr and Si elements were developed with the goals to promote osteoporotic bone defect repair. The effects of the ionic extract from SrCS on osteogenic differentiation of bone marrow mesenchymal stem cells derived from ovariectomized rats (rBMSCs-OVX), angiogenic differentiation of human umbilical vein endothelial cells (HUVECs) were investigated. The in vitro results showed that Sr and Si ions released from SrCS enhanced cell viability, alkaline phosphatase (ALP) activity, and mRNA expression levels of osteoblast-related genes of rBMSCs-OVX and expression of vascular endothelial growth factor (VEGF) without addition of extra osteogenic and angiogenic reagents. The activation in extracellular signal-related kinases (ERK) and p38 signaling pathways were observed in rBMSCs-OVX cultured in the extract of SrCS, and these effects could be blocked by ERK inhibitor PD98059, and P38 inhibitor SB203580, respectively. Furthermore, the ionic extract of SrCS stimulated HUVECs proliferation, differentiation and angiogenesis process. The in vivo experiments revealed that SrCS dramatically stimulated bone regeneration and angiogenesis in a critical sized OVX calvarial defect model, and the enhanced bone regeneration might be attributed to the modulation of osteogenic differentiation of endogenous mesenchymal stem cells (MSCs) and the inhibition of osteoclastogenesis, accompanying with the promotion of the angiogenic activity of endothelial cells (ECs).

Strontium-containing hydroxyapatite/polyetheretherketone (Sr-HA/PEEK) composites were developed as alternative materials for load-bearing orthopaedic applications. The amount of strontium-containing hydroxyapatite (Sr-HA) incorporated into polyetheretherketone (PEEK) polymer matrix ranged from 15 to 30 vol% and the composites were successfully fabricated by compression molding technique. This study presents the mechanical properties and in vitro human osteoblast-like cell (MG-63) response of the composite material developed. The bending modulus and strength of Sr-HA/PEEK composites were tailored to mimic human cortical bone. PEEK reinforced with 25 and 30 vol% Sr-HA exhibited bending modulus of 9.6 and 10.6 GPa, respectively; alternatively, the bending strengths of the composites were 93.8 and 89.1 MPa, respectively. Based on the qualitative comparison of apatite formation in SBF and quantitative measurement of MG-63-mediated mineralization in vitro, the Sr-HA/PEEK composite was proven to outperform HA/PEEK in providing bioactivity. However, no difference was found in the trend of cell proliferation and alkaline phosphatase activity between different composites. Strontium, in the form of strontium-containing hydroxyapatite (Sr-HA), was confirmed to enhance bioactivity in the PEEK composites.