Age is the primary risk factor for osteoarthritis (OA), yet surgical OA mouse models such as destabilization of the medial meniscus (DMM) used for evaluating disease-modifying OA targets are frequently performed on young adult mice only. This study investigates how age affects cartilage and subchondral bone changes in mouse joints following DMM. DMM was performed on male C57BL/6 mice at 4 months (4 M), 12 months (12 M) and 19+ months (19 M+) and on females at 12 M and 18 M+. Two months after surgery, operated and unoperated contralateral knees were harvested and evaluated using cartilage histology scores and μCT quantification of subchondral bone plate thickness and osteophyte formation. The 12 M and 19 M+ male mice developed more cartilage erosions and thicker subchondral bone plates after DMM than 4 M males. The size of osteophytes trended up with age, while the bone volume fraction was significantly higher in the 19 M+ group. Furthermore, 12 M females developed milder OA than males as indicated by less cartilage degradation, less subchondral bone plate sclerosis and smaller osteophytes. Our results reveal distinct age/gender-dependent structural changes in joint cartilage and subchondral bone post-DMM, facilitating more thoughtful selection of murine age/gender when using this surgical technique for translational OA research.
Preventing orthopedic implant-associated bacterial infections remains a critical challenge. Current practices of physically blending high-dose antibiotics with bone cements is known for cytotoxicity while covalently tethering antibiotics to implant surfaces is ineffective in eradicating bacteria from the periprosthetic tissue environment due to the short-range bactericidal actions, which are limited to the implant surface. Here, we covalently functionalize poly(ethylene glycol) dimethacrylate hydrogel coatings with vancomycin via an oligonucleotide linker sensitive to Staphylococcus aureus (S. aureus) micrococcal nuclease (MN) (PEGDMA-Oligo-Vanco). This design enables the timely release of vancomycin in the presence of S. aureus to kill the bacteria both on the implant surface and within the periprosthetic tissue environment. Ti6Al4V intramedullary (IM) pins surface-tethered with dopamine methacrylamide (DopaMA) and uniformly coated with PEGDMA-Oligo-Vanco effectively prevented periprosthetic infections in mouse femoral canals inoculated with bioluminescent S. aureus. Longitudinal bioluminescence monitoring, μCT quantification of femoral bone changes, end point quantification of implant surface bacteria, and histological detection of S. aureus in the periprosthetic tissue environment confirmed rapid and sustained bacterial clearance by the PEGDMA-Oligo-Vanco coating. The observed eradication of bacteria was in stark contrast with the significant bacterial colonization on implants and osteomyelitis development found in the absence of the MN-sensitive bactericidal coating. The effective vancomycin tethering dose presented in this on-demand release strategy was >200 times lower than the typical prophylactic antibiotic contents used in bone cements and may be applied to medical implants and bone/dental cements to prevent periprosthetic infections in high-risk clinical scenarios. This study also supports the timely bactericidal action by MN-triggered release of antibiotics as an effective prophylactic method to bypass the notoriously harder to treat periprosthetic biofilms and osteomyelitis.
Orthopedic implant-associated bacterial infection presents a major health threat due to tendency for periprosthetic bacterial colonization/biofilm formation that protects bacteria from host immune response and conventional antibiotic treatment. Using surface-initiated atom transfer radical polymerization and copper-catalyzed azide–alkyne cycloaddition (CuAAC), alkynylated vancomycin is conjugated to azido-functionalized side chains of polymethacrylates grafted from Ti6Al4V. High-efficiency CuAAC across the substrate is confirmed by complete surface conversion of azides by X-ray photoelectron spectroscopy (XPS) and elemental mapping of changing characteristic elements. The vancomycin-modified surface (Ti-pVAN) significantly reduces in vitro adhesion and colonization of Staphylococcus aureus (S. aureus), a main bacterial pathogen responsible for periprosthetic infection and osteomyelitis, compared to untreated Ti6Al4V, supporting retained antibacterial properties of the covalently conjugated antibiotics. When the surface-modified intramedullary Ti-pVAN pins are inserted into mouse femoral canals infected by bioluminescent Xen29 S. aureus, significantly reduced local bioluminescence along with mitigated blood markers for infection are detected compared to untreated Ti6Al4V pins over 21 days. Ti-pVAN pins retrieved after 21 days are confirmed with ∼20-fold reduction in adherent bacteria counts compared to untreated control, supporting the ability of surface-conjugated vancomycin in inhibiting periprosthetic S. aureus adhesion and colonization.
Graft-guided regenerative repair of critical long bone defects achieving facile surgical delivery, stable graft fixation, and timely restoration of biomechanical integrity without excessive biotherapeutics remains challenging. Here, we engineered hydration-induced swelling/stiffening and thermal-responsive shape-memory properties into scalable, three-dimensional–printed amphiphilic degradable polymer-osteoconductive mineral composites as macroporous, non–load-bearing, resorbable synthetic grafts. The distinct physical properties of the grafts enabled straightforward surgical insertion into critical-size rat femoral segmental defects. Grafts rapidly recovered their precompressed shape, stiffening and swelling upon warm saline rinse to result in 100% stable graft fixation. The osteoconductive macroporous grafts guided bone formation throughout the defect as early as 4 weeks after implantation; new bone remodeling correlated with rates of scaffold composition-dependent degradation. A single dose of 400-ng recombinant human bone morphogenetic protein-2/7 heterodimer delivered via the graft accelerated bone regeneration bridging throughout the entire defect by 4 weeks after delivery. Full restoration of torsional integrity and complete scaffold resorption were achieved by 12 to 16 weeks after surgery. This biomaterial platform enables personalized bone regeneration with improved surgical handling, in vivo efficacy and safety.
Effective repair of critical-size long bone defects presents a significant clinical challenge. Electrospun scaffolds can be exploited to deliver protein therapeutics and progenitor cells, but their standalone application for long bone repair has not been explored. We have previously shown that electrospun composites of amphiphilic poly(d,l-lactic acid)-co-poly(ethylene glycol)-co-poly(d,l-lactic acid) (PELA) and hydroxyapatite (HA) guide the osteogenic differentiation of bone marrow stromal cells (MSCs), making these scaffolds uniquely suited for evaluating cell-based bone regeneration approaches. Here we examine whether the in vitro bioactivity of these electrospun scaffolds can be exploited for long bone defect repair, either through the participation of exogenous MSCs or through the activation of endogenous cells by a low dose of recombinant human bone morphogenetic protein-2 (rhBMP-2). In critical-size rat femoral segmental defects, spiral-wrapped electrospun HA-PELA with preseeded MSCs resulted in laminated endochondral ossification templated by the scaffold across the longitudinal span of the defect. Using GFP labeling, we confirmed that the exogenous MSCs adhered to HA-PELA survived at least 7 days postimplantation, suggesting direct participation of these exogenous cells in templated bone formation. When loaded with 500 ng of rhBMP-2, HA-PELA spirals led to more robust but less clearly templated bone formation than MSC-bearing scaffolds. Both treatment groups resulted in new bone bridging over the majority of the defect by 12 weeks. This study is the first demonstration of a standalone bioactive electrospun scaffold for templated bone formation in critical-size long bone defects.
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