Titanium alloy composited with dual-cytokine releasing polysaccharide hydrogel to enhance osseointegration via osteogenic and macrophage polarization signaling pathways

Titanium alloy has been widely used in orthopedic surgeries as bone defect filling. However, the regeneration of high-quality new bones is limited due to the pro-inflammatory microenvironment around implants, resulting in a high occurrence rate of implant loosening or failure in osteological therapy. In this study, extracellular matrix (ECM)-mimetic polysaccharide hydrogel co-delivering BMP-2 and IL-4 was composited with 3D printed titanium alloy to promote the osseointegration and regulate macrophage response to create a pro-healing microenvironment in bone defect. Notably, it is discovered from the bioinformatics data that IL-4 and BMP-2 could affect each other through multiple signal pathways to achieve a synergistic effect towards osteogenesis. The composite scaffold significantly promoted the osteoblast differentiation and proliferation of human bone marrow mesenchyme stem cells (hBMSCs). The repair of large-scale femur defect in rat indicated that the dual-cytokine-delivered composite scaffold could manipulate a lower inflammatory level in situ by polarizing macrophages to M2 phenotype, resulting in superior efficacy of mature new bone regeneration over the treatment of native titanium alloy or that with an individual cytokine. Collectively, this work highlights the importance of M2-type macrophages-enriched immune-environment in bone healing. The biomimetic hydrogel-metal implant composite is a versatile and advanced scaffold for accelerating in vivo bone regeneration, holding great promise in treating orthopedic diseases.

Treatment of chronic osteomyelitis with antibiotic-impregnated polymethyl methacrylate (PMMA) – the Cierny approach: is the second stage necessary?

Background Chronic osteomyelitis is a challenge for orthopedic surgeons. Most patients with osteomyelitis receive two-stage management according to Cierny-Mader. The first stage includes radical debridement and insertion of an antibiotic-impregnated cement spacer (ACS) (beads, rods, nails, or blocks) into the bone defect. The second stage is performed 6–8 weeks later, when the spacer is removed and a cancellous autograft is placed within the bone defect. The possibility of ACS as definitive management for osteomyelitis, avoiding the second stage, is presented. Methods Sixteen patients with osteomyelitis received radical debridement and insertion of an ACS in all forms into the bone defect as a definitive management. In 8 patients, the tibia was infected, 4 had femur infection, 2 humerus, 1 fibula, and 1 ankle. The mean age at the time of the first stage of reconstruction was 49 years (range, 13–71 years). According to the Cierny-Mader classification, 1 patient was C-M IA, another was IB, 7 IIIA, 6 IIIB, and 1 was 4A. All B hosts had systemic illnesses. The mean follow-up period was 6 years (1.5–16 years). Results No patient exhibited radiographic evidence of excessive bone loss. Signs of recurrence of osteomyelitis were not noted in any of the patients, and no fractures had occurred by the last follow-up. Conclusion Our study suggests that a proportion of patients with planned retention of ACS appear to function well without requiring further surgical intervention, especially in elderly or vulnerable patients.

Metformin-Incorporated Gelatin/Nano-Hydroxyapatite Scaffolds Promotes Bone Regeneration in Critical Size Rat Alveolar Bone Defect Model

In this study, we fabricated gelatin/nano-hydroxyapatite/metformin scaffold (GHMS) and compared its effectiveness in bone regeneration with extraction-only, Sinbone, and Bio-Oss Collagen® groups in a critical size rat alveolar bone defect model. GHMS was synthesized by co-precipitating calcium hydroxide and orthophosphoric acid within gelatin solution, incorporating metformin, and cross-linked by microbial transglutaminase. The morphology, characterization, and biocompatibility of scaffold were examined. The in vitro effects of GHMS on osteogenic gene and protein expressions were evaluated. In vivo bone formation was assessed in a critical size rat alveolar bone defect model with micro-computed tomography and histological examination by comparing GHMS with extraction-only, Sinbone, and Bio-Oss Collagen®. The synthesized GHMS had a highly interconnected porous structure with a mean pore size of 81.85 ± 13.8 µm. GHMS exhibited good biocompatibility; promoted ALPL, RUNX2, SP7, BGLAP, SPARC and Col1a1 gene expressions; and upregulated the synthesis of osteogenic proteins, including osteonectin, osteocalcin, and collagen type I. In critical size rat alveolar bone defects, GHMS showed superior bone regeneration compared to extraction-only, Sinbone, and Bio-Oss Collagen® groups as manifested by greater alveolar ridge preservation, while more bone formation with a lower percentage of connective tissue and residual scaffold at the defect sites grafted with GHMS in histological staining. The GHMS presented in this study may be used as a potential bone substitute to regenerate alveolar bone. The good biocompatibility, relatively fast degradation, interconnected pores allowing vascularization, and higher bioactivity properties of the components of the GHMS (gelatin, nHA, and metformin) may contribute to direct osteogenesis.