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

Abstract

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.

BMP-2 functional polypeptides relieve osteolysis via bi-regulating bone formation and resorption coupled with macrophage polarization

“…To simultaneously enhance the differentiation of MSCs to osteoblasts and induce the polarization of macrophages to the M2-type, there have been several studies on the co-administration of BMP-2 and immunomodulatory cytokines (IL-4) or metal ions (Zn 2+ ) on Ti implants. These dual-modified implants could create a favorable osteoimmune microenvironment by switching macrophages from the M1 to M2 phenotypes at the bone-implant interface and improve bone regeneration and osseointegration for successful implantation 50,51 . Interestingly, the results also showed the synergistic effect of IL-4 or Zn 2+ combined with BMP-2 (rhBMP-2 or BMP-2 peptide) on M2-type macrophage polarization.…”

“…BMMs (1 × 10 4 cells/well, 96-well plate) were cultured in osteoclast induction medium (GM supplemented with 30 ng/mL M-CSF and 50 ng/mL RANKL, R&D Systems) with different concentrations of BMP2pp (25,50,100,200, 400 ng/mL) for 5 days. The cells were then stained for TRAP (Sigma-Aldrich, USA).…”

The role of macrophages in fracture healing: a narrative review of the recent updates and therapeutic perspectives

“…M o d i f i c a t i o n o f b i o m a t e r i a l s a s a s t r a t e g y t o immunomodulate the fracture microenvironment has also been recently explored. Applying a biomimetic polysaccharide hydrogel-metal scaffold composite loaded with IL-4 and BMP-2 within femoral defects in rats, Wang et al observed an increase in the number of M2 macrophages and in the proliferation and differentiation of skeletal progenitors into osteoblasts, which significantly improved bone regeneration (69). In another study, Xu et al (70) developed an intramedullary nail composed of a copper-containing stainless steel as a strategy to deliver copper ions at the injury site, as this ion had been previously shown to considerably induce M2 macrophage polarization in vitro (71).…”

Recent advances in regenerative biomaterials

“…The two phenotypes of macrophages work differently in regeneration of various tissues [ 447 ]. M2 macrophages enhance bone repairing via cytokine production whereas M1 macrophages work conversely [ 448 ]. For tumor treatment, M1 macrophages are important for antigen presentation, which helps the immune cells to attack tumor cells.…”