Interleukin-4 assisted calcium-strontium-zinc-phosphate coating induces controllable macrophage polarization and promotes osseointegration on titanium implant

Abstract

Titanium (Ti) and its alloys are believed to be promising scaffold materials for dental and orthopedic implantation due to their ideal mechanical properties and biocompatibility. However, the host immune response always causes implant failures in the clinic. Surface modification of the Ti scaffold is an important factor in this process and has been widely studied to regulate the host immune response and to further promote bone regeneration. In this study, a calcium-strontium-zinc-phosphate (CSZP) coating was fabricated on a Ti implant surface by phosphate chemical conversion (PCC) technique, which modified the surface topography and element constituents. Here, we envisioned an accurate immunomodulation strategy via delivery of interleukin (IL)-4 to promote CSZP-mediated bone regeneration. IL-4 (0 and 40 ng/mL) was used to regulate immune response of macrophages. The mechanical properties, biocompatibility, osteogenesis, and anti-inflammatory properties were evaluated. The results showed that the CSZP coating exhibited a significant enhancement in surface roughness and hydrophilicity, but no obvious changes in proliferation or apoptosis of bone marrow mesenchymal stem cells (BMMSCs) and macrophages. In vitro, the mRNA and protein expression of osteogenic related factors in BMMSCs cultured on a CSZP coating, such as ALP and OCN, were significantly higher than those on bare Ti. In vivo, there was no enhanced bone formation but increased macrophage type 1 (M1) polarization on the CSZP coating. IL-4 could induce M2 polarization and promote osteogenesis of BMMSCs on CSZP in vivo and in vitro. In conclusion, the CSZP coating is an effective scaffold for BMMSCs osteogenesis, and IL-4 presents the additional advantage of modulating the immune response for bone regeneration on the CSZP coating in vivo.

Current Understanding of Osteoimmunology in Certain Osteoimmune Diseases

“…Until now, dentists still face the dilemma of undesirable biocompatibility and commit to designing a clinical-friendly implant surface and exploring effective methods to blend bioactive factors in dental implants. In recent years, the osteoimmunomodulation has been viewed as an available strategy in the implant modification instead of enhancing osteogenesis directly (Gao et al, 2020;Zhao et al, 2021;Zhu et al, 2021), and we propose that in future study, researchers can further explore the synergistic effect of osteogenesis, angiogenesis, immune response, and even neurogenesis to accelerate the osseointegration and promote the stability of dental implants. Besides FBR, peri-implant mucositis and peri-implantitis caused by bacteria invasion also draw clinicians' attention for their potential impacts on stable osseointegration, while recent studies questioned if the cause-effect relationship really existed between plaque accumulation and the occurrence of peri-implant inflammation and between peri-implant inflammation and marginal bone loss (Albrektsson et al, 2019;Coli and Jemt, 2021).…”

Antibacterial and Anti-Inflammatory Coating Materials for Orthopedic Implants: A Review

“…In addition, reverse-transcription polymerase chain reaction (RT-PCR) and ELISA results showed that compared with an SLA-Ti surface loaded with PDA coating and a simple SLA-Ti surface, the SLA-Ti surface with PDA/IL-4 coating showed a significant reduction in inflammation. Zhao et al [158] added IL-4 to a calcium strontium zinc phosphate (CSZP) coating on Ti implants, which induced the phenotypic transformation of macrophages from M1 to M2, while the levels of IL-1β and IL-6 were significantly reduced to exert anti-inflammatory effects. Li et al [159] studied the release of IL-4 from a graphene oxide (GO) coating on Ti implants, and concluded that GO/IL-4 showed good biocompatibility in vitro and promoted the transformation of macrophage polarization from M1 to M2 phenotype, while the levels of IL-4β and TNF-α decreased significantly.…”

Sequential gastrodin release PU/n-HA composite scaffolds reprogram macrophages for improved osteogenesis and angiogenesis

“…Aberrant immunomodulation (suppression or enhancement) may delay bone regeneration by blocking the transformation of macrophages from the M1 to M2 phenotype [ 14 , 26 ]. Therefore, a combined immunomodulatory tool capable of effectively controlling the density of activated M2 macrophages at the early stage of bone injury could significantly influence bone healing events and the in vivo fate of bone repair biomaterials [ [27] , [28] , [29] ].…”