Zinc-based biodegradable metals (BMs) have been developed for biomedical implant materials. However, the cytotoxicity of Zn and its alloys has caused controversy. This work aims to investigate whether Zn and its alloys possess cytotoxic effects and the corresponding influence factors. According to the guidelines of the PRISMA statement, an electronic combined hand search was conducted to retrieve articles published in PubMed, Web of Science, and Scopus (2013.1–2023.2) following the PICOS strategy. Eighty-six eligible articles were included. The quality of the included toxicity studies was assessed utilizing the ToxRTool. Among the included articles, extract tests were performed in 83 studies, and direct contact tests were conducted in 18 studies. According to the results of this review, the cytotoxicity of Zn-based BMs is mainly determined by three factors, namely, Zn-based materials, tested cells, and test system. Notably, Zn and its alloys did not exhibit cytotoxic effects under certain test conditions, but significant heterogeneity existed in the implementation of the cytotoxicity evaluation. Furthermore, there is currently a relatively lower quality of current cytotoxicity evaluation in Zn-based BMs owing to the adoption of nonuniform standards. Establishing a standardized in vitro toxicity assessment system for Zn-based BMs is required for future investigations.

High-purity magnesium (Mg) is a promising biodegradable metal for oral and maxillofacial implants. Appropriate surface roughness plays a critical role in the degradation behavior and the related cellular processes of biodegradable Mg-based metals. Nevertheless, the most optimized surface roughness has been questionable, especially for Mg-based oral and maxillofacial implants. Three representative scales of surface roughness were investigated in this study, including smooth (Sa < 0.5 µm), moderately rough (Sa between 1.0–2.0 µm), and rough (Sa > 2.0 µm). The results indicated that the degradation rate of the Mg specimen in the cell culture medium was significantly accelerated with increased surface roughness. Furthermore, an extract test revealed that Mg with different roughness did not induce an evident cytotoxic effect. Nonetheless, the smooth Mg surface had an adversely affected cell attachment. Therefore, the high-purity Mg with a moderately rough surface exhibited the most optimized balance between biodegradability and overall cytocompatibility.

Mesenchymal stem cells (MSCs) have gained attraction not only in the field of regenerative medicine but also in the field of autoimmune disease therapies or organ transplantation due to their immunoregulatory and/or immunosuppressive features. Dendritic cells (DCs) play a crucial role in initiating and regulating immune reactions by promoting antigen-specific T cell activation. In this study, we investigated the effect of human jaw periosteal progenitor cells (JPCs) seeded in beta-tricalcium phosphate (β-TCP) scaffolds on monocyte-derived DC differentiation. Significantly lower numbers of differentiated DCs were observed in the presence of normal (Co) and osteogenically induced (Ob) JPCs-seeded β-TCP constructs. Gene expression analysis revealed significantly lower interleukin-12 subunit p35 (IL-12p35) and interleukin-12 receptor beta 2 (IL-12Rβ2) and pro-inflammatory cytokine interferon-gamma (IFN-γ) levels in DCs under Ob conditions, while interleukin-8 (IL-8) gene levels were significantly increased. Furthermore, in the presence of JPCs-seeded β-TCP constructs, interleukin-10 (IL-10) gene expression was significantly induced in DCs, particularly under Ob conditions. Analysis of DC protein levels shows that granulocyte-colony stimulating factor (G-CSF) was significantly upregulated in coculture groups. Our results indicate that undifferentiated and osteogenically induced JPCs-seeded β-TCP constructs have an overall inhibitory effect on monocyte-derived DC maturation.

Clinical application of tissue engineering products requires the exclusion of immune responses after implantation. We used jaw periosteal cells (JPCs) as a suitable stem cell source and analyzed herein the effects of JPCs on dendritic cell maturation after co-culturing of both cell types. Peripheral blood mononuclear cells (PBMCs) were differentiated to dendritic cells (DCs) by the addition of differentiation cocktails for 7 days in co-culture with undifferentiated and osteogenically induced JPCs. The effects of JPCs on DC maturation were analyzed at the beginning (day 7), in the middle (day 14), and at the end (day 21) of the osteogenesis process. We detected significantly lower DC numbers after co-culturing with JPCs that have previously been left untreated or osteogenically differentiated for 7, 14, and 21 days. Using gene expression analyses, significantly lower IL-12p35 and -p40 and pro-inflammatory cytokine (IFN-γ and TNF-α) levels were detected, whereas IL-8 mRNA levels were significantly higher in DCs. Furthermore, osteogenic media conditions enhanced significantly IL-10 gene expression. We concluded that undifferentiated and osteogenically differentiated JPCs had an overall inhibiting influence on dendritic cell maturation. Further studies should clarify the underlaying mechanism in depth.

Polyetherketoneketone (PEKK) has emerged as a potential alternative to titanium (Ti) for bone implants. Nevertheless, its osseointegration performance is inferior to that of Ti, primarily due to the limited understanding of its early immune reactions. To address this limitation, this study utilized single-cell RNA sequencing to investigate the distinct early macrophage responses triggered by Ti-based and PEKK-based implants. This approach enabled the characterization of macrophage-polarization dynamics and intercellular interactions within the bone-marrow microenvironment post-implantation. The findings revealed a material-dependent dichotomy in macrophage phenotype: Ti implants preferentially recruited Cd99⁺ macrophages, establishing an anti-inflammatory microenvironment that promotes osseointegration. Conversely, PEKK implants recruited Icam1⁺ macrophages, leading to persistent inflammation and hematopoietic stem cells (HSCs) stress. Additionally, Ti surfaces facilitated CD99-dependent crosstalk between macrophages and T cells, enhancing Th2 responses, which are indicative of an anti-inflammatory effect. In contrast, PEKK-associated macrophages triggered ICAM1-driven necroptosis in HSCs, disrupting hematopoietic homeostasis. These results indicate the early macrophage-related responses as key determinants of the clinical-outcome differences between Ti and PEKK implants.