Endothelial Cellular Responses to Biodegradable Metal Zinc

Abstract

Biodegradable zinc (Zn) metals, a new generation of biomaterials, have attracted much attention due to their excellent biodegradability, bioabsorbability, and adaptability to tissue regeneration. Compared with magnesium (Mg) and iron (Fe), Zn exhibits better corrosion and mechanical behaviors in orthopedic and stent applications. After implantation, Zn containing material will slowly degrade, and Zn ions (Zn2+) will be released to the surrounding tissue. For stent applications, the local Zn2+concentration near endothelial tissue/cells could be high. However, it is unclear how endothelia will respond to such high concentrations of Zn2+, which is pivotal to vascular remodeling and regeneration. Here, we evaluated the short-term cellular behaviors of primary human coronary artery endothelial cells (HCECs) exposed to a concentration gradient (0−140 μM) of extracellular Zn2+. Zn2+ had an interesting biphasic effect on cell viability, proliferation, spreading, and migration. Generally, low concentrations of Zn2+ promoted viability, proliferation, adhesion, and migration, while high concentrations of Zn2+ had opposite effects. For gene expression profiles, the most affected functional genes were related to cell adhesion, cell injury, cell growth, angiogenesis, inflammation, vessel tone, and coagulation. These results provide helpful information and guidance for Zn-based alloy design as well as the controlled release of Zn2+in stent and other related medical applications.

Interfacial Zinc Phosphate is the Key to Controlling Biocompatibility of Metallic Zinc Implants

“…When compared with Mg materials, the pH change and hydrogen gas release for Zn materials are much less because of their different corrosion mechanism 5c,6a,12,13. It has been previously indicated that Zn ion affects the cell responses in a concentration‐dependent manner in vitro 7b,8,14. Although Zn ion plays significant and beneficial roles in cell behaviors and functions,7b,8 overdosed Zn ion could induce harmful cellular responses in vascular smooth muscle cells and endothelial cells after its concentration reached a limit of 3.9 and 5.2 µg mL −1 , respectively .…”

“…It has been previously indicated that Zn ion affects the cell responses in a concentration‐dependent manner in vitro 7b,8,14. Although Zn ion plays significant and beneficial roles in cell behaviors and functions,7b,8 overdosed Zn ion could induce harmful cellular responses in vascular smooth muscle cells and endothelial cells after its concentration reached a limit of 3.9 and 5.2 µg mL −1 , respectively . In the present study, the Zn ion concentration reached 40 and 60 µg mL −1 after 3 days culture with endothelial cells and preosteoblasts, respectively (Figure d,e and Figure c,d), which are significantly higher than the concentration limits for normal cell behaviors and functions.…”

The Prospects of Zinc as a Structural Material for Biodegradable Implants—A Review Paper

“…Thus, the cellular responses to high extracellular Zn 2+ will impact the healing process and biocompatibility with zinc-bearing implants [16]. Furthermore, the response of the host's immune system will determine whether the implant becomes biointegrated and continues to function as designed, or encapsulated in a dense fibrous tissue that may compromise the intended function of the implant.…”

“…The cellular response of human bone marrow mesenchymal stem cells (hMSC) and human vascular cells (HCECs, HASMC, HAEC) to Zn 2+ was recently investigated [16,26,69,70]. According to Zhu et al [70], Zn biomaterial can support hMSC adhesion and proliferation and zinc ions can lead to enhanced regulation of genes, cell survival/growth and differentiation, extracellular matrix (ECM) mineralization, and osteogenesis.…”

“…Gene expression profiles revealed that the most affected functional genes were related to angiogenesis, inflammation, cell adhesion, vessel tone, and platelet aggregation [26]. Since the Zn 2+ concentration is intrinsically related to the implant degradation rate, a slow corrosion rate with controlled release of Zn 2+ is desirable to maintain a low concentration profile of Zn 2+ in the local tissues, in order to benefit cellular functions [16]. A high concentration of Zn 2+ may overwhelm metal divalent ion-dependent intracellular signaling pathways, stimulate oxidative stress pathways, inducing apoptosis or necrosis, and generally contribute to negative side effects in cell populations adjacent to the implant.…”