Biological applications of copper-containing materials

Abstract

Copper is an indispensable trace metal element in the human body, which is mainly absorbed in the stomach and small intestine and excreted into the bile. Copper is an important component and catalytic agent of many enzymes and proteins in the body, so it can influence human health through multiple mechanisms. Based on the biological functions and benefits of copper, an increasing number of researchers in the field of biomaterials have focused on developing novel copper-containing biomaterials, which exhibit unique properties in protecting the cardiovascular system, promoting bone fracture healing, and exerting antibacterial effects. Copper can also be used in promoting incisional wounds healing, killing cancer cells, Positron Emission Tomography (PET) imaging, radioimmunological tracing and radiotherapy of cancer. In the present review, the biological functions of copper in the human body are presented, along with an overview of recent progress in our understanding of the biological applications and development of copper-containing materials. Furthermore, this review also provides the prospective on the challenges of those novel biomaterials for future clinical applications.

Keywords: Angiogenesis; Antibacterial; Biomaterials; Copper; Osteogenesis.

Graphical abstract

Fig. 1

Copper metabolism in human body. Copper is supplied entirely by food in the human body, which is mainly absorbed in stomach and small intestine, especially in duodenum. In the duodenal enterocyte, Cu²⁺ requires reduction prior to absorption, which may be mediated by DCYTB (duodenal cytochrome B). After reduction, Cu⁺ is transported into enterocytes by CTR1 (copper transporter 1) or DMT1 (divalent metal-ion transporter 1). Then copper is pumped into the TGN (trans Golgi network) by ATP7A, supporting cuproenzyme synthesis, or exported from the cell by ATP7A. When exported from enterocyte, Cu⁺ is spontaneously oxidized into Cu²⁺ by dissolved oxygen in blood, then mainly bounded to albumin and α2-macrogloubuoin in the portal blood and finally delivered to the liver. In the hepatocyte, firstly, Cu²⁺ requires a reduction, which may be mediated by reductase. After reduction, Cu⁺ is taken up into hepatocytes via CTR1. Then, ATOX1 (antioxidant protein 1) delivers Cu⁺ to ATP7B, which transports Cu⁺ into TGN for incorporation into CP (cuproenzymes). ATP7B also transports excessive Cu⁺ across the canalicular membrane into bile for excretion. CP, which is released into blood, is transported to blood vessels, brain, bone and other tissues for biological functions.

Fig. 2

Structure of 316-Cu stent and it promotes vascular endothelialization. Ⅰ. The vWF staining and F-actin filament staining of HUVECs seeded on 316L and 316L-Cu, respectively. Ⅱ. Scanning electron micrographs of surface characterization of explanted endovascular stent. Ⅲ. Hematoxylin-eosin stain of explanted stents of 316L-Cu-BMS (A a), DES (B b), and 316L-BMS (C c). Ⅳ. Tube formation induced by the extracts of 316L and 316L-Cu, respectively. Ⅴ. CCK-8 proliferation assay of HUVECs cultured on different substrates. Ⅵ. Cell migration induced by the extracts of 316L and 316L-Cu, respectively. Reproduced with permission from Ref. [15], copyright 2017, Nature.

Fig. 3

Promoting osteogenesis and its mechanism of copper-containing implants. Ⅰ. General view and scanning electron microscope view of 317L SS and 317L-Cu SS (A and B); The fracture line is clearly observed in X-ray (C); Micro-CT showed the callus formation stage (D and E); Callus bone mineral density in the 317L-Cu SS group is higher than that of 317L SS group (F). Ⅱ. H&E staining displays the general evolution of 317L-Cu SS group calluses and 317L SS group, respectively (A); Masson staining showed the amount of fibrous tissue of 317L-Cu SS group calluses and 317L SS group, respectively (B); Safranin O/fast green staining (C); Van Gieson staining (D); Calcein/alizarin red double labeling (E). Ⅲ. 317L-Cu stainless steel significantly promoted the osteogenic differentiation of human bone mesenchymal stem cells in vitro. Reproduced with permission from Ref. [63], copyright 2017, Dove Press. Ⅳ. Schematic diagram for copper-containing implants stimulated osteogenesis. Reproduced with permission from Ref. [4], copyright 2019, Elsevier. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 4

Antibacterial activity and its mechanism of copper-containing materials. Ⅰ. Scanning electron microscope image of S. aureus cells on 317L-Cu SS surface. Ⅱ. Scanning electron microscope images showed the deformation process of S. aureus, which incubated with 317L-Cu SS. Ⅲ. Confocal laser scanning microscopy images of the S. aureus biofilm on 317L SS. Reproduced with permission from Ref. [116], copyright 2016, Nature Publishing Group. Ⅳ. Transmission electron microscopy images (A) and fluorescence images (B) of copper-containing coatings. Ⅴ. Cu entrapment and release of the copper-containing coatings. Ⅵ. Field emission scanning electron microscopy images and Live/Dead stain fluorescent images showed that copper-containing coatings inhibit proliferation of E. coli. Ⅶ. copper-containing coatings may inhibit proliferation of E. coli and S. aureus. Reproduced with permission from Refs. [82], copyright 2017, Dove Press.

Fig. 5

The schematic image of hypothesis about the antibacterial mechanism of Cu²⁺. Reproduced with permission from Ref. [128], copyright 2016, Nature Publishing Group.

Fig. 6

Schematic diagram for fabrication and properties of copper-containing coating materials. Reproduced with permission from Refs. [82], copyright 2017, Dove Press. Abbreviations: G, gelatin; CS, chitosan.