2.2.9. Copper

Copper ions stimulate the proliferation of human vein endothelial cells and mesenchymal stem cells (MSCs) but not human dermal fibroblasts [415,416]. Copper nanoparticles can also act as antifungal and antibacterial agents [417]. Copper is commonly used in bone implants for its antimicrobial activity against a wide range of pathogens [418]. As copper is an essential component of the body, it may be more suitable for in vivo applications [25].

The importance of copper has been studied extensively because its deficiency can lead to osteoporosis [419]. Cu also stimulates angiogenesis and collagen deposition, which are key elements in wound healing [420]. The use of copper-based biomaterials is cost-effective compared to other vital materials based on gold and silver [421].

Copper ions were incorporated into biologically active scaffolds for controlled release to improve vascular strengthening and antimicrobial action for prolonged periods [422]. Copper-doped wollastonite (Cu–Ws) particles (1184 nm) have shown biocompatibility towards mouse mesenchymal stem cells (mMSC) up to 0.05 mg/ml concentration [423]. A freeze-dried chitosan/hydroxyapatite/copper-zinc alloy (CS/nHAp/nCu–Zn) composite-based scaffold showed lower degradation and higher protein adsorption without producing toxicity towards rat osteoprogenitor cells [422]. Collagen-copper-doped bioactive glass (CuBG-CS) scaffolds exhibited enhanced mechanical properties (up to 1.9-fold) and osteogenesis (up to 3.6-fold) than chitosan [424].

Copper nanoparticles were investigated also for wound healing applications. 1 μM concentration of 80 nm CuNPs was found not to be toxic to the cultured fibroblast, endothelial, and keratinocyte cells, and it supported endothelial cell migration and proliferation [425]. CuNPs may alter the structure of proteins and enzymes, affecting their normal functions and causing inactivation of bacterial functions at the injury site [426]. Chen et al. reported the cytotoxic effect of copper NPs towards human histolytic lymphoma (U937) and human cervical cancer cells by inducing apoptosis [427]. CuNPs were used to design a special drug delivery system for chemotherapy. For example, Figure 20 illustrates a mesoporous, upconversion, nanoparticles (mUCNPs)-based controlled-release drug carrier system exhibiting higher upconversion luminescence emission intensity [428].

**Figure 20.** Schematic illustration of the mUCNPs-based redox-stimuli responsive drug delivery system for tumor diagnosis and synergetic chemo-phototherapy (adapted with permission from Elsevier © 2017 [428]).
