Table 1.

Composition and biochemical applications of ceria-polymeric composites.

Polymer	CeNPs Characteristics and Content (w/v%)	Nanocomposite Products	Applications	Results	Ref.
Tissue engineering
Cellulose	Cubic CeNPs, 3.2–32 nm; 300 mL of water containing 1- or 5-mM cerium nitrate and 1% cellulose was used as a precursor.	Three-dimensional scaffolds	Tissue engineering	Nanobiocomposites are not cytotoxic to HeLa cells at a concentration as high as >1 mg·mL−1 and scavenge ROS.	[48]
PCL	Size 9–16 nm; 0.5%, 1%, 2% and 3%.	Electrospun fiber scaffolds	Tissue engineering	In vitro (MSC): higher cell adhesion and proliferation were evident relative to bare PCL. In vivo (rats): high cell proliferation rate and blood formation. Angiogenesis was activated by HIF-1α, as shown by the upregulation of VEGF expression in the nanocomposite scaffolds.	[55]
PL	CeNPs having different Ce4+ and Ce3+ ratios	Scaffold/artificial-niche	Tissue engineering	Mesenchymal stem (MSCs) and osteoblast-like (MG63) cells were cultured on PL/CNP surfaces with Ce4+- or Ce3+-enriched regions. Despite cell type (MSCs and MG63 cells), different cerium valence state regions promoted or inhibited cell spreading, migration or adhesion behavior, resulting in rapid or slow cell proliferation.	[56]
PL	~5 nm, oleylamine-capped CeNPs, up to 10 wt%: cancellous bone impregnated by PL + CeNPs	Scaffolds	Bone tissue engineering	In vitro: coculture of endothelial progenitor cells and MSC on scaffold supplemented with CeNPs showed the improvement of cell viability and the differentiation process for endothelial progenitor cells. In vivo (mice): higher level of vascularization for scaffold supplemented with CeNPs in comparison with the bare scaffold.	[57]
Gelatin	CeNPs by AlfaAesar as a 20% aqueous solution at acidic pH, with nominal size <5 nm. 15% gelatin and 1 mg/mL CeNPs were used as a precursor, GPTMS as a cross-linker	Electrospun fiber scaffolds	Neuronal tissue engineering and regenerative medicine	The scaffolds demonstrate strong antioxidant properties and beneficial multi-cue effects in terms of neurite development and alignment on neuron-like SH-SY5Y cells.	[58]
Gelatin/alginate	Mean diameter 35.5 nm, zeta potential −12.35 ± 1.39 mV; 100 μg/mL, 500 μg/mL and 1000 μg/mL	Scaffolds	Bone regeneration	Highest mesenchymal stem cells (MSCs) proliferation rate was observed for 1000 μg/mL CeNPs scaffolds; application of the scaffolds resulted in enhanced osteogenic differentiation of MSCs, as well as free radical scavenging.	[59]
POC	<25 nm particle size (Sigma-Aldrich), 10 or 20 wt% relative to POC	Scaffolds	Bone tissue regeneration	Scaffolds are biocompatible and supported cell attachment, proliferation, mineralization and infiltration. They possess protective properties against ROS via the reduction in cytotoxicity, improving mineralization of osteoblast cells in vitro. Cells are able to infiltrate through the scaffolds, the surrounding tissues elicit a minimal immune response. Nanocomposite scaffold system is capable of supporting bone-remodeling processes while providing a protective free radical scavenging effect.	[60]
PLGA	CeNPs size ~5 nm; 20 mg of CeNPs in 200 mg of PLGA	Microparticles and scaffolds	CeNPs delivery, tissue engineering including bone remodeling and regeneration	The release kinetics of CNPs from PLGA matrix was investigated under acidic, basic and near-neutral pHs. Superoxide dismutase (SOD) mimetic activity was retained in released CNPs for a long period of time (∼90 days). PLGA encapsulated CeNPs showed excellent biocompatibility.	[61]
Wound healing/dressing
Chitosan/PVA	zeta potential 50 mV, ∼5 nm in diameter, 0.5% and 1%	Hydrogels	Wound healing	Enhanced cell compatibility and survival, antibacterial activity against MRSA	[62]
PHBV	8.6 ± 3.8 nm in diameter (TEM); 0.5%, 1%, 2% and 4%	Electrospun membranes	Diabetic wound healing	In vitro: For less than 1% w/w of CeNPs content, human mammary epithelial cells adhered parallel to individual fibers; for higher CeNPs content, cells started to flatten and spread over the fibers. In ovo: enhanced blood vessel formation. In vivo (rats): promotes healing of diabetic wounds	[63]
Chitosan/cellulose acetate	<25 nm particle size (Sigma-Aldrich), 0.1% and 1%	Films	Wound dressing	Good water vapour transmission rates (WVTR) and water vapour permeability (WVP) values, antibacterial behavior for S. aureus and E. coli.	[64]
PCL/gelatin (1:1)	<25 nm particle size, 1.5, 3 and 6%	Electrospun films	Wound dressing	In vitro: 1.5% CeNPs exhibited the highest cell proliferation with L929 cells. In vivo: 1.5% CeNPs accelerated wound healing compared with the sterile gauze.	[65]
PCL/gelatin (1:1)	~42 nm in size, zeta potential 30.8 mV. The nanofibers were fabricated from a polymer solution of 10% w/v PCL, 20% w/v gelatin and 25% v/v 30 mM CeNPs	Electrospun fibers	Wound healing	Enhanced proliferation of 3T3-L1 cells (by ~48%), ROS scavenging ability, three-fold increase in the viability and proliferation of cells.	[66]
Gelatin	2.5–6.5 nm in size. From 50 μg/mL to 500 μg/mL dispersed into gelatin solution (5%, w/v), optimal concentration 250 μg/mL	Composite hydrogels	Wound healing	In vitro: 250 μg/mL provided 86 ± 1.4% cell viability and increased bound water content (swelling ratio was three-fold to that of native gelatin). In vivo (rats): more infiltration of leukocytes and larger deposition of collagen, the wound was healed in 12 days.	[67]
GelMA-DOPA	10–30 nm in size (US Research Nanomaterials), 100.0 μg/mL	Sprayable hydrogel	Wound dressing	Hydrogel provided a multifunctional wound dressing with desired antimicrobial, ROS-scavenging, adhesive, and degradative properties both in vitro and in vivo.	[68]
PCL	Mesoporous CeO2 nanorods, 5–25%, optimal 15%	Nanomembranes	Cutaneous wound healing	High antimicrobial activity against E. coli and S. aureus, strong wound healing effect, good biocompatibility.	[69]
Zwitterionic cryogel of CBMA or SBMA and HEMA	CeNPs size range of 3–5 nm; 68 μL of aqueous 36.6 μM FITC-labelled CeNPs were added to 250 μL of gel prior to polymerization	Injectable gels	Wound healing	The gels speed up diabetic wound healing and significantly reduce inflammation.	[70]
Gelatin/oxidized dextran	Particle size < 50 nm, 430 ug in 1 mL of gel	Hydrogel dressings	Wound healing	Prolonged drug (curcumin) release (∼63% in 108 h), accelerated cell migration, significant antioxidant and anti-inflammatory activity in vivo (∼39%).	[71]
PAA/curcumin	220 by 30–75 nm CeNPs; 0.1 mM, 0.2 mM and 0.4 mM	Hydrogel dressings	Scarless healing of injury	In a full-thickness acute wound healing model of rat, a single application of dressing demonstrated higher wound healing efficacy (78%) and negligible scarring in 7 days. Enhanced cell proliferation, higher collagen content, advanced wound maturity, re-epithelialization and granulation tissue formation were observed.	[50]
Drug delivery
PArg/DS	Citrate-stabilized CeNPs, 4–7 nm, ζ-potential ~–40 mV	LbL microcapsules	Drug delivery	CeNPs provide “active” protection of loaded content (luciferase enzyme) against hydrogen peroxide and “passive” shielding against small molecules.	[72]
Alginate/Chitosan	Citrate-stabilized CeNPs, diameter ~5 nm, ζ-potential −16.99 ± 2.72 mV	LbL-coated silicone containers	Drug delivery	CeNPs functionality prevents burst blowout of model drug (curcumin).	[73]
PArg/DS	Citrate-stabilized CeNPs, 2–2.5 nm, negative ζ-potential	LbL microcapsules	Drug delivery, radioprotection	CeNPs microcapsules provide enhanced cellular internalization and good radioprotection.	[74]
PEG/PLGA	Mostly uniform spherical CeNPs 5–10 nm in size	~40 nm nanoparticles	Cerebral ischemic therapy, brain targeted drug delivery	10 mg/kg concentration resulted in 60–78% lessening of focal ischemia in middle cerebral artery occlusion model of brain stroke.	[75]
PLGA	Diameter of 2–3 nm; 1 μM of CeNPs was suspended in 2.5% aqueous PVA solution containing 40 mg of PLGA as a precursor	Microparticles	CeNPs and drugs co-delivery	PLGA is a suitable encapsulating carrier for simultaneous delivery of nanoceria and SOD. This combination effectively reduces oxidative stress in vitro.	[76]
Other biomedical applications
PVA	0.5, 1.5 and 3%	Electrospun mats of nanocomposite hydrogels	Various biomedical applications	Better platelet adhesion and accelerated wound healing	[77]
TPU	CeNPs size ∼60 nm; 0.1–0.7 wt%		Various biomedical applications	Enhanced blood compatibility, cell viability, chemical resistance, mechanical and thermal properties of TPU.	[53]
Alginate	Dextran-coated CeNPs, 2.7–9 nm radius (23.8% polydispersity); 0.1, 1.0 and 10 mM CeNPs in hydrogel.	Composite hydrogel microcapsules	Cellular transplantation	Cytoprotection of encapsulated insulin-producing MIN6 beta cells from free radical attack. No cytotoxicity up to 10 mM CeNPs.	[49]
PLGA	5 to 8 nm in size; 5, 10 and 20 wt%	Hybrid 2D polymeric-ceramic biosupports	Regenerative medicine	Better murine derived cardiac and mesenchymal stem cells’ proliferative activity is observed for CeO2 polymer composites with respect to either TiO2-filled or unfilled PLGA films.	[78]
PL/Gelatin	Polyhedral nanoparticles 5–10 nm in size; 0.25%,0.5% and 1%	Electrospun fibro-porous membranes	Scaffolds for angiogenesis	Good hydrophilicity, water absorption and improved mechanical properties; scaffolds were shown to be biocompatible both in vitro (somatic hybrid endothelial cells) and in vivo (chick embryo angiogenesis assay); pro-angiogenic activities of the scaffolds are comparable to VEGF.	[79]
Alginate	Particle size < 5 nm, 20 wt% in H2O, pH~4 (Sigma Aldrich)	LbL-coated alginate microbeads	Biomedical implants, including cellular transplantation	12 layers of CeNPs/alginate provided complete protection to the entrapped beta cells from exposure to 100 μM H2O2, with no significant changes in metabolic activity, oxidant capacity or insulin secretion dynamics, when compared to untreated control.	[80]
PU with CA/Zein	CeO2 nanofibers were composed of nanoparticles ca.10–20 nm in size; 10%	Electrospun fiber mats	Antibacterial smart material	Composite nanofibers demonstrated notable toxicity against Escherichia coli, Klebsiella pneumoniae, Salmonella enterica (Gram-negative), Staphylococcus aureus and Enterococcus faecalis (Gram-positive) strains.	[81]

CA = Cellulose acetate; CBMA = 3-[[2-(Methacryloyloxy)ethyl] dimethylammonium] propionate; CeNPs = Ceria nanoparticles; GPTMS = (3-glycidyloxypropyl) trimethoxysilane; DOPA = dopamine; HEMA = 2-Hydroxyethyl methacrylate; GelMA = gelatin methacryloyl; PAA = Poly(acrylamide); PArg = poly-L-arginine; DS = dextran sulfate; PCL = Poly(ε-caprolactone); PEG = Polyethylene glycol; PHBV = Poly(3-hydroxybutyrate-co-3-hydroxyvalerate); PL = Poly-(l-lactide); PLGA = Poly(lactide-co-glycolide); POC = Poly(1,8-octanediol-co-citrate); PU = Polyurethane; PVA = Polyvinyl alcohol; SBMA = [2-(methacryloloxy) ethyl] dimethyl-(3-sulfopropyl) ammonium hydroxide; TMC = Trimethyl chitosan; TPU = Thermoplastic polyurethane.