Table 4.
Empirical relationships determined between biomaterial physicochemical properties and immune cell activity.
| Physicochemical properties | Immunological variables | References | |||||
|---|---|---|---|---|---|---|---|
| Composition | Size | Zeta potential/charge | Surface coating/functionalization | Cell type | Animal models | Biological effect | |
| Polymers | |||||||
| Poly(N-isopropylacrylamide) | 80–300 nm | Neutral charge, hydrophobic | Erythrocytes | Human | Sequestration and neutralization of lipid-based toxins with erythrocyte sparing | (74, 75) | |
| Poly(lactic acid) | 350–500 nm | −50 to −40 mV | Poly(ethylene-alt-maleic acid) | Bone marrow-derived macrophages | Mice (C57BL/6) | Decreased secretion of IL-6, TNF-α, and MCP-1; decreased expression of MHC II, MARCO, CD80, CD86 | (93) |
| Poly(lactic acid) | 430–470 nm | −47 to −31 mV | Poly(ethylene-alt-maleic acid) | Inflammatory monocytes, neutrophils | Mice (SJL/J) | Negligible sequestration of inflammatory monocytes and neutrophils away from sites of inflammation | (107) |
| Poly(lactic acid) | 350–500 nm | −25 mV | Poly(vinyl alcohol) | Bone marrow-derived macrophages | Mice (C57BL/6) | Partial decreased secretion of IL-6, TNF-α, and MCP-1 | (93) |
| Poly(lactic-co-glycolic acid) | 100–104 nm | −7 to −5 mV | Neutrophils | Human | Cationic surfactant leads to dramatic neutrophil death and LDH release | (122) | |
| Poly(lactic-co-glycolic acid) | 100–105 nm | −30 to −23 mV | Macrophage cell membrane | J774 macrophages, human umbilical vein endothelial cells | Mice (C57BL/6, BALB/c) | Sequestration of LPS; sequestration of IL-6, TNF-α, IFNɤ; decreased iNO production; decreased E-selectin expression; decreased serum IL-6, TNF-α, IFNɤ; survival benefit in E. coli bacteremia | (54) |
| Poly(lactic-co-glycolic acid) | 140–165 nm | 0 to 0.5 mV | di(α2 → 8)N-acetylneuraminic acid | Peritoneal macrophages | Mice (C57BL/6) | Decreased secretion of TNF-α, IL-6; increased Siglec-E expression; increased serum IL-10; decreased serum IL-6; increased survival benefit in LPS-induced endotoxemia | (94) |
| Poly(lactic-co-glycolic acid) | 214–226 nm | 35 to 43 mV | Soyaethyl morpholinium ethosulfate | Neutrophils | Human | Cationic surfactant leads to dramatic neutrophil death and LDH and elastase release, moderate increase in superoxide production | (122) |
| Poly(lactic-co-glycolic acid) | 240–252 nm | 24 to 34 mV | Cetyltrimethylammonium bromide | Neutrophils | Human | Cationic surfactant leads to dramatic neutrophil death and LDH and elastase release, dramatic increase in superoxide production | (122) |
| Poly(lactic-co-glycolic acid) | 350–500 nm | −50 to −40 mV | Poly(ethylene-alt-maleic acid) | Bone marrow-derived macrophages | Mice (C57BL/6) | Decreased secretion of IL-6, TNF-α, and MCP-1; decreased expression of MHC II, MARCO, CD80, CD86; survival benefit in LPS-induced endotoxemia | (93) |
| Poly(lactic-co-glycolic acid) | 350–500 nm | −25 mV | Poly(vinyl alcohol) | Bone marrow-derived macrophages | Mice (C57BL/6) | Partial decreased secretion of IL-6, TNF-α, and MCP-1 | (93) |
| Poly(lactic-co-glycolic acid)—low molecular weight | 330–510 nm | −56 to −40 mV | Poly(ethylene-alt-maleic acid) | Inflammatory monocytes, neutrophils | Mice (SJL/J) | Negligible sequestration of inflammatory monocytes and neutrophils away from sites of inflammation | (107) |
| Poly(lactic-co-glycolic acid)—high molecular weight | 510–590 nm | −43 to −36 mV | Poly(ethylene-alt-maleic acid) | Inflammatory monocytes, neutrophils | Mice (C57BL/6, SJL/J, BALB/c) | Sequestration of inflammatory monocytes and neutrophils away from sites of inflammation | (107) |
| Poly(lactic-co-glycolic acid) | 500 nm | Negatively charged | Poly(ethylene-alt-maleic acid) | MARCO+ macrophages | Mice (C57BL/6, SJL/J, BALB/c) | Sequestration of inflammatory monocytes away from sites of inflammation; functional reprogramming of macrophages from M1 to M2 at site of spinal cord injury | (95, 108) |
| Polystyrene | 100–117 nm | Denatured albumin | Neutrophils | Mice | Albumin nanoparticles taken up by activated neutrophils through endocytosis mediated with FcɤRIII to reduce neutrophil adhesion and migration across the endothelium to limit vascular inflammation modulated via adherent neutrophils; protective against lung injury with Syk inhibitor to prevent inside-out signaling | (102, 103) | |
| Polystyrene | 500 nm | Negatively charged | Poly[ethylene-alt-maleic acid) | MARCO+ macrophages | Mice (C57BL/6, SJL/J, BALB/c) | Sequestration of inflammatory monocytes away from sites of inflammation | (108) |
| LIPIDS | |||||||
| Liposomes−3.2% soybean phosphatidylcholine and 0.8% cholesterol | 51–60 nm | 37 to 55 mV | Cetyltrimethylammonium bromide | Neutrophils | Human | Dramatic neutrophil death, LDH release, high superoxide production, Ca2+ mobilization, promptly induces NET formation | (123) |
| Liposomes−3.2% soybean phosphatidylcholine and 0.8% cholesterol | 73–81 nm | 19 to 36 mV | Soyaethyl morpholinium ethosulfate | Neutrophils | Human | Increased neutrophil death at increasing concentrations, LDH release at high concentrations of surfactant | (123) |
| Liposomes−3.2% soybean phosphatidylcholine and 0.8% cholesterol | 88–92 nm | −49 to 39 mV | Neutrophils | Human | Inert for neutrophils in vitro | (123) | |
| Solid lipid nanoparticles (SLNs)−12% cetyl palmitate and 1% soybean phosphatidylcholine | 192 nm | −41 mV | Neutrophils | Human | Inert for neutrophils in vitro | (124) | |
| Solid lipid nanoparticles (SLNs)−12% cetyl palmitate and 1% soybean phosphatidylcholine | 195 nm | 44 mV | Cetyltrimethylammonium bromide | Neutrophils | Human | Dramatic neutrophil death, LDH release, superoxide production, elastase release, Ca2+ mobilization, p38 and JNK activation, and NET development | (124) |
| Nanostructured lipid carriers (NLCs)—composed of both solid and liquid lipids with a soft core matrix of 6% w/w soybean oil, 65% cetyl palmitate, 1% soybean phosphatidylcholine (SPC) | 162–177 nm | 51 to 53 mV | Cetyltrimethylammonium bromide | Neutrophils | Human | Dramatic neutrophil death and LDH and elastase release, moderate increase in superoxide production | (122) |
| Nanostructured lipid carriers (NLCs)—composed of both solid and liquid lipids with a soft core matrix of 6% w/w soybean oil, 65% cetyl palmitate, 1% soybean phosphatidylcholine (SPC) | 248–261 nm | −44 to −41 mV | Neutrophils | Human | Inert for neutrophils in vitro | (122) | |
| Nanostructured lipid carriers (NLCs)—composed of both solid and liquid lipids with a soft core matrix of 6% w/w soybean oil, 65% cetyl palmitate, 1% soybean phosphatidylcholine (SPC) | 257–261 nm | 51 to 52 mV | Soyaethyl morpholinium ethosulfate | Neutrophils | Human | Cationic surfactant leads to dramatic neutrophil death and LDH release | (122) |
| DENDRIMER | |||||||
| Poly(phosphorHydrazone) | Acid azabisphosphorous | Monocytes | Human volunteers, cynomolgus monkeys | Increased expression of MRC1, IL1RN, IL10, CCL18, CD23, CCL5; increased expression of cell surface CD206, decreased cell surface expression of CD64, CD13, HLA-DR, HLA-A/B/C, CD86 | (96, 97) | ||
| METALS/METAL OXIDES | |||||||
| Gold | 2 nm (core) | Neutral charge | Tetraethylene glycol with end hydroxyl group | Monocytes | Mice | Decreased ROS production in vitro, decreased TNF-α production in vitro; decreased serum TNF-α following LPS-induced endotoxemia | (98) |
| Gold | 2 nm (core) | Neutral charge, hydrophobic | Tetraethylene glycol with hydrophobic end group | Monocytes | Mice | Decreased ROS production in vitro, decreased TNF-α production in vitro; increased serum TNF-α following LPS-induced endotoxemia | (98) |
| Gold | 2 nm (core) | Neutral charge, hydrophilic | Tetraethylene glycol with hydrophilic end group | Monocytes | Mice | No change over LPS treatment alone in vitro or in vivo | (98) |
| Gold | 5 nm | Inner lipid: 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[3-(2-pyridyldithio)propionate] (PDP PE 16:0) or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[3-(2-pyridyldithio)propionate (PDP PE 18:1) Outer lipid: 1,2-dipalmitoyl-sn-glycero-3-phsphocholine (DPPC), spingomyelin, cardiolipin, 1,2-dilinoleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (18:2 PG), 1,2-dimyristoyl-sn-glycer-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (14:0 Liss Rhod PE) |
Monocytes | Human | Decreased NF-κB activation; decreased expression of Il1b; decreased secretion of IL-1β, TNF-α, IL-6, IL-8, CCL5/RANTES, CCL2/MCP-1, GM-CSF | (99) | |
| Gold | 13–20 nm | Negative charge | Peptides with hydrophobic and aromatic residues | Monocytes | Decreased NF-κB and IRF3 activation following TLR agonist treatment, decreased CCL2 and CCL4 production; decreased lung damage and survival benefit in LPS-induced ALI; larger particles are more protective | (105, 106) | |
| Silver | 4 nm | −25 to −8 mV | Poly(vinyl alcohol) | Neutrophils | Human | Induces apoptosis and increases ROS generation at high concentrations (50 μM) | (125) |
| Silver | 10 nm | Poly(vinyl pyrrolidone) | Neutrophils | Human | Increased cell death at greater concentrations (range of 25–100 μg/mL) with corresponding increases in neutrophil oxidative burst | (126) | |
| Silver | 15 nm | −9 to −7 mV | Neutrophils | Human | Atypical cell death at low concentrations (≤25 μg/mL) with no CD16 shedding, caspase-1 and caspase-4 dependent IL-1β activation, and caspase-1 and caspase-4 independent NET formation; necrosis at high concentrations (>50 μg/mL) | (127) | |
| Silver | 20 nm | −11 to −8 mV | Neutrophils | Human | High concentrations (100 μg/mL) induce apoptosis of neutrophils and inhibition of de novo protein synthesis | (128) | |
| Silver | 50 nm | Poly(vinyl pyrrolidone) | Neutrophils | Human | Limited cell death at greater concentrations (range of 25–100 μg/mL) | (126) | |
| Ceria-zirconia (Ce0.7Zr0.3O2) | 2–4 nm | Monocytes | Rats, mice | Antioxidant activity (SOD, catalase, CAT, mimetic and hydroxyl radical antioxidant capacity, HORAC) decreased; decreased LDH; decreased CD68+ monocytes at site of injury; survival benefit in LPS-induced endotoxemia and CLP | (119) | ||
| CARBON-BASED | |||||||
| Carbon nanotube | 0.4–4.2 nm (length), 12–34 nm (diameter) | Carboxymethyl cellulose | Macrophages | Sequestration of complement proteins triggering opsonization | (57) | ||
| Carbon nanotube | 0.4–4.2 nm (length), 12–34 nm (diameter) | RNA | Macrophages | Sequestration of complement proteins triggering opsonization | (57) | ||
| Hydroxylated fullerene (C60[OH]44) | Peritoneal macrophages | Mice (C57BL/6) | Decreased ROS production; decreased expression of Il6, Il1b, Tnf; decreased preterm birth | (100) | |||
| Nanodiamond | 5 nm | Negatively charged | Octadecylamine | Macrophages | Human | Decreased TNF-α, IL-1β secretion and increased IL-10 secretion | (101) |
| BIOMIMETIC | |||||||
| Cell-derived nanoparticle (CDNPs)—composed of annexins, actin, histones, heat shock proteins, myosin, peroxiredoxines and vimentin and small traces of nucleic acids, with annexin A5 (AnxA5) being one of the most abundant components; [protein] = 150 μL/mL, [DNA] = 2 μg/mL, [RNA] = 4 μg/mL | 50–200 nm | Source of CDNPs: MC3T3-E1 fibroblast cells, peritoneal lavage Takes up CDNPs: neutrophils, inflammatory monocytes, macrophages |
Mice | Decreased peritoneal IL-6 and IL-10 following CLP; decreased bacterial growth in vitro; increased expression of CD11b and MHCII on the cell surface of neutrophils, inflammatory monocytes, and macrophages | (55) | ||
| Cell membrane-formed nanovesicles (cell disruption by nitrogen cavitation, centrifugation, and extrusion—contains integrin β2 | 200 nm | −20 to −12 mV | Source of nanovesicles: HL 60 myeloid cells | Binds ICAM-1 on HUVEC to deliver NF-κB inhibitors and stop diapedesis | (104) | ||