Table 1. Strategies to modulate inflammatory responses toward nonomaterials.

	Size & Shape Considerations	Chemical Modifications	Drug Loading & Release
Nanoparticles	Nanoparticle Diameter > 20 nm ; Absence of Mac-1 receptor activation in monocytes in vitro 75 nm (in contrast to 200 nm) particles elicit limited PMN recruitment in vivo Nanospheres induce higher levels of TNF-α in macrophages, while nanosheets induce higher TNF-α in dendritic cells Ref: 40, 41, 43, 44	Zn nanoparticles (as opposed to Ti & Si) decrease activation of inflammasomes and IL-1β release in macrophages Biodegradable & anionic polymers induce less inflammation. E.g. PLGA, PLA Ref: 46, 47	Liopocortin-1 delivery reduces neutrophil infiltration in peritonitis siRNA delivery to decrease TNF-α levels in macrophages Other potent targets: NF-kB, P-selectin, Cyclin D Ref: 52-57
Nanoporous Scaffolds	20 nm pores attract more macrophages, but induce lower levels of IL-1β in vitro as compared to 200nm pores. 20 nm pores, as opposed to 200nm pores, induce lower levels of pro-inflammatory cytokines in vivo. Ref: 38, 63	PEG and Collagen coatings decrease serum albumin deposition and ROS production. POC, rather than PLGA, reduces inflammatory cell recruitment & induces less fibrosis in vivo. Ref: 65-68	Release of NSAIDs, catalase, ascorbic acid from nonporous scaffolds decrease inflammation. Ref: 68-71
Nanopatterned Surfaces	Neutrophils on Mac-1 conjugated nanodots: Inter-nanodot spacing of 100 nm induced minimal neutrophil spreading. Macrophages on nanoridges: Inter-ridge spacing of 600 nm reduces macrophage adhesion in vivo. Intergroove spacing of 150 nm decreases cytokine production and macrophage fusion. Nanopillars with aspect ratios higher than 5 reduce collagen production in fibroblasts. Ref: 14, 39, 74, 77-79.	Preliminary evidence suggests that topographical cues override chemical cues: macrophage adhesion and elongation is similar on nanopatterned polymers (PCL, PLA etc.) Contact angle of water droplets on polystyrene and polypropylene are similar. Ref: 14, 75.	______
Nanofibers & Nanowires	Nanofiber diameter < 600 nm induces minimal production of pro-inflammatory cytokines in macrophages. Nanofiber aspect ratio < 40 reduces lymphocyte and granulocyte infiltration. Aligned nanofibers reduce macrophage recruitment and fibrous capsule formation. Ref: 86-89	Slowly degrading polymers such as PCL reduce acidic byproduct accumulation. Collagen elicits a lower degree of inflammation than gelatin. Heparin based nanofibers gels reduce macrophage fusion in vivo. Ref: 87, 91, 92	Site-specific delivery of NSAIDs, curcumin and other drugs can reduce inflammation towards nanofibers. Ref: 83-85
Carbon Nanotubes	Nanotubes with aggregate size < 10 μm do not induce granuloma formation. Nanotubes at conc. < 0.6 μg/ml do not stimulate fibroblast growth. Ref: 22,94,101-103	Nanotubes functionalized with triton and inert polymers such as PEG attenuate inflammation in vivo. Nitrogen doping also decreases inflammatory reaction to nanotubes. Ref: 109, 111	Localized delivery of dexamethoasone and ketoprofen from carbon nanotubes reduces inflammation. Ref: 104-106