TABLE 3.

Main types of nanostructured delivery systems used in bone regeneration, with their respective advantages and disadvantages.

	Advantages	Disadvantages	References
Inorganic nanostructured delivery systems
Ceramics (e.g., HA, TCP)	Intrinsic osteoconductivity Surface functionalization Widely available	Unfavorable biodegradability profile Low yield of payload loading	Matsumoto et al., 2004; Dong et al., 2007; Habraken et al., 2007; LeGeros, 2008; Yuan et al., 2010; Xie et al., 2010; Bose and Tarafder, 2012; Jeon et al., 2012; Fielding and Bose, 2013; Fan et al., 2014; Wen et al., 2017
Metallic or metalloid oxides (e.g., silica)	Tailorable mesoporous structure Surface functionalization with and/or encapsulation of bioactive molecules Modifiable architecture and topography Optimization of cell adhesion and proliferation	Cytotoxicity at certain particle sizes and/or concentrations	Oh et al., 2005; Raja et al., 2005; Magrez et al., 2009; Lai et al., 2011; Lallana et al., 2012; Portan et al., 2012; Tang et al., 2012; Setyawati et al., 2013; Shadjou and Hasanzadeh, 2015; Zhou et al., 2015; Cui et al., 2018; Tang et al., 2014; Hu et al., 2012; Huang et al., 2014; Kwon et al., 2017; Liu et al., 2017
Organic nanostructured delivery systems
Synthetic polymers (e.g., PLA, PLGA)	Widely available Overall favorable biocompatibility Many modifiable properties: e.g., L/G ratio, molecular weight. Modifiable with cross-linkers or surface functionalization	Low yield of payload loading Burst release Difficulty in accomplishing sustained release Certain polymers have cytotoxic degradation products	Alcantar et al., 2000; Habraken et al., 2007; Lü et al., 2009; Puppi et al., 2010; Anderson and Shive, 2012; Makadia and Siegel, 2011; Jacob et al., 2018
Natural polymers (e.g., gelatin, chitosan)	Widely available Favorable biocompatibility and biodegradability Biomimetic properties Modifiable with cross-linkers or surface functionalization	Low yield of payload loading Rapid degradation in vivo Burst release Difficulty in accomplishing sustained release	Friess, 1998; Aframian et al., 2002; Malafaya et al., 2007; Niu et al., 2009; He et al., 2011; Vo et al., 2012; Farokhi et al., 2014; Amjadian et al., 2016; Cai et al., 2016; Ding et al., 2016; Shen et al., 2016; Jacob et al., 2018; Oliveira et al., 2019
Composite nanostructured delivery systems
Composites	High loading efficiency Highly tunable release kinetics Sustained release Optimization of unique properties of each material	Generally require more complex syntheses	Li et al., 2006; Liu et al., 2009; Niu et al., 2009; Reves et al., 2011; Fan et al., 2012; Singh et al., 2015; Minardi et al., 2015b; Kim B.-S. et al., 2018; Wang et al., 2018; Zhang Q. et al., 2018; Minardi et al., 2020