2.1.3. Dendrimers

Dendrimers are the newest class of highly-defined macromolecules, which differs from simple polymers by branching at each repeating unit [97]. Their step-by-step controlled synthesis is used worldwide for molecular chemistry, while their repeating structure made of monomers relate them to the world of polymers [98,99]. The repetitively branched nanometer-scale dimension of dendrimers is an ideal candidate for a variety of tissue engineering [100], molecular imaging [101], and drug delivery [102] applications. Dendrimers can be a main component of scaffolds mimicking cross-linkers, chemical surface modifiers, and charge modifiers, as well as natural extracellular matrices [103].

The combination of dendrimers with other conventional structural polymers, such as proteins, carbohydrates and linear synthetic polymers, leads to obtain new physical, mechanical and biochemical properties of hybrid structures [100,104]. The center of dendrimer may be composed of polypropylimine (PPI), di-aminobutyl (DAB), polyamidoamine (PAMAM), and ethylenediamine (EDA), along with various surface residues such as amine, carboxyl, and alcoholic groups [105]. A dendrimer can be synthesized for particular use in different parts with controlled properties like solubility and thermal stability [106].

Dendrimer–drug conjugation is a better approach to the encapsulation of cytotoxic pharmaceuticals. In this way, numerous cytotoxic and anticancer drugs, and targeted individuals such as monoclonal antibodies, peptides, and folic acid, can be conjugated to a single dendrimer molecule [107]. The drug is covalently conjugated to the dendrimer rather than complexed (Figure 5) [108] and these conjugates are relatively more stable.

Dendrimers are a good choice for hydrophobic moieties and poorly water-soluble drugs [109]. PAMAM dendrimer/DNA complexes were employed to encapsulate functional fast biodegradable polymer films used for substrate-mediated gene delivery [110].

The physicochemical characteristics, such as solubility and pharmacokinetics, of dendrimers are better than those of linear polymers. Therefore, dendrimers are ideal candidates for incorporation into scaffolds used for tissue engineering applications [111,112]. A few scaffolds were fabricated with dendrimers such as poly(caprolactone) chains conjugated to a poly(L-lysine) dendritic core to fabricate an HA-composite [113], linear PCL/n-HA hybrids [114], N-hydroxy succinimide/1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (NHS/EDC) cross-linked scaffold [115], and dexamethasone carboxymethyl chitosan/PAMAM [116] for in vitro bone regeneration.

**Figure 5.** Structure of a typical dendrimer–drug conjugate (Reused with permission from Elsevier [108].)

### 2.1.4. Polymeric Nanomaterials

Polymeric nanoparticles of size range 10 nm to 1 μm are the most advanced noninvasive approaches to tissue engineering and drug delivery applications [117]. They are comprised of repeating units of chain-like macromolecules with multiple structures and compositions [118]. In general, polymeric nanoparticles can be used for different applications by changing the physicochemical properties of nanoparticles. Polymers are differently processed to produce nanofibers [119], spherical nanoparticles [120] and polymeric micelles [121] for specific applications.

There are several techniques to synthesize polymer-based nanoparticles, applied in tissue engineering [122]. Gelation [123], emulsion–solvent evaporation [124], nanoprecipitation [125], salting-out [122], and desolvation process [126] are generally preferred for natural polymers, like proteins and polysaccharides. Similar to other nanoparticle systems, polymer-based nanoparticles or nanocomposites can be functionalized to perform active targeting [127].

Polymeric nanoparticles alter and may enhance the pharmacokinetic and pharmacodynamic properties used for various drug types because they show controlled and sustained release properties [128]. They offer a variety of benefits ranging from the administration of non-soluble drugs to protection of unstable compounds [129]. These nanoparticles can be loaded with therapeutic or bioactive molecules (Figure 6) either by dispersion or adsorption within the polymer matrix, or encapsulation [130,131].

**Figure 6.** Bioactive/drug molecules loaded polymeric nanoparticles.

Drug release may occur directly from nanoparticles through diffusion and polymeric nanoparticles may dissociate into monomers [132]. Polymers used for nanoparticle fabrication should be degradable via enzymatic or non-enzymatic routes under common metabolic pathways [133,134]. Drug-containing polymeric nanoparticles must be stable during migration to the plasma, that is, at almost neutral pH [135].

Chitosan, collagen, gelatin, hyaluronic acid, alginate, and albumin are representative examples of natural biopolymers [136,137]. Polymeric nanoparticles are one of the fastest-growing platforms for the applications in tissue engineering because of their biocompatibility, biodegradability, low cytotoxicity, high permeation, ability to deliver poorly soluble drugs, and retaining bioactivity after degradation [117]. Some newly designed polymeric nanoparticles are sensitive to pH, temperature, oxidizing/reducing agents, and magnetic field which support a high efficiency and specificity for tissue engineering applications [138,139]. Due to good biocompatibility and adjustable chemical composition, and their ability to reorganize, polymeric nanoparticles are very promising as nanobiomaterials for the fabrication of scaffolds or bone substitutes [140]. Plasma protein-based nanoparticles have shown high biodegradability, bioavailability, long in vivo half-lives, and long shelf lives without any toxicity. Blood plasma is a complex mixture of 100,000 proteins, but only two of these proteins have been used in drug administration and tissue regeneration [141,142].
