Poly (Lactic-co-glycolic) acid (PLGA)

PLGA is considered as one of the most efficient tissue engineering materials due to its (i) high biocompatibility, (ii) biodegradability, (iii) potential to interact with biological materials, and (iv) clinical use approved by FDA [193]. Biodegradable biomolecule-loaded PLGA nanoparticles can be used for the preparation of a drug delivery system, which can be further utilized in scaffold fabrications [194–196]. These nanoparticles may increase the mechanical properties of the scaffolds but decrease swelling behavior without changing the morphology of the scaffold [197]. Afterward, this system is effective to prepare a controlled release platform for model drugs that favors the bio-distribution and development of clinically relevant therapies [198]. Different methods such as gas foaming [199], porogen leaching [200], solid freedom fabrication [201], and phase separation [202] can be used for PLGA scaffolds fabrication.

### 2.1.5. Carbon Nanostructures

Carbon nanomaterials are great candidate materials for bone tissue engineering due to their conductivity, lightweight, stability and strength [203]. Nanostructures such as fullerenes, carbon nanotubes, carbon nanofibers, and graphene are the most common structures (Figure 11) [204,205].

Han et al. [205] pointed out that carbon is biocompatible and can be used in many clinical applications, such as prosthetic heart valves. However, a pure form of carbon nanomaterials cannot be used as a substrate for bone tissue [206]. Therefore, carbon-based materials are used in combined form to fabricate scaffolds [207]. Carbon nanostructures doped or reinforced compositions became more popular due to their high performance and compatibility with bone tissues [203].

Carbon nanofibers (CNF) are cylindrical or conical structures of various diameters and lengths. The interior structure of the CNF contains an improved layout of graphene sheets. Graphene is a single-layer two-dimensional material composed of long-edged reactive carbon atoms. Graphene leaves are characterized by stable dispersion and orientation of nanofillers [208–210].

Carbon nanotubes (CNT) enhance mechanical and electrical properties, which helps to generate innovative products. CNTs are one of the ideal and favorable materials used for designing novel polymer composites [211]. Many authors focused on the progress of composite materials fabrication-integrating CNTs to enhance its applications in biomedical field [212–216].

Nanodiamonds (4–10 nm) are typically different from other nanostructures as they are sp<sup>3</sup> hybridized [203]. They show admirable protein binding ability and can be used as a carrier for some biomolecules such as BMP-2 [217]. The carbon nanotube/gold hybrids are employed commonly for the delivery of the anticancer drug doxorubicin hydrochloride into A549 lung cancer cell line [218].

Nanoscaffolds can be produced by electrospinning poly(ε-caprolactone) (PCL) and different types of carbon nanomaterials such as carbon nanotubes, graphene, and fullerene [219]. Mesoporous silica (mSiO2) decorated carbon nanotubes (CNTs) hybrid composite were used for the simultaneous applications of gentamicin and protein cytochrome C delivery and imaging [220]. Single-walled carbon nano-horns encapsulated with positively charged lipids complex were used for targeted drug and protein delivery [221].

**Figure 11.** Structure of various allotropes of carbon (adapted with permission from Royal Society of Chemistry [205]). In the figure, "BCB" stands for "benzocyclobutene".

2.1.6. Summary and Statistical Analysis of the Survey on Organic Nanobiomaterials

The survey on organic nanobiomaterials presented in Section 2.1 regarded some 200 articles. Polymeric nanomaterials, carbon nanostructures, and nanocomposite materials are the most widely investigated subject (60.8% of the studies), followed by dendrimers (21.1%) and lipids/liposomes (18.1%). While dendrimers and lipid/liposomes are mainly utilized as nanocarriers, the other nanomaterials cover a much broader spectrum of applications. The development of new nanomaterials (especially carbon nanomaterials or materials including natural bone constituents such as, for example, collagen) that can improve tissue regeneration, cell growth, and drug/protein delivery currently represents the main research area in the field of organic nanobiomaterials with a strong tendency to design hybrid materials and improve fabrication techniques of the resulting nanocomposite materials/scaffolds/structures. Such a trend has become very clear in the last 5–6 years. However, much work remains to be done

in order to fully understand interactions between different phases of nanocomposite materials and cell/tissues to be repaired/treated. Another important issue strictly related to the above mentioned one is how to "optimize" the composition of the nanocomposite for the specific purposes on which the material itself is designed.
