**1. Introduction**

Nanobiomaterials denote nanometer-sized materials whose structures and constituents have significant and novel characteristics with a strong impact on healing and medicine [1,2]. They include metals, ceramics, polymers, hydrogels, and novel self-assembled materials [3]. Rapid developments in nanotechnology not only led to create new materials and tools for biomedical applications, but also changed the way of using these materials in science and technology [4,5].

Human bone is a dynamic tissue that can rebuild and remodel in the body throughout life [6]. The human bone is a hierarchical assembly of nano- to macro-scale organic and inorganic components involved in transmitting physio-chemical and mechano-chemical cues [7,8]. The schematic of Figure 1 shows that normal human bone contains 30% organic collagen fibrils and 70% inorganic minerals [9–12],

while 2% of the total volume is occupied by bone cells, osteoblasts, osteoclasts, lining cells, progenitor cells, and adipocytes [13,14]. Crystalline phases form 65% of the dry weight of the mineral matrix and most part of calcined fraction in calcium phosphate [15,16].

**Figure 1.** Composition of natural bone.

The continuously growing population and the higher complexity of human interactions have generated new bone-related diseases (e.g., bone tumors, bone infections, and bone loss). This requires effective handling and treatment for bone regeneration [17,18]. Tissue engineering has revolutionized orthopedic and surgical studies, providing a new direction in the field based on nanoscale surface modification to simulate properties of extracellular matrix (ECM) and new foundations of structural variables of autologous tissue [19,20]. Tissue engineering is used to generate, restore, and/or replace tissues and organs by using biomaterials and helps to produce similar native tissue or organ [21].

Nanotechnology solved many questions in tissue engineering by modifying regenerative strategies [22]. Biomedical applications of nanotechnology became a hot subject because different nanomaterials are utilized for the synthesis of scaffolds or implants [23,24]. These nanomaterials may be metallic [25], ceramic, or polymeric [26] with different structural forms such as tubes, rods, fibers, and spheres [27]. Various properties of materials such as physiochemical, electrical, mechanical, optical, catalytic, and magnetic properties can be improved at the nanoscale [28] and tailored to specific applications. Nanomaterials synthesized through top-down or bottom-up approaches [29] (Figure 2) have outstanding properties, which are used for biomedical applications particularly in tissue engineering [22].

Existing biomaterials often do not integrate with host tissue completely. This may cause infection and foreign body reactions that lead to implant failure [30]. Indeed, nanostructured biomaterials imitate the natural bone's extracellular matrix (ECM), producing an artificial microenvironment that promotes cell adhesion, proliferation and differentiation [31]. The specific biological, morphological, and biochemical properties of nanobiomaterials attract researchers to use them for the hard tissue engineering [32]. Nanostructured biomaterials can be used to fabricate high-performance scaffolds or implants with tailored physical, chemical, and biological properties. Several natural and synthetic nanostructured biomaterials are now available for the fabrication of scaffolds with decent bioactivity [33].

This survey article presents the most relevant applications of nanobiomaterials to bone tissue engineering, trying to highlight how organic and inorganic nanobiomaterials can deal with the above mentioned requirements on bone regeneration and the multiple challenges entailed by such a complicated subject. A broad overview of the various types of nanobiomaterials and their applications in the field of hard tissue engineering is provided.

**Figure 2.** Design of bioactive materials based on top-down and bottom-up approaches.

Besides the introductory articles mentioned above and other general articles on topics related to nanomaterials and the different contexts where they operate, the present survey covers some 550 technical papers focusing on types, fabrication, and applications of nanobiomaterials. These articles have been selected using three widely used academic search engines: Scopus, Web of Science, and Google Scholar. For that purpose, keywords such as "tissue engineering", "bone tissue engineering", "tissue regeneration", "scaffolds", "nanomaterials", and "nanobiomaterials" as well as their combinations have been used as input for the search process. High priority is given to peer-reviewed journal articles with respect to book chapters and conference proceedings, which count for some 10 papers, less than 1.75% of the total number of surveyed articles. More detailed statistics on the articles surveyed for each topic will be reported at the end of the corresponding subsections.

The paper is structured as follows. Sections 2 and 3 describe the various types of organic and inorganic nanobiomaterials and their applications in bone tissue engineering/regenerative medicines, drug/gene delivery, anti-infection properties, coatings, scaffold fabrication, and cancer therapy; generalizing conclusions are given at the end of each section. The conclusion section summarizes the main findings of this survey.
