**2. Bone-Grafting Techniques**

Preventive (such as atraumatic tooth extraction and filling the socket soon after extraction) or regenerative techniques (such as grafting to gain bone volume after healing the ridge) have been suggested to minimize the esthetic and phonetics effects caused by the bone defects and enable the placement of dental implants [11,13] (Figures 4 and 5). Both techniques employ bone grafts to promote bone repair and the reduction of bone defects. In preventive techniques, the bone grafts help to maintain the volume for cell infiltration and proliferation, as well as assist in closing the surgical wound [14]. In regenerative techniques, the bone grafts have been used to increase the vertical and/or horizontal volume of the alveolar ridge, being the guided bone regeneration (GBR) indicated as the best technique, with satisfactory results over time [15–17].

**Figure 4.** Diagram showing a preventive technique after tooth extraction. (**A**) Dental implantation. (**B**) Dental extraction. (**C**) Filling the dental socket with biomaterial. (**D**) Closure with a membrane. (**E**) Suturing the grafted area.

**Figure 5.** Diagram showing a regenerative technique in an area with the bone defect. (**A**) Alveolar ridge with a bone defect in thickness. (**B**) Bone graft adapted to the area of the defect and membrane positioned. (**C**) Suturing the grafted area.

Since bone repair depends on mechanisms of osteoconduction, osteoinduction, and osteogenesis, the ideal bone graft should guide the bone growth three-dimensionally, establishing cell recruitment, inducing differentiation of resident bone cells, and providing cells at the implantation site [18] (Figure 6). For many years, autogenous bone grafts had been considered the reference standard for the treatment of bone defects. In addition to having imunocompatible cells, they are osteogenic, osteoconductive, and osteoinductive presenting characteristics of bioabsorption and angiogenesis, which guarantees high clinical predictability [19,20]. While osteoinductors are biomaterials that stimulate undifferentiated cells to differentiate into osteoblasts, osteoconductors act as a framework for the proliferation of blood vessels, perivascular tissue, and osteoprogenitor cells of the patient. Osteogenitors biomaterials are capable of forming bone tissue by themselves since they have viable precursor cells and/or osteoblasts [21].

**Figure 6.** Diagram showing mechanisms of osteoconduction, osteoinduction, and osteogenesis.

In autogenous grafts, the patient is both the donor and the graft receptor. When used to correct intra-oral bone defects, autogenous bone grafts have been obtained from the oral cavity (such as the mental area, mandible body, or maxillary tuberosity) or extra-oral donor areas (such as the iliac crest, tibia, or skullcap) [19]. However, limitations such as the restricted availability of bone for removal, increased surgical morbidity, high rates of graft bone remodeling, and difficulty in predicting the rate of degradation over time, have been associated with autogenous bone grafts [22–24]. Therefore, autogenous bone grafts have declined in use over time, especially from the extra-oral area.

In order to minimize the inherent limitations of autogenous bone grafts, bone substitutes such as homologous, xenogenous, and alloplastic grafts have been suggested in the literature [19,25–27]. Homologous bone grafts are originated from another individual of the

same species from cadavers (e.g., DFDBA: demineralized freeze-dried bone allograft; FDBA: freeze-dried bone allograft), while xenogenous grafts are obtained from another species (ex: CB-BB: chemically deproteinized bovine bone; TD-BB: thermally deproteinized bovine bone). Despite being available in large amounts, the main disadvantages of homologous bone grafts are high costs, the requirement for complex sterilization and storage techniques, difficulty in predicting the rate of degradation over time, the risks of disease transmission, variable osteoinductive and osteoconductive properties, and lower osteogenic potential compared to autografts [28,29]; while risks of zoonotic diseases transmission (e.g., bovine spongiform encephalopathy), prion infections, and immunological activation of diseases have been related to xenogenous grafts [30,31].

Conversely, alloplastic bone grafts are fabricated from inorganic or synthetic biomaterials, which, despite not having the osteogenesis and osteoinduction capacity, considerably reduce surgical morbidity rates and the risk of disease transmission [32,33]. Therefore, alloplastic bone grafts have been developed to overcome the limitations of autogenous, homologous, and xenogenous grafts. Indeed, these biomaterials have demonstrated advantages such as a reduction in surgical time, an abundance of materials with no amount limitation, ease of handling, no risk of disease transmission, and very low antigenicity potential [34–36].

Alloplastic bone grafts are fabricated from absorbable or non-absorbable synthetic materials, with different sizes and shapes, and variations in their physical and chemical properties, such as granule morphology, crystalline or amorphous phase, and pore size and interconnectivity [37]. Composed of osteoconductive biomaterials, these grafts provide a framework, which will be populated by cells originated from osteoprogenitor cells (from the defect margins), thus promoting bone neoformation until the biomaterial is completely replaced by the new bone [33,35,36]. Alloplastic grafts can be used alone, or in association with autogenous bone, biomaterials, or bioactive substances [35,37,38].

#### **3. Scaffolds**

With the advancement and diversity of alloplastic bone grafts, the concept of "bone tissue engineering (BTE)" stands out, which aims to combine biological knowledge concerning the histology and morphology of bone tissues with the development of appropriate biomaterials and techniques for the three-dimensional (3D) structure's construction, capable of simulating the bone environment on a micro and nanoscale [39]. These structures, better known as scaffolds, are carriers for cellular interactions (migration, adhesion, and cell proliferation), allowing the deposition of a new bone extracellular matrix on its porous surface [40–42]. Additionally, they also provide temporary support for newly formed bone tissue and vessels [43,44].

Metals (tantalum, magnesium, titanium and titanium alloys, nickel-titanium alloy [nitinol]); natural polymers (collagen, gelatin, silk fibroin, chitosan, alginate, hyaluronic acid); synthetic polymers (polylactic acid [PLA], polyglycolic acid [PGA], polylactic-co-glycolic acid [PLGA], polycaprolactone [PCL], polyvinyl alcohol [PVA], polypropylene fumarate [PPF], polyurethane [PU]); bioactive ceramics (hydroxyapatite [HAp], tricalcium phosphate [TCP], beta-tricalcium phosphate [β-TCP], calcium sulfate [CaSO4], akermanite [Ca, Si, Mg], diopside [MgCaSi2O6], bioactive glass [BGs]); and bioinert ceramics (aluminum oxide, zirconia) have been proposed for the manufacture of scaffolds-based bone tissue engineering [41,45,46]. Additionally, the materials most used in clinical practices to repair intra-oral defects are HAp, dicalcium, tricalcium phosphates, and bioactive glasses [47–50]. The materials used in scaffolds for implant dentistry are shown in Table 1.



**Table 1.** *Cont.*

More recently, hybrid scaffolds, which combine polymers and ceramics have been proposed to associate the advantages of polymeric materials with the favorable properties of ceramic such as bioactivity and mechanical resistance [41]. It is relevant to mention that there is still no single synthetic biomaterial that offers all the desirable properties for a scaffold; thus, the association of biomaterials combines the best properties of each one, in order to meet the needs of the bone-grafted area [48]. These 3D structures can also be associated with growth factors (such as recombinant human bone morphogenetic protein-2 (rhBMP-2) and platelet-derived factors-BB), bioactive substances (such as simvastatin), and specific cells which stimulate bone tissue regeneration (such as mesenchymal stem cells or osteoblasts) [64–66].
