Bone Graft Materials for Alveolar Bone Defects in Orthodontic Tooth Movement

Introduction

In the clinical scenario, the resorption of alveolar bone in dental extraction sites normally takes ∼6 months, while too quick resorption would make the alveolar ridge shrink, either in height or in width, or both. Moreover, the alteration of cancellous bone to dense cortical bone after alveolar bone reduction renders difficulty to orthodontic tooth movement (OTM) within these areas, coupled with dental root resorption, gingival recession, periodontal diseases, or traumatic injuries to pulp vitality of moved teeth. ¹ Hence, some orthodontists propose re-establishment of the alveolar bone before OTM through the alveolar defects.

The most prevalent approach to mitigation of alveolar resorption or regeneration of alveolar bone rests on surgical augmentation with the application of bone grafts in the defect sites (Fig. 1). Of the bone grafts, the autogenous bone is acknowledged as the gold standard for bone regeneration owing to its biocompatibility and viability of transferred osteogenic cells. ² However, the requirement for secondary surgery to isolate autogenous bone from the donor site restricts the widespread clinical application. Hence, other types of bone grafts, such as allografts, xenografts, and synthetic bone grafts, are currently widely used in the dental clinic (Table 1).

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FIG. 1.

The diagram of bone defect augmentation using bone grafts. (a, b) Alveolar ridge atrophy because of long-term tooth loss or alveolar cleft. (c, d) The atrophic bone exposed after flapping. (e, f) Bone defect augmentation using bone grafts. (g) Four different types of bone grafts. Color images are available online.

Due to the diversity and distinction of the materials, only a few bone grafts biodegrade and resorb quickly after implantation, while most materials may retain in place for years.^3,4 With respect to safety, the tooth movement should theoretically be initiated after the resorption of bone grafts and the formation of new self-bone, with the orthodontists practically encountered with the dilemma that too rapid biodegradation and resorption of bone materials may imply insufficient window phase of tooth movement, whereas retardation or absence of resorption could impede dental movement. Therefore, the ideal bone grafts for OTM should not only possess the stability of alveolar bone reconstruction and increase alveolar ridge volume but also provide a window phase for different algorithms of OTM.

Bone substitutes mainly feature in the combination of mechanical support and osteoconduction, embedded with another two crucial biological properties: osteoinduction and osteogenesis. ⁵ Osteoconduction involves the attached osteoblasts and osteoprogenitor cells to migrate and ingrowth within the three-dimensional graft structure. ⁶ Osteoinduction requires the cells void of specialization and differentiation and with pluripotency to develop into an osteoprogenitor lineage, thereby further inducing osteogenesis, ⁷ or rather the differentiation and subsequent formation of new bone tissues from donor cells derived from either the host or grafts. ⁸

Herein, this review aimed to evaluate the application of different bone graft materials to the reconstruction of alveolar ridge defects for OTM. Despite the lack of a unified standard in orthodontic clinics, our review may at least provide some recommendations and guidance for OTM through alveolar ridge defect area.

Autografts

Autogenous bone was first postulated for bone defects augmentation, ⁹ since it was isolated from the patient per se and has been documented to readily proliferate and differentiate from progenitor cells (osteoinduction), which release osteogenic growth factors such as bone morphogenetic proteins. ¹⁰ Furthermore, it can exempt the incidence of immune response or infection spreading, thereby providing a framework of osteogenesis (osteoconduction), and creating optimal microenvironment for the angiogenesis and migration of osteoprogenitor cells. ¹¹ Hence, autogenous bone grafts are recognized ideal for regimens for bone defects.

The variety of autogenous bone grafts ranges from ribs, tibia, solid single piece of iliac crest, particulate from the iliac crest, and combinations of particulate grafts and solid cortical grafts from the iliac crest. Of the factors affecting the osteogenesis of autogenous bone grafts, graft size plays a crucial role. Particulate grafts are superior to large bone blocks on the grounds of the greater surface area they provide for the proliferating progenitor cells. Large bone blocks are dense, solid, and impermeable tissues, which may obstruct the cell migration and potentially inhibit the formation of new vessels and bone tissues. ¹² Moreover, the osteocytes and osteoblasts within autogenous bone significantly improve the bone formation.

Clinically, the size and cell viability of autografts are susceptible to harvesting methodology. Miron et al. ¹¹ described four different techniques (bone-block powder from grinding with a bone mill, harvest with piezosurgery, bone particles from drilling with a slurry, and the use of a bone scraper) to harvest autogenous bone grafts, with their respective capacities of promoting an osteogenic response compared in vitro. The results showed that fine particles harvested from piezosurgery and bone slurry remarkably prevented osteoblasts to attach and differentiate in contrast to major particles harvested with the use of bone mill and bone scraper. Furthermore, autogenous bone obtained from bone slurry and piezosurgery presented with greatly diminished cell population.

There are two different forms of autogenous bone grafts, cancellous and cortical, with the former more prevailing in the clinic. Despite the relatively few osteoblasts and osteocytes compared with mesenchymal stem cells (MSCs) in cancellous autografts, the abundance of surviving MSCs suffices to maintain the potential and potency of osteogenesis from the graft. ¹³ Furthermore, the vastness of surface area of a cancellous autograft allows for the local angiogenesis in the graft and integration to the host bone. ¹⁴ Meanwhile, the release of the embedded proteins in cancellous autografts also favors the osteogenesis in bone defects. ¹² In parallel, cortical autogenous bone grafts display remarkable integrity in structural and mechanical support, owing to the minority of osteoprogenitor cells. ¹⁵

The different components of cancellous and cortical autogenous bone grafts lead to the divergence of bone formation process. As for cancellous autogenous bone grafts, the onset of hematoma and inflammation rapidly follows the initial autograft transplant, with the recruited MSCs underlaying fibrous granulated tissue. In parallel, tissue necrosis is gradually eradicated through phagocytosis in line with neovascularization. Thereafter, in the course of the autograft incorporation, osteoblasts attach to the necrotic tissue so as to form osteoid seams, which is consistent with the osteogenesis from hematopoietic cell accumulation within the transplanted bone. ¹⁶ This process of the complete graft resorption and replacement typically requires 6–12 months. ¹⁷

Distinctive from the autologous cancellous grafts, the cortical autografts undergo a series of gradual but more complicated processes, from the rapid onset of hematoma to development of inflammatory response in the early phase of osteoclast-mediated osteogenesis, on the grounds that the angiogenesis and reconstruction are severely bridled by the dense bone structure.^12,17 Therefore, subsequent to osteoclastic resorption, the simultaneous osteogenesis at a necrotic site becomes predominant in the process of incorporation of the cortical autograft, which may even take years to complete, dependent on the graft size and implantation site. ¹²

A paucity of literature has been available regarding the application of autogenous bone grafts to ridge augmentation for OTM through bone defect area. The earliest reports that can be traced dated up to the middle of the twentieth century. Boyne and Sands ¹⁸ reported a series of cases with residual palatoalveolar cleft defects, for which marrow and cancellous bone grafts were employed to reconstruct the bone defects for tooth eruption. Since grafting is aimed to retain the well-being of alveolar bone after OTM, the graft material should retain viability both at transplantation and after surgical transplantation. Autogenous rib grafts are not considered as desirable, owing to the large content of nonviable cortical bone, which could not meet such postgrafting functional requirements. Thence, autogenous particulate cancellous bone and marrow were selected for defect reconstruction in this research. Active OTM was commenced ∼2 months after grafting surgery. The results showed that a dental arch with good integrity was achieved, and teeth were moved into the original cleft area with normal periodontal tissues.

Although cancellous iliac bone has been documented as the most frequent donor site, bone grafts from other sites are also available. Nadal et al. ¹⁹ conducted a retrospective study of reconstruction of alveolar cleft bone with graft harvested from the olecranon process. The isolated graft, which was a single piece of bone with periosteum attachment, was fitted in the alveolar cleft defect and benefited early vascularization and volume maintenance. The results showed that ∼90% of embedded teeth in the cleft sites spontaneously erupted after bone grafting, which however would have only occurred in the case of completion of embedded tooth root for one-fourth or two-thirds. Sun et al. ²⁰ analyzed the biological effects of OTM into the grafted alveolar cleft area. Intriguingly, in patients with cleft lip and palate, bone graft surgery before orthodontic treatment promoted the bone reconstruction, which can well illustrate the mechanical stress by the orthodontic manipulation. In this case, after the induction of bone resorption by osteoclasts, osteoblasts manufacture new bone tissues to restore the cleft. Orthodontic manipulation after OTM allows for stimulation that accelerates bone reconstruction, wherein the graft bone was remodeled into the autogenous bone, thus providing a bone substrate for tooth movement.

Beyond alveolar cleft defect, autogenous bone grafts have gained reputation in other regimens. In a case report by Collett and Fletcher, ²¹ autogenous bone graft was harvested from the maxillary tuberosity in the patient, covered with a biomembrane and fixed with a bone screw in the canine extraction site. At the end of 7 months of bone graft consolidation and another 18 months of orthodontic treatment, retraction of the lateral incisor and protraction of the first premolar into the graft site were successfully achieved, and esthetics proved the successful regeneration of bone and soft tissues. In this study, the corticocancellous grafts (consisting of cortical and cancellous bone) were employed for the duration of ∼37 months, wherein the cortical bone grafts served an osteoconductive role for their excellent structural integrity by long-lasting mechanical support. Nonetheless, the cancellous bone served to trigger osteoinduction and osteogenesis, which resulted in the complete resorption and replacement of the grafts that would normally take 6–12 months. Another factor to be mentioned of the female patient is the age of 17, which simply equals to high potency of bone regeneration. Pithon et al. ²² reported a case with similar results, in which the graft was isolated from the retromolar region in a 33-year-old woman, inserted and fixed in the bone defect with two screws. At the end of 4 months of the bone graft consolidation, the teeth with improved periodontal condition were moved into the graft site for suture closure between the teeth.

Beyond the conventional methods of bone augmentation, Ozer et al. ²³ adopted a novel technique to augment the bone defect, and the teeth were moved into the graft site to close the edentulous space. Rather than harvest of bone grafts from the specified anatomical structures (such as the maxillary tuberosity and retromolar region), two cylindrical bone blocks (3 mm in diameter) were isolated from the proximal site and filled in the expanded atrophic alveolar crest to stabilize the splitting alveolar ridges in their expanded positions. Notwithstanding some extent of root resorption and slight remnant of interdental space at the end of the treatment, the results were acceptable for this long distance (∼15 mm). Table 2 highlights the study characteristics of using autografts for bone defects augmentation and tooth movement.

However, autografts along with the harvesting maneuver have been extensively recognized as correlated with a high incidence of complications and postoperative pain in the donor site, increased blood loss, prolonged operative duration, potential risk of infection of donor site, and limited dose of materials available. ²⁴ These drawbacks significantly restrain the widespread of this type of autografts. Therefore, alternatives such as bone allografts, xenografts, and synthetic bone graft biomaterials are deemed to bring prospect of grafting procedures.

Allografts

Allogenous bone materials are derived from the same species and are processed with various techniques, for example, freeze drying or exposure to radiation. ⁸ Due to the limitations of autologous bone grafts, bone allograft has been recognized as the optimal substitute for autografts and is applied in the clinical scenario with efficacy and efficiency, particularly in the patients with limited healing potential or nonunion. The most popular allografts include freeze-dried bone allograft (FDBA) and decalcified freeze-dried bone allograft (DFDBA). ²⁵ Although both FDBA and DFDBA are osteoconductive, only DFDBA has the theoretical potential to be osteoinductive. The osteoinductive potency of DFDBA depends on the content of bone morphogenic proteins (BMPs) reserved (such as BMP-2, BMP-4, and BMP-7) from commercialized processing.^26,27 There is also evidence that not all commercial DFDBAs are osteoinductive, and that their osteoinductive ability depends on the age of the donor as well as the sample processing methods,^28,29 which may justify the addition of BMPs to induce bone formation.

FDBA does not possess the same osteoinductive capability. It is because the BMPs trapped in the mineralized particles of FDBA could not be eluted quickly for the lack of osteoclasts. ³⁰ The soluble osteoinductive proteins of DFDBA are able to function immediately after implantation, which, however, cannot provide a tenacious scaffold. In contrast, FDBA provides a superior scaffold, which proves to be more osteoconductive. However, in the early period of implantation in the bone site, FDBA cannot exhibit osteoinductive capability, which could be revived only after the mineral content of FDBA is decomposed by osteoclasts in the recipient and the soluble osteoinductive proteins become available so as to induce osteoinduction. Wood and Mealey ³¹ compared the effects of DFDBA and FDBA in alveolar ridge preservation, with the findings that there were insignificant differences in changes of alveolar ridge dimensions between DFDBA and FDBA groups. However, the percentage of vital bones in DFDBA group was significantly greater versus FDBA group. The mean percentage of residual graft particles in DFDBA group was significantly lower versus FDBA group. Accordingly, DFDBA could be postulated as a superior bone graft material in alveolar bone defects reconstruction in OTM.

There are similarities between the autogenous bone grafts and the allogenous bone grafts in typology (cancellous and cortical) and the incorporation process, whereas allogenous bone grafts differ from autografts with respect to biological response. Specifically, the autogenous bone graft may induce angioblastic proliferation in the recipient site as of the first postoperative week. The viable osteoblasts thence transplanted initiate osteogenesis for the healing process in first few weeks. To the contrary, the allogeneic bone graft presents with a retarded revascularization, ³² thus delaying the migrating and proliferating endothelial cells (ECs) for 1–2 weeks thereafter. Moreover, allogeneic graft contains no viable osteogenic cells, which play important role in promoting osteogenesis.

The angiogenesis is in line with osteogenesis, in which new bone gradually substitutes the osteoid and underlays the periphery of the recipient site, with the nonviable graft particles sequestered or eliminated as aliens by macrophages. ³³ Furthermore, osteointegration of allogenous bone grafts may be retarded due to an inflammatory response in host, resulting in the fibrosis surrounding the graft, ³⁴ with the transplanted allografts entrapped and unabsorbed. ³⁵ Ruellas et al. ³⁶ reported a successful case of OTM into the severe bone defect site augmented by a corticocancellous bone-block allograft, in which a medullary cortical bone block (20 by 10 by 6 in mm) obtained from a tissue bank as the allograft to reconstruct the bone defect in the site of the first molar. As mentioned afore, any OTM within 3 months postgrafting would involve dental movement across immature bone tissues, which would result in severe root resorption on the grounds that the numerous resorption growth factors and cytokines in immature bone.

However, the OTM was initiated at the early stage of bone grafting, which was further supported by a report ³⁷ of a significant bony defect due to an accidental fracture in the entire buccal bone in the area corresponding to the maxillary right first premolar. The authors adopted DFDBA to reconstruct the defected alveolar ridge. Only 2.5 months after implantation, the regenerated bone site was available for tooth movement. OTM per se is regarded as a stimulation for bone regeneration. In a study by Cabbar et al., ³⁸ the neighboring teeth were orthodontically moved into the edentulous space, and the tooth roots that were moved across the alveolar bone served to induce significant osteogenesis, as mirrored in the clinical scenario that the extrusion of residual roots contributes to alveolar bone regeneration, which might account for the function of periodontal tissue during the tooth movement. Moreover, there is a notion that synthetic molecular signaling pathway explicates the transduction of mechanical stresses to biochemical events that evoke bone resorption and/or apposition. In this regard, the time course for tooth movement subsequent to bone grafting awaits further investigation.

Another unique type of allogenous bone grafts, demineralized bone matrix (DBM), is manufactured from acid decalcification, but meanwhile preservation of collagen (mainly type I and a minor proportion of types IV and X), noncollagen proteins, variable proportions of osteoinductive growth factors (like BMPs), mineral remnant of calcium phosphate (1–6%), and lesser proportions of cellular debris. ³⁹ DBM and DFDBA are commercial products employing different processing methods, with some differences in mechanical properties and bone induction. As an excellent bone inducer, DBM is superior to DFDBA in terms of bone induction capacity. DBM is promising for its provision of a scaffold for cell multiplication and osteogenesis after the demineralization disposal. ⁴⁰ The preparation method also predisposes the content of growth factors, and is indispensable to osteoinductive property of DBM. Similar to the autogenous graft, the incorporation of DBM with the host can also be triggered by growth factors for endochondral ossification cascade and culmination in osteogenesis at the site of implantation. ⁴¹ Currently, the most preferable product of DBM is a moldable bone paste or putty, readily available for consistent and constant filling in defect sites.

DBM has been surgically applied to alveolus clefts. ⁴² Unlike bone defects from dental exfoliation or extraction, the alveolar cleft is a defect in the bone due to the failure of premaxilla to fuse with the maxilla. The presence of the cleft severely hampers the teeth to move into the site of the cleft, especially for canine eruption or traction in the cleft area. Alveolar cleft reconstruction conventionally involved autologous iliac crest bone grafting (ICBG), whereas the high incidences of postoperative complications and pain in donor site as well as the prolonged hospitalization have invited the necessity for bone graft substitutes. Hammoudeh et al. ⁴³ studied a total of 501 cases of alveolar cleft to compare the effects of ICBG with DBM in line with recombinant human bone morphogenetic protein (rhBMP)-2 on alveolar cleft reconstruction, revealing comparable success rate of canine eruption (a type of tooth movement) in the cleft area irrespective of bone graft selection. Another retrospective study of 228 cases of DBM/rhBMP-2 versus 242 cases of iliac crest bone graft by Liang et al. ⁴⁴ confirmed insignificance in canine eruption, also indicative of the incapacity of DBM to prevent canine eruption and OTM. Table 3 highlights the study characteristics of using allografts for bone defects augmentation and tooth movement.

Despite the noteworthy advantages of allograft substitutes, that is, avoidance of secondary surgery for graft harvest, reduction of donor-site morbidities, provision of prompt structural support, etc., there are disadvantages such as immunogenic reactions, disease transmission, retarded incorporation at the host site, as well as divergence in structural integrity and mechanical strength due to varied techniques of allograft preparation.

Xenografts

Xenografts are bone grafts derived from the species other than human, such as bovine. ⁴⁵ The properties of xenografts are dependent on the origin, constitution, and processing techniques. The heat-drying process of xenografts, in particular, can be applicable to a variety of thermal treatments, ranging from room temperature, mid-high temperature between 250°C and 600°C, or ultrahigh temperature from 900°C to 1200°C. The crystals of calcium phosphate in the xenograft, when treated at a high temperature, tend to exhibit a greater crystallinity, hence the slow resorption. Conversely, xenografts processed at a low temperature have a minor calcium-to-phosphate (Ca/P) ratio in contrast to xenografts prepared at high temperatures. ⁴⁶ In parallel, a xenograft processed at a lower temperature reportedly demonstrates quicker resorption versus a xenograft processed at a higher temperature owing to greater crystallinity and density, ⁴⁷ which might be of importance in the evaluation and selection of xenografts for a given clinical indication.

Bio-Oss (Geistlich), the most prevalent commercialized xenograft in the field of stomatology, is a product with all proteins in bovine cortical or cancellous bone eliminated to create a mineral matrix under low temperature.^48,49 With respect to structural characterization, Bio-Oss comprises hydroxyapatite (HA) crystals with high porosity and provides ample surface area, which confers high compatibility and good mechanical stability for the migration and adhesion of osteogenic cells. All these characteristics seem to make Bio-Oss a perfect candidate for bone reconstruction. Despite the relatively low temperature (300°C to 500°C) of heat drying, the degradation of Bio-Oss still requires a long process. Araújo and Lindhe ⁵⁰ designed a series of experiments in the dog to evaluate the alterations of dimensional ridge after tooth extraction and effects of implantation of the Bio-Oss in site immediately after extraction. The results showed that the dimensions of the walls of the grafted sockets as well as the profile of the edentulous ridges remained intact, whereas marked resorption occurred in the nongrafted sites 3 months thereafter.^51–53 However, solid tissues with a large quantity of Bio-Oss particles developed in the graft marginal sites, surrounded by immature woven bone.

In theory, the slow degradation process of Bio-Oss would hinder the dental movement through the augmented alveolar ridge. Intriguingly, Araújo et al. ⁵⁴ noted that the augmented bone region did not obstruct the OTM, nor did the grafts aggravate the root resorption versus the control group. Nonetheless, there is a paucity of evidence with respect to the use of Bio-Oss alone in alveolar ridge augmentation related to dental movement. Bio-Oss was usually reported in combination with other bone materials in bone regeneration. ⁵⁵ Ahn et al. ⁵⁶ described the alveolar osteotomy of bone defects, which was filled with Bio-Oss and OrthoBlast II (DBM) (1:1 ratio), followed by OTM at different time points. The results revealed that OTM performed immediately after bone grafting yielded the highest tooth movement rate, which was similar to OTM performed 2 weeks after alveolar osteotomy alone. However, the grafted group showed more OTM than did the nongrafted group during the earlier stages. Moreover, with respect to the quality of formed bone, the grafted groups showed greater bone mineral density and the percentile bone volume than did the nongrafted groups at each time point. Despite the evident root absorption in the groups with bone grafts, there was insignificant difference when compared with nongrafted group.

Beyond Bio-Oss, Gen-Tech has been reported in OTM-related alveolar ridge augmentation. Gen-Tech (Baumer, Brazil) is a commercial product comprising inorganic cancellous bovine bone, organic bovine cortical bone matrix, bovine BMPs combined with absorbable ultrathin-powdered HA, and bone collagen agglutinant. ⁵⁷ The element of BMPs in Gen-Tech confers a high osteoinductive capacity. Oltramari et al. ⁵⁸ described experimental jaw defects in 12-month-old minipigs, which were treated with the Gen-Tech xenogenic graft. Three months later, the teeth were moved into the grafted defects. The evaluation of root resorption, alveolar bone height, and volume density of newly formed bone showed that teeth could be bodily moved into the grafted defects with a small amount of root resorption. Further analysis demonstrated that contrary to Bio-Oss, the Gen-Tech xenogenic graft ended with nearly complete substitution by structured bone tissue. The authors ascribed this distinction to the compositional dissimilarity between Bio-Oss and Gen-Tech, with the former exclusively composed of inorganic bovine bone, whereas Gen-Tech comprising demineralized bovine bone, readily resorbable to the organism. Table 4 highlights the characterization of xenografts for bone defects augmentation and tooth movement.

In conclusion, xenograft bone represents unlimited material availability with respect to material supply across species. However, nonhuman origins also result in more pronounced immunological issues than allografts when transplanted in a human host. Patients may be panicked regarding “mad cow disease” or bovine spongiform encephalitis (BSE), a condition known to be caused by a protein termed prion. ⁵⁹

Nevertheless, the risk of BSE transmission is negligible since the organic components in the bone have been depleted. Despite the null report of BSE cases in humans to date, researchers have shown concern about the long-term effects and the risk of transmission of unheard-of pathogenic proteins. ⁶⁰

Another disadvantage of the xenografts rests on their inability of osteoinduction and osteogenesis due to the processing techniques. Although some proteins such as rhBMP-2 are available to combine with xenograft to potentiate the osteoinduction and osteogenesis of grafts, the long-term safety is still a puzzle. rhBMP-2 is a member of the transforming growth factor-β superfamily of proteins, and is a robust inducer of osteogenesis and chondrogenesis. ⁶¹ At present, rhBMP-2 has been approved by the Food and Drug Administration (FDA) of United States as a bone graft substitute for maxillary sinus augmentation, tibial nonunion, and spinal fusion. ⁶² Despite the final Open Data Access Project finding that rhBMP-2 slightly increased the risk of cancer if in combination with bone morphogenetic protein, it is notable that “the absolute risk remains very small and therefore most likely clinically insignificant.” ⁶³ By and large, it will challenge clinicians to place the “slight increased risk” of cancer in patients.

Synthetic Bone Grafts

As discussed, various drawbacks of natural bone grafts motivated researchers to create new synthetic substitute materials. Currently, the most popular synthetic bone substitutes available include calcium phosphate ceramics (CaP ceramics), calcium sulfate, calcium phosphate cements, bioactive glass, or compounds thereof.

Synthetic bone graft materials notably CaP ceramics, including HA and β-tricalcium phosphate (β-TCP), are predominantly employed. Their compositional similarity in chemistry confers to the identical property in calcified bone matrix, and all these products share the mechanism in osteoconductive regeneration. ⁶⁴ The manufacture technique for these synthetic mineral salts involves sintering at high-temperature compaction and high-pressure modeling to rid of water vapor, ⁶⁵ wherein the determinant property of CaP ceramics (absorption rate and mechanical properties) involves Ca/P ratios. In addition, the crystal and porous architecture plays a key role in the quality of CaP ceramics. ⁶⁶

HA is a naturally available mineral form of calcium phosphate, and constitutes ∼50% of the principal storage form of calcium and phosphorus in bone, thus explicating the ideal osteoconductive and osteointegrative properties. ⁶⁷ Moreover, HA shares the initial mechanical characteristics with the cancellous bone: crisp and fragile under stress and shear but resistant to compression. ⁶⁸ However, HA has a relatively great Ca/P ratio and crystallinity, which retards its resorption rate. By contrast, β-TCP has a lower Ca/P ratio (1.5) than that of HA, ⁶⁹ which may facilitate its degradation and absorption. Porous HA cylinders, when implanted in the cancellous bone in rabbits, reportedly resulted in the volume reduction of only 5.4% after 6 months, in contrast to the 85.4% for β-TCP. ⁷⁰ Biphasic calcium phosphate (BCP), another synthesized bone graft material, is a composite of HA and β-TCP. BCP combines the bioactivity of HA with the bioresorbability of β-TCP, and has been successfully applied to the elevation of maxillary sinus floor and augmentation of mandibular bone defects. ⁷¹

Findings from OTM by augmentation with HA in bone defects have been reported,^72–75 as exemplified in cases of successful dental movement into grafted-bone defects, authenticated both clinically and radiologically, with no signs of detectable root resorption. Nevertheless, nanocrystalline HA in 70% of natural bone is essentially 20–80 nm in length and 2–5 nm in width, ⁷⁶ a microsize almost unattainable for commercialized synthetic HA in powders, bulk bodies, and fibers. Such products have macrosized HA and exhibit poor bioresorbability and evident fragility, ⁷⁷ which theoretically impede the efficacy of OTM. In addition, HA has been reportedly related to the inhibition of tooth eruption (another type of tooth movement) through grafted-bone areas.^78–80

Advancement in bionics and hylology has benefited the development of nanophase HA to imitate the structure of naturally occurring HA. NanoBone (Artoss, Inc.) is a unique, cutting-edge, and patented bone grafting material, which incorporates nanocrystalline particles of HA with similar size, composition, and morphology into the natural HA particles in human bone. ⁸¹ NanoBone is a granular material with nanocrystalline HA embedded in a porous silica gel matrix. The porosities in silica gel, ranging from 15 to 25 nm, enhance the material porosity up to 60%. Moreover, the silica gel stimulates the formation of collagen and bone.^82,83 Contrary to conventional HA ceramic materials, which are hardly degradable, NanoBone is fully biodegradable. NanoBone biodegradation is deemed to be similar to the natural bone remodeling process. ⁸⁴

Reichert et al.^85,86 performed a series of prospective controlled clinical trials to investigate the effect of NanoBone in augmentation of the extraction socket. With the employment of split-mouth technique, NanoBone was implanted in the side with extraction of premolars in the patients. The primary outcome of a 6-week period of wound healing confirmed the completion of space closure under the defined biomechanical conditions. Of note, the degree of gingival invaginations in the extraction sites served as a pivotal parameter in the evaluation of the OTM-related graft bone regeneration. Gingival invagination into the extraction site means poor bone regeneration and difficult closure of the dental space. Consequently, the mean degree of gingival invaginations on the intervention sides was significantly lower compared with the controls. Two other studies^72,73 of this material unanimously reported the absence of negative effects on the OTM-related augmentation of bone defects.

In contrast to HA, β-TCP has been fascinating to restore alveolar ridge defects for OTM, owing to its capacity of quicker degradation and absorption. Furthermore, the highly interconnected porous architecture of β-TCP promotes fibrovascular invasion and bony replacement while mitigating mechanical stress. ⁸⁷ β-TCP has been evidenced as promising in accumulating research of OTM-related augmentation of bone defects.

More recently, Machibya et al. ⁸⁸ compared the effects of Bio-Oss and β-TCP in bone regeneration and the timing of OTM through grafted alveolar bone defects. Their findings indicated delayed OTM rate in the Bio-Oss group versus β-TCP group and nongrafted group. Paradoxically, subsequent to β-TCP grafting, the OTM rate in late tooth movement (2-month healing duration) group was accelerated, and exceeded that in the early tooth movement (1-month healing time) group. Furthermore, comparison with the β-TCP and nongrafted groups revealed higher alveolar bone level and bone density in the Bio-Oss group, which might account for the retarded tooth movement. Also, the difference in the resorption rates between β-TCP and Bio-Oss may count.

However, no further information could be inferred from the report as to the causation for the faster tooth movement rate in the group of initially late tooth movement with β-TCP graft, which was however expounded by another study. ⁸⁹ The tooth movement should be initialed when the graft has been well degraded, for the presence of undegraded grafts inside the defects may hamper the movement of teeth into this area. In addition, there would be no concern for any detrimental effect of the root on the moved teeth with the utility of well-degraded graft. With regard to β-TCP, radiographic study reveals that the majority of the grafted materials is absorbed at 4 weeks after implantation, with marked osteogenesis at 8 weeks in the tissue-engineered bone group, justifying the commencement of the OTM at 4 weeks after implantation. Another point in this study rested on the recruitment of human bone marrow stromal cells (hMSCs). The tissue-engineered hMSCs/β-TCP complex drastically promoted osteogenesis and mineralization, and yielded a favorable alveolar height in contrast to β-TCP alone, which was unduly overabsorbed. The selection of hMSCs as the cell source is grounded for the simplicity in isolation from bone marrow aspirated from iliac crest and cell passage, ensuring the mass grafting and transplantation. More importantly, hMSCs are highly capable of promoting osteogenesis, which confers good cell candidature in tissue engineering.

Recently, the synthetic bone grafts (BCP) comprising a composite of HA and β-TCP have been popular in bone augmentation in OTM, ⁹⁰ notably BoneCeramic (Straumann), which consists of 60% HA and 40% β-TCP. Once grafted, β-TCP allows for rapid resorption and complete substitution by regenerative bone, coupled with the slow resorption of HA, which provides ideal matrix scaffold for ingrowth of neovasculature and attachment of osteoblasts. ⁹¹ Ru et al. ⁹⁰ studied the effects of BoneCeramic and Bio-Oss in alveolar defects augmentation and OTM. The findings showed that the degree of dental movement was higher in the Bio-Oss group than in the BoneCeramic group, whereas the trabecular number and thickness of the new bone in the BoneCeramic group were greater than those in the Bio-Oss group, which accounted for the lower degree of OTM in the BoneCeramic group.

In given clinical situations, retardment of dental movement by bone graft materials is beneficial, owing to the prevention of adjacent teeth from drifting into the site reserved for the implant. The authors concluded that the designation of either graft Bio-Oss or BoneCeramic rested on size of the alveolar ridge defect, as well as the OTM regimen designed. In the event of the duration of extraction space closure within 6 months, Bio-Oss can be grafted in site with no influence on OTM. Otherwise, with respect to the site closure of over 6 months, BoneCeramic should be employed instead. Nonetheless, a more recent case report ⁹² confirmed the opposing result of BCP in OTM in a 13-year-old patient with skeletal Class II undergoing tooth extraction, in which BCP acted as an obstacle for space closure in the case of unilateral BCP grafting and contralateral healing per se, leaving a residual alveolar space of 3 mm unclosed on the grafted side 3 years after OTM whatsoever.

As a class of synthetic silicate-based ceramics, bioglass has also been reported in alveolar augmentation before OTM.^93–95 Bioglass possesses a potent physical affinity with host bone on implantation, and this affinity is attributable to the leaching and accumulation of silicon ions by the exposure to body fluids upon implantation, and the consequent HA coating on the bioglass surface. ⁹⁶ In addition, the porosity and relatively rapid resorption rate of bioglass in the initial fortnight of implantation facilitate the neovascular ingrowth subsequent to osteogenesis and precipitation. Attia et al.^93,94 reported that the combination of bioglass grafting with OTM enhanced the process of osteogenesis on the bench with animal study and at the clinic. Furthermore, immediate application of OTM for the defects yielded superior results to the delayed tooth movement group. Table 5 highlights the study characteristics of using synthetic bone grafts for bone defects augmentation and tooth movement.

Prospects

Despite the distinction and diversity of bone substitutes, tissue responses to graft implant are almost identical; that is, the procedures ranging from hematoma formation surrounding the graft, graft necrosis, followed by inflammation and formation of a fibrovascular stroma, angiogenesis in the graft and infiltration by osteogenic precursor cells, and ultimately, osteogenesis and bone resorption. The whole process involves active participation of ECs, immune cells, osteoblasts, osteoclasts, osteocytes, and their precursors. The inflammatory reaction evokes a series of biological responses, which result in the restoration of bone tissue homeostasis. Osteogenesis also requires appropriate vascularization, thereby rendering nutrients, oxygen, osteoclastogenic and osteogenic precursor cells, and discharging waste materials.

Clinically, the ideal bone-substitute materials should represent the property of less inflammation, efficient vascularization, and osteogeneration. The biomaterials qualified for immune responses should undergo determination of the biophysical properties; that is, composition, durability, topography, porosity, and geometry. The vascularization and osteogeneration depend upon the cell viability in biomaterials. Encouragingly, remarkable biological advancement in endogenous regenerative technology in cell homing has been achieved both on the bench and bedside. Endogenous cell populations can be activated and recruited toward the locus of injury. Hence, a biomaterial that could enhance the cell homing and govern the cell destiny is becoming more promising.

Conclusion