Advanced biomaterials for repairing and reconstruction of mandibular defects

Materials Science & Engineering C 103 (2019) 109858

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Review

Advanced biomaterials for repairing and reconstruction of mandibular defects

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Qiang Zhanga,b,1, Wei Wuc,1, Chunyu Qianb, Wanshu Xiaob, Huajun Zhub, Jun Guoa, ⁎ ⁎ Zhibing Menga, Jinyue Zhua, Zili Geb, , Wenguo Cuid, a Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, 368 Hanjiang Middle Road, Yangzhou, Jiangsu 225000, PR China b Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Soochow University, Soochow University, 188 Shizi St, Suzhou, Jiangsu 215006, PR China c Department of General Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, 368 Hanjiang Middle Road, Yangzhou, Jiangsu 225000, PR China d Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, PR China

A R T I C LE I N FO

A B S T R A C T

Keywords: Mandibular defects Biomaterials Bone materials Post-reconstruction Drug-loaded bioscaffolds

Mandibles are the largest and strongest bone in the human face and are often severely compromised by mandibular defects, compromising the quality of life of patients. Mandibular defects may result from trauma, inflammatory disease and benign or malignant tumours. The reconstruction of mandibular defect has been a research hotspot in oral and maxillofacial surgery. Although the principles and techniques of mandibular reconstruction have made great progress in recent years, the development of biomedical materials is still facing technical bottleneck, and new materials directly affect technological breakthroughs in this field. This paper reviews the current status of research and application of various biomaterials in mandibular defects and systematically elaborates different allogeneic biomaterial-based approaches. It is expected that various biomaterials, in combination with new technologies such as digital navigation and 3D printing, could be tuned to build new types of scaffold with more precise structure and components, addressing needs of surgery and post-reconstruction. With the illustration and systematization of different solutions, aims to inspire the development of reconstruction biomaterials.

1. Introduction The mandible is a bone scaffold that forms the lower 1/3 of the face. It is not only related to the maintenance of facial contour and shape, but also closely related to the patient's chewing, articulation and speech. Injury, tumor, infection, functional atrophy, congenital disease, periodontitis, and iatrogenic injuries (such as excessive osteotomy in the mandible hypertrophy plastic surgery) can result in the loss of bone tissue in the oral cavity, affecting the patient's facial appearance to varying degrees and the corresponding oral function [1]. These will inevitably bring a heavy psychological burden to patients and trauma, many patients can be characterized by pain, inferiority, eccentricity, etc. Most of these patients are more sensitive to feelings of beauty, intense, and the feelings is very fragile, can appear even pessimistic thoughts of suicide [2]. How to repair the defects better has always been the research direction, the reconstruction of the mandible defects

has been a constant concern [3,4]. Searching for the ideal method to repair bone defect has been the subject of long-term efforts of related disciplines. The traditional autologous bone graft is the gold standard for bone graft [5]. However, shortage of sources and donor complications (such as chronic pain and hypofunction) limit their application and are prone to secondary bone resorption [6,7]. Nowadays, allograft and xenogeneic are commonly used in clinical practice. In order to reduce the inducement of severe immune rejection of the host, the allogeneic bone is often treated with freezing, freezedrying, decalcification or other chemical treatments, and its cell components are mostly necrotic. Therefore, the allogeneic has certain differences from the autograft in the aspects of osteogenesis, manifestation in the healing process and immune response [8,9]. An ideal bone-graft substitute should be: osteoconductive, osteoinductive, biocompatible, bioresorbable, structurally similar to bone, easy to use, and cost-effective. At the same time, it can form bone bonding interface early with

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Corresponding authors. E-mail addresses: [email protected] (Z. Ge), [email protected] (W. Cui). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.msec.2019.109858 Received 15 February 2019; Received in revised form 26 May 2019; Accepted 2 June 2019 Available online 05 June 2019 0928-4931/ © 2019 Published by Elsevier B.V.

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Fig. 1. Schematic of biomaterial for repairing and reconstruction of mandibular defect by 3D printing.

bone tissue, and decompose in time, and finally be completely replaced by autologous bone tissue [10,11]. In recent years, with the rapid development of biological materials and the need of modern regenerative medicine, the research of bone substitute biomaterials which have been applied to the mandibular defects are becoming more and more concerned by scholars (Fig. 1). Biomaterials include three types: metal materials (such as titanium and its alloys), inorganic materials (such as bioactive ceramics, hydroxyapatite, etc.) and organic materials. Biomaterials not only have or complete certain biological functions, but also have good biocompatibility. However, there are many kinds of biomaterials applied in mandible defects and the properties can be varied. Therefore, this review focuses on the development of biomaterials in this field, evaluating their advantages and disadvantages, in order to look towards the future development of mandibular substitute biomaterials.

3. Materials from animal and human 3.1. Allograft materials Allograft refers to the transplantation of tissue taken from one animal to another animal of the same species [23]. There are mainly three forms of allograft in clinical practice: fresh or fresh frozen bone, freezedried allograft (FDBA), and demineralized freeze-dried allograft (DFDBA), which are primarily derived from the cadaver. Compared with autologous transplantation, allotransplantation reduced the deficiency of donor restriction and complications. However, allograft has potential antigenic reactions, the risk of disease transmission, poor osteogenic properties, unstable bone induction, limited supply, and their biological and mechanical properties can be altered by processing and preparation, while limiting their widespread use in some areas due to religious beliefs and costs [24–27]. Due to the mandible defects repair with allograft, surgical operation is simplified with autologous bone graft, avoiding the further operation, and so far, more and more surgical physicians have been concerned and clinically used. Allograft is a kind of bone substitute material that is widely used in clinical practice. However, due to its slow process of “creeping substitution”, the effect of its individual application is still far from clinical requirements. At present, the theory is that, allogeneic bone composite immunosuppressants, autologous stem cells and bone morphogenetic protein (BMP) can reduce the incidence of complications after the transplantation, but its mechanisms of the cellular and molecular level are not clear.

2. Mandibular defects classification Different parts and areas of the mandible defect have different effects on the morphology and function of the maxillofacial. The difficulty and prognosis of reconstruction and repair are also different. Therefore, the systematic classification of the mandible defect is conducive to the assessment of the patient's condition and better guidance for the repair of the mandible defect. Since Pavlov [12] proposed the first classification method for mandible defects in 1974, domestic and foreign scholars have proposed more than 10 classification methods, mainly including descriptive classification and reconstructive classification. The descriptive classification is mainly on the basis of some mandible anatomical structures, which are classified according to the structure or range of defect involvement, including David classification, Urken classification, Hashikawa classification, etc. Reconstruction oriented classification is not a simple description of the defect parts, but to guide clinical work (as shown in Fig. 2), for the purpose of on defect caused by the lack of form and function and the difficulty of the reconstruction, including Jewer classification [13], Iizuka classification [14], Urken classification [15], David classification [16], Hashikawa classification [17] and Brown classification, etc. (Table 1) [18–20]. These methods have their own advantages, but also have a certain degree of limitation, there is no ideal classification method that can meet the above requirements. How to propose an accurate, practical and concise classification of mandible defects remains to be further explored by scholars.

3.2. Xenogeneic bone materials Xenograft refers to the transfer of tissues taken from one animal and transplanted to another of a different species such as bovine, porcine, and ostrich bone which can be freeze-dried, demineralized, and deproteinized or decellularized, then used to repair bone defects [28]. Despite xenograft with availability, good physical properties and low cost, but its besides having all the shortcomings of allogeneic bone, also passing the spread risks of carrying a zoonotic diseases such as BSE (bovine spongiform encephalopathy) or PERV (porcine endogenous retrovirus), and the rejection response of grafts is stronger than the allograft [25,29]. In addition, some researchers suggest that after months of transplanting frozen allografts, one of the components, called proteoglycans, breaks down in large quantities, causing the vessels to regenerate slowly, and the new bone slows down, and even forms a loose bone. The long-term effects of inducing and generating new bone vitality are uncertain [30]. However, other scholars have proposed that the disadvantages of xenograft can be remedied by the combination of allograft and autologous bone marrow, and the osteogenesis effect is 2

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Fig. 2. New classification system based on the four corners of the mandible. (A). Dimensions (mm) of an average adult mandible: Diagrammatic representation of a scaled model to show the dimensions of an average adult mandible as reported by Ongkosuwito and colleagues [21]. The four corners of the mandible are shaded to draw attention to the increasing size and complexity of the defect from class I (one corner) to class IV (three or more corners). (B). Proposed classification of mandibular defects. (C). Postoperative orthopantomograms for class I-III mandibular defects. (D). Example of class IV reconstruction after ablation for ameloblastoma [22]. (with permission from Elsevier, copyright 2016.)

4. Artificial biomaterials

greatly enhanced after transplantation. They even suggest that spongiform xenograft may provide a suitable culture medium for osteogenesis of bone marrow cell [31]. The author thinks that there are many deficiencies in bone allografts at present, and they are not perfect bone substitute materials, such as immune rejection, infection, bone resorption, bone nonunion, etc. It is believed that using the principles of tissue engineering and the method of compound transplantation to activate the allogeneic bone is the development direction of the research and application of allogeneic bone transplantation in the future.

4.1. Metal materials There are several metallic materials commonly used for mandibular defect implantation include 316L stainless steel (ASTM F138), co-based alloys (primarily ASTM F75 and ASTM F799) and titanium alloys [32]. The reconstruction plate was originally made of stainless steel, and according to Luhr, Hansmann may be the first surgeon to apply plates and screws to a mandible fracture in 1886 [33]. Metal materials have remarkable elastic modulus, mechanical strength, and sufficient

Table 1 Classifications of the mandibular segmental bone defects by different scholars. Scholars

Classification

Jewer et al. [13]

H = unilateral condyle but can cross midline; L = unilateral no condyle but can cross midline; C = both canines; HC = lateral and condyle including both canines; LC = lateral and both canines; LCL = bilateral lateral defects including canines but not condyles; HCL = condyle lateral, central, and control ateral lateral, HCH = entire mandible. Class I–IV based on the number of osteotomies of the fibula flap C = condyle, R = ramus, B = body, S = symphysis, SH = stops at the midline A = lateral; B = unilateral angle to symphysis; C = angle and body of other side; D = angle to angle; E = symphysis; F = hemimandible including condyle C = loss of condylar head; A = loss of angle, T = loss of mental tubercle; CAT = hemimandible. Based on the four corners of the mandible: Class I (angle); Class Ic (angle and condyle); Class II (angle and canine); Class IIc (angle, canine, and condyle); Class III (both canines); Class IV (both canines and at least one angle); Class IVc (both canines and at least one condyle)

Iizuka et al. [14] Urken et al. [15] David et al. [16] Hashikawa et al. [17] Brown et al. [18–20]

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release of magnesium ions in magnesium and its alloy materials is high, and there is a risk of overdose poisoning [45]. In addition, magnesium (Mg) alloy of the present study focuses on the degradation and mechanical stability. In order to confirm whether Mg and its alloy can promote the repair of the mandible defect area, Guo et al. applied magnesium and calcium alloy to repair the mandible of dogs and found that magnesium and calcium alloy can maintain a large osteogenic space and accelerate the formation of new bone, but did not achieve the amount of bone needed for the repair of the defect area [46]. Wang et al. also found that mg-sr alloy has good biocompatibility and osteogenesis, which can promote bone repair in dogs' mandibular defects [47]. Magnesium alloys are characterized by excellent comprehensive mechanical properties, good biocompatibility with human body and biodegradable absorbability. New medical instruments prepared by magnesium alloys have great potential and broad market prospect. At present, there are still many problems to be solved from the materials to the product development, including the regulation of corrosion degradation rate of magnesium and its alloys, mechanical property degradation and the establishment of biocompatibility evaluation standards for degradable metals. As previously stated, so far, there is no perfect metal bone substitute material in clinical practice. Some metals are too weak to be made into porous support materials, or some metals are too hard and will break when they are made into the desired forms. In addition, regardless of the metal material, its performance will change in different degrees during processing. In recent years, porous metal scaffolds such as Tantalum, nickel‑titanium Alloy (Nitinol), etc. and bioactive metal scaffolds such as coated cells and osteogenic active material scaffolds, have attracted more and more attention from researchers, but they are still at experimental stage or lack of long-term clinical data and have not been widely used clinically. In particular, tantalum metal has good three-dimensional configuration and biocompatibility, which can promote the adhesion, proliferation and expression of osteoblast genes. At present, tantalum products have been applied in the field of orthopaedics, which has achieved encouraging results and is expected to become an excellent repair material for mandible defects [32].

condition of biological healing with bone tissue. However, most metal materials have the risk of inflammation, allergic reaction and cancer due to the release of toxic metal ions and/or particles [34]. For example, the release of nickel ions in nickel or nickel titanium alloy has allergic toxicity and even potential carcinogenicity [35]. On the other hand, the clinical application of metallic materials is limited by the fact that their metal properties cannot be made into the desired three-dimensional porous structure, or even the possibility of fracture [36]. Therefore, development of a metal material with good tissue compatibility, bioactivity, stable physical and chemical properties and low cost ease is a major trend in future development. 4.1.1. Non-degradable metal materials At present, the non-degradable metal material for mandible defect is titanium and its alloy, which is widely used in clinic. Titanium is one of the few materials that naturally meet the requirements of human implantation due to its light weight, high strength weight ratio, low toxicity and high corrosion resistance [37]. Titanium plates and screws made of titanium alloy are used in the repair of mandible defects due to their simple methods and can largely restore the patient's chewing function and facial appearance. Based on the size of the defect of the mandible, the titanium plate reconstruction methods include: (1) a single titanium plate reconstruction, (2) non-vascularization (no internal blood supply) titanium plate reconstruction of bone graft, (3) vascularization (blood supply) titanium plate reconstruction of bone graft [38]. Due to its low elastic modulus, the titanium plate can obviously reduce the stress shielding effect in fracture healing. Advances in three-dimensional (3D) technologies have enabled to synchronize Computer-Aided Design/Computer-Aided Manufacture (CAD/CAM) bimaxillary orthognathic surgery and mandibular reconstruction using selective-laser sintered titanium implant [39]. For instance, Sang-Woon Lee et al. used CAD/CAM technology to manufacture individual custom implant derived from titanium powder for rabbit mandibular defect model. Compared with the 5-hole micro-plate without bone graft, the rabbits in the experimental group had a faster recovery of daily food intake and less screw looseness [40]. There had been successful cases reported that the method of computer aided simulation was used to fabricate customized 3D titanium implant for repairing the defect postoperative mandibular tumor resection [41,42]. However, compared with stainless steel, titanium has poor ductility, which makes it difficult to process titanium. At the same time, the tensile strength of titanium contact bone plate in application is also greatly restricted. Some studies have reported various complications associated with the use of titanium plate reconstruction, such as wound cracks in contact with the titanium plate, infection caused by loosening and cracking of screws, the fracture of reconstruction titanium plate and the dissatisfaction with the morphology of the following facial contour [43,44]. The current gold standard for load bearing defect sites for mandible reconstruction remains titanium meshes and titanium 3-D scaffolds. While it is difficult to install dental implants after mandible reconstruction using titanium meshes or titanium 3-D scaffolds. Therefore, the future research direction of titanium and its alloys should be: (1) avoid the use of toxic elements in alloys, such as vanadium; (2) the titanium alloy with higher fatigue strength and lower elastic modulus is studied in order to minimize the stress shielding effect and promote fracture healing; (3) Further modification of overall design would be required for dental implant installation of the customized 3D titanium implant.

4.2. Polymer materials The first successful clinical application of polymer materials goes back over 50 years, with Sir John Charnley using polymethyl methacrylate (PMMA) and acrylic cement to attach femoral head prostheses [48]. Since then, more and more polymer studies have been done, broadening their applications [49]. Polymeric materials used as bone substitute materials, due to their good elasticity, can avoid the stress of the metal and bioceramic implant materials with shading effect (The implant changes or removes the host bone stress, which is easy to cause bone absorption and bone mineral density decrease after surgery) [50]. Polymer materials are usually biocompatible and much easier to make. They can be molded into desired shape and size based on the needs of the physician. By adjusting their mechanical properties and degradation properties, they can be tailored and targeted to implant specific tissue [51], as depicted in Fig. 3. 4.2.1. Non-degradable polymer materials Polymers can be broadly classified on the basis of the reactivity of their chemical backbone (or susceptibility of the backbone to breakdown upon exposure to water, i.e., hydrolysis) as non-degradable and degradable. Non-degradable polymers in biomedical applications include Poly(ethylene) (PE) (HDPE, UHMWPE), Poly(propylene) (PP), Poly(tetrafluroethylene) (PTFE), Poly(methymethacrylate), Ethyleneco-vinylacetate (EVA), PMMA, etc. Compared with degradable polymer materials, non-degradable polymer materials can eliminate the lack of degradation kinetics caused by degradation products in vitro. PTFE and PMMA are widely used in maxillofacial reconstruction surgery. PTFE can be used as a new biomolecule to guide tissue regeneration in the

4.1.2. Degradable metal materials Recently, more attention has been paid to the research of magnesium (Mg) and its alloy as degradable metal materials in bone repair and reconstruction. Magnesium and its alloy are used as implants in the mandible, which not only have the mechanical strength of metal materials, but also can degrade and avoid the removal of implants after the second surgery. However, due to the high solubility of magnesium, the 4

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Fig. 3. 3D bioprinted human-scale mandible and calvarial bone constructs. (a) 3D computeraided design model of mandible bony defect obtained by converting the medical computed tomography scan data. (b) Visualized motion program depicting the required dispensing paths of cell-laden hydrogel (red); a mixture of PCL and tricalcium phosphate (green) as a scaffold; and Pluronic F127 (blue), which is used as a temporary support structure. (c) 3D patterning of cell-laden hydrogel on PCL platform. (d) Macroscopic image of the 3D-printed mandible bone defect construct, grown in osteogenic medium for 28 days. (e) Alizarin red S staining indicates terminal osteogenic induction and mineral deposition in human amniotic fluid-derived stem cell [52]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) (with permission from Springer Nature, copyright 2016.)

glycol) (PEG), poly(vinyl alcohol) (PVA), and polyacrylates such as poly (2-hydroxyethyl methacrylate) (PHEMA) [55,56]. After years of extensive research, we've found that hydrogels have a number of applications: (I) using hydrogels for bone regeneration, including porous scaffolds, bioactive membranes and injectable bone fillers, and (ii) developing model ECM studies for basic bone biology (Fig. 4) [57,58]. Polymer biomaterials are the hotspot of the present study. Combining with the development of tissue engineering, the manufacture of ideal polymer bioscaffolds is still a great challenge. The combination of polymer biomaterials and other materials to improve biological properties is the future research trend, which can provide a new perspective for the development of tissue engineering and regenerative medicine.

defect area [53], PMMA bone cement can be used as a bone substitute in skull reconstruction, and can also be used as a drug carrier for embedding bioactive substances to promote bone healing [54]. However, non-degradable polymer materials have the risk of releasing toxic substances, such as unreacted methylacrylate monomers in material synthesis have toxicity in long-term contact with human body, which limiting their application. Therefore, improving manufacturing process, purifying materials, reducing toxicity and improving histocompatibility can expand the clinical application of non-degradable polymer materials in the future. 4.2.2. Degradable polymer materials Degradable polymer materials include natural polymers and degradable polymers in synthetic materials. Natural polymers include polysaccharides such as chitosan, proteins such as collagen and slik, and polynucleotides such as DNA and RNA. Synthetic polymers, also known as artificial polymers, have a better service life than natural polymers, and can be processed as needed to give different properties. Commonly used biodegradable synthetic polymers in bone tissue reconstruction include poly (lactic acid) (PLA), polycaprolactone (PCL) and polyhydroxybutyrate (PHB) [55]. In recent years, it is relatively novel to use hydrogel for bone repair. As a gel with water as the dispersive medium, some hydrophobic groups are introduced into water-soluble polymers with crosslinking structure to form cross-linking polymers which can expand with water. As a polymer three-dimensional network system, it can maintain a certain shape with soft properties, and can absorb large amounts of water without dissolving. Hydrogels can be fabricated from both natural polymers of agarose, alginate, chitosan, hyaluronic acid, fibrin, collagen and others, as well as synthetic polymers such as poly(ethylene

4.3. Bioceramics Ceramics are inorganic solids that form crystalline structures through sintering (a heat treatment process) of non-metallic salts. In some cases, the surface features become to biocompatible and support bone inwards. So, these ceramic are called bioceramics. Bioceramic materials can be divided into bioinert ceramics (such as Al2O3, ZrO2, etc.) and Bioactive ceramics (such as hydroxyapatite (HA), tricalcium phosphate (TCP), Bioactive glasses, etc.) [7]. Bioactive ceramics are characterized by partial or total absorption and can induce the growth of new bone in organisms. Bioactive ceramics have bone conductibility, and as a scaffold, osteogenesis on its surface; It can also be used as a coating or filling material for bone defects. Therefore, these materials are suitable as bone substitutes [59]. Hydroxyapatite (Ca10(PO4)6(OH)2) (HA) is a bioceramics material. With the development of nanomaterials, nano-HA is similar to the 5

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Fig. 4. (A) 2D cell culture on plastic; (B) 3D cell culture inside hydrogel constructs; (C) bioprinting of 3D constructs; (D) biological maturation of the 3D bioprinted construct forming a tissue analog; and (E) implantation and integration of the tissue analog into the defect site [58]. (with permission from Elsevier, copyright 2016.)

hybrids [66–68]. They can promote cell adhesion, proliferation and differentiation, such as chitosan/hydroxyapatite (CS/HA), collagen/3-D hydroxyapatite (Coll/HA, glutaraldehyde crosslinked), porous nano hydroxyapatite/collagen/alginate (nano–HA/Coll/Alg) and PCL/chitosan/zinc doped composite nano hydroxyapatite (PCL/CS/nano–ZnHA) [69–72]. PCL/HA, P3HB/HA, PLGA/HA and PLGA/β-TCP/HA can enhance bone induction and osteogenesis [73–76]. In the past few years, calcium silicate (CaSiO3; CSi) ceramics have been applied to bone regeneration due to good bone conductivity and bone induction. Their rapid degradation speed and lower strength, however, make them less desirable in bone remediation. Magnesium is the fourth abundant element in bone tissue, which can promote bone formation. Xie et al. found that CSi-mg formed by the doping of diluted Mg and CSi ceramics has better mechanical strength and unexpected high fracture toughness [77]. At the same time, they considered that in CSi, the mechanical parameters of csi-mg10, which formed by the substitution of 10 mol% Ca with Mg were the best [78]. Kaskos et al. found that hydroxyapatite granules combining with autogenous bone marrow (excavated from femur bone) were better than hydroxyapatite or granules alone in promoting new bone formation when filling the mandible defect model of the dog [79]. Another widely used strategy is the combined use of HA and TCP as granules that exhibit interconnected pores, each measuring 100–400 μm [80]. Some other researchers produced calcium sulfate semihydrate from calcium sulfate dihydrate by microwave heating and grinded autogenous bones to generate autogenous bone powder, then they mixed with calcium sulfate and autogenous bone powder to form bone repair materials [81]. Octacalcium phosphate (OCP) has osteoconductive and bone inducible, it is believed to be a direct precursor to hydroxyapatite. This material has higher potential for bone induction and bone conduction than other calcium phosphate derivatives. It can be gradually absorbed and replaced by new bone [82]. Bone matrix gelatin contains type I collagen and high protein content, including bone morphogenetic protein (BMP), which can induce mesenchymal cells to differentiate into osteoblasts at bone defects. The synergism of BMP and most calcium phosphate derivatives has achieved good results in clinical applications [83]. Zhang et al. synthesized BMG/OCP composite by dehydrated thermal crosslinking, which can enhance bone repair in New Zealand rabbits' mandibular defects [84]. Composite biological scaffolds avoid the deficiency of single bone substitute materials. The new materials are formed by optimizing the combination or surface modification and have the ability to stimulate specific reactions in the bone defect area at the molecular level, so they

mineral composition of vertebrate bones and teeth, and in the human bone, the HA is 70% and 5% water and 25% organic matters. HA has good biological activity, biocompatibility and bone conductivity [60], making it an alternative for maxillofacial defect repair [61]. β-tricalcium phosphate is now one of the most common synthetic materials used for bone reconstruction in orthopedic and maxillofacial surgery, β-TCP-Ca3(PO4)2 belongs to the family of tricalcium phosphate in the beta phase. This biomaterial is easier to be absorbed than hydroxyapatite, so it has highly biocompatible when it is implanted to the bone, and it can be used to fill the bone cavity after mandibular sac excision [62]. However, when HA and TCP are applied separately, there are disadvantages such as insufficient biomechanical strength and insufficient biodegradation [49]. Currently, more and more research is focused on the work of HA-TCP composites to improve the mechanical properties and strength of implants. Bioactive glass is a hard solid (non-porous) material consisting of calcium, phosphorous and silica (silicate, main components). By changing the ratio of sodium oxide, calcium oxide and silicon dioxide, various forms can be produced ranging from soluble to non-absorbable. They all have osteointegrative and bone conduction properties. Bioglass ceramics are biocompatible, when the material is implanted in the body, it's non-rejection, inflammatory and tissue necrosis, and can be combine with bone to form osteogenesis, having high binding strength, good interfacial binding ability and fast osteogenesis with bone. However, due to the low strength of bioactive glass, it is easy to break in the process of processing and making. At present, it can only be used for parts of the human body with little stress, such as the repair of small ear bones or bone graft expander [63,64]. Bioactive ceramics as bone substitute materials have good biocompatibility and mechanical compatibility, and have become an important and indispensable part in the modern medicine. In the future, with technological advancements, bioceramics will be improved continuously, which will have great research space and broad development prospects, as shown in Fig. 5.

4.4. Composite materials As mentioned above, in the study of mandibular defect reconstruction, bioceramics, when be used alone, may have poor biological performance, limiting their potential clinical application [61]. The problem can be solved by mixing the synthetics and natural polymers or using composites–improving and enhancing the biological properties of the scaffold to promote bone repair. These products are often called 6

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Fig. 5. Customized 3D bioceramic scaffold for mandible reconstruction. (top) 3D model of the scaffold geometry for the mandible defect; (bottom) Various views of the bioceramic scaffold manufactured by direct writing 3D printing [65]. (with permission from Wiley, copyright 2005.)

increases recovery of preoperative daily feed intake amount in a rabbit model of mandibular continuity defects [87]. In addition, It was postulated that carbon plates are cosmetically and functionally more suitable than titanium plates in clinical applications [88]. However, a disadvantage of the carbon composite is its durability [87]. For this reason, perfect adaptation of carbon plate during the operation could not be achieved in spite of reshaping to the mandibular curvature. This limitation of carbon plate system can be overcome through the material modification or the prefabricated technique using a prototype model.

can generate or enhance the ability of bone healing. The research and application of composite scaffold is the mainstream of bone substitute biomaterials in the future. 4.5. Carbon plate (CP) Over the past 30–40 years, various carbon implant materials have become more interesting. Pyrolytic carbon based materials have already been applied in medicine, including for artificial heart valves, orthopedic joint arthroplasty, and bone implants [85]. Carbon plate is composed of a carbon-fibre-reinforced carbon composite [86]. Carbon plate shows even distribution of stress, decreases screw loosening, and 7

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Fig. 6. (A) Macroscopic evaluation of the bone samples 4 weeks after surgery. a) the control defect, b) the defect was filled by fibrin glue alone, c) the defect was filled by autologous bone graft. (B) Macroscopic evaluation of the bone samples 8 weeks after surgery. a) the control defect, b) the defect was filled by fibrin glue alone, c) the defect was filled by autologous bone graft. Arrows denote the defect area [89]. (The publisher is opened for access).

5. Drug and biological treatment for mandible defects

GFs for a variety of cells and may be candidates for commercially available products such as BMP and PDGF [91]. Both IGF and TGFβhave been found to play key roles in cartilage regeneration and TMJ repair [91]. In conclusion, growth factors are one of the most promising methods to promote the repair of mandibular defects. However, the release and transfer of growth factors as drugs in human body have not been well solved. For example, intravenous injection has adverse reactions, it is even reported that long-term low-dose exposure to VEGF having a tumorigenic risk [93,95]. Therefore, the future research trend is to focus on the development of technologies for accurate delivery of GF to the defect area, such as microfluidic controlled release technology that can regulate the release rate of target drugs.

The ideal repair material for the mandible is not only easy to be manufactured, but also can promote the rapid healing of bone defects. The rapid healing of bone defect and promoting bone regeneration need healing promotive factors. Such as growth factor, stem cell therapy, gene therapy and platelet, they can promote cell migration, proliferation, differentiation and enhance angiogenesis as well (Fig. 6). 5.1. Growth factor Growth factor (GF) is an essential substance found in human to promote cell growth, proliferation and cell differentiation. These factors also play a vital role in tissue engineering and regeneration. GFs is a large group of cytokines which are widely used in the treatment of bone defects, existing in healthy bone matrix, and can be provided by clots or damaged bone itself during different stages of tissue healing; they play an important role in promoting bone regeneration [25]. GFs can have a variety of functions, and different GFs can play a role in the reconstruction of oral and maxillofacial tissue defects, Such as promoting angiogenesis [90], bone morphogenetic protein (BMP) endows bone cells with the ability to differentiate, and fibroblast GF and vascular endothelial GF help to stimulate vascular differentiation [91]. Refractory diseases such as bisphosphonate-related mandible necrosis have also been attempted to treat with BMP [92]. Platelet-derived growth factor (PDGF) has been identified as the “starting point” of wound healing in tissue regeneration, providing good results in soft and hard tissue regeneration, and the original example is the application in alveolar bone defects [93,94]. Insulin-like growth factor (IGFs) and transformed growth factor (TGF-β) have also been found to be effective

5.2. Stem cell therapy Stem cells are defined as pluripotent cells that can renew and maintain their identity for longer periods of time and have the potential to differentiate into specific functional cell or tissue lineages [96]. Currently, the commonly used stem cells are Bone mesenchymal stem cell (BMSCS), Adipose stem cells (ADSCs), and Embryonic stem cell (ESCs). Since cell therapy alone is not enough to regenerate and replace the entire organ in a major tissue defect, the method of combining stem cells with biocompatible scaffolds is currently a hot topic research [96,97]. BMSCs can produce essential cytokines and differentiate into a variety of cell types, such as fat cells, cartilage cells and bone cells, stimulate vascular responses and generate matrix and new bone. Due to its wide source, easy in vitro amplification culture and multi-differentiation potential, it is the most studied seed cells in the reconstruction of mandible defects now [98]. As seed cells, stem cells are widely used 8

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Choukroun PRF combined with autologous micro-morselized bone (autologous) in the treatment of mandibular bone defects, and respectively compared to the groups treated with Choukroun PRF or autologous alone. They found the combined group showed more bone regeneration, more fibrous tissue regeneration, and greater bone maturity than other groups [107]. Azizollah et al. used autologous plasma to extract fibrinogen and thrombin, and then mixed them into gelatinous fibrin glue to fill the defects of the mandible. The experiment proved that fibrin glue as a non-invasive biological material could promote the bone repair in the defect area [89]. In a similar study in 2014, Backly et al. proved that PRP can enhance osteoconductivity of HA and β-TCP composite [108]. Platelet concentrate has many advantages, and applications are promising. Now, although it has been gradually applied to the repair of the soft tissue defect of the maxillofacial tissue, the molecular level of its effects has not been sufficiently advanced, and it has yet to be tested for the time that it's metabolized in the body, and it has to be observed for the long-term effects of the osteogenesis. It is necessary to continue to study and enrich that result of basic research and clinical trial to make the platelet concentrate play a more important role.

in bone tissue engineering, but most of the current research is limited to making various stem cells differentiate into bone under ideal experimental conditions. Whether such osteogenesis can meet the standards of clinical trials needs further examination. In the future, we still need to explore more suitable seed cells for bone tissue engineering by improving the culture method of existing stem cells that can differentiate into bone or find new stem cells. How to reduce the immune rejection of allogeneic stem cell and find a more appropriate seed cells for bone tissue engineering, still we need to solve. 5.3. Gene therapy Another promising approach to bone repair is the use of gene therapy. Gene therapy involves the transfer of genetic information into the genome of target cells, enabling the long expression of bioactive factors from the cells themselves to promote bone regeneration and reduce systemic side effects [5,99]. As mentioned above, many growth factors can regulate bone growth and absorption and thus become candidate genes for gene therapy [25]. The specific operation is to transfer the candidate gene with osteogenic effect into the target cell, transcription from the target cell into mRNA and translating into osteogenic proteins, and then promoting the osteogenic repair of the bone defect by the sustained self-secretion of the target cell. Additionally, in bone reconstruction studies, monoclonal antibody therapies that stimulate osteoblast activity are increasingly attracting attention. AntiSclerostin antibody (Scl-Ab) is a promising new bone anabolic therapy. Scl-ab can bind and inhibit sclerosing proteins (glycoproteins expressed by bone embedded cells, effective inhibitors of the osteogenic Wnt pathway), thus promoting bone anabolism. Tamplen et al. injected sclab intravenously into a down's syndrome-dependent mouse bone defect model, and found that the quality of the mandible and the height of the alveolar bone were significantly increased [100]. Gene therapy is an emerging therapeutic approach with innovative value in the past decade, which can flexibly express the active protein in targeted organs or tissues according to the need of treatment and reduce the amounts of therapeutic molecules [101]. However, there are still some limitations in gene therapy now. For example, there are technical difficulties in how to correctly transfer exogenous genes to target cells and how to correctly locate target genes to target cells. It is hoped that we can improve the way of gene transfer and rationally regulate transgenic genes through deep research on the basic knowledge of oral and maxillofacial molecules structure in the future. The appropriate expression of the transferred genes needs to be further studied to avoid adverse results, such as hyperplasia and malignant transformation.

6. Biomaterials combination with drugs 6.1. Bioscaffolds loaded with drugs So far, most experiments have proved that bioactive substances can promote bone growth and bone regeneration, such as growth factors, stem cells and platelets. However, there are still many defects in the use of these substances alone. Due to growth factor in vivo instability, stem cell immune rejection, it is not possible to use one of the healing promotive factors alone to replace the larger tissue overall through regeneration [101,109]. Cell/Active materials– based bone tissue engineering strategies are thought to be an attractive option to improve bone repair [110]. For the regeneration of the mandible, the study of new biomaterials is focused on the manufacture of encapsulated drugs (active substances), 3D micro−/nano-scale structures of cells or functional scaffolds, and has made certain progress [111]. Researchers believe that the release of active substances must match the rate of tissue healing and regeneration [112,113]. The best delivery system can be achieved by binding active molecules to the scaffolds. The sustained release of active substances (such as growth factors) in scaffolds can promote cell proliferation and differentiation, thus accelerating tissue healing and regeneration [114]. Aval et al. found that the combination of octagon phosphate (OCP) and bone matrix gelatin (BMG) could be a good biomaterial for the treatment of mandible defects in rats [115]. Fan et al. aimed to determine the effects of adipocyte stem cells (ASCs) and bone morphogenetic protein-2 (bmp-2) in 3D scaffolds on mandible repair in a small animal model. Noggin expression levels in ASCs were down-regulated by a lentiviral shRNA strategy to enhance ASC osteogenesis (ASCsNog-). Chitosan (CH) and chondroitin sulfate (CS), natural polysaccharides, were fabricated into 3D porous scaffolds, which were further modified with apatite coatings for enhanced cellular responses and efficient delivery of BMP-2. In the experiment, they found that ASCsNog- + BMP-2 in 3D scaffold microenvironment can significantly promote mandible regeneration [116]. Klein et al. found that sialoprotein (BSP)-coated (3D-plotted calcium phosphate cement) CPCs can enhance the activity of human primary osteoblasts in vitro [117]. Cai et al. used nano-hydroxyapatite (nHAP) and collagen (COL) to form nHAP/COL composite, and then laden basic fibroblast growth factor (bFGF), which was modified to form new bFGF/nHAP/COL biological material, and implanted into the rabbit model of mandibular defect. The sustained release of bFGF was utilized to promote osteogenesis in the defect area [118]. FG is a biocompatible material that could be employed as a delivery vehicle for controlled release of VEGF protein single or dual release. Hamid et al. used FG to combine with a porous biphasic calcium phosphate (BCP) to form a composite material and

5.4. Platelet In recent years, platelet concentrate (PC) has been identified as a satisfactory bioactive material, and the importance of these bioactive materials in stimulating the healing process has been demonstrated in some clinical studies, providing good expectations for clinical applications in the future [102]. PC can be used as autologous sources of growth factors and healing cytokine biomolecules, such as platelet rich plasma, aplastic plasma and platelet-rich fibrin (PRF), playing a key role in promoting hemostasis and wound healing [103]. The regenerative capacity of platelet concentrate (PC) is formed by containing various growth factors (GF), which can stimulate the proliferation and differentiation of bone host cells in host bone and graft materials [104]. It is currently considered that Choukroun PRF is the new generation platelet concentrate from platelet-enriched platelets [105]. It has been demonstrated that Choukroun PRF can successfully stimulate the proliferation and migration of canine pulp cells at appropriate concentrations. Clinical studies have shown that Choukroun PRF can be used for bone tissue regeneration, which has a good effect on bone healing and reattachment of bone to surrounding tissue [106]. Zhou et al. used 9

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mandibular defect. They found that hydroxyapatite (HAp) nanobelt surface can speed up the repair and regeneration of bone defect, and PLA surface can prevent postoperative adhesion between bone defect and soft tissue around [128]. Imamura K etc. used OsseoGuard, a kind of crosslinked bovine type I collagen to make collagen membranes (CMs), and then with fibroblast growth factor18 (FGF-18) reorganization, forming unique drug delivery system to improve the activity of osteoblasts [129]. S Saska etc. used bacterial cellulose (BC), collagen (COL) and OGP (10–14) peptide to synthesize BC-COL OGP(10–14) membranes, they found these biopolymer-based membranes can promote bone regeneration [130]. A series of studies have shown that with the continuous progress of tissue engineering technology, complex biomembranes will receive more and more attention and research, and their unique chemical synthesis, tissue structure and component load will greatly improve their functions, thus becoming an effective method to treat bone defects. However, biomembranes mainly have good repairing effect on a small mandibular defect or bone resorption, and cannot be applied to a massive mandibular defect repair currently.

loaded dental stem cells, then they found the release of VEGF protein can lead to the expression of BMP-2 gene and angiogenesis VEGF gene in the dental stem cells. They believed this method can improve osteogenesis and angiogenesis processes of reconstruction critical-sized bone defects [119]. Combined with collagen sponge, bmp-2 and bmp-7 can be used for reconstruction of mandibular defect, augmentation of maxillary sinus and filling of alveolar cleft [120]. Wang et al. incorporated insulin-loaded poly lactic-co-glycolic-acid (PLGA) nanoparticles into nanoscale hydroxyapatite/collagen (nHAC) scaffolds and studied the biological activity of the composite scaffolds in vitro and in vivo. It was found that the bioactive insulin could be successfully released from the nanoparticles in the scaffolds, and the release kinetics of insulin could be effectively controlled by homogeneous nanoparticles. The composite scaffolds can enhance bone tissue regeneration [111]. The structure-functional model of bone has shown that its mechanical properties depend on nano-scale minerals occupying specific locations in the collagen matrix. Baskin et al. made the mineralization of cattle dermal collagen fibers into nano-bone substitute materials. After crosslinking, BMP-2 was loaded. Then the biomaterial was used for the repair of mouse mandible defects. It was found that the material had good biological properties and could promote bone healing [121]. Nandin et al. applied electroblown technique to form electroblown cotton-like foam (EBC) composite scaffold by using poly(e-caprolactone) (PCL) and the bioactive glass nanoparticles (BGn), then loaded dental stem cells and applied to the mouse model of mandibular alveolar bone defect. It was found that the composite had good plasticity and bone induction regeneration capacity [122]. Sadhasivam et al. synthesized HAP/CS/HA-Col biomaterials by using hydroxyapatite, calcium sulfate semi-hydrate and hyaluronic acid laden collagenase as a substitute for alveolar bone defect in mouse, and utilized the sustained release of collagenase in HAP/CS/HA complex to accelerate the repair and reconstruction of alveolar bone [123]. Whether a metal scaffold, polymeric material, bioceramic or composite material, has been reported as a bioscaffold loaded with drugs. Drug-loading bioscaffolds not only have the characteristics of biological scaffolds, but also have advantages over traditional drug delivery methods. Although some drug delivery biological scaffolds have been developed, no breakthrough has been made in the improvement of drug sustained release, the main reasons include low encapsulation rate, limited absorption, and difficult control of dose and high cost. Most studies are limited to the experimental stage. How to make high efficiency and quality drug delivery biological scaffolds and applying them in clinical trials needs further development and research.

7. Computer-assisted techniques for mandible defects reconstruction 7.1. Digital navigation technology In recent years, with the rapid development of computer technology and imaging, computer assisted navigation system (CANS) technology has been widely applied in the surgical reconstruction of hard tissue. Computer aided design and manufacturing (CAD/CAM) technology combined with bone transplantation and individualized titanium stent implantation has been increasingly mature and achieved ideal results. Its advantages are that it can simulate various surgical schemes before surgery, carry out the design of digital guide plate, reconstruction titanium plate and fixation position of titanium screw, optimize the biomechanics of the prosthesis (aiming to protect the ligaments and muscle attachment for the maintenance of chewing function and promote bone healing), simplify the surgical process and shorten the operation time [131–133]. Gutwald R et al. found that the incidence rate of titanium plate nail loosening and fracture caused by excessive stress (either by strength or fatigue) in the reconstruction area was 2.9%–10.7%, during the follow-up in two years (and in most cases less than six months)after titanium plate reconstruction surgery [134]. In order to solve the above problems, Hoefert et al. used computer threedimensional finite element analysis software to evaluate the biological performance of the titanium bone plate in clinical practice, and simulated the stress changes after the mandible defect reconstruction of the titanium plate. The stress was reduced by the auxiliary fixation of the second titanium plate in the stressed area, so as to reduce the incidence of fracture of the titanium plate and nail (Fig. 7). However, the current research is limited to theory, and the clinical application needs further demonstration [135]. The application of computer aided technology can obviously shorten the operation time, improve the operation accuracy and reduce the postoperative adverse reactions, showing its great application prospect, and has become one of the indispensable tools in the mandible reconstruction. Through the research of digital medical technology, three-dimensional visualization of human tissue can be realized, and some complex clinical diagnosis and treatment activities can be simulated and treatment plans can be made in advance, which may fundamentally change the clinical research work and have a broad application prospect in the field of medicine.

6.2. Functional biological membrane How to maintain the integrity and original contour shape after tissue defects repair is a very important issue for tissue engineering. An ideal mandible bone regeneration should consider two aspects: effective bone regeneration and reliable protection, which can prevent the adjacent soft tissue around the defect growing into the newly formed bone, so as to achieve the precise repair of the bone defect area [124]. Guided bone regeneration (GBR) is a kind of treatment method in order to promote the new bone formation [125]. Based on the biological principle of selective cell rejection, GBR mechanically excluded nonosteoblasts from surrounding soft tissues by using a closed membrane. As a result, the defect space is protected, with only bone marrow cells penetrating and promoting bone formation, preventing the rapidly growing tissue (fibers or epithelium) from invading the defect site [126,127]. The bio-membrane is usually divided into two categories: a biodegradable, it can be self-degradable, such as polylactate, collagen, etc. and doesn't have to be taken out again; a non-degradable membrane, such as titanium metal film, teflon film, etc., its obvious deficiencies is secondary surgery, but it is given sufficient time to osteogenesis. B Ma, etc. synthesized hydroxyapatite (HAp) nanobelt/ polylactic acid (PLA) (HAp/PLA) Janus membrane, and used in rat

7.2. 3D printing technology 3D printing technology is a kind of CAD/CAM rapid prototyping technology. The common bioprinting techniques used for the 10

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Fig. 7. (I) Hemimandibular defect models: A: Short defect from canine to second molar (Model 1); B: Extended defect model from canine to mandibular angle (Model 2). C, D: Both defect models refined with complex screw geometry (Model 5, Model 6); E: Local reinforcement with a second plate with 3 screws in the short distance defect and 2 screws in the bony stump side (Model 3); F: Reinforcement with a second plate with 2 screws to both sides in the extended defect model (Model 4). G, H: Short local partial reinforcement with 2 plates on heavily loaded segments as calculated (Model 7, Model 8). (II) Extended defect (ED) model. (III) Display of forces applied: Application of Loads 1 to 5. Boundary conditions on points 7 and 9. Forces by muscle simulated on points 6 and 8 [135]. (with permission from Elsevier, copyright 2018.)

Fig. 8. Schematic illustration of the preparation of 3D printed PCL scaffolds for alveolar bone augmentation in a beagle defect model. In the animal, alveolar bone defects were formed and the wax (white) was applied into the defect to maintain the defect volume during the scaffold production. Computed tomography images of the animal were obtained, and a defective mandible model was obtained. The scaffolds were designed using a CAD program and fabricated from PCL using 3D bioprinting techniques. Subsequently, the fabricated scaffolds were implanted into the defects previously formed, and 3 months of healing was allowed [143]. (The publisher is opened for access).

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an ideal and best option to promote bone regeneration in different clinical conditions. Therefore, the field of biomaterials for mandibular defects repairing and reconstruction requires new tools and approaches. Important topics being currently addressed but requiring further development are detailed in the following, serving as hints for future research:

deposition and patterning of biological materials using different bioink designs are: extrusion-based, inkjet bioprinting, laser-assisted bioprinting and stereolithography (SLA) [136]. Two more traditional methods of 3D printing were developed through laser printing technology. The first method uses extrusion, whereby layer upon layer of substrate is placed on the build platform, usually with added energy that can cause melting, fusion, or polymerization. The second method is powder-based and consists of layering of a substrate in powder form, followed by addition of energy to cause polymerization or other chemical processes such as melting, selective laser sintering, or crystallization to the desired shape [137]. Based on the principle of discrete stacking, 3D entities are formed by layer-by-layer stacking under the aid of computer [138]. Due to its unique advantage in high accuracy, personalized manufacturing and complex shape construction, 3D printing of biological materials has attracted more and more attention and been widely used in clinical research (Fig. 8). Julius et al. performed CT scan of the head of cats with mandible osteosarcoma before surgery, and used CAD/CAM processing technology to customize the reconstruction titanium plate through 3D printing, and then performed mandible periodic resection, followed by reconstruction of the defect using a custom-made titanium plate intraoperative. During postoperative follow-up, no signs of feeding difficulty were found except for pulp injury in the lesion area. The cat was alive and disease free 14 months postoperatively [139]. Moiduddin et al. used additive manufacturing and computer three-dimensional finite element analysis to make a corresponding model of titanium plate for the reconstruction of mandible defects [140]. Shao et al. used 3D printing technology to manufacture CSi-Mg10 bioceramics scaffolds, which can precisely match the model of rabbit mandible defect in macro and micro, and have high mechanical strength, excellent biological activity and appropriate biodegradation ability. They could easily stimulate bone regeneration without the help of any osteogenic factors [141]. Christopher et al. also proposed a novel 3D-printed bioactive ceramic scaffold with osseoconductive properties to treat segmental mandibular defects in a rabbit model [142]. Su et al. used 3D printing technology to customize 3D polycaprolactone (3D PCL) scaffold and implanted tricalcium phosphate powder in the scaffold to evaluate the efficacy of alveolar bone defect regeneration in beagle dog. They found the 3Dprinted porous PCL scaffolds can promote alveolar bone regeneration for defect healing in dentistry [143]. 3D printing technology, especially the development of biomimetic 3D printing, offers a promising prospect for the repair of the mandible defect in the future and even for the transplantation of other tissue organs. Individualization, precision, minimally invasive will be an important direction for the development of bone reconstruction of the oral and maxillofacial surgical in the future, but the present biomimetic printing technology is still immature, and there are many challenges and disadvantages. The tissue and even organ regeneration of 3D biomimetic printing is still limited in theory, and the innovation of technology and the extension of application still need to be explored constantly.

(I). (I). A high biomimetic scaffold can be formed by combining allogeneic bone with bone morphogenetic protein, autologous bone marrow and growth factor, so as to promote bone induction and bone healing without immune rejection. (II). To construct the metal scaffolds with coated cells and osteoblast active substances, that is, combining the metal scaffolds strength with cells and active components inductivity, so that they can achieve the function of active metal scaffolds. (III). The ideal biological scaffold can be made by combining polymer materials and bioceramics. Under the precondition of high biocompatibility, the biomimetic scaffold with precise structure and composition can be synthesized, which can better realize the functionality of various materials. (IV). Combined with drug therapy and biological therapy for mandibular defect, through gene delivery regulating protein and transgenic expression to regulate host immune system to suppress negative effects on bone healing, so as to construct a composite biological scaffold with drug controlled release and targeted positioning to promote bone regeneration. (V). According to the characteristics of different mandibular defects, a personalized biological scaffold can be manufactured by 3D printing and other techniques, which can be precisely matched with the defect area and reduce the stress, so as to better realize the repair function of the scaffold. Declaration of Competing Interest The authors declare no competing financial interest. Acknowledgements This work was supported by the National Natural Science Foundation of China (K112222616 and 81671028), Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20171906) and Shanghai Talent Development Fund (2018099). References [1] J. Rubio-Palau, A. Prieto-Gundin, A.A. Cazalla, M.B. Serrano, G.G. Fructuoso, F.P. Ferrandis, A.R. Baro, Three-dimensional planning in craniomaxillofacial surgery, Ann Maxillofac Surg 6 (2016) 281–286. [2] E. Mala, E. Vejrazkova, J. Bielmeierova, M. Jindra, M. Vosmik, J. Novosad, L. Sobotka, Long term monitoring of nutritional, clinical status and quality of life in head and neck cancer patients, Klin. Onkol. 28 (2015) 200–214. [3] S. Ishida, Y. Shibuya, M. Kobayashi, T. Komori, Assessing stomatognathic performance after mandibulectomy according to the method of mandibular reconstruction, Int. J. Oral Maxillofac. Surg. 44 (2015) 948–955. [4] B.P. Kumar, V. Venkatesh, K.A. Kumar, B.Y. Yadav, S.R. Mohan, Mandibular reconstruction: overview, J Maxillofac Oral Surg 15 (2016) 425–441. [5] S.K. Sarkar, B.T. Lee, Hard tissue regeneration using bone substitutes: an update on innovations in materials, Korean Jintern Med 30 (2015) 279–293. [6] E. Bartaire, F. Mouawad, Y. Mallet, P. Milet, S. El Bedoui, J. Ton Van, D. Chevalier, J.L. Lefebvre, Morphologic assessment of mandibular reconstruction by free fibula flap and donor-site functional impairment in a series of 23 patients, Eur. Ann. Otorhinolaryngol. Head Neck Dis. 129 (2012) 230–237. [7] R.E. McMahon, L. Wang, R. Skoracki, A.B. Mathur, Development of nanomaterials for bone repair and regeneration, J Biomed Mater Res B Appl Biomater 101 (2013) 387–397. [8] O. Cornu, X. Banse, P.L. Docquier, S. Luyckx, C. Delloye, Effect of freeze-drying and gamma irradiation on the mechanical properties of human cancellous bone, J. Orthop. Res. 18 (2000) 426–431. [9] H. Nguyen, D.A. Morgan, M.R. Forwood, Sterilization of allograft bone: effects of gamma irradiation on allograft biology and biomechanics, Cell Tissue Bank. 8

8. Conclusions and future perspectives Because of the complex morphology and function of the mandible, the reconstruction and repair after the defect is always the hot point for maxillary surgeon. It is an inevitable trend to seek individualized and precise reconstruction for mandible defects. So far, researchers have been exploring the use of various materials (bone graft, natural or synthetic materials) as bone substitutes, studying growth factors, stem cells and gene therapy to enhance bone regeneration, and using computer technology to personalize design of bio-materials. In order to optimize the design and application of bone substitute materials, this paper reviews the main biomaterials and techniques for mandible defects repair. Despite many advances, each method and material has its particular advantage, it is somehow difficult to note a single method as 12

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