Bone regeneration by stem cell and tissue engineering in oral and maxillofacial region

Abstract

Clinical imperatives for the reconstruction of jaw bone defects or resorbed alveolar ridge require new therapies or procedures instead of autologous/allogeneic bone grafts. Regenerative medicine, based on stem cell science and tissue engineering technology, is considered as an ideal alternative strategy for bone regeneration. In this paper, we review the current choices of cell source and strategies on directing the osteogenic differentiation of stem cells. The preclinical animal models for bone regeneration and the key translational points to clinical success in oral and maxillofacial region are also discussed. We propose comprehensive strategies based on stem cell and tissue engineering researches, allowing for clinical application in oral and maxillofacial region.

Keywords

bone regeneration / animal models / translational strategies / oral and maxillofacial region

Introduction

The repair of jaw bone defects caused by tumor resection, infection, trauma, or congenital malformation and the regeneration of resorbed alveolar ridge with aging are challenging problems for oral and maxillofacial surgeons [1-3]. Autogenous bone grafting, due to the virtue of its osteoconductive and osteoinductive properties, remains the “gold standard” for repairing bone defects. However, its main disadvantages, such as infection, pain, and loss of function, limit its further application. In addition, the use of allograft may lead to complications such as disease transmission, immunogenic response and supply limitation [3-7]. Fortunately, regenerative medicine strategy based on the development of stem cell and bone tissue engineering techniques provides an applicable alternative to achieve better effects for repairing bone defects [8-10].

To understand the current basic research on bone regeneration in oral and maxillofacial region, the cell sources chosen for bone regeneration and the strategies for the osteogenic differentiation are expatiated in detail in this review. Animal models on bone regeneration in oral and maxillofacial region, and vascularization of newly formed bone and the osseointegration with dental implants in vivo are also evaluated. Finally, translational strategies and clinical developments from bench to clinical are discussed.

Cell sources for bone regeneration

Osteoblasts

Osteoblasts possess strong osteogenic potential, and can be used as seed cells for bone regeneration [11,12]. As bone-forming cells, osteoblasts are able to synthesize and secrete bone matrix, thereby promoting mineralization and bone formation [13]. Compared with stem cells, the main disadvantages of osteoblasts application include less availability of donor tissue, less proliferative capacity in vitro, and longer incubation time [14].

Stem cells

Stem cells are undifferentiated cells with the capacity to self-renew, produce more stem cells, and differentiate into different cell lineages under appropriate conditions [15,16]. Stem cells are classified as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and adult stem cells according to their source, while it also often correlates with their plasticity [17].

Embryonic stem cells (ESCs), the only truly totipotent cell lineage cells, are isolated from the inner cell mass of blastocysts (5- to 7-day-old embryo). More importantly, ESCs have the capability to replicate indefinitely in vitro and, theoretically, are able to differentiate into any cell type or an entire organism [18-20]. Recently, considerable attempts have been made towards directing ESC differentiation into osteogenic lineage and the potential use of ESCs for bone regeneration [21,22]. However, research on human ESCs has caused worldwide controversy with regards to tumorigenicity, immunogenicity, and ethical issues [22].

Recently, extensive studies on nuclear reprogramming, in which one somatic cell type is converted into a different unrelated one through a switch of the gene expression pattern, have resulted in the generation of induced pluripotent stem cells (iPSCs, pluripotent reprogramming) [23-25]. Such iPSCs are promising prospect for regenerative medicine. The generation of bone matrix-forming osteoblasts from mouse and human iPSCs based on differentiation protocols for ESCs was recently reported [26]. This finding has also been reported in other studies on new bone formation by iPSCs for periodontal tissue regeneration in nude mice. A similar outcome was reached in repairing critical-size calvarial bone defects in a mouse model with silk scaffolds and SATB2-modified iPSCs [27,28]. However, the relevant mechanisms and optimized induction approaches require further study and improvement.

Adult stem cells, the subject of most investigations in bone regeneration research, show great promise for use in the oral and maxillofacial region. Defined as undifferentiated cells found among specialized cells in the post natal state, adult stem cells are able to self-replicate and differentiate into various cell types [17]. The potential bone-generating adult stem cells include bone marrow mesenchymal stem cells (BMSCs), adipose derived stem cells (ASCs), dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHED), and periodontal ligament stem cells (PDLSCs) [29].

The adult bone marrow stroma contains a subset of nonhematopoietic cells referred to as BMSCs. BMSCs are one of the most well-characterized postnatal stem cell populations, and have the capacity to differentiate into different kinds of cells, such as osteoblasts and chondrocytes. Despite the nature of heterogeneity in in vitro expanded BMSCs, successful repair of bone defects with autologous BMSCs has been achieved in various animal models [30-33]. In addition, optimal outcome has been achieved by using autologous BMSCs to repair human bone defects, particularly mandible defects [34,35]. These studies have shown that BMSCs possessed favourable potential for bone regeneration in oral and maxillofacial region.

ASCs, another possible source of bone-generating cells, were first described in 2001 [36]. Compared with BMSCs, ASCs are easier to obtain, carry relatively lower donor site morbidity, and are available in large numbers [37]. The osteogenic capacity of ASCs has received considerable attention with respect to bone regeneration. Various studies have reported that successful repair of bone defects can be achieved by transplanting autologous ASCs into the bone defect sites [38-40]. More importantly, a clinical case in 2004 reported that the combination of autologous ASCs and fibrin glue successfully repaired widespread traumatic calvarial defects in a 7-year-old girl [41].

DPSCs, a population of postnatal stem cells residing in the dental pulp, are also capable of differentiation towards osteoblasts. Several previous studies have demonstrated that, similar to osteoblasts, DPSCs express bone markers such as alkaline phosphatase (ALP), type I collagen, and osteocalcin. More importantly, DPSCs are capable of forming bones in vivo. DPSCs represent a novel potential cell source for bone regeneration in oral and maxillofacial region [42,43]. Furthermore, SHED have been identified as a novel population of stem cells that are able to repair critical-sized calvarial defects in mice with substantial bone formation. Although BMSCs and ASCs have been proven to achieve a certain outcome for repairing bone defects, these cells originate from the mesoderm, whereas SHED, with matched neural crest origin, may offer advantageous effect for craniomaxillofacial bone regeneration [44,45]. PDLSCs, which are derived from periodontal ligament, are able to adopt osteogenic phenotypes in vitro. Several findings suggest that PDLSCs have many osteoblast-like properties, including the potential for high ALP activity, calcium uptake, osteocalcin content in vitro, and new bone formation in vivo [46-48].

Strategies on directing the differentiation of stem cells into the osteogenic lineage

Stem cell application in bone regeneration requires well-defined and efficient protocols to direct the differentiation of the stem cells into the osteogenic lineage, followed by their selective purification and proliferation in vitro. The ideal protocols would reduce the likelihood of spontaneous differentiation of stem cells into divergent lineages on transplantation, as well as reduce the risk of teratoma formation for ESCs or iPSCs application. Additionally, such protocols could provide useful in vitro models to study osteogenesis and bone development, and facilitate the genetic manipulation of stem cells for therapeutic applications [49]. The osteoinductive chemical factors, cytokines/growth factors, and biomaterials could be used to direct the osteogenic differentiation of stem cells.

Osteoinductive chemical factors

A number of chemical compounds have been proven to promote osteogenic differentiation of stem cells in vitro. These chemical compounds tend to be less labile and have a longer active half-life in solution compared with protein-based cytokines and growth factors, which may be beneficial for prolonging in vitro cell culture over several days or even weeks. Moreover, these chemical compounds can be manufactured via chemical reactions in the laboratory. This allows for more structural and chemical definitions as compared with proteins, which need to be synthesized in living cells and subjected to complex post-translational modifications (i.e. glycosylation, peptide splicing, and conformational folding) [49].

In previous studies, stem cells were induced to differentiate in vitro into mineralized osteoblasts under the influence of prostaglandin E₂, 1,25-dihydroxyvitamin D₃, L-ascorbic acid, dexamethasone, β-glycerol phosphate, TAK-778, teriparatide, and a family of statin compounds, etc. Prostaglandin E₂, which is a naturally occurring eicosanoid derived from arachidonic acid metabolism, has been reported to enhance proliferation and osteogenic differentiation of BMSCs [50,51]. An active form of vitamin D, 1,25-dihydroxyvitamin D₃ (also known as calcitriol) has been proven to inhibit adipogenic differentiation of BMSCs for promotion of osteogenic differentiation [52,53]. Dexamethasone is a synthetic steroid drug used for cell culture experiments to induce proliferation, maturation, and extracellular matrix (ECM) mineralization of both ESCs and adult stem cells [21,54]. Dexamethasone is also often used in combination with L-ascorbic acid (vitamin C) and β-glycerol phosphate [55]. As a novel synthetic compound, TAK-778 has been shown to be a potent inducer of osteogenesis in in vitro and in vivo studies [56,57]. Statins, which are a family of naturally-occurring and synthetic chemical compounds as 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitors, play an integral role in hepatic cholesterol biosynthesis. Aside from their widespread pharmacological application for reducing blood cholesterol, statins also have a profound enhancement effect on osteogenesis, as shown in previous studies [58-60].

Osteoinductive cytokines/growth factors

The use of exogenous cytokines and growth factors, which are essential for bone regeneration, could lead to different cellular responses, such as promoting cell adhesion, proliferation, migration, and osteogenic differentiation. A large number of growth factors have been used in bone regeneration, such as bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), insulin-like growth factors I and II (IGF I/II), platelet-derived growth factor (PDGF), and NEL-like molecule-1 (NELL-1) [61,62]. In addition, vascular endothelial growth factor (VEGF) expressed in the vascularized tissues could also regulate the vascular tissue regeneration during new bone formation process [63]. Of particular interest among these growth factors are the various isoforms of BMP, such as BMP-2, -4, -6, and-9, which have been reported to be potent inducers for osteogenic differentiation. In addition, structurally related TGF-β proteins have been reported as having an inhibitory effect on BMP-induced osteogenic differentiation of the mesenchymal pluripotent cell line, C3H10T1/2 [64-66].

Osteoinductive biomaterials

Bone tissue is composed of a heterogeneous mixture of cell types embedded in a mineralized ECM with three-dimensional (3D) structures. As a scaffold for bone regeneration, biomaterial should provide the necessary support for cells to proliferate while maintaining their potential to differentiate, possess suitable architecture to match the final shape of the newly formed bone, and be suitably biodegradable to provide space for newly formed tissue [67,68]. To fabricate ideal biomaterial for bone regeneration, several strategies have been investigated, including (1) chemical composition, (2) electrostatic charge, (3) surface texture/roughness, (4) geometrical configuration, and (5) biomimetic modification.

Clearly, the chemical composition of the biomaterial is a critical factor to determine its osteoinductive and osteoconductive properties. The scaffolds could be fabricated based on either collagen, hyaluronan, mineralized calcium [hydroxyapatite (HA), tricalcium phosphate (TCP), calcium phosphate cement (CPC), etc.], fibrin, or their composites, which belong to the major constituents of bone ECM. Likewise, matrix scaffolds are based completely on synthetic polymer materials, such as poly(lactic-co-glycolic acid) (PLGA), poly(ethylene glycol), poly(ϵ-caprolactone) (PCL), and alumina, which have also been used for bone regeneration [49].

Inorganic ions, which are indispensable in the process of bone formation, could be added to biomaterial to promote osteogenic differentiation of stem cells. The minerals Ca, Mg, and Si containing akermanite ceramics have been found to promote osteogenic differentiation of BMSCs, ASCs, and PDLSCs, as compared with β-TCP ceramics (Fig. 1) [69-71]. In addition, the electrostatic charge on the surface of a scaffold could also enhance osteogenic differentiation of adult stem cells. Electrospun PCL scaffolds were found to be beneficial for the adhesion, spreading, and osteogenic differentiation of MSCs. However, surface texture/roughness might have moderate effects on the adhesion and osteogenic differentiation of MSCs [49,72], whereas their enhancement effects depend on MSCs sensitivity to surface texture/roughness. More importantly, geometric configuration for scaffold may have profound effects on the proliferation and osteogenic differentiation of MSCs. Among the various geometrical parameters, shape, porosity, and size have been widely evaluated for osteogenic differentiation [73-75]. Lower porosity stimulates osteogenesis by suppressing cell proliferation and forcing cell aggregation, whereas scaffolds with larger pores rapidly become well-vascularized and lead to direct osteogenesis. Considering the above factors, scaffolds with pore sizes and pore interconnections of>300 µm are recommended for bone regeneration [76]. Recently, nanoscale porous-based scaffolds were reported to successfully promote cell proliferation and osteogenic differentiation of MSCs in vitro and enhance new bone formation in vivo [68].

Recently, biomimetic modification biomaterials have been fabricated to functionally replicate the ECM of natural bone tissue. An ideal scaffold for bone regeneration should be designed based on the constituents and micro- and macrostructure of the native ECM [77]. Several strategies have been investigated as follows: (1) biomimetic biomaterials composed of the inorganic or organic constituents of natural bone, such as nano HA/collage composite biomaterials [78,79]; (2) biomaterials loaded with adhesion promoting molecules, such as sequence Arg–Gly–Asp (RGD), laminin, fibronectin, and vitronectin [68]; and (3) biomaterials loaded with osteoinductive cytokines/growth factors, including BMP-2, BMP-7, IGF-1, and VEGF [68].

Animal models for bone regeneration in oral and maxillofacial region

In vivo animal models are used for proof of functionality of newly formed bone based on stem cells and bone tissue engineering. Animal tests build a bridge between in vitro studies and clinical applications [68,80]. For bone regeneration in oral and maxillofacial region, the available animal models include ectopic bone formation of subcutaneous/intramuscular implants using nude and SCID mice, bone formation in situ using small animal models, such as rats and rabbits, and large animal models, such as canines, goats, pigs, and monkeys, among others. The animal models for bone formation in situ may be close and relevant to a particular clinical situation. These include models for mandible defect restoration, vertical alveolar ridge augmentation, maxillary sinus augmentation, and other bone defect restoration models in oral and maxillofacial region.

Mandible defects models

For mandible defects, rat, canine, goat, and monkey models have been used to evaluate the effect of bone regeneration based on stem cells and tissue engineering technology. Our group has successfully established and optimized the rat 5 mm diameter circular defect model, canine border defects of 20 mm × 10 mm, and segmental defects of 30 mm length model (Fig. 2) [1,5,30,81]. These models are critical size defects (CSD), which means that complete calcification of the defect will not occur during the lifetime of the animal [82]. More importantly, tissue-engineered bone constructed with BMSCs and scaffolds could achieve similar effect on bone regeneration in these models comparable to that of autogenous iliac bone graft, and the combination of growth factors could further enhance the effect.

Vertical ridge augmentation models

The use of dental implants has become an increasingly useful treatment to replace the missing teeth in completely and partially edentulous patients. However, such patients frequently lack sufficient bone support and retention for implants and dentures, which may dramatically affect their quality of life. To investigate the optimal conditions for bone regeneration on vertical ridge augmentation, different large animal models have been used. Kawakatsu created a bone defect approximately 30 mm long in mesiodistal direction, 6 mm deep in apicocoronal direction, and 8 mm wide in the buccoligular direction, on both sides of canine mandible, with a steel bar after teeth extraction [83]. Similarly, we have established vertical ridge augmentation models in canine (Fig. 2). We took the alveolar augmentation surgery after tooth extraction of bilateral premolars and molars for eight weeks. A tissue-engineered bone combination of cubic β-TCP scaffold (20 mm × 6 mm × 6 mm) and autologous osteoblasts achieved repair effectiveness comparable to that of autogenous iliac bone graft [11].

Maxillary sinus augmentation models

The repair of resorbed alveolar ridge in upper jaw after teeth loss is another common challenge. In addition, maxillary sinus floor elevation is recognized as an effective method to restore the edentulous posterior maxilla. Various animal maxillary sinus floor elevation models have been created to evaluate bone substitutes, including tissue-engineered bone. The maxillary sinus of the rabbit has a well-defined ostium similar to that of humans. Our group conducted a series of studies using different tissue-engineered strategies to complete a rabbit maxillary sinus floor elevation model. These results could provide evidence for screening a potential and efficient method for further evaluation in preclinical large animal models [84-88]. A canine maxillary sinus floor elevation model was also created (Fig. 2). Moreover, the combinations of biomaterials and osteoblasts achieve beneficial effects and have the potential for clinical applications as better alternative to autologous bone [12]. In addition, we took an anatomic survey in canine and goat maxillary sinus to locate the optimal position for dental implantation and to evaluate the potential for simultaneous implant placement (Fig. 3) [89,90]. The tissue-engineered complexes of BMSCs and CPC were reported to achieve repair effectiveness superior to autogenous bone for maxillary sinus floor augmentation and simultaneous implantation.

Jaw malformation model

Although soft tissue flap can be used to repair soft tissue defects for jaw malformation such as lip/palate cleft and facial cleft, many problems still need to be resolved regarding bone fracture repair. In our group, an alveolar cleft model was created in a canine. In this study, alveolar defect (10 mm × 5 mm × 15 mm) extending to the nasal floor was created bilaterally between the second incisor and canine. A tissue-engineered bone construct with β-TCP and BMSCs was then used to repair the alveolar cleft. The construct dramatically promoted new bone formation and mineralization, and achieved a favorable height of the repaired alveolar. More importantly, the functional effects of the tissue-engineered bone were equivalent to autologous bone, which could support the physiologic function of the alveolar by allowing the adjacent teeth to move into the newly formed bone in the grafted region [91].

Strategies for neovascularization and osseointegration

In the process of new bone formation, the survival of seed cells in the center of large cell-containing constructs might be limited by suboptimal oxygenation and nutrition. Adequate vascularization would be beneficial for cell survival, integration, and functionality of newly formed bone. Strategies to improve vascularization for bone regeneration in oral and maxillofacial region include (1) extrinsic angiogenesis and vasculogenesis and (2) surgical angiogenesis and neovascularization [92].

Several methods used for extrinsic angiogenesis and vasculogenesis are described as follows. (1) Prevascularization in vivo: this process entails implanting a bone graft into environments with a rich vascular supply, such as subcutaneous, intraperitoneal, and intramuscular tissues, such that the construct can be invaded with new vascular networks [92]. (2) Prevascularization in vitro: this approach can achieve vascularization of the engineered bone graft by seeding and coculturing adult endothelial cells or MSCs and osteogenic cells into the bone constructs in vitro. By this method, endothelial cells or MSCs are used with their potentiality to form new vessels within the scaffolds and to further anastomose with the host’s vasculature in vivo [92]. Prevascularized bone constructs were reported to have been successfully constructed in vitro using biomaterials seeded with human dermal microvascular endothelial cells and primary osteoblasts [93]. (3) Angiogenic factors/transcription factor: various angiogenic growth factors, such as VEGF, PDGF, and FGF, have been proven to accelerate vascularization of implanted engineered graft. These factors could be applied by directly incorporating into the scaffolds, or delivered by gene therapy method [94,95]. Recently, a transcription factor, HIF-1α, was shown to promote angiogenesis and osteogenesis via gene therapy in rat critical-sized calvarial defect models (Fig. 4) [96].

For surgical angiogenesis and neovascularization, the following methods have been evaluated. (1) Prefabrication of bone flaps. This approach is a two-step procedure. First, the tissue component is shaped into the desired form and implanted into a region with a vascular axis suitable for microsurgical transfer, such as cutaneous, fasciocutaneous, or muscle. Alternatively, a vascular axis may be also implanted into the bone graft. In the second step, the autologous implant is harvested en bloc with the vascular pedicle and surrounding tissue as a free flap. The vascularized bone graft can then be transferred to the recipient site using microsurgical techniques and vascular anastomosis [95,97]. (2) Free vascularized engineered bone grafts. Using an arteriovenous (AV) loop, which might be superior compared with the vascular bundle in terms of vascular density and capacity to generate new tissue, could successfully achieve vascularization of prefabricated flap [98].

Reconstruction with dental implant is a most important procedure for function restoration in oral and maxillofacial region. Osseointegration, which is histologically defined as “direct bone-to-implant contact (BIC),” is believed to provide rigid fixation of a dental implant within the bone (newly formed bone) and promote the long-term success of dental implants. The quantity and quality of newly formed bone, as well as implant surface properties, have been suggested to possibly influence osseointegration. In consequence, these two strategies are currently used to improve osseointegration. (1) Osteogenesis or angiogenesis of bone grafts might influence the osseointegration with dental implant. (2) The chemical composition or surface modification for dental implant is critical for protein adsorption and cell attachment, which might enhance implant osseointegration. Hydrophilic sand-blasted, acid-etched (SLA) implant surface was reported to yield higher BIC than a regular SLA surface. Likewise, dental implant coated with CaP could increase the saturation of body fluids and result in the formation of a biologic apatite onto the implant surface. Moreover, endogenous proteins contained in biologic apatite might serve as matrix for attachment and proliferation of osteogenic cells [99,100]. Recently, dental implant with inorganic ions, such as magnesium and strontium, was reported to enhance osseointegration [101,102]. Implant surface topography, such as blasted, etched, oxidized, and plasma spraying and laser surfaces, could also influence the bone response. Nanotopography surface modification for implant could modulate cell activity, such as enhancing migration, attachment, proliferation, and osteogenic differentiation [103]. An example of dental implant surface with nanoscale structure to promote adhesion, proliferation, and osteogenic differentiation of BMSCs is shown in Fig.5[104].

The translational strategies for bone regeneration in oral and maxillofacial region

The aim of research on bone regeneration is to reconstruct lost bone function to address clinical medical problems. Current studies apply several strategies to achieve widespread clinical application in oral and maxillofacial region, based on different techniques and methods. (1) Cell-based tissue engineering with bone marrow aspirate. In this approach, bone marrow aspirate could provide stem cells and undifferentiated precursor cells for bone regeneration. A tissue-engineering construct with a resorbable collagen and bone marrow aspirate could successfully repair alveolar cleft defects in clinical cases [105]. (2) Bone regeneration with growth factors. A number of bone growth factors have been used clinically, such as a variety of BMPs. Human BMP-2/absorbable collagen sponge was reported to be effective in repairing osseous defects and large critical-size mandibular defects in several clinical cases [106]. More importantly, the combination with bone marrow aspirate could further promote new bone formation. In 2004, a patient’s mandible de novo was prepared for clinical use. In this study, BMP-7 loaded titanium mesh external scaffold loaded coated HA blocks were seeded with autologous bone marrow, and then grown within the latissimus dorsi muscle prior to implanting into the defect site [35]. (3) Bone regeneration with ECM proteins or nonproteinaceous chemical compounds. When the use of growth factors has significant cost implications, ECM proteins have also been used to enhance osteogenic differentiation. Polylactic acid scaffold treatment with fibronectin was indicated to promote bone formation in a rabbit critical-sized skull defect [107]. In addition, teriparatide, as a recombinant fragment of human PTH (rhPTH), might offer therapeutic potential for localized bone defects in the jaw [108]. (4) Cell-based tissue engineering with enriched bone mesenchymal stem cells or mesenchymal stem cells expanded in vitro. MSCs represent a small (0.001%-0.01%) fraction of the total population of the nucleated cells (NCs) in marrow, as well as in other tissues. To increase the quantity of MSCs to meet clinical needs, several techniques have been developed, such as cell centrifugation and in vitro expansion technique. Recently, the enrichment of autologous marrow MSCs combined with porous β-TCP perioperatively was found to be as effective as autologous bone grafting for instrumented posterior spinal fusion surgery in 41 patients [109]. Likewise, the injectable tissue-engineered bone construct with expanded BMSCs and platelet-rich plasma was successfully applied for ridge augmentation and dental implant placement in 14 cases [110]. Therefore, the combination of a patient’s enriched bone mesenchymal stem cells or mesenchymal stem cells after in vitro expansion, combined with an appropriate biomimetic scaffold seems to be promising technique for bone regeneration.

Conclusions

The requirement for bone regeneration to reconstruct the function of jaw bone is a major clinical and socioeconomic need. Regenerative medicine based on stem cell application and tissue engineering method has been heralded as the alternative strategy of the 21st century to regenerate bone. Currently, these exciting developments in bone regeneration by stem cell and tissue engineering, provide information and direction for achievements, offer tremendous scope for understanding the mechanism of bone regeneration, and enter clinical arena in oral and maxillofacial region.

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