BONE SUBSTITUTE VERSUSSTEM CELLS IN REGENERATION OF ALVEOLAR BONE DEFECTS IN HUMANS: SYSTEMATIC REVIEW

Abeer Kamal 1 , Walaa Aboelalaa 2 and Mushira Dahaba 3 . 1. Associate prof. Oral and Maxillofacial Surgery, College of Oral and Dental Surgery, Misr University for Science and Technology, Giza, Egypt. 2. Lecturer of Oral and Maxillofacial Radiology, Faculty of Oral and Dental Medicine, Beni-seuf University,Benisuef, Egypt. 3. Professor of Oral and Maxillofacial Radiology, Faculty of Dentistry, Cairo University, Cairo, Egypt. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History Received: 01 October 2018 Final Accepted: 03 November 2018 Published: December 2018


ISSN: 2320-5407
Int. J. Adv. Res. 6 (12), 237-251 238 Stem cells are primitive cells foundin all multicellular organisms characterized by self-renewal and have the capability of differentiation into any mature cell type. Stem cells have the potential for regeneration and repair ofdamaged cells. According to the origin and differentiation potential of the stem cells, there are two main types, embryonic stem cells derived fromfetal tissue and adult stem cellsthat can be harvested from bone marrow and other sources such as liver, umbilical cord, placenta, adipose tissue, synovial membrane, amniotic fluid and teeth. Stem cellshave multipotency to differentiate and develop into various types of tissues as adipose, cartilage, and bone (7)(8)(9)(10)(11) .
Dental pulp (DPSCs) is a niche housing neural-crest-derived stem cells. It is easily available with limited morbidity after collection. DPSCs are capable of differentiating into osteoblasts that secrete abundant extracellular matrix that can build a woven bone in vitro. It is also capable of forming acomplete and well-vascularized lamellar bone after grafting. Dental pulp could be considered an interesting and possibly an important source of autologous stem/progenitor cells that are ready for use for therapeutic purposes, as the repair/regeneration of craniofacial bones (12)(13)(14)(15)(16)(17) .
The ideal graft material should not only be a bone substitute but a bone regeneration material that is completely resorbed simultaneously with the formation of new bone. Its decomposition products should be reused for building new bone (18) . It should serve as space keeper preventing invasion of soft and connective tissue and should not carry any immunological risk. Autogenous bone grafts which are still regarded as a gold standard appear to be ideal but their availability and storability is limited and secondary surgical sites with all related risks are still founded (19)(20)(21) . Allogenic or xenogenic grafting materials do not require secondary surgery.They are readily available and can be stored but the risk of immunological reaction due to foreign protein and transmission of viral or other infections cannot completely be prevented, making their use doubtful. The resorption of xenogenic materials has been the subject of controversy and may be identified histologically after many years (22)(23)(24)(25) . Synthetic calcium phosphate as hydroxyapatite, alpha and beta tri-calcium phosphate are artificial, sterializable, free from any risk of material induced infections and easily available. The gradual dissolution and resorption of the synthetic bone substitute in physiologic environment occurs predominantly through physiochemical means without osteoclast activity. This procedure leads to interlocking porosity, allowing an invasion of fluids, migration of cells and ingrowth of vessels and newly formed bone, thus being osteoconductive (26,27) .
Human dental stem cells that have been isolated and characterizedderived from different sources include,dental pulp stem cells (DPSCs), human exfoliated deciduous teeth, stem cells from apical papilla (SCAP) and periodontal ligament stem cells (PDLSCs) (28). In the last ten yearsstem cells have gained more interest because of their high differentiation potential and their availability. Different types of stem cells represent a potential key component in autologous graft for bone regeneration.In contrast, bone substitute materials that were commonly used for reconstruction of alveolar bone defect including autogenous bone graft, allograft, xenograftand synthetic bone materials. The aim of the present investigation was to systematically review and assess all relevant literature concerning the regeneration of alveolar bone defect using bone substitute versus stem cell in humans

Materials and Methods:-Search Strategy:
Identification of studies to be considered for inclusion was based on a search strategy for each electronic database PubMed, Booksc.org, LILACS, and Google scholar. In,accordance with guidelines of the preferred reporting items for systematic reviews and meta-analysis (prisma) statement and Cochrane handbook from January 1990 up to April 2017. LILACSsearch lead toarticles in different language so it was excluded. The search used the following keywords: (bone regeneration OR alveolar bone defect ORbone substitute OR dental pulpstem cell OR adipose derived stem cell OR autograft OR allograft OR alloplast OR xenograft)that was combined with manual search.
The search was limited to randomized clinical trials involving human subjects with restrictions to English.
All original research and review articles bibliographies were identified to be relevant to the scanned subject for any possible additional studies. Title and abstract of identified studies were screened bytwo reviewers for eligibility (AK and WA).Consensus was obtained by discussion or consultation with the third reviewer (MD). The detailed search sequence presented in table (1).

Selection criteria:
Allrandomized controlled clinical trial (RCT) assessing stem cells and bone substitute in regeneration of alveolar bone defects were included. No limitation was positionedin regard the number of patients treated. Studies published between January 1990 and April 2017 were included.    The heterogeneity between trials prevented meta-analysis. Rather, a descriptive analysis of the reported studies was performed. Table (3    Immune florescence analyses Significant differences were observed for BMP-2 and VEGF expression: they were expressed at much higher levels (p<0.001) in the T group with respect to the C group One year Bone regeneration Higher in T group with p<0.01, vs C group for all patients except N. 7.

Discussion:-
Bone substituteand stem cells can be used as alternatives for regenerationand restoration of damaged and lost alveolarbone defects in humans in oral and maxillofacial field.Clinical analyses of the bone defect after replacement and augmentation demonstrated that there was bone regenerative response determined radiographically, and 247 histologically. Stem cells is easily accessible with limited morbidity, capable ofdifferentiating into osteoblasts and producing well-vascularized lamellar bone. Thus,it could be used for bone regeneration forcraniofacial bones (29)(30)(31)(32) . Bone substitute can restore and maintain facial boneand help soft tissue support with reasonableesthetics, easy to use and handling, with favorable cost and time advantages and adaptability to a variousoral and maxillofacial areas (33)(34)(35)(36) .Review of literature revealed that both bone substitute and stem cellshave several advantages and disadvantagesand,hence,the research hypothesis was established,to comparebone Substitute versus stem cell in regeneration of alveolar bone defects in humans.
Alveolar bone defects is an esthetic and functional problem for many patients. Bony defects can be resulted fromoncologic surgery, traumatology, and implant surgery. Reconstruction of such a defect represent clinical challenges. Different modalities have been proven its effectiveness in restoring the bony defects. These modalities included bone substitute and stem cells with its different sources, advantages, and disadvantages. However, up to date, no evidencebasedapproval for either to replace the bony defectswith conventionalmodalities including bone substitute or replace it with the recent technique including stem cells and its variety. The trials presented in this review agreed that both modalities are efficiently used for reconstruction of alveolar bone defects but further discussion is recommended to advocate one over the other.
Frequency of bone grafting is the second most frequent tissue for transplantation, worldwide (33)(34)(35)(36) . Bone substitutes with different types and forms considered the best method for replacement the different types and sizes of alveolar bone defects being biocompatible, easily molded into the bone defect.Also bone substitute is consideredosteoconductive,osteoinductive, thermally nonconductive, sterilizable, as well as readily available at a reasonable cost. This concept in agreement with Mironet al (37) and Pryor et al (38) .
Several studies (39)(40)(41)(42) proved that autografts are the gold standard method in bone substitution for several reconstruction procedures. The autografts possess an osteoconductive and osteoinductive properties, contain many growth factors and osteogenic cells for bone formation as well as slowly replaced by newly formed bone. The disadvantages of autografts was the second surgical donor site with possibility of post-operative pain and complications; infection, fracture, or neurovascular injury, as well as cosmetic deformity, and longer operative time.Tomford (43) and Lomas et al (44) recommended the use of allograft asa suitable alternative to autogenous bone graft. But, the disadvantages are costs, difficult procedure (tissue processing, harvesting), and its mechanical resistance limited the process of osteoinduction as well as it has risk of infectiontransmission (43,44) .
Xenograftsa can be used for reconstruction of alveolar bone defects being osteoconductive with good mechanical properties, low costs and easy available (45)(46)(47)(48)(49) .Alloplastic material in form of hydroxyapatitemost commonly dueto its osteoconduction, hardness, and acceptability by bone. However, calcium carbonate was completely resorbed in short time that lead to bone fracture.Tricalcium phosphate in combination with hydroxyapatite giving the effect of both, resorbable and steoconduction (50) .
Despite that bone substitute has been the brillianttechnique for reconstruction of defective alveolar bone, stem cells start to gain importance in that fieldbecause itpossess superior osteogenic ability. Using of stem cells for reconstruction provides benefits not only to oral and maxillofacial surgeon but also for the patients. Patient-centered outcomes are the main target for researches in the last decade.
Concerning prevention of facial deformity as one of the complication resulted from defective alveolar bone theosteoinductive stem cells based therapies can be used to improve and accelerate the clinical outcomes. One of the advantages of using stem cellsis more predictable regenerative outcomesand improved esthetics. Local immune responses by the host cells against the stem cell are highly relevantin regenerative medicine. Mesenchymal stem cells may be applicable to suppress the local immune response during transplantation to attain ideal tissue regeneration. Stem cells and tissue engineering therapies are expected to provide a novel capability to regenerate large defects in periodontal tissues (51) and alveolar bone (52)(53)(54) , and to ultimately replace the lost tooth itself (55,56) .
The present review ascertained that stem cells hold several advantage over bone substitute in reconstruction procedures. This idea was supported by the opinion of Watt (10) and Graziano (12) . Beingautologous and harvested form a natural source, easy and faster method to repair and regenerate damaged tissues with low-risk and effective therapeutic strategy,exhibits minor morbidity of the collection site, free from diseases experienced by disease transmission, and no need for secondary bone grafting procedures in small defect.However, on grafting a defective 248 area with stem cells, it must be taken into consideration their behavior as it might be relatively variable on the differentiation process. It may be affected by their origin rather than by the local signals arise from the treated area. The clinical advantages afforded by the grafting of autologous stem cells may be more significant than the disadvantages arising from the tissue that regenerated.
A doubt remains regarding the use of stem cells to find adverse effects. Stem cells are usually introduced to find common and intended outcomes, whereas adverse effects tend to be less frequent and unintended. Trials upon which this review is based might be useful to detect systematic adverse effects as the type of regenerated tissuesbut might be less advantageous as mentioned above.In contrast, in the 4 human clinical trials that met the eligibility criteria for this systematic review (Tables 1)and encompassed 71 adult subjectsin various clinical settings between January 1990 and April 2017, all the 4publications concluded thatthe use in stem cells or bone substitute for reconstruction of alveolar bone defect produced uncounted safety outcomes. (17,(57)(58)(59) The finding could be categorized in one or more ways: stem cells and bone substitute can be used for alveolar ridge reconstruction; dental pulp stem cells seeded on an appropriate scaffold as collagen can repair bone and produces an efficient biocomplex, tissue repair cells isolated from bone marrowaccelerated alveolar bone regeneration and reduced the need for secondary bone grafting at the time of dental implant placement and finallythe use of platelet rich plasma with autogenous or alloplastic bone substitute can accelerate vascularization of the graft, improves soft tissue healing, reduces postoperative morbidity and enhances bone regeneration. Besides, it improves handling of graft material particles and help to manage and packing it easily into the proposed graft site therefore, assisting maintenance of the space with rapidly bone regeneration.

Conclusion:-
Clinical studies that encountered in this research are too limited in number and so it displays small sample sizes. It is clinically heterogeneous with nosolid conclusion can be reached. Investigators should pay their attention to this remarkable subjectand investigate it deeply. Each kind of stem cells should pull attention of researchers in oral and maxillofacial field to close obvious, yet important, research gaps of lack of enough randomized clinical trials that can be more trustedand get a standard evidence based clinical practice. Within the limitations of this review, it can be concluded that stem cells can be used as a safer and effective treatment modality to provide reconstruction of small maxillofacial bone defects. However, bone substitute ishigher cost-effective procedure reconstruction of such defects. The easily availability and less disease transmission with less morbidity of the donor site and cost of surgical approach to harvest stem cellsmake this technique superior to higher cost alloplastic bone graft. Further studies with a larger study samples and a longer follow-up period would be desirable with special concern on technique is recommended for larger bone defect site.