Review of literature of considerations regarding anterior maxillary implant placement

Since osteointegration has been introduced by Branemark et al. (1969), oral rehabilitation using dental implants has become an advancing field. Moreover, implant-supported prosthesis in edentulous or partially edentulous patients have been shown to be highly predictable in numerous studies (Buser et al., 2002; Lekholm, Wannfors, Isaksson & Adielsson, 1999).

        Esthetics has become more important to the success of the final restoration. Many recent studies have focused on the challenges of implant rehabilitation in the esthetic zone (Cooper et al., 2001; Belser, Bernard & Buser, 1996).

        Belser et al. (1996) reported that the success rate of implant surgery in the anterior maxilla is comparable to other segments of the jaw. Also, Henry et al. (1996) reported an implant success rate of about 96% for the replacement of a single tooth in the anterior maxilla.

2.1 Considerations regarding anterior maxillary implant placement

Implant placement in the esthetic zone is a challenging task that requires a careful clinical evaluation prior to surgery. A mistake in the positioning of the implant can lead to esthetic failure (Testori, Weinstein, Scutellà, Wang & Zucchelli, 2000).

Adequate bony support is essential for immediate and long-term implant stability, as well as for future aesthetic outcome (Cordaro, Amade & Cordaro, 2002). Long-term survival rates may require ridge reconstruction before implant placement. A minimum of six-millimeter ridge width is necessary, in order to have 0ne to one and a half millimeters of bone around the implant (Tatum, 1986).                                                                                                 

The presence of deficiencies in soft tissue or bone-in the esthetic zone makes implant rehabilitation very challenging. Soft tissue preservation is important to create the illusion of a natural tooth but this is difficult to achieve (Magne, Magne & Belser, 1993).

A Narrow anterior maxillary alveolar ridge is a common clinical problem that can be a result of long-term tooth loss, periodontal diseases, and removable appliances or after removal of cysts and tumors (Wang & Al-Shammari, 2002). In addition, Tooth extraction leads to loss of alveolar bone height and width from 40% to 60% within two to three years (Ashman, 2000).

Horizontal bone resorption is much more-faster than vertical resorption leading to progressive loss of ridge width (Lekovic et al., 1997). The palatal wall may be maintained but the labial plate deficiency will be more prominent which will not facilitate aesthetic implant placement. The resorption of the buccal/palatal walls occurs in two phases. The first bundle bone will be resorbed and replaced with woven bone. Then in the second phase, the outer surface of both bone walls undergoes resorption (Araújo & Lindhe, 2005).

Hansson and Halldin (2012) demonstrated that alveolar ridge resorption after tooth extraction can be a result of the absence of stress stimulus.

Some studies suggested that the immediate placement of the dental implants into extraction sockets will maintain the dimensions of the alveolar ridge (Werbitt & Goldberg, 1992; Paolantonio et al., 2001). However, Botticelli, Berglundh, and Lindhe (2004) concluded that bone resorption would occur from the outside of the ridge. The placement of an implant in the fresh extraction site obviously failed to prevent the re-modeling that occurred in the walls of the socket (Araújo, Sukekava, Wennström & Lindhe, 2005).

2.2Classification of the available alveolar bone

Different classifications were proposed for the evaluation and assessment of the available alveolar bone including:

1. Misch and Judy classification

The available alveolar bone was classified by Misch and Judy (1987) into four divisions according to alveolar ridge width, length, and height. (Table 1)

2. ABC classification

Khojasteh, Morad, and Behnia (2013) also classified the defects in both vertical and horizontal dimensions. The defects were classified according to the surrounding walls and width “ABC classification”. (Table 2)

3. Fu J. decision tree

Other classifications such as Fu and Wang (2011)decision tree included the treatment options suggested according to the condition of the available bone. (Table 3)

4. Garber classification

Garber and Rosenberg (1981) have suggested a classification depending on the type of management needed. (Table 4)

5.  Len Tolstunov classification

A recent classification of alveolar ridge width was published by Tolstunov (2014) based on the radiographic evaluation by cone-beam CT (Table 5)

Table (2.1): Misch and judy classification of the available bone.

Table (2.2): ABC classification of the available bone.

Table (2.3): The Decision Tree.

 Table (2.4): Garber classification.

Table (2.5): Len Tolstunov classification.

2.3 Esthetic problems associated with implant placement in anterior maxillary narrow ridges

Implant surgery in a narrow alveolar ridge offers an esthetic problem, especially at the anterior maxillary region. Facial bone deficiency is a critical factor that may lead to esthetic implant failures (Chen & Buser, 2009). Labial bone resorption will create dehiscence around the implant and result in a metal shade at the gingival tissues covering the implant.

Soft tissue deficiency may also result in esthetic problems such as the black triangle, which means the absence of interproximal papilla. This problem not only causes an esthetic problem but also leads to food impaction, gingival inflammation and periodontal disease (Singh, Uppoor, Nayak & Shah, 2013).

Reduced bone and soft tissue volume should be corrected to achieve satisfactory esthetic results. Surgical correction of this esthetic problem depends on whether the available bone is enough to allow implant placement or not. Soft tissue augmentation, bone augmentation procedures or combination of both could be applied according to the amount of ridge deficiency present (Tirone & Salzano, 2018; Oikarinen, Sàndor, Kainulainen & Salonen-Kemppi, 2003).

2.4 Surgical management of narrow alveolar ridge

2.4.1 Ridge splitting

Tatum (1986) introduced this technique for the management of horizontally deficient alveolar ridge.  The main advantage of this technique is maintaining the periosteal attachment so promoting the healing process. This technique could be used in both maxilla and mandible (Summers, 1995). Narrow edentulous ridge less than 3.5 mm is not recommended for ridge splitting.

A modification of this technique was described by Simion, Baldoni, and Zaffe (1992) and later by Scipioni et al. (1994) which is known as ridge expansion or split-crest technique for implant placement. They demonstrated 1-4mm width gained mm after the procedure and success rate of 98.9%. González-García, Monje, and Moreno (2011) demonstrated an excellent implant survival rate after more than 2 years of follow-up.

However, Sohn et al. (2010) reported that delayed implant insertion is safer and more predictable for ridge expansion technique especially in patients with thick bone cortex.

2.4.2 Block bone grafting

Block bone grafting is indicated when a severe deficiency in the alveolar ridge width is present. Autogenous bone or alloplastic block materials such as Bio-Oss® Spongiosa Block could be used for block bone grafting. Autogenous bone blocks could be harvested from many intraoral or extraoral donor sites. A healing period from 4‑6 months is necessary before dental implants insertion. This staged technique showed a high clinical success rate and high predictability (Stevenson, Li, Davy, Klein, & Goldberg, 1997).

The selection of donor site depends on clinical evaluation and treatment plan. The symphyseal block bone grafts is a cortical cancellous graft that can be used for ridge augmentation up to 6 mm vertically or horizontally. While the ramus buccal shelf graft is only a cortical graft that could provide 3-4 mm ridge augmentation in both vertical and horizontal dimensions (Pikos, 2005).

However, Soft tissue deficiencies must be evaluated as some cases may require soft tissue procedures either before or simultaneously with block bone grafting (Parthasarathy, Ramachandran, Tadepalli& Ponnaiyan, 2017).

2.4.3 Distraction osteogenesis

Alveolar distraction osteogenesis was introduced by Chin and Toth(1996). An intentional osteotomy is done at a particular area and a distraction device is used to apply a traction force to the callus (Zaffe, Bertoldi, Palumbo & Consolo, 2002). Alveolar distraction can be divided into vertical distraction and horizontal distraction.

The Clinical Steps of the distraction procedure includes surgical osteotomy followed by a latency period and a distraction period then consolidation and remodeling (Samchukov, Cope & Cherkashin, 2001).Chiapasco, Consolo, Bianchi, and Ronchi(2004) presented that distraction osteogenesis can be applied successfully in total or partially edentulous alveolar ridge.

Some complications may occur as a result of this procedure such as infections, bone fracture and malposition of the bony segments (Saulačić, Martín, Camacho & García, 2007).

2.4.4 Guided bone regeneration

Using a barrier membrane to enhance the growth of new bone at sites of bone dimensions insufficiency is called “guided bone regeneration” GBR. The aim is to reconstruct the alveolar ridge to achieve proper function, esthetics or prosthetic restoration.

Melcher (1976) pointed out the need to exclude undesirable cells from healing sites to allow bone regrowth. Osteoprogenitor cells do repopulate bone defect site exclusively (Retzepi & Donos, 2010). Fibrous tissue proliferates much faster than bone during healing so without placement of a barrier membrane the graft will be invaded quickly by soft tissue.

In order to allow adequate bone development, the grafting material should be placed in a bone preparation or should be covered with an effective barrier membrane (Chang, Matukas & Lemons, 1983). The borders of the bony defect and the contour of membrane will control the dimensions of the newly formed bone (Buser, Dahlin & Schenk, 1994). Furthermore, adequate blood supply and stabilization of the grafting material are essential for success as micro-movement or blood supply disruption will lead to fibrous tissue formation.

Bornstein, Halbritter, Harnisch, Weber, and Buser(2008)conclude that up to 40% of patients require implants rehabilitation GBR as part of treatment. The survival rate is similar to conventional implant surgery according to some studies (Donos, Mardas & Chadha, 2008; Clementini, Morlupi, Canullo, Agrestini & Barlattani, 2012). Majority of studies are indicating a survival rate of more than 90% after one year (Hämmerle, Jung, & Feloutzis, 2002).

2.5 Types of membrane

Many types of membranes could be used for guided bone regeneration. Some types are resorbable and some are non-resorbable which requires a second surgery to be removed.

Synthetic polymers such as Polytetrafluoroethylene that is non-resorbable inert stable polymer that resists breakdown by the biological system (Sheikh et al., 2014) and metals such as titanium alloy and cobalt-chrome alloy are used as tough non-resorbable membrane. Using a titanium mesh with bone grafts enhance localized alveolar ridge augmentation (Artzi, Dayan, Alpern & Nemcovsky, 2003; Roccuzzo, Ramieri, Bunino & Berrone, 2007).

 In addition, Aliphatic polyesters (e.g. polylactic acid PLA, polyglycolide acid PGA, and polycaprolactone PCL) which are resorbable but lacks rigidity and stability and may cause a strong inflammatory response (Piattelli, Scarano, Coraggio & Matarasso, 1998).Resorption rate depends on the type of polymer used. For example, PCL has a higher hydrophobicity and lower water‐solubility than PGA or PLA (Gentile, Chiono, Tonda‐Turo, Ferreira & Ciardelli, 2011).

Natural polymers such as collagen and chitosan are resorbable stable membranes that consist of biological components promoting healing and bone regeneration (Bunyaratavej &Wang, 2001). Although, Degradation of Collagen membranes depends on their source, methods were applied to slow their degradation through physical/chemical cross‐such as ultraviolet (UV) radiation and chemical treatment with genipin and glutaraldehyde (Jorge-Herrero et al., 1999).However, chemical cross‐linking might cause severe inflammation (Rothamel et al., 2004).

Calcium sulfate and calcium phosphate are examples of inorganic compounds that are used as a resorbable membrane and have the advantage of osteoconductivity (Elgali, Omar, Dahlin & Thomsen, 2017). Hydroxyapatite‐containing membranes have been shown to promote bone formation (Song et al., 2014). Also, beta‐tricalcium phosphate (β‐TCP) have been incorporated in resorbable membranes and has been shown to promote osteogenesis (Shim et al., 2012).

2.6 Bone grafting

Different types of materials could be used as augmentation material associated with the GBR procedure. Grafting materials enhance bone formation by either osteogenesis, osteoinduction or osteoconduction.

2.6.1 Osteogenesis

Osteogenesis occurs when new bone is formed by viable osteoblasts transferred from the bone graft material, this occurs only in autogenous bone grafting especially cancellous bone, which provides the largest number of bone cells (Klokkevold & Jovanovic, 2002). Early vascularization of the graft site is essential for osteogenesis.

2.6.2 Osteoinduction

Osteoinduction refers to the stimulation of the undifferentiated osteoprogenitor cells by osteoinductive signals to differentiate into osteoblasts that will contribute to new bone formation (Wilson-Hench, 1987). The most important osteoinductive mediator is a soluble glycoprotein called Bone morphogenic proteins (BMP). BMP is naturally released in response to trauma to promote bone remodeling. (Lind, 1996)

Allografts and autogenous graft is both considered as osteoinductive materials. Osteoinductive materials enhance bone formation effectively even in the ectopic site in the absence of bone (Glowacki & Mulliken, 1985).

2.6.3 Osteoconduction 

Osteoconduction occurs when the bone graft material act as a scaffold for bone formation. Osteoblasts invade the bone graft material that will become a framework for the newly formed bone (Klokkevold & Jovanovic, 2002).

Bone growth factors are necessary for osteoconduction as they are considered signaling agents, that’s why osteoconduction depends on full vascularization through a proper blood supply (Albrektsson, 1980).The grafting material should be biodegradable in order to provide a stable structure for tissue formation but resorbs as tissue forms (Porter et al., 2000).Resorption time depends on the porosity of the grafting material.

2.7 Types of graft material

2.7.1 Autogenous bone graft

Autogenous the bone graft is considered as the standard bone substitute as it provides bone regeneration by osteogenesis, osteoinduction, and osteoconduction. Autologous bone is obtained from the same individual and harvested from either extraoral sites such as the iliac crest, ribs and the fibula or from intraoral sites such as the chin and the anterior ramus.

The autogenous graft should be used immediately or it may be stored in a sterile saline solution to maintain cellular survival. Advantages include minimizing the risk of graft rejection and also minimizing the risk of cross-infection. An autologous bone graft stimulates bone growth by osteogenesis, osteoinduction, and osteoconduction so that it is considered as most efficient grafting material (Koole, Bosker & van der Dussen, 1989). However, there are several drawbacks of autologous grafts; the main disadvantages include both surgical problems or complications as well as its limited supply.

2.7.2 Allografts of Considerations regarding anterior maxillary implant placement

Allografts are derived from humans but it is obtained from another individual. Allograft bone can be taken from cadavers or living human donors and stored at bone banks. There are three types of bone allograft available: fresh-frozen bone, Freeze-dried bone allograft (FDBA) and Demineralized freeze-dried bone allograft (DFDBA).

Disadvantages of allografts includes risk of transmission of infection, antigenicity especially in fresh allografts(Mellonig, Prewett & Moyer, 1992) and absence of osteogenic effect (Misch & Dietsh, 1993). The main advantage is that a secondary surgical site is not needed. The mechanism of action is through osteoconduction and osteoinduction.

Fresh-frozen bone is rarely used in dentistry because of the risk of an immune reaction and disease transmission (Buck & Malinin, 1994).Freeze dried bone allografts maintain both organic and inorganic matrix and exhibits mainly osteoconductive properties because osteoinductive bone morphogenic proteins are only released after resorption of the hydroxyapatite mineral, (Mellonig, 1984) and since FDBA is mineralized, it elicits a slow rate of resorption. In addition, cortical bone allograft was found to be less antigenic than cancellous bone and exhibit more osteoinductive properties (American Academy of Periodontology & Mellonig, 1994).

On the opposite side the demineralization process of Demineralized freeze-dried bone allograft (DFDBA) leads to exposure of bone collagen and growth factors such as BMPs (Mellonig, Bowers & Cotton, 1981) so the main mechanism of bone formation is through osteoinduction. The risk of antigenicity and graft rejection is not present.

The ability of DFDBA to induce new bone formation depends on the age of the bone donor and some of the commercial preparations of DFDBA had no activity at all (Schwartz et al., 1998).Khosropanah, Lashkarizadeh, Ayatollahi, Kaviani, and Mostafavipour (2018) suggested that the combination of Calcium hydroxide with DFDBA enhance the osteoinductive properties.

2.7.3 Alloplastic graft of Considerations regarding anterior maxillary implant placement

Alloplasts are synthetic biocompatible graft material. They are classified into polymers, ceramics, and bioactive glasses. The Process of bone formation is only through osteoconduction.

Polymers such as methylmethacrylate and hard tissue replacement polymer (HTR) were commonly used in ridge augmentation(Stahl, Frown & Tarnow, 1990).Although it has been reported that tumors might develop(Oppenheimer, Oppenheimer, Stout, Willhite& Danishefsky, 1958).

Bioactive glasses such as Bioglass, Perioglas and biogran are composed of calcium salts and phosphate that is essential for bone mineralization. The materials have the capability to bond with collagen so prevents down the growth of epithelium (Johnson, Sullivan, Rohrer & Collier, 1997). Perioglas bonds to both bone and connective tissue so promote cementum and bone regeneration (Fetner, Hartigan & Low, 1994).

Ceramics are either bioinert or bioactive also biodegradable or non-degradable. Bioinert ceramics such as aluminum oxide and titanium oxide, bioactive ceramics such as hydroxyapatite (HA) and Tricalcium phosphate (TCP) bonds to the host bone chemically.

Resorption of the ceramic material depends mainly on porosity, particle size, and crystallinity. The high degree of material porosity not only accelerates resorption but also contribute to scaffolding provided for bone ingrowth while large particle size delays the rate of resorption. The rate of resorption depends also on crystallinity. For example, Crystalline HA resorb slowly compared to amorphous HA (Ong et al., 1998).

Studies reported that hydroxyapatite HA has a slow resorption rate. On the other hand, Tri calcium phosphate acts as a resorbable biological filler that promotes osseous repair but has a very fast resorption rate. The combination of tricalcium and hydroxyapatite provides benefits of both osteoconduction and resorbability (Kumar, Vinitha & Fathima, 2013). Also, their composition is very similar to natural bone, which enhances biocompatibility.

2.7.4 Xengrafts of Considerations regarding anterior maxillary implant placement

Xenografts are bone substitutes obtained from a species other than human. Animal bones were chemically treated to remove the organic components. These graft materials are osteoconductive, which act as a scaffold for bone formation.  Xenograft materials are derived from two sources either bovine bone or natural coral. The grafting material becomes incorporated into the human bone and is slowly replaced by new bone.

Calcium carbonate bone graft (Caroline) is a resorbable graft material made of natural coral with porosity more than 45% thus promoting osteoconduction and replacement by newly formed bone. The material is found to offer easy manipulation and handling during surgery (Yukna, 1994) and exhibit good heamostatic properties. However, the main disadvantage is the rapid rate of resorption. Mora and Ouhayoun (1995)pointed out that despite the difference in chemical composition between natural coral and porous HA the two materials revealed similar properties and effects.

Bovine xenografts are prepared by removing the organic components and preserving the hydroxyapatite skeleton, which is highly porous and similar to human cancellous bone. This similarity allows integration with the bone and enhances osteoconductivity. This structure undergoes resorption and replacement with new bone. However, some reports showed that replacement of the bovine graft is not complete even after 18 months (Van Steenberghe, Callens, Geers &Jacobs, 2000).Moreover, there is a possibility of transmission of infection and the risk of the immune response (Lane, 1995).

Cerabone® is a xenograft bone grafting material that is composed of pure bovine hydroxyapatite ceramic with surface porosity and chemical composition resembles human bone (Seidel & Dingeldein, 2004). In addition, the 3-dimensional pore network acts as an osteoconductive scaffold for bone ingrowth.

High temperature treatment during manufacturing eliminates the risk of disease transmission (Brown et al., 2000; Tadic & Epple, 2004), removes the organic component and leads to sintering of the calcium phosphate Crystals. Despite some shrinking, the interconnecting porosity of the natural bone is still present (Tadic, Beckmann, Donath & Epple, 2004). However, this thermal treatment might provoke an inflammatory tissue response to the biomaterial (Barbeck et al., 2015).

Fienitz et al. (2017)in a clinically controlled randomized study compared between sintered and a non-sintered bovine xenografts in sinus augmentation procedures and revealed that both radiological evaluation and histological analysis did not show any significant difference between groups.

In addition, Cerabone® offers easy handling due to the strong hydrophilicity of the surface, which provides stickiness and enables contouring of cerabone when mixed with blood or saline. Trajkovski et al. (2018) compared between the hydrophilicity of several bone grafting substitutes and pointed out that cerabone® and maxresor® had the highest level of hydrophilicity.

Seebach, Schultheiss, Wilhelm, Frank and Henrich (2010) compared between six types of bone substitutes regarding their cell seeding efficiency and pointed out that all of them did influence cell seeding but the number of adhering cells was higher in human cancellous allografts followed by alloplastic materials and Cerabone® xenografts.

Janko et al. (2018) also compared autologous bone graft, demineralized bone matrix, beta-tricalcium phosphate and bovine xenograft when preseeded with human bone marrow mononuclear cells. Gene expression, bony bridging and callus formation was found higher in autogenous bone graft.

In addition, Riachi et al. (2012) pointed out that the rate of resorption of cerabone® was significantly lower when compared to other xenografts such as Bio-oss by means of radiographic analysis.

Furthemore, Huber et al. (2008)evaluated the effectiveness of Cerabone by treating a critical size bone defect on New Zealand rabbits and concluded that after 60 days The critical size defect of the cerabone® group was replaced with a median of 55% of newly formed bone.

Moreover, Wainwright et al. (2016) used Cerabone® in a transrectal sinus grafting procedure and the average percentage of new vital bone was 33.4% ± 17.05% after 6 months. Rothamel et al. (2011) also evaluated histologically and clinically cerabone® for sinus floor elevation in 12 patients and after a healing period of six months, the average percentage of newly formed bone 25.8-49.6%. Mazor, Lorean, Mijiritsky, and Levin (2012) also demonstrated that nasal floor elevation with cerabone® might serve as a predictable procedure and bone addition with cerabone® was 3.4 +/- 0.9mm.

Furthermore, Cerabone® could be used effectively for the rehabilitation of the atrophic alveolar ridge (Panagiotou et al., 2015).Deepika-Penmetsa, Thomas, Baron, Shah, and Mehta (2017) suggested that the combination of mineralized allograft and xenograft for horizontal ridge augmentation would enhance bone regeneration and provide satisfactory results. Jegham et al. (2017) also recommended that the combination between autogenous and the bovine xenografts could be used effectively for alveolar ridge reconstruction.

2.8 Platelet rich plasma (PRP) of Considerations regarding anterior maxillary implant placement

Platelet-rich plasma PRP can be defined as platelet concentrates that is driven from the patient's own blood, also termed autologous platelet gel and contains platelets and leukocytes. The platelets contained in this concentrate release their alpha granules after the coagulation process begin. These alpha granules contain growth factors, which promote wound healing (Kang et al., 2010) and accelerates bone regeneration (Miron et al., 2017).

Growth factors found in platelet rich plasma includes platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), fibroblast growth factor, vascular endothelial growth factor (VEGF), Epidermal growth factor (EGF), a platelet-derived angiogenic factor (PDAF), and transforming growth factor-beta (TGF-β) (Borrione, Di Gianfrancesco, Pereira & Pigozzi, 2010).

Growth factors are polypeptide molecules involved in chemotaxis, proliferation, differentiation, and angiogenesis which are stages in wound healing (Bennett & Schultz, 1993). Growth factors also regulate migration, attachment, and proliferation of nearly all cell types (Caffesse, Nasjleti, Morrison & Sanchez, 1994).In addition, they are considered as hormones that play a major role in soft tissue healing and bone regeneration.

In order to evoke a biologic response, growth factors are synthesized by an originated cell such as platelets, macrophages, fibroblasts, and osteoblasts then travels to interact with a target receptor on the effector cell. Autocrine factors are those being synthesized, released and bind to a receptor on the same cell while Paracrine factors are synthesized and released from one cell and binds to the surface receptor of another cell in the local environment (Hill et al., 1989).

Growth factors modulate bone formation by promoting osteoblasts activity and proliferation. Some of the growth factors secreted by osteoblasts diffuse to the extracellular fluid and exhibit an autocrine or paracrine effect on the neighboring osteoblasts while the remaining are being stored in the bone matrix to stimulate delayed paracrine action after bone resorption (Mohan& Baylink, 1991). This counter-regulatory mechanism maintains bone volumes as the amount of bone formation is proportional to bone resorption. This local regulatory mechanism depends on controlling Osteoblastic proliferation and activity by growth factors (Mundy, 1993).

2.8.1 Platelet derived growth factor (PDGF)

Platelet-derived growth factor is a glycoprotein that is synthesized by platelets, macrophages and endothelial cells (Ross, Raines & Bowen-Pope, 1986). It is composed of two subunits having the same size and activity either (PDGF-AA), (PDGF-BB) or (PDGF-AB). PDGF plays a significant role in angiogenesis, the proliferation of mesenchymal cells such as fibroblasts, osteoblasts, and chemotaxis. PDGF acts locally in the tissues but not in the circulation level and its amount is 0.06 mg per one million platelets and about 1200 molecule per platelet (Singh, Chaikin & Stiles, 1982).

PDGF can initiate the repair by its chemotactic on fibroblasts and leukocytes and stimulate endothelial cells proliferation leading to the formation of new capillaries “angiogenesis’. In addition, PDGF regulates the effect of other growth factors stimulating fibroblastic and osteoblastic activity (Lynch, Genco & Marx, 1999).

Pierce et al. (1991) pointed out that PDGF plays a critical role in regulating extracellular matrix deposition within healing wounds so reducing the time of the healing process to occur. PDGF enhances synthesis of collagen type-I in periodontal tissues by promoting the migratory effect of fibroblasts derived from gingival tissue and periodontal ligament (Pierce, Mustoe, Altrock, Deuel& Thomason, 1991).

Kratchmarova, Blagoev, Haack-Sorensen, Kassem, and Mann (2005) demonstrated that mesenchymal stem cells MSCs have stronger differentiation into bone-forming cells when provoked by epidermal growth factor (EGF) versus PDGF. They also suggested that the addition of Wortmannin which is A phosphoinositide 3-kinase inhibitor (PI3K inhibitor) that is a part of important signaling pathway for cellular functions could make PDGF a potential growth factor for osteogenic differentiation.

2.8.2 Insulin-like growth factors (IGF-I and IGF-II)

Insulin-like growth factors are synthesized by multiple tissues including bone cells and are being stored in their inactive forms within the bone matrix. Also epithelium, endothelium, fibroblasts and sooth muscles contribute to its secretion. In addition, the molecular structure is very similar to insulin and binds to distinct surface receptors (IGF receptor).

Both of them regulate bone cells proliferation and differentiation promotes bone matrix formation by synthesis of collagen and proteoglycans and inhibition of bone collagen degradation (McCauley & Somerman, 1998).

IGF-I is a better stimulator of osteoblast marker expression than is PDGF in an old bone. Periodontal tissue regeneration is influenced by the synergetic effect of both PDGF and IGF-I through the stimulation of both fibroblasts and cementoblasts. In addition, studies showed that treatment with the PDGF plus IGF-I combination was slightly better than that of IGF-I alone (Tanaka, Wakisaka, Ogasa, Kawai & Liang, 2002).

The application of a combination of PDGF and IGF-I around titanium implants increased significantly peri-implant bone fill and also increased bone density (Lynch et al., 1991). Moreover, Placement of this combination in the extraction sockets around immediate implants promotes bone repair and osteointegration (Stefani et al., 2000).

2.8.3 Transforming growth factor beta (TGF-β)

Transforming growth factor-beta (TGF-β) belongs to the transforming growth factors family and itis found in highest concentration in platelets (Assoian, Komoriya, Meyers, Miller & Sporn, 1983). The most common factors are TGF-β1 and TGF-β2. TGF-β influences tissue repair by regulating immune, epithelial, connective tissue cells.

After TGF-β it is synthesized, it interacts with a Latency Associated Peptide (LAP) forming a complex called Small Latent Complex (SLC). This complex binds to another a protein called Latent TGF-β-Binding Protein (LTBP), forming the Large Latent Complex (LLC) which is secreted to the extracellular matrix (Rifkin et al., 2005).

TGF-β is synthesized by platelets, macrophages, T-lymphocytes, osteoblasts, and bone matrix. (Cornelini et al., 2003).Activation of TGF-β could occur by Proteases, acidic condition, reactive oxygen species following irradiation and thrombospondin-1 due to injury(Lyons, Keski-Oja & Moses, 1988; Schultz-Cherry & Murphy-Ullrich, 1993).

TGF-β stimulates fibroplasts proliferation, collagen synthesis, angiogenesis, osteoprogenitor cell differentiation, and bone matrix production. Messadi and Bertolami (1991) also suggested that TGF-β influences connective tissue contraction and wound closure.

Bone contains copious amounts of TGF-β which is synthesized by osteoblasts promoting the formation of bone matrix and inhibiting its degradation (Wrana et al., 1988). The higher level of osteointegration around implants was demonstrated in animals treated with recombinant TGF-β1(Clokie, & Bell, 2003). Also Healing of mandibular bone defects in rats were enhanced with TGF-β1 (Srouji, Rachmiel, Blumenfeld & Livne, 2005). Therefore, it is considered as a promising bone regeneration stimulator.

2.8.4 Fibroblast growth factor (FGF)

Twenty-two members of the FGF family have been identified in humans, which are signaling molecules having a similar structure (Finklestein & Plomaritoglou, 2001). FGF-1 is also called acidic FGF (aFGF) and FGF-2 is called basic FGF (bFGF) both are stored in the extracellular matrix of bone. bFGF is found in macrophages, endothelial cells, osteoblasts, and bone matrix. bFGF is found to be more potent as it stimulates other growth factors such as TGF.

FGF stimulate bone formation by promoting osteoblastic proliferation but less effect on bone collagen production. They also stimulate angiogenesis to allow neovascularization during bone healing. FGF is more powerful angiogenic factors than platelet-derived growth factor (PDGF) or vascular endothelial growth factor (VEGF) (Cao et al., 2003).Jingushi, Heydemann, Kana, Macey, and Bolander (1990) pointed out that systemic administration of FGF increase callus formation in animal bone fractures.

2.8.5 Vascular endothelial growth factor (VEGF)

It is also known as a vascular permeability factor (VPF). It was identified by Senger et al. (1983).VRGF stimulates the formation of blood vessels “angiogenesis”, endothelial cells proliferation, and is chemotactic to macrophages and migration of endothelial cells(Johnson, Serio & Dai, 1999). The serum concentration of VEGF is elevated in case of diabetes mellitus and bronchial asthma as it participates in restoring the oxygen supply to the tissues (Palmer & Clegg, 2014).

2.8.6 Epidermal growth factor (EGF)

It is found in many human tissues including the saliva secreted from submandibular and parotid gland (Venturi & Venturi, 2009). It is also present in urine, plasma, semen, and sweat. EGF act through promoting cellular proliferation and differentiation, thus accelerating epidermal regeneration (Herbst et al., 2004).

It was suggested that EGF promotes osteogenic differentiation of dental pulp stem cells (DPSCs) so that the combination between EGF and DPSCs could be used for bone regeneration in oral implantology (Del Angel-Mosqueda et al., 2015).

2.9 Benefits of platelet rich plasma

Platelet-rich plasma is being used in both soft and hard augmentation as it accelerates soft tissue healing, improve vascularization and promote bone regeneration (Anitua, 1999).

Platelet-rich plasma enhances soft tissue healing through stimulation of many processes including fibroblast cell differentiation, angiogenesis and collagen synthesis (Petrungaro, 2001).It is estimated that soft tissue healing is not only 2-3 times faster than normal by the effect of PRP but also scar formation is diminished (Anitua, Andia, Ardanza, Nurden & Nurden, 2004). Platelet-rich plasma promotes bone regeneration by its angiogenic and osteogenic effect (Lucarelli, Donati, Cenacchi & Fornasari, 2004).

Medical uses of platelet-rich plasma PRP also includes treatment of chronic tendinitis, (Mishra, Woodall Jr & Vieira, 2009) osteoarthritis, (Andia, Sánchez & Maffulli, 2012) musculoskeletal injuries, (Foster, Puskas, Mandelbaum, Gerhardt & Rodeo, 2009)and in plastic surgery (Por, Shi, Samuel, Song & Yeow, 2009).

Furthermore, using an autologous PRP eliminates the risk of immune reaction or disease transmission (Weibrich, Kleis, Kunz-Kostomanolakis, Loos & Wagner, 2001). Freymiller and Aghaloo (2004) pointed out that the addition of PRP facilitates the handling and manipulation of the grafting material.

Preparation of platelet-rich plasma is done different forms of center fusion principles and the end result is separation of the whole blood into red blood cells RBC’s, platelet poor plasma PPP and platelet-rich plasma PRP. The addition of thrombin or calcium will activate the platelets to release growth factors and convert the PRP into a gelatinous consistency.

Da Silvaet al. (2016) demonstrated that platelet activation with thrombin, or calcium chloride before PRP application is not crucial since activation also occur under conditions of preparation, such as thepressure inside the needle, manual manipulation and temperature. Vahabi, Yadegari, and Mohammad-Rahimi (2017) showed that activated PRP had a greater effect than non-activated PRP

2.10 Application of PRP in oral sugery

PRP promotes healing in many procedures in oral surgery including mandibular reconstruction, treatment of infrabony periodontal defects, alveolar ridge augmentation, socket preservation and procedures related to the placement of dental implants (Albanese, Licata, Polizzi & Campisi, 2013). Recently, it has been suggested for treatment of osteonecrosis of the jaw (Cetiner et al., 2009).

There is the value of using platelet-rich plasma in the treatment of periodontal defects. Hanna, Trejo, and Weltman (2004) showed that treatment of intrabony defects was significantly improved by addition of platelet-rich plasma to a bovine xenograft.

 Okuda et al. (2005) concluded that the addition of PRP to HA resulted in a significantly favorable clinical improvement in intrabony periodontal defects.Also a significant improvement in probing pocket depth and bone radio-density were detected (Kaushick, Jayakumar, Padmalatha & Varghese, 2011).

PRP is also effective in promoting bone regeneration after tooth extraction (Sammartino et al., 2005). PRP has some benefits in minimizing post-extraction complications such as alveolar osteitis, post-operative pain and improving healing of soft tissue of extraction sockets(Alissa, Esposito, Horner & Oliver, 2010).Rutkowski, Johnson, Radio andFennell (2010) demonstrated a significant increased radiographic density in PRP- treated extraction sites. Moreover, Ogundipe, Ugboko, and Owotade (2011) reported improvement in postoperative pain, swelling and bone density after extraction of impacted wisdom in the PRP group.

Oyama, Nishimoto, Tsugawa, and Shimizu (2004) suggested the use of a combination of autogenous iliac bone graft and PRP in cleft lip and palate patients to stimulate osteogenesis and bone regeneration.

Anitua (2006) showed that coating the implant surface with PRP before insertion promotes osteointegration around dental implants. The use of platelet-rich plasma leads to the improvement of early bone apposition around the implant and enhances the ability of peri-implant healing (Anand & Mehta, 2012).Nikolidakis, Van Den Dolder, Wolke & Jansen (2008)observed a significant effect on bone opposition to roughened titanium implants bioactivated with PRP, in the early phase of healing. However, Garcia et al. (2010) concluded that PRP did not affect bone formation around acid-etched implants. Monov et al. (2005) used a split-mouth setting and evaluated resonance frequency analysis but no difference was found between the PRP group and the control group.

Treatment of bone defects around dental implants could be improved successfully by adding PRP to the grafting material (Kim, Kim, Park & Kim, 2002; Kim, Chung, Kim, Park & Lim, 2002). Kassolis, Rosen, and Reynolds (2000)combined freeze-dried bone allograft and platelet-rich plasma for ridge augmentation before implant placement and pointed out that this combination allows earlier implant placement. In addition, Treatment of infected implant sites with combined bone grafting, tissue regeneration, and platelet-rich plasma was suggested By Petrungaro (2002) to enhance healing.

When used in maxillary sinus augmentation, the combination of the grafting material and PRP enhances the rate of formation of bone and shorten healing time (Kassolis & Reynolds, 2005). According to Khairy, Shendy, Askar and El-Rouby (2013), the Addition of PRP to the bone graft was associated with higher bone density at 6 months post-operative. However, Esposito et al. (2010) argued that PRP use in sinus lifts associated with implant placement did not offer any benefit.

2.11 Combination Between bovine xenograft and platlete rich plasma PRP

The combination of bovine xenograft and platelet-rich plasma has been reported to be effective periodontal therapy in the management of intrabony defects (Camargo et al., 2002). This combination benefits the regenerative capability of PRP and the osteoconductivity of the bovine xenograft.

Lekovic, Kenney, Carranza, and Martignoni (1991) pointed out that this combination between PRP and bovine xenografts reduced the probing depth and gained clinical attachments in mandibular molars with class II furcation involvement.

Yilmaz, Cakar, Kuru, Dirikan, and Yildirim (2009) reported that adding platelet-rich plasma to bovine xenograft results in a significantly favorable radiographic and clinical improvement in deep intrabony periodontal defects.

Furthermore, Zahran and Hosni (2005) concluded that guided bone regeneration around immediate implants using a mixture of bovine xenograft and PRP covered with a collagen membrane did enhance bone regeneration and osteointegration effectively. ArRejaie, Al-Harbi, Alagl, and Hassan (2016) also concluded that Autogenous PRP gel combined with bovine xenograft demonstrate superior results compared to the bovine xenograft alone when used for augmenting dehiscence around immediate implants.

On the other hand Peng et al. (2016) concluded that the addition of PRP to bovine xenograft in the repair of bone defects around the implant may delay bone healing.

Moreover, Cabbar, Güler, Kürkcü, Işeri, and Şençift (2011) evaluated the effect of PRP on xenograft for augmentation of the maxillary sinus. On one side the sinuses were filled with xenograft and PRP combination, while on the opposite side sinuses were filled with xenograft alone. There were no statistically significant differences found.

In addition, Froum, Wallace, Tarnow and Cho (2002) reported that Histomorphometric analysis of patients undergoing sinus floor augmentation treated with bovine xenograft with and without PRP did not show a significant difference either in vital bone formation or in bone contact on the implants