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The mastery of surgery was no longer associated with speed or flamboyance, but instead focused on meticulous dissection, careful handling of tissues, hemostasis, and correct approximation of tissue planes to promote adequate healing. Among operative specialties, this transition from “art” to “science” of surgery was most profound in the neurosurgical field, enabling rapid advances to occur.
\nEarly in the evolution of modern surgery, the issue of hemostatic control became prominent, as the heavily vascularized central nervous system and its propensity to bleed resulted in limitations of procedures and posed significant challenges [3, 4, 5]. Surgical ligation was utilized sparingly for fear of vessel rupture or vascular occlusion that may compromise entire vascular distributions. The instruments and techniques in neurosurgical armamentarium therefore relied predominately on application of pressure with gauze to combat bleeding [3, 6]. As a result, a search and incorporation of novel alternatives in hemostatic techniques would effectively lead to the development of modern neurosurgery as represented by Horsley’s use of bone wax and other pioneering hemostatic maneuvers [7, 8] and the introduction of electrosurgery by Cushing and Bovie in the 1920’s [9, 10]. Later in the revolutionary era of neurosurgery, biosurgical materials were introduced [6, 11].
\nIn its broadest sense, the term biosurgery relates to the utilization of biomaterials that are defined as systemically and pharmacologically inert substances designed for implementation within or incorporation with living systems [12, 13, 14]. In the context of the current chapter, biosurgical materials (BSMs) are defined as biomaterials that are intended as adjuncts in attaining surgical hemostasis [15, 16]. The gradual development of hemostatic techniques has greatly impacted not only the field of neurosurgery, but all of surgery. The application of biosurgical agents first developed in the neurosurgical theater proved immensely valuable across virtually all surgical applications.
\nOne of the earliest neurosurgical applications of biosurgical hemostats involved the control of bleeding in inaccessible areas with difficult tissue topography and in situations where use of electrocautery, sutures, or clips may simply not be feasible [4, 13, 17]. This chapter will review the categories, mechanism of action, efficacy, advantages, disadvantages, and complications of the various biological materials currently available for hemostasis in neurosurgery.
\nThe abundance of biosurgical materials available for use requires a system of categorization. These agents can be divided into specific categories based on their mechanism of action, including passive or active hemostatics, flowable agents, and sealants [18, 19, 20]. Passive or mechanical agents act through contact with the site of bleeding to promote platelet aggregation [21, 22]. They form a matrix type network at the site of bleeding, thereby activating the coagulation pathway to provide a platform for platelet aggregation and clot formation. At the same time, these agents will be ineffective if used on patients with known coagulopathies due to factor deficiencies or platelet dysfunction. These products include gelatins, collagens, cellulose, and polysaccharide spheres. They require no special storage, minimal or no preparation, and are relatively inexpensive [23, 24].
\nActive hemostatic agents act biologically and directly participate in the coagulation cascade to stimulate fibrinogen at the site of bleeding to produce a fibrin clot [21, 25]. These agents primarily include the different forms of thrombin, and are useful in patients with coagulopathies or platelet dysfunction [18, 26]. However, they rely on the presence of fibrinogen in the patient’s blood to be effective. In general, they control bleeding more effectively than passive agents, are more costly, and are prepared/available in various forms and formulations.
\nFlowable hemostatic agents consist of various combinations of active and passive components within a single application [20, 27]. This category includes products that work by providing a physical barrier to blood flow while actively converting fibrinogen in blood into fibrin at the bleeding site [26, 28]. Finally, sealants work by the formation of a barrier impervious to flow [24, 29]. There are several types of sealants currently available for use. Our subsequent discussion will focus on each of the various types of biosurgicals utilized, with emphasis on neurosurgical applications.
\nThis material contains 1-μm microcrystals of purified bovine dermal collagen available as flour-like or sheet-like format [30, 31]. The microcrystalline collagenous network provides surface for platelets to aggregate while coagulation factors are released [30, 31]. The effectiveness of microfibrillar materials may be decreased in cases of severe thrombocytopenia (<10,000 mL) [32]. The material should be kept dry prior to use because moisture may decrease its activity and the hydrophilic nature of product results in adherence to surgical gloves and possible mis-application. Consequently, the material is best handled with sterile forceps. As with other biologic hemostats, optimally the smallest amount required to arrest bleeding should be utilized, although this may not be precisely known in every situation.
\nOf importance, microfibrillar collagen is considered a foreign substance and can therefore serve as a nidus for infection and/or foreign body reaction [33]. The small particles of the flour-like material are useful for arresting bleeding from cancellous bone. In this setting, it has demonstrated superior efficacy when compared with other agents, such as thrombin alone or thrombin combined with gelfoam [7]. It also does not seem to interfere with bone healing in contrast to oxidized cellulose or bone wax [34]. It is recommended to firmly pack product into bone surface followed by direct pressure for 5–10 minutes. In terms of clinical application considerations, it should not be used in areas where it may exert pressure on adjacent structures because of fluid absorption and expansion. Also, excessive expansion along a dural sinus may lead to occlusion after bone flap replacement. Although collagen is relatively less antigenic and only results in minor inflammation there remains the very small risk of allergic reactions [35, 36]. Finally, it can also lead to infection, abscess, pseudo-abscess or granuloma formation [37, 38, 39].
\nThis type of biomaterial was developed in the 1940’s to help facilitate hemostasis [40, 41]. It is available as pads, strips or powder [40, 42, 43]. It can absorb seven to ten times its own weight [44]. This ubiquitous hemostatic agent is one of the most frequently used. Upon contact with blood, the material reacts to form a reddish black gelatinous mass containing hematin (accounts for the color change) [45]. The oxidation of cellulose results in a product of low pH with resultant bacteriostatic properties [46, 47]. Despite the antimicrobial properties the rates of infection do appear to correlate with the amount of retained product [48]. Consequently, though often left in place in surgical beds, excess amounts should be removed prior to wound closure. Of note, the addition of saline or thrombin to oxidized regenerated cellulose may decrease its effectiveness in addition to inactivating thrombin as a result of the acidic environment [49]. It may also interfere with bone healing and may cause blood vessel compression [49]. Finally, there are reports of excessive postoperative swelling of this type of biomaterial [50].
\nAlso introduced in the 1940’s this type of hemostatic material consists of water-insoluble sponges prepared from purified porcine skin gelatin [11]. It provides hemostasis by absorbing up to 45x its weight in fluid, thus restricting blood flow and providing stable matrix for clot formation [51]. Gelfoam with gentle pressure can tamponade and treat most dural sinus bleeding without occlusion of the sinus. Although hemostatically beneficial, this capacity to expand physically can lead to compression of neural (and vascular) structures [52]. Absorbable gelatin material is considered relatively nonreactive, however there have been case reports of giant-cell granuloma formation at the implantation site [53, 54]. Although generally non-antigenic, this type of biosurgical material is considered a foreign body and can serve as a nidus for infection [55].
\nThis is a relatively new category of biosurgicals, derived from vegetable starch containing no animal or human components [56, 57, 58]. It is available in powder form with a bellows-type applicator [56, 59]. The material requires no mixing and is available for immediate use. It produces a hydrophilic effect to dehydrate blood and concentrate solid components to increase barrier formation [59, 60]. It poses little risk to patients since it lacks any human or animal components and should not be used in closed spaces because of physical expansion / swelling.
\nThere are three forms of thrombin products differentiated based on type of plasma used to provide concentrated thrombin to rapidly convert fibrinogen to fibrin clot [61, 62, 63]. This class of biosurgicals should be used in cases of mild to moderate bleeding, mainly because such products tend to be easily washed off in the setting of brisk arterial bleeding or surgical irrigation [64]. In addition, thrombin-based hemostatic agents may be less effective in situations of severe fibrinogen deficiency [15]. Finally, thrombin products should not be allowed to enter the vascular system as intravascular thrombosis can occur [65].
\nAntibody formation represents a risk with the use of bovine thrombin, leading to coagulopathy and even death in rare cases [66, 67]. In fact, there is a “Black Box” warning associated with this complication. The use of bovine thrombin is contraindicated if the patient is allergic or has known sensitives to materials of bovine origin [23, 68]. On the other hand, pooled human plasma carries a potential risk of viral or prion disease transmission since multiple units of blood are required to manufacture each lot of product [69, 70].
\nThese products represent a combination of absorbable passive and active hemostatic components [71, 72]. One of the flowables currently available is a combination of bovine gelatin particles and pooled human thrombin [73, 74], while the other consist of absorbable porcine gelatin particles combined with stand-alone thrombin [27, 75]. In order to become effective, the flowables require direct contact with blood as fibrinogen source [76]. Reconstitution is required, with these products having a paste-like consistency and the ability to “remain in place” compared to liquid thrombin [43]. Flowables are applied with a syringe-like applicator and require 2–3 minutes of preparation time [28, 77]. Direct injection into emissary veins or venous sinuses should be avoided to decrease the risk of dural venous sinus thrombosis and post-operative venous stroke.
\nThis group of agents consists of concentrated fibrinogen and thrombin. They increase the rate of blood clot formation by providing higher concentrations of both fibrinogen and thrombin [78]. There are three available types: (a) Pooled human plasma [79, 80]; (b) Individual human plasma, bovine collagen, and bovine thrombin [81]; and (c) Pooled human plasma and equine collagen [82].
\nSealants may be used in coagulopathic patients with insufficient fibrinogen [64, 78, 83]. These agents can also be used in heparinized patients since they do not rely on host factors for hemostasis [84, 85, 86]. Typical indications are hemostasis during cardiopulmonary bypass, splenic injuries, and a number of less commonly utilized general surgical applications [23]. However, they are widely used as hemostatic adjuncts and sealants during neurosurgical procedures, including the prevention of cerebrospinal fluid (CSF) leaks [87, 88].
\nThere are three different product types in this class of biosurgicals [89, 90]. They tend to be most efficacious when used on a relatively dry field to allow sufficient time for polymerization [91]. One type of polyethylene glycol polymers (PGPs) consists of a combination of 2 polyethylene glycol (PEG) polymers that cross-link to each other and contact tissue following application [92]. In effect, the PGP-based network acts as a sealant to tissue fluids as well as barrier to cell ingrowth and adhesion formation [92, 93].
\nAnother type of PGP material consists of a combination of PEG polymer, trilysine amine, and blue dye [94, 95]. This particular component mix produces a hydrogel able to help with dural closure because of its ability to form a watertight seal [96]. A modified derivative using a reduced molecular weight PEG component can be used in sutured dural repair during spinal surgery [96, 97]. The built-in blue dye is used to provide accurate placement of sealant [98, 99]. Some concerns about this particular material being associated with cases of postoperative spinal cord compression have been voiced [94, 100, 101, 102]. As such, specific non-expanding formulations exist for usage in the spinal canal [103].
\nThe third class of PEG polymer compound consists of a combination with human serum albumin. This substance is biodegradable and fairly well studied in terms of safety and effectiveness [104]. It provides a strong barrier, as evidenced by the FDA approval for use on visceral pleura to close air leaks of >2 mm during pulmonary surgeries [105]. There may also be associated economic benefits of using this type of biologic sealant [106].
\nIt is important to realize that biosurgical agents are adjuncts to hemostasis when standard methods like direct pressure, suturing, or cautery are impractical or ineffective [107, 108]. Good knowledge of the mechanism of action of different available biosurgical hemostats is critical, with multiple considerations including the patient’s anticoagulation status, the rate of bleeding, the presence of thrombocytopenia, fibrinogen level assessment, and many other factors. The choice of a specific biosurgical product should be dependent on the type of surgery, site of bleeding, other anatomic considerations, cost, and preference of the operating neurosurgeon [3, 16, 32, 109, 110].
\nThe continuous oozing encountered from dilated varicose intraspinal veins and bone during spinal surgery can be effectively managed with topical hemostats [111, 112]. With that said, such materials should not be left in contact with intra or extradural nerve roots due to possibility of granuloma formation [39, 53, 54, 113]. There have been reports of paraplegia from use of oxidized cellulose during thoracotomy from passage of material through the intervertebral foramen resulting in spinal cord compression [114, 115]. Therefore, it is recommended to use only the minimum required amount and any excess material should be removed once adequate hemostasis is attained.
\nBiosurgical materials are increasingly applied during spinal cord surgery to help with hemostasis since opportunities for electrocautery use are limited in this setting. Bipolar cautery, although more focused than monopolar cautery, can also allow dissipation of heat from the tips inducing thermal injury to vascular and neural structures. Fibrin glues are commonly used as hemostatic agents in neurosurgical procedures, including the management of epidural, cortical, and dural sinus bleeding [116].
\nDuring surgical resection of brain tumors, from craniotomy to extradural hemostasis following dural closure, one will find that these agents are generally used throughout the procedure. For example, oxidized regenerated cellulose is widely used during ablation of lesion(s) and at the end to prevent and abate any bleeding in the remaining cavity. However, excess agent should not be left along the surgical cavity. A single layer of oxidized regenerated cellulose should be sufficient for hemostasis without significant risk. Evaluations of the efficacy and safety of polysaccharide hemospheres reported no adverse events after use in brain surgery. There have been several reports of signal anomalies on post-operative imaging mimicking residual tumor or early recurrence, or even abscess when oxidized regenerated cellulose or gelatin sponges are left in the operative field. A pediatric case series of 3 patients who underwent intracerebral surgery with use of microfibrillar collagen reported that all required second surgery for new or recurrent seizures [38]. An MRI of preoperatively suspected tumor recurrence or abscess subsequently confirmed to be microfibrillar collagen-centric necrotizing granuloma surrounded with macrophages and eosinophils. One must remain aware of the above considerations and remove any local hemostatic agent prior to dural closure.
\nBleeding during surgery on the pituitary via a transsphenoidal approach may significantly impede visualization while not being conducive of the use of electrocautery [117]. The use of oxidized cellulose and Floseal (Baxter, Deerfield, IL) can be useful in this situation. Mild persistent oozing from brain tissue following excision can be controlled with application of oxidized regenerated cellulose followed by its removal from the remaining cavity prior to closure. Defects of the skull base in some cases require filling of the defect with bone graft, followed by suture and/or grafting of the dura reinforced with fibrin sealant. A minimally invasive treatment of spontaneous supratentorial intracerebral hemorrhage was also described using Floseal. Floseal was placed in 31 patients without evidence of vascular anomalies or coagulopathy following evacuation of hematoma from a 3 cm craniotomy. Hemostasis was achieved in all but 1 patient who required re-exploration [118].
\nA multicenter, prospective randomized study with 237 patients undergoing elective cranial surgery demonstrated PEG hydrogel (DuraSeal, Integra LifeSciences, Princeton, NJ) similarly safe when used with common dural sealing techniques (eg, sutures, autologous grafts, gelatin or collagen sponges, fibrin glues) or when used as dural closure augmentation in cranial surgery [99]. The incidences of neurosurgical complications, surgical site infections and CSF leaks were similar between treatment groups using PEG hydrogel and the control group using standard dural sealing techniques. DuralSeal was also found to be statistically significantly superior to fibrin sealant at preventing CSF leaks following posterior fossa craniotomy or craniectomy [119]. However, the special formulation of DuraSeal Exact should be used in areas where expansion can lead to neurologic compromise – such as the spinal canal [120]. This is because neurologic compromise after expansion has been described in the literature [101, 121]. This again emphasizes mindfulness to use to least amount of material to achieve closure and/or hemostasis while precluding migration or expansion of any excess materials.
\nHemostasis in neurosurgery – more so that many other surgical disciplines – is challenged by the closed space environment of the brain, spinal cord, and other critical structures [3, 122, 123]. Unlike other areas in which the “bulk” or space-occupying characteristics of biosurgicals may represent a potential benefit as they expand, this is less desirable in neurosurgical applications. In the closed environment of the skull, brain, or the spinal cord – even if bone is removed to help minimize the effect of swelling from edema – a relatively small amount of compression, especially in critical areas, like the brain stem, can have devastating consequences. As discussed in previous sections of this chapter, such compressive complications, if left untreated can result in irreversible neurologic damage [94, 100, 101, 102], with resultant “Black Box” warnings clearly outlining biomaterial-specific restrictions.
\nOf growing concern in all aspects of surgery is the increasing utilization of anticoagulants and anti-platelet therapies – and often various combinations of both [124, 125]. While the indications for such therapies are outside of the scope of this review, it is clear that more and more patients are being prescribed agents belonging to these broad medication classes. This is of special significance in the elderly population, where anticoagulants and antiplatelet drugs are used for stroke reduction (e.g., in non-valvular atrial fibrillation); various prophylaxis indications (e.g., orthopedic surgery); and of most concern, being used without any clear indications [126]. However, many clinical factors that prompt physicians to initiate antiplatelet or anticoagulant use also increase the neurosurgical risk associated with even minor traumatic events (e.g., falls and minor head injuries). Under such circumstances, even minor neurological injuries can quickly evolve into bleeding-related catastrophes when patients are anticoagulated [127, 128, 129].
\nNeurosurgical interventions in the setting of traumatic (or even spontaneous) subdural, epidural, and intraventricular hemorrhage, when confounded by drugs that inherently interfere with hemostasis can compound the difficulties and risks of an already complex clinical scenario [130, 131]. The overall challenge can be magnified even further as acute reversal agents tend to be expensive, may not always be available, reliable/effective, and could result in thrombotic complications in high-risk scenarios such as multi-trauma or massive transfusion [131, 132, 133, 134]. Furthermore, reversal algorithms and guidelines, while helpful do not always definitively address the acute problem once significant bleeding starts, and regardless of the mechanism and defect in the clotting cascade, a consumptive process may be triggered that might require a multi-faceted approach to effectively and timely manage the associated coagulopathy [134, 135, 136, 137]. Similar to other surgical scenarios, such as major trauma and cardiothoracic surgery, at times the best way of managing bleeding is via a timely and aggressive operative intervention. The above concepts are critical in the setting of neurosurgical applications of biosurgical hemostats in that it must be recognized that “bleeding” is a complex problem and often requires a combination of tools to control. Such basic tools require an understanding of the primary question – why is this patient bleeding?
Other patient factors and comorbidities can have unpredictable effects on hemostasis, but must be considered in the bleeding neurosurgical patients. Elderly, debilitated, and frail patients might be malnourished and hence have impaired protein stores which contribute to diminished clotting factor reserves – even in the setting of normal clotting tests. Patients might be taking herbal supplements (which might not even be reported in a medical record or medication lists) that have been correlated with bleeding risks [140, 141, 142].
Each of the above considerations requires a focused approach and highly specific management strategy. It is important to recognize that good surgical technique must be augmented with a broader understanding of the biologic mechanisms that contribute to the overall disease process and that there is no single tool that is ideal for all circumstances [108, 138]. Conversely, it must be recognized that there is a growing concern that using the wrong or inappropriate therapy for a given clinical scenario can be just as problematic, if not intrinsically ineffective or potentially dangerous. More so than ever in the past, optimal management of the neurosurgical patient (especially one who is bleeding) requires an in-depth and comprehensive understanding of the complex mechanisms of hemostasis pathways and the clotting cascade while also recognizing those variables, such as pharmaceutical therapies, that might adversely impact the normal balance between clotting and bleeding.
\nIn summary, in the setting of neurosurgical bleeding management, several key concepts must be recognized:
Use the right tool for the right job
Sometimes more than one approach is necessary to control bleeding
Different types of bleeding might require different management strategies
Difficult to access areas
Risk for post-operative re-bleeding
Compressive or expanding agents can cause devastating complications
Recognizing the differences between arterial and venous bleeding and how management of each might be different
Understanding the specific reasons why bleeding is occurring and what interventions – such as biosurgical agents – should be central to the overall hemostatic management.
Sometimes the best approach to managing bleeding is preventing it in the first place with strict attention to surgical technique and anatomy. It might sound inherently obvious, but the best way to avoid a dural sinus bleeding is to avoid injury in the first place.
Uncontrolled or difficult to control bleeding in neurosurgery is a challenging clinical problem and one that is becoming more common with wider use of anti-coagulant and anti-platelet agents in a population that is aging, becoming more frail, has more co-morbidities, and is at increasingly greater risk for neurotrauma. In addition, as more patients are undergoing major surgical interventions and re-interventions for complex neuro-axial pathologies the risks for bleeding complications also increase. Effective management of bleeding and bleeding related morbidity requires a thorough understanding of the mechanisms of bleeding and potential biologic defects in the normal hemostatic process. With such an understanding, management can be more focused and targeted towards the specific problem. Hence, an understanding of the adjuvant therapies, such as the full-spectrum of biosurgical agents that can be used to manage bleeding is imperative in achieving optimal patient outcomes.
\nThe authors would like to acknowledge Dr. Roy S. Hwang, for his support and expertise during the preparation of this manuscript.
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\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\\n\\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nOAI-PMH
\\n\\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\\n\\nLicense
\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\\n\\nPeer Review Policies
\\n\\nAll scientific works are Peer Reviewed prior to publishing. Read more
\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\\n\\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\\n\\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
\\n\\n\\n"}]'},components:[{type:"htmlEditorComponent",content:'
The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. 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After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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The most histologic type of carcinoma is squamous cell carcinoma, seen in oral and oropharyngeal region with the incidence of 90%. Prevention or early diagnosis of premalignant and oral cancer requires increased public awareness and educating practitioners to be skillful in identifying oropharyngeal region pathology. To prevent oral cancers, the etiological factors should be known, and measures must be taken according to those factors. Premalignant lesions are leukoplakia, lichen planus in oral and cutaneous form, erythroplakia, stomatitis nicotina, and submucous fibrosis. Premalignant lesions should be treated, if possible, or followed up on carefully. To date, there are many clinical, histopathological, radiological, and optical techniques to diagnose or capture precancerous and oral cancer lesions early. The routine management of oral cancers is firstly surgical resection with or without postoperative adjuncts and other therapies such as the use of postoperative chemoradiation and radiation. Successful treatment of oral cancer patients is a complex issue that requires a multidisciplinary approach, including oral and maxillofacial surgeons, oral and maxillofacial radiologists, ENT specialists, medical and radiological oncologists, prosthodontists, dentists, speech therapists, supportive care experts, and also pathologists or, if possible, oral and maxillofacial pathologists.",book:{id:"8631",slug:"prevention-detection-and-management-of-oral-cancer",title:"Prevention, Detection and Management of Oral Cancer",fullTitle:"Prevention, Detection and Management of Oral Cancer"},signatures:"Nihat Akbulut and Ahmet Altan",authors:[{id:"262769",title:"Dr.",name:"Nihat",middleName:null,surname:"Akbulut",slug:"nihat-akbulut",fullName:"Nihat Akbulut"},{id:"268500",title:"Dr.",name:"Ahmet",middleName:null,surname:"Altan",slug:"ahmet-altan",fullName:"Ahmet Altan"}]},{id:"63395",title:"The Impact of Sequencing Human Genome on Drug Design to Treat Oral Cancer",slug:"the-impact-of-sequencing-human-genome-on-drug-design-to-treat-oral-cancer",totalDownloads:892,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Of all the known cancers, oral cancer is the most preventable and it is the second most deadly cancer after the breast cancer. 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She is now a lecturer at the University of Witwatersrand, South Africa, and a principal researcher at the Health Economics and Epidemiology Research Office (HE2RO), South Africa. Dr. Moolla holds a Ph.D. in Psychology with her research being focused on mental health and resilience. In her professional work capacity, her research has further expanded into the fields of early childhood development, mental health, the HIV and TB care cascades, as well as COVID. She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. 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