Dental Hypotheses

REVIEW ARTICLE
Year
: 2019  |  Volume : 10  |  Issue : 4  |  Page : 85--90

Applications of Fibrin-based products in Endodontics: A Literature Review


Behnam Bolhari, Naghmeh Meraji, Abdollah Ghorbanzadeh, Pegah Sarraf, Razieh Moayeri 
 Department of Endodontics, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran

Correspondence Address:
DDS, MSc, DoIBoE Naghmeh Meraji
Department of Endodontics, School of Dentistry, Tehran University of Medical Sciences, North Kargar st., Tehran
Iran

Abstract

Introduction: Endodontic treatment of necrotic immature teeth is quite challenging. Current concepts for revitalization of these teeth known as regenerative endodontic treatment (RET) is based on key elements necessary for tissue engineering including stem cells, three-dimensional (3D) scaffolds, and growth factors. Utilizing an applicable scaffold for narrow root canal space with adequate properties is essential for successful outcome. Fibrin-based products are materials with various advantages as a scaffold. This review article aims to discuss the properties of different types of fibrin-based products and debates whether they are appropriate scaffolds for RET or not? Methods: An electronic search was performed using databases such as Google Scholar, PubMed, PubMed Central, Science Direct, and Scopus. Keywords such as (“scaffold”)AND (“fibrin gel” OR “fibrin sealant” OR “fibrin glue” OR “fibrin tissue adhesive” OR “fibrin hydrogel” OR “platelet concentrate”) AND (“tooth” OR “teeth”) AND/OR (“regenerative endodontics” OR “dentistry”) were used. Exclusion criteria included studies published in a language other than English and abstracts from congress. Results: Fibrin gel is a protein-based natural polymer hydrogel scaffold which can be easily used in the root canal. Platelet concentrates are autologous fibrin-based products used as scaffolds for RET with various favorable properties especially due to containing various growth factors. Conclusion: It seems that fibrin gel and platelet concentrates have adequate properties for use in RET; however, more evidence is required regarding the clinical outcome of applying these products as scaffolds for RET.



How to cite this article:
Bolhari B, Meraji N, Ghorbanzadeh A, Sarraf P, Moayeri R. Applications of Fibrin-based products in Endodontics: A Literature Review.Dent Hypotheses 2019;10:85-90


How to cite this URL:
Bolhari B, Meraji N, Ghorbanzadeh A, Sarraf P, Moayeri R. Applications of Fibrin-based products in Endodontics: A Literature Review. Dent Hypotheses [serial online] 2019 [cited 2020 Sep 19 ];10:85-90
Available from: http://www.dentalhypotheses.com/text.asp?2019/10/4/85/277006


Full Text



 Introduction



Endodontic treatment on necrotic immature teeth is a clinically challenging procedure. As pulp necrosis has occurred during root development due to damages caused by traumatic injuries, dental anomalies, or caries, these teeth have short roots, thin dentinal walls, and lack the apical root canal constriction; thus, usually they cannot be treated by routine endodontic procedures.[1] Regenerative endodontic treatment (RET) is a biologically based approach aimed to regenerate the dentin–pulp complex[2] and consequently cause continuation of root development.[3],[4] RET is a subset of tissue engineering; thus, it pursues the same goals and principles of tissue engineering, in conjunction with principles of routine endodontic treatments, such as root canal disinfection. Tissue engineering is based on the following necessary key elements: stem cells, 3D scaffold, and growth factors or morphogens.[4]

The presence of an appropriate scaffold is necessary for regeneration. Scaffolds should promote a 3D support for stem/progenitor cell adhesion, migration, and proliferation, all of which paramount for tissue regeneration.[5] In the case of RETs, the suggested protocol for scaffold creation entails the intentional induction of bleeding from the periapex and the formation of an intracanal blood clot.[6] Several reports have been published demonstrating good success with blood clot scaffolds[7],[8]; however, because it is not always possible to invoke bleeding in the root canal,[9] researchers have begun examining other 3D scaffolds. Some examples include organic collagen-based scaffolds,[10],[11] synthetic polymers,[12],[13] calcium phosphate,[14] platelet-rich plasma,[15],[16] platelet-rich fibrin,[17],[18] and hydrogel.[19]

Fibrin-based products are materials having various advantages as a scaffold. This review article aims to discuss the properties of different types of fibrin-based products and evaluate if they can be acceptable scaffolds for RET.

 Methods



An electronic search was performed using databases such as Google Scholar, PubMed, PubMed Central, Science Direct, and Scopus by using keywords such as (“scaffold”) AND (“fibrin gel” OR “fibrin sealant” OR “fibrin glue” OR “fibrin tissue adhesive” OR “fibrin hydrogel” OR “platelet concentrate”) AND (“tooth” OR “teeth”) AND/OR (“regenerative endodontics” OR “dentistry”). The last search was performed in March 2019.

Inclusion criteria were all in vitro, ex vivo, clinical studies, case reports or series, and review articles about fibrin gels and/or sealants and/or adhesives and/or glue and/or platelet concentrates in dentistry. Exclusion criteria included studies published in a language other than English and abstracts from congress. The articles were selected to address the following research question: Can fibrin-based products be acceptable scaffolds for RET?

 Results



A total of 570 articles were identified after elimination of duplicates and articles in languages other than English by our search strategy. After evaluation of the titles, abstracts, and full texts, 103 references were included for review and evaluation. Among these articles, 14 were review articles, nine were clinical trials, and four were case reports/series.

 Discussion



Scaffolds in regenerative dentistry

An ideal scaffold for regeneration should facilitate the attachment, migration, proliferation, and 3D spatial organization of cell populations in the target tissue.[5],[20] Biocompatibility of a scaffold is also critical to prevent adverse tissue reactions.[20] Biodegradability is also a crucial property and must be tunable to facilitate constructive remodeling.[21] This phenomenon is described as scaffold degradation in an appropriate rate corresponding to the rate of cell/tissue infiltration, cellular migration, proliferation and differentiation, vascularization, and replacement of the scaffold by the appropriate tissues.[20] Another important property required for scaffolds is adequate porosity and pore size. Porosity facilitates cell seeding and diffusion of both cells and nutrients throughout whole structure of the scaffold.[22]

Based on their origin, scaffolds can be classified into two groups: biological/natural or synthetic/artificial. They can also be classified into four groups based on their form: solid blocks, sheets, porous sponges, and hydrogels (injectable scaffolds).[23]

Fibrin-based products are protein-based natural polymers having several advantages such as exceptional biocompatibility, controllable degradation rate,[24] production of nontoxic degradation products, having similar viscoelastic properties to connective tissue, efficient diffusion of nutrients and waste, having tunable morphology, adequate mechanical properties,[20],[24],[25] uniform cell distribution,[24],[26] and promotion of angiogenesis.[24],[27] Fibrin allows the growth and differentiation of dental stem cells and thus accelerates tissue regeneration in the oral cavity.[28] These scaffolds can be very practical for regenerative endodontics as they can be easily used and can deliver chemotactic and angiogenic factors to resident stem cells.[1]

Structure and properties of fibrin-based products

Fibrin-based products have been initially used as bioadhesives for hemostasis in surgical procedures, wound closure, and a sealant,[25] and their application has been growing in the past decades. Recently, the application of fibrin gels in tissue engineering has become more common.

Fibrin is a biopolymer of the fibrinogen monomer. Fibrinogen and thrombin are the main components involved in the blood-clotting process. Thrombin is a protease existing in the plasma. Thrombin-mediated cleavage of fibrinopeptide A and fibrinopeptide B from fibrinogen initiates the formation of fibrin[29] thus creating a 3D gel.[30]

Fibrin glue (fibrin sealant) is one of the first available fibrin-based products. It was prepared from pooled plasma. Human plasma was used as a source for fibrinogen (homologous or autologous) to reduce the potential risks of immunological reaction.[31] Thrombin was purified from bovine plasma. Each of these two precursor solutions are stored in a separate syringe. Fibrin glue has two components: first, a freeze-dried concentrate of clotting proteins (the sealant), mainly fibrinogen, factor XIII, and fibronectin, and second, the catalyst containing freeze-dried thrombin and CaCl2 and antifibrinolytic drugs.[28],[32] After mixing the two components, it is directly injected to the wound site.[31] Fibrin glue is used to create a fibrin clot for hemostasis, wound healing, and tissue adhesion. Fibrin glue can protect against infection in the wound site.[24],[33] Fibrin-stabilizing factor XIII found in fibrin glue can favor the migration of undifferentiated mesenchymal cells and enhances the proliferation of these cells.[34] Fibrin glue can also be prepared from allogeneic pooled plasma, which is commercially available (i.e., Tissucol/Tisseel, Beriplast, and Quixil).

Fibrin hydrogels are another type of fibrin-based products constructed from commercially purified allogeneic fibrinogen and purified thrombin unlike fibrin glue.[24],[35] Fibrin hydrogels have been widely applied in tissue engineering in medicine. They have many advantages such as high seeding efficiency and uniform cell distribution,[26] cell adhesion capabilities,[24] and promotion of angiogenesis,[27] and if produced from the patient’s own blood, it can be used as an autologous scaffold without the potential risk of foreign body reaction or infection.[36] By changing the kinetic parameters, the structure of the fibrin gel can be modified. For instance, to accelerate the gelation time, the concentration of thrombin can be increased. This also can result in a more densely cross-linked network with thinner fibers, contrarily, reducing the thrombin concentration results in gel with a higher porosity.[37]

Fibrin hydrogels are able to function as both two-dimensional (2D) and 3D cell culture scaffold.[38] In the 2D application, the scaffold is prepared and undergoes gelation prior to cell seeding; thus, after the gelation of fibrin hydrogel, cells are seeded into the scaffold.[38],[39] In the 3D application, isolated cells are initially suspended in the scaffold precursor solution. Then the cell–fibrin gel precursor solution mixture can be directly injected into the target lesion in which, afterward, the fibrin gel cures.[38],[39] Thus, fibrin hydrogels can also act as a vehicle for cell transplantation.[25]

Fibrin hydrogels have three major disadvantages: shrinkage, low mechanical stiffness, and rapid degradation prior to proper tissue formation.[24] Depending on the application site and whether the disadvantages adversely affect the outcome of regenerative treatments, these disadvantages can be compensated by applying modifications to this scaffold. For instance, to increase the mechanical properties of this scaffold, if necessary, fibrin hydrogels can be combined with other scaffold materials such as polyurethane,[40] polycaprolactone,[41] b-tricalciumphosphate,[42] and polyethylene glycol.[43] For creating a more stable hydrogel with slower degradation, concomitantly optimizing the pH and concentrations of fibrinogen and calcium ion,[44] modifying and stabilizing fibrin with a molecules such as polyethylene glycol,[28],[45] adding protease inhibitors specific for plasmin and matrix metalloproteinases,[35] or adding fibrin microbeads, small spherical dense beads with a diameter ranging from 50 to 250 μm consisting of highly condensed and cross-linked fibrin,[46] is suggested. Its shrinkage can be reduced by adding fixing agents such as poly L-lysine.[47] This modifiability can be an advantage for clinical regenerative treatments.

Autologous platelet concentrates (APCs) are another type of fibrin-based products that are derived from the patient him/herself. They contain high concentrations of platelets. Platelets contain various growth factors in their alpha granules such as VEGF, IGF, TGF-β, which upon activation are release due to degranulation.[48] Therefore, can attract stem cells and induce proliferation and differentiation in them.[48] APCs are divided into two generations: the first generation are those types which require addition of activating agents (i.e. Calcium Chloride, Bovine Thrombin) for initiation of platelet degranulation and fibrin matrix formation; whereas, in the second generation platelet activation and fibrin polymerization are triggered immediately without requiring the addition of activating agents as they are produced without any anticoagulants or gelifying agents.[49] Platelet Rich Plasma (PRP), Plasma rich in growth factors (PRGF) and Pure Platelet Rich Fibrin (P-PRF) are categorized as the first generation whereas, Leucocyte and Platelet Rich Fibrin (L-PRF), Advanced Platelet Rich Fibrin (A-PRF) and Concentrated Growth Factor (CGF) are categorized as the second generation.[49]

As PRP encountered major disadvantages including having a technique-sensitive and time-consuming preparation method, possibility of transmission of unknown infections from bovine thrombin to PRP recipients, susceptibility of its fibrin matrix to washout due to rapid polymerization, occurrence of maximum growth factors release before cell ingrowth, PRF was developed.[50],[51] PRF has several advantages over PRP including having a strong and flexible 3D fibrin network supporting cytokine enmeshment and cellular migration due to slow physiologic polymerization and also steady release of growth factors lasting up to 14-21 days.[49],[52]

Application of fibrin gel in dentistry

Fibrin sealants are widely used in oral and maxillofacial surgery to treat bone defects, in preimplantation sinus lifting, mandibular nerve displacement procedures, or for simple tooth extractions to prevent bleeding in patients with hemostatic disorders. They are also used in periodontal surgery to anchor gingival grafts and enhance reconstructive procedures.[53]

One study used fibrin sealants in patients with bleeding disorders for stopping local bleeding in tooth extraction sites and showed that the rate of postoperative bleeding was similar to that obtained with other local treatments such as gelatin sponges, sutures, or tranexamic acid mouthwash.[54]

Autologous formulations of fibrin sealants are also used in maxillofacial surgery to affectively reduce the risk of virus infection.[53] Furthermore, fibrin sealants have been used to approximate soft or hard tissues in surgical procedures.[55]

Regarding the effect of fibrin sealants on bone healing, animal studies have shown that they produced an early enhancement of bone repair and the physical properties of the bony callus; however, these effect appeared to be short term and their strength after 5 to 7 weeks was similar to that those healed without these sealants.[56],[57] Lucht et al.[58] reported that fibrin sealant had no affect on the new bone formation in tibia defects filled with autologous cancellous bone in dogs. The use of the mixture of homologous fibrin sealant and bone substitutes in bone defects has also been used in several studies, only resulting in easier handling properties and securing of the bone substitutes in the surgical site.[59] Fibrin sealants have been used in dental implant procedures and shown to give promising outcomes.[34]

Fibrin gel has also been used as a surgical tissue adhesive and hemostatic agent to enhance healing in bone defects[60] and has shown promising effects.[61] The osteoinductive properties of fibrin gels have been enhanced by combining it with bone morphogenetic proteins.[62] It has also been used as a delivery system for other growth factors.[63] This scaffold has been used both as a 2D and a 3D cell culture scaffold.[38] This fibrin-based scaffold has been used as a delivery system for human mesenchymal stem cell for osteoconduction.[64],[65]

Another application for fibrin gels is in salivary gland regeneration.[66],[67] In this application, fibrin gels have been used as a delivery system for laminin-111 protein, important for salivary gland cell cluster formation and organization, showing favorable outcome.[66],[67]Additionally, fibrin gels have been used for dental pulp regeneration.[68],[69]

Application of fibrin gel in endodontics

Other than common applications in endodontic surgical procedures, fibrin gels have been investigated for use in RET. Fibrin gels have the advantage of having excellent handling characteristics for dental applications, especially RET. As defects in the oral cavity are small, injectable mode of application is preferred especially in the case of RET in which the scaffold should be inserted into the root canal system, which is small and irregular.[28] Galler et al.[70] demonstrated that natural scaffolds were superior to synthetic scaffolds with regard to dental stem cell viability and differentiation into dental pulp-like tissue. In addition, they reported fibrin hydrogels to be the most suitable to enable generation of a pulp-like tissue and differentiation of cells into odontoblasts compared to other natural scaffolds. In another study, Galler et al.[28] reported that fibrin hydrogels modified with polyethylene glycol allowed for the proliferation of dental stem cells and osteogenic and odontogenic differentiation depending on the source of stem cells.

Another advantage of fibrin hydrogels for RETs is that growth factors such as VEGF and FGF-2[71] or TGF-β[72] can indirectly be bound to fibrin hydrogels via heparin. Additionally, bioactive short peptides can be synthesized and covalently bound to fibrin, if necessary.[24]

Ruangsawasdi et al.[73] studied effect of the fibrin gel in human immature premolars implanted in rats and demonstrated that the use of fibrin gel affected not only the extent of tissue ingrowth but also tissue morphology and differentiation of cells contacting the dentinal wall. The newly formed tissue was similar to normal pulp, having an inner pulp, cell-rich zone, cell-free zone, and an apparent odontoblast layer. Additionally, newly formed blood vessels were also more abundant in canals in which fibrin gel was used.

Widbiller et al.[74] used custom-made fibrin and fibrin sealants as a scaffold for RET in an ectopic animal model. They observed tissue ingrowth when fibrin-based scaffolds were used and the amount of tissue ingrowth increased with the addition of dentin matrix proteins.

Up to now, no clinical study has evaluated the use of fibrin gels in RET cases and its outcomes. In vitro studies are fundamental and prerequisites but studies with higher levels of evidence is required.

Applications of autologous platelet concentrates in dentistry

APCs have a variety of applications in dentistry including the use in socket preservation after extraction or avulsion of tooth, bone healing[34], periodontal lesions, in gingival recession coverage procedure[53], in sinus lift procedures, in the repair of articular cartilage defects[38], in various cosmetic, reconstructive and facial surgery and in regenerative endodontic procedures.[16] Studies have shown that the application of APCs caused faster radiographic bone healing[34],[53],[75].

Some studies have applied APCs for RET. Many have reported high incidence of apical closure[15],[16],[76],[77],[78],[79], root lengthening[15],[16],[76],[77],[79] and/or dentinal wall thickening[76],[77],[79], all being among favorable outcomes for RETs. Histological evaluations revealed the formation of an odontoblastic cell layer or dentin-like structure and neoformed intracanal tissues were mainly cementum-like, bone-like, and connective tissues.[18],[80]More studies with high levels of evidence are required.

 Conclusion



Fibrin gels are commercially available scaffolds having favorable properties including adhesion, proliferation and differentiation of stem cells, induction of angiogenesis, and excellent handling characteristics, especially for RETs. Its properties can be desirably tailored according to its application. Platelet concentrates are autologous fibrin-based materials containing growth factors with various favorable properties for RET. In vitro and animal studies have shown good results for the use of these materials as scaffolds in RETs. They seem to have the potentials to be used in this treatment modality. Further clinical studies with higher levels of evidence is required.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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