Efficacy of i-PRF in regenerative endodontics therapy for mature permanent teeth with pulp necrosis: study protocol for a multicentre randomised controlled trial

Yuee Liang, Rongyang Ma, Lijuan Chen, Xingzhu Dai, Shiya Zuo, Weiyi Jiang, Naiming Hu, Zilong Deng, Wanghong Zhao, Yuee Liang, Rongyang Ma, Lijuan Chen, Xingzhu Dai, Shiya Zuo, Weiyi Jiang, Naiming Hu, Zilong Deng, Wanghong Zhao

Abstract

Background: Dental pulp necrosis, a common health problem, is traditionally treated with root canal therapy; however, it fails in restoring the vitality of damaged pulp. Most studies regarding regenerative endodontic therapy (RET) are limited to the treatment of immature necrotic teeth. Given that injectable platelet-rich fibrin (i-PRF) has shown great potential in regenerative medicine as a novel platelet concentration, this study is designed to explore whether i-PRF can serve as a biological scaffold, extending the indications for RET and improving the clinical feasibility of RET in mature permanent teeth with pulp necrosis.

Methods: This is a randomised, double-blind, controlled, multicentre clinical trial designed to evaluate the clinical feasibility of RET for mature permanent teeth with pulp necrosis and to compare the efficacy of i-PRF and blood clots as scaffolds in RET. A total of 346 patients will be recruited from three centres and randomised at an allocation ratio of 1:1 to receive RET with either a blood clot or i-PRF. The changes in subjective symptoms, clinical examinations, and imaging examinations will be tracked longitudinally for a period of 24 months. The primary outcome is the success rate of RET after 24 months. The secondary outcome is the change in pulp vitality measured via thermal and electric pulp tests. In addition, the incidence of adverse events such as discolouration, reinfection, and root resorption will be recorded for a safety evaluation.

Discussion: This study will evaluate the clinical feasibility of RET in mature permanent teeth with pulp necrosis, providing information regarding the efficacy, benefits, and safety of RET with i-PRF. These results may contribute to changes in the treatment of pulp necrosis in mature permanent teeth and reveal the potential of i-PRF as a novel biological scaffold for RET.

Trial registration: ClinicalTrials.gov NCT04313010 . Registered on 19 March 2020.

Keywords: Blood clot; Dental pulp necrosis; Injectable platelet-rich fibrin; Mature permanent teeth; Pulp regeneration; Regenerative endodontics therapy.

Conflict of interest statement

All authors have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
Study flowchart
Fig. 2
Fig. 2
Schedule of intervention and assessments. All study-related procedures are outlined in this figure. RET, regenerative endodontic therapy; CBCT, cone beam computed tomography
Fig. 3
Fig. 3
Regenerative endodontics therapy procedures. The steps of regenerative endodontics therapy (RET) with injectable platelet-rich fibrin (i-PRF) and with blood clot are shown. A After 2–4 weeks of intercanal medication, B the temporary seal is removed. C The root canal is irrigated and D dried with sterile paper points. E Bleeding is provoked. F i-PRF and cavity restoration are performed in the test group. G Blood clot and cavity restoration are performed in the control group
Fig. 4
Fig. 4
The preparation of injectable platelet-rich fibrin. After centrifugation (800 rpm, 3 min), injectable platelet-rich fibrin (i-PRF) is collected from the upper yellow fluid liquid

References

    1. Peres MA, Macpherson LMD, Weyant RJ, Daly B, Venturelli R, Mathur MR, Listl S, Celeste RK, Guarnizo-Herreño CC, Kearns C, Benzian H, Allison P, Watt RG. Oral diseases: a global public health challenge. Lancet. 2019;394(10194):249–260. doi: 10.1016/S0140-6736(19)31146-8.
    1. Righolt AJ, Jevdjevic M, Marcenes W, Listl S. Global-, regional-, and country-level economic impacts of dental diseases in 2015. J Dent Res. 2018;97(5):501–507. doi: 10.1177/0022034517750572.
    1. Sasaki H, Hirai K, Martins C, Furusho H, Battaglino R, Hashimoto K. Interrelationship between periapical lesion and systemic metabolic disorders. Curr Pharm Des. 2016;22(15):2204–2215. doi: 10.2174/1381612822666160216145107.
    1. Schmalz G, Widbiller M, Galler KM. Clinical perspectives of pulp regeneration. J Endod. 2020;46(9S):S161–SS74. doi: 10.1016/j.joen.2020.06.037.
    1. Kim SG, Malek M, Sigurdsson A, Lin LM, Kahler B. Regenerative endodontics: a comprehensive review. Int Endod J. 2018;51(12):1367–1388. doi: 10.1111/iej.12954.
    1. Paryani K, Kim SG. Regenerative endodontic treatment of permanent teeth after completion of root development: a report of 2 cases. J Endod. 2013;39(7):929–934. doi: 10.1016/j.joen.2013.04.029.
    1. Mao J, Kim S, Zhou J, et al. Regenerative endodontics: barriers and strategies for clinical translation. Dent Clin N Am. 2012;56(3):639–649. doi: 10.1016/j.cden.2012.05.005.
    1. Adnan S, Ullah R. Top-cited articles in regenerative endodontics: a bibliometric analysis. J Endod. 2018;44(11):1650–1664. doi: 10.1016/j.joen.2018.07.015.
    1. Saoud TM, Martin G, Chen YH, et al. Treatment of mature permanent teeth with necrotic pulps and apical periodontitis using regenerative endodontic procedures: a case series. J Endod. 2016;42(1):57–65. doi: 10.1016/j.joen.2015.09.015.
    1. Nosrat A, Seifi A, Asgary S. Regenerative endodontic treatment (revascularization) for necrotic immature permanent molars: a review and report of two cases with a new biomaterial. J Endod. 2011;37(4):562–567. doi: 10.1016/j.joen.2011.01.011.
    1. Saoud TM, Sigurdsson A, Rosenberg PA, Lin LM, Ricucci D. Treatment of a large cystlike inflammatory periapical lesion associated with mature necrotic teeth using regenerative endodontic therapy. J Endod. 2014;40(12):2081–2086. doi: 10.1016/j.joen.2014.07.027.
    1. Wang Y, Zhu X, Zhang C. Pulp revascularization on permanent teeth with open apices in a middle-aged patient. J Endod. 2015;41(9):1571–1575. doi: 10.1016/j.joen.2015.04.022.
    1. Gomes-Filho JE, Duarte PC, Ervolino E, et al. Histologic characterization of engineered tissues in the canal space of closed-apex teeth with apical periodontitis. J Endod. 2013;39(12):1549–1556. doi: 10.1016/j.joen.2013.08.023.
    1. Lovelace TW, Henry MA, Hargreaves KM, Diogenes A. Evaluation of the delivery of mesenchymal stem cells into the root canal space of necrotic immature teeth after clinical regenerative endodontic procedure. J Endod. 2011;37(2):133–138. doi: 10.1016/j.joen.2010.10.009.
    1. Torabinejad M, Turman M. Revitalization of tooth with necrotic pulp and open apex by using platelet-rich plasma: a case report. J Endod. 2011;37(2):265–268. doi: 10.1016/j.joen.2010.11.004.
    1. Eramo S, Natali A, Pinna R, Milia E. Dental pulp regeneration via cell homing. Int Endod J. 2018;51(4):405–419. doi: 10.1111/iej.12868.
    1. Lv H, Chen Y, Cai Z, Lei L, Zhang M, Zhou R, Huang X. The efficacy of platelet-rich fibrin as a scaffold in regenerative endodontic treatment: a retrospective controlled cohort study. BMC Oral Health. 2018;18(1):139. doi: 10.1186/s12903-018-0598-z.
    1. Murray PE. Platelet-rich plasma and platelet-rich fibrin can induce apical closure more frequently than blood-clot revascularization for the regeneration of immature permanent teeth: a meta-analysis of clinical efficacy. Front Bioeng Biotechnol. 2018;6:139. doi: 10.3389/fbioe.2018.00139.
    1. Shivashankar VY. Comparison of the Effect of PRP, PRF and induced bleeding in the revascularization of teeth with necrotic pulp and open apex: a triple blind randomized clinical trial. J Clin Diagn Res. 2017;11(6):ZC34–ZC39. doi: 10.7860/JCDR/2017/22352.10056.
    1. Narang I, Mittal N, Mishra N. A comparative evaluation of the blood clot, platelet-rich plasma, and platelet-rich fibrin in regeneration of necrotic immature permanent teeth: a clinical study. Contemp Clin Dent. 2015;6(1):63–68. doi: 10.4103/0976-237X.149294.
    1. Seo B, Miura M, Gronthos S, et al. Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet (London, England) 2004;364(9429):149–155. doi: 10.1016/S0140-6736(04)16627-0.
    1. Chrepa V, Henry MA, Daniel BJ, Diogenes A. Delivery of apical mesenchymal stem cells into root canals of mature teeth. J Dent Res. 2015;94(12):1653–1659. doi: 10.1177/0022034515596527.
    1. Nageh M, Ahmed GM, El-Baz AA. Assessment of regaining pulp sensibility in mature necrotic teeth using a modified revascularization technique with platelet-rich fibrin: a clinical study. J Endod. 2018;44(10):1526–1533. doi: 10.1016/j.joen.2018.06.014.
    1. Nurden AT. Platelets, inflammation and tissue regeneration. Thromb Haemost. 2011;105(Suppl 1):S13–S33.
    1. Barbeck M, Najman S, Stojanovic S, et al. Addition of blood to a phycogenic bone substitute leads to increased in vivo vascularization. Biomed Mater. 2015;10(5):055007. doi: 10.1088/1748-6041/10/5/055007.
    1. Cabaro S, D'Esposito V, Gasparro R, Borriello F, Granata F, Mosca G, Passaretti F, Sammartino JC, Beguinot F, Sammartino G, Formisano P, Riccitiello F. White cell and platelet content affects the release of bioactive factors in different blood-derived scaffolds. Platelets. 2018;29(5):463–467. doi: 10.1080/09537104.2017.1319046.
    1. Fujioka-Kobayashi M, Katagiri H, Kono M, Schaller B, Zhang Y, Sculean A, Miron RJ. Improved growth factor delivery and cellular activity using concentrated platelet-rich fibrin (C-PRF) when compared with traditional injectable (i-PRF) protocols. Clin Oral Investig. 2020;24(12):4373–4383. doi: 10.1007/s00784-020-03303-7.
    1. El Bagdadi K, Kubesch A, Yu X, et al. Reduction of relative centrifugal forces increases growth factor release within solid platelet-rich-fibrin (PRF)-based matrices: a proof of concept of LSCC (low speed centrifugation concept) Eur J Trauma Emerg Surg. 2019;45(3):467–479. doi: 10.1007/s00068-017-0785-7.
    1. Lei L, Yu Y, Han J, Shi D, Sun W, Zhang D, Chen L. Quantification of growth factors in advanced platelet-rich fibrin and concentrated growth factors and their clinical efficacy as adjunctive to the GTR procedure in periodontal intrabony defects. J Periodontol. 2020;91(4):462–472. doi: 10.1002/JPER.19-0290.
    1. Aydinyurt HS, Sancak T, Taskin C, Basbugan Y, Akinci L. Effects of ınjectable platelet-rich fibrin in experimental periodontitis in rats. Odontology. 2021;109(2):422–432. doi: 10.1007/s10266-020-00557-1.
    1. Varela HA, Souza JCM, Nascimento RM, Araújo RF, Jr, Vasconcelos RC, Cavalcante RS, Guedes PM, Araújo AA. Injectable platelet rich fibrin: cell content, morphological, and protein characterization. Clin Oral Investig. 2019;23(3):1309–1318. doi: 10.1007/s00784-018-2555-2.
    1. Gasparro R, Adamo D, Masucci M, Sammartino G, Mignogna MD. Use of injectable platelet-rich fibrin in the treatment of plasma cell mucositis of the oral cavity refractory to corticosteroid therapy: a case report. Dermatol Ther. 2019;32(5):e13062. doi: 10.1111/dth.13062.
    1. Choukroun J, Ghanaati S. Reduction of relative centrifugation force within injectable platelet-rich-fibrin (PRF) concentrates advances patients' own inflammatory cells, platelets and growth factors: the first introduction to the low speed centrifugation concept. Eur J Trauma Emerg Surg. 2018;44(1):87–95. doi: 10.1007/s00068-017-0767-9.
    1. Zhang J, Yin C, Zhao Q, Zhao Z, Wang J, Miron RJ, Zhang Y. Anti-inflammation effects of injectable platelet-rich fibrin via macrophages and dendritic cells. J Biomed Mater Res A. 2020;108(1):61–68. doi: 10.1002/jbm.a.36792.
    1. Jasmine S, Thangavelu A, Janarthanan K, Krishnamoorthy R, Alshatwi AA. Antimicrobial and antibiofilm potential of injectable platelet rich fibrin-a second-generation platelet concentrate-against biofilm producing oral staphylococcus isolates. Saudi J Biol Sci. 2020;27(1):41–46. doi: 10.1016/j.sjbs.2019.04.012.
    1. Rafiee A, Memarpour M, Najibi Y, et al. Antimicrobial efficacy of a novel antibiotic-eluting injectable platelet-rich fibrin scaffold against a dual-species biofilm in an infected immature root canal model. Biomed Res Int. 2020;2020:6623830. doi: 10.1155/2020/6623830.
    1. Wang X, Zhang Y, Choukroun J, Ghanaati S, Miron RJ. Effects of an injectable platelet-rich fibrin on osteoblast behavior and bone tissue formation in comparison to platelet-rich plasma. Platelets. 2018;29(1):48–55. doi: 10.1080/09537104.2017.1293807.
    1. Kyyak S, Blatt S, Pabst A, Thiem D, Al-Nawas B, Kammerer PW. Combination of an allogenic and a xenogenic bone substitute material with injectable platelet-rich fibrin - a comparative in vitro study. J Biomater Appl. 2020;35(1):83–96. doi: 10.1177/0885328220914407.
    1. Amaral Valladao CA, Jr, Freitas Monteiro M, Joly JC. Guided bone regeneration in staged vertical and horizontal bone augmentation using platelet-rich fibrin associated with bone grafts: a retrospective clinical study. Int J Implant Dent. 2020;6(1):72. doi: 10.1186/s40729-020-00266-y.
    1. Ucak Turer O, Ozcan M, Alkaya B, Surmeli S, Seydaoglu G, Haytac MC. Clinical evaluation of injectable platelet-rich fibrin with connective tissue graft for the treatment of deep gingival recession defects: a controlled randomized clinical trial. J Clin Periodontol. 2020;47(1):72–80. doi: 10.1111/jcpe.13193.
    1. Kontakiotis E, Filippatos C, Tzanetakis G, Agrafioti A. Regenerative endodontic therapy: a data analysis of clinical protocols. J Endod. 2015;41(2):146–154. doi: 10.1016/j.joen.2014.08.003.
    1. Thanasrisuebwong P, Kiattavorncharoen S, Surarit R, Phruksaniyom C, Ruangsawasdi N. Red and yellow injectable platelet-rich fibrin demonstrated differential effects on periodontal ligament stem cell proliferation, migration, and osteogenic differentiation. Int J Mol Sci. 2020;21(14):5153. 10.3390/ijms21145153.
    1. AAE clinical considerations for a regenerative procedure [].
    1. Galler KM, Krastl G, Simon S, Van Gorp G, Meschi N, Vahedi B, Lambrechts P. European Society of Endodontology position statement: revitalization procedures. Int Endod J. 2016;49(8):717–723. doi: 10.1111/iej.12629.
    1. Ruparel NB, Teixeira FB, Ferraz CC, Diogenes A. Direct effect of intracanal medicaments on survival of stem cells of the apical papilla. J Endod. 2012;38(10):1372–1375. doi: 10.1016/j.joen.2012.06.018.
    1. He L, Kim SG, Gong Q, Zhong J, Wang S, Zhou X, Ye L, Ling J, Mao JJ. Regenerative endodontics for adult patients. J Endod. 2017;43(9S):S57–S64. doi: 10.1016/j.joen.2017.06.012.
    1. Marx RE. Platelet-rich plasma: evidence to support its use. J Oral Maxillofac Surg. 2004;62(4):489–496. doi: 10.1016/j.joms.2003.12.003.
    1. Li X, Hou J, Wu B, Chen T, Luo A. Effects of platelet-rich plasma and cell coculture on angiogenesis in human dental pulp stem cells and endothelial progenitor cells. J Endod. 2014;40(11):1810–1814. doi: 10.1016/j.joen.2014.07.022.
    1. Khademi AA, Dianat O, Mahjour F, Razavi SM, Younessian F. Outcomes of revascularization treatment in immature dog's teeth. Dent Traumatol. 2014;30(5):374–379. doi: 10.1111/edt.12100.
    1. Kobayashi E, Fluckiger L, Fujioka-Kobayashi M, Sawada K, Sculean A, Schaller B, Miron RJ. Comparative release of growth factors from PRP, PRF, and advanced-PRF. Clin Oral Investig. 2016;20(9):2353–2360. doi: 10.1007/s00784-016-1719-1.
    1. Torabinejad M, Milan M, Shabahang S, Wright KR, Faras H. Histologic examination of teeth with necrotic pulps and periapical lesions treated with 2 scaffolds: an animal investigation. J Endod. 2015;41(6):846–852. doi: 10.1016/j.joen.2015.01.026.
    1. Miron RJ, Chai J, Zheng S, Feng M, Sculean A, Zhang Y. A novel method for evaluating and quantifying cell types in platelet rich fibrin and an introduction to horizontal centrifugation. J Biomed Mater Res A. 2019;107(10):2257–2271. doi: 10.1002/jbm.a.36734.
    1. Dohle E, El Bagdadi K, Sader R, Choukroun J, James Kirkpatrick C, Ghanaati S. Platelet-rich fibrin-based matrices to improve angiogenesis in an in vitro co-culture model for bone tissue engineering. J Tissue Eng Regen Med. 2018;12(3):598–610. doi: 10.1002/term.2475.
    1. Bakhtiar H, Esmaeili S, Fakhr Tabatabayi S, Ellini MR, Nekoofar MH, Dummer PM. Second-generation platelet concentrate (platelet-rich fibrin) as a scaffold in regenerative endodontics: a case series. J Endod. 2017;43(3):401–408. doi: 10.1016/j.joen.2016.10.016.
    1. Wend S, Kubesch A, Orlowska A, al-Maawi S, Zender N, Dias A, Miron RJ, Sader R, Booms P, Kirkpatrick CJ, Choukroun J, Ghanaati S. Reduction of the relative centrifugal force influences cell number and growth factor release within injectable PRF-based matrices. J Mater Sci Mater Med. 2017;28(12):188. doi: 10.1007/s10856-017-5992-6.
    1. Kubesch A, Barbeck M, Al-Maawi S, et al. A low-speed centrifugation concept leads to cell accumulation and vascularization of solid platelet-rich fibrin: an experimental study in vivo. Platelets. 2019;30(3):329–340. doi: 10.1080/09537104.2018.1445835.
    1. Miron RJ, Chai J, Zhang P, Li Y, Wang Y, Mourão CFAB, Sculean A, Fujioka Kobayashi M, Zhang Y. A novel method for harvesting concentrated platelet-rich fibrin (C-PRF) with a 10-fold increase in platelet and leukocyte yields. Clin Oral Investig. 2020;24(8):2819–2828. doi: 10.1007/s00784-019-03147-w.
    1. Andreasen J, Paulsen H, Yu Z, Bayer T. A long-term study of 370 autotransplanted premolars. Part IV. Root development subsequent to transplantation. Eur J Orthod. 1990;12(1):38–50. doi: 10.1093/ejo/12.1.38.
    1. Laureys WG, Cuvelier CA, Dermaut LR, De Pauw GA. The critical apical diameter to obtain regeneration of the pulp tissue after tooth transplantation, replantation, or regenerative endodontic treatment. J Endod. 2013;39(6):759–763. doi: 10.1016/j.joen.2013.02.004.
    1. Silujjai J, Linsuwanont P. Treatment outcomes of apexification or revascularization in nonvital immature permanent teeth: a retrospective study. J Endod. 2017;43(2):238–245. doi: 10.1016/j.joen.2016.10.030.
    1. Trevino EG, Patwardhan AN, Henry MA, Perry G, Dybdal-Hargreaves N, Hargreaves KM, Diogenes A. Effect of irrigants on the survival of human stem cells of the apical papilla in a platelet-rich plasma scaffold in human root tips. J Endod. 2011;37(8):1109–1115. doi: 10.1016/j.joen.2011.05.013.
    1. Petrino J, Boda K, Shambarger S, Bowles W, McClanahan S. Challenges in regenerative endodontics: a case series. J Endod. 2010;36(3):536–541. doi: 10.1016/j.joen.2009.10.006.
    1. Berkhoff JA, Chen PB, Teixeira FB, Diogenes A. Evaluation of triple antibiotic paste removal by different irrigation procedures. J Endod. 2014;40(8):1172–1177. doi: 10.1016/j.joen.2013.12.027.
    1. Liu S, Wang S, Dong Y. Evaluation of a bioceramic as a pulp capping agent in vitro and in vivo. J Endod. 2015;41(5):652–657. doi: 10.1016/j.joen.2014.12.009.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe