Effect of single-dose locally applied lactoferrin on autograft healing in peri-implant bone in rat models

Published:December 07, 2021DOI:https://doi.org/10.1016/j.injury.2021.11.065

      Highlights

      • This study is the first study to evaluate the effect of single dose and locally applied LF with autograft on peri‑implant bone healing.
      • Locally applied single dose of LF increases the efficiency of autograft and increases bone-implant contact with its osteoinductive effect.
      • The healing of the defect was evaluated by histomorphometric, immunohistochemical and micro-Ct analysis.
      • Bone implant contact values was examined with the micro-ct which is a gold standard.
      • The effect of LF administration method on bone metabolism - especially osteoclasts, has a key role.

      Abstract

      Immediate dental implant installation into fresh extraction sockets has become a common surgical technique and yields successful clinical results. In addition, complete contact may not be possible with this procedure cause of defects between the bone wall and the implant surface. Therefore, different graft materials have been used in the literature to increase the peri‑implant bone volume. The aim of the present study was to evaluate the effect of single-dose and locally applied lactoferrin on autograft healing in peri‑implant area and bone implant contact value. Twenty-four Sprague-Dawley rats were included in this study. Firstly, a trephine drill was used for creating a cylindrical bony defects (6.5 mm in diameter and 3 mm in depth) under sterile saline irrigation in the lateral side of the femur. Subsequently, implant beds –2.5 mm diameter and 6 mm depth – were prepared in the middle of each defect with special implant drills. All of the implants were installed and primary stability was achieved. Rats were randomly divided into 3 groups (n = 8 each): Group-1 had empty defects, Group-2 had defects filled with autograft, and Group-3 had defects filled with autograft and lactoferrin solution (100 μg/ml) combination. All of the rats were sacrificed at postoperative 4th week and samples were analyzed with micro-computed tomography, histomorphometry and immunohistochemistry respectively. It was found that Group 3 had the least area of fibrous tissue (6.75±0.83mm2) according to the other 2 groups (p<0.001). On the other hand, Group 3 had the highest osteoblast number (25.50±3.29), osteoclast number (21.25±1.03), newly formed bone area (20.50±1.30 mm2), total healing area (22.62±0.93 mm2), defect closure rate (80.37±1.40%), bone implant contact value (23.2%±0.6%), and percentage bone volume (18.2%±0.3%) (p<0.001). Matrix metalloproteinase-3 expression was found to be highest in Group 3 by immunohistochemistry analysis. In this study it was observed that the results of the different analysis techniques supported each other. According to these findings it can be stated that a single-dose and locally applied lactoferrin solution plays an important role in the autograft healing in peri‑implant area and increasing bone implant contact value. These findings will shed light on further clinical studies of implant osseointegration.

      Keywords

      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to Injury
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Görmez U.
        • Kürkcü M.
        • Benlidayı M.E.
        • Ulubayram K.
        • Sertdemir Y.
        • Dağlioğlu K.
        Effects of bovine lactoferrin in surgically created bone defects on bone regeneration around implants.
        J Oral Sci. 2015; 57: 7-15
        • Simsek S.
        • Özec I.
        • Kürkcü M.
        • Benlidayi E.
        Histomorphometric evaluation of bone formation in peri-implant defects treated with different regeneration techniques: an experimental study in a rabbit model.
        J Oral Maxillofac Surg. 2016; 74: 1757-1764
        • Trento G.
        • Carvalho P.H.A.
        • Reis E.N.R.C.
        • Spin-Neto R.
        • Bassi A.P.F.
        • Pereira-Filho V.A
        Bone formation around two titanium implant surfaces placed in bone defects with and without a bone substitute material: a histological, histomorphometric, and micro-computed tomography evaluation.
        Clin Implant Dent Relat Res. 2020; 22: 177-185
        • Zandi M.
        • Dehghan A.
        • Gheysari F.
        • Rezaeian L.
        • Mezerji N.M.G
        Evaluation of teriparatide effect on healing of autografted mandibular defects in rats.
        J Oral Maxill Surg. 2019; 47: 120-126
        • Gonzalez-Chavez S.A.
        • Arevalo-Gallegos S.
        • Rascon-Cruz Q
        Lactoferrin: structure, function and applications.
        Int J Antimicrob Agents. 2009; 33: 301.e1-301.e8
        • Hou J.M.
        • Xue Y.
        • Lin Q.M
        Bovine lactoferrin improves bone mass and micro-structure in overiectomized rats via OPG/RANKL/RANK pathway.
        Acta Pharmacol Sin. 2012; 33: 1277-1284
        • Naot D.
        • Grey A.
        • Reid I.R.
        • Cornish J
        Lactoferrin-a novel bone growth factor.
        Clin Med Res. 2005; 3: 93-101
        • Cornish J
        Lactoferrin promotes bone growth.
        Biometals. 2004; 17: 331-335
        • de Araujo Munhoz F.B.
        • Nogara P.R.B.
        • da Costa Junior F.R.
        • Branco F.P.
        • dos Santos M.C.L.G
        Analysis of MMP-3 polymorphism in osseointegrated implant failure.
        Braz J Oral Sci. 2016; 15: 304-307
        • Trybek G.
        • Jedlinski M.
        • Jaron A.
        • Preuss O.
        • Mazur M.
        • Grzywacz A
        Impact of lactoferrin on bone regenerative processes and its possible implementation in oral surgery-a systematic review of novel studies with metanalysis and metaregression.
        BMC Oral Health. 2020; 20: 1-12
        • Kuzu T.E.
        • Özdemir H
        Histomorphometric evaluation of bone regeneration in peri-implant osseous defects treated with titanium prepared platelet rich fibrin: an experimental study in a rabbit model.
        Med J SDU. 2018; 25: 243-250
        • Jung I.
        • Lim H.
        • Lee E.
        • Lee J.
        • Jung U.
        • Choi S
        Comparative analysis of carrier systems for delivering bone morphogenetic proteins.
        J Periodontal Implant Sci. 2015; 45: 136-144
      1. Araujo A.S., Fernandes A.B., Maciel J.V., Netto Jde N., Bolognese A.M. New methodology for evaluating osteoclastic.

        • Tanaka Y.
        • Nakayamada S.
        • Okada Y.
        Osteoblasts and osteoclasts in bone remodeling and inflammation.
        Curr Drug Targets Inflamm Allergy. 2005; 4: 325-328
        • Rosenberg N.
        • Rosenberg O.
        • Soudry M
        Osteoblasts in bone physiology-mini review.
        Rambam Maimonides Med J. 2012; 3: e0013
        • Langdahl B.
        • Ferrari S.
        • Dempster D.W
        Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis.
        Ther Adv Musculoskelet Dis. 2016; 8: 225-235
        • Froum S.
        • Cho S.C.
        • Rosenberg E.
        • Rohrer M.
        • Tarnow D.
        Histological comparison of healing extraction sockets implanted with bioactive glass or demineralized frieze-dried bone allograft: a pilot study.
        J Periodontol. 2002; 73: 94-102
        • Jensen O.T
        Dental extraction, immediate placement of dental implants, and immediate function.
        Oral Maxillofac Surg Clin North Am. 2015; 27: 273-282
        • Altundal H.
        • Sayrak H.
        • Yurtsever E.
        • Göker K
        Inhibitory effect of alendronate on bone resorption of autogenous free bone grafts in rats.
        J Oral Maxill Surg. 2007; 65: 508-516
        • Li P.
        • Honda Y.
        • Arima Y.
        • Yasui K.
        • Inami K.
        • Nishiura A.
        • et al.
        Interferon-γ enhances the efficacy of autogenous bone grafts by inhibiting postoperative bone resorption in rat calvarial defects.
        J Prosthodont Res. 2016; 60: 167-176
        • Gao R.
        • Watson M.
        • Callon K.E.
        • Tuari D.
        • Dray M.
        • Nao D.
        • et al.
        Local application of lactoferrin promotes bone regeneration in a rat critical-sized calvarial defect model as demonstrated by micro-CT and histological analysis.
        J Tissue Eng Regen Med. 2018; 12: 620-626
        • Takaoka R.
        • Hikasa Y.
        • Hayashi K.
        • Tabata Y
        Bone regeneration by lactoferrin released from a gelatin hydrogel.
        J Biomater Sci. 2011; 22: 1581-1589
        • Paknejad M.
        • Rokn A.R.
        • Yaraghi A.A.S.
        • Elhami F.
        • Kharazifard M.J.
        • Moslemi N.
        Histologic and histomorphometric evaluation of the effect of lactoferrin combined with anorganic bovine bone on healing of experimentally induced bony defects on rabbit calvaria.
        J Dent Res. 2012; 9: 75-80
        • Yoshimaki T.
        • Sato S.
        • Kigami R.
        • Tsuchiya N.
        • Oka S.
        • Arai Y.
        • et al.
        Bone regeneration by lactoferrin in non-critical-sized rat calvarial bone defects.
        Journal of Medical Biological Engineering. 2014; 34: 256-260
        • Amini A.A.
        • Nair L.S
        Lactoferrin a biological active molecul for bone regeneration.
        Curr Med Chem. 2011; 18: 1220-1229
        • Xue Q.
        • Li H.
        • Zou X.
        • Bünger M.
        • Egund N.
        • Lind M.
        • et al.
        The influence of alendronate treatment and bone graft volume on posterior lateral fusion in a porcine model.
        Spine. 2005; 30: 1116-1121
        • Grottkau B.E.
        • Lin Y
        Osteogenesis of adipose-derived stem cells.
        Bone Res. 2013; 1: 133-145
        • Cheung W.K.
        • Working D.M.
        • Galuppo L.D.
        • Leach J.K
        Osteogenic comparison of expanded and uncultured adipose stromal cells.
        Cytotherapy. 2010; 12: 554-562
        • Negri S.
        • Wang Y.
        • Sono T.
        • Qin Q.
        • Yun-Hsu G.C.
        • Cherief M.
        • et al.
        Systemic DKK1 neutralization enhances human adipose-derived stem cell mediated bone repair.
        Stem Cells Transl Med. 2021; 10: 610-622
        • Folkman M.
        • Becker A.
        • Meinster I.
        • Masri M.
        • Ormianer Z
        Comparison of bone-to-implant contact and bone volume around implants placed with or without site preparation: a histomorphometric study in rabbits.
        Sci Rep. 2020; 10: 1-10
        • Alghamdi H.S
        Methods to improve osseointegration of dental implants in low quality (Type-IV) bone: an overview.
        J Funct Biomater. 2018; 9: 1-8
        • Ito K.
        • Yamada Y.
        • Naiki T.
        • Ueda M.
        Simultaneous implant placement and bone regeneration around dental implants using tissue-engineered bone with fibrin glue, mesenchymal stem cells and platelet-rich plasma.
        Clin Oral Implants Res. 2006; 17: 579-586
        • Cochran D.L.
        • Schenk R.K.
        • Lussi A.
        • Higginbottom F.L.
        • Buser D
        Bone response to unloaded and loaded titanium implants with a sandblasted and acid-etched surface: a histometric study in the canine mandible.
        J Biomed Mater Res. 1998; 40: 1-11
        • Kustro T.
        • Kiss T.
        • Chernohorskyi D.
        • Chepurnyi Y.
        • Helyes Z.
        • Kopchak A
        Quantification of the mandibular defect healing by micro CT morphometric analysis in rats.
        J Craniomaxillofac Surg. 2018; 46: 2203-2213
        • Paiva K.B.S.
        • Granjeiro J.M
        Chapter Six-Matrix metalloproteinases in bone resorption, remodelling, and repair.
        Prog Mol Biol Transl Sci. 2017; 148: 203-303
        • Zheng L.
        • Amano K.
        • Iohara K.
        • Ito M.
        • Imabayashi K.
        • Into T.
        • et al.
        Matrix Metalloproteinase-3 accelerates wound healing following dental pulp injury.
        AJP. 2009; 175: 1905-1914
        • Teja K.V.
        • Ramesh S.
        • Priya V
        Regulation of matrix metalloproteinase-3 gene expression in inflammation: a molecular study.
        J Conserv Dent. 2018; 21: 592-596
        • Dai Y
        Correlation of circulating matrix metalloproteinase-3 and osteopontin levels with postmenopausal osteoporosis.
        J Trauma Treat. 2013; 2: 1-3
        • Breckon J.J.
        • Papaioannou S.
        • Kon L.W.
        • Tumber A.
        • Hembry R.M.
        • Murphy G.
        • et al.
        Stromelysin (MMP-3) synthesis is up-regulated in estrogen-deficient Mouse osteoblasts in vivo and in vitro.
        J Bone Miner Res. 1999; 14: 1880-1890
        • Nakayama K.
        • Otsuki K.
        • Yakuwa K.
        • Hasegawa A.
        • Sawada M.
        • Mitsukawa K.
        • et al.
        Recombinant human lactoferrin inhibits matrix metalloproteinase (MMP-2, MMP-3, and MMP-9) activity in a rabbit preterm delivery model.
        J Obstet Gynaecol Res. 2008; 34: 931-934
        • Brandl N.
        • Zemann A.
        • Kaupe I.
        • Marlovits S.
        • Huettinger P.
        • Goldenberg H.
        • et al.
        Signal transduction and metabolism in chondrocytes is modulated by lactoferrin.
        Osteoarthritis and Cartilage. 2010; 18: 117-125