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In vivo imaging of nerve regeneration following ventral root replantation with fluo-stained fibrin sealant associated with mesenchymal stem cells

Grant number: 12/08101-8
Support Opportunities:Regular Research Grants
Start date: October 01, 2013
End date: September 30, 2015
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Rui Seabra Ferreira Junior
Grantee:Rui Seabra Ferreira Junior
Host Institution: Centro de Estudos de Venenos e Animais Peçonhentos (CEVAP). Centro Virtual de Toxinologia. Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
Associated researchers:Alexandre Leite Rodrigues de Oliveira ; Fernanda da Cruz Landim ; Lucilene Delazari dos Santos ; Romain Aimé Duval

Abstract

Serine proteases (SPases) isolated from snake venoms present thrombin-like enzymatic activity that acts on the haemostatic system to convert fibrinogen into fibrin. The latter can be polymerized to acquire sealant and adhesive properties via the formation of a stable net. Based on these premises, researchers at CEVAP (Center for the Study of Venoms and Venomous Animals at UNESP) proposed, about 20 years ago, the prospect of a new sealant from the SPase obtained from Crotalus durissus terrificus venom and fibrinogen extracted from large animals. This product enables numerous biotechnological applications without presenting a risk of transmitting infectious diseases; furthermore, being genuinely Brazilian, its production cost is lower.Although it is known from the literature that SPases contribute significantly to tissue recovery this reconstruction has never been monitored dynamically in vivo in a non-invasive manner. We chose to study this phenomenon, for the first time in the world, utilizing near-infrared fluorescent imaging (fluo-IVP) in vivo in murine models of avulsion and re-implantation of motor neuron roots, utilizing the sealant as a biological scaffold in association with mesenchymal stem cells that must act synergetically to stimulate regeneration. This non-invasive strategy is based on the use of stained and synthesized fluorescent probes, of the enzyme-indocyanine (SPase-ICA) type, and of fluo-stained stem cells for in vivo monitoring, with the results observed by the modern imaging apparatus fluo-IVP, which is still unavailable in Brazil. The latter has greater potential for use in basic research as well as translational medicine. Based on these new molecular tools and stained cells, the reconstructive action from associating SPase with stem cells at the nervous system level will be evaluated in a dynamic, integrated and non-invasive manner.To elucidate and execute this translational project, it will be divided into two subprojects, namely: 1-Fluor-staining, by means of chemical synthesis, and evaluation of the bioactivity of the new fluorescent conjugates of SPase (SPase-ICA) as imaging probes in vivo; Fluo-staining the mesenchymal stem cells for in vivo monitoring together with fluor-stained sealant. 2-Imaging in vivo of nerve regeneration of rats avulsed at / from the interface of the central and peripheral nervous systems treated with mesenchymal stem cells and fluor-stained fibrin sealant as biological scaffolding.The present translational project, besides augmenting knowledge on the action mechanisms of the sealant with the stem cells, will have applications both in fundamental research (accompanying the tissue regeneration in vivo in a non-invasive manner), and in the clinical setting, by means of applied biotechnology (imaging in vivo with stained fluorescent enzyme employing the fibrin sealant as a biological scaffold and mesenchymal stem cells). The nerve regeneration subproject, in the case of experimental success, would then be immediately applicable in patients, in phase I clinical trials, after due approval by the Research Ethics Committee, since until the present date, there is still no successful gold standard restorative surgery for these patients. (AU)

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Scientific publications (18)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DA CUNHA, MARCELO RODRIGUES; MENEZES, FERNANDA ARAUJO; DOS SANTOS, GEOVANE RIBEIRO; LOPES PINTO, CLOVIS ANTONIO; BARRAVIERA, BENEDITO; AMARO MARTINS, VIRGINIA DA CONCEICAO; DE GUZZI PLEPIS, ANA MARIA; FERREIRA JUNIOR, RUI SEABRA. Hydroxyapatite and a New Fibrin Sealant Derived from Snake Venom as Scaffold to Treatment of Cranial Defects in Rats. MATERIALS RESEARCH-IBERO-AMERICAN JOURNAL OF MATERIALS, v. 18, n. 1, p. 196-203, . (12/08101-8, 09/06280-0, 12/02689-3, 09/53846-9)
BARBIZAN, ROBERTA; CASTRO, MATEUS V.; FERREIRA, JR., RUI SEABRA; BARRAVIERA, BENEDITO; OLIVEIRA, ALEXANDRE L. R.. Long-Term Spinal Ventral Root Reimplantation, but not Bone Marrow Mononuclear Cell Treatment, Positively Influences Ultrastructural Synapse Recovery and Motor Axonal Regrowth. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 15, n. 11, p. 19535-19551, . (14/06892-3, 12/08101-8, 11/23236-4, 09/53846-9)
GASPAROTTO, VINICIUS P. O.; LANDIM-ALVARENGA, FERNANDA C.; OLIVEIRA, ALEXANDRE L. R.; SIMOES, GUSTAVO FERREIRA; LIMA-NETO, JOAO F.; BARRAVIERA, BENEDITO; FERREIRA, JR., RUI S.. A new fibrin sealant as a three-dimensional scaffold candidate for mesenchymal stem cells. STEM CELL RESEARCH & THERAPY, v. 5, . (12/08101-8, 09/06280-0, 09/53846-9)
BARBOSA, LIDIANE NUNES; FERREIRA, JR., RUI SEABRA; MELLO, PRISCILA LUIZA; GARCES, HANS GARCIA; CHECHI, JESSICA LUANA; FRACHIN, TARSILA; DE BARROS, LUCIANA CURTOLO; GUIMENES BOSCO, SANDRA DE MORAES; BAGAGLI, EDUARDO; FERNANDES JUNIOR, ARY; et al. Molecular identification and phylogenetic analysis of Bothrops insularis bacterial and fungal microbiota. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A-CURRENT ISSUES, v. 81, n. 6, p. 142-153, . (12/08101-8)
DA SILVA, D. A. F.; BISCOLA, N. P.; DOS SANTOS, L. D.; SARTORI, M. M. P.; DENADAI, J. C.; DA SILVA, E. T.; DUCATTI, C.; BICUDO, S. D.; BARRAVIERA, B.; FERREIRA, JR., R. S.. Detecting animal by-product intake using stable isotope ratio mass spectrometry (IRMS). VETERINARY JOURNAL, v. 217, p. 119-125, . (09/53846-9, 12/02689-3, 12/08101-8)
DA CUNHA, MARCELO RODRIGUES; MENEZES, FERNANDA ARAUJO; DOS SANTOS, GEOVANE RIBEIRO; LOPES PINTO, CLOVIS ANTONIO; BARRAVIERA, BENEDITO; AMARO MARTINS, VIRGINIA DA CONCEICAO; DE GUZZI PLEPIS, ANA MARIA; FERREIRA JUNIOR, RUI SEABRA. Hydroxyapatite and a New Fibrin Sealant Derived from Snake Venom as Scaffold to Treatment of Cranial Defects in Rats. MATERIALS RESEARCH-IBERO-AMERICAN JOURNAL OF MATERIALS, v. 18, n. 1, p. 8-pg., . (12/02689-3, 12/08101-8, 09/06280-0, 09/53846-9)
BARBIZAN, ROBERTA; CASTRO, MATEUS V.; FERREIRA, RUI SEABRA, JR.; BARRAVIERA, BENEDITO; OLIVEIRA, ALEXANDRE L. R.. Long-Term Spinal Ventral Root Reimplantation, but not Bone Marrow Mononuclear Cell Treatment, Positively Influences Ultrastructural Synapse Recovery and Motor Axonal Regrowth. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 15, n. 11, p. 17-pg., . (14/06892-3, 09/53846-9, 12/08101-8, 11/23236-4)
BISCOLA, NATALIA PERUSSI; CARTAROZZI, LUCIANA POLITTI; FERREIRA JUNIOR, RUI SEABRA; BARRAVIERA, BENEDITO; RODRIGUES DE OLIVEIRA, ALEXANDRE LEITE. Long-Standing Motor and Sensory Recovery following Acute Fibrin Sealant Based Neonatal Sciatic Nerve Repair. NEURAL PLASTICITY, v. 2016, p. 19-pg., . (14/06892-3, 09/53846-9, 12/08101-8, 11/23236-4, 11/23377-7)
RUI SEABRA FERREIRA JR; LUCIANA CURTOLO DE BARROS; LUCIANA PATRÍCIA FERNANDES ABBADE; SILVIA REGINA CATHARINO SARTORI BARRAVIERA; MARIA REGINA CAVARIANI SILVARES; LETICIA GOMES DE PONTES; LUCILENE DELAZARI DOS SANTOS; BENEDITO BARRAVIERA. Heterologous fibrin sealant derived from snake venom: from bench to bedside – an overview. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 23, . (12/08101-8, 14/13299-7, 09/53846-9)
NATALIA PERUSSI BISCOLA; LUCIANA POLITTI CARTAROZZI; SUZANA ULIAN-BENITEZ; ROBERTA BARBIZAN; MATEUS VIDIGAL CASTRO; ALINE BARROSO SPEJO; RUI SEABRA FERREIRA JR.; BENEDITO BARRAVIERA; ALEXANDRE LEITE RODRIGUES OLIVEIRA. Multiple uses of fibrin sealant for nervous system treatment following injury and disease. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 23, . (13/23030-2, 11/23377-7, 12/02689-3, 12/20456-6, 14/06892-3, 14/11405-4, 11/02889-0, 13/04409-0, 12/08101-8, 09/53846-9, 12/22750-9, 12/13514-0, 10/00729-2)
BISCOLA, NATALIA PERUSSI; CARTAROZZI, LUCIANA POLITTI; FERREIRA JUNIOR, RUI SEABRA; BARRAVIERA, BENEDITO; RODRIGUES DE OLIVEIRA, ALEXANDRE LEITE. Long-Standing Motor and Sensory Recovery following Acute Fibrin Sealant Based Neonatal Sciatic Nerve Repair. NEURAL PLASTICITY, . (12/08101-8, 14/06892-3, 11/23377-7, 11/23236-4, 09/53846-9)
FERREIRA, JR., RUI SEABRA; DE BARROS, LUCIANA CURTOLO; FERNANDES ABBADE, LUCIANA PATIRCIA; CATHARINO SARTORI BARRAVIERA, SILVIA REGINA; CAVARIANI SILVARES, MARIA REGINA; DE PONTES, LETICIA GOMES; DOS SANTOS, LUCILENE DELAZARI; BARRAVIERA, BENEDITO. Heterologous fibrin sealant derived from snake venom: from bench to bedside - an overview. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 23, n. 1, . (09/53846-9, 12/08101-8, 14/13299-7)
DE OLIVEIRA, LAUDICEIA ALVES; FERREIRA, JR., RUI SEABRA; BARRAVIERA, BENEDITO; TAVARES DE CARVALHO, FRANCILENE CAPEL; DE BARROS, LUCIANA CURTOLO; DOS SANTOS, LUCILENE DELAZARI; PIMENTA, DANIEL CARVALHO. Crotalus durissus terrificus crotapotin naturally displays preferred positions for amino acid substitutions. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 23, . (12/08101-8)
BARBOSA, ALEXANDRE NAIME; BOYER, LESLIE; CHIPPAUX, JEAN-PHILIPPE; MEDOLAGO, NATALIA BRONZATTO; CARAMORI, CARLOS ANTONIO; PAIXAO, ARIANE GOMES; VASCONCELOS POLI, JOAO PAULO; MENDES, MONICA BANNWART; DOS SANTOS, LUCILENE DELAZARI; FERREIRA, JR., RUI SEABRA; et al. A clinical trial protocol to treat massive Africanized honeybee (Apis mellifera) attack with a new apilic antivenom. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 23, n. 1, . (12/08101-8)
BISCOLA, NATALIA PERUSSI; CARTAROZZI, LUCIANA POLITTI; ULIAN-BENITEZ, SUZANA; BARBIZAN, ROBERTA; CASTRO, MATEUS VIDIGAL; SPEJO, ALINE BARROSO; FERREIRA, JR., RUI SEABRA; BARRAVIERA, BENEDITO; RODRIGUES OLIVEIRA, ALEXANDRE LEITE. Multiple uses of fibrin sealant for nervous system treatment following injury and disease. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 23, n. 1, . (12/20456-6, 12/08101-8, 14/06892-3, 12/22750-9, 12/02689-3, 11/23377-7, 11/02889-0, 13/04409-0, 09/53846-9, 14/11405-4, 10/00729-2, 13/23030-2, 12/13514-0)
DE PONTES, LETICIA GOMES; VIEIRA CAVASSAN, NAYARA RODRIGUES; DE BARROS, LUCIANA CURTOLO; FERREIRA JUNIOR, RUI SEABRA; BARRAVIERA, BENEDITO; DOS SANTOS, LUCILENE DELAZARI. Plasma proteome of buffaloes. PROTEOMICS CLINICAL APPLICATIONS, v. 11, n. 9-10, . (14/13299-7, 12/08101-8)
ORSI, PATRICIA RODRIGUES; LANDIM-ALVARENGA, FERNANDA CRUZ; JUSTULIN, JR., LUIS ANTONIO; KANENO, RAMON; GOLIM, MARJORIE DE ASSIS; DOS SANTOS, DANIELA CARVALHO; ZORZELLA CRESTE, CAMILA FERNANDA; OBA, EUNICE; MAIA, LEANDRO; BARRAVIERA, BENEDITO; et al. A unique heterologous fibrin sealant (HFS) as a candidate biological scaffold for mesenchymal stem cells in osteoporotic rats. STEM CELL RESEARCH & THERAPY, v. 8, . (14/06001-1, 09/53846-9, 12/02689-3, 12/08101-8)
CARTAROZZI, LUCIANA P.; SPEJO, ALINE B.; FERREIRA, JR., RUI S.; BARRAVIERA, BENEDITO; DUEK, ELIANA; CARVALHO, JULIANA L.; GOES, ALFREDO M.; OLIVEIRA, ALEXANDRE L. R.. Mesenchymal stem cells engrafted in a fibrin scaffold stimulate Schwann cell reactivity and axonal regeneration following sciatic nerve tubulization. Brain Research Bulletin, v. 112, p. 14-24, . (14/06892-3, 12/08101-8, 11/23236-4, 09/53846-9)