title: Bioengineered Temporomandibular Joint Disk Implants: Study Protocol for a Two-Phase Exploratory Randomized Preclinical Pilot Trial in 18 Black Merino Sheep (TEMPOJIMS).
abstract: BACKGROUND
  Preclinical trials are essential to test efficacious options to substitute the temporomandibular joint (TMJ) disk. The contemporary absence of an ideal treatment for patients with severe TMJ disorders can be related to difficulties concerning the appropriate study design to conduct preclinical trials in the TMJ field. These difficulties can be associated with the use of heterogeneous animal models, the use of the contralateral TMJ as control, the absence of rigorous randomized controlled preclinical trials with blinded outcomes assessors, and difficulties involving multidisciplinary teams.
  
  
  OBJECTIVE
  This study aims to develop a new, reproducible, and effective study design for preclinical research in the TMJ domain, obtaining rigorous data related to (1) identify the impact of bilateral discectomy in black Merino sheep, (2) identify the impact of bilateral discopexy in black Merino sheep, and (3) identify the impact of three different bioengineering TMJ discs in black Merino sheep.
  
  
  METHODS
  A two-phase exploratory randomized controlled preclinical trial with blinded outcomes is proposed. In the first phase, nine sheep are randomized into three different surgical bilateral procedures: bilateral discectomy, bilateral discopexy, and sham surgery. In the second phase, nine sheep are randomized to bilaterally test three different TMJ bioengineering disk implants. The primary outcome is the histological gradation of TMJ. Secondary outcomes are imaging changes, absolute masticatory time, ruminant time per cycle, ruminant kinetics, ruminant area, and sheep weight.
  
  
  RESULTS
  Previous preclinical studies in this field have used the contralateral unoperated side as a control, different animal models ranging from mice to a canine model, with nonrandomized, nonblinded and uncontrolled study designs and limited outcomes measures. The main goal of this exploratory preclinical protocol is to set a new standard for future preclinical trials in oromaxillofacial surgery, particularly in the TMJ field, by proposing a rigorous design in black Merino sheep. The authors also intend to test the feasibility of pilot outcomes. The authors expect to increase the quality of further studies in this field and to progress in future treatment options for patients undergoing surgery for TMJ disk replacement.
  
  
  CONCLUSIONS
  The study has commenced, but it is too early to provide results or conclusions.
authors.affiliation: Centro Hospitalar de Setúbal, EPE, Stomatology Department, Setúbal, Portugal.|Instituto Politécnico de Leiria, Centre for Rapid and Sustainable Product Development (CDRSP), Leiria, Portugal.|Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: David Faustino
authors.identifier: http://orcid.org/0000-0001-8411-9946
authors.initials: DF
authors.lastname: Ângelo
authors.affiliation: University Hospital Infanta Cristina, Badajoz, Spain, Department of Oral and Maxillofacial Surgery, Badajoz, Spain.
authors.forename: Florencio Gil
authors.identifier: http://orcid.org/0000-0003-0184-3758
authors.initials: FG
authors.lastname: Monje
authors.affiliation: University Hospital Infanta Cristina, Badajoz, Spain, Department of Oral and Maxillofacial Surgery, Badajoz, Spain.
authors.forename: Raúl
authors.identifier: http://orcid.org/0000-0003-4801-8712
authors.initials: R
authors.lastname: González-García
authors.affiliation: Kolling Institute, Institute of Bone and Joint Research, University of Sydney, Sydney, Australia.
authors.forename: Christopher B
authors.identifier: http://orcid.org/0000-0002-0353-7634
authors.initials: CB
authors.lastname: Little
authors.affiliation: Coimbra University, Coimbra, Portugal.
authors.forename: Lisete
authors.identifier: http://orcid.org/0000-0002-9374-2702
authors.initials: L
authors.lastname: Mónico
authors.affiliation: Faculdade de Medicina Veterinaria, Interdisciplinary Centre of Research in Animal Health (CIISA), Lisbon University, Lisboa, Portugal.
authors.forename: Mário
authors.identifier: http://orcid.org/0000-0003-4502-667X
authors.initials: M
authors.lastname: Pinho
authors.affiliation: Faculdade de Medicina Veterinaria, Interdisciplinary Centre of Research in Animal Health (CIISA), Lisbon University, Lisboa, Portugal.
authors.forename: Fábio Abade
authors.identifier: http://orcid.org/0000-0002-0696-7322
authors.initials: FA
authors.lastname: Santos
authors.affiliation: Faculdade de Medicina Veterinaria, Lisbon University, Lisboa, Portugal.
authors.forename: Belmira
authors.identifier: http://orcid.org/0000-0002-1936-5697
authors.initials: B
authors.lastname: Carrapiço
authors.affiliation: Instituto Nacional de Investigação Agrária e Veterinária (INIAV I.P.), Santarém, Portugal.
authors.forename: Sandra Cavaco
authors.identifier: http://orcid.org/0000-0003-1280-229X
authors.initials: SC
authors.lastname: Gonçalves
authors.affiliation: Instituto Politécnico de Leiria, Centre for Rapid and Sustainable Product Development (CDRSP), Leiria, Portugal.
authors.forename: Pedro
authors.identifier: http://orcid.org/0000-0002-5956-9790
authors.initials: P
authors.lastname: Morouço
authors.affiliation: Instituto Politécnico de Leiria, Centre for Rapid and Sustainable Product Development (CDRSP), Leiria, Portugal.
authors.forename: Nuno
authors.identifier: http://orcid.org/0000-0002-5016-0868
authors.initials: N
authors.lastname: Alves
authors.affiliation: Instituto Politécnico de Leiria, Centre for Rapid and Sustainable Product Development (CDRSP), Leiria, Portugal.
authors.forename: Carla
authors.identifier: http://orcid.org/0000-0003-0998-5929
authors.initials: C
authors.lastname: Moura
authors.affiliation: University of Pittsburgh, Chemical Engineering and Surgery Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: Yadong
authors.identifier: http://orcid.org/0000-0003-2067-382X
authors.initials: Y
authors.lastname: Wang
authors.affiliation: University of Pittsburgh, Chemical Engineering and Surgery Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: Eric
authors.identifier: http://orcid.org/0000-0001-8491-8596
authors.initials: E
authors.lastname: Jeffries
authors.affiliation: University of Pittsburgh, Chemical Engineering and Surgery Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: Jin
authors.identifier: http://orcid.org/0000-0002-6200-4141
authors.initials: J
authors.lastname: Gao
authors.affiliation: Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Rita
authors.identifier: http://orcid.org/0000-0002-6096-8182
authors.initials: R
authors.lastname: Sousa
authors.affiliation: Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Lia Lucas
authors.identifier: http://orcid.org/0000-0001-7880-9625
authors.initials: LL
authors.lastname: Neto
authors.affiliation: Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Daniel
authors.identifier: http://orcid.org/0000-0002-2520-5673
authors.initials: D
authors.lastname: Caldeira
authors.affiliation: Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Francisco
authors.identifier: http://orcid.org/0000-0002-1095-8090
authors.initials: F
authors.lastname: Salvado
keywords: temporomandibular joint bioengineered disk implants; temporomandibular joint disorders (TMD); temporomandibular randomized preclinical trial protocol