May-June 2014
Volume 93 - Number 3

Find Your Way by the Star of the North

Development of a National TMJ Implant Registry and Repository - NICDR's TIRR

The Thought That Counts

Golden: Recognizing the MDA's 25-Year Members and Retirees

















Development of a National TMJ Implant Registry and Repository - NICDR's TIRR


Sandra L. Myers, D.M.D.*,
Shanti Kaimal, M.D.S.**,
Jennifer Springsteen, B.S.***,
Joao Ferreira, D.D.S., M.S.+,
Ching-Chang Ko, D.D.S., Ph.D.++, and
James Fricton, D.D.S., M.S.+++




The National TMJ Implant Registry and Repository

Established at the University of Minnesota School of Dentistry and funded by the National Institutes of Health’s National Institute of Dental and Craniofacial Research, the project is the first in the world for supporting research into human TMJ disorders and implants.

Purpose: To provide a national systematic program to collect removed TMJ implants and biological tissues, make them available to researchers, and study them in conjunction with long-term clinical follow-up, with the ultimate goal of stimulating research toward understanding the safety and outcomes of TMJ implants.

Process: Two synchronized divisions:  The Registry, recruiting clinicians and/or surgeons and patients, and collecting comprehensive clinical patient data over time; the Repository, procuring and archiving high quality, well characterized biological specimens and retrieved implants for dissemination.

Participation: Clinicians, surgeons, patients, researchers, pilot studies.

Progress: October 2002-present:  Recruited 34 TMJ surgeons, 34 TMJ clinicians; registered 723 surgical/non-surgical TMJD patients and control subjects; collected 542 specimens, blood, saliva; initiated 19 projects using TIRR resources; produced 60 publications and presentations nationally and internationally; sent ten grants into review, with more being developed.

Prospects/Projections: Continuing collection of long-term data for the development of new and improved implant designs and materials and investigation into understanding pathological mechanisms of TMJD.


Background

Surgical interventions to correct structural problems associated with disorders of the temporomandibular joint (TMJ) have included arthro-scopy, discectomy, condylotomy, condylectomy, disc repair, and other procedures. Synthetic implants have been utilized to replace the condyle, fossa, and articular disc. Disc implants have been placed to provide interpositional support between the condyle and fossa. From the late 1960s to early 1990s, in excess of 30,000 TMJ interpositional disc implants were placed, composed of Proplast-Teflon® or Silastic® materials.1 High biomechanical forces in the TMJ resulted in fracture, perforation, or structural breakdown in many of these implants, as well as robust foreign body reactions, functional joint impairment, and/or chronic orofacial pain conditions.2,3 Numerous adverse clinical events were reported with Silastic® and Proplast-Teflon® TMJ implants, leading to the establishment of patient-based advocacy organizations and a series of Congressional hearings in the House of Representatives One Hundred Second Congress Second Session beginning June 4, 1992. In addition, the American Association of Oral and Maxillofacial Surgeons conducted a 1992 workshop on TMJ implant surgery and published a set of recommendations for the management of patients with TMJ implants. The consensus of the 23 participating experts was that Proplast-Teflon® implants be discontinued, and Silastic® implants be used only to prevent ankylosis in the TMJ.4

An estimated 100,000 patients have received synthetic TMJ implants nationally since 1993.1 Despite new designs and materials, some TMJ implants continue to be problematic, with patients experiencing significant morbidity and undergoing multiple surgical procedures.5,6 To date, there has been no national systematic program to collect removed TMJ implants and biological tissues and to study them in conjunction with long-term clinical follow-up. Comprehensive studies of both patients and removed implants are critical to further improve the design and performance of these devices.

Research in humans to improve TMJ implant design and performance and to develop new materials is complicated by many obstacles. In 2000, The National Institutes of Health (NIH) examined a number of barriers to research in its Technology Assessment Conference (TAC) titled “Improving Medical Implant Performance Through Retrieval Information: Challenges and Opportunities” (http://consensus.nih.gov/ta/2000/2000medicalimplantsa019htm/.htm). The conference consensus report recognized as barriers the complexities of implant research and lack of a dedicated program to analyze removed implants. It urged the NIH to fund studies focusing on long-term outcomes rather than those associated with shorter pre-market approval.7 In 2002, The NIH’s National Institute of Dental and Craniofacial Research (NIDCR) supported and funded the development of a new National TMJ Implant Registry and Repository (NIDCR’s TIRR, http://tmjregistry.org) (Figures 1 and 2) at the University of Minnesota School of Dentistry. The purpose of the Registry and Repository is to collect comprehensive clinical data and biological specimens from patients with TMJD and/or TMJ implants and to supply them to researchers. To fulfill these objectives, NIDCR’s TIRR was structured to have two synchronized divisions: (1) a Registry to recruit clinicians and/or surgeons and patients and collect comprehensive clinical patient data over time, and (2) a Repository to procure and archive high quality, well characterized biological specimens and retrieved implants for dissemination. The ultimate goal of these two divisions is to stimulate research toward understanding the safety and outcomes of TMJ implants. This article provides an overview of the two divisions of NIDCR’s TIRR.

Participation

Clinicians and/or surgeons play a critical role in patient participation in NIDCR’s TIRR and are recruited through personal contacts, displays, brochures, and presentations at professional meetings. Support is provided throughout the patient recruitment and consent processes, including obtaining Institutional Review Board (IRB) approval. Benefits of participation for clinicians and/or surgeons in NIDCR’s TIRR include: (1) a secure website for their individual patients to facilitate tracking and long-term follow-up, and (2) contributing to a national project to improve treatment outcomes for patients with TMJD and/or TMJ implants.

Surgical and non-surgical TMJD patients, with or without implants, are screened and invited to participate in NIDCR’s TIRR by their clinician and/or surgeon or a TIRR recruiter. Written consent to participate is obtained from all patients, and all personal data is handled in strict compliance with HIPAA regulations. Benefits for patients include: (1) a personal portable electronic health database (Figure 3), and (2) contribution to a national effort to improve care for TMJD patients. Clinicians and/or surgeons or calibrated examiners perform a comprehensive TMJ diagnostic examination, and the findings are entered into the Registry database. Authorization is obtained from patients for transfer of pertinent past medical and dental records and diagnostic imaging.

Clinical Database

NIDCR’s TIRR maintains a secure, web-based database for collection and storage of extensive phenotypic data on patients. This searchable database contains extensive clinical information, including pain and jaw function questionnaires, medical findings, laboratory data, and radiographs. Registry data collected includes many of the items proposed in the 2000 NIH TAC report, such as patient demographics, primary diagnosis, co-morbid conditions, patient-derived functional status, specific surgical and implant data, imaging, and any pertinent circumstances associated with implant failure. Past medical, dental, and imaging records are electronically incorporated in the patient’s record. The database is evaluated at regular intervals by a data management team.

Biological Specimens

Biological specimens from consenting patients are procured nationwide by participating clinicians and transported to the Repository laboratory for analysis and processing (Figure 4). Procurement and transport methods, processing, and storage conditions are carefully documented for all specimens. This provides important details in determining suitability for future research use. Saliva, serum, and DNA isolated from whole blood are aliquoted and stored frozen. Hard and soft TMJ surgical tissues are received fresh, frozen, or in fixative. Samples of tissues are routinely processed into paraffin blocks for histologic evaluation. Implants are processed and stored based on material composition and physical state either frozen, in fixative, or under vacuum in a dessicator. The Repository strives to procure, process, and archive the highest quality biological specimens for dissemination to researchers. Measures to ensure optimal specimen quality include standardized handling and processing protocols, well-controlled storage conditions, and careful documentation of all specimen treatments. However, the best measure of specimen quality is proven research usability.

Current Research

A number of important pilot studies were recently undertaken utilizing biological specimens archived in NIDCR’s TIRR. These pilot studies, based on current topics in TMJD and orofacial pain, included analysis of:

(1) Cytokines in serum and saliva.

Cytokines are produced by a wide variety of cells and modulate host response to infection, injury, and inflammation. The underlying mechanism of TMJD pain and inflammation was investigated by analyzing serum and salivary cytokines in patients with TMJD compared to controls. Ongoing sample collection to increase sample size will determine if levels of inflammatory cytokines (IL-1a, IL-1b, IL6, IL-8, TNF alpha) are increased in serum and saliva samples grouped by age, sex, and TMJD.8-11

(2) Catecholamine-o-methyltransferase (COMT)
gene in DNA.

Genetic variation in the catechol-o-methyltransferase (COMT) was found to be associated with experimental pain sensitivity and risk of developing TMJ pain.12,13 The met158 allele that produces COMT may partially contribute to variation in pain perception.14 A pilot study was conducted to determine the quality of the DNA isolated from whole blood in two groups of TMJD patients. The COMT gene was evaluated for polymorphisms; thus, half of patients had low levels and half had high levels of chronic pain, muscle tenderness, and widespread pain as documented in the TIRR database. The DNA was subjected to polymerase chain reaction to amplify DNAs spanning 17 single polymorphic targets. Single nuclear polymorphism (SNP) genotyping was performed using Sequenom MALDI-TOF mass spectrometry.15 SNPs were genotyped in flanking regions of exon1 through exon6 of the COMT gene.14 While the sample size used for this pilot study restricts definitive conclusions, the results support the suggestion that the DNA archived at the NIDCR’s TIRR repository is a high quality bio-specimen for genetic analysis of TMJD.

(3) Neuroanatomical elements
in tissues.

One of the major problems associated with failed TMJ implants has been the chronic pain found in those patients who are implant recipients. The possible role played by peripheral innervation in chronic pain following TMJ implants is currently unknown. The purpose of this pilot project was to develop methods that allow characterization of innervation in TMJ and associated tissues. Preliminary findings provide evidence that innervation changes may occur in response to the chronic presence of TMJ implant wear debris.16-18

(4) Physical characteristics of failed implants.

Analysis of failed TMJ disc implants (Proplast-Teflon® and Silastic®) was undertaken. Surface wear and structural damage of the implant (catastrophic fracture) were recorded and measured after surgical removal, and failure pattern evaluation was conducted using a light stereomicroscope. Electron microscopy identified Teflon®-rich areas and calcium-phosphate enriched areas in the Proplast-Teflon® implant. Structural analysis of implants was compared to patient clinical symptoms and degree of mandibular function impairment. Results have shown that persistence of pain was significantly related to the presence of perforation in disc implants.19-21

(5) Histopathology associated with implant wear debris.

A pilot study was undertaken to: (1) provide a general assessment of the cellular responses to different types of implant materials seen in repository tissues, and (2) demonstrate the quality and potential use of archived formalin-fixed paraffin embedded tissues. Inflammation is a major factor in TMJ implant failure. Selected implant cases were utilized to illustrate the foreign body reactions and complex interactions between implant particles and cells (Figure 5). Preliminary findings show that the number and total area of Proplast® wear particles are correlated to the number and total area of multinucleated giant cells. The same correlation was not seen with Silastic® particles. Statistically greater numbers of inflammatory cells are present in tissues from TMJ implant subjects than non-implant surgical TMJD subjects or cadaver controls. Non-implant surgical tissues, and rarely cadaver tissues, contain scattered lymphocytes (almost exclusively T cells), while tissues from implant subjects exhibit predominantly multinucleated giant cells.22-24

(6) Perfluorochemicals in patients with a history of Proplast Teflon implants.

Perfluorochemicals are a class of compounds that have been used extensively as synthetic polymers for industrial and domestic applications. One compound in particular, perfluorooctanoic acid (PFOA), has been used in the manufacture of polytetrafluoroethylene (PTFE), also known as Teflon. PFOA concentrations in serum donated by patients who had Proplast Teflon® implants removed were compared to levels reported for the general population of the United States. The hypothesis was that use of this implant material would result in elevated PFOA levels in patients that are measurable in serum for an extended period following implant removal.25-27 Small sample size precluded definitive conclusions, and expanded sample collections are ongoing.

These and other ongoing pilot studies demonstrate the high quality of archived materials available in NIDCR’s TIRR and the diverse areas of research yet to be explored.

Progress Report

Since October 2002, NIDCR’s TIRR has nationally recruited and registered 34 TMJ surgeons and 34 TMJ clinicians. Seven hundred twenty three surgical/non-surgical TMJD patients and control subjects have consented to participate and have been registered in the electronic database. Six hundred twenty-six (86.6%) of the participants are female, and 97 (13.4%) are male. Collection of comprehensive clinical data on these patients is ongoing. Tissue and implant specimens have been procured from 130 joints in 102 patients, and 440 patients have provided blood and/or saliva. The types of surgical specimens procured by the Repository have included both hard and soft tissues, and whole and fragmented implants, including Proplast-Teflon®, Silastic®, TMJ Concepts®, and Christensen® prostheses (Figure 6).

In July of 2005, NIDCR’s TIRR approved dissemination of archived data and biological materials for research use. To date, 19 projects at 17 different institutions are in progress using TIRR resources, and more than 60 publications and presentations at national and international meetings illustrate the value of NIDCR’s TIRR in TMJD and implant research.  Four abstracts alone were presented in March 2007 at the annual meeting of the International/American Association of Dental Research. Ten grants proposing use of TIRR resources are currently under review, and many more are in progress. TIRR has provided extensive support to investigators in preparation and submission of research proposals.

The Future

The utilization of human data registries and biological specimen repositories in medical research has grown rapidly over the past two decades. Centralized collection of human data and specimens has increased the availability of materials to the research community, and shifted reliance away from animal and cell-culture models. The TMJ Implant Registry and Repository funded by NIDCR is unique, and the first for human TMJ disorders and implants in the nation and world. It marks the first critical step in initiating a systematic approach for procuring removed implants for analysis. Long-term data on the behavior of TMJ implant devices, combined with precise documentation of host response, is vital for the development of new and improved implant designs and materials. Further development and utilization of these resources is critical for comprehensive investigations into understanding pathological mechanisms of TMJD including TMJ implant failures. The project is a unique resource for dentists, oral surgeons, and orofacial pain specialists in Minnesota who are interested in TMJD and implant research. In the years to come, NIDCR’s TIRR is poised to lead
the way.

 

References

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          2.  Hartman L, Bessette, RW, Baier, RE, Meyer, AE, Wirth, J. Silicone rubber temporomandibular joint (TMJ) meniscal replacements: postimplant histopathologic and material evaluation. J Biomed Mater Res 1988;22:457-84.

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          14.  Zubieta J, Heitzeg M, Smith Y, Bueller J, Xu K, Xu Y, Koeppe R, Stohler C, Goldman D. COMT val158met genotype affects µ-opiod neurotransmitter responses to a pain stressor. Science 2003;299:1240-43.

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          16. Haeuchi Y, Matsumoto K, Ichikawa H, Maeda S. Immunohistochemical demonstration of neuropeptides in the articular disk of the human temporomandibular joint. Cell Tissues Organs 1999;164:205-11.

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          23. Davies A, Willert H, Campbell P, Learmonth I, Case C. An unusual lymphocytic perivascular infiltration in tissues around contemporary metal-on-metal joint replacements. J Bone Joint Surg Am 2005;87:18-27.

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          25.  Kudo N, Kawashima Y. Toxicity and toxicokinetics of perfluorooctanoic acid in humans and animals. J Toxicological Sci 2003;28:49-57.

          26. Simcik M, Dorweiler K. A ratio of perflurochemical concentrations as a tracer of atmospheric deposition to surface waters. Environ Sci Technol 2005;39:8,678-83.

          27. Olsen G, Church T, Miller J, Burris J, Hansen K, Lundberg J, Armitage J, Herron R, Medhdizadehkashi Z, Nobiletti J, O’Neill E, Mandel J, Zobel L. Perfluorooctanesulfonate and other fluorochemicals in the serum of American Red Cross adult blood donors. Environ Health Perspect 2003;111:1,892-1,901.

 

*Dr. Myers is Associate Professor and Director of NIDCR’s TIRR Laboratory, Department of Diagnostic & Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, Minnesota 55455.

**Dr. Kaimal is from the University of Minnesota School of Dentistry, Minneapolis, Minnesota 55455.

***Ms. Springsteen is from the University of Minnesota School of Dentistry, Minneapolis, Minnesota 55455.

†Dr. Ferreira is from the University of Minnesota School of Dentistry, Minneapolis, Minnesota 55455.

‡Dr. Ko is from the University of North Carolina School of Dentistry, Chapel Hill, North Carolina.

†††Dr. Fricton is from the University of Minnesota School of Dentistry, Minneapolis, Minnesota 55455.






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