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.
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*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.
