Panel on Repair and Regeneration of Oral, Dental and Craniofacial
Tissues
A Scientific Expert Panel
Final Report
September 5, 2002
Sponsored by:
The National Institute of Dental and Craniofacial Research
National Institutes of Health
I. Executive Summary
The Repair and regeneration of oral, dental, and craniofacial tissues is a
priority for the National Institute of Dental and Craniofacial Research (NIDCR).
A panel of scientists actively engaged in related research was assembled to
address the challenges and opportunities in the field that should be addressed
between 2004 and 2009 and that have the greatest potential to positively impact
the dental profession and health of the nation. Primary frontiers were
identified and include elucidation of the influence of infection and the oral
microbial environment on healing and regeneration; the role of angiogenesis
on repair and restoration of oral, dental, and craniofacial tissues; optimization
of the non-biological scaffold-tissue response; self-assembly to control nanoscale
informational texture; models to aid translation of basic science information
to clinical therapeutics; and the utility of using muscle-derived cells to regenerate
bone and tendon.
After lively discussion, the panel recommended that:
The research opportunities and agenda over the next few years in tissue
engineering include regenerative medicine and the functional histogenesis
of oral, dental and craniofacial structures.
The hindrances to in-situ stem cell participation in healing be identified
with the aim to reduce or remove these hindrances and to achieve optimal healing.
A hierarchical integration/interaction between research in supramolecular
assemblies should be explored through chemical approaches to supramolecular
assemblies and functional tissue engineering (involving the study of cellular
responses and histogenesis).
Research should aim at understanding and manipulating the interface between
the extracellular matrix and the diversity of cells in the craniofacial complex,
at bioinspired (molecular) design, at building scaffolds at the nanoscale
and at developing and optimizing informational control of the various cellular
processes and cell interactions with other cells and the extracellular matrix
across all length scales.
Support should be provided to attract expertise from complementary fields
and to create unconventional, cross disciplinary teams who can perform high
risk research.
Additional support should be given to the development of suitable animal
models and to the translation to human applications
Research should be supported through a broad, non-prescriptive RFA-type
announcement based on the concepts and themes discussed and involving glue
grants or interactive R01s that highlight translational applications (including
the translation of genomic data into tissue regeneration) and early clinical
trials.
Training opportunities for young investigators as well as more senior investigators
transitioning disciplines should be included in the research agenda for the
period 2004 - 2009. Training models incorporating both basic scientists
and clinicians and emphasizing team science and translational research
should be enhanced. Future practitioners should be incorporated into
these models.
NIDCR should continue to facilitate SBIR grant utilization at early phases
of translational research.
NIDCR should partner with the FDA to minimize the loss of competing technology
and maintain translational technologic options. This might include maintaining
"boutique" trials to sort optimal approaches before closing down
competing approaches. This might be achieved through new partnership arrangements
with industrial sources.
NIDCR should continue its efforts to eliminate disparities in research
support, training, and translation/implementation of results to underserved
and low economic groups.
II. Background:
The National Institute of Dental and Craniofacial Research (NIDCR) is the primary
sponsor of biomedical and behavioral research and of research training in oral,
dental and craniofacial diseases in the United States. The mission of
the Institute is to promote and improve health through research. It accomplishes
this mission by supporting research and training programs in intramural laboratories
and in an extended external community of investigators working in academic institutions
and in other research organizations. Support of extramural researchers
is provided through the programs and initiatives of the Divisions of Basic and
Translational Sciences and of Population and Health Promotion Sciences.
Major programs in the first of these Divisions include biotechnology and biomaterials,
developmental biology and mammalian genetics, epithelial cell regulation and
transformation, oral infectious diseases and immunology, AIDS and oral manifestations
of immunosuppression, pain, and autoimmune disease. The Division of Population
and Health Sciences supports programs in behavioral and social sciences research,
population sciences, clinical trials and patient-oriented research and health
disparities. The Division of Intramural Research includes laboratories
located on the NIH campus in Bethesda, MD. Intramural scientists perform
research in Craniofacial and skeletal diseases, craniofacial development, gene
therapy, oral and pharyngeal cancer, oral infection and immunity and pain.
Recognizing the importance of long-term scientific planning to capitalize on
the rapid and significant advances that are occurring in biomedical and behavioral
research, NIDCR established an internal study group with representatives from
all its Divisions to identify broad areas of importance for the Institute's
long-range scientific agenda. This group identified three priority areas
of emphasis:
Genomics and Proteomics of Dental, Oral and Craniofacial Diseases
Repair and Regeneration of Dental, Oral and Craniofacial Tissues
Clinical Approaches to the Diagnosis, Treatment and Prevention of Dental,
Oral and Craniofacial Disorders.
The study group recommended that panels of experts be convened to work with
the Institute to identify and catalogue potential opportunities for significant
scientific advances within these areas of emphasis. A panel of eight scientists
along with scientific administrators from NIDCR and the National Institute of
Biomedical Imaging and Bioengineering (NIBIB) met on September 5, 2002 to address
challenges and opportunities in Repair and Regeneration of Dental, Oral, and
Craniofacial Tissues for the period of 2004 - 2009. A summary of the discussions
and recommendations follows. Before the meeting, background materials
were provided by the Institute, summarizing the level and breadth of current
support for biomimetics and tissue engineering as well as recently released
requests for proposals (RFAs) on stem cells and tissue repair. Summaries
and recommendations from reports for each of the panels are to be posted on
the NIDCR website. The first, on the Genomics and Proteomics of
Dental, Oral and Craniofacial Diseases is already available at the NIDCR website.
This panel was held on May 22, 2002.
III. General Issues:
Opening Remarks:
Dr. Lawrence Tabak, director of the NIDCR, underscored the importance of expert
scientific panels for establishing the NIDCR's future directions and for
identifying where the most promising scientific opportunities are. The focus
of the discussions is basic science with emphasis on the uniqueness of oral
structures. The input received from the panelists is critical as the
Institute moves forward in identifying initiatives for the period 2004 - 2009
and implementing longer-range science planning. The focus of the panel
should center around two questions: (1) what should NIDCR be known for in
5 years? and (2) how should the multiple possible initiatives that emerge
be prioritized?
Clearly, there are 2 extremes to approaching the questions: be all things
to all people and dilute the available resources in multiple programs or focus
on a few selected and potentially high impact areas of emphasis. Dr.Tabak,
emphasized NIDCR's continuing goal of supporting the best science to capitalize
on advances which improve dental, oral and craniofacial health. The
challenge is that the NIDCR has limited resources and limitations in the infrastructure
of its primary constituent institutions to perform cutting-edge research.
A particularly important challenge is how to ensure the appropriate training
of future researchers who can successfully address the challenges and opportunities
that exist in repair and regeneration of tissues. NIDCR needs to marshal
its resources efficiently and to enter into partnerships in order to leverage
resources and to build the research and training capacity of its client community.
Dr. Tabak reminded the panel that NIDCR has a strategic emphasis on clinical
research and clinical trials as well as a long-standing commitment to the
reduction/elimination of disparities in oral health. NIDCR's strengths
are in matrix biology, biomaterials and craniofacial development. The Institute
supports efforts in biomimetics and tissue engineering and is well positioned
to take advantage of emerging and exciting opportunities in the these frontiers.
Its FY2001 commitment to extramural funding of biomimetics and tissue engineering
is $17 million (12% of the Institute's extramural budget), which represents
an 85% increase in funding since FY1999. This investment has had some
important outcomes that can be used to leverage other areas of tissue engineering
research. The question is how to accomplish this and assume/maintain
a leadership position in this area of research.
Panel Discussion
The Panel's general discussion explored an array of questions, opportunities,
and challenges addressing the science itself and the enabling aspects of scientific
endeavors, including funding issues, partnerships, and research infrastructure
related to repair and regeneration of oral, dental, and craniofacial tissues.
The goal of tissue engineering is to create and preserve permanent, functional
tissues through the application of life science and engineering principles.
The challenge is to identify the areas of research opportunity with the greatest
potential to positively impact the dental profession and the health of the
nation. The creation of fully functional craniofacial bone, salivary
glands, and artificial teeth with performance properties equal to natural
tissue are among the areas with great promise and impact.
While great strides have occurred, some basic biology about regeneration of
craniofacial tissues remains unknown. For example, it is unclear how
different germ layers can give rise to cell lineages that contribute to the
formation of tissues that perform the same function. There are gaps
in our knowledge of how cells interact. Interactions and signaling pathways
involved in cellular and tissue interactions are not completely elucidated.
The challenge of how to engineer three-dimensional constructs at the nanoscale
level remains unanswered. Replacement tissues have been created but
many have severe limitations when compared with natural tissues. The
extracellular matrix and its interactions with various cells are critically
important yet not fully described. Our understanding and application
of research in chemistry and nanoscience needs to be strengthened to capitalize
on the natural synergy between nanoscience and self-assembling molecules.
The scope and emphasis of the NIDCR-sponsored clinical research/clinical trials
support portfolio and the ways practitioners stay attuned to science advances
and are amenable to try bioengineering approaches was discussed. NIDCR
supports clinical trials to address issues of safety and efficacy and has
recently implemented a new pathway for this support emphasizing phase III
definitive trials in areas such as oral infectious diseases. Dental
students currently have little exposure to research activities during their
training. Perhaps future practitioners would become more attuned to
scientific advances if they have broader positive exposure to research and
its implications to clinical practice while in school. Research, while
exceptionally strong in some dental schools, is almost non-existent in others;
of the 55 dental schools in the United States, between 50 and 60% of the $150
million of NIDCR support is concentrated in 10 schools. Successful tissue
engineering research often capitalizes on expertise outside of dental schools
(engineering schools, in particular are usually strong partners). Issues
of strengthening dental school research infrastructure and teams with researchers
from the broader academic and industrial communities were addressed.
Multidisciplinary teams are important in overcoming current barriers to breakthroughs.
Partnerships across disciplines, between intra- and extra-mural scientists,
and between academia and industry should be explored. NIDCR-funded
basic research, leveraged with translational and applied research from industry
may facilitate impacting clinical practice faster than with either group working
alone. Relations with industry, however, are complicated and an unavoidable
problem is that, in general, the dental market is quite small. The NIDCR is
truly a leader in the area of tissue repair and regeneration and has maintained
intramural and extramural research that contributed to this leadership role
among all NIH institutes. The Panel noted that the Institute has accomplished
a great deal considering that it is a small Institute among many larger ones.
Other Institutes (NHLBI, NIAMS) have also demonstrated commitment and leadership
in this area and have served as valuable partners for NIDCR. Nonetheless,
the majority of research to date, and funding targeted to tissue engineering
research, has been industry-based. Approximately 90% of
the total funding has come from industry in the U.S., with the expected associated
emphasis on applied research. Federal support provides resources that
are critical to the development of a more expansive basic science foundation
for this emerging field critical to surmounting the challenges of restoring
some of the most complex tissues in the human system.
The impact of the new NIH Institute of Biomedical Imaging and Bioengineering
(NIBIB) on programs such as the one supported by NIDCR was considered.
The panel voiced concern that NIBIB may draw financial resources from NIDCR
but Dr. Tabak responded that the outlook is actually brighter because of this
new Institute. The opportunities for partnering with NIBIB are great,
particularly if they support the technology and the other NIH institutes and
centers support the actual research based on these technologies. NIDCR
considers NIBIB as a primary partner and can take advantage of its strengths
in matrix biology and biomaterials through this interaction. The time
is right for this kind of partnership. The new Director of NIH has a
background in imaging and talks about the critical importance of inter- and
multidisciplinary research, and this will likely provide an additional advantage
for this interdisciplinary approach to tissue engineering.
Much new information has been obtained about the genetic control of oral and
maxillofacial and craniofacial morphogenesis, mechanisms of cell and tissue
differentiation in normal and pathological settings, pathophysiology of oral
infectious agents, interactions between oral health and systemic diseases,
etc. It is necessary to determine what other knowledge or technologies
are needed to apply this information to problems in oral, dental, and craniofacial
health. To help the translation of basic science information into clinical
care, new model systems need to be developed and validated for connectivity
to clinical therapeutics. There is renewed enthusiasm about the value
of animal models and the need to develop further this type of research in
academic health science centers.
Both near and long term realistic goals, especially those that provide fundamental
building blocks in the knowledge base, are needed. The challenge is that resources
are needed for both immediate and future initiatives. Equally
critical, innovative approaches are needed to link the two types of goals.
An immediate, near term need is, for example, how to replace the alveolar
ridge. Tissue responses are to be measured in situ using imaging techniques
and surrogate biomarkers and other enabling technologies, perhaps with the
help of NIBIB. Dental and oral tissues are complex and incorporate a
variety of cell types. The key scientific issue is the complex interface
between these tissues and between them and the host. This needs to be investigated
both from the basic and clinical viewpoints. Temporomandibular joint
disorders are a good example. This is a difficult, complex disease,
which has been mismanaged, but that offers the possibility of a scientific
"home run" if it is solved in the future. The tissue engineering approach
should include cell-based and cell-free techniques and the issue could be
approached from the point of view of hard and soft tissues, rather than from
specific disease perspective. Pre clinical studies should be part of
the initiative.
Other general ideas were discussed in response to the question of what can
be done more rapidly, including the biological responses to transplants in
the aging or chronically ill population and the complex problem of tooth regeneration.
An area of concern is the pathogenesis of mucositis that appears to be triggered
in transplanted patients. The view was expressed that building teeth is really
important. Regrettably because many people see teeth as expendable it
has not gained the attention that it deserves nor have all of the achievements
in understanding normal tooth development been marshaled into regenerative
strategies. Intramural scientists have achieved regeneration of odontoblasts
from stem cell populations and tooth regeneration is an incredibly complex
problem, requiring sophisticated materials science to create molecularly designed
materials and the application of nanotechnology principles. This requires
a significant interdisciplinary collaboration that includes people who are
not being supported but should, such as cell biologists and people working
in vascular biology. A range of expertise is needed and scientists from
different fields will enhance progress in this field. In situ repair
of teeth can be the ultimate challenge. It was suggested that outcomes from
successful tissue engineering be referred to as regenerative medicine or "functional
histogenesis of complex tissues and organs" and that these may be tractable
concepts when dealing with Congress and the public and when dealing
with the scientific community. It remains largely unknown if regeneration
works for all people regardless of gender, age or chronic disease status or
if there are specific population restrictions on optimal tissue engineering
outcomes. One way to address this area of concern is to map the genomic
analysis of populations to their regeneration response. Similarly, it is not
clear if regeneration produces tissues and/or organs of similar or identical
properties as the original. Do cells that contribute to regeneration
become incorporated with pre-existing cells or is the regenerated organs a
chimeric outcome with distinctive partitions (boundaries for pattern formation)
for regenerated cells versus original cells? Is the cellular organization
of regenerated tissues similar to or identical with the original? How
does a regeneration outcome compare to outcomes gained from device placement?
The NIH Bioengineering Consortium (BECON) requires a continuous exchange between
supported investigators and this scientific exchange builds bridges between
them that result in new areas of inquiry and reduction to implementation.
NIDCR could attempt a similar approach to entice investigators from complementary
expertise to participate in this area of research and help bridge the range
of expertise that is required to address the complexities facing the field.
The use of so-called "glue grants" or interactive ROIs was suggested.
Supplements to ROIs would be another way to encourage interaction among established
research projects and which would serve to expand the interactions between
separate groups. The objective would be to bring together these separate
groups and fields of expertise. The current portfolio encompasses an
appropriate cadre of grants, including some in bioengineering partnerships
and the challenge is to expand these partnerships further.
The Panel's discussion of general issues can be summarized as follows:
The goal of tissue engineering is to create/preserve permanent, functional
tissues.
Dental and oral tissues are complex and incorporate a variety of cell
types. The key scientific issue is to elucidate and control the
interface between these tissues.
The repair and regeneration of dental, oral and craniofacial tissues
requires, therefore, a range of expertise and significant interdisciplinary
collaborations.
These collaborations should include people who are currently not in
this field (such as cell biologists and vascular biologists).
The research approach should include the measurement of tissue responses
in situ using imaging techniques, biomarkers and nano-technology and also
the development of molecularly designed materials through sophisticated
materials science.
Anticipated outcomes from tissue engineering include the emergent fields
of regenerative medicine and functional histogenesis of complex
tissues and organs.
NIDCR can stimulate research interactions and the recruitment of additional
expertise into this field by a variety of approaches such as glue grants,
interactive RO1s and supplements. Partnerships (including those
between extramural and intramural scientists as well as academia and industry)
should be supported and enhanced.
IV. Recommendations
Following much enthusiastic discussion, the panel concluded that the primary
frontiers in tissue engineering for repair and regeneration of dental, oral,
and craniofacial tissues are the elucidation of:
The influence of infection and the oral microbial environment on healing
and regeneration
The role of angiogenesis in repair and restoration of oral/dental tissues.
A great deal is known in general about the process but this knowledge is not
being utilized and carried to the pre-clinical level or clinical practice.
Optimization of non-biological scaffolds, including applications of nanotechnology,
for multiple tissue types (often within the same scaffol). Broader understanding
of tissue response to scaffold features across length scales (from nano- to
macro-scale features) and over time is needed.
Self-assembly, capitalizing on supramolecular chemistry, to control nanoscale
informational texture such as integrin response pathways or growth factor
pathways or both simultaneously. Scaffold building begins with design
but the ultimate goal of bioengineering efforts is to make tissues that
perform physiologic requirements. Aspects of cell biology
may be used to effect desired interaction between cells and scaffolds and/or
supramolecular assemblies.
New in vivo, in vitro, and in silica models (e.g. computational/informatic
resources). Models need to be both developed and validated to aid in
the translation of basic science information to clinical therapeutics.
The utility of using muscle derived cells to regenerate bone and tendons.
Several major themes emerged, including, (1) the interface issue (e.g. biosynthesized
materials between different cell types and the self-assembled protein boundary
between cells as well as between the cell and the extracellular matrix environment),
(2) cell functions in the real universe (i.e. under conditions of load bearing,
infection, etc), (3) an immediate need that could impact a significiant portion
of the population is an effective method to augment the alveolar ridge and (4)
the role of tissue engineering for future practitioners needs to be incorporated
into the education curriculum.
Based on the panel's discussion, the following recommendations were made:
The research opportunities and agenda over the next few years in tissue
engineering include regenerative medicine and the functional histogenesis
should focus on oral, dental and craniofacial structures.
The hindrances to in situ stem cell participation in healing need to be
identified with the aim of reducing and removing these hindrances and to achieve
optimal healing.
A hierarchical integration/interaction between research in supramolecular
assemblies should be explored through chemical approaches to supramolecular
assemblies and functional tissue engineering (involving the study of cellular
responses and histogenesis).
Research should aim at understanding and manipulating the interface between
the extracellular matrix and the diversity of cells in the craniofacial complex,
at bioinspired (molecular) design, at building scaffolds at the nanoscale
and at developing and optimizing informational control of the various cellular
processes and cell interactions with other cells and the extracellular matrix
across all length scales.
Support should be provided to attract expertise from complementary fields
and to create unconventional, cross disciplinary teams who can perform high
risk research.
Additional support should be given to the development of suitable animal
models and to the translation to human applications.
Research should be supported through a broad, non-prescriptive RFA-type
announcement based on the concepts and themes discussed and involving glue
grants or interactive R01s that highlight translational applications (including
the translation of genomic data into tissue regeneration) and early clinical
trials.
Training opportunities for young investigators and more senior investigators
transitioning disciplines should be included in the research agenda for the
period 2004 - 2009. Training models incorporating both basic scientists
and clinicians and emphasizing team science and translational research
should be enhanced. Future practitioners should be incorporated into
these models.
NIDCR should continue to facilitate SBIR grant utilization at early phases
of translational research.
NIDCR should partner with the FDA to minimize the loss of competing technology
and maintain translational technologic options. This might include maintaining
"boutique" trials to sort optimal approaches before closing down
competing approaches. This might be achieved through new partnership arrangements
with industrial sources.
NIDCR should continue its efforts to eliminate disparity in research support,
training, and translation/implementation of results to underserved and low
economic groups.
V. Next Steps
NIDCR will capitalize on the expertise and resulting recommendations of the
Panel as a framework for the development of specific initiatives, programs and
program announcements in the period 2004 - 2009. This summary report will
be posted on the NIDCR home page as a first step in informing the community
of this important area of NIDCR's long-range research agenda.
NIDCR Scientific Expert Panel
Repair and Restoration of Oral, Dental and Craniofacial Tissues
Panel II
September 5, 2002
Panel Members:
Julie Glowacki
Brigham and Women's Hospital
Linda Griffith
Massachusetts Technology Institute (MIT)
Christine Kelley
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
David Mooney
University of Michigan
Dianne Rekow
New York University and
NIDCR Advisory Council Member
Pamela Robey
National Institute of Dental and Craniofacial Research (NIDCR)
National Institute of
Dental and Craniofacial Research
National Institutes of Health
Bethesda, MD 20892-2190
e-mail: nidcrinfo@mail.nih.gov
phone: 301/496-4261