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:

1. 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.
2. 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.
3. 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).
4. 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.
5. Support should be provided to attract expertise from complementary fields and to create unconventional, cross disciplinary teams who can perform high risk research.
6. Additional support should be given to the development of suitable animal models and to the translation to human applications
7. 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.
8. 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.
9. NIDCR should continue to facilitate SBIR grant utilization at early phases of translational research.
10. 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.
11. 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:

1. Genomics and Proteomics of Dental, Oral and Craniofacial Diseases
2. Repair and Regeneration of Dental, Oral and Craniofacial Tissues
3. 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:

1. 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.
   
   
2. 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:
   1. The goal of tissue engineering is to create/preserve permanent, functional tissues.
   2. 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.
   3. The repair and regeneration of dental, oral and craniofacial tissues requires, therefore, a range of expertise and significant interdisciplinary collaborations.
   4. These collaborations should include people who are currently not in this field (such as cell biologists and vascular biologists).
   5. 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.
   6. Anticipated outcomes from tissue engineering include the emergent fields of regenerative medicine and functional histogenesis of complex tissues and organs.
   7. 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:

1. The influence of infection and the oral microbial environment on healing and regeneration
2. 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.
3. 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.
4. 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.
5. 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.
6. 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:

1. 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.
2. 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.
3. 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).
4. 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.
5. Support should be provided to attract expertise from complementary fields and to create unconventional, cross disciplinary teams who can perform high risk research.
6. Additional support should be given to the development of suitable animal models and to the translation to human applications.
7. 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.
8. 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.
9. NIDCR should continue to facilitate SBIR grant utilization at early phases of translational research.
10. 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.
11. 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)

Malcolm Snead
University of Southern California

Samuel Stupp
North Western University