Biotechnology Program
Center for Biotechnology and Innovation
Objective: The long-term goal of this initiative is to move from isolated discoveries and the non-systematic accumulation of data to integrated, quantitative analyses such that each tooth structure and surrounding tissues can be fully understood as a unified system. The endpoint of this activity will be the complete characterization of teeth and their supporting tissues as an integrated biological and biomechanical system that can provide the engineering specifications and design principles required to create blueprints for the design of new dental and associated structures.
Background: The generation of a tooth relies upon a sequence of tightly regulated and reciprocal signaling interactions between the ectoderm lining, the future oral cavity and the neural crest-derived ectomesenchymal cells, followed by precisely choreographed cell interactions with extracellular matrix molecules to generate the tooth and its crucial supporting structures. New genes and their encoded structural and regulatory proteins have been discovered, and their function(s) have been characterized. Nanostructures and nanomachines on the cell surface that control the deposition of matrix and the movement of cells have recently been discovered. Although considerable progress has been made over the last decade in identifying the molecular mechanisms involved in early dental development, areas remain where relatively little is known. A new, integrated approach is needed to acquire information at the nano-, meso- and the macroscale towards achieving the following:
- understand cell-protein, protein-protein and protein-crystal interactions associated with the creation of hydroxyapatite composite tissues;
- understand the cell-to-cell interactions and cell-to-extracellular matrix interactions required for dental tissue formation and biomineralization;
- understand how interfaces between one mineralized tissue and another (from enamel to dentine to cementum to bone) are formed and how biology mediates their association and the dynamic, but firm anchorage of teeth to the jaw;
- acquire an understanding of how mineral formation is initiated and shaped to achieve the esthetic, mechanical and scale properties of the original tissue;
- understand and ultimately control the organization of extracellular matrix by cell surface nano-mechanisms;
- develop stem cell technologies for tooth and supporting connective tissue regeneration.
- finally, be able to recreate functional teeth using biological principles.
Recent experimental advances made in post-natal stem cell research, including isolation and characterization of stem cells derived from human dental pulp, craniofacial bone and other orofacial tissues, provide the basis upon which to develop stem cell technologies for tooth and supporting connective tissue regeneration. More importantly with respect to the reconstruction of dental and associated tissues, these stem cells are capable of forming both mineralized and non-mineralized tissues when they are transplanted into a variety of animal models with suitable carrier vehicles.
Modern technologies (at the atomic, nanoscale and microscopic levels) and innovative approaches are emerging to manipulate and control fabrication of crystalline materials and tissue supporting structures with complex forms and novel properties. The collection of precise quantitative data at each size scale and complexity level of tooth development and dynamic adult anchorage will help develop the concepts, models, and physical tools required for manipulating these processes and components in living cells and tissues at all lengths of scale to produce functional replacements.
Current Portfolio Overview: The NIDCR extramural research portfolio includes 51 grants on: i) tooth formation and eruption ii) genetic diseases, such amelogenesis imperfecta, that affect tooth structures; iii) the functions of ameloblasts, odontoblasts, periodontal ligament cells, cementoblasts, gingival fibroblasts and pulp cells. The portfolio also includes 24 grants on: i) growth and remodeling of calcified dense tissues (e.g., enamel, dentine and cementum); and ii) the regulation of biomineralization. A small number (5) grants in the biomimetics portfolio focus on the: i) physical properties such as hardness, elastic modulus and fracture mechanics of the dentine/enamel junction (DEJ); ii) design of a three-dimensional framework for enamel biomineralization; and iii) design of copolymers based on proteins extracted from the polychaete worms such as Glycera and Nereis for the production of biomimetic films that can serve as mineralization templates.
Recommendations From Workshops: Much has been learned about the development, structure, biomineralization, function, disease and disorders of teeth from NIDCR-supported research. However, this accumulated information has yet to produce the design principles that could drive novel approaches to tooth regeneration. To better understand these deficiencies and encourage investigators to consider research in the area the NIDCR convened a workshop titled “Strategies for Tooth Structure Regeneration” in May of 2000. The conference members identified several knowledge gaps that need to be addressed:
- development of quantitative and integrated data sets for the components of a tooth so that a computational model could be created as a step towards an engineering blueprint for tissue replacement and tooth regeneration
- improvement of our understanding of the structural code for protein-to-protein and protein to mineral interactions during biomineralization of tooth tissues
- improvement of the understanding of the interactions between the cell membrane and extracellular proteins and mineral
- improvement of the understanding of gradients between tissue (enamel to dentin; dentin to cementum) and the role of gradients to achieve optimal materials properties including self-healing, fracture toughness, failure resistance, crack termination and wear resistance;
- enhancement of our understanding of hard tissue integration into soft tissue, including suspensory ligaments between hard tissues and the integration of epithelial attachment to hard tissues
- adaptation of new scientific discoveries to these questions, including the incorporation of new instrumentation, advances in parallel fields and the inclusion of new members into a collaborative team of multi-disciplinary and inter-disciplinary scientists.
Several of the knowledge gaps identified by the workshop participants are still apparent, and addressed in this initiative.
Collaborative Activities: Because of the specific focus of this initiative we do not anticipate participation of other NIH Institutes.
Funding Mechanisms: The broad scope of this initiative will require the efforts of well-integrated, interdisciplinary teams of investigators with significant expertise in cell and developmental biology, genomics and proteomics, chemistry, material sciences, biophysics, and engineering as well as biocomputational sciences. Such groups do not spontaneously self-assemble, but can successfully coalesce around a common challenge. Therefore, innovative administrative mechanisms will be utilized to form and maintain these teams.
We propose the combined use of the P20 (exploratory grant mechanism) and the U54 funding mechanisms. The U54 is a cooperative agreement, an assistance mechanism (rather than an acquisition mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activities. The NIDCR will designate a Program Scientist who will have substantial scientific-programmatic involvement during conduct of this activity. This includes facilitating the partnership between NIDCR and those funded under this RFA, provide relevant scientific expertise and overall knowledge, helping to maintain the overall scientific balance in the program commensurate with new research and emerging research opportunities, assist in promoting the U54 to the scientific community at large and assist in developing meaningful millstones to assess progress of the activity. To be eligible to submit an application for U54 applicants should have received a P20 award and have submitted a concept plan.
The P20 mechanism will be structured to provide funds for six months, to allow applicants to assemble potential team members, hold workshops, etc., to facilitate the planning and writing of the concept plan. Those awarded a P20 will be invited to a meeting to share and discuss ideas for the U54. Based on discussions at the meeting, NIDCR staff will develop the final solicitation for the U54 “Building a Tooth: Bridging Biology and Material Sciences” to be issued in fiscal year 2006.