Integrative Biology and Infectious Diseases Branch, DER, NIDCR
The goal of this initiative is to establish a multidisciplinary Dental, Oral and Craniofacial (DOC) Tissue Regeneration Consortium (DOCTRC) that will develop effective clinically-applicable strategies for regeneration of functional tissues of the human dental, oral and craniofacial complex. The composite tissues of interest include: vascularized and innervated craniofacial bone and musculoskeletal complex, periodontium, tooth and temporomandibular joint (TMJ). The outcome of the DOCTRC effort will be the development of combination products based on cells, biologics and devices and associated protocols ready for the initiation of clinical trials. To meet the goals of an accelerated translational timeline, DOCTRC will employ tissue regeneration tools and approaches that previously have been tested in small animal models, and which have demonstrated significant translational potential and readiness to be tested in DOC disease-relevant large animal models.
DOCTRC will be structured in three stages:
- Planning Stage: Duration 1 year. The goal of stage 1 will be to establish interactive teams to function as centralized Resource Centers (RCs), and to provide initial evidence of expertise in navigating through the regulatory pathway.
- Resource Centers (RC) Development Stage: Duration 2-3 years. One or several most meritorious teams from stage 1 will be selected to establish centralized RCs. The goal of stage 2 will be to build a robust infrastructure to deliver uniform high-quality technical support to Interdisciplinary Translational Projects (ITPs), which will be initiated during stage 3. To this end, each RC will develop, optimize and validate tools and strategies for DOC tissue regeneration in the following areas: (i) cells and biomaterials, (ii) large animal models, (iii) functional assays, and (iv) government regulatory interactions.
- Interdisciplinary Translational Projects Stage: Duration 4-5 years. The goal of stage 3 will be to advance specific tissue regeneration strategies through the translational pipeline to complete their validation and preclinical testing. The ITPs will utilize the resources developed by the RCs during stage 2, and will work in continuous close collaboration with the RCs while seeking advice from the FDA. The outcome of stage 3 will be FDA-approved tissue regeneration combination products and phase 1 clinical trial protocols.
Many scientific and technological advances have emerged from interdisciplinary efforts addressing reconstruction and regeneration of DOC tissues affected by disease and trauma. For example, numerous synthetic and natural scaffolds have been developed to promote maturation of engineered constructs in vitro or facilitate tissue regeneration in vivo. Such scaffolds can be designed to recapitulate the properties of extracellular matrices of natural tissues, deliver active biomolecules to cells, degrade at a pre-determined rate, control inflammatory responses, and exhibit many other useful properties. Also, important strides have been made in elucidating the mechanisms of DOC tissue-specific stem and progenitor cell function, and deriving new tools and technologies for cell isolation, expansion, and differentiation. Furthermore, robust functional assays have been developed for testing the safety and efficacy of Tissue Engineering and Regenerative Medicine (TE/RM) protocols and for monitoring the progression of tissue regeneration in vivo. Unfortunately, despite this progress, only a few TE/RM-based prospective therapies have reached the stage of clinical trials.
Given the promise of TE/RM to improve human health, and the considerable investments that NIDCR and NIH are making in this area, we addressed the nature of the obstacles interfering with TE/RM translation by consulting with the broad extramural research community, and carrying out a detailed analysis of our current TE/RM portfolio. Several significant insights have emerged from these inquiries. In particular, it was concluded that specific clinical needs and well-defined product design criteria should be the primary driving force of the translational effort. Moreover, such clinical needs should be aligned with tools and technologies that have sufficiently matured in discovery research to pass stringent safety and efficacy review criteria by the FDA. Building an infrastructure to satisfy these objectives will require close partnership among clinicians, bioengineers, biologists, and regulatory experts.
Based upon this feedback, we are proposing to establish the DOCTRC where an interdisciplinary group of professionals will work together for a common goal of translating advances of TE/RM to clinic. In the consortium, the clinicians will define the areas of clinical needs as well as develop product design criteria for the tools and technologies to meet these needs. On the basis of the clinicians’ recommendations, the bioengineers, biologists and regulatory experts will then develop specific technical strategies to meet the clinical needs that are compatible with the FDA requirements for preclinical studies. However, given a multitude of TE/RM-based biomaterials, cell sources, assays, and animal models developed to date, a preparatory stage will be needed before optimal technical strategies for preclinical studies could be developed. Specifically, it will be necessary to conduct side by side quantitative comparisons, as well as to optimize and validate the available materials and protocols in DOC disease-relevant large animal models with respect to their safety, efficacy, and other functional outcome parameters, and to identify those candidates that are most likely to succeed in translation. The DOCTRC will systematically address these technical issues during its two initial stages; the third stage will then focus on driving the candidates most-likely to succeed through the translational pipeline.
Current Portfolio Overview
Discovery research projects occupy the greater part of the current NIDCR TE/RM portfolio. These projects address regeneration of NIDCR mission-relevant tissues with bone regeneration being the most prevalent area followed by tooth and cartilage regeneration. The majority of the studies focus on regeneration of single rather than complex composite tissues (vascularized bone is the exception). Among specific diseases, craniofacial abnormalities are addressed in the largest number of studies followed by periodontal diseases, tooth defects, and TMJ disorders. Only a few current projects have reached the state of maturity to begin advancing through the translational pipeline. Also, since the portfolio is structured around individual awards, no significant work is being conducted to aid side-by-side comparisons and validation of different tools and technologies that are being pursued by individual investigators. NIDCR’s TE/RM program has shared interests with NIAMS and NIBIB in bone, cartilage, and skeletal muscle regeneration; however, NIDCR has a unique interest in regeneration of DOC tissues. Additionally, NIDCR has common interests with the Craniofacial Reconstruction program of the Armed Forces Institute of Regenerative Medicine (AFIRM), a virtual Institute supported by the Department of Defense, NIH, other Federal agencies, and private businesses. While AFIRM and NIDCR both address reconstruction of trauma-related defects, NIDCR has unique interests in the reconstruction of DOC tissues resulting from cancer-related surgeries, birth defects, as well as oral and dental diseases and abnormalities.
Individuals and Groups Whose Input was Solicited for This Initiative
Over the last several years, program staff have regularly solicited input on translational opportunities and roadblocks from the broad scientific community via moderated panel discussions convened at international meetings, such as the Gordon Research Conference “Craniofacial Morphogenesis and Regeneration” in 2010, and the Keystone Symposium “Regenerative Tissue Engineering and Transplantation” in 2012. Most recently, in July 2013, NIDCR convened a Programmatic Consultation with a group of fourteen interdisciplinary extramural participants, including one FDA representative, on the approaches to identify optimal strategies for translating NIDCR mission-relevant TE/RM research into clinical applications. The Consultation was structured as a moderated roundtable discussion on a series of relevant topics with active participation of the NIDCR Director and the Executive Staff, NIDCR Program Staff, Training and Review Staff as well as several representatives from NIAMS and NIBIB. The input from the Consultation was summarized in a report. This report in combination with the input from earlier panel discussions at international meetings informed the preparation of this concept.
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