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ARRA Investments in Regenerative Medicine for Dental and Craniofacial Disorders

Public Health Burden
Many significant human diseases arise from the loss or dysfunction of specific cell types in the head and mouth, including oral cancer, orofacial clefts, autoimmune diseases such as Sjogren's Syndrome and HIV/AIDS-associated oral diseases, dental caries, periodontal disease, and trauma-associated damage. The ultimate goal of tissue engineering and regenerative medicine is to create, rebuild and preserve permanent, functional tissues by applying both biological and engineering principles -- thus it offers unique opportunities for developing new therapeutic approaches to prevent and treat these debilitating and life-threatening diseases

Basic Research
In order to fulfill the promise of regenerative medicine, researchers have to explore fundamental questions of biology. ARRA-funded basic science projects include studies of the nature of normal and cancerous stem cells from oral mucosal linings, molecular mechanisms of tooth and bone regeneration, and development of new approaches for reprogramming non-stem cells into stem cells.
  • In an effort to develop cancer stem cell (CSC)-based therapies for oral cancer and finally improve oral cancer survival rates, which have remained unchanged for 20 years, one grant will focus on the identification of cell surface markers of oral stem cells and oral cancer stem cells – a critical step in allowing future therapeutic approaches to specifically target oral cancer stem cells without affecting normal oral stem cells.1
  • Tooth loss is a major health problem in the U.S., experienced by up to 42% of the population in some states and disproportionately affecting minority and economically disadvantaged communities. Another project seeks to reactivate embryonic dental signaling pathways in adult oral cells for regeneration of natural teeth and their associated support tissues, including bone, blood vessels, nerves and periodontal ligament, providing improved function, sensitivity, durability and appearance rather than relying on artificial synthetic implants which are prone to mechanical failure and infections.2
  • Scientists are investigating whether erythropoietin (Epo) can be used to reprogram certain forms of stem cells that can then be harnessed for cell-based therapies to heal and restore non-healing bone wounds following disease or trauma.3
  • One project applies a cocktail of signaling agents to in vitro cultures of differentiated epithelial cells in order to reprogram them to stem cells that can promote wound healing.  This approach is applicable to a wide range of differentiated epithelial cells, including the mucosa of the mouth, suggesting that one day clinicians will be able to replace the badly damaged mucosa in people with oral cancer, chronic periodontitis, and other serious oral conditions.4
Translational Research
Ultimately, researchers hope to create fully functional craniofacial bone, salivary glands, and artificial teeth with performance properties equivalent to natural tissues or organs. ARRA-funded translational projects test several regenerative medicine strategies in preclinical models that will move them significantly closer to testing in humans.
  • One grant assembles a critical mass of scientists and multi-disciplinary surgeons into a consortium with the goal of regenerating dental pulp-dentin grafts and facial soft tissue-bone grafts in a pre-clinical, large animal model, as well as plan for the first-in-human clinical trials of these grafts. These advances would transform treatment options for patients experiencing dental/oral and craniofacial infection, trauma, or defects.5
  • One project seeks to develop a point-of-care method for surgical reconstruction of living bone by developing a novel, high-throughput device to identify, protect, and return a subset of patient-derived cells that are capable of growing into new bone structures.6

  1. 1RC1DE020649-01 -- Identification of normal and cancer stem cells and their niche in oral mucosa -- Wang, Xiao-jing -- (CO)
  2. 1RC1DE020337-01 -- Manipulation of beta-catenin signaling in adult oral cells for tooth regeneration -- Millar, Sarah E -- (PA)
  3. 1RC1DE020721-01 -- The Use of Erythropoietin to Reprogram Oral and Craniofacial Stem Cells -- Taichman, Russell S -- (MI)
  4. 1RC1DE020817-01 -- Creation of adult epithelial stem cells from differentiated epithelial -- Weinberg, Robert A -- (MA)
  5. 1RC2DE020767-01 -- Regeneration of Clinically Relevant Orofacial Tissues in Pre-Clinical Models -- Mao, Jeremy J. -- (NY)
  6. 1RC2DE020771-01 -- Calvarial Regeneration using Biomatrix-Encapsulated Skeletal Progenitors -- Longaker, Michael T -- (CA)

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