We seek to recruit interdisciplinary translational project (ITP) teams from universities and industry nationwide that align with our clinical indication priorities in dental, oral, and craniofacial tissue engineering/regenerative medicine. Our first RFP was issued in May 2017 and the first cohort of ITP teams was selected in November 2017. The second cohort of ITP teams was selected in June 2018. We are currently reviewing additional proposals submitted in response to our Summer 2018 RFP.

We are developing an ITP team pipeline, as shown in the figure at right, through a process of structured innovation, during which we recruit, select, and advance only those technologies that optimally align with priorities of four key stakeholder groups — providers (clinicians and healthcare networks); producers (industry); payors; and patients.

ITP teams funded through our Winter 2017/2018 cycle

Novel drug candidate for therapy of arthritis of the TMJ - Denis Evseenko, MD, PhD (USC)

Temporomandibular joint disorders (TMJDs) are a multifaceted group of chronic pain disorders characterized by pain and/or stiffness in the jaw, limited jaw mobility and pain when opening or closing the mouth. TMJDs are relatively common, with incidence rates in the range of 5-12%, with nearly twice as many women as men being affected. One of the primary cause of TMJDs is arthritis, with both rheumatoid and osteoarthritis associated with the condition in between 40-75% of the cases. We have recently discovered a novel class of small molecule regulators called Regulators of Cartilage Growth and Differentiation (RCGD 423), acting as a modulators of gp130 receptor. One of these molecules selected for drug development evidenced a remarkable ability to prevent cartilage degeneration and induction of catabolic enzymes and promote cartilage repair, respectively. Preliminary studies have also shown strong anti-degenerative and anti-inflammatory effect of RCGD 423 in a rat model of TMJ arthritis. Current proposal will demonstrate proof-of-concept efficacy of RCGD 423 following the previously described large animal model of TMJ arthritis. We predict that this compound could represent a novel, first-in-class treatment for TMJ-related arthritis that could have a major societal impact.

Replacement salivary tissues for relief of xerostomia - Mary C. Farach-Carson, PhD (University of Texas)

Our initial product is an autologous stem-cell derived replacement tissue implant returning functional salivary neotissues to patients with hyposalivation disorders after radiation therapy. We hope to expand to the allogeneic market after proof-of-concept including biointegration and return of salivary flow. From normal, resected salivary tissue, stem/progenitor cells (hS/PCs) are isolated, expanded, and encapsulated in customized hyaluronate-based hydrogels where they form functional salivary neotissues. We have strong evidence that hS/PCs can differentiate along all salivary lineages. Using two radiated models, we are examining integration of implants with host tissue to determine if neotissue produces saliva to relieve xerostomia and restore oral health. Future development as an allograft can expand the market to the millions of individuals worldwide with hyposalivation disorders.

PILP: a novel method to repair dentin caries - Stefan Habelitz, PhD (UCSF)

This project aims to translate the Polymer-Induced Liquid Precursor (PILP) method into a clinical approach as part of a restorative dental treatment procedure. The PILP method has been used successfully to functionally remineralize artificial lesions in dentin by restoring its mechanical properties through intrafibrillar collagen mineralization. In this grant we are designing novel dental cements to release PILP-components and test their ability to remineralize natural lesions in carious dentin of extracted human molars in order to demonstrate the feasibility of these cements for use in a clinical setting. Ultimately we aim to generate a dental device that conserves tooth structure and allows the functional repair of dentin through remineralization previously not possible.

HB-EGF for radiation-induced oral mucositis - Peter Santa Maria, MD, PhD (Stanford)

This project aims to translate a topical therapy to prevent the development of radiation or chemotherapy induced oral mucositis. By combining tehniques for sustained release HB-EGF with a mucoadhesive drug delivery system we are able to reduce the development of oral mucositis. If we achieve this we will have an impact on one of the more costly side effects of cancer treatment.

ITP teams funded through our Summer 2017 cycle

Stem cell-based therapies for bone regeneration around ailing dental implants - Tara Aghaloo, DDS, MD, PhD (UCLA)

An osteoconductive growth factor-free antimicrobial adhesive for treatment of peri-implantitis - Nasim Annabi, PhD (Northeastern University)

As dental implants have become the standard of care for tooth replacement, postoperative complications affecting the peri-implant tissues have emerged as a serious health concern. Peri-implantitis (PI) constitutes the leading cause of implant failure. PI refers to a severe inflammatory process affecting the soft and hard tissues surrounding an implant, which is characterized by a progressive loss of the supporting bone. Currently, there are no commercially available products that combine high adhesion to soft and hard oral tissues, and antimicrobial and osteoinductive properties for the treatment of PI. The goal of this project is to engineer an osteoinductive, antimicrobial, and growth factor-free hydrogel adhesive for treatment of PI, which can be rapidly crosslinked in situ via exposure to visible light.

Calvarial bone regeneration using mesenchymal stem cells in swine - Yang Chai, DDS, PhD (USC)

Calvarial defects are common in patients with craniofacial birth defects and diseases. Stem cells combined with biomimetic scaffolds offer a bio-inspired solution to problems like this one, holding the potential for excellent neuroprotective and aesthetic outcomes. Our ITP team is using mesenchymal stem cells (MSCs) delivered on a 3D-printed scaffold to regenerate bone to fill a calvarial critical-sized defect (CSD). We aim to improve care for patients with calvarial CSDs and will fill an extensive need in a sizable market. Our success in this project will also have a direct impact on using 3D-printed scaffold and MSCs in bone regeneration to repair other skeletal defects.

Prevention of scar formation in the skin using topical focal adhesion kinase inhibitors - Geoffrey Gurtner, MD (Stanford University)

Craniofacial injuries from trauma, burns, radiation, and surgery often result in hypertrophic scar (HTS) formation. HTS may cause disfigurement and psychological distress, and is associated with exorbitant healthcare costs. We have demonstrated that activation of focal adhesion kinase (FAK) during the healing process results in excessive scarring. Our porcine model has revealed that disrupting this signaling pathway through topical delivery of a small molecule inhibitor of focal adhesion kinase (FAKI) is effective in reducing scar formation and improving the attributes of the healed skin in deep partial-thickness excisional wounds. We propose to implement clinically-relevant non-invasive scar assessment techniques, and complete certified GMP manufacturing of clinical grade FAKI hydrogel patches in preparation for an investigator-initiated clinical trial.

Promoting salivary gland regeneration using therapeutic delivery of carbachol - Sarah Knox, PhD (UCSF)

Mitigating radiation induced hyposalivation by activation of ALDH3A1 - Quynh-Thu Le, MD, FACR, FASTRO (Stanford University)

We have found that activation of ALDH3a1 enzyme, which is enriched in salivary stem cells, increased stem cell yield, and preserved saliva functions after irradiation in mice. We have discovered a natural product compound, Alda-341, that selectively activates ALDH3a1, is safe to use in humans, and when given to mice, can preserve saliva function after radiation without tumor protection. Therefore, we propose to conduct additional animal studies to optimize the duration of Alda-341 treatment, the sequencing between Alda-341 and radiation therapy, and human studies to determine the distribution of the drug to salivary glands.

Transdermal deferoxamine to enhance fat graft retention for reconstruction of irradiated soft tissue defects - Derrick Wan, MD (Stanford University)

Soft tissue defects following cancer resection of the head and neck present a reconstructive challenge with substantial medical burden. Adjuvant radiation therapy can be highly effective at reducing local recurrence, however detrimental collateral changes including macroscopic discoloration, loss of skin elasticity, microscopic obliteration of small vessels, and dermal thickening make management difficult. To mitigate some of these changes and facilitate reconstruction of irradiated defects, we have developed a transdermal drug delivery system to provide sustained cutaneous delivery of deferoxamine, an FDA approved iron chelator for treatment of acute iron poisoning and chronic iron overload. Local iron chelation can also in increase revascularization of ischemic tissue, and we have already demonstrated local injection of this medication to reverse many hallmarks of chronic radiation-induced soft tissue injury. Our proposal seeks to evaluate the effectiveness of transdermal deferoxamine delivery to improve blood flow and skin biomechanics of irradiated tissue, as well as to determine the ability for our novel patch to improve fat graft based reconstructive strategies.

Peptide-impregnated hydrogel system for improving cleft lip and palate wound healing - Zhong Zheng, PhD (Scarless Laboratories)

Development of therapeutic suture devices that can accelerate the reestablishment of tensile strength in high risk, high tension wounds can significantly minimize wound dehiscence and hypertrophic scarring to improve functional and aesthetic outcomes. To this end, we have found that a fibromodulin-derived peptide (PGP) can significantly promote fibroblast migration and increase wound tensile strength in both rodent and pig models. Additionally, PGP-coated absorbable surgical sutures showed a 50% increase in wound tensile strength compared with control non-peptide-coated sutures in porcine models, which are preferred by the US FDA for testing human cutaneous products. Given the broad indication for surgical sutures, using a gel formulation that can be applied with any suture configuration may provide application flexibility and a streamlined manufacturing strategy for commercialization. Thus, the goal of the current C-DOCTOR ITP Team award is to develop and accomplish key efficacy objectives to expedite the commercialization of a peptide-impregnated gel-type device that can be applied with any suture configuration (with respect to needle specifications, suture composition, and size) for accelerating the reestablishment of tensile strength and minimizing wound dehiscence. If successful, this product can significantly improve the quality of life of patients suffering from poor wound healing or dehiscence.