Mineral Scaffold-Modulated Senescence in Irradiated Bone - PROJECT SUMMARY/ABSTRACT Poor bone quality in the jaw is a significant clinical problem that leads to pain, along with an increased risk of fracture and infection. Multiple clinical conditions may lead to poor jawbone quality, but two of the leading causes are osteoporosis and osteonecrosis as a result of radiation therapy (RT). Osteoporosis affects 200 million people worldwide and while the focus is often on the appendicular skeleton, craniofacial bones, including the jaw, become brittle and diseased. While not as pervasive, head and neck cancer (HNC) is the sixth most common cancer type worldwide with a predicted 30% global increase annually by 2030. RT is the standard treatment for HNC, and osteoradionecrosis (ORN) of the jaw is a frequent and severe complication. Interestingly, the molecular mechanisms underlying the poor bone quality in these two conditions are similar, with cellular senescence and dysregulation of osteoblast to osteoclast management playing a significant role in disease etiology. Senescence is a cellular-level response that restricts aged or damaged cell proliferation and represents a major cause of aging due to genomic instability and telomere damage. Studies have demonstrated an increase in senescent cells as a person ages, contributing to diseases associated with aging (e.g., osteoporosis). Additionally, we have identified a strong correlation between cellular senescence and increased expression of the bone inhibitor sclerostin (SOST). The long-term goal of this project is to tune a novel 3D-printed (3DP) mineral framework infiltrated with cryogel scaffold to resist destructive structural and cellular modulations following radiation in order to improve bone regeneration. We propose the central hypothesis that a combined cryogel scaffold/mineralized 3DP framework will induce osseointegration and bone formation in HNC patients, while modulating senescence caused by radiation. We test this hypothesis through three main aims: i) enhancement of bone formation in the setting of radiation through the fabrication of combined tissue- engineered cryogel/3DP mineral constructs; ii) systematic modulation of in vitro senescence through optimization of scaffold mineralization, with or without the addition of senolytic drugs; and iii) quantification of senescent cells and overall bone healing in an established in vivo osteonecrosis mandible murine model exposed to RT. This approach will allow for the creation of a cost-effective and biologically improved targeted treatment option consisting of uniquely combined mineralized 3DP framework and cryogel technology. The potential to induce osteogenesis and modulate senescence, both in vitro and in vivo, is innovative and impactful mechanistically, where our fabrication expertise and mechanistic knowledge will establish a scaffold capable of stimulating/accelerating bone formation. Further, the innovative impact of the combined scaffolding for modulating senescence has the potential to be highly translational to additional complex bone defects, especially those in aging patients. This will fit a need in the research and clinical community for improved patient-specific treatment options while supporting the NIDCR mission of improving oral, dental, and craniofacial health.
