Multimodal Bioelectroceutical Strategies for Alveolar Bone Regeneration in Diabetes and Aging - Project Summary/Abstract: Diabetic and aged patients exhibit impaired alveolar bone regeneration, leading to poor bone quality that undermines implant placement, stability, and long-term outcomes. Current grafting strategies often fail because chronic inflammation, oxidative stress, and elevated cytokines (IL-1, IL-6, TNF-α) impair osteogenesis, angiogenesis, and neurogenesis. Thus, new therapies are needed to overcome inflammatory barriers and restore high-quality bone regeneration in compromised hosts. This project develops a multimodal bioelectroceutical strategy that integrates electrical stimulation (ES), small molecules, and ionically conductive (IC) scaffolds to create a regenerative microenvironment. ES leverages the piezoelectric properties of bone to enhance Ca²⁺ influx, activate osteoblasts, stimulate extracellular matrix synthesis, promote angiogenesis, and direct macrophage polarization toward healing phenotypes. Pharmacologic modulation of ion channels with agents such as amlodipine or amiloride, or 4-aminopyridine (4-AP) further mimics ES effects, enhancing osteogenesis and neurovascular repair. Small molecules such as SAG (SHH agonist) and WAY- 316606 (Wnt activator) augment osteogenic differentiation while reducing bone resorption. Embedding these agents in biodegradable IC scaffolds enables localized delivery, sustained activity, and reduced systemic toxicity. Our preliminary work established proof-of-concept in soft tissue repair, where IC scaffolds delivering 4- AP combined with ES promoted regeneration, vascularization, immune modulation, and functional recovery in nerve injury and wound healing models. Building on this foundation, we now extend this approach to alveolar bone regeneration in diabetic and aged hosts. Central Hypothesis: IC scaffolds delivering small molecules with ES will suppress chronic inflammation and oxidative stress while stimulating osteogenesis, angiogenesis, and neurogenesis, thereby restoring alveolar bone regeneration in compromised microenvironments. Specific Aims: AIM-1) Screen and optimize small molecules with ES for osteogenic differentiation of diabetic and aged patient derived mesenchymal stem cells (MSCs). AIM-2) Define regenerative and immunomodulatory pathways activated by combined small-molecule and ES treatments using RNA-seq, proteomics, and targeted validation. AIM-3) Assess safety and efficacy of IC scaffold–based multimodal therapy in aged diabetic rodent models of alveolar bone regeneration using μCT, histology, cytokine profiling, and systemic toxicity analysis. Impact: This work introduces the first bioelectroceutical platform for alveolar bone repair in diabetic and aged patients. By addressing both inflammatory barriers and regenerative deficits, the project will generate mechanistic insights, establish safety, and deliver a clinically translatable strategy with significant potential to improve dental implant therapy and craniofacial reconstruction.
