Bioinspired Synthetic High-Density Lipoprotein (sHDL) nanotherapeutics with immunomodulatory and regenerative potential in endodontics

/ABSTRACT Dental pulp necrosis, whether caused by tooth decay or injury, can progress to apical periodontitis (AP) if left untreated. AP is a common condition characterized by inflammation of the tissues surrounding the tooth roots and bone destruction, affecting about 52% of the global population. In the United States, this condition leads to at least 15 million root canal procedures annually for treatment. Suppose the tooth is a mature permanent tooth with a closed apex. In that case, treatment typically involves orthograde root canal therapy by mechanical instrumentation, and the use of outdated and toxic chemical agents, such as sodium hypochlorite. In contrast, when pulpal necrosis occurs in immature permanent teeth in children, the death of odontoblasts disrupts normal root development. Treatment options in such cases include apexification or regenerative endodontic procedures (REP). However, these approaches often involve harmful substances for root canal cleaning and antibiotic combinations in pastes that are highly detrimental to mesenchymal stem cells, ultimately compromising the tooth's regenerative potential. Thus, there is a pressing need to develop clinical therapies that can predictably resolve AP in permanent teeth, regardless of their developmental stage. To address this issue, I will split the effort into three specific aims. First, I will identify a non-toxic synthetic high- density lipoprotein (sHDL)-antibiotic-loaded formulation with enhanced antimicrobial and immunomodulatory properties (Aim 1). Then, I will identify the mechanisms and pathways these nanoparticles activate when treating necrotic mature permanent teeth with AP in rats (Aim 2), and I will determine their ability to promote pulp and dentin regeneration and root formation in rats’ partial or fully necrotic immature permanent teeth (Aim 3). A highly experienced advisory team has been assembled to guide the candidate. Dr. Marco Bottino is the primary mentor, offering valuable support throughout the training, scientific plan, academic job search, and career transition. The advisory team also includes Dr. Anna Schwendeman, an expert in the manufacturing of potent and safe sHDL nanomedicines; Dr. Joshua D. Welch, a leading expert in computational methods related to high-throughput sequencing technologies; and Dr. Hajime Sasaki, a world-renowned scientist specializing in inflammation related to apical and marginal periodontitis, who serves as an advisor/consultant. The candidate, a dentist-scientist, is currently a postdoctoral research fellow at the University of Michigan School of Dentistry. This proposal outlines a comprehensive mentorship and training plan to enhance the candidate’s expertise in lipid nanoparticle manufacturing, high-throughput transcriptomics, and bioinformatics. Project Number: 1K99DE035132-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Renan Dal Fabbro | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $135,000 | Activity Code: K99 | Study Section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11213214