The Host Defense Peptide LL37 in the Treatment and Prevention of Osteoradionecrosis of the Jaws

• Applicant: Privatdozent Dr. Steffen Koerdt
• Subject Area: Dentistry, Oral Surgery
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545646513

In the treatment of head and neck cancer (HNSCC), radiation therapy (RT) is a pillar of oncologic treatment, whether in an adjuvant setting or as the primary definitive therapy. Nevertheless, RT is often accompanied by side events that compromise the patient’s quality of life. Osteoradionecrosis of the jaws (ORNJ) is a severe, long-term complication of head and neck RT. Throughout irradiation, the bone quality of the maxilla and mandible, and wound healing capacities in general, decrease. Even small surgical interventions (e.g., tooth extraction) can trigger the onset of ORNJ. Characteristically, ORNJ presents as chronic, non-healing intraoral wounds with exposed bone. Moreover, bacterial superinfections promote the disease’s progress and are suspected to play a major role in the pathogenesis of ORNJ. Currently, the only preventative method is perioperative antibiosis and plastic wound closure during surgical interventions, which includes the resectioning of all infected bone. Advanced stages of ORNJ can require (sub-) total resections of the maxilla or mandible, which often lead to a significant reduction in patients’ quality of life and require extensive reconstruction, including microvascular tissue transfer. Furthermore, increasing resistance to conventional antibiotics and disease recurrences despite antibiotic therapy necessitate alternative treatment options.Host defense peptides (HDPs), also known as antimicrobial peptides (AMPs), are endogenous short peptides. They are known to have antimicrobial, antiviral, and antifungal effects as well as being anti-inflammatory and immunomodulating. Some HDPs, in particular the HDPs LL-37 and β-defensins, can promote wound healing by inducing keratinocyte proliferation and migration or stimulating neovascularization. Our previous studies demonstrated that the expression of human-β-defensins (hBD) is decreased in tissues post-RT. Despite the multiple useful characteristics that HDPs provide, there is a lack of clinical data examining their therapeutic use. Based on our previous work and the special characteristics of HDPs described in the literature, we hypothesize that HDPs can provide a preventive effect for the onset of ORNJ or a limitation of its clinical manifestation.This proposal is designed to evaluate the in-vitro effects of the HDP LL-37 in the prevention and treatment of ORNJ using a small-animal model with a split-mouth design. We hypothesize that wound healing will be significantly improved (i.e., having fewer complications, less inflammation, and faster healing) in extraction sockets treated with HDPs. In addition to clinical evaluation, micro-CT analysis, histology, immunohistochemical staining, and analysis of the oral microbiome following RT will be performed.The therapeutical use of HDPs in ORNJ could result in the reduced use of conventional antibiotics and could help to reduce the number of surgical interventions in this meticulous group of patients.

• DFG Programme: Research Grants
• Co-Investigators: Dr. Heilwig Fischer; Privatdozentin Dr. Katharina Schmidt-Bleek