Periodic Reporting for period 2 - HIPPOX (The mechanobiology of hypoxia during bone regeneration)
Reporting period: 2023-09-01 to 2024-08-31
Bone regeneration is a challenging clinical problem. Each year, millions of patients worldwide experience bone fractures and 10-15% of these fractures do not fully heal. Two critical events early in fracture repair determine the outcome of the healing process: changes in oxygen supply caused by blood vessel rupture and mechanical instability between the broken bone ends. Thus, cells that will eventually form cartilage and bone to heal the bone must simultaneously adapt to both different local oxygen levels and a mechanical microenvironment to ensure full tissue regeneration. The project aims to define new cellular and molecular mechanisms that mediate crosstalk between the local oxygen environment and mechanical signaling during fracture repair and target this crosstalk in an innovative regenerative therapy to accelerate fracture repair. Improvement in therapeutic strategies and rehabilitation will have a global impact and are already included in European health care efforts to ensure health throughout the life course, and to reduce hospitalization time and mortality in the (elderly) population.
The second part of the project and content of this report has been conducted at the Technical University of Dresden (TUD). During this reporting period, my work has led to groundbreaking discoveries that challenge the traditional understanding of oxygen’s role in bone repair. We have introduced a new paradigm advocating for hypoxia-promoting therapies to enhance bone healing, with significant clinical potential for accelerating fracture recovery and addressing complications such as non-unions. These findings were formalized in a provisional patent filed with the University of Pennsylvania titled "Devices and Methods for Bone Fracture Healing and Segmental Defect Healing," which involves novel orthopedic devices and methods that modulate oxygen levels at fracture sites.
To disseminate these important findings, I intensified engagement with the scientific community through conferences, seminars, and networking opportunities. Additionally, a shift from in vitro approaches to in-depth genomics data analysis was necessary to explore the underlying mechanisms of these discoveries. I received specialized training in genomics data analysis, including the use of the R toolkit (Seurat) and gene set enrichment analysis (GSEA), enabling me to extract key insights from our datasets.
Key achievements include:
1. Analysis of cell population changes 3 days post-fracture.
2. Evidence supporting the role of erythroid progenitors in fracture repair.
3. Identification of mechanisms governing intracellular oxygen binding.
These findings provide valuable contributions to the field of bone fracture research.
To disseminate these important findings, I intensified engagement with the scientific community through conferences, seminars, and networking opportunities. Additionally, a shift from in vitro approaches to in-depth genomics data analysis was necessary to explore the underlying mechanisms of these discoveries. I received specialized training in genomics data analysis, including the use of the R toolkit (Seurat) and gene set enrichment analysis (GSEA), enabling me to extract key insights from our datasets.
Key achievements include:
1. Analysis of cell population changes 3 days post-fracture.
2. Evidence supporting the role of erythroid progenitors in fracture repair.
3. Identification of mechanisms governing intracellular oxygen binding.
These findings provide valuable contributions to the field of bone fracture research.
The HIPPOX project has achieved significant breakthroughs that challenge the current paradigm of oxygen’s role in fracture repair. By identifying a mechanism that promotes hypoxia by targeting intracellular oxygen-binding mechanism and enhances bone healing, I have laid the foundation for the development of new regenerative therapies. My findings have already resulted in a patent filing and the establishment of a new therapeutic concept, demonstrating the substantial potential of this research to improve outcomes in patients with bone fractures or defects.