Non-healing bone defects represent a significant public health concern, leading to decreased life expectancy and quality of life, particularly among an aging population with increasing comorbidities. Conventional treatments for these defects are ineffective in 5-10% of fractures, exacerbating patient burden and complicating medical interventions. This underscores the need for more effective treatment strategies and early identification of at-risk patients.

Our systematic proteomic meta-analysis addresses this issue by identifying universally affected proteins and functions crucial for bone regeneration. These insights can be leveraged to develop novel bioactive biomaterials, therapeutic targets, and diagnostic biomarkers. To this end, we developed and applied the first high-quality meta-analysis and standardized proteomics workflow that integrates multi-disciplinary, multi-species studies assessing bone healing at the local and systemic level in multiple cellular, tissue and (pre)-clinical experimental set-ups. This integrated framework involves cross-studie data harmonization, protein selection, network construction, module mining, functional enrichment, drug repurposing, and protein scoring metrics.

By applying this framework to synthesize 29 proteomics studies in the context of bone healing, we identified 51 key proteins potentially essential for bone healing, including well-known ECM components such as collagens, fibronectin, and periostin, alongside eleven less-studied proteins like YWHAE, HSPG2, and TGFBI. These proteins offer new opportunities for advancing bone biomaterial development. Moreover, we discovered compounds such as Trifluoperazine and Quercetin that target critical proteins involved in bone regeneration, presenting new therapeutic options to mitigate the socio-economic impact of non-healing bone defects.

Our findings represent a significant step forward in bridging fundamental research and clinical application, providing a foundation for improved diagnostic, treatment, and predictive measures in bone healing. The integration of multidisciplinary and multi-species data highlights the robustness of our approach, enabling the identification of novel molecular mechanisms and potential drug targets. This work not only advances the field of tissue engineering but also illustrates the power of interdisciplinary research connecting fundamental and translational research with computational sciences in developing clinical solutions. This framework, detailed in our published tutorial, is designed to be broadly applicable to other research areas.