TRANSCRIPTOME-DRIVEN DESIGN OF A HYDROGEL NICHE FOR ENHANCED STEM CELL-MEDIATED TENDON REGENERATION

Bioactive hydrogels are promising for enhancing stem cell-mediated tendon repair, yet there remains a significant gap in understanding the optimal features of these niches, leading to prolonged development cycles and inconsistent healing results. A comprehensive assessment tool is necessary to elucidate how various material features influence cellular responses. Materiomics, which integrates data science with biological omics data, offers a systematic approach for optimizing biomaterials. Despite advancements in RNA-seq for global transcriptomic analysis and machine learning for predicting stem cell lineage and biomaterial functionality, their application in tendon phenotype is limited, hindering insights into critical tendon biomaterial characteristics. This study aims to develop a transcriptome-guided materiomics approach to create TenoGel, a tendon-mimetic hydrogel to enhance stem cell-mediated tendon repair. TenoGel was designed to modulate specific tendon niche features, focusing on tendon extracellular matrix (tECM) and uniaxial tensile loading due to their roles in tenogenesis. The TenoGel platform was evaluated using an innovative RNA-seq-based materiomics strategy, integrating bioinformatics and mathematical modeling to provide insights into the tenogenic effects of TenoGel on adipose-derived stem cells (ASCs). A rat patellar tendon injury model was employed to assess the healing efficacy of the optimized TenoGel with rat ASCs. The TenoGel platform modulates essential tendon niche aspects, including tECM concentration and tensile loading. The materiomics approach, facilitated by bioinformatics and modeling, addressed key design factors for TenoGel, such as the relative importance of tECM and tensile loading, optimal tECM concentration, and pre-conditioning duration. The optimized TenoGel underwent validation through in silico, in vitro, and in vivo analyses. Results indicated enhanced tendon regeneration and reduced ectopic ossification in the rat model. The correlation between materiomics-guided TenoGel design and in vivo healing outcomes highlights the efficacy of this data-driven strategy for biomaterial engineering. This study demonstrates the potential of a transcriptome-guided approach for rational biomaterial design to enhance stem cell-mediated tendon repair. The optimized TenoGel could significantly improve the effectiveness of stem cell therapies for tendon injuries. Additionally, the materiomics strategy represents a substantial advancement in assessment and predictive tools, promoting predictable and efficient healing outcomes in tendon regeneration and beyond. Acknowledgements: research grants council of hong kong sar (grf 14118620 and 14121121, dmw; early career scheme award 24201720, dfek; n_cuhk409/23, dmw), the innovation and technology commission (its/090/18, dmw; health@innohk cnrm, dmw, dfek, rst).