The Role of Spatial Heterogeneity in Modulating Tendon Mechanics and Cellular Responses to Load

Tendons are essential tissues that connect muscles to bones and transfer forces to enable movement. Instead of being uniform mechanical links, tendon properties can vary significantly across individuals and even within a single tendon. These differences in local properties may play a key role in determining how tendons function, adapt to physical activity, and respond to injury. However, most studies simplify tendons as uniform materials, overlooking potentially important variations that could influence health and healing. This research project will reveal how local changes in tissue properties affect tendon performance and cellular behavior. By improving understanding of how tendons function, this research will provide valuable information to guide translational efforts aimed at improving injury prevention, refining rehabilitation strategies, and inspiring new regenerative therapies. This study will also integrate research with education by developing new course materials on tissue heterogeneity, training interdisciplinary teams of student scientists, and engaging middle and high school students through interactive outreach activities that highlight the value of teamwork and interdisciplinary science. This project will determine how local tissue properties and spatial heterogeneity drive tendon mechanics and mechanobiology. Full-field maps of morphological, microstructural, compositional, and mechanical properties will be determined in tendons with differing levels of inherent heterogeneity. Spatial statistical approaches, including autocorrelation metrics and cross-correlation analyses, will quantify heterogeneity and identify relationships between local tissue properties and mechanical function. Multivariate regression models will determine which spatial features best predict local- and tissue-level mechanics. To investigate how spatial heterogeneity influences tendon mechanobiology, cellular responses to load will be measured in calcium-tagged mouse tendons then correlated with local properties and heterogeneity metrics. Comparisons between native and recellularized tissues will isolate matrix-driven effects, and regression models of multi-modal spatial data will determine best predictors of active responses to load. By integrating high-resolution mapping with advanced spatial analysis, this work will establish a new framework for linking tissue heterogeneity to mechanical and mechanobiological responses of biological tissues. Results will guide translational interventions to prevent tendon injury and inspire novel biotechnology advances to enhance treatment strategies. In addition, these innovative techniques could enable transformative advances in understanding the mechanics and mechanobiology of other soft tissues, enhancing overall impact. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria. NSF Award ID: 2545817 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Spencer Lake | Institution: Washington University, SAINT LOUIS, MO | Award Amount: $519,529 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2545817 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2545817.html