Soft Tissue Mechanobiology

Mechanical forces govern the structure and biology of nearly all soft connective tissues. We are interested in understanding how cells sense mechanical forces through the extracellular matrix, and how increased or decreased forces disrupt homeostasis and lead to extracellular matrix adaptation or degeneration. To this end, we use novel in vitro tendon models combined with custom-built controllable mechanical bioreactors to understand how external mechanical forces influence tissue biology, specifically extracellular matrix remodeling, tissue inflammation, and apoptosis. In addition, we use sophisticated mechanical testing methods at multiple hierarchical scales to measure the dynamic mechanical function of many soft connective tissues. This includes whole tissue mechanical properties, measurements of tissue viscoelasticity and poroelasticity/fluid flow, and nano- and micro-mechanics. Current projects include investigating how different loading directions and intensities influence tendon biology, as well as studying permeability and solute transport properties using nanoscale rheology in various soft tissues.

Tendon and Ligament Aging

Aging is a primary risk factor for degenerative tendon injuries and
is strongly linked to dysfunctional extracellular matrix (ECM) remodeling. We utilize tendon explants and primary cell lines from aged mice to directly interrogate the impact of age on cell and tissue remodeling and injury responses. Coupled with mechanical loading bioreactors, we can directly control both mechanical environment and culture conditions (inflammation, energy availability, ect) experienced by tendon explants ex vivo. We have shown that that aged tendons exhibit impaired ECM remodeling to various mechanical stimuli including complete mechanical unloading, acute compression, and cyclic tensile strain. Our current work aims to uncover the underlying mechanisms driving this response such as absent mechanosensitive adaptations, aberrant inflammatory signaling, and dysregulated metabolic pathways.

Intertissue Crosstalk

We have been working to develop in vitro models of tissue homeostasis to understand normal processes of ECM remodeling, as well as in vitro injury models. Specifically, we developed a clinically-relevant whole tendon explant model, as well as a rotator cuff organ culture injury model. Unlike single-cell analyses or tissue-engineered approaches, these models allow us to explore the biological response to altered mechanical loading in a controllable environment while preserving native structure, cell-cell junctions, and interaction with adjacent tissues. Furthermore, this platform allows us to identify key molecular pathways that can be explored through additional cell culture experiments and can be used as a testbed for potential therapeutics that can be evaluated using in vivo approaches. In our bone-tendon-muscle injury model, we have been recently investigating the roles of inflammation and tissue crosstalk in tendon degeneration.

Cellular Senescence

Cellular senescence is a permanent state of cell arrest in response to external damage or stress. Senescent cells have been associated with many degenerative pathologies in aged and injured musculoskeletal tissues, including tendon. However, the role of senescent cells in the dysregulation of tendon ECM homeostasis is largely unknown. To assess this, we developed an in vitro model of DNA damage induced cellular senescence in murine tendon explants, enabling us to study the isolated interactions of senescent cells and their native ECM without interference from age-related systemic changes. We have found that senescent tendon explants exhibit altered ECM-related gene expression, reduced protein synthesis, and changed tissue composition, suggesting that cellular senescence plays a role in the altered mechano-response of aged tendons.  Our current work aims to explore the various inducers and phenotypes of senescent cells, uncover the role of ECM and mechanical cues in driving senescent profiles, and investigate ability of senolytic therapeutics to restore healthy remodeling mechanisms.

Sex Differences and Hormonal Influence in ECM Remodeling

Much of the animal and human research studying tendon and ligament injuries has been performed only in male specimens. However, several groups have recently been investigating sex differences in tendon biology, finding significant alterations that will impact clinical treatment of tendon disease. We have also been interested in sex differences, specifically as they relate to aging, and have found a number of differences in the inflammatory profile of young specimens following injury, as well as differences in the regulation of senescence pathways in aging. Current projects include investigation into the ECM remodeling processes in male versus female tendons following alterations to macroscale mechanical loading.