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.

Aging & Senescence

Aging is a primary risk factor for degenerative tendon injuries and is strongly linked to dysfunctional extracellular matrix (ECM) remodeling. To investigate the mechanisms underlying this age-related decline, we employ complementary experimental approaches, including primary cell lines and tissues from aged mice and and an in vitro models of accelerated aging. We have demonstrated that both senescent and aged tendons exhibit altered ECM-related gene expression, reduced protein synthesis, and impaired ECM remodeling in response to various mechanical stimuli. Our current work aims to delineate the roles of cellular senescence, metabolic dysfunction, mechanosensitive adaptations, and inflammatory signaling in driving altered tendon remodeling. We are also investigating the ability of senolytic therapeutics and other interventions to restore healthy remodeling mechanisms in aged tendons.

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.

Microdamage Repair

​While tendons are generally considered resilient and fatigue-resistant, it’s thought that the ability to sense and resolve microtraumas from everyday motion is impaired with aging and disease, leading to persistent inflammation, increased probability of macroscopic tears, and eventual tendon degeneration. However, little is understood about the biological mechanisms involved in the healthy regeneration of tendon in response to microdamage. We developed a novel model of localized microdamage injury to address this gap in knowledge. By capitalizing on a nanosecond pulsed laser to create repeatable and tunable holes in the tissue ECM, we may study the structure and composition of ECM during microdamage repair at a high spatiotemporal resolution. Our previous studies suggest that efficient clearance of damaged ECM is required for enhanced defect closure and complete regeneration. Ongoing studies aim to identify the cell-mediated mechanisms essential in promoting these processes and leverage these pathways to accelerate healing.​

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 investigated the hormonal mechanisms underlying these sex differences, demonstrating that estrogen and progesterone play distinct yet coordinated roles in regulating tendon ECM remodeling. Current projects continue to explore the individual and combined influences of biological sex, hormonal exposure, and hormonal signaling on ECM remodeling processes in male and female tendons following alterations to macroscale mechanical loading. Ongoing work additionally focuses on developing experimental tools and models to better replicate hormonal fluctuations across the reproductive lifespan experimentally and investigating how these changes influence tendon ECM remodeling.​