Research

Tendon and ligament injuries account for 20-30% of all musculoskeletal disorders, which are the most common occupational injuries in the United States. Such injuries are the end result of a degenerative process involving altered tendon/ligament cell behavior.

Our research investigates the interplay between tendon multiscale mechanics and mechanobiology in the context of tissue remodeling (e.g. degeneration, repair, and development). The ultimate goals of our work are to identify the causes of tendon pathology, discover novel therapeutic options, and direct the design of biomaterials that can recapitulate the behavior of native tissue. We aim to conduct science that will produce a fundamental knowledge regarding the feedback loop between local tissue mechanics and cellular mechanobiology, which is an important contributor to numerous diseases outside of orthopaedics, including tissue fibrosis and cancer. Our multidisciplinary work uses the following techniques:

 

A primary cause of tendon degeneration is overuse (i.e., fatigue loading), which produces repeated microscale damage of the load-bearing collagen fibrils. In addition to direct mechanical damage, tendon degeneration is characterized by the accumulation of atypical tissue components (e.g., cartilaginous, fat, and calcium deposits), which further weakens the tissue and drives the progression of degeneration. Why resident tenocytes produce these atypical matrix deposits rather than repair the native tissue structure is unknown. We hypothesize that fatigue damage induces changes in the local tissue mechanical microenvironment (e.g., strains, stiffness, topography), which alters the biophysical stimuli presented to tenocytes and leads to their adoption of abnormal (i.e., non-tenogenic) phenotypes. However, it is unclear whether the changes in tendon microscale mechanics caused by fatigue damage are responsible for the altered cellular activity observed with tendon degeneration. Therefore, the objectives of this project are to identify the in situ changes in tendon microscale mechanics caused by fatigue damage and to determine whether the altered mechanical microenvironment modifies tenocyte behavior leading to tendon degeneration.

Selected Papers: 

 

Currently, tissue engineered tendon constructs fail to replicate the native structural and mechanical properties of native tendons. One of the suggested reasons is that traditional scaffold approaches hindering cell self-assembly and do not replicateing normal embryonic development. Scaffold-free constructs built through cell self-assembly and ECM production have been able to replicate the mechanical and structural properties of early embryonic tendon, but they fail to match the rapid increase of structural and mechanical properties that occur during late tendon development. Although our lab has previously established that mechanical stimulation is essential to tendon development, there is still a lack of knowledge regarding the key biological mechanisms driving late tendon development. The aim of this project is to investigate the mechanotransduction signaling pathways and biological mechanisms driving embryonic tendon development, and use this information to inform genetically engineered tendon constructs

Selected papers: 

  • Peterson BE, Rolfe RA, Kunselman A, Murphy P, Szczesny SE (2021) Mechanical Stimulation via Muscle Activity Is Necessary for the Maturation of Tendon Multiscale Mechanics During Embryonic Development. Front Cell Dev Biol. 9:725563.

 

Anterior cruciate ligaments (ACLs) are one of the most commonly torn ligament affecting more than 200,000 people in the United States each year with the occurrence being 2-8 times greater in females compared to males. Given the lack of spontaneous tissue repair, reconstruction of the ACL is the standard treatment.  While outcomes between graft types are similar in the general patient population, the rerupture rate of non-irradiated allografts are 3-4 times greater than autografts in young active individuals. A potential driver of increased rupture rate of female primary ACL tears and allograft ACL reconstruction ruptures could be failed tissue remodeling in response to mechanical loading. Therefore, the objective of this proposal is to understand the effect of mechanical loading on primary ACL tears and ACL reconstruction reruptures.

Selected Papers: 

  • Paschall L, Carrozzi S, Tabdanov E, Dhawan A, Szczesny SE. Cyclic loading induces anabolic gene expression in ACLs in a load-dependent and sex-specific manner. J Orthop Res. 2023 Aug 21. doi: 10.1002/jor.25677. Epub ahead of print. PMID: 37602554.
  • Paschall, L., Pedaprolu, K., Carrozzi, S., Dhawan, A., Szczesny, S. (2022). Mechanical Stimulation as Both the Cause and the Cure of Tendon and Ligament Injuries. In: Greising, S.M., Call, J.A. (eds) Regenerative Rehabilitation. Physiology in Health and Disease. Springer, Cham. https://doi.org/10.1007/978-3-030-95884-8_11