Mechanobiology in Tendon, Ligament, and Skeletal Muscle Tissue Engineering

Abstract

Tendon, ligament, and skeletal muscle are highly-organized tissues that largely rely on a hierarchical collagenous matrix to withstand high tensile loads experienced in activities of daily life. This critical biomechanical role predisposes these tissues to injury, and current treatments fail to recapitulate the biomechanical function of native tissue. This has prompted researchers to pursue engineering functional tissue replacements, or dysfunction/disease/development models, by emulating in vivo stimuli within in vitro tissue engineering platforms; specifically mechanical stimulation, as well as active contraction in skeletal muscle. Mechanical loading is critical for matrix production and organization in the development, maturation, and maintenance of native tendon, ligament, and skeletal muscle, as well as their interfaces. Tissue engineers seek to harness these mechanobiological benefits using bioreactors to apply both static and dynamic mechanical stimulation to tissue constructs, and induce active contraction in engineered skeletal muscle. The vast majority of engineering approaches in these tissues are scaffold-based, providing interim structure and support to engineered constructs, and sufficient integrity to withstand mechanical loading. Alternatively, some recent studies have employed developmentally-inspired scaffold-free techniques, relying on cellular self-assembly and matrix production to form tissue constructs. Whether utilizing a scaffold or not, incorporation of mechanobiological stimuli has been shown to improve the composition, structure, and biomechanical function of engineered tendon, ligament, and skeletal muscle. Together, these findings highlight the importance of mechanobiology and suggest how it can be leveraged to engineer these tissues and their interfaces, and to create functional multi-tissue constructs.

Mechanoresponsive regulation of fibroblast-to-myofibroblast transition in three-dimensional tissue analogues: mechanical strain amplitude dependency of fibrosis

“…The 4%, 8%, and 12% uniaxial tensile strain at 0.1 Hz frequency was applied to the tissue analogues to mimic the dynamic physiological environment of musculoskeletal tissues such as tendon, ligament, and muscle for 2 h per day throughout the 7-day culture period. The different uniaxial tensile strains represent the stress experienced by skeletal tissues, reaching as much as 12.5 times body weight during exercise, a 5–9% change in length during moderate physical activities, and up to 12% during high-intensity activity 12 , 33 – 36 . Unstrained (0%) cell-laden tissue analogue was used as the control group.…”

Micro/Nanosystems for Magnetic Targeted Delivery of Bioagents

“…The dispersed MNPs entrapped in the scaffold matrix can be stimulated by a static or alternated external magnetic field, and the effects that such stimulation has on the cells can be different [131,138,210,211]. Magnetic cell stimulation is typically mediated by the action of mechanical forces that apply to the cell membrane and activate specific molecular signaling pathways in a process known as mechano-transduction [131,212]. For remote cell mechanostimulation through externally applied magnetic fields and magnetic nano-transducers, magnetic fields of moderate intensities (ranging from 1mT to 1T) are sufficient to trigger specific cell responses, which can be used to guide the process of tissue repair [131].…”

Dynamic Load Model Systems of Tendon Inflammation and Mechanobiology

“…Mechanical loading of tendon tissue is essential for tendon maturation during development, tendon homeostasis, and degeneration. Many reviews focus in-depth on the history of understanding matrix turnover, tendon biomechanics, and the methods/models used to understand tendon as well as ligament mechanobiology (Lavagnino et al, 2015;Thomopoulos et al, 2015;Wang and Chen, 2018;Dyment et al, 2020;Friese et al, 2020;Gracey et al, 2020;Wang et al, 2020;Bramson et al, 2021). In addition, in vivo models of tendon degeneration are the focus of another review (Theodossiou and Schiele, 2019).…”