Ligaments respond to mechanical stress to maintain homeostasis under both healthy and healing

conditions, a process dependent on the immune system and termed "homeostatic response."
Thus, mechanical loading is a biological stressor that causes a homeostatic response to ensure the
health and survival of the ligaments and other soft tissues to which it is applied. The immune
system is essential in responding to and orchestrating the repair of damaged tendons and
ligaments.
Because tendons and ligaments share the same structural and physiological components,
ligament healing responses are similar to tendon healing in some ways. Mechanical signals and
immune responses can influence tendon cell regulation and tissue regeneration. Inflammation
and mechanical signals can influence cell differentiation by regulating the transcription of
markers (Yang et al., 2021). Tendons and ligaments adapt to mechanical stress by modifying
their extracellular matrix to adjust stiffness (Lavagnino et al., 2015) via the tenocytes, which
convert mechanical signals into adaptive responses — a process known as mechanotransduction
(Gracey et al., 2020). Tenocytes' indirect responses to mechanical stress function to elicit a
homeostatic response. If mechanical stress in tendons and ligaments exceeds the physiological
upper or lower thresholds, tenocyte death can occur within hours (Sakabe et al., 2018), triggering
tissue repair processes. This is particularly important in the early stages of ligament injury
healing.
Further, early ligament stretching, for example, may trigger anti-inflammatory responses during
the early stages of healing in medial collateral ligament (MCL) injury rehabilitation because low-
magnitude stretch has been shown to have anti-inflammatory effects (Berrueta et al., 2015).
Without appropriate biomechanical cues, new tissue formation lacks the necessary collagenous
organization and alignment for adequate load-bearing capacity. Through the response of
ligament fibroblasts to mechanical loading, mechanical conditioning is used to guide tissue
remodelling and improve ligament healing. Additionally, the mechanical stretch has increased
type I collagen synthesis in ligament cells (Hsieh et al., 2000). Although type III collagen is also
upregulated in the knee when strain is applied to MCL cells, not anterior cruciate ligament
(ACL) (Hsieh et al., 2000; Lee et al., 2004). These differences in collagen expression profiles
could explain the lack of healing in ACL due to a lack of type III collagen production (Hsieh et
al., 2000).
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