Increased volume and collagen crosslinks drive soft tissue contribution to post‐traumatic elbow contracture in an animal model

Abstract

Post‐traumatic joint contracture (PTJC) in the elbow is a biological problem with functional consequences. Restoring elbow motion after injury is a complex challenge because contracture is a multi‐tissue pathology. We previously developed an animal model of elbow PTJC using Long‐Evans rats and showed that the capsule and ligaments/cartilage were the primary soft tissues that caused persistent joint motion loss. The objective of this study was to evaluate tissue‐specific changes within the anterior capsule and lateral collateral ligament (LCL) that led to their contribution to elbow contracture. In our rat model of elbow PTJC, a unilateral surgery replicated damage that commonly occurs due to elbow dislocation. Following surgery, the injured limb was immobilized for 42 days. The capsule and LCL were evaluated after 42 days of immobilization or 42 days of immobilization followed by 42 days of free mobilization. We evaluated extracellular matrix protein biochemistry, non‐enzymatic collagen crosslink content, tissue volume with contrast‐enhanced micro‐computed tomography, and tissue mechanical properties. Increased collagen content, but not collagen density, was observed in both injured limb capsules and LCLs, which was consistent with the increased tissue volume. Injured limb LCLs exhibited decreased normalized maximum force, and both tissues had increased immature collagen cross‐links compared to control. Overall, increased tissue volume and immature collagen crosslinks in the capsule and LCL drive their contribution to elbow contracture in our rat model.

Mechano-biological and bio-mechanical pathways in cutaneous wound healing

“…Similarly, the ratio between such crosslinks and those typical of soft connective tissues was upregulated in idiopathic pulmonary fibrosis, as were the density of mature crosslinks and the tissue stiffness, but not the collagen content [85]. Further supporting our modeling approach, the mature/immature crosslink ratio correlated positively with changes in the mechanical stiffness of lateral collateral ligament following injury [72], suggesting a dominant role of tissue ‘quality’ over its ‘quantity’ towards determining tissue fibrosis.…”

“…Based on the inadequacy of a proportional link between k 1 and ϕ c , we hypothesize that this constitutive relation should additionally account for the progressive maturation of the newly-formed collagen network. Indeed, alterations in the degree and type of crosslinking have been reported to affect the emergent mechanical behavior of soft tissues such as tendons [72], uterine cervix [73], and skin wounds [10]. For simplicity, we focus on the degree of network crosslinking and consider a nonlinear relation between k 1 and ϕ c , mediated by a crosslinking agent, ξ c : where a ≥ 1 is a phenomenological exponent controlling the degree of tissue nonlinearity associated with a given crosslinking.…”

Females and males exhibit similar functional, mechanical, and morphological outcomes in a rat model of posttraumatic elbow contracture

“…Previous work in the same rat elbow model found that the LCL was a significant contributor to contracture at late time points; the increase in BV or TV of the EC object due to injury could be a factor. 11,12 Focusing on the largest EC object in each limb, injury, but not sex, was a significant factor for BV, TV and BV/TV (Figure 6B-D). The increase in TV and relatively small increase in BV that occurred with limb injury and immobilization showed that the larger EC objects were structurally less dense compared to similar (smaller) objects in control and contralateral limbs (Figure 6B-D).…”

“…to contracture have also been evaluated. [10][11][12] However, these previous studies that investigated disease etiology, progression and recovery were conducted only with male animals; it remains unknown whether female animals would exhibit similar responses.…”

Pleiotropic Effects of Simvastatin and Losartan in Preclinical Models of Post-Traumatic Elbow Contracture

“…Therefore, this study aimed to evaluate the effects of SV and LS in two established preclinical models of contracture. Two SV and LS dosing strategies were tested in an elbow-specific rat injury model in vivo , which normally causes loss of elbow function, capsule fibrosis, and mild arthritis ( Lake et al, 2016 ; Dunham et al, 2017a ; Dunham et al, 2017b ; Dunham et al, 2018a ; Dunham et al, 2018b ; Dunham et al, 2019 ; Dunham et al, 2020 ; Dunham et al, 2021 ; Reiter et al, 2019 ; Reiter et al, 2021a ; Reiter et al, 2021b ) . The in vivo model provides translatability of SV and LS therapy and joint-wide impact on multiple soft tissues (i.e., capsule and cartilage).…”