Assessing the effects of intratendinous genipin injections: Mechanical augmentation and spatial distribution in an ex vivo degenerative tendon model

Abstract

BackgroundTendinopathy is a common musculoskeletal disorder and current treatment options show limited success. Genipin is an effective collagen crosslinker with low cytotoxicity and a promising therapeutic strategy for stabilizing an intratendinous lesion. PurposeThis study examined the mechanical effect and delivery of intratendinous genipin injection in healthy and degenerated tendons. Study design Controlled laboratory study MethodsBovine superficial digital flexor tendons were randomized into four groups: Healthy control (N = 25), healthy genipin (N = 25), degenerated control (N = 45) and degenerated genipin (N = 45). Degeneration was induced by Collagenase D injection. After 24h, degenerated tendons were subsequently injected with either 0.2ml of 80mM genipin or buffer only. 24h posttreatment, samples were cyclically loaded for 500 cycles and then ramp loaded to failure. Fluorescence and absorption assays were performed to analyze genipin crosslink distribution and estimate tissue concentration after injection. ResultsCompared to controls, genipin treatment increased ultimate force by 19% in degenerated tendons (median control 530 N vs. 633 N; p = 0.0078). No significant differences in mechanical properties were observed in healthy tendons, while degenerated tendons showed a significant difference in ultimate stress (+23%, p = 0.049), stiffness (+27%, p = 0.037), work to PLOS ONE PLOS ONE | https://doi.failure (+42%, p = 0.009), and relative stress relaxation (-11%, p < 0.001) after genipin injection. Fluorescence and absorption were significantly higher in genipin treated tendons compared to control groups. A higher degree of crosslinking (+45%, p < 0.001) and a more localized distribution were observed in the treated healthy compared to degenerated tendons, with higher genipin tissue concentrations in healthy (7.9 mM) than in degenerated tissue (2.3 mM). ConclusionUsing an ex-vivo tendinopathy model, intratendinous genipin injections recovered mechanical strength to the level of healthy tendons. Measured by genipin tissue distribution, injection is an effective method for local delivery. Clinical relevanceThis study provides a proof of concept for the use of intratendinous genipin injection in the treatment of tendinopathy. The results demonstrate that a degenerated tendon can be mechanically augmented by a clinically viable method of local genipin delivery. This warrants further in vivo studies towards the development of a clinically applicable treatment based on genipin. PLOS ONEEffects of intratendinous genipin injections: Mechanical augmentation and spatial distribution PLOS ONE | https://doi.org/10.

Regeneration of skeletal system with genipin crosslinked biomaterials

“…This increases the tensile strength of the injured tendon so that it can resist traction and further damage. 133 However, the effective dose of genipin required to significantly improve the mechanical properties of the tendon is extremely high. Genipin at a concentration >20 mM/L was shown to stop tendon tear propagation, though it was also shown to cause side effects such as tissue swelling.…”

Exogenous Crosslinking of Tendons as a Strategy for Mechanical Augmentation and Repair: A Narrative Review

“…: 30% [ 21 ] Bovine digital flexor (healthy) GP Suture coating UTS: 45% [ 23 ] w.t.f. : 86% Equine digital flexor GP Suture coating UTS: 67% [ 24 ] Stiffness: 21% Toughness: 135% Bovine digital flexor (degenerated) GP Injection UTS: 23% [ 25 ] Stiffness: 27% w.t.f. 42% Human biceps long head GP Suture coating UTS: 55% [ 26 ] w.t.f.…”

“… 24 The tendons coming in contact with the GP that resides on, or is released from the sutures, displayed enhanced ultimate tensile stress, load to failure, and stiffness. In a later study, 25 the group investigated the intratendinous injection of GP in ex-vivo bovine superficial digital flexor tendons, either healthy or degenerated (by in-vitro collagenolysis). The injectable solution consisted of 80 mmol/L GP in a solution of buffer and dimethyl sulfoxide.…”

Physiotherapy treatment of lateral epicondylitis: A systematic review

“…Regarding pain, other studies evaluated the pressure 394 pain threshold (PPT) [15,23,33], which is a specially 395 relevant variable in tendinopathies [39] and in the eval-396 uation of chronic pain [40,41]. This variable showed 397 improvements with the interventions based on SW [15], 398 orthosis [33], HILT [33], DF [23] and US, TENS and 399 stretching exercises [23], since they can all affect hy-400 percellularity, the collagen matrix, the proteoglycan 401 content and neovascularisation, which is generated by 402 the accumulation of microinjuries, due to the repetitive 403 overload that exceeds the healing capacity of the ten-404 don [42].…”