Ibuprofen-Loaded Hyaluronic Acid Nanofibrous Membranes for Prevention of Postoperative Tendon Adhesion through Reduction of Inflammation

Abstract

A desirable multi-functional nanofibrous membrane (NFM) for prevention of postoperative tendon adhesion should be endowed with abilities to prevent fibroblast attachment and penetration and exert anti-inflammation effects. To meet this need, hyaluronic acid (HA)/ibuprofen (IBU) (HAI) NFMs were prepared by electrospinning, followed by dual ionic crosslinking with FeCl3 (HAIF NFMs) and covalent crosslinking with 1,4-butanediol diglycidyl ether (BDDE) to produce HAIFB NFMs. It is expected that the multi-functional NFMs will act as a physical barrier to prevent fibroblast penetration, HA will reduce fibroblast attachment and impart a lubrication effect for tendon gliding, while IBU will function as an anti-inflammation drug. For this purpose, we successfully fabricated HAIFB NFMs containing 20% (HAI20FB), 30% (HAI30FB), and 40% (HAI40FB) IBU and characterized their physico-chemical properties by scanning electron microscopy, Fourier transformed infrared spectroscopy, thermal gravimetric analysis, and mechanical testing. In vitro cell culture studies revealed that all NFMs except HAI40FB possessed excellent effects in preventing fibroblast attachment and penetration while preserving high biocompatibility without influencing cell proliferation. Although showing significant improvement in mechanical properties over other NFMs, the HAI40FB NFM exhibited cytotoxicity towards fibroblasts due to the higher percentage and concentration of IBU released form the membrane. In vivo studies in a rabbit flexor tendon rupture model demonstrated the efficacy of IBU-loaded NFMs (HAI30FB) over Seprafilm® and NFMs without IBU (HAFB) in reducing local inflammation and preventing tendon adhesion based on gross observation, histological analyses, and biomechanical functional assays. We concluded that an HAI30FB NFM will act as a multi-functional barrier membrane to prevent peritendinous adhesion after tendon surgery.

An Integrative Dual-Layer Poly-L-Lactic Acid Fibrous Membrane Prevents Peritendinous Adhesions

“…However, current innovations cannot completely restrict adhesion during extrinsic healing. Furthermore, biochemical drugs applied on membranes (such as ibuprofen, microRNAs, basic fibroblast growth factor, and silver nanoparticles) cause side effects or reduce the quality of tendon healing (Shalumon et al, 2018;Zhou et al, 2018;Chen et al, 2019;Zhao et al, 2019).…”

Hyaluronic Acid Treatment Improves Healing of the Tenorrhaphy Site by Suppressing Adhesions through Extracellular Matrix Remodeling in a Rat Model

“…Focal adhesions were fewer in number and smaller in size, and the vinculin and vimentin staining intensities were lower in the HA group than in the NS group ( Figure 5 ). Similarly, Chen et al have recently developed HA-based multi-functional nanofibrous membranes (NFMs) loaded with ibuprofen to mimic the anti-adhesive function of the native tendon sheath, as well as to induce anti-inflammatory responses at the tenorrhaphy sites [ 50 ]. They successfully demonstrated that ibuprofen-loaded HA-NFM could minimize the cell attachment, as evidenced by the minimal expression of vinculin and restricted cytoskeleton organization, resulting in the prevention of cell penetration and tendon adhesion formation during tendon healing.…”

Two Sides of Electrospun Fiber in Promoting and Inhibiting Biomedical Processes

“…The HAIFB NFMs reduced inflammation, prevented cell attachment and infiltration, and reduced and formed tissue adhesions (Figure 8B,C). [ 206 ] IBU was assessed as a nonepitope of macrophages in tendon tissue, and the spacing between the barrier and tendon can be distinguished.…”