Localized delivery of ibuprofen via a bilayer delivery system (BiLDS) for supraspinatus tendon healing in a rat model

Abstract

The high prevalence of tendon retear following rotator cuff repair motivates the development of new therapeutics to promote improved tendon healing. Controlled delivery of non-steroidal anti-inflammatory drugs to the repair site via an implanted scaffold is a promising option for modulating inflammation in the healing environment. Furthermore, biodegradable nanofibrous delivery systems offer an optimized architecture and surface area for cellular attachment, proliferation, and infiltration while releasing soluble factors to promote tendon regeneration. To this end, we developed a bilayer delivery system (BiLDS) for localized and controlled release of ibuprofen (IBP) to temporally mitigate inflammation and enhance tendon remodeling following surgical repair by promoting organized tissue formation. In vitro evaluation confirmed the delayed and sustained release of IBP from Labrafil-modified poly(lactic-co-glycolic) acid microspheres within sintered poly(ε-caprolactone) electrospun scaffolds. Biocompatibility of the BiLDS was demonstrated with primary Achilles tendon cells in vitro. Implantation of the IBP-releasing BiLDS at the repair site in a rat rotator cuff injury and repair model led to decreased expression of proinflammatory cytokine, tumor necrotic factor-α, and increased anti-inflammatory cytokine, transforming growth factor-β1. The BiLDS remained intact for mechanical reinforcement and recovered the tendon structural properties by 8 weeks. These results suggest the therapeutic potential of a novel biocompatible nanofibrous BiLDS for localized and tailored delivery of IBP to mitigate tendon inflammation and improve repair outcomes. Future studies are required to define the mechanical implications of an optimized BiLDS in a rat model beyond 8 weeks or in a larger animal model.

Evaluation of patches for rotator cuff repair: A systematic review and meta-analysis based on animal studies

“…Four studies added different components on the PLGA scaffolds, among which one study [ 114 ] reported the addition of ibuprofen could control the release of drugs and promote the reconstruction of tendon tissue. Zhao, S [ 32 ] added basic fibroblast growth factor (bFGF) to the scaffold, and found that the added factor group had better results than the factor free scaffold group.…”

Nonsurgical treatment reduces tendon inflammation and elevates tendon markers in early healing

“…Other anti‐inflammatories such as corticosteroids 38 may also be suitable to reduce inflammation in this model but will likely require further refinement to the optimal timing of release and dosage. Immune modulation may be possible through taking aspirin which inhibits inflammation and scarring in injured tendon through JNK/STAT3 pathway 39 or through novel biomaterials that deliver ibuprofen locally 40 . Higher levels of MMP in muscle may be tuned through diet supplementation following injury with vitamin D 41,42 .…”

“…Immune modulation may be possible through taking aspirin which inhibits inflammation and scarring in injured tendon through JNK/STAT3 pathway 39 or through novel biomaterials that deliver ibuprofen locally. 40 Higher levels of MMP in muscle may be tuned through diet supplementation following injury with vitamin D. 41,42 The role of NFκB in tendinopathy has been recently explored. 43 Here, too, NFκB F I G U R E 4 Tendon repair increases expression of inflammatory genes and proteins in tendon 1-week post-injury.…”

Nanofiber Scaffolds by Electrospinning for Rotator Cuff Tissue Engineering

“… 65 Since then, electrospun nanofibers have widely been tested as experimental constructs for tissue engineering research and have been proposed as scaffolds for not only the repair of tendons, 66 67 but also bone, 68 cartilage, 69 meniscus, 63 ligaments, 70 liver, 71 blood vessels, 72 nerves, 73 and for drug delivery. 74 …”