Fibrin-genipin annulus fibrosus sealant as a delivery system for anti-TNFα drug

Abstract

Background context Intervertebral discs (IVD) are attractive targets for local drug delivery because they are avascular structures with limited transport. Painful IVDs are in a chronic inflammatory state. While anti-inflammatories show poor performance in clinical trials their efficacy treating IVD cells suggests that sustained, local drug delivery directly to painful IVDs may be beneficial. Purpose To determine if genipin crosslinked fibrin (FibGen) with collagen type I hollow spheres (CHS) can serve as a drug delivery carrier for the anti-TNFα drug, infliximab. Infliximab was chosen as a model drug because of the known role of TNFα in increasing downstream production of several pro-inflammatory cytokines and pain mediators. FibGen was used as drug carrier because it is adhesive injectable, slowly degrading hydrogel with potential to seal annulus fibrosus (AF) defects. CHS allow simple and non-damaging drug loading and could act as a drug reservoir to improve sustained delivery. Study Design/Setting Biomaterials and human AF cell culture study to determine drug release kinetics and efficacy. Methods Infliximab was delivered at low and high concentrations using FibGen with and without CHS. Gels were analyzed for structure, drug release kinetics, and efficacy treating human AF cells following release. This work was funded by grants from the NIAMS/NIH (R01 AR057397), AO Foundation, and from the Icahn School of Medicine at Mount Sinai. Results Fibrin showed rapid infliximab drug release but degraded quickly. CHS alone showed a sustained release profile but the small spheres may not remain in a degenerated IVD with fissures. FibGen showed steady and low levels of infliximab release that was increased when loaded with higher drug concentrations. Infliximab was bound in CHS when delivered within FibGen and was only released following enzymatic degradation. The infliximab released over 20 days retained its bioactivity as confirmed by the sustained reduction of IL-1β, IL-6, IL-8, and TNFα concentrations produced by AF cells. Conclusions Direct mixing of infliximab into FibGen was the simplest drug loading protocol capable of sustained release. Results show feasibility of using drug-loaded FibGen for delivery of infliximab and, in the context with the literature, show potential to seal AF defects and partially restore IVD biomechanics. Future investigations are required to determine if drug-loaded FibGen can effectively deliver drugs, seal AF defects, and promote IVD repair or prevent further IVD degeneration in vivo.

Intervertebral Disk Degeneration and Repair

“…Anular repair techniques have great potential to work in conjunction with other treatment modalities in DDD including drug and cell delivery. 79 …”

Tumor necrosis factor-α: a key contributor to intervertebral disc degeneration

“…Since IVDs are the largest avascular structures in the body with limited transport, there is an urgent need to establish ideal in vivo delivery systems of anti-TNF-α drugs for clinical application. Recently, Likhitpanichkul et al [167] reported that direct mixing of infliximab into genipin cross-linked fibrin shows steady and sustained release of infliximab over 20 days. Moreover, genipin cross-linked fibrin as drug carrier is adhesive, injectable, and slowly-degrading hydrogel with the potential to seal AF defects.…”

Equiaxial Strain Modulates Adipose-derived Stem Cell Differentiation within 3D Biphasic Scaffolds towards Annulus Fibrosus

“…Discectomy is the most common surgical procedure to treat herniation and chronic low back pain 3 , 4 . Yet, the unrepaired annulus fibrosus (AF) defects following the discectomy lead to accelerated IVD degeneration because of increased inflammation and altered biomechanics 5 – 8 . Thus, discectomy procedures have up to 27% risk of re-herniation requiring repeated surgeries 3 .…”

“…Thus, discectomy procedures have up to 27% risk of re-herniation requiring repeated surgeries 3 . The outcome of discectomy can be improved through sealing the AF defects and delivering biologics to the injury site 3 , 5 . In fact, cell-based therapies are required for AF repair due to the avascular and hypocellular nature of the tissue 9 , 10 .…”