Fibrin-genipin annulus fibrosus sealant as a delivery system for anti-TNFα drug.
BACKGROUND
Intervertebral discs (IVDs) are attractive targets for local drug delivery because they are avascular structures with limited transport. Painful IVDs are in a chronic inflammatory state. Although 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.


OBJECTIVE
The purpose of this study was to determine if genipin cross-linked fibrin (FibGen) with collagen Type I hollow spheres (CHS) can serve as a drug-delivery carrier for infliximab, the anti-tumor necrosis factor α (TNFα) drug. 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. Genipin cross-linked fibrin was used as drug carrier because it is adhesive, injectable, and slowly degrading hydrogel with the potential to seal annulus fibrosus (AF) defects. CHS allow simple and nondamaging drug loading and could act as a drug reservoir to improve sustained delivery.


METHODS
This is a study of biomaterials and human AF cell culture 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 after release.


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. Genipin cross-linked fibrin 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 after enzymatic degradation. The infliximab released over 20 days retained its bioactivity as confirmed by the sustained reduction of interleukin (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.
Leni & Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Collaborative Research Partner, Annulus Fibrosus Rupture Program, AO Foundation, Davos, Switzerland.
Morakot
M
Likhitpanichkul
Leni & Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Yesul
Y
Kim
Leni & Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Olivia M
OM
Torre
Centre for Research in Medical Devices (CÚRAM), National University of Ireland, Galway, Ireland.
Eugene
E
See
Collaborative Research Partner, Annulus Fibrosus Rupture Program, AO Foundation, Davos, Switzerland; Centre for Research in Medical Devices (CÚRAM), National University of Ireland, Galway, Ireland.
Zepur
Z
Kazezian
Collaborative Research Partner, Annulus Fibrosus Rupture Program, AO Foundation, Davos, Switzerland; Centre for Research in Medical Devices (CÚRAM), National University of Ireland, Galway, Ireland.
Abhay
A
Pandit
Leni & Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Andrew C
AC
Hecht
Leni & Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Collaborative Research Partner, Annulus Fibrosus Rupture Program, AO Foundation, Davos, Switzerland. Electronic address: james.iatridis@mssm.edu.
James C
JC
Iatridis
D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D004337:Drug Carriers / Q000009:adverse effects* / Q000737:chemistry; D015718:Fibrin Tissue Adhesive / Q000009:adverse effects* / Q000737:chemistry; D006801:Humans; D000069285:Infliximab / Q000008:administration & dosage* / Q000494:pharmacology; D007403:Intervertebral Disc / Q000187:drug effects*; D039823:Iridoids / Q000009:adverse effects* / Q000737:chemistry
D018501:Antirheumatic Agents; D004337:Drug Carriers; D015718:Fibrin Tissue Adhesive; D039823:Iridoids; C007834:genipin; D000069285:Infliximab
Annulus fibrosus repair; Anti-inflammatory drug; Biomaterials; Drug delivery; Intervertebral disc; Spinal injection