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Abstract
Locally delivered anti-inflammatory compounds can restore the homeostasis of the degenerated intervertebral disc (IVD). With beneficial effects on IVD cells, epigallocatechin 3-gallate (EGCG) is a promising therapeutic candidate. However, EGCG is prone to rapid degradation and/or depletion. Therefore, the purpose of this study was to develop a method for controlled EGCG delivery in the degenerated IVD. Primary IVD cells were isolated from human donors undergoing IVD surgeries. EGCG was encapsulated into microparticles by electrospraying of glutaraldehyde-crosslinked gelatin. The resulting particles were characterized in terms of cytocompatibility and anti-inflammatory activity, and combined with a thermoresponsive carrier to produce an injectable EGCG delivery system. Subsequently, electrospraying was scaled up using the industrial NANOSPIDER™ technology. The produced EGCG microparticles reduced the expression of inflammatory (IL-6, IL-8, COX-2) and catabolic (MMP1, MMP3, MMP13) mediators in pro-inflammatory 3D cell cultures. Combining the EGCG microparticles with the carrier showed a trend towards modulating EGCG activity/release. Electrospray upscaling was achieved, leading to particles with homogenous spherical morphologies. In conclusion, electrospray-based encapsulation of EGCG resulted in cytocompatible microparticles that preserved the activity of EGCG and showed the potential to control EGCG release, thus favoring IVD health by downregulating local inflammation. Future studies will focus on further exploring the biological activity of the developed delivery system for potential clinical use.
Highlights
epigallocatechin 3-gallate (EGCG) is prone to rapid degradation and/or depletion
Degenerative disc disease (DDD), a pathology of the intervertebral disc (IVD), is associated with inflammation, premature senescence, and cell death, all of which contribute to the loss of extracellular matrix (ECM) and the development of discogenic back pain [1,2,3]
EGCG interferes with the pro-inflammatory IL-1β cascade by reducing the activity of IRAK1–NF-κB/JNK/p38 signaling and subsequent expression of inflammatory and catabolic genes, namely interleukins (IL-6, IL-8), matrix metalloproteinases (MMP-1, MMP-3, MMP-13), toll-like receptor 2 (TLR-2), cyclooxygenase 2 (COX-2), nerve growth factor (NGF), and inducible nitric oxide synthase [4,5]
Summary
Degenerative disc disease (DDD), a pathology of the intervertebral disc (IVD), is associated with inflammation, premature senescence, and cell death, all of which contribute to the loss of extracellular matrix (ECM) and the development of discogenic back pain [1,2,3]. In addition to its anti-inflammatory effects, EGCG inhibits oxidative stress-induced death of IVD cells by activating the PI3K/Akt pathway and protecting mitochondrial membranes from depolarization [6]. As cytokines play an important role in IVD homeostasis [7], their natural (balanced) levels should be preserved. Given its mechanism of action, EGCG might be able to preserve natural (low) levels of cytokines and ECM enzymes, reducing the potentially damaging side effects in the IVD
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