An Injectable Hydrogel Scaffold Loaded with Dual-Drug/Sustained-Release PLGA Microspheres for the Regulation of Macrophage Polarization in the Treatment of Intervertebral Disc Degeneration

Abstract

Due to the unique physical characteristics of intervertebral disc degeneration (IVDD) and the pathological microenvironment that it creates, including inflammation and oxidative stress, effective self-repair is impossible. During the process of intervertebral disc degeneration, there is an increase in the infiltration of M1 macrophages and the secretion of proinflammatory cytokines. Here, we designed a novel injectable composite hydrogel scaffold: an oligo [poly (ethylene glycol) fumarate]/sodium methacrylate (OPF/SMA) hydrogel scaffold loaded with dual-drug/sustained-release PLGA microspheres containing IL-4 (IL-4-PLGA) and kartogenin (KGN-PLGA). This scaffold exhibited good mechanical properties and low immunogenicity while also promoting the sustained release of drugs. By virtue of the PLGA microspheres loaded with IL-4 (IL-4-PLGA), the composite hydrogel scaffold induced macrophages to transition from the M1 phenotype into the M2 phenotype during the early induced phase and simultaneously exhibited a continuous anti-inflammatory effect through the PLGA microspheres loaded with kartogenin (KGN-PLGA). Furthermore, we investigated the mechanisms underlying the immunomodulatory and anti-inflammatory effects of the composite hydrogel scaffold. We found that the scaffold promoted cell proliferation and improved cell viability in vitro. While ensuring mechanical strength, this composite hydrogel scaffold regulated the local inflammatory microenvironment and continuously repaired tissue in the nucleus pulposus via the sequential release of drugs in vivo. When degenerative intervertebral discs in a rat model were injected with the scaffold, there was an increase in the proportion of M2 macrophages in the inflammatory environment and higher expression levels of type II collagen and aggrecan; this was accompanied by reduced levels of MMP13 expression, thus exhibiting long-term anti-inflammatory effects. Our research provides a new strategy for promoting intervertebral disc tissue regeneration and a range of other inflammatory diseases.

Transplantation of active nucleus pulposus cells with a keep-charging hydrogel microsphere system to rescue intervertebral disc degeneration

“…Zhou et al [ 52 ] used HA and GelMA double-network hydrogels as 3D printing inks for skin regeneration. Nevertheless, microspheres of other materials such as PLGA may result in denaturation of growth factors, and the acidic degradation products of PLGA may worse the poor microenvironment in IVD [ 53 , 54 ]. Henry et al developed a biphasic injectable hydrogel system that serves as a vehicle for sustained release of TGF-β1 and GDF-5, allowing their sustained release to prevent the growth factors from degradation during the treatment of disc degeneration [ 55 ].…”

Hydrogel-Based Strategies for Intervertebral Disc Regeneration: Advances, Challenges and Clinical Prospects

“…found a three-dimensional cell encapsulating synthetic hydrogel that mimicked the native intervertebral disc structure and function, as well as provided a suitable environment for cell survival [19]. Similarly, Cheng et al determined that a hydrogel scaffold loaded with microspheres had good mechanical properties and a low immunogenicity that allowed for a restoration of the biomechanical properties of the intervertebral disc, while minimizing the incidence of re-herniation events [20]. These studies' outcomes, in conjunction with outcomes from a variety of other studies, make it evident that hydrogels hold a great degree of potential as viable intervertebral disc replacement options following disc degeneration events.…”

Analysis of global research hotspots and trends in immune cells in intervertebral disc degeneration: A bibliometric study

“…It can inhibit IDD by inhibiting macrophage polarization. 95 A study has developed a unique nano-scaffold that scavenges reactive oxygen species, inhibits immune cell responses and inflammatory stimuli, relieves pain and promotes IVD regeneration. 96 Multifunctional and multidimensional biomaterials, especially those that can self-scavenge inflammatory mediators, pro-ECM regenerative properties, or protect tissues from apoptotic signals, are considered as a means for long-term immunomodulation and effective tissue regeneration.…”