Hydrogen Ion Capturing Hydrogel Microspheres for Reversing Inflammaging.

Inflammaging is deeply involved in aging-related diseases and can be destructive during aging. The maintenance of pH balance in the extracellular microenvironment can alleviate inflammaging and repair aging-related tissue damage. In this study, the hydrogen ion capturing hydrogel microsphere (GMNP) composed of mineralized transforming growth factor-ß (TGF-ß) and catalase (CAT) nanoparticles is developed via biomimetic mineralization and microfluidic technology for blocking the NLRP3 cascade axis in inflammaging. This GMNP can neutralize the acidic microenvironment by capturing excess hydrogen ions through the calcium carbonate mineralization layer. Then, the subsequent release of encapsulated TGF-ß and CAT can eliminate both endogenous and exogenous stimulus of NLRP3, thus suppressing the excessive activation of inflammaging. In vitro, GMNP can suppress the excessive activation of the TXNIP/NLRP3/IL-1ß cascade axis and enhance extracellular matrix (ECM) synthesis in nucleus pulposus cells. In vivo, GMNP becomes a sustainable and stable niche with microspheres as the core to inhibit inflammaging and promote the regeneration of degenerated intervertebral discs. Therefore, this hydrogen ion-capturing hydrogel microsphere effectively reverses inflammaging by interfering with the excessive activation of NLRP3 in the degenerated tissues.

Oxygen metabolism-balanced engineered hydrogel microspheres promote the regeneration of the nucleus pulposus by inhibiting acid-sensitive complexes.

Intervertebral disc degeneration (IVDD) is commonly caused by imbalanced oxygen metabolism-triggered inflammation. Overcoming the shortcomings of antioxidants in IVDD treatment, including instability and the lack of targeting, remains challenging. Microfluidic and surface modification technologies were combined to graft chitosan nanoparticles encapsulated with strong reductive black phosphorus quantum dots (BPQDs) onto GelMA microspheres via amide bonds to construct oxygen metabolism-balanced engineered hydrogel microspheres (GM@CS-BP), which attenuate extracellular acidosis in nucleus pulposus (NP), block the inflammatory cascade, reduce matrix metalloproteinase expression (MMP), and remodel the extracellular matrix (ECM) in intervertebral discs (IVDs). The GM@CS-BP microspheres reduce H2O2 intensity by 229%. Chemical grafting and electrostatic attraction increase the encapsulation rate of BPQDs by 167% and maintain stable release for 21 days, demonstrating the antioxidant properties and sustained modulation of the BPQDs. After the GM@CS-BP treatment, western blotting revealed decreased acid-sensitive ion channel-3 and inflammatory factors. Histological staining in an 8-week IVDD model confirmed the regeneration of NP. GM@CS-BP microspheres therefore maintain a balance between ECM synthesis and degradation by regulating the positive feedback between imbalanced oxygen metabolism in IVDs and inflammation. This study provides an in-depth interpretation of the mechanisms underlying the antioxidation of BPQDs and a new approach for IVDD treatment.

Intradiscal injection of human recombinant BMP-4 does not reverse intervertebral disc degeneration induced by nuclectomy in sheep.

Background: Intervertebral disc (IVD) degeneration is suggested as a major cause of chronic low back pain (LBP). Intradiscal delivery of growth factors has been proposed as a promising strategy for IVD repair and regeneration. Previously, BMP-4 was shown to be more potent in promoting extracellular matrix (ECM) production than other BMPs and TGF-ß in human nucleus pulposus (NP) cells, suggesting its applicability for disc regeneration. Methods: The effects of BMP-4 on ECM deposition and cell proliferation were assessed in sheep NP and annulus fibrosus (AF) cells in a pellet culture model. Further, a nuclectomy induced sheep lumbar IVD degeneration model was used to evaluate the safety and effects of intradiscal BMP-4 injection on IVD regeneration. Outcomes were assessed by magnetic resonance imaging, micro-computed tomography, histological and biochemical measurements. Results: In vitro, BMP-4 significantly increased the production of proteoglycan and deposition of collagen type II and proliferation of NP and AF cells. Collagen type I deposition was not affected in NP cells, while in AF cells it was high at low BMP-4 concentrations, and decreased with increasing concentration of BMP-4. Intradiscal injection of BMP-4 induced extradiscal new bone formation and Schmorl's node-like changes in vivo. No regeneration in the NP nor AF was observed. Conclusion: Our study demonstrated that although BMP-4 showed promising regenerative effects in vitro, similar effects were not observed in a large IVD degeneration animal model. The Translational Potential of This Article: The contradictory results of using BMP-4 on IVD regeneration between in vitro and in vivo demonstrate that direct BMP-4 injection for disc degeneration-associated human chronic low back pain should not be undertaken. In addition, our results may also shed light on the mechanisms behind pathological endplate changes in human patients as a possible target for therapy.