Local lactate accumulation greatly hinders tissue repair and regeneration under ischemic condition. Herein, an injectable microsphere (MS@MCL) for local lactate exhaustion was constructed by grafting manganese dioxide (MnO₂) -lactate oxidase (LOX) composite nanozyme on microfluidic hyaluronic acid methacrylate (HAMA) microspheres via chemical bonds, achieving a long-term oxygen-promoted lactate exhaustion effect and a long half-life in vivo. The uniform and porous microspheres synthesized by microfluidic technology is beneficial to in situ injection therapy and improving encapsulation efficiency. Furthermore, chemical grafting into HAMA microspheres through amide reactions promoted local enzymatic concentration and activity enhancement. It was showed that the MS@MCL eliminated oxidative and inflammatory stress and promoted extracellular matrix metabolism and cell survival when co-cultured with nucleus pulposus cells (NPCs) in vitro. In the rat degenerative intervertebral disc model caused by lactate injection, MS@MCL showed a long-term therapeutic effect in reducing intervertebral height narrowing and preventing extracellular matrix (ECM) degradation as well as inflammatory damage in vivo. Altogether, this study confirms that this nanozyme-functionalized injectable MS@MCL effectively improves the regenerative and reparative effect in ischemic tissues by disposing of enriched lactate in local microenvironment.

Intervertebral disc degeneration (IVDD) is rising worldwide and leading to significant health issues and financial strain for patients. Traditional treatments for IVDD can alleviate pain but do not reverse disease progression, and surgical removal of the damaged disc may be required for advanced disease. The inflammatory microenvironment is a key driver in the development of disc degeneration. Suitable anti-inflammatory substances are critical for controlling inflammation in IVDD. Several treatment options, including glucocorticoids, non-steroidal anti-inflammatory drugs, and biotherapy, are being studied for their potential to reduce inflammation. However, anti-inflammatories often have a short half-life when applied directly and are quickly excreted, thus limiting their therapeutic effects. Biomaterial-based platforms are being explored as anti-inflammation therapeutic strategies for IVDD treatment. This review introduces the pathophysiology of IVDD and discusses anti-inflammatory therapeutics and the components of these unique biomaterial platforms as comprehensive treatment systems. We discuss the strengths, shortcomings, and development prospects for various biomaterials platforms used to modulate the inflammatory microenvironment, thus providing guidance for future breakthroughs in IVDD treatment.

In diabetic wounds, hyperglycemia-induced cytotoxicity and impaired immune microenvironment plasticity directly hinder the wound healing process. Regulation of the hyperglycemic microenvironment and remodeling of the immune microenvironment are crucial. Here, we developed a nanozymatic functionalized regenerative microenvironmental regulator (AHAMA/CS-GOx@Zn-POM) for the effective repair of diabetic wounds. This novel construct integrated an aldehyde and methacrylic anhydride-modified hyaluronic acid hydrogel (AHAMA) and chitosan nanoparticles (CS NPs) encapsulating zinc-based polymetallic oxonate nanozyme (Zn-POM) and glucose oxidase (GOx), facilitating a sustained release of release of both enzymes. The GOx catalyzed glucose to gluconic acid and (H₂O₂), thereby alleviating the effects of the hyperglycemic microenvironment on wound healing. Zn-POM exhibited catalase and superoxide dismutase activities to scavenge reactive oxygen species and H₂O₂, a by-product of glucose degradation. Additionally, Zn-POM induced M1 macrophage reprogramming to the M2 phenotype by inhibiting the MAPK/IL-17 signaling diminishing pro-inflammatory cytokines, and upregulating the expression of anti-inflammatory mediators, thus remodeling the immune microenvironment and enhancing angiogenesis and collagen regeneration within wounds. In a rat diabetic wound model, the application of AHAMA/CS-GOx@Zn-POM enhanced neovascularization and collagen deposition, accelerating the wound healing process. Therefore, the regenerative microenvironment regulator AHAMA/CS-GOx@Zn-POM can achieve the effective conversion of a pathological microenvironment to regenerative microenvironment through integrated control of the hyperglycemic-immune microenvironment, offering a novel strategy for the treatment of diabetic wounds.

Surgery is the final choice for most patients with intervertebral disc degeneration (IDD). Operation-caused trauma will cause inflammation in the intervertebral disc. Serious inflammation will cause tissue defects and induce tissue degeneration, IDD recurrence and the occurrence of other diseases. Therefore, we proposed a scheme to treat recurrence after discectomy by inhibiting inflammation with an aspirin (ASP)-loaded hydrogel to restore the mechanical stability of the spine and relieve local inflammation. ASP-liposomes (ASP-Lips) were incorporated into a photocrosslinkable gelatin-methacryloyl (GelMA) via mixing. This material can effectively alleviate inflammation by inhibiting the release of high mobility group box 1 (HMGB1) from the nucleus to the cytoplasm. We further assessed the expression of inflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α), and degeneration-related factors, such as type II collagen (COL-2), Aggrecan, matrix metallopeptidases-3 (MMP-3), MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 in rat nucleus pulpous cells. The level of IDD was analyzed through H&E, safranin-O staining and immunohistochemistry in rabbit samples. In vitro, we found that ASP-Lip@GelMA treatment significantly decreased inflammatory cytokines, MMP-3 and -13, and ADAMTS-4 and -5 and up-regulated COL-2 and Aggrecan via the inhibited release of HMGB-1 from the nucleus. In vivo, ASP-Lip@GelMA can effectively inhibit inflammation of local tissue after disc surgery and fill local tissue defects. This composite hydrogel system is a promising way to treat the recurrence of IDD after surgery without persistent complications.

Graphical Schematic illustrations of the fabrication of the bone defect model and action of β-Ecd in promoting bone regeneration and repair of bone defects. We established a rat model of a femoral bone defect in vivo to evaluate the effect of β-Ecd on bone regeneration. Rats injected intraperitoneally with 72 mg/kg β-Ecd showed a higher degree of ossification of regenerated bone tissue at the site of the bone defect at weeks 4 and 8. β-ecdysterone binding to the BMP2 receptor activates SMAD1 to bind to SMAD1/5/8, promotes RUNX2 and OSTERIX replication in the nucleus, and mediates bone regeneration. This study provides a new approach to the treatment of bone injury and degenerative diseases represented by bone defects and osteoporosis.