Controlled Release of TGF-β3 for Effective Local Endogenous Repair in IDD Using Rat Model

Abstract

Introduction Intervertebral disc (IVD) degeneration (IDD) is one of the most widespread musculoskeletal diseases worldwide and remains an intractable clinical challenge. Currently, regenerative strategies based on biomaterials and biological factors to facilitate IVD repair have been widely explored. However, the harsh microenvironment, such as increased ROS and acidity, of the degenerative region impedes the efficiency of IVD repair. Here, an intelligent biodegradable nanoplatform using hollow manganese dioxide (H-MnO 2 ) was developed to modulate the degenerative microenvironment and release transforming growth factor beta-3 (TGF-β3), which may achieve good long-term therapeutic effects on needle puncture-induced IDD. Methods Surface morphology and elemental analysis of the MnO 2 nanoparticles (NPs) were performed by transmission electron microscopy and an energy-dispersive X-ray spectroscopy detector system, respectively. The biological effects of MnO 2 loaded with TGF-β3 (TGF-β3/MnO 2 ) on nucleus pulposus cells (NPCs) were assessed via cytoskeleton staining, EdU staining, qPCR and immunofluorescence. The efficacy of TGF-β3/MnO 2 on needle puncture-induced IDD was further examined using MRI and histopathological and immunohistochemical staining. Results The MnO 2 NPs had a spherical morphology and hollow structure that dissociated in the setting of a low pH and H 2 O 2 to release loaded TGF-β3 molecules. In the oxidative stress environment, TGF-β3/MnO 2 was superior to TGF-β3 and MnO 2 NPs in the suppression of H 2 O 2 -induced matrix degradation, ROS, and apoptosis in NPCs. When injected into the IVDs of a rat IDD model, TGF-β3/MnO 2 was able to prevent the degeneration and promote self-regeneration. Conclusion Use of an MnO 2 nanoplatform for biological factors release to regulate the IDD microenvironment and promote endogenous repair may be an effective approach for treating IDD.

Aggressive strategies for regenerating intervertebral discs: stimulus-responsive composite hydrogels from single to multiscale delivery systems

“…It was found that hollow manganese dioxide (H-MnO 2 ) biodegradable nanocomponents could be used as a biofactor slow release carrier. Zhu et al 207 explored the biological effects of H-MnO 2 loaded TGF-β3 on NPCs and found that the nanocomponents could dissociate under low pH and H 2 O 2 environment, releasing TGF-β3 to inhibit ECM degradation and promote NP repair in a rat IVDD model.…”

Repair Strategies and Bioactive Functional Materials for Intervertebral Disc

“…It was demonstrated that H-MnO2 can be used to develop intelligent biodegradable nanoplatforms to modulate the degenerative microenvironment, which could achieve longterm therapeutic effects on degenerative discs (Figure 11l,m). [129] Ding et al synthesized a ROS-responsive cationic copolymer with poly β-amino ester poly ε-caprolactone (PBC) and a high plasmid DNA (pDNA) compression affinity. The TGF-β1 plasmid can be transfected into NPCs through self-assembly into nanosized polyplexes (pTGFβ1@PBCs).…”

“…Reproduced under the terms of CC‐BY‐NC licensewith permission. [ 129 ] Copyright 2022, The Authors, Published by Dove Medical Press Limited. n) LUT‐TGF‐β1 plasmid combinatorial therapy of IDD.…”

“…m) Immunohistochemical analysis of iNOS and Col-II expression. Reproduced under the terms of CC-BY-NC license [129]. Copyright 2022, The Authors, Published by Dove Medical Press Limited.…”

Application and prospect of ROS-related nanomaterials for orthopaedic related diseases treatment

“…Kumar et al mentioned that MnO 2 nanoparticles can protect cartilage from oxidative stress caused by inflammation ( Kumar et al, 2019 ). Zhu et al designed a hollow MnO 2 nanoparticles loaded with TGF-β3 to treat intervertebral disc degeneration, and the authors indicated that the hollow MnO 2 nanoparticles played an important role in the antioxidation ( Zhu et al, 2022 ). In addition to cerium oxide and manganese dioxide nanoparticles, other metal oxides such as molybdenum oxide and nickel oxide nanoparticles may also be used as functional nanoparticles for ROS scavenging ( Mu et al, 2016 ; Duan et al, 2022 ).…”