Exhausted local lactate accumulation via injectable nanozyme-functionalized hydrogel microsphere for inflammation relief and tissue regeneration

Jieliang Shen; Ao Chen; Zhengwei Cai; Zhijie Chen; Ruichao Cao; Zongchao Liu; Yuling Li; Jie Hao

doi:10.1016/j.bioactmat.2021.10.013

Exhausted local lactate accumulation via injectable nanozyme-functionalized hydrogel microsphere for inflammation relief and tissue regeneration

Bioact Mater. 2021 Oct 21:12:153-168. doi: 10.1016/j.bioactmat.2021.10.013. eCollection 2022 Jun.

Authors

Jieliang Shen¹, Ao Chen², Zhengwei Cai³, Zhijie Chen³, Ruichao Cao¹, Zongchao Liu⁴, Yuling Li⁵, Jie Hao¹

Affiliations

¹ Department of Orthopedics, Orthopedic Laboratory of Chongqing Medical University, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Chongqing, 40042, PR China.
² School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai, 200030, PR China.
³ Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, PR China.
⁴ Department of Orthopaedics, Affiliated Hospital of Traditional Chinese Medicine, Southwest Medical University, No.182 Chunhui Road, Sichuan, 646699, PR China.
⁵ Department of Orthopaedics, Affiliated Hospital of North Sichuan Medical College, No.63 Wenhua Road, Nanchong, Sichuan, 637000, PR China.

Abstract

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.

Keywords: Hydrogel microsphere; Injection; Lactate; Microfluidic; Tissue regeneration.