Dual-functional hydrogel system for spinal cord regeneration with sustained release of arylsulfatase B alleviates fibrotic microenvironment and promotes axonal regeneration. (May 2022)

• Record Type: Journal Article
• Authors: Park, Hee Hwan; Kim, Young-Min; Anh Hong, Le Thi; Kim, Hyung Soon; Kim, Sung Hoon; Jin, Xuelian; Hwang, Dong Hoon; Kwon, Min Jung; Song, Soo-Chang; Kim, Byung Gon
• Is Part Of: Biomaterials. Volume 284(2022)
• Publication Date: 2022-05
• Subjects: Fibrotic microenvironment -- Injectable hydrogel -- Spinal cord injury -- Axon regeneration -- Arylsulfatase B -- Chondroitin sulfate proteoglycan; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2022.121526
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: Traumatic damage to the spinal cord does not spontaneously heal, often leading to permanent tissue defects. We have shown that injection of imidazole-poly(organophosphazene) hydrogel (I-5) bridges cystic cavities with the newly assembled fibronectin-rich extracellular matrix (ECM). The hydrogel-created ECM contains chondroitin sulfate proteoglycans (CSPGs), collagenous fibrils together with perivascular fibroblasts, and various fibrotic proteins, all of which could hinder axonal growth in the matrix. In an in vitro fibrotic scar model, fibroblasts exhibited enhanced sensitivity to TGF-β1 when grown on CSPGs. To alleviate the fibrotic microenvironment, the I-5 hydrogel was equipped with an additional function by making a complex with ARSB, a human enzyme degrading CSPGs, via hydrophobic interaction. Delivery of the I-5/ARSB complex significantly diminished the fibrotic ECM components. The complex promoted serotonergic axonal growth into the hydrogel-induced matrix and enhanced serotonergic innervation of the lumbar motor neurons. Regeneration of the propriospinal axons deep into the matrix and to the lumbar spinal cord was robustly increased accompanied by improved locomotor recovery. Therefore, our dual-functional system upgraded the functionality of the hydrogel for spinal cord regeneration by creating ECM to bridge tissue defects and concurrently facilitating axonal connections through the newly assembled ECM. Graphical abstract: Schematic diagram of the dual functional hydrogel system depicting potential contributions to axon regeneration and locomotory recovery after spinal cord injury. (A) Formation of the I-5/ARSB complex via hydrophobic interactions and its dual functions in the injured spinal cord. ARSB = arylsulfatase B, IleOEt = isoleucine ethyl ester, AMPEG = aminopolyethylene glycol. (B) I-5/ARSB complex promotes axon regeneration with recovery of locomotor function in an animal model of contusive spinal cord injury (SCI) via alleviation of the fibrotic microenvironment. Image 1