Abstract
Objective. Severe traumatic brain injury (sTBI) induced neuronal loss and brain atrophy contribute significantly to long-term disabilities. Brain extracellular matrix (ECM) associated chondroitin sulfate (CS) glycosaminoglycans promote neural stem cell (NSC) maintenance, and CS hydrogel implants have demonstrated the ability to enhance neuroprotection, in preclinical sTBI studies. However, the ability of neuritogenic chimeric peptide (CP) functionalized CS hydrogels in promoting functional recovery, after controlled cortical impact (CCI) and suction ablation (SA) induced sTBI, has not been previously demonstrated. We hypothesized that neuritogenic (CS)CP hydrogels will promote neuritogenesis of human NSCs, and accelerate brain tissue repair and functional recovery in sTBI rats. Approach. We synthesized chondroitin 4-O sulfate (CS-A)CP, and 4,6-O-sulfate (CS-E)CP hydrogels, using strain promoted azide-alkyne cycloaddition (SPAAC), to promote cell adhesion and neuritogenesis of human NSCs, in vitro; and assessed the ability of (CS-A)CP hydrogels in promoting tissue and functional repair, in a novel CCI-SA sTBI model, in vivo. Main results. Results indicated that (CS-E)CP hydrogels significantly enhanced human NSC aggregation and migration via focal adhesion kinase complexes, when compared to NSCs in (CS-A)CP hydrogels, in vitro. In contrast, NSCs encapsulated in (CS-A)CP hydrogels differentiated into neurons bearing longer neurites and showed greater spontaneous activity, when compared to those in (CS-E)CP hydrogels. The intracavitary implantation of (CS-A)CP hydrogels, acutely after CCI-SA-sTBI, prevented neuronal and axonal loss, as determined by immunohistochemical analyses. (CS-A)CP hydrogel implanted animals also demonstrated the significantly accelerated recovery of ‘reach-to-grasp’ function when compared to sTBI controls, over a period of 5-weeks. Significance. These findings demonstrate the neuritogenic and neuroprotective attributes of (CS)CP ‘click’ hydrogels, and open new avenues for the development of multifunctional glycomaterials that are functionalized with biorthogonal handles for sTBI repair.
Original language | English |
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Article number | 036058 |
Journal | Journal of neural engineering |
Volume | 21 |
Issue number | 3 |
DOIs | |
Publication status | Published - 27 Jun 2024 |
Bibliographical note
Publisher Copyright:© 2024 The Author(s). Published by IOP Publishing Ltd.
Funding
This work was supported by National Institute of Health (NIH)- National Institute of Neurological Disorders and Stroke (Grants R01NS099596, and R21NS130468) to Lohitash Karumbaiah and NIH-National Heart, Lung, and Blood Institute (HLBI) (Grant R01HL151617) to Geert-Jan Boons. We thank UGA\u2019s Biomedical Core Facility (BMC) for providing us access to the Zeiss LSM 710 and 880 confocal microscopes. We thank the Complex Carbohydrate Research Centre (CCRC) NMR facility. We also thank Shanmathi Ramasubramanian and Md. Marzan Sarkar for their assistance with suction ablation (SA) and hydrogel implantation surgeries. We thank Amin Davarzani for 3D printing and designing a functional setup of the Biopsy tool.
Funders | Funder number |
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National Institutes of Health | |
National Heart, Lung, and Blood Institute | |
BMC Software | |
UGA’s Biomedical Core Facility | |
Complex Carbohydrate Research Centre | |
National Institute of Neurological Disorders and Stroke | R21NS130468, R01NS099596 |
HLBI | R01HL151617 |
Keywords
- SPAAC click chemistry
- chimeric peptide
- chondroitin sulfate glycosaminoglycans
- reach-to-grasp function
- traumatic brain injury