Bone Mesenchymal Stem Cell-Derived Exosome-Loaded Injectable Hydrogel for Minimally Invasive Treatment of Spinal Cord Injury

Abstract

Aim: Bone mesenchymal stem cell-derived exosomes (Exos) have been shown to exert therapeutic effects in spinal cord injury (SCI). In this study, we aimed to apply bioengineering approaches to promote Exo retention and their sustained release for SCI repair. Materials & methods: 3D gelatin methacrylate hydrogel (GelMA) was used as a transplanted Exo delivery system (GelMA-Exos). The viability, proliferation, and differentiation of neural stem cells cultured on hydrogel were assessed. Further, GelMA-Exos was injected into the damaged lesions to assess its repair potential. Results: GelMA hydrogel enhanced the retention of Exos, which promoted the neuronal differentiation and extension in vitro. Furthermore, GelMA-Exos promoted neurogenesis and attenuated glial scars in the damaged lesions. Conclusion: The injectable Exo-loaded 3D hydrogel induced neurological functional recovery post SCI.

Sustained released of bioactive mesenchymal stromal cell‐derived extracellular vesicles from 3D‐printed gelatin methacrylate hydrogels

“…27,28 Hydrogel formulations using a variety of materials have been proposed for EV-controlled release in various applications. 19,24,29,30 We chose to investigate GelMA in these studies due to its widespread use as a 3D printable bioink based on its biocompatibility, biodegradability, and amenability to a wide array of chemical modifications. The GelMA synthesized for this work had comparable viscoelasticity to prior reports, 31 and the decreased pore size associated with increasing LAP content (Figure 2) is also consistent with a previous report showing an inverse relationship between photoinitiator (Irgacure 2959) concentration and GelMA hydrogel porosity.…”

“…The choice of MSCs as the source cells for EVs in these experiments was made based on their broad therapeutic potential as indicated above, and the MSC ECs utilized here were of the expected composition and activity (Figure 1) as indicated in the literature 27,28 . Hydrogel formulations using a variety of materials have been proposed for EV‐controlled release in various applications 19,24,29,30 . We chose to investigate GelMA in these studies due to its widespread use as a 3D printable bioink based on its biocompatibility, biodegradability, and amenability to a wide array of chemical modifications.…”

“…Hydrogels are also useful as bioinks for 3D printing, enabling reproducible and custom‐designed therapeutic interventions 21 . EVs have been shown to be compatible with 3D‐bioprinting, 22 and MSC EVs specifically have been integrated into bioprinted hydrogels to promote osteochondral repair 23 as well as neurogenesis in a spinal cord injury model 24 . However, reports of release profiles and bioactivity of MSC EVs from bioprinted constructs remain scarce.…”

Development of gelatin methacrylate (GelMa) hydrogels for versatile intracavitary applications

“…31 These photoinitiators have been used in conjunction with GelMa to form hydrogels suitable for tissue regeneration, wound healing, drug delivery, etc. 32,33 Irgacure 2959 is the most commonly used photoinitiator with GelMa as it has moderate water solubility along with being biocompatible with a low degree of immunogenicity. 34 Recently, LAP has been a preferred choice of photoinitiator to crosslink with GelMa and this can be attributed to its higher aqueous solubility in comparison to Irgacure along with a higher molar extinction coefficient which results in more efficient crosslinking with GelMa at UV exposure of 365 nm wavelength.…”

The Role of Exosomes and Exosomal Noncoding RNAs From Different Cell Sources in Spinal Cord Injury

“…MSCs-Exos were separated and concentrated by ultracentrifugation and differential centrifugation in many studies (Huang et al, 2017 , 2020a ; Lankford et al, 2018 ; Wang et al, 2018 ; Guo et al, 2019 ; Ji et al, 2019 ; Kang et al, 2019 ; Li et al, 2019 ; Li C. et al, 2020 ; Li et al, 2021 ; Chen et al, 2021 ; Cheng et al, 2021 ; Han et al, 2021 ; Jia et al, 2021 ; Jiang and Zhang, 2021 ; Liu W. Z. et al, 2021 ; Liu et al, 2022 ; Nakazaki et al, 2021 ; Nie and Jiang, 2021 ; Noori et al, 2021 ; Sheng et al, 2021 ; Xiao et al, 2021 ; Xin et al, 2021 ; Zhang A. et al, 2021 ; Liang et al, 2022 ; Zhou et al, 2022 ) and by precipitation kits/polymer (PEG or others) in some studies (Li et al, 2018 ; Ren et al, 2019 ; Xu et al, 2019 ; Yu et al, 2019 ; Zhao et al, 2019 ; Fan et al, 2021 ; Jia et al, 2021a , b ; Kang and Guo, 2022 ). To achieve better specificity of MSCs-Exos separation, many researchers isolated MSCs-Exos using ultrafiltration-centrifugation combined with density-gradient ultracentrifugation (Liu et al, 2020 ; Shao et al, 2020 ; Chang et al, 2021 ; Luo et al, 2021 ; Huang et al, 2022 ).…”