Injectable Gelatin Hydrogel Suppresses Inflammation and Enhances Functional Recovery in a Mouse Model of Intracerebral Hemorrhage.

Jiake Xu,Xin Qi,Hao Li,Meng Tian,Lu Ma,Chao You,Yang Wei,Liu Zi,Zhongxin Duan,Hao Liu,Yi Ou,Xi Guo

doi:10.3389/fbioe.2020.00785

Abstract

Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with high morbidity and mortality. However, there is no effective therapy method to improve its clinical outcomes to date. Here we report an injectable gelatin hydrogel that is capable of suppressing inflammation and enhancing functional recovery in a mouse model of ICH. Thiolated gelatin was synthesized by EDC chemistry and then the hydrogel was formed through Michael addition reaction between the thiolated gelatin and polyethylene glycol diacrylate. The hydrogel was characterized by scanning electron microscopy, porosity, rheology, and cytotoxicity before evaluating in a mouse model of ICH. The in vivo study showed that the hydrogel injection into the ICH lesion reduced the neuron loss, attenuated the neurological deficit post-operation, and decreased the activation of the microglia/macrophages and astrocytes. More importantly, the pro-inflammatory M1 microglia/macrophages polarization was suppressed while the anti-inflammatory M2 phenotype was promoted after the hydrogel injection. Besides, the hydrogel injection reduced the release of inflammatory cytokines (IL-1β and TNF-α). Moreover, integrin β1 was confirmed up-regulated around the lesion that is positively correlated with the M2 microglia/macrophages. The related mechanism was proposed and discussed. Taken together, the injectable gelatin hydrogel suppressed the inflammation which might contribute to enhance the functional recovery of the ICH mouse, making it a promising application in the clinic.

Highlights

Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with high morbidity and mortality, there is no effective therapy method to improve its clinical outcomes to date (Krishnamurthi et al, 2013; Poon et al, 2014)
The hydrogel was characterized by Scanning Electron Microscopy (SEM), rheology, and cytotoxicity before an in vivo evaluation was performed in a mouse model of ICH (Figure 1B)
The content of thiol in thiolated gelatin was determined by Ellman method, and the results showed that the product has a thiol content of 0.48 mmol/g, which corresponds to 39.2% degree of substitution (DS)

Summary

Introduction

Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with high morbidity and mortality, there is no effective therapy method to improve its clinical outcomes to date (Krishnamurthi et al, 2013; Poon et al, 2014). Injectable hydrogels have attracted more and more research interests due to their innate merits, e.g., capable of minimally invasive implantation (Dimatteo et al, 2018; Wang C. et al, 2019), especially for stroke, since they can be injected initially as a fluid through a needle into the brain with stereotactic procedures, and formed the gel upon crosslinking to irregularly shaped cavities at the implant site (Nih et al, 2016) In this context, there are some reports that injectable hydrogel has been used to promote host cell infiltrate and endogenous brain tissue repair (Ghuman et al, 2016), encourage angiogenesis and recovery of nerve circuits through guided drug and growth factor delivery (Nih et al, 2018), and injectable hydrogel could be applied to transplant stem cells to restore lost neurons (Hu, 2016). How to modulate the immune response and neuroinflammation through the implanted biomaterials such as hydrogel remains a great challenge to date

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Discussion

Conclusion