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

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.

Rosuvastatin Nanomicelles Target Neuroinflammation and Improve Neurological Deficit in a Mouse Model of Intracerebral Hemorrhage

“…As previously mentioned, a 28-point neurologic deficit scale (NDS) was used to assess neurologic deficits, including body symmetry, gait, climbing, circling behavior, front limb symmetry, compulsory circling, and whisker response. 27,28 Mice (n=6 per group) were tested for three consecutive days before operation to exclude abnormal mice and form baseline data. And NDS was measured on days 1, 3, and 7 after ICH.…”

PEGylation of Deferoxamine for Improving the Stability, Cytotoxicity, and Iron-Overload in an Experimental Stroke Model in Rats

“…Following a stroke, neurons may be damaged by necrosis, apoptosis, autophagic cell death, and ferroptosis ( Shao et al, 2019 ), which seriously affect the density of neurons around the lesions and cause serious nerve function injury ( Chen et al, 2019 ; Xu et al, 2020 ). Our results showed that mPEG 5 K -DFO exhibited a similar therapeutic effect (in reducing the degeneration of neurons) compared with DFO, which might result from their iron-chelating effect ( Guo et al, 2019 ).…”

“…This is why, by day 14, the neurological behavior of all the groups was restored to a reasonable level as previously reported ( Karki et al, 2009 ; Yang et al, 2011 ). The density of the neurons around the lesion is closely related to the recovery of nerve function injury ( Chen et al, 2019 ; Xu et al, 2020 ). The FJC staining showed that both mPEG 5 K -DFO and DFO treatment could reduce the number of degenerated neurons, which may explain, in part, why both the mPEG 5 K -DFO and DFO groups exhibited better recovery of function compared with the saline group.…”

Regenerative Potential of Hydrogels for Intracerebral Hemorrhage: Lessons from Ischemic Stroke and Traumatic Brain Injury Research

“…[ 56,58,91,92 ] The degree of scaffold porosity is also critical for facilitating cell invasion and circulation of nutrients and metabolites in the transplanted hydrogel. Several ICH papers assessing hydrogel porosity by scanning electron microscopy [ 55,57,58,92 ] reported the presence of interconnected network of pores with sizes between 20 and 100 µm, which falls within the range of mammalian cell diameter to facilitate cell infiltration. Conversely, hydrogels with smaller pore sizes, as reported for RADA‐I‐based SAPH (5–200 nm), may preclude or hinder cell infiltration.…”

“…[ 58 ] Finally, examination of material interaction with the hematoma revealed that the hydrogel may prevent the formation of a visible hemosiderin scar, which is a common feature of ICH pathology. [ 92 ] Hydrogels such as RADA‐based hydrogels may also reduce the hematoma volume, revealing possible hemostatic properties. [ 46 ]…”