Figure - available from: Frontiers in Bioengineering and Biotechnology
This content is subject to copyright.
Gelatin hydrogel affects the activation of microglia/macrophages and astrocytes. (A) Double immunofluorescence staining was performed with astrocyte marker GFAP (green) and microglia/macrophages marker Iba-1 (red) in brain sections, scale bar = 20 μm. (B) Representative images for Immunofluorescence staining of Iba-1, scale bar = 50 μm. (C) The percentage of Iba-1 positive area analysis. (D) Representative images for Immunofluorescence staining of GFAP, scale bar = 50 μm. (E) The percentage of GFAP positive area analysis. *Represents the hydrogel. Data are mean ± SD, n = 4 mice per group, *P < 0.05, ***P < 0.001.
Source publication
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 ge...
Similar publications
Background
Tumor-associated macrophages (TAMs) are indispensable to mediating the connections between cells in the tumor microenvironment. In this study, we intended to research the function and mechanism of Calmodulin2 (CALM2) in gastric cancer (GC)-TAM microenvironment.
Materials and methods
CALM2 expression in GC tissues and GC cells was determ...
Macrophages infiltrating tumour tissues or residing in the microenvironment of solid tumours are known as tumour-associated macrophages (TAMs). These specialized immune cells play crucial roles in tumour growth, angiogenesis, immune regulation, metastasis, and chemoresistance. TAMs encompass various subpopulations, primarily classified into M1 and...
Acute lung injury (ALI) is an acute and progressive pulmonary inflammatory disease that is difficult to cure and has a poor prognosis. Macrophages, which have various phenotypes and diverse functions, play an essential role in the pathogenesis of ALI. Grape seed proanthocyanidin (GSP) has received much attention over several decades, and many biolo...
Background
The peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent upregulation of fatty acid oxidation (FAO) mediates protumor (also known as M2-like) polarization of tumor-associated macrophages (TAMs). However, upstream factors determining PPAR-γ upregulation in TAM protumor polarization are not fully identified. S100A4 plays crucial...
The effects of mesenchymal stem cells (MSCs) on different types of diseases are controversial, and the inner mechanisms remain unknown, which retards the utilization of MSCs in disease therapy. In this study, we aimed to elucidate the mechanisms of MSCs-extracellular vesicles (EVs) carrying transforming growth factor-beta 1 (TGF-β1) in M2 polarizat...
Citations
... Gelatin (Gel) is a fibrous protein extracted from collagen-containing materials, being rich in arginine-glycine-aspartic acid sequence [14] as peptide motif for cell adhesion [15,16]. Gel has been also attested to have a positive effect on angiogenesis [17]. However, the use of regenerated or processed Gel materials in tissue engineering is limited due to their significantly poor mechanical properties [18,19]. ...
... Similarly, a study by Ghuman and colleagues found that an ECM-based hydrogel administered at a chronic time point after ischaemic stroke was retained for several weeks and allowed host cell infiltration but had neutral effects on a battery of functional tests [51]. However, some studies using alternative hydrogels have reported a beneficial effect on the behavioural impairments seen in the neuroscore and corner test after ICH [12,48,[52][53][54], although functional benefits are sometimes seen only when the hydrogel is combined with other factors, such as growth factors ( [54]). ...
... Ki67-expressing cells appeared to be positive for DCX, indicating the presence of proliferating neural progenitors in the lesion. Several reports using hydrogels in ICH have studied the expression of neurogenic markers [15,52,54,55]. Interestingly, Lim and colleagues found a significant increase in the number of nestin-positive neural stem cells, after delivery of a EGF and gelatin-hydrogel combination therapy, but no increase with the hydrogel scaffold alone [54]. ...
Intracerebral haemorrhage (ICH) is the deadliest form of stroke, but current treatment options are limited, meaning ICH survivors are often left with life-changing disabilities. The significant unmet clinical need and socioeconomic burden of ICH mean novel regenerative medicine approaches are gaining interest. To facilitate the regeneration of the ICH lesion, injectable biomimetic hydrogels are proposed as both scaffolds for endogenous repair and delivery platforms for pro-regenerative therapies. In this paper, the objective was to explore whether injection of a novel self-assembling peptide hydrogel (SAPH) Alpha2 was feasible, safe and could stimulate brain tissue regeneration, in a collagenase-induced ICH model in rats. Alpha2 was administered intracerebrally at 7 days post ICH and functional outcome measures, histological markers of damage and repair and RNA-sequencing were investigated for up to 8 weeks. The hydrogel Alpha2 was safe, well-tolerated and was retained in the lesion for several weeks, where it allowed infiltration of host cells. The hydrogel had a largely neutral effect on functional outcomes and expression of angiogenic and neurogenic markers but led to increased numbers of proliferating cells. RNAseq and pathway analysis showed that ICH altered genes related to inflammatory and phagocytic pathways, and these changes were also observed after administration of hydrogel. Overall, the results show that the novel hydrogel was safe when injected intracerebrally and had no negative effects on functional outcomes but increased cell proliferation. To elicit a regenerative effect, future studies could use a functionalised hydrogel or combine it with an adjunct therapy.
... Similarly, a study by Ghuman and colleagues found that an ECM-based hydrogel administered at a chronic time point after ischaemic stroke, was retained for several weeks and allowed host cell in ltration but had neutral effects on a battery of functional tests [48]. However, some studies using alternative hydrogels, have reported a bene cial effect on the behavioral impairments seen in the neuroscore and corner test after ICH [12,45,[49][50][51], although functional bene ts are sometimes seen only when the hydrogel is combined with other factors, such as growth factors ( [51]). Although this study found no detrimental or bene cial effect of hydrogel administration on functional outcomes, it is important to note that there may be other domains of impairment, such as ne motor dexterity or sickness behaviour that are not captured by the tests selected. ...
... Ki67-expressing cells appeared to be positive for DCX, indicating the presence of proliferating neural progenitors in the lesion. Several reports using hydrogels in ICH have studied the expression of neurogenic markers [15,49,51,52]. ...
Intracerebral haemorrhage (ICH) is the deadliest form of stroke but current treatment options are limited, meaning ICH survivors are often left with life-changing disabilities. The significant unmet clinical need and socioeconomic burden of ICH means novel regenerative medicine approaches are gaining interest. To facilitate regeneration of the ICH lesion, injectable biomimetic hydrogels are proposed as both scaffolds for endogenous repair and delivery platforms for pro-regenerative therapies. In this paper, the objective was to explore whether injection of a novel self-assembling peptide hydrogel (SAPH) Alpha2 was feasible, safe and could stimulate brain tissue regeneration, in a collagenase-induced ICH model in rat. Alpha2 was administered intracerebrally at 7 days post ICH and functional outcome measures, histological markers of damage and repair and RNA-sequencing were investigated for up to 8 weeks. The hydrogel Alpha2 was safe, well-tolerated and was retained in the lesion for several weeks, where it allowed infiltration of host cells. The hydrogel had a largely neutral effect on functional outcomes and expression of angiogenic and neurogenic markers but led to increased numbers of proliferating cells. RNAseq and pathway analysis showed that ICH induced genes related to inflammatory and phagocytic pathways and these changes were also observed after administration of hydrogel. Overall, the results show that the novel hydrogel was safe when injected intracerebrally, had no negative effects on functional outcomes but increased cell proliferation. To elicit a regenerative effect, future studies could use a functionalised hydrogel or combine it with an adjunct therapy.
... The researchers demonstrated that inflammation was suppressed in the intervention group. Macrophage polarization was observed to shift towards the M2 phenotype leading to a decline in the secretion of inflammatory cytokines, resulting in reduced neuronal loss and enhanced functional recovery [220]. Shiratori et al. showed that drugs could polarize macrophages into different subtypes. ...
The understanding of macrophages and their pathophysiological role has dramatically changed within the last decades. Macrophages represent a very interesting cell type with regard to biomaterial-based tissue engineering and regeneration. In this context, macrophages play a crucial role in the biocompatibility and degradation of implanted biomaterials. Furthermore, a better understanding of the functionality of macrophages opens perspectives for potential guidance and modulation to turn inflammation into regeneration. Such knowledge may help to improve not only the biocompatibility of scaffold materials but also the integration, maturation, and preservation of scaffold-cell constructs or induce regeneration. Nowadays, macrophages are classified into two subpopulations, the classically activated macrophages (M1 macrophages) with pro-inflammatory properties and the alternatively activated macrophages (M2 macrophages) with anti-inflammatory properties. The present narrative review gives an overview of the different functions of macrophages and summarizes the recent state of knowledge regarding different types of macrophages and their functions, with special emphasis on tissue engineering and tissue regeneration.
... Native fish gelatin does not possess traceable thiol, therefore, successful thiolation was first determined through 5,5 -dithio-bis-[2-nitrobenzoic acid] (DTNB) assay ( Figure 1C). The degree of thiolation influences the amount of Gel-SH and PEG-4MAL materials required to reach an equimolar (SH:MAL) ratio, which is optimal for hydrogel formation [57,58]. With increased degree of Gel-SH thiolation, there is a higher number of click bonds between Gel-SH and PEG-4MAL that can occur using the same concentration of Gel-SH, and therefore more stability in the matrix. ...
Basement membrane extracts (BME) derived from Engelbreth–Holm–Swarm (EHS) mouse sarcomas such as Matrigel® remain the gold standard extracellular matrix (ECM) for three-dimensional (3D) cell culture in cancer research. Yet, BMEs suffer from substantial batch-to-batch variation, ill-defined composition, and lack the ability for physichochemical manipulation. Here, we developed a novel 3D cell culture system based on thiolated gelatin (Gel-SH), an inexpensive and highly controlled raw material capable of forming hydrogels with a high level of biophysical control and cell-instructive bioactivity. We demonstrate the successful thiolation of gelatin raw materials to enable rapid covalent crosslinking upon mixing with a synthetic poly(ethylene glycol) (PEG)-based crosslinker. The mechanical properties of the resulting gelatin-based hydrogels were readily tuned by varying precursor material concentrations, with Young’s moduli ranging from ~2.5 to 5.8 kPa. All hydrogels of varying stiffnesses supported the viability and proliferation of MDA-MB-231 and MCF-7 breast cancer cell lines for 14 and 21 days of cell culture, respectively. Additionally, the gelatin-based hydrogels supported the growth, viability, and osteogenic differentiation of patient-derived preosteoblasts over 28 days of culture. Collectively, our data demonstrate that gelatin-based biomaterials provide an inexpensive and tunable 3D cell culture platform that may overcome the limitations of traditional BMEs.
... A hydrogel can be tuned to modulate its perm selectivity properties to specific uploaded drugs or molecules, controlling the releasing rate and thereby reducing the necessity to administer a compound or biomolecule frequently given the short half-life of the compound and the consequential decay of its activity [89]. Using injectable gelatin hydrogel and thiolated gelatin, Xu and colleagues [90] investigated the possibility of regulating neuroinflammation and increasing functional recovery in a mouse model of intracerebral hemorrhage (ICH). Reduced neuron loss, promoted nerve functional recovery, lowered microglia/macrophage, and astrocyte activation, and regulated microglia/macrophage polarization to minimize the production of inflammatory cytokines such as IL-1 and TNF-α after hydrogel injection in vivo. ...
An immune system responds to pathogens, toxic compounds, or certain physiological conditions which lead to inflammation. However, uncontrolled and excessive inflammation is associated with a variety of severe chronic conditions including intestinal disorders, cancer, diabetes, and myocardial infarction. The development of anti-inflammatory therapies to treat and manage relevant chronic diseases has resulted from a better understanding of inflammation. However, clinical outcomes vary among patients and serious adverse effects are often observed. Furthermore, clinical anti-inflammatory therapeutics have some limitations due to their insolubility in water, low bioavailability, and poor accessibility to subcellular compartments. To address these challenges, the drug delivery system specific to inflammation offers significant potential. A hydrogel is attractive as a drug delivery platform because of its outstanding characteristics, including swellability, biocompatibility, controlled degradation, and sustained drug release. Hydrogels have been widely used in biomedical applications for several reasons, using diverse polymers of synthetic and natural origin. The design of hydrogels relies heavily on proteins and peptides because proteins are the fundamental macromolecules in living organisms for biochemical, mechanical, and structural functions. Therefore, they provide us with a wide range of structural building blocks for the formation of various types of biomaterials, including hydrogels. Since natural proteins and peptides are biocompatible and biodegradable, they have features advantageous for their use as the building blocks of hydrogels for biomedical applications. This review aims to focus on hydrogels derived from protein and peptide-based systems and highlights recent trends in the use of protein and peptide-based hydrogels as drug delivery systems for inflammation.
... Several findings showed that almost five different types of microglia morphology were identified in control and experimental status epilepticus (SE) tissues, and were categorized as follows: (1) ramified; (2) hypertrophic; (3) bushy; (4) amoeboid; and (5) rod-shaped (19) (Figure 1). Microglial polarization plays a major role in promoting brain injury and nerve recovery (20). As the main source of inflammatory cells in ischemic brain injury, microglia play a key role in the inflammatory response after stroke (21). ...
Stroke is the leading cause of disability and death worldwide, with ischemic stroke occurring in ~5% of the global population every year. Recently, many studies have been conducted on the inflammatory response after stroke. Microglial/macrophage polarization has a dual function and is critical to the pathology of ischemic stroke. Microglial/macrophage activation is important in reducing neuronal apoptosis, enhancing neurogenesis, and promoting functional recovery after ischemic stroke. In this review, we investigate the physiological characteristics and functions of microglia in the brain, the activation and phenotypic polarization of microglia and macrophages after stroke, the signaling mechanisms of polarization states, and the contribution of microglia to brain pathology and repair. We summarize recent advances in stroke-related microglia research, highlighting breakthroughs in therapeutic strategies for microglial responses after stroke, thereby providing new ideas for the treatment of ischemic stroke.
... A 28-point neurologic deficit scale was used to assess neurologic deficits, including body symmetry, gait, climbing, circling behavior, front limb symmetry, compulsory circling, and whisker response, as previously mentioned (Fang et al., 2014;Xu et al., 2020). A higher score represents a more severe injury. ...
Objective
Intracerebral hemorrhage (ICH) is the most lethal subtype of stroke, without effective treatment. Necrosulfonamide (NSA), a specific inhibitor for mixed lineage kinase domain-like protein, has been reported to exert neuroprotective effects in neurological diseases by ameliorating neuroinflammation and necroptosis. We hypothesized that NSA would alleviate acute brain injury and improve behavioral outcomes after ICH.
Materials and Methods
Male adult C57BL/6 mice were assigned randomly into three groups. In vehicle and treatment groups, animals were injected with collagenase VII to induce ICH. The solvent (0.25% DMSO) and NSA (5 mg/kg) were administrated intraperitoneally twice a day, respectively. The sham group was injected with saline and administrated with DMSO. The brain hematoma volume, inflammatory factors, and blood-brain barrier permeability were measured on day 3 after the operation. Fluorescent double immunostaining was performed to evaluate the neuronal death. Neurological functions were assessed.
Results
In the NSA group, the hematoma size was significantly reduced, inflammatory cells and cytokines were suppressed, and the blood-brain barrier was protected compared to vehicle controls. NSA dramatically reduced the death of neurons and improved the performance of neurological functions after ICH.
Conclusion
Necrosulfonamide has a neuroprotective role in alleviating acute brain injury in a mouse ICH model, and this is associated with reduced neuroinflammation and necroptosis.
... 92,93 Gel systems with anti-inflammatory and hemostatic effects were used for neuroprotection and hemostatic therapy after hemorrhagic stroke. 94,95 Exosomes are extracellular vesicles secreted by different cell types that have been used as carriers for drugs and different types of molecules (mRNA, miRNA, and protein). 96 Otero-Ortega et al used proteomics analysis to identify protein in exosomes derived from mesenchymal stem cells (MSCs). ...
... Injection of the gelatin hydrogel reduced inflammation and attenuated neurological deficits after ICH. 94 Keratin-based hydrogel with hemostatic effect have also successfully been applied in ICH therapy. 95 ...
Hemorrhagic stroke is one of the most devastating diseases worldwide due to a high rate of disability and mortality with few effective treatments. Recent advances in nanomedicines to promote hemostasis, drug delivery, neuroprotection, and nerve regeneration may provide insight into hemorrhagic stroke treatment. In this review, we first view the pathophysiology and conventional therapeutics of hemorrhagic stroke. Second, we comprehensively summarize the current nanomedicines applied in hemorrhagic stroke, including inorganic nanomaterials, polymer-based nanomaterials, lipid-based nanomaterials, self-assembling peptide-based hydrogel, exosomes, and gel systems. Finally, the challenges, opportunities, and future perspectives of nanomedicines for hemorrhagic stroke are discussed. Thus, this review promotes greater exploration of effective therapies for hemorrhagic stroke with nanomedicines.
... Hydrogel is considered a biocompatible material that can be injected during minimally invasive surgery and form a matrix for cell infiltration and adhesion to facilitate tissue repair after stroke [214,215]. Gelatin hydrogel injection into the lesion three days post collagenase-induced ICH is reported to alleviate neurological deficits of mice due to conversion of M/M from pro-inflammatory to regulatory [216]. Moreover, hydrogels may carry medications, neurotrophic factors, and stem cells as well as receive chemical modifications to enhance therapeutic effects [215,217]. ...
Despite marked advances in surgical techniques and understanding of secondary brain injury mechanisms, the prognosis of intracerebral hemorrhage (ICH) remains devastating. Harnessing and promoting the regenerative potential of the central nervous system may improve the outcomes of patients with hemorrhagic stroke, but approaches are still in their infancy. In this review, we discuss the regenerative phenomena occurring in animal models and human ICH, provide results related to cellular and molecular mechanisms of the repair process including by microglia, and review potential methods to promote tissue regeneration in ICH. We aim to stimulate research involving tissue restoration after ICH.
