The blood-brain barrier (BBB) is one major roadblock to stroke treatment. So, to have a good outcome in stroke treatment, different interventions must get efficiently to the ischemic brain location. The latest discoveries in biomaterials are a promising new possibility for pursuing new stroke therapies. Of all the different biomaterials, hydrogels were the most researched because of their chemical and mechanical specificities. Hydrogels could be biosensors, drug carriers, cell carriers in tissue engineering or matrices that far outperform most standard therapeutic drugs, procedures, and materials. As a result, hydrogels have become a popular scaffold option for the treatment of stroke, where they deliver therapeutic agents to the post-stroke site in a controlled manner, aiming to enhance intrinsic repair and regeneration.

Fig.1. Hydrogels can provide significant benefits in individual and clinical stroke treatment. (Wu, et al., 2024)

Ace Therapeutics can use hydrogels to help clients effectively deliver stem cells or stroke drugs to ischemic brain.

Related Services

• Development of Stem Cell-Based Therapy for Stroke
• Drug Delivery System Development for Stroke

Properties and Composition of Hydrogels

• Hydrogels are complex structures made up of a three-dimensional network of hydrophilic polymers that can absorb and retain large amounts of moisture.
• These polymers have an increased affinity for water molecules and form a porous structure that allows them to trap and retain water-based solutions within their structure.
• It is possible for hydrogels to swell several times their original size while maintaining their structural integrity. Due to this property, they are indispensable in a wide range of biomedical applications.
• By selecting specific polymers and employing various cross-linking methods, hydrogel properties can be adjusted, including porosity, swelling behavior, strength, and degradability.

Designing Hydrogels for Neurological Applications

Biocompatibility and Biodegradability

For effective delivery of stem cells or biomolecules to the injured brain, hydrogels must exhibit biocompatibility at two levels: cytocompatible with the encapsulated cells and histocompatible with the host tissue. Long-term biocompatibility is essential for successful implantation, as brain tissue damage can trigger inflammatory responses that negatively impact the survival of transplanted cells. Biologically inert hydrogels can evade the immune system, enhancing graft survival during the post-implantation neuroimmune response. Additionally, the use of chemically biocompatible and mechanically stable hydrogels with non-toxic degradation products helps reduce the infiltration of activated macrophages and microglia at the injury site.

Functionalization

A great deal of the biopolymer hydrogels that are deployed in neural tissue engineering (alginate, agarose, poly(ethylene glycol) (PEG)) must be functionalized so that they are suitable for growth, proliferation and differentiation of cells. Neural ECM materials could also be scaffold functionalized as they are biocompatible, harbor adhesion moieties and promote the growth and differentiation of cells. ECM molecules are another aspect that must be taken into account when developing hydrogels for cell transplantation to the brain.

Elasticity

Elasticity is a crucial factor in designing hydrogels for neurological applications, as it significantly influences both the fate of encapsulated cells and the integration with host tissue. Additionally, elasticity affects the distribution of the hydrogel at the injury site.

Porosity and Pore Size

Hydrogels are complex macromolecular scaffolds that stimulate tissue regeneration through infiltration of cells, angiogenesis at the site and cell-to-cell interaction. Tissue engineering for stroke is aimed at rebuilding damaged tissue using the development of cell proliferation and axonal regeneration within a 3D tissue structure that is constructed. Pore patterns in the hydrogel allow an environment of permissible cell migration, which facilitates tissue repair and integration into the host. Hydrogel matrices can be tailored with various pore microgeometries, such as macroporosity for tissue expansion and micro- and mesoporosity for cellular and molecular interactions. These structural parameters not only influence neural ingrowth and cell distribution but also enhance oxygen and mass transfer in the absence of functional vasculature.

Stimuli-Responsive Hydrogels

Researchers are creating "smart" hydrogels that respond to various external stimuli, including physical (temperature, light, electric fields), chemical (pH, ionic strength, glucose), and biological (enzymes, DNA, glutathione) factors. These polymeric systems can undergo significant changes in physical configuration or chemical behavior in response to environmental stimuli. Such stimuli-responsive changes in shape, surface characteristics, solubility, sol-gel transitions, and molecular self-assembly have broadened the applications of hydrogels in tissue engineering, drug delivery, gene therapy, bioseparation, sensors, and actuator systems.

Hydrogels Used in Ischemic Stroke Treatment

Hydrogels for Neuroprotection and Tissue Repair

Hydrogel scaffolds support therapeutic cell growth and survival in a biocompatible three-dimensional environment. This environment is vital for evaluating the efficacy and safety of various stem cells (SCs) used in stroke treatment, including neural stem cells (NSCs), mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs). Hydrogels can also enhance neuron survival, neurogenesis, and angiogenesis by incorporating growth factors such as brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF).

Moreover, hydrogels can release peptides or proteins that inhibit apoptotic pathways, protecting neurons from ischemic damage. By incorporating anti-apoptotic agents, hydrogels help preserve neurons and promote recovery while ensuring a sustained therapeutic effect through controlled release. Additionally, hydrogels can be designed to degrade at specific rates, providing a continuous supply of therapeutic agents over time, which is particularly beneficial during the chronic phase of stroke recovery. Hydrogels are ideal for supporting long-term recovery processes in brain tissue due to their tailored degradation.

Hydrogels as Drug Delivery Systems

Hydrogels are particularly suitable for biomedical applications because of their ability to release therapeutic agents in a controlled manner. By designing their composition and structure, hydrogels can provide sustained release of drugs such as thrombolytic agents like tissue plasminogen activator (tPA). In addition, hydrogels can be loaded with neuroprotective drugs to modulate the inflammatory response and minimize neuronal damage after ischemic stroke.

When applied directly to the affected area of the brain, the hydrogel optimizes the delivery of highly concentrated drugs to the exact site where they are most needed. This local delivery method minimizes the potential systemic side effects of oral or intravenous administration. By targeting the delivery of the drug to the site of injury, hydrogels can increase the effectiveness of the treatment while reducing the risk of adverse reactions elsewhere in the body.

Hydrogels for Reducing Secondary Injury

Excitotoxicity occurs due to excessive glutamate release, which overstimulates NMDA receptors, leading to neuronal death. Hydrogels can be engineered to release NMDA receptor antagonists, blocking these receptors and preventing excitotoxic damage.

Oxidative stress, caused by the overproduction of reactive oxygen species (ROS) during ischemic injury, also contributes to cellular damage. Hydrogels can be loaded with antioxidants like superoxide dismutase (SOD) or catalase to neutralize ROS and protect cells from oxidative damage.

Inflammation exacerbates injury post-stroke as activated microglia and astrocytes release pro-inflammatory cytokines, further damaging neurons. Hydrogels can deliver anti-inflammatory agents, such as dexamethasone or interleukin-10 (IL-10), to the affected area, reducing inflammation and limiting additional damage.

Hydrogels' Involvement in BBB Protection

Hydrogels, made from natural or synthetic polymers, can be engineered to deliver therapeutic agents that protect and repair the BBB, which is vital for safeguarding brain tissue from harmful substances during ischemic stroke. The BBB regulates substance passage between the bloodstream and the brain, and its integrity is often compromised during a stroke. Hydrogels can be loaded with agents such as growth factors, matrix metalloproteinase inhibitors, and tight junction proteins to restore the BBB's structure and function.

Hydrogels can also be designed to be responsive to specific stimuli, allowing for controlled release of therapeutic agents. They mimic the ECM by providing a scaffold for cell adherence and migration, promoting cellular health through mechanical cues. The integration of iPSC technology with hydrogel scaffolds, along with advancements like 3D bioprinting and microfluidic devices, has led to the development of models of the neurovascular unit.

Fig. 2. Schematic description of the hydrogel application in the treatment of ischemic strokes. (Tian, et al., 2021)

1. Wu, X., et al. (2024). Perspective insights into versatile hydrogels for stroke: From molecular mechanisms to functional applications. Biomedicine & Pharmacotherapy, 173, 116309.
2. Tian, X., et al. (2021). Recent advances in the development of nanomedicines for the treatment of ischemic stroke. Bioactive materials, 6(9), 2854-2869.