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According to Mayo Clinic, a stroke is a medical event that occurs when blood supply is interrupted or reduced in a part of the brain, which blocks brain tissue from oxygenation and nutrients, leading to tissue death and causing brain damage. Nowadays, less patients die from a stroke; however, it is one of the leading causes of disability in adults, since approximately 15 million people in the world suffer from a stroke every year, as the brain has a reduced capacity for repair. It is also important to know that once damage is present after a stroke, very little can be done to restore the loss of function (Gund, B. M. G., et al., 2013).
That is why biomaterials, especially hydrogels, are a great answer for stroke treatment. Biomaterials are any kind of materials that can interact with biological compounds without having any immune reaction. In this category we have hydrogels, these are 3D polymer chain networks that have the ability of absorbing solutions (water or medicine), elastic consistency and swelling capacity. Making them suitable materials for applications related to tissues, as they have biocompatibility properties (Arredondo P. A., Londoño L. M., 2009).
Due to their absorption properties, hydrogels can be used as transportation for certain drugs that need to be placed into the infarct core. Many researchers have studied this phenomenon; the “tricky part” is finding out what med combination is going to work.
One option is the use of self-assembly injectable peptide hydrogels, which are natural-derived components presenting ideal biocompatibility due to their amino acid fundamental structure. They can also be tailored to target specific injuries by modifying their peptide sequence. However, they present plenty disadvantages, such as low mechanical properties, high probability of unwanted contaminants, and long-term permanency (fast degradation in vivo). We need to point out that, self-assembly injectable peptide hydrogels use UV light and toxic cross-linkers (chemicals that are impossible to use in the central nervous system) in their creation process. In consequence, this type of hydrogels are not ready for in vivo testing. Therefore, they are not an immediate possibility for treatment. According to Madhusudanan “SAP hydrogel systems have generally exhibited favorable outcomes for neural regeneration, but there are several questions related to immune response towards peptides, functional and behavioral changes in response to SAP hydrogel incorporation in the brain and long-term tissue effects that need to be addressed” (Madhusudanan et al., 2020).
For us, the most promising one is the hyaluronic acid–based microporous annealed particle (HA-MAP): this experiment had strong results in terms of tissue regeneration. After strokes happen, the dying cells create a cytotoxic environment, causing more damage and preventing the brain from healing. However, studies show that cytokines could activate repair mechanisms. This hydrogel stimulates the repair mechanisms and uses the cells to produce alternative microglia (macrophages are residue collectors in the central nervous system) leading to more astrocyte (responsible for synaptic support) infiltration and axonal penetration. This is important because it changes the microglia from deteriorating brain tissue to stimulate brain cells so they can restore certain parts of the tissue.
HA-MAP is a porous material made from hyaluronic acid, MMP degradable peptides, and a scaffold made from HMP and enzyme crosslinking. This hydrogel is injected directly into the infarct core (Figure 1). Two tests were made, in the first one an ischemic stroke photothrombotic (PT) model was made to determine the brain tissue response in short term and long term. Reaching full success on day 7.
Figure 1. HA-MAP hydrogel being injected in the infarct core
The in vivo test (Figure 2) injected in mice 5 days after an induced stroke. It showed that the hydrogel degrades 120 days after being applied. Degradation was seen using a fluorescent hydrogel. After testing, results showed the following advantages: Inflammation decreased by reducing the microglial and astrocytic population in the injury. Brain atrophy was diminished and nigrostriatal bundles (dopaminergic nerve fibers) were kept; it promoted the production of astrocytes phenotype and microglia towards a pro-repair kind; plus, it also crates support for the brain tissue, this prevents fibrotic pulling (cerebral atrophy).
Figure 2. Evolution of hydrogel HA-MAP in the infarct core
Since the HA-MAP experiment is an in vivo experiment, it is expensive to perform. When dealing with animals, there is a lot need that must be considered, from the mice themselves (C57BL/6 8–12-week male mice, which go from $34-$53 USD per 199 subjects) to diet expenses, air conditions, and day/night regimen among other factors. That is why the estimated cost of this experiment production rises above the $80,000 dollars, besides all other laboratory equipment.
In terms of authorization, the U.S Food and Drug Administration (FDA), under the ASTM F2900-11 norm, approved the use of hydrogels with the Standard Guide for Characterization of Hydrogels used in Regenerative Medicine. In Mexico things change; there is no record of hydrogels being accepted by Comisión Federal para la Protección Contra Riesgos Sanitarios (COFEPRIS) in Mexico, as an element of tissue regeneration. The last permits in Mexico are from 2019 as hygiene products or materials for surgery.
We can conclude that HA-MAP is a promising material, nevertheless it has an important improvement area which blocks their possibilities of becoming a real alternative. This problem is the vascularization of the tissue since the oxygen diffusion of the material is ~200 µm. Oxygen diffusion is a determinant factor for tissue survival, since it refers to the capacity of oxygen going into the tissue. When observing the astrocytes and axons, they could tell that vessel response is the limiting factor. If solved, HA-MAP could be used in the treatment for other diseases, like Alzheimer’s or Parkinson’s, which are related to brain tissue degeneration. Providing hope and chances for brain degenerative diseases patients, and probably amplifying the field of hydrogels in tissue regeneration.
References
Arredondo Peñaranda, A., & Londoño López, M. E. (2009). Hydrogels. Potential biomaterials for controlled drug release. http://www.scielo.org.co/pdf/rinbi/v3n5/v3n5a13.pdf
Cost Estimates & Fees | Transgenic Animal Model. (n.d.). U-M Biomedical Research Core Facilities. Retrieved April 29, 2021, from https://brcf.medicine.umich.edu/cores/transgenic-animalmodel/fees/
Costs of Animal and Non-Animal Testing. (2012, October 23). Humane Society International. https://www.hsi.org/news-media/time_and_cost/
Gund, B. M. G., Jagtap, P. N., Ingale, V. B., & Patil, R. Y. (2013). Stroke: A Brain Attack. http://www.iosrphr.org/papers/v3i8/part.2/A038201023.pdf
Hong, Andrew; Aguilar, Marie Isabel; Del Borgo, Mark; Sobey, Christopher; Broughton, Bradley; Forsythe, John S (2019). Self-assembling injectable peptide hydrogels for emerging treatments of ischemic stroke. Journal of Materials Chemistry B, (), 10.1039.C9TB00257J–. doi:10.1039/C9TB00257
Recognized Consensus Standards. (n.d.). Retrieved April 8, 2021, from https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfstandards/detail.cfm?standard__identification_no=3 0083
Sideris, E., Yu, A., Chen, J., Carmichael, S. T., & Segura, T. (2019). Hyaluronic acid particle hydrogels decrease cerebral atrophy and promote pro-reparative astrocyte/axonal infiltration in the core after ischemic stroke [Preprint]. Bioengineering. https://doi.org/10.1101/76829
Stroke—Symptoms and causes. (n.d.). Mayo Clinic. Retrieved April 30, 2021, from https://www.mayoclinic.org/diseases-conditions/stroke/symptoms-causes/syc-20350113
About the author
Alexandra Rodríguez Cárdenas is a 6th semester student in Biomedical Engineering, nowadays participates in La Catarina as chief of information. She also belongs to the IEEE-UDLAP Student Branch as a student member and as social media coordinator.
Last modified: 12 mayo, 2021