The clinical dream of chitosan-based self-healing hydrogels: big surprises with small materials
Self-healing chitosan-based hydrogel (top: the hole punched in the middle self-healed after 2 hours) compared with gelatin without self-healing (bottom)
Magnetic chitosan-based self-healing hydrogels squeezed through narrow channels, proving the synergy between self-healing and magnetic properties.
At the "2012 Life Science Forum" held in November, a report from Tao Lei, associate professor of the Professor Wei Yan's research group at the Department of Chemistry, Tsinghua University, attracted the attention of the participating doctors: Chitosan (principal sources are shrimp shell and crab Shells, etc.) are the main raw materials, and hydrogels with self-healing ability are prepared through simple material synthesis.
The dangerous rock research group with polymer materials as the research direction does not seem to be directly related to the field of life sciences. This self-healing hydrogel raw material is cheap and easy to obtain, has simple preparation method and good biocompatibility, and is expected to play a role in targeted administration and controlled release.
Why study self-healing hydrogels
"Scientific research should be people-oriented", there is such a line at the end of the report PPT. This is also the research philosophy and dream of the Weiyan research group for many years-to form a strong team, use cheap raw materials, and use simple preparation methods to synthesize polymer materials with practical application prospects.
Why choose self-healing hydrogel as a research topic? This should start from the problems faced by traditional administration methods.
At present, when a traditional intravenous drug is injected, after the drug enters the human blood circulation system, it needs to pass through the heart, lung, arteries and other channels to reach the lesion. This process causes a large amount of drug to be lost and the drug delivery efficiency is low. At the same time, when injecting drugs at high concentration, the side effects of the drugs cannot be ignored. In addition, frequent administration also increases the physical and economic burden on patients.
Wei Yan told the reporter of China Science News that the research team hoped to use the self-healing hydrogel as a drug carrier and injected it into the lesion site. During the injection process, the broken hydrogel quickly repaired itself and "fixed" the drug as expected The site is then slowly released to achieve the purpose of treatment, and it is expected to solve the deficiencies in traditional intravenous administration methods.
"The self-healing hydrogels reported in the existing literature have some bottleneck problems in practical application: the selection of peptides, proteins, DNA fragments, etc. as gel-forming elements is relatively expensive; some gels cannot achieve self-healing under physiological conditions; Safety and biocompatibility are not ideal, etc. "Tao Lei said.
The research group chose chitosan as the main raw material to prepare self-healing hydrogels for the following reasons: the main sources of chitosan are shrimp shells, crab shells, etc., with a wide range of sources and low prices. In addition, chitosan can be degraded into natural metabolites by various enzymes in the body, has good biosecurity and biocompatibility, and has great advantages when used as a biomedical material.
Big surprise with small materials
The time goes back to November 2010, and a distant idea is now truly stuck in the test tube.
The doctoral student Zhang Yaling made a simple experiment. At room temperature without any additional catalyst, the chitosan solution and the functionalized polyethylene glycol solution with benzaldehyde groups at both ends were mixed in a test tube, less than 1 Within minutes, a hydrogel formed in the test tube.
When analyzing the molecular structure of the research group, the research group believed that the hydrogel system was constructed by dynamic chemical bonds, conjectured that the hydrogel might be self-healing. To this end, they did the following experiment: stick two pieces of hydrogels of different colors together, and make a 9mm hole in the middle. Over time, the "wound" on the hydrogel gradually shrank and the colors penetrated each other. After 2 hours, the hydrogel completely healed.
The self-healing chitosan hydrogel is made!
Can this self-healing hydrogel achieve self-healing under physiological conditions? Is it responsive under biological stimuli? Otherwise its clinical application can only be on paper.
To this end, the research group combined water, vitamin B6, papain, lysozyme, etc. with each other to try to find the response law of chitosan hydrogel under different biological stimuli.
Zhang Yaling added a water-soluble dye as a drug model to the hydrogel and recorded the release rate of the dye under different biological stimuli. The experimental results show that under the condition of adding vitamin B6 and papain, the drug release rate in the hydrogel is significantly faster than that in the control group added with water or lysozyme.
The discussion group believes that this experiment provides two pieces of information: one is that the drug can achieve controlled release under biological stimulation; the other is that lysozyme has little degradation effect on chitosan in this system.
"Lysozyme is a protein, so we thought we could use chitosan-based hydrogel as a protein drug release carrier." The team member said.
When recording protein release data, the researchers were pleasantly surprised to find that not only can lysozyme be released in a controlled manner, but the activity of the enzyme before and after release is almost unchanged. It can be used as a release carrier for protein and other biological macromolecular drugs. The experimental results were published in Biomacromolecules (American "Biomacromolecules" magazine) in June 2011, and became one of the annual hot reading articles.
Clinical feasibility
With this achievement, the research group turned its attention to cell therapy.
Still using a derivative of chitosan, plus functionalized polyethylene glycol, this time they also brought the cells. The living conditions of cells are more severe, can it survive in this magical hydrogel?
The experimental results once again excited the researchers. PhD student Yang Bin mixed cells and gel-forming elements under mild conditions at room temperature and a pH of 7.0. Within a minute, the hydrogel containing cells quickly formed. Observing the cell survival in the 3D hydrogel under a laser confocal microscope, Yang Bin found that there were very few dead cells. The observation results of 24 hours and 72 hours after the start of the experiment showed that the cells survived well in the hydrogel, and the number of dead cells did not increase significantly. Experimental results show that this hydrogel has good biocompatibility and may become a new carrier for cell therapy. The experimental results have been published in 2012 Polymer Chemistry (British "polymer chemistry" magazine).
Next, there is a more interesting experiment-let the hydrogel move!
They added magnetism to the hydrogel, giving this chitosan-based self-healing hydrogel behavior controllability.
The preparation method is still very simple: adding ferroferric oxide nanoparticles with good biocompatibility to the chitosan solution, together with functionalized polyethylene glycol.
Experimental results show that this magnetic hydrogel is like a "soft octopus"! Driven by an external magnetic field, it can move through a narrow gap by changing its shape. It is understood that the preparation of hydrogels with both magnetic and self-healing properties is the first case.
"Does this mean that it is a potential smart drug carrier?" The Weiyan research group envisioned.
Make dreams happen
At present, the Weiyan research group is continuing to extend this research direction: one is to integrate more functional elements into the hydrogel system to prepare more new materials; the second is to use their hydrogel materials as drug carriers In vivo experiments.
"What we hope to make is simple, cheap and useful. This multifunctional hydrogel may be close to our dream." Tao Lei said.
The reporter was informed that the research team recently added biologically inert silica to their hydrogel system to obtain an organic-inorganic hybrid material with a multi-stage pore structure. Is a potential hemostatic material. The experimental results have been published in 2012 Advanced Healthcare Materials (German "Advanced Medical Materials" magazine), and has applied for a patent.
Next, if we want to make this self-healing hydrogel truly from the laboratory to the clinic, there may be many unknown factors and problems to be solved. The research team is communicating and cooperating with clinicians.
Perhaps one day in the future, this chitosan-based hydrogel can really be injected directly into the vicinity of the lesion with cells or drugs, and then through the action of an external magnetic field, it can accurately "swim" to the lesion like an "octopus" The medicine is fixed here, and the medicine can be controlledly released according to the material ratio and the biological stimulation environment.
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