Hydrogels are systems with three-dimensional spatial network structures using water as the dispersing medium, which are soft in nature, can maintain a certain shape and have strong water absorption capacity (water content can be as high as 99%). In addition, hydrogels also have good biocompatibility, biodegradability, etc. They are widely used in biomedical fields, such as drug release, medical dressing, gum tissue regeneration, bone repair, etc., which are one of the most promising medical materials in the future.
History of Hydrogels
The term hydrogel dates back to 1894 and was first used to describe a colloid of some inorganic salts. The world's first mature hydrogel product, Ivalon (polyvinyl alcohol), was introduced in 1949, while the market for hydrogels was brought to prosperity with the introduction of PHEMA (polyhydroxyethyl methacrylate) in 1960. Looking back on the history of hydrogels, there are three broad generations.
First Generation Hydrogels
(i) The first group is polymers of alkene monomers subjected to radical-induced chain addition reactions, such as polyacrylamide (PAM) and polyhydroxyethyl methacrylate (pHEMA), which are still important biomaterials despite having been invented more than 70 years ago.
(ii) The second group is covalently cross-linked hydrophilic polymers, mainly represented by polyvinyl alcohol (PVA) and polyethylene glycol (PEG), which are mainly used in tissue engineering.
(iii) The third category is cellulose based hydrogels, which are mainly used as drug dispersion matrices in drug delivery.
Second Generation Hydrogels
The second generation hydrogels are mainly PEG/polyester block copolymers. Compared to the first generation, the second generation is characterized by the ability to convert the chemical energy of the hydrogel into the mechanical energy of the hydrogel to achieve a specified function. In the 1970s, a class of stimulus-responsive hydrogels emerged on the market that could respond to external environmental changes such as temperature or pH.
Third Generation Hydrogels
The third-generation hydrogels are mainly characterized by "cross-linking", which regulates the mechanical and degradation properties of hydrogels mainly through steric complexation, inclusion, metal-ligand coordination and synthesis of peptide chains.
Properties Analysis of Hydrogel for Biomedical Applications
Biocompatibility is the concept that the interaction between biological materials and the human body generates various complex reactions, and the research on biocompatibility of hydrogels started in the 1960s. The research scholars confirmed the good biocompatibility of hydrogels by injecting them into the experimental body and using them to treat bone and joint injuries without inflammatory reactions.
Biodegradable materials are materials that can be gradually degraded into monomers or low molecular weight compounds after a series of reactions by interacting with biological environment. Medical implant Interventional therapy and in vivo drug delivery is currently a key concern in the medical field and is one of the frontier medical technologies. However, the rejection of interventional materials and the difficult metabolism of drug delivery systems pose serious safety problems. Hydrogels, as biocompatible materials, can be modified or compounded to produce high-performance hydrogels with biodegradability. Several experiments have demonstrated the biodegradability of hydrogels without inflammation, confirming their great potential for implant intervention and drug delivery.
3、High Water Absorption and Water Retention
Hydrogels have cross-linked networks, so they can dissolve and retain a large amount of water, and their water content can be as high as 99%. The dressing made of hydrogel absorbs the wound exudate while maintaining a moist environment, so it will not cause secondary trauma by adhesion with the wound. And the hydrogel absorbs a large amount of fluid, so it does not need to be changed frequently. In addition, the surface of hydrogel is smooth and highly elastic, and when used as a dressing, it can fit closely to the wound without adhesion and reduce bacterial contact, which is the most advanced medical dressing at present.
Hydrogels For Biomedical Applications
From low-value medical consumables to high-end drug delivery technologies, from external dressings to in vivo tissue scaffolds, hydrogels shine in the biomedical field because of their unique properties.
1. Medical dressing
Trauma and trauma infection are the most frequent cases in hospitals. Medical dressings can act as a protective barrier to cover wounds, absorb wound exudate fluid and help wounds heal. With good flexibility and biocompatibility, hydrogel dressing absorbs liquid well and can create a moist environment for tissue regeneration, and the slip elastic state of the hydrogel can effectively avoid secondary injury caused by wound adhesion, so it becomes an excellent choice for medical dressing.
2. Drug delivery
Drug delivery systems are engineered technologies for the targeted delivery and/or controlled release of therapeutic agents.
Hydrogels have the functions of storing drugs, controlling the rate of drug release and driving the release, regulating the hardness and strength of formulations as well as promoting decomposition, and masking the odor of pharmaceuticals, which have greater potential for application in the field of drug delivery carriers.
3. Pulp regeneration
Pulp regeneration is the application of the principles of tissue engineering, where pulp stem cells are cultured in vitro and implanted on a biocompatible and absorbable degradable biological scaffold to induce pulp stem cells to form pulp-dentin complexes and pulp-like tissues to repair damaged pulp tissue and restore its physiological function.
The hydrogels can be prepared in injectable form and the fluid can be injected to fully fill the pulp chamber and root canal before gelation. After the gelation reaction occurs, the formed hydrogel adheres closely to the surrounding tissue and is well suited for application in pulp regeneration studies. In addition, the hydrogel encapsulates the cells and then undergoes a sol-gel transition, which allows for a more uniform distribution of cells inside the gel and may solve the problem of exogenous cells in pulp regeneration that are difficult to penetrate deep into the scaffold within the root canal.
4. Cardiac repair
Myocardial infarction is one of the major diseases that threaten human health. After myocardial infarction, a large number of myocardial cells undergo necrosis and form scarring, leading to heart failure. The use of direct heart transplantation for cardiac repair treatment is affected by the number of donors and rejection reactions, with low success rate. Therefore, cardiac repair using cell transplantation is a more effective method for treating heart failure, but the low retention rate and low survival rate of cells after transplantation greatly limit its widespread clinical application.
Hydrogels can be composed of a variety of natural or synthetically derived polymers and assembled into a three-dimensional polymer network with high water content. These characteristics allow hydrogels to mimic the extracellular matrix environment as a vehicle for cell transplantation, promoting cell survival, proliferation, differentiation and migration, and facilitating tissue regeneration. Injectable hydrogels provide a better survival environment for transplanted cells, and in addition to meeting biocompatibility, low immunogenicity, high permeability and tunable mechanical properties, they can be infused into the myocardium via catheter for minimally invasive treatment and are an important component of cardiac tissue engineering.
5. Neural Tissue Repair
Peripheral nerve injury (PNI) causes disruption of axonal continuity, distal nerve fiber degeneration and neuronal death, resulting in loss of motor, sensory and other autonomic functions, which seriously affects patients' normal life. The traditional surgical approach to treat PNI is to use autologous nerves and artificial biomaterials for bridging repair, but the limited source of autonomic nerves and mismatch in size limit its application. Tissue scaffolds can be used as a carrier for nerve cell growth and a platform for efficient delivery of neuropharmaceuticals, which can overcome the autologous nerve problem for therapeutic nerve repair.
Natural polymer hydrogels are a class of highly biocompatible materials that resemble the human extracellular matrix environment and are a hot medical material for neural tissue repair applications in recent years. Its mechanical properties such as hardness and viscoelasticity are similar to human nerve tissues, and the dense three-dimensional structure constructed after swelling can promote nerve growth, and the hydrogel neural tissue scaffold with drug slow release function can be prepared by carrying bioactive substances. In addition, the natural polymer hydrogel can be used as a cell culture platform to orientate cells, promote nerve axon growth, and compensate for damaged neural gaps, thus repairing peripheral nerve damage.
6. Bone tissue repair
Bone defects caused by aging, disease, trauma and other factors are extremely harmful to the human body, so effective treatment methods are needed to achieve bone tissue repair and regeneration. Bone grafting is an important means of treating bone defects, however, the lack of bone grafting material sources, unsound donor bone tissue for allogeneic bone grafting, and the risk of infection and complications have limited the application of bone grafting.
Stimulus-responsive hydrogels contain the advantages of ordinary hydrogels and are capable of sensing external physicochemical stimuli such as temperature, light, pH and magnetic field, which in turn trigger transformations in properties such as three-dimensional shape and solid-liquid phase state, resulting in properties such as injectability, self-healing, and shape memory. These hydrogels can be used to carry active cells and cell growth factors and implanted into defective tissues for bone tissue damage repair and functional reconstruction.
7. Spinal Cord Injury Repair
A spinal cord injury (SCI) is damage to the spinal cord that causes temporary or permanent changes in its function. Most patients with SCI have severe sequelae such as tetraplegia and intractable neuralgia. Transplantation of mesenchymal stem cells (MSCs) is an important tool for the treatment of spinal cord injury, but the low survival rate after cell transplantation limits its further application in clinical practice.
Hydrogel materials are widely used in tissue engineering because of their good biocompatibility and biodegradability. when MSCs are combined with hydrogel, the hydrogel can stabilize the inflammatory environment at the lesion site while loading MSCs to deliver them in situ to the injured area for repair and provide a suitable environment for regeneration of the injured tissue, which has good prospects for application in SCI repair.
8. Osteoarthritis cartilage damage repair
Osteoarthritis is a degenerative disease in which chronic inflammation of cartilage tissue leads to cartilage damage through immune response and other mechanisms. Tissue engineering consisting of biological scaffolds, seed cells and favorable growth factors developed as the most promising strategy for cartilage tissue repair. However, after transplantation of seed cells, the extracellular matrix causes massive cell death due to insufficient support and inflammation, and cartilage repair does not achieve the expected results, so it is required that the biological scaffold should be biocompatible and bioresorbable, while supporting cell growth and differentiation, providing an adapted mechanical environment and allowing transport of cellular nutrients.
Hydrogels, as cross-linked hydrophilic polymers, are important biomaterials in the biomedical field with excellent biocompatibility leading to minimal inflammatory response and tissue damage. Hyaluronic acid is found throughout connective, epithelial and neural tissues and is an important component of the extracellular matrix, contributing to cell proliferation and migration. Therefore, hyaluronic acid hydrogels combining the advantages of both have good biocompatibility, biodegradability and low immunogenicity, and are widely used in cartilage repair in osteoarthritis.
9. Hydrogel-mediated delivery of interventions
Hydrogel-mediated delivery of interventions is a novel application of hydrogels in the biomedical field. Through the interfacial in situ polymerization technology of hydrogel, a thin layer of hydrogel coating is formed on the inner surface of blood vessels, thus isolating the contact between blood and injured vessel walls and inhibiting platelet deposition, thrombosis and new endothelial expansion. In addition, the bioactive hydrogel coating can promote endothelial healing by introducing bioactive factors, thus restoring the normal function of the blood vessel.
By combining conductive fillers with different types of polymer matrices, several types of conductive polymer hydrogels can be synthesized. As a new functional hydrogel material, conductive hydrogels are favored by researchers, and scientists have used conductive hydrogels to develop capacitive sensors for applications in monitoring human activities. Experimental results have shown that the conductive hydrogel capacitive sensors exhibit sensitive response behavior to different strengths of finger touch and different degrees of finger bending deformation.
As a new functional material, hydrogels and their derivatives are increasingly used in the pharmaceutical field because of their flexibility, high water absorption and retention, good biocompatibility, and other characteristics, coupled with the specific properties given by research scholars by means of modification and compounding. However, hydrogel materials also have the shortcomings of low mechanical properties and weak tissue adhesion.
In future research, for the biomedical field, hydrogels can be considered from the following three aspects of in-depth research: first, improve the mechanical properties to meet the demand of its application in tissue engineering; second, in-depth compound modification research with other materials to develop better properties (such as rapid degradation, biocompatibility, etc.) for medical applications; third, combined with new molding means, such as 3D printing technology, to prepare a personalized hydrogel.
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