Hydrogel

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Gelatin, here in sheets for cooking, is a hydrogel. Gelatine.png
Gelatin, here in sheets for cooking, is a hydrogel.
Peptide hydrogel formation shown by the inverted vial method. Picture of peptide hydrogel formation shown by the inverted vial method.jpg
Peptide hydrogel formation shown by the inverted vial method.

A hydrogel is a biphasic material, a mixture of porous and permeable solids and at least 10% of water or other interstitial fluid. [1] [2] The solid phase is a water insoluble three dimensional network of polymers, having absorbed a large amount of water or biological fluids. [2] [3] [4] [5] Hydrogels have several applications, especially in the biomedical area, such as in hydrogel dressing. Many hydrogels are synthetic, but some are derived from natural materials. [6] [7] The term "hydrogel" was coined in 1894. [8]

Contents

IUPAC definition for a hydrogel IUPAC definition for a hydrogel.png
IUPAC definition for a hydrogel

Chemistry

Classification

The crosslinks which bond the polymers of a hydrogel fall under two general categories: physical hydrogels and chemical hydrogels. Chemical hydrogels have covalent cross-linking bonds, whereas physical hydrogels have non-covalent bonds.[ citation needed ] Chemical hydrogels can result in strong reversible or irreversible gels due to the covalent bonding. [9] Chemical hydrogels that contain reversible covalent cross-linking bonds, such as hydrogels of thiomers being cross-linked via disulfide bonds, are non-toxic and are used in numerous medicinal products. [10] [11] [12] Physical hydrogels usually have high biocompatibility, are not toxic, and are also easily reversible by simply changing an external stimulus such as pH, ion concentration (alginate) or temperature (gelatine); they are also used for medical applications. [13] [14] [15] [16] [17] Physical crosslinks consist of hydrogen bonds, hydrophobic interactions, and chain entanglements (among others). A hydrogel generated through the use of physical crosslinks is sometimes called a 'reversible' hydrogel. [13] Chemical crosslinks consist of covalent bonds between polymer strands. Hydrogels generated in this manner are sometimes called 'permanent' hydrogels.

Hydrogels are prepared using a variety of polymeric materials, which can be divided broadly into two categories according to their origin: natural or synthetic polymers. Natural polymers for hydrogel preparation include hyaluronic acid, chitosan, heparin, alginate, gelatin and fibrin. [18] Common synthetic polymers include polyvinyl alcohol, polyethylene glycol, sodium polyacrylate, acrylate polymers and copolymers thereof. [6] Whereas natural hydrogels are usually non-toxic, and often provide other advantages for medical use, such as biocompatibility, biodegradability, antibiotic/antifungal effect and improve regeneration of nearby tissue, their stability and strength is usually much lower than synthetic hydrogels. [19] There are also synthetic hydrogels that can be used for medical applications, such as polyethylene glycol (PEG), polyacrylate, and polyvinylpyrrolidone (PVP). [20]

Preparation

Simplified scheme to show the self-assembly process involved in hydrogel formation. Peptide hydrogel formation simplified scheme.png
Simplified scheme to show the self-assembly process involved in hydrogel formation.

There are two suggested mechanisms behind physical hydrogel formation, the first one being the gelation of nanofibrous peptide assemblies, usually observed for oligopeptide precursors. The precursors self-assemble into fibers, tapes, tubes, or ribbons that entangle to form non-covalent cross-links. The second mechanism involves non-covalent interactions of cross-linked domains that are separated by water-soluble linkers, and this is usually observed in longer multi-domain structures. [21] Tuning of the supramolecular interactions to produce a self-supporting network that does not precipitate, and is also able to immobilize water which is vital for to gel formation. Most oligopeptide hydrogels have a β-sheet structure, and assemble to form fibers, although α-helical peptides have also been reported. [22] [23] The typical mechanism of gelation involves the oligopeptide precursors self-assemble into fibers that become elongated, and entangle to form cross-linked gels.

One notable method of initiating a polymerization reaction involves the use of light as a stimulus. In this method, photoinitiators, compounds that cleave from the absorption of photons, are added to the precursor solution which will become the hydrogel. When the precursor solution is exposed to a concentrated source of light, usually ultraviolet irradiation, the photoinitiators will cleave and form free radicals, which will begin a polymerization reaction that forms crosslinks between polymer strands. This reaction will cease if the light source is removed, allowing the amount of crosslinks formed in the hydrogel to be controlled. [24] The properties of a hydrogel are highly dependent on the type and quantity of its crosslinks, making photopolymerization a popular choice for fine-tuning hydrogels. This technique has seen considerable use in cell and tissue engineering applications due to the ability to inject or mold a precursor solution loaded with cells into a wound site, then solidify it in situ. [25] [24]

Physically crosslinked hydrogels can be prepared by different methods depending on the nature of the crosslink involved. Polyvinyl alcohol hydrogels are usually produced by the freeze-thaw technique. In this, the solution is frozen for a few hours, then thawed at room temperature, and the cycle is repeated until a strong and stable hydrogel is formed. [26] Alginate hydrogels are formed by ionic interactions between alginate and double-charged cations. A salt, usually calcium chloride, is dissolved into an aqueous sodium alginate solution, that causes the calcium ions to create ionic bonds between alginate chains. [27] Gelatin hydrogels are formed by temperature change. A water solution of gelatin forms an hydrogel at temperatures below 37–35 °C, as Van der Waals interactions between collagen fibers become stronger than thermal molecular vibrations. [28]

Peptide based hydrogels

Peptide based hydrogels possess exceptional biocompatibility and biodegradability qualities, giving rise to their wide use of applications, particularly in biomedicine; [2] as such, their physical properties can be fine-tuned in order to maximise their use. [2] Methods to do this are: modulation of the amino acid sequence, pH, chirality, and increasing the number of aromatic residues. [29] The order of amino acids within the sequence is crucial for gelation, as has been shown many times. In one example, a short peptide sequence Fmoc-Phe-Gly readily formed a hydrogel, whereas Fmoc-Gly-Phe failed to do so as a result of the two adjacent aromatic moieties being moved, hindering the aromatic interactions. [30] [31] Altering the pH can also have similar effects, an example involved the use of the naphthalene (Nap) modified dipeptides Nap-Gly-Ala, and Nap- Ala-Gly, where a drop in pH induced gelation of the former, but led to crystallisation of the latter. [32] A controlled pH decrease method using glucono-δ-lactone (GdL), where the GdL is hydrolysed to gluconic acid in water is a recent strategy that has been developed as a way to form homogeneous and reproducible hydrogels. [33] [34] The hydrolysis is slow, which allows for a uniform pH change, and thus resulting in reproducible homogenous gels. In addition to this, the desired pH can be achieved by altering the amount of GdL added. The use of GdL has been used various times for the hydrogelation of Fmoc and Nap-dipeptides. [33] [34] In another direction, Morris et al reported the use of GdL as a 'molecular trigger' to predict and control the order of gelation. [35] Chirality also plays an essential role in gel formation, and even changing the chirality of a single amino acid from its natural L-amino acid to its unnatural D-amino acid can significantly impact the gelation properties, with the natural forms not forming gels. [36] Furthermore, aromatic interactions play a key role in hydrogel formation as a result of π- π stacking driving gelation, shown by many studies. [37] [38]

Other

Hydrogels also possess a degree of flexibility very similar to natural tissue due to their significant water content. As responsive "smart materials", hydrogels can encapsulate chemical systems which upon stimulation by external factors such as a change of pH may cause specific compounds such as glucose to be liberated to the environment, in most cases by a gel–sol transition to the liquid state. Chemomechanical polymers are mostly also hydrogels, which upon stimulation change their volume and can serve as actuators or sensors.

Mechanical properties

Hydrogels have been investigated for diverse applications. By modifying the polymer concentration of a hydrogel (or conversely, the water concentration), the Young's modulus, shear modulus, and storage modulus can vary from 10 Pa to 3 MPa, a range of about five orders of magnitude. [40] A similar effect can be seen by altering the crosslinking concentration. [40] This much variability of the mechanical stiffness is why hydrogels are so appealing for biomedical applications, where it is vital for implants to match the mechanical properties of the surrounding tissues. [41] Characterizing the mechanical properties of hydrogels can be difficult especially due to the differences in mechanical behavior that hydrogels have in comparison to other traditional engineering materials. In addition to its rubber elasticity and viscoelasticity, hydrogels have an additional time dependent deformation mechanism which is dependent on fluid flow called poroelasticity. These properties are extremely important to consider while performing mechanical experiments. Some common mechanical testing experiments for hydrogels are tension, compression (confined or unconfined), indentation, shear rheometry or dynamic mechanical analysis. [40]

Hydrogels have two main regimes of mechanical properties: rubber elasticity and viscoelasticity:

Rubber elasticity

In the unswollen state, hydrogels can be modelled as highly crosslinked chemical gels, in which the system can be described as one continuous polymer network. In this case:

where G is the shear modulus, k is the Boltzmann constant, T is temperature, Np is the number of polymer chains per unit volume, ρ is the density, R is the ideal gas constant, and  is the (number) average molecular weight between two adjacent cross-linking points. can be calculated from the swell ratio, Q, which is relatively easy to test and measure. [40]

For the swollen state, a perfect gel network can be modeled as: [40]

In a simple uniaxial extension or compression test, the true stress, , and engineering stress, , can be calculated as:

where  is the stretch. [40]

Viscoelasticity

For hydrogels, their elasticity comes from the solid polymer matrix while the viscosity originates from the polymer network mobility and the water and other components that make up the aqueous phase. [42] Viscoelastic properties of a hydrogel is highly dependent on the nature of the applied mechanical motion. Thus, the time dependence of these applied forces is extremely important for evaluating the viscoelasticity of the material. [43]

Physical models for viscoelasticity attempt to capture the elastic and viscous material properties of a material. In an elastic material, the stress is proportional to the strain while in a viscous material, the stress is proportional to the strain rate. The Maxwell model is one developed mathematical model for linear viscoelastic response. In this model, viscoelasticity is modeled analogous to an electrical circuit with a Hookean spring, that represents the Young's modulus, and a Newtonian dashpot that represents the viscosity. A material that exhibit properties described in this model is a Maxwell material. Another physical model used is called the Kelvin-Voigt Model and a material that follow this model is called a Kelvin–Voigt material. [44] In order to describe the time-dependent creep and stress-relaxation behavior of hydrogel, a variety of physical lumped parameter models can be used. [40] These modeling methods vary greatly and are extremely complex, so the empirical Prony Series description is commonly used to describe the viscoelastic behavior in hydrogels. [40]

In order to measure the time-dependent viscoelastic behavior of polymers dynamic mechanical analysis is often performed. Typically, in these measurements the one side of the hydrogel is subjected to a sinusoidal load in shear mode while the applied stress is measured with a stress transducer and the change in sample length is measured with a strain transducer. [43] One notation used to model the sinusoidal response to the periodic stress or strain is:

in which G' is the real (elastic or storage) modulus, G" is the imaginary (viscous or loss) modulus.

Poroelasticity

Poroelasticity is a characteristic of materials related to the migration of solvent through a porous material and the concurrent deformation that occurs. [40] Poroelasticity in hydrated materials such as hydrogels occurs due to friction between the polymer and water as the water moves through the porous matrix upon compression. This causes a decrease in water pressure, which adds additional stress upon compression. Similar to viscoelasticity, this behavior is time dependent, thus poroelasticity is dependent on compression rate: a hydrogel shows softness upon slow compression, but fast compression makes the hydrogel stiffer. This phenomenon is due to the friction between the water and the porous matrix is proportional to the flow of water, which in turn is dependent on compression rate. Thus, a common way to measure poroelasticity is to do compression tests at varying compression rates. [45] Pore size is an important factor in influencing poroelasticity. The Kozeny–Carman equation has been used to predict pore size by relating the pressure drop to the difference in stress between two compression rates. [45]

Poroelasticity is described by several coupled equations, thus there are few mechanical tests that relate directly to the poroelastic behavior of the material, thus more complicated tests such as indentation testing, numerical or computational models are utilized. Numerical or computational methods attempt to simulate the three dimensional permeability of the hydrogel network.

Toughness and hysteresis

The toughness of a hydrogel refers to the ability of the hydrogel to withstand deformation or mechanical stress without fracturing or breaking apart. A hydrogel with high toughness can maintain its structural integrity and functionality under higher stress. Several factors contribute to the toughness of a hydrogel including composition, crosslink density, polymer chain structure, and hydration level. The toughness of a hydrogel is highly dependent on what polymer(s) and crosslinker(s) make up its matrix as certain polymers possess higher toughness and certain crosslinking covalent bonds are inherently stronger. [46] Additionally, higher crosslinking density generally leads to increased toughness by restricting polymer chain mobility and enhancing resistance to deformation. The structure of the polymer chains is also a factor in that, longer chain lengths and higher molecular weight leads to a greater number of entanglements and higher toughness. [47] A good balance (equilibrium) in the hydration of a hydrogel leads is important because too low hydration causes poor flexibility and toughness within the hydrogel, but too high of water content can cause excessive swelling, weakening the mechanical properties of the hydrogel. [48] [49]

Model of Hysteresis Loop R. V. Lapshin, Model of hysteresis loop, Fig.16.png
Model of Hysteresis Loop

The hysteresis of a hydrogel refers to the phenomenon where there is a delay in the deformation and recovery of a hydrogel when it is subjected to mechanical stress and relieved of that stress. This occurs because the polymer chains within a hydrogel rearrange, and the water molecules are displaced, and energy is stored as it deforms in mechanical extension or compression. [50] When the mechanical stress is removed, the hydrogel begins to recover its original shape, but there may be a delay in the recovery process due to factors like viscoelasticity, internal friction, etc. [51] This leads to a difference between the stress-strain curve during loading and unloading. Hysteresis within a hydrogel is influenced by several factors including composition, crosslink density, polymer chain structure, and temperature.

The toughness and hysteresis of a hydrogel are especially important in the context of biomedical applications such as tissue engineering and drug delivery, as the hydrogel may need to withstand mechanical forces within the body, but also maintain mechanical performance and stability over time. [52] Most typical hydrogels, both natural and synthetic, have a positive correlation between toughness and hysteresis, meaning that the higher the toughness, the longer the hydrogel takes to recover its original shape and vice versa. [47] This is largely due to sacrificial bonds being the source of toughness within many of these hydrogels. Sacrificial bonds are non-covalent interactions such as hydrogen bonds, ionic interactions, and hydrophobic interactions, that can break and reform under mechanical stress. [53] The reforming of these bonds takes time, especially when there are more of them, which leads to an increase in hysteresis. However, there is currently research focused on the development of highly entangled hydrogels, which instead rely on the long chain length of the polymers and their entanglement to limit the deformation of the hydrogel, thereby increasing the toughness without increasing hysteresis as there is no need for the reformation of the bonds. [47]

Environmental response

The most commonly seen environmental sensitivity in hydrogels is a response to temperature. [54] Many polymers/hydrogels exhibit a temperature dependent phase transition, which can be classified as either an upper critical solution temperature (UCST) or lower critical solution temperature (LCST). UCST polymers increase in their water-solubility at higher temperatures, which lead to UCST hydrogels transitioning from a gel (solid) to a solution (liquid) as the temperature is increased (similar to the melting point behavior of pure materials). This phenomenon also causes UCST hydrogels to expand (increase their swell ratio) as temperature increases while they are below their UCST. [54] However, polymers with LCSTs display an inverse (or negative) temperature-dependence, where their water-solubility decreases at higher temperatures. LCST hydrogels transition from a liquid solution to a solid gel as the temperature is increased, and they also shrink (decrease their swell ratio) as the temperature increases while they are above their LCST. [54]

Applications can dictate for diverse thermal responses. For example, in the biomedical field, LCST hydrogels are being investigated as drug delivery systems due to being injectable (liquid) at room temp and then solidifying into a rigid gel upon exposure to the higher temperatures of the human body. [54] There are many other stimuli that hydrogels can be responsive to, including: pH, glucose, electrical signals, light, pressure, ions, antigens, and more. [54]

Additives

The mechanical properties of hydrogels can be fine-tuned in many ways beginning with attention to their hydrophobic properties. [54] [55] Another method of modifying the strength or elasticity of hydrogels is to graft or surface coat them onto a stronger/stiffer support, or by making superporous hydrogel (SPH) composites, in which a cross-linkable matrix swelling additive is added. [7] Other additives, such as nanoparticles and microparticles, have been shown to significantly modify the stiffness and gelation temperature of certain hydrogels used in biomedical applications. [56] [57] [58]

Processing techniques

While a hydrogel's mechanical properties can be tuned and modified through crosslink concentration and additives, these properties can also be enhanced or optimized for various applications through specific processing techniques. These techniques include electro-spinning, 3D/4D printing, self-assembly, and freeze-casting. One unique processing technique is through the formation of multi-layered hydrogels to create a spatially-varying matrix composition and by extension, mechanical properties. This can be done by polymerizing the hydrogel matrixes in a layer by layer fashion via UV polymerization. This technique can be useful in creating hydrogels that mimic articular cartilage, enabling a material with three separate zones of distinct mechanical properties. [59]

Another emerging technique to optimize hydrogel mechanical properties is by taking advantage of the Hofmeister series. Due to this phenomenon, through the addition of salt solution, the polymer chains of a hydrogel aggregate and crystallize, which increases the toughness of the hydrogel. This method, called "salting out", has been applied to poly(vinyl alcohol) hydrogels by adding a sodium sulfate salt solution. [60] Some of these processing techniques can be used synergistically with each other to yield optimal mechanical properties. Directional freezing or freeze-casting is another method in which a directional temperature gradient is applied to the hydrogel is another way to form materials with anisotropic mechanical properties. Utilizing both the freeze-casting and salting-out processing techniques on poly(vinyl alcohol) hydrogels to induce hierarchical morphologies and anisotropic mechanical properties. [61] Directional freezing of the hydrogels helps to align and coalesce the polymer chains, creating anisotropic array honeycomb tube-like structures while salting out the hydrogel yielded out a nano-fibril network on the surface of these honeycomb tube-like structures. While maintaining a water content of over 70%, these hydrogels' toughness values are well above those of water-free polymers such as polydimethylsiloxane (PDMS), Kevlar, and synthetic rubber. The values also surpass the toughness of natural tendon and spider silk. [61]

Applications

Soft contact lenses

Molecular structure of silicone hydrogel used in flexible, oxygen-permeable contact lenses. Siliconehydrogel.svg
Molecular structure of silicone hydrogel used in flexible, oxygen-permeable contact lenses.

The dominant material for contact lenses are acrylate-siloxane hydrogels. They have replaced hard contact lenses. One of their most attractive properties is oxygen permeability, which is required since the cornea lacks vasculature.

Research

Human mesenchymal stem cell interacting with 3D hydrogel - imaged with label-free live cell imaging Hydrogel MSC Nanolive.gif
Human mesenchymal stem cell interacting with 3D hydrogel - imaged with label-free live cell imaging
An adhesive bandage with a hydrogel pad, used for blisters and burns. The central gel is clear, the adhesive waterproof plastic film is clear, the backing is white and blue. Blasenpflaster.jpg
An adhesive bandage with a hydrogel pad, used for blisters and burns. The central gel is clear, the adhesive waterproof plastic film is clear, the backing is white and blue.

Biomaterials

Implanted or injected hydrogels have the potential to support tissue regeneration by mechanical tissue support, localized drug or cell delivery, [2] local cell recruitement or immunomodulation, or encapsulation of nanoparticles for local photothermal therapy or brachytherapy. [80] Polymeric drug delivery systems have overcome challenges due to their biodegradability, biocompatibility, and anti-toxicity. [91] [92] Materials such as collagen, chitosan, cellulose, and poly (lactic-co-glycolic acid) have been implemented extensively for drug delivery to organs such as eye, [93] nose, kidneys, [94] lungs, [95] intestines, [96] skin [97] and brain. [2] Future work is focused on reducing toxicity, improving biocompatibility, expanding assembly techniques [98]

Hydrogels have been considered as vehicles for drug delivery. [99] [77] [78] [79] They can also be made to mimic animal mucosal tissues to be used for testing mucoadhesive properties. [100] [101] They have been examined for use as reservoirs in topical drug delivery; particularly ionic drugs, delivered by iontophoresis.

Related Research Articles

<span class="mw-page-title-main">Biopolymer</span> Polymer produced by a living organism

Biopolymers are natural polymers produced by the cells of living organisms. Like other polymers, biopolymers consist of monomeric units that are covalently bonded in chains to form larger molecules. There are three main classes of biopolymers, classified according to the monomers used and the structure of the biopolymer formed: polynucleotides, polypeptides, and polysaccharides. The Polynucleotides, RNA and DNA, are long polymers of nucleotides. Polypeptides include proteins and shorter polymers of amino acids; some major examples include collagen, actin, and fibrin. Polysaccharides are linear or branched chains of sugar carbohydrates; examples include starch, cellulose, and alginate. Other examples of biopolymers include natural rubbers, suberin and lignin, cutin and cutan, melanin, and polyhydroxyalkanoates (PHAs).

<span class="mw-page-title-main">Gel</span> Highly viscous liquid exhibiting a kind of semi-solid behavior

A gel is a semi-solid that can have properties ranging from soft and weak to hard and tough. Gels are defined as a substantially dilute cross-linked system, which exhibits no flow when in the steady state, although the liquid phase may still diffuse through this system.

<span class="mw-page-title-main">Soft matter</span> Subfield of condensed matter physics

Soft matter or soft condensed matter is a type of matter that can be deformed or structurally altered by thermal or mechanical stress which is of similar magnitude to thermal fluctuations.

<span class="mw-page-title-main">Chitosan</span> Chemical compound

Chitosan is a linear polysaccharide composed of randomly distributed β-(1→4)-linked D-glucosamine and N-acetyl-D-glucosamine. It is made by treating the chitin shells of shrimp and other crustaceans with an alkaline substance, such as sodium hydroxide.

<span class="mw-page-title-main">Alginic acid</span> Polysaccharide found in brown algae

Alginic acid, also called algin, is a naturally occurring, edible polysaccharide found in brown algae. It is hydrophilic and forms a viscous gum when hydrated. When the alginic acid binds with sodium and calcium ions, the resulting salts are known as alginates. Its colour ranges from white to yellowish-brown. It is sold in filamentous, granular, or powdered forms.

<span class="mw-page-title-main">Nanofiber</span> Natural or synthetic fibers with diameters in the nanometer range

Nanofibers are fibers with diameters in the nanometer range. Nanofibers can be generated from different polymers and hence have different physical properties and application potentials. Examples of natural polymers include collagen, cellulose, silk fibroin, keratin, gelatin and polysaccharides such as chitosan and alginate. Examples of synthetic polymers include poly(lactic acid) (PLA), polycaprolactone (PCL), polyurethane (PU), poly(lactic-co-glycolic acid) (PLGA), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), and poly(ethylene-co-vinylacetate) (PEVA). Polymer chains are connected via covalent bonds. The diameters of nanofibers depend on the type of polymer used and the method of production. All polymer nanofibers are unique for their large surface area-to-volume ratio, high porosity, appreciable mechanical strength, and flexibility in functionalization compared to their microfiber counterparts.

<span class="mw-page-title-main">Biomaterial</span> Any substance that has been engineered to interact with biological systems for a medical purpose

A biomaterial is a substance that has been engineered to interact with biological systems for a medical purpose – either a therapeutic or a diagnostic one. The corresponding field of study, called biomaterials science or biomaterials engineering, is about fifty years old. It has experienced steady growth over its history, with many companies investing large amounts of money into the development of new products. Biomaterials science encompasses elements of medicine, biology, chemistry, tissue engineering and materials science.

Thiolated polymers – designated thiomers – are functional polymers used in biotechnology product development with the intention to prolong mucosal drug residence time and to enhance absorption of drugs. The name thiomer was coined by Andreas Bernkop-Schnürch in 2000. Thiomers have thiol bearing side chains. Sulfhydryl ligands of low molecular mass are covalently bound to a polymeric backbone consisting of mainly biodegradable polymers, such as chitosan, hyaluronic acid, cellulose derivatives, pullulan, starch, gelatin, polyacrylates, cyclodextrins, or silicones.

Poly(N-isopropylacrylamide) (variously abbreviated PNIPA, PNIPAM, PNIPAAm, NIPA, PNIPAA or PNIPAm) is a temperature-responsive polymer that was first synthesized in the 1950s. It can be synthesized from N-isopropylacrylamide which is commercially available. It is synthesized via free-radical polymerization and is readily functionalized making it useful in a variety of applications.

<span class="mw-page-title-main">Temperature-responsive polymer</span> Polymer showing drastic changes in physical properties with temperature

Temperature-responsive polymers or thermoresponsive polymers are polymers that exhibit drastic and discontinuous changes in their physical properties with temperature. The term is commonly used when the property concerned is solubility in a given solvent, but it may also be used when other properties are affected. Thermoresponsive polymers belong to the class of stimuli-responsive materials, in contrast to temperature-sensitive materials, which change their properties continuously with environmental conditions. In a stricter sense, thermoresponsive polymers display a miscibility gap in their temperature-composition diagram. Depending on whether the miscibility gap is found at high or low temperatures, either an upper critical solution temperature (UCST) or a lower critical solution temperature (LCST) exists.

A nanogel is a polymer-based, crosslinked hydrogel particle on the sub-micron scale. These complex networks of polymers present a unique opportunity in the field of drug delivery at the intersection of nanoparticles and hydrogel synthesis. Nanogels can be natural, synthetic, or a combination of the two and have a high degree of tunability in terms of their size, shape, surface functionalization, and degradation mechanisms. Given these inherent characteristics in addition to their biocompatibility and capacity to encapsulate small drugs and molecules, nanogels are a promising strategy to treat disease and dysfunction by serving as delivery vehicles capable of navigating across challenging physiological barriers within the body. 

A fibrin scaffold is a network of protein that holds together and supports a variety of living tissues. It is produced naturally by the body after injury, but also can be engineered as a tissue substitute to speed healing. The scaffold consists of naturally occurring biomaterials composed of a cross-linked fibrin network and has a broad use in biomedical applications.

Materials that are used for biomedical or clinical applications are known as biomaterials. The following article deals with fifth generation biomaterials that are used for bone structure replacement. For any material to be classified for biomedical applications, three requirements must be met. The first requirement is that the material must be biocompatible; it means that the organism should not treat it as a foreign object. Secondly, the material should be biodegradable ; the material should harmlessly degrade or dissolve in the body of the organism to allow it to resume natural functioning. Thirdly, the material should be mechanically sound; for the replacement of load-bearing structures, the material should possess equivalent or greater mechanical stability to ensure high reliability of the graft.

<span class="mw-page-title-main">Self-healing hydrogels</span> Type of hydrogel

Self-healing hydrogels are a specialized type of polymer hydrogel. A hydrogel is a macromolecular polymer gel constructed of a network of crosslinked polymer chains. Hydrogels are synthesized from hydrophilic monomers by either chain or step growth, along with a functional crosslinker to promote network formation. A net-like structure along with void imperfections enhance the hydrogel's ability to absorb large amounts of water via hydrogen bonding. As a result, hydrogels, self-healing alike, develop characteristic firm yet elastic mechanical properties. Self-healing refers to the spontaneous formation of new bonds when old bonds are broken within a material. The structure of the hydrogel along with electrostatic attraction forces drive new bond formation through reconstructive covalent dangling side chain or non-covalent hydrogen bonding. These flesh-like properties have motivated the research and development of self-healing hydrogels in fields such as reconstructive tissue engineering as scaffolding, as well as use in passive and preventive applications.

Nanocomposite hydrogels are nanomaterial-filled, hydrated, polymeric networks that exhibit higher elasticity and strength relative to traditionally made hydrogels. A range of natural and synthetic polymers are used to design nanocomposite network. By controlling the interactions between nanoparticles and polymer chains, a range of physical, chemical, and biological properties can be engineered. The combination of organic (polymer) and inorganic (clay) structure gives these hydrogels improved physical, chemical, electrical, biological, and swelling/de-swelling properties that cannot be achieved by either material alone. Inspired by flexible biological tissues, researchers incorporate carbon-based, polymeric, ceramic and/or metallic nanomaterials to give these hydrogels superior characteristics like optical properties and stimulus-sensitivity which can potentially be very helpful to medical and mechanical fields.

Hydrogel dressing is a medical dressing based on hydrogels, three-dimensional hydrophilic structure. The insoluble hydrophilic structures absorb polar wound exudates and allow oxygen diffusion at the wound bed to accelerate healing. Hydrogel dressings can be designed to prevent bacterial infection, retain moisture, promote optimum adhesion to tissues, and satisfy the basic requirements of biocompatibility. Hydrogel dressings can also be designed to respond to changes in the microenvironment at the wound bed. Hydrogel dressings should promote an appropriate microenvironment for angiogenesis, recruitment of fibroblasts, and cellular proliferation.

Bio-inks are materials used to produce engineered/artificial live tissue using 3D printing. These inks are mostly composed of the cells that are being used, but are often used in tandem with additional materials that envelope the cells. The combination of cells and usually biopolymer gels are defined as a bio-ink. They must meet certain characteristics, including such as rheological, mechanical, biofunctional and biocompatibility properties, among others. Using bio-inks provides a high reproducibility and precise control over the fabricated constructs in an automated manner. These inks are considered as one of the most advanced tools for tissue engineering and regenerative medicine (TERM).

<span class="mw-page-title-main">Hydrogel fiber</span>

Hydrogel fiber is a hydrogel made into a fibrous state, where its width is significantly smaller than its length. The hydrogel's specific surface area at fibrous form is larger than that of the bulk hydrogel, and its mechanical properties also changed accordingly. As a result of these changes, hydrogel fiber has a faster matter exchange rate and can be woven into different structures.

Bioprinting drug delivery is a method for producing drug delivery vehicles. It uses three-dimensional printing of biomaterials via additive manufacturing. Such vehicles are biocompatible, tissue-specific hydrogels or implantable devices. 3D bioprinting prints cells and biological molecules to form tissues, organs, or biological materials in a scaffold-free manner that mimics living human tissue. The technique allows targeted disease treatments with scalable and complex geometry.

Ultrasound-triggered drug delivery using stimuli-responsive hydrogels refers to the process of using ultrasound energy for inducing drug release from hydrogels that are sensitive to acoustic stimuli. This method of approach is one of many stimuli-responsive drug delivery-based systems that has gained traction in recent years due to its demonstration of localization and specificity of disease treatment. Although recent developments in this field highlight its potential in treating certain diseases such as COVID-19, there remain many major challenges that need to be addressed and overcome before more related biomedical applications are clinically translated into standard of care.

References

Creative Commons by small.svg  This article incorporates text by Jessica Hutchinson available under the CC BY 3.0 license.

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