porous
Porosity or void fraction is a measure of the void (i.e. "empty") spaces in a material, and is a fraction of the volume of voids over the total volume, between 0 and 1, or as a percentage between 0% and 100%. Strictly speaking, some tests measure ...
and permeable solids and at least 10% of water or other
interstitial fluid
In cell biology, extracellular fluid (ECF) denotes all body fluid outside the Cell (biology), cells of any multicellular organism. Body water, Total body water in healthy adults is about 50–60% (range 45 to 75%) of total body weight; women ...
. The solid phase is a water
insoluble
In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution.
The extent of the solub ...
three dimensional network of
polymer
A polymer () is a chemical substance, substance or material that consists of very large molecules, or macromolecules, that are constituted by many repeat unit, repeating subunits derived from one or more species of monomers. Due to their br ...
s, having absorbed a large amount of water or biological fluids. 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. The term "hydrogel" was coined in 1894.
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. Chemical hydrogels can result in strong reversible or irreversible gels due to the covalent bonding. Chemical hydrogels that contain reversible covalent cross-linking bonds, such as hydrogels of
thiomer 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-S ...
s being cross-linked via disulfide bonds, are non-toxic and are used in numerous medicinal products. 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
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 k ...
) or temperature (
gelatin
Gelatin or gelatine () is a translucent, colorless, flavorless food ingredient, commonly derived from collagen taken from animal body parts. It is brittle when dry and rubbery when moist. It may also be referred to as hydrolyzed collagen, coll ...
e); they are also used for medical applications. Physical crosslinks consist of
hydrogen bond
In chemistry, a hydrogen bond (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently b ...
s,
hydrophobic interactions
The hydrophobic effect is the observed tendency of nonpolar substances to aggregate in an aqueous solution and to be excluded by water. The word hydrophobic literally means "water-fearing", and it describes the segregation of water and nonpolar ...
, and chain entanglements (among others). A hydrogel generated through the use of physical crosslinks is sometimes called a 'reversible' hydrogel. 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
Hyaluronic acid (; abbreviated HA; conjugate base hyaluronate), also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminog ...
,
chitosan
Chitosan is a linear polysaccharide composed of randomly distributed β-(1→4)-linked D-glucosamine (deacetylated unit) and ''N''-acetyl-D-glucosamine (acetylated unit). It is made by treating the chitin shells of shrimp and other crusta ...
,
heparin
Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Heparin is a blood anticoagulant that increases the activity of antithrombin. It is used in the treatment of myocardial infarction, ...
,
alginate
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 k ...
,
gelatin
Gelatin or gelatine () is a translucent, colorless, flavorless food ingredient, commonly derived from collagen taken from animal body parts. It is brittle when dry and rubbery when moist. It may also be referred to as hydrolyzed collagen, coll ...
and
fibrin
Fibrin (also called Factor Ia) is a fibrous protein, fibrous, non-globular protein involved in the Coagulation, clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerization, polymerize. ...
. Common synthetic polymers include
polyvinyl alcohol
Polyvinyl alcohol (PVOH, PVA, or PVAl) is a water- soluble synthetic polymer. It has the idealized formula H2CH(OH)sub>''n''. It is used in papermaking, textile warp sizing, as a thickener and emulsion stabilizer in polyvinyl acetate (PVAc) a ...
,
polyethylene glycol
Polyethylene glycol (PEG; ) is a polyether compound derived from petroleum with many applications, from industrial manufacturing to medicine. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on its molecular wei ...
acrylate polymer
An acrylate polymer (also known as acrylic or polyacrylate) is any of a group of polymers prepared from acrylate monomers. These plastics are noted for their transparency, resistance to breakage, and elasticity.
Acrylate polymer is commonly used ...
s and
copolymer
In polymer chemistry, a copolymer is a polymer derived from more than one species of monomer. The polymerization of monomers into copolymers is called copolymerization. Copolymers obtained from the copolymerization of two monomer species are som ...
s thereof. Whereas natural hydrogels are usually non-toxic, and often provide other advantages for medical use, such as
biocompatibility
Biocompatibility is related to the behavior of biomaterials in various contexts. The term refers to the ability of a material to perform with an appropriate host response in a specific situation. The ambiguity of the term reflects the ongoin ...
antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...
/
antifungal
An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as ...
effect and improve regeneration of nearby tissue, their
stability
Stability may refer to:
Mathematics
*Stability theory, the study of the stability of solutions to differential equations and dynamical systems
** Asymptotic stability
** Exponential stability
** Linear stability
**Lyapunov stability
** Marginal s ...
and
strength
Strength may refer to:
Personal trait
*Physical strength, as in people or animals
*Character strengths like those listed in the Values in Action Inventory
*The exercise of willpower
Physics
* Mechanical strength, the ability to withstand ...
is usually much lower than synthetic hydrogels. There are also synthetic hydrogels that can be used for medical applications, such as polyethylene glycol (PEG),
polyacrylate
An acrylate polymer (also known as acrylic or polyacrylate) is any of a group of polymers prepared from acrylate monomers. These plastics are noted for their transparency, resistance to breakage, and elasticity.
Acrylate polymer is commonly used ...
There are two suggested mechanisms behind physical hydrogel formation, the first one being the gelation of nanofibrous
peptide
Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...
assemblies, usually observed for
oligopeptide
An oligopeptide ('' oligo-'', "a few"), is a peptide consisting of two to twenty amino acids, including dipeptides, tripeptides, tetrapeptides, and other polypeptides. Some of the major classes of naturally occurring oligopeptides include aerugi ...
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. 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. 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,
photoinitiator
In chemistry, a photoinitiator is a molecule that creates reactive species (free radicals, cations or anions) when exposed to radiation (Ultraviolet, UV or Visible spectrum, visible). Synthetic photoinitiators are key components in photopolymers ...
s, 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
Ultraviolet radiation, also known as simply UV, is electromagnetic radiation of wavelengths of 10–400 nanometers, shorter than that of visible light, but longer than X-rays. UV radiation is present in sunlight and constitutes about 10% of ...
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. The properties of a hydrogel are highly dependent on the type and quantity of its crosslinks, making
photopolymerization
In polymer chemistry, polymerization (American English), or polymerisation (British English), is a process of reacting monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks. There are many form ...
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.
Physically crosslinked hydrogels can be prepared by different methods depending on the nature of the crosslink involved.
Polyvinyl alcohol
Polyvinyl alcohol (PVOH, PVA, or PVAl) is a water- soluble synthetic polymer. It has the idealized formula H2CH(OH)sub>''n''. It is used in papermaking, textile warp sizing, as a thickener and emulsion stabilizer in polyvinyl acetate (PVAc) a ...
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.
Alginate
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 k ...
hydrogels are formed by ionic interactions between alginate and double-charged cations. A salt, usually
calcium chloride
Calcium chloride is an inorganic compound, a Salt (chemistry), salt with the chemical formula . It is a white crystalline solid at room temperature, and it is highly soluble in water. It can be created by neutralising hydrochloric acid with cal ...
, is dissolved into an aqueous sodium alginate solution, that causes the calcium ions to create ionic bonds between alginate chains.
Gelatin
Gelatin or gelatine () is a translucent, colorless, flavorless food ingredient, commonly derived from collagen taken from animal body parts. It is brittle when dry and rubbery when moist. It may also be referred to as hydrolyzed collagen, coll ...
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.
Peptide based hydrogels
Peptide based hydrogels possess exceptional
biocompatibility
Biocompatibility is related to the behavior of biomaterials in various contexts. The term refers to the ability of a material to perform with an appropriate host response in a specific situation. The ambiguity of the term reflects the ongoin ...
and biodegradability qualities, giving rise to their wide use of applications, particularly in biomedicine; as such, their physical properties can be fine-tuned in order to maximise their use. Methods to do this are: modulation of the
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
chirality
Chirality () is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object.
An object or a system is ''chiral'' if it is distinguishable fro ...
, and increasing the number of
aromatic
In organic chemistry, aromaticity is a chemical property describing the way in which a conjugated system, conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibits a stabilization stronger than would be expected from conjugati ...
residues. 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. 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. 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. 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. In another direction, Morris et al reported the use of GdL as a 'molecular trigger' to predict and control the order of gelation. 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. Furthermore, aromatic interactions play a key role in hydrogel formation as a result of π- π stacking driving gelation, shown by many studies.
Other
Hydrogels also possess a degree of flexibility very similar to natural tissue due to their significant water content. As responsive "
smart material
Smart materials, also called intelligent or responsive materials, are designed materials that have one or more properties that can be significantly changed in a controlled fashion by external stimuli, such as stress, moisture, electric or magneti ...
s", 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
An actuator is a component of a machine that produces force, torque, or displacement, when an electrical, pneumatic or hydraulic input is supplied to it in a system (called an actuating system). The effect is usually produced in a controlled way. ...
or
sensor
A sensor is often defined as a device that receives and responds to a signal or stimulus. The stimulus is the quantity, property, or condition that is sensed and converted into electrical signal.
In the broadest definition, a sensor is a devi ...
s.
File:Hydrogel micropump.webm, A
micropump
Micropumps are devices that can control and manipulate small fluid volumes. Although any kind of small pump is often referred to as a micropump, a more accurate definition restricts this term to pumps with functional dimensions in the micrometer ...
based on a hydrogel bar (4×0.3×0.05 mm size) actuated by applied voltage. This pump can be continuously operated with a 1.5 V battery for at least 6 months.
File:Short-peptide-based hydrogel, electron microscope image.jpg, A short-peptide-based hydrogel matrix, capable of holding about one hundred times its own weight in water. Developed as a medical dressing.
File:Crosslinked ultrashort peptide hydrogel.jpg, Photo of the same short-peptide-based hydrogel, held in forceps to demonstrate its stiffness and transparency.
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
Young's modulus (or the Young modulus) is a mechanical property of solid materials that measures the tensile or compressive stiffness when the force is applied lengthwise. It is the modulus of elasticity for tension or axial compression. Youn ...
,
shear modulus
In materials science, shear modulus or modulus of rigidity, denoted by ''G'', or sometimes ''S'' or ''μ'', is a measure of the Elasticity (physics), elastic shear stiffness of a material and is defined as the ratio of shear stress to the shear s ...
, and storage modulus can vary from 10 Pa to 3 MPa, a range of about five orders of magnitude. A similar effect can be seen by altering the crosslinking concentration. 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. 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
In materials science and continuum mechanics, viscoelasticity is the property of materials that exhibit both viscous and elastic characteristics when undergoing deformation. Viscous materials, like water, resist both shear flow and strain lin ...
, 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
Compression may refer to:
Physical science
*Compression (physics), size reduction due to forces
*Compression member, a structural element such as a column
*Compressibility, susceptibility to compression
* Gas compression
*Compression ratio, of a ...
(confined or unconfined), indentation, shearrheometry or
dynamic mechanical analysis
Dynamic mechanical analysis (abbreviated DMA) is a technique used to study and characterize materials. It is most useful for studying the viscoelastic behavior of polymers. A sinusoidal stress is applied and the strain in the material is measured, ...
.
Hydrogels have two main regimes of mechanical properties:
rubber elasticity
Rubber elasticity is the ability of solid rubber to be stretched up to a factor of 10 from its original length, and return to close to its original length upon release. This process can be repeated many times with no apparent Material failure th ...
and
viscoelasticity
In materials science and continuum mechanics, viscoelasticity is the property of materials that exhibit both viscous and elastic characteristics when undergoing deformation. Viscous materials, like water, resist both shear flow and strain lin ...
:
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
In materials science, shear modulus or modulus of rigidity, denoted by ''G'', or sometimes ''S'' or ''μ'', is a measure of the Elasticity (physics), elastic shear stiffness of a material and is defined as the ratio of shear stress to the shear s ...
, ''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.
For the swollen state, a perfect gel network can be modeled as:
In a simple uniaxial extension or compression test, the true stress, , and engineering stress, , can be calculated as:
where is the stretch.
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. 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.
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
A Maxwell model is the most simple model viscoelastic material showing properties of a typical liquid. It shows viscous flow on the long timescale, but additional elastic resistance to fast deformations. It is named for James Clerk Maxwell who p ...
. Another physical model used is called the Kelvin-Voigt Model and a material that follow this model is called a
Kelvin–Voigt material
A Kelvin–Voigt material, also called a Voigt material, is the most simple model viscoelastic material showing typical rubbery properties. It is purely elastic on long timescales (slow deformation), but shows additional resistance to fast deformat ...
. In order to describe the time-dependent creep and stress-relaxation behavior of hydrogel, a variety of physical lumped parameter models can be used. 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.
In order to measure the time-dependent viscoelastic behavior of polymers
dynamic mechanical analysis
Dynamic mechanical analysis (abbreviated DMA) is a technique used to study and characterize materials. It is most useful for studying the viscoelastic behavior of polymers. A sinusoidal stress is applied and the strain in the material is measured, ...
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. 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. 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. 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.
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
In materials science and metallurgy, toughness is the ability of a material to absorb energy and plastically deform without fracturing. 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.
The
hysteresis
Hysteresis is the dependence of the state of a system on its history. For example, a magnet may have more than one possible magnetic moment in a given magnetic field, depending on how the field changed in the past. Plots of a single component of ...
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. 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. 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
Temperature is a physical quantity that quantitatively expresses the attribute of hotness or coldness. Temperature is measurement, measured with a thermometer. It reflects the average kinetic energy of the vibrating and colliding atoms making ...
.
The toughness and hysteresis of a hydrogel are especially important in the context of biomedical applications such as
tissue engineering
Tissue engineering is a biomedical engineering discipline that uses a combination of cells, engineering, materials methods, and suitable biochemical and physicochemical factors to restore, maintain, improve, or replace different types of biolo ...
and
drug delivery
Drug delivery involves various methods and technologies designed to transport pharmaceutical compounds to their target sites helping therapeutic effect. It involves principles related to drug preparation, route of administration, site-specif ...
, as the hydrogel may need to withstand mechanical forces within the body, but also maintain mechanical performance and stability over time. 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. 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 bond
In chemistry, a hydrogen bond (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently b ...
hydrophobic interactions
The hydrophobic effect is the observed tendency of nonpolar substances to aggregate in an aqueous solution and to be excluded by water. The word hydrophobic literally means "water-fearing", and it describes the segregation of water and nonpolar ...
, that can break and reform under mechanical stress. 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.
Environmental response
The most commonly seen environmental sensitivity in hydrogels is a response to temperature. Many polymers/hydrogels exhibit a temperature dependent phase transition, which can be classified as either an
upper critical solution temperature
The upper critical solution temperature (UCST) or upper consolute temperature is the critical temperature above which the components of a mixture are miscible in all proportions. The word ''upper'' indicates that the UCST is an upper bound to a te ...
(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. 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.
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. There are many other stimuli that hydrogels can be responsive to, including: pH, glucose, electrical signals,
light
Light, visible light, or visible radiation is electromagnetic radiation that can be visual perception, perceived by the human eye. Visible light spans the visible spectrum and is usually defined as having wavelengths in the range of 400– ...
,
pressure
Pressure (symbol: ''p'' or ''P'') is the force applied perpendicular to the surface of an object per unit area over which that force is distributed. Gauge pressure (also spelled ''gage'' pressure)The preferred spelling varies by country and eve ...
, ions,
antigen
In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.
...
s, and more.
Additives
The mechanical properties of hydrogels can be fine-tuned in many ways beginning with attention to their hydrophobic properties. 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. Other additives, such as
nanoparticle
A nanoparticle or ultrafine particle is a particle of matter 1 to 100 nanometres (nm) in diameter. The term is sometimes used for larger particles, up to 500 nm, or fibers and tubes that are less than 100 nm in only two directions. At ...
s and
microparticle
Microparticles are particles between 0.1 and 100 μm in size. Commercially available microparticles are available in a wide variety of materials, including ceramics, glass, polymers, and metals. Microparticles encountered in daily life incl ...
s, have been shown to significantly modify the stiffness and gelation temperature of certain hydrogels used in biomedical applications.
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
Self-assembly is a process in which a disordered system of pre-existing components forms an organized structure or pattern as a consequence of specific, local interactions among the components themselves, without external direction. When the ...
, 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.
Another emerging technique to optimize hydrogel mechanical properties is by taking advantage of the
Hofmeister series
The Hofmeister series or lyotropic series is a classification of ions in order of their lyotrophic properties, which is the ability to salt out or salt in proteins. The effects of these changes were first worked out by Franz Hofmeister, who s ...
. 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
Salting out (also known as salt-induced precipitation, salt fractionation, anti-solvent crystallization, precipitation crystallization, or drowning out) is a purification technique that utilizes the reduced solubility of certain molecules in a s ...
", has been applied to poly(vinyl alcohol) hydrogels by adding a
sodium sulfate
Sodium sulfate (also known as sodium sulphate or sulfate of soda) is the inorganic compound with formula Na2SO4 as well as several related hydrates. All forms are white solids that are highly soluble in water. With an annual production of 6 mill ...
salt solution. 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. 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
Polydimethylsiloxane (PDMS), also known as dimethylpolysiloxane or dimethicone, is a silicone polymer with a wide variety of uses, from cosmetics to industrial lubrication and passive daytime radiative cooling.
PDMS is particularly known for its ...
(PDMS),
Kevlar
Kevlar (para-aramid) is a strong, heat-resistant synthetic fiber, related to other aramids such as Nomex and Technora. Developed by Stephanie Kwolek at DuPont in 1965, the high-strength material was first used commercially in the early 1970s as ...
, and
synthetic rubber
A synthetic rubber is an artificial elastomer. They are polymers synthesized from petroleum byproducts. About of rubber is produced annually in the United States, and of that amount two thirds are synthetic. Synthetic rubber, just like natural ru ...
. The values also surpass the toughness of natural
tendon
A tendon or sinew is a tough band of fibrous connective tissue, dense fibrous connective tissue that connects skeletal muscle, muscle to bone. It sends the mechanical forces of muscle contraction to the skeletal system, while withstanding tensi ...
and
spider silk
Spider silk is a protein fibre or silk spun by spiders. Spiders use silk to make webs or other structures that function as adhesive traps to catch prey, to entangle and restrain prey before biting, to transmit tactile information, or as nest ...
.
Applications
Soft contact lenses
The dominant material for contact lenses are acrylate-
siloxane
In organosilicon chemistry, a siloxane is an organic compound containing a functional group of two silicon atoms bound to an oxygen atom: . The parent siloxanes include the oligomeric and polymeric hydrides with the formulae and . Siloxanes ...
hydrogels. They have replaced hard contact lenses. One of their most attractive properties is oxygen permeability, which is required since the cornea lacks
vasculature
In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart an ...
.
Research
* Scalephobicity and antifouling
* Coatings for gas evolution reaction electrodes for efficient bubble detachment
*
Breast implant
A breast implant is a prosthesis used to change the size, shape, and contour of a person's breast. In reconstructive plastic surgery, breast implants can be placed to restore a natural looking breast following a mastectomy, to correct congenita ...
s
*
Contact lens
Contact lenses, or simply contacts, are thin lenses placed directly on the surface of the eyes. Contact lenses are ocular prosthetic devices used by over 150 million people worldwide, and they can be worn to correct vision or for cosmetic ...
es (
silicone
In Organosilicon chemistry, organosilicon and polymer chemistry, a silicone or polysiloxane is a polymer composed of repeating units of siloxane (, where R = Organyl group, organic group). They are typically colorless oils or elastomer, rubber ...
hydrogels,
polyacrylamide
Polyacrylamide (abbreviated as PAM or pAAM) is a polymer with the formula (-CH2CHCONH2-). It has a linear-chain structure. PAM is highly water-absorbent, forming a soft gel when hydrated. In 2008, an estimated 750,000,000 kg were produced, ...
s,
polymacon
Polymacon is a non-proprietary (i.e., generic) term for a hydrophilic polymer
A polymer () is a chemical substance, substance or material that consists of very large molecules, or macromolecules, that are constituted by many repeat unit, ...
)
* Water sustainability: Hydrogels have emerged as promising materials platforms for solar-powered water purification, water disinfection, and
atmospheric water generator
An atmospheric water generator (AWG), is a device that extracts water from humid ambient air, producing potable water. Water vapor in the air can be extracted either by condensation - cooling the air below its dew point, exposing the air to des ...
.
* Disposable
diapers
A diaper (, North American English) or a nappy (British English, Australian English, Hiberno-English) is a type of underwear that allows the wearer to urinate or defecate without using a toilet, by absorbing or containing waste products to ...
where they absorb
urine
Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...
, or in
sanitary napkin
A menstrual pad is an absorbent item worn in the underwear when menstruating, bleeding after giving birth, recovering from gynecologic surgery, experiencing a miscarriage or abortion, or in any other situation where it is necessary to absorb ...
s
* Dressings for healing of
burn
A burn is an injury to skin, or other tissues, caused by heat, electricity, chemicals, friction, or ionizing radiation (such as sunburn, caused by ultraviolet radiation). Most burns are due to heat from hot fluids (called scalding), soli ...
or other hard-to-heal
wound
A wound is any disruption of or damage to living tissue, such as skin, mucous membranes, or organs. Wounds can either be the sudden result of direct trauma (mechanical, thermal, chemical), or can develop slowly over time due to underlying diseas ...
s. Wound gels are excellent for helping to create or maintain a moist environment.
*
EEG
Electroencephalography (EEG)
is a method to record an electrogram of the spontaneous electrical activity of the brain. The bio signals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in the neoc ...
and
ECG
Electrocardiography is the process of producing an electrocardiogram (ECG or EKG), a recording of the heart's electrical activity through repeated cardiac cycles.
It is an electrogram of the heart which is a graph of voltage versus time of ...
medical electrodes using hydrogels composed of
cross-link
In chemistry and biology, a cross-link is a bond or a short sequence of bonds that links one polymer chain to another. These links may take the form of covalent bonds or ionic bonds and the polymers can be either synthetic polymers or natural ...
ed polymers (
polyethylene oxide
Polyethylene glycol (PEG; ) is a polyether compound derived from petroleum with many applications, from industrial manufacturing to medicine. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on its molecular we ...
polyvinylpyrrolidone
Polyvinylpyrrolidone (PVP), also commonly called povidone, is a water-soluble polymer compound made from the monomer ''N''-vinylpyrrolidone. PVP is available in a range of molecular weights and related viscosities, and can be selected according ...
)
* Encapsulation of quantum dots
* Environmentally sensitive hydrogels (also known as 'smart gels' or 'intelligent gels'). These hydrogels have the ability to sense changes of pH, temperature, or the concentration of metabolite and release their load as result of such a change.
*
Fibers
Fiber (spelled fibre in British English; from ) is a natural or artificial substance that is significantly longer than it is wide. Fibers are often used in the manufacture of other materials. The strongest engineering materials often inco ...
*
Glue
Adhesive, also known as glue, cement, mucilage, or paste, is any non-metallic substance applied to one or both surfaces of two separate items that binds them together and resists their separation.
The use of adhesives offers certain advantage ...
* Granules for holding
soil
Soil, also commonly referred to as earth, is a mixture of organic matter, minerals, gases, water, and organisms that together support the life of plants and soil organisms. Some scientific definitions distinguish dirt from ''soil'' by re ...
moisture in arid areas
* Air bubble-repellent (superaerophobicity). Can improve the performance and stability of electrodes for water
electrolysis
In chemistry and manufacturing, electrolysis is a technique that uses Direct current, direct electric current (DC) to drive an otherwise non-spontaneous chemical reaction. Electrolysis is commercially important as a stage in the separation of c ...
.
* Culturing cells: Hydrogel-coated wells have been used for cell culture.
*
Biosensors
A biosensor is an analytical device, used for the detection of a chemical substance, that combines a biological component with a physicochemical detector.
The ''sensitive biological element'', e.g. tissue, microorganisms, organelles, cell rece ...
: Hydrogels that are responsive to specific molecules, such as glucose or antigens, can be used as biosensors, as well as in DDS.
* Cell carrier: Injectable hydrogels can be used to carry drugs or cells for applications in tissue regeneration or 3D bioprinting. Hydrogels with reversible chemistry are required to allow for fluidization during injection/printing followed by self-healing of the original hydrogel structure.
* Investigate cell biomechanical functions combined with holotomography microscopy
* Provide absorption, desloughing and debriding of necrotic and fibrotic tissue
*
Tissue engineering
Tissue engineering is a biomedical engineering discipline that uses a combination of cells, engineering, materials methods, and suitable biochemical and physicochemical factors to restore, maintain, improve, or replace different types of biolo ...
scaffolds. When used as scaffolds, hydrogels may contain human cells to repair tissue. They mimic 3D microenvironment of cells. Materials include
agarose
Agarose is a heteropolysaccharide, generally extracted from certain red algae. It is a linear polymer made up of the repeating unit of agarobiose, which is a disaccharide made up of D-galactose and 3,6-anhydro-L-galactopyranose. Agarose is on ...
,
methylcellulose
Methyl cellulose (or methylcellulose) is a compound derived from cellulose. It is sold under a variety of trade names and is used as a thickener and emulsifier in various food and cosmetic products, and also as a bulk-forming laxative. Like cell ...
,
hyaluronan
Hyaluronic acid (; abbreviated HA; conjugate acid, conjugate base hyaluronate), also called hyaluronan, is an anion#Anions and cations, anionic, Sulfation, nonsulfated glycosaminoglycan distributed widely throughout connective tissue, connective ...
drug delivery
Drug delivery involves various methods and technologies designed to transport pharmaceutical compounds to their target sites helping therapeutic effect. It involves principles related to drug preparation, route of administration, site-specif ...
systems. Ionic strength, pH and temperature can be used as a triggering factor to control the release of the drug.
* The swelling behavior exhibited by charged hydrogels can be used as a valuable tool for investigating interactions between charged
polymer
A polymer () is a chemical substance, substance or material that consists of very large molecules, or macromolecules, that are constituted by many repeat unit, repeating subunits derived from one or more species of monomers. Due to their br ...
s and various species, including multivalent ions,
peptide
Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...
s, and
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s. This response arises due to fluctuating
osmotic
Osmosis (, ) is the spontaneous net movement or diffusion of solvent molecules through a selectively-permeable membrane from a region of high water potential (region of lower solute concentration) to a region of low water potential (region o ...
swelling forces resulting from the exchange of counterions within the gel matrix. Particularly significant is its application in assessing the binding of peptide drugs to biopolymers within the body, as the swelling response of the gel can provide insights into these interactions.
* Window coating/replacement: Hydrogels are under consideration for reducing infrared light absorption by 75%. Another approach reduced interior temperature using a temperature-responsive hydrogel.
* Thermodynamic electricity generation: When combined with ions allows for heat dissipation for electronic devices and batteries and converting the heat exchange to an electrical charge.
* Water gel explosives
* Controlled release of agrochemicals (pesticides and fertilizer)
* Talin shock absorbing materials - protein-based hydrogels that can absorb supersonic impacts
* Computational tasks, including emergent memory.
Biomaterials
Hydrogels are three-dimensional network structures with high hydrophilicity that can absorb and retain large amounts of water. Due to their excellent biocompatibility, they are widely used in the field of biomaterials. The main feature of hydrogels is their high water content, which is similar to the aqueous environment in biological systems, making them ideal for applications in tissue engineering, drug delivery, wound dressings, and artificial skin. Hydrogels can be classified into natural and synthetic types. Natural hydrogels, such as gelatin and chitosan, are derived from biological materials and offer good biodegradability and biocompatibility. Synthetic hydrogels, on the other hand, typically have higher mechanical strength and tunability but may exhibit lower biocompatibility. Additionally, hydrogels can be categorized as environmental-responsive or non-responsive based on their response to external stimuli. Environmental-responsive hydrogels, which can react to changes in temperature, pH, or ion concentration, are particularly useful in drug delivery systems. Due to their tunability, hydrogels continue to expand their applications in the biomedical field and are expected to play a crucial role in various medical applications in the future.
Implanted or injected hydrogels have the potential to support tissue regeneration by mechanical tissue support, localized drug or cell delivery, local cell recruitement or immunomodulation, or encapsulation of nanoparticles for local photothermal therapy or
brachytherapy
Brachytherapy is a form of radiation therapy where a sealed radiation, radiation source is placed inside or next to the area requiring treatment. The word "brachytherapy" comes from the Ancient Greek, Greek word , meaning "short-distance" or "s ...
. Polymeric drug delivery systems have overcome challenges due to their biodegradability, biocompatibility, and anti-toxicity. Materials such as
collagen
Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
, chitosan,
cellulose
Cellulose is an organic compound with the chemical formula, formula , a polysaccharide consisting of a linear chain of several hundred to many thousands of glycosidic bond, β(1→4) linked glucose, D-glucose units. Cellulose is an important s ...
, and poly (lactic-co-glycolic acid) have been implemented extensively for drug delivery to organs such as eye, nose, kidneys, lungs, intestines, skin and brain. Future work is focused on reducing toxicity, improving biocompatibility, expanding assembly techniques
Hydrogels have been considered as vehicles for drug delivery. They can also be made to mimic animal mucosal tissues to be used for testing mucoadhesive properties. They have been examined for use as reservoirs in topical drug delivery; particularly ionic drugs, delivered by
iontophoresis
Iontophoresis is a process of transdermal drug delivery by use of a voltage gradient on the skin. Molecules are transported across the stratum corneum by electrophoresis and electroosmosis and the electric field can also increase the permeabilit ...