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REVIEW ARTICLE Ahsan Habib et.al / IJIPSR / 3 (9), 2015, 1372-1388

Department of Pharmacy ISSN (online) 2347-2154

Available online: www.ijipsr.com September Issue 1372

HYDROGEL: A NOBLE APPROACH TO HEALTHCARE

1Md. Ahsan Habib,

2Mst. Asma Akter,

1Md. Ershad Alam,

3Ziaul Karim,

4Md. Tanzir Ahmed Joarder

1M.Pharm, Department of Pharmacy, University of Asia Pacific, Dhaka, BANGLADESH

2M.Pharm, Department of Pharmacy, Stamford University, Dhaka, BANGLADESH

3M.Pharm, Department of Pharmacy, State University of Bangladesh, BANGLADESH

4B.Pharm, Department of Pharmacy, Manarat International University, Dhaka, BANGLADESH

Corresponding Author Md. Ahsan Habib

M.Pharm (Pharmaceutical Technology)

Department of Pharmacy,

University of Asia Pacific,

Dhaka, BANGLADESH

E-mail: [email protected]

Phone: +88-01713865486

International Journal of Innovative

Pharmaceutical Sciences and Research www.ijipsr.com

ABSTRACT

Hydrogels are crosslinked polymeric networks, which have the ability to hold water within

the spaces available among the polymeric chains. Hydrogels are water swollen polymer

matrices, with a huge tendency to absorb water. Their ability to swell, under physiological

conditions, makes them an ideal material for biomedical applications. The hydrophilicity of

the network is due to the presence of chemical residues such as hydroxylic, carboxylic,

amidic, primary amidic, sulphonic and others that can be found within the polymer

backbone or as lateral chains. The hydrogels have been used extensively in various

biomedical applications, viz. drug delivery, cell carriers and/or entrapment, wound

management, tissue engineering, growing new body part, contact lens applications etc.

Hydrogels can serve as scaffolds that provide structural integrity to tissue constructs,

control drug and protein delivery to tissues and cultures, and serve as adhesives or barriers

between tissue and material surfaces. This review presents an overview to the advances in

hydrogel based drug delivery that have become the interest of most researchers.

Key words: Hydrogels, biomedical applications, cross linked polymer.




INTRODUCTION

Hydrophilic gels called hydrogels are three-dimensional (3D), cross-linked materials absorbing

large quantities of water without dissolving. Softness, smartness, and the capacity to store water

make hydrogels unique materials [1]. The ability of hydrogels to absorb water arises from

hydrophilic functional groups attached to the polymer backbone while their resistance to

dissolution arises from cross-links between network chains. Water inside the hydrogel allows free

diffusion of some solute molecules, while the polymer serves as a matrix to hold water together.

Another aspect of hydrogel is that the gel is a single polymer molecule, that is, the network chains

in the gel are connected to each other to form one big molecule on macroscopic scale. It is natural

to expect that the conformational transitions of the elastically active network chains become

visible on the macroscopic scale of hydrogel samples. The gel is a state that is neither completely

liquid nor completely solid. These half liquid-like and half solid-like properties cause many

interesting relaxation behaviors that are not found in either a pure solid or a pure liquid. From the

point of view of their mechanical properties, the hydrogels are characterized by an elastic

modulus which exhibits a pronounced plateau extending to times at least of the order of seconds,

and by a viscous modulus which is considerably smaller than the elastic modulus in the plateau

region. The amount of water absorbed in hydrogels is related to the presence of specific groups

such as –COOH, –OH, –CONH2, –CONH–, and –SO3H. Capillary effect and osmotic pressure

are other variables that also influence the equilibrium water uptake of hydrogels [2].

History of hydrogels

The word polymer has been derived from the Greek words polys (meaning many) and meros (part

or unit). The polymers (e.g. proteins and celluloses) form the basic building block of life. For over

fifty years hydrogels have been used in numerous biomedical disciplines, in ophthalmology as

contact lenses and in surgery as absorbable sutures, as well as in many other areas of clinical

practice to cure such illnesses as diabetes mellitus, osteoporosis, asthma, heart diseases and

neoplasms. It was in 1955 that Professors Lim and Wichterle of Prague, Czech Republic,

synthesized the first hydrogel with potential biomedical uses. That was synthetic poly-2-

hydroxyethyl methacrylate, used – soon after its discovery – in contact lens production. The main

advantage of that revolutionary biomaterial was its stability under varying pH, temperature and

tonicity conditions. In the 1980s hydrogels were modified for other applications. Lim and Sun

obtained calcium alginate microcapsules for cell engineering, and Yannas’ group modified




synthetic hydrogels with some natural substances, such as collagen and shark cartilage to obtain

novel dressings, providing optimal conditions for healing burns. Nowadays, hydrogels continue to

interest scientists. They are obtained from new materials using the latest techniques to make them

safe and non-toxic. The final hydrogel product is present in very advanced applications, e.g. tissue

engineering and regeneration, where they can be applied in a non-invasive manner. They can

serve in the prevention of thrombosis, post-operative adhesion formation, drug delivery systems,

coatings for biosensors and cell transplantation.

What are Hydrogels?

According to the latest medical and pharmaceutical encyclopaedias, there is still no precise and

limiting definition of the term hydrogel. Most often, a hydrogel is considered to be a material

made when a water-insoluble polymer absorbs a large amount of water, or else it is simply a

water-swollen polymer network. Polymer hydrogels can be of either synthetic or natural origin,

homopolymers or copolymers [3].

Hydrogel is a permanent or chemical gel stabilized by covalently cross-linked networks. These

chemical hydrogels may be prepared either by crosslinking water-soluble polymers or by

converting hydrophobic polymers into hydrophilic polymers that are then cross-linked to form a

network. With such a structure, hydrogels are able to swell, absorbing a large amount of water

without the polymer dissolving, which gives them characteristics similar to those of soft tissue.

Although the water content in hydrogels may be as little as a few percents or as much as over 99

%, hydrogels retain the properties of solids [4].

Fig.1: Hydrogels

Characterization of hydrogels

Generally hydrogels are characterized for their morphology, swelling property and elasticity.

Morphology is indicative of their porous structure. Swelling determines the release mechanism of

the drug from the swollen polymeric mass while elasticity affects the mechanical strength of the

network and determines the stability of these drug carriers [5]. Some of the important features for

characterization of hydrogels are as follows:




X-ray diffraction

It is also used to understand whether the polymers retain their crystalline structure or they get

deformed during the processing pressurization process [6] [7].

In-vitro release study for drugs

Since hydrogels are the swollen polymeric networks, interior of which is occupied by drug

molecules, therefore, release studies are carried out to understand the mechanism of release over a

period of application [6,7].

FTIR (Fourier Transform Infrared Spectroscopy)

FTIR (Fourier Transform Infrared Spectroscopy) is a useful technique for identifying chemical

structure of a substance. It is based on the principle that the basic components of a substance, i.e.

chemical bonds, usually can be excited and absorb infrared light at frequencies that are typical of

the types of the chemical bonds. The resulting IR absorption spectrum represents a fingerprint of

measured sample. This technique is widely used to investigate the structural arrangement in

hydrogel by comparison with the starting materials [8].

Scanning Electron Microscopy (SEM)

SEM can be used to provide information about the sample's surface topography, composition, and

other properties such as electrical conductivity. Magnification in SEM can be controlled over a

range of up to 6 orders of magnitude from about 10 to 500,000 times. This is a powerful

technique widely used to capture the characteristic ‘network’ structure in hydrogels [9].

Light scattering

Gel permeation chromatography coupled on line to a multi angle laser light scattering (GPC-

MALLS) is a widely used technique to determine the molecular distribution and parameters of a

polymeric system. Hydrogel in a polymeric system can be quantified using this technique. This

technique is widely used in quantifying the hydrogels of several hydrocolloids such as gum

arabic, gelatine and pullulan [10].

Rheology

Hydrogels are evaluated for viscosity under constant temperature of usually 4°C by using Cone

Plate type viscometer [11].

Swelling behavior of hydrogels

When a hydrogel in its initial state is placed in an aqueous solution, water molecules will

penetrate into the polymer network. The entering molecules are going to occupy some space, and

as a result some meshes of the network will start expanding, allowing other water molecules to




enter within the network. Evidently, swelling is not a continual process; the elasticity of the

physically (e.g. hydrogen bonding) or chemically (covalent, atomic, ionic) cross-linked network

will counter-balance the infinite stretching of the network to prevent its destruction. Thus, by

balancing these two opposite forces, a net force, known as the swelling pressure (Psw) is produced,

which is equal to zero at equilibrium obtained with pure water, and that can be expressed as [12]:

Psw = k × Cn

Where, k and n are constants, and C is the polymer concentration. At the equilibrium there is no

additional swelling.

In the case of ionic polymers, the swelling equilibrium of the polymeric matrix is more

complicated as it heavily depends also on the ionic strength.

Classifications of hydrogels

Depending on the preparation methods, ionic charges, sources, nature of swelling with changes in

the environment, rate of biodegradation or the nature of crosslinking, hydrogels can be classified

in several ways are presented.

Among all, one of the important classifications is based on their crosslinking nature. The network

stability of hydrogels in their swollen state is due to the presence of either chemical or physical

crosslinking. Chemically crosslinked hydrogels are also known as thermosetting hydrogels or

permanent gels. They cannot be dissolved in any solvents unless the covalent crosslink points are

cleaved. Moreover, they cannot be reshaped through heat melting.

Fig.2: Classifications of hydrogels




Table 1: Stimuli-sensitive Hydrogel

Structure and bonding

Scientists still do not fully understand how hydrogels manage to absorb so much water, and there

is still plenty of ongoing research into their properties and uses. Understanding the structure and

bonding of these advanced materials helps to explain these properties; this in turn helps chemists

to design new hydrogels which can perform different functions. Many hydrogels are polymers of

carboxylic acids. The acid groups stick off the main chain of the polymer. When these polymers

are put into water, the hydrogen atoms react and come off as positive ions. This leaves negative

ions along the length of the polymer chain. When polymer chains are in solution, they tend to coil

up. However, the hydrogel now has lots of negative charges down its length.

Fig.3: The polymer chain of a hydrogel

Fig.4: A polymer chain coiled up in solution

Fig.5: A hydrogel polymer chain with lots of negative charges along its length

Type of Stimuli-Sensitive

Hydrogel Key Points

Thermo Release of medicine occurs, through abrupt decrease in surface area due to

temperature change.

pH Swelling controlled through the interactions between protons in solution and

ions within hydrogel

Electro Drug release occurs when electric filed acts on the hydrogel

Enzyme After swelling occurs, from increase in pH, enzymes degrade hydrogel,

therefore releasing medicine




Preparation of Hydrogels

Hydrogels are usually prepared from polar monomers. According to their starting materials, they

can be divided into natural polymer hydrogels, synthetic polymer hydrogels and combinations of

the two classes. Hydrogels can be classified as physically and chemically cross-linked gels. In the

first case the networks are held together by physical forces, including ionic, H-bonding or

hydrophobic forces, while in the second case the gel has covalently crosslinked networks.

Hydrogels are prepared by various methods. Some of the important methods are discussed below:

Isostatic ultra high pressure (IUHP)

Here the suspension of natural biopolymers like starch, are subjected to ultrahigh pressure of 300-

700 MPa for 5 or 20 min in a chamber which brings about changes in the morphology of the

polymer (i.e. gelatinization of starch molecules occur). It is different from heat-induced

gelatinization where a change in ordered state of polymer occurs. Usually the temperature within

the chamber varies from 40 to 52°C [6].

Use of cross linkers

Since hydrogels are the polymers which swell in presence of water and they entrap drug within

their pores; therefore, to impart sufficient mechanical strength to these polymers, cross linkers are

incorporated like glutaraldehyde, calcium chloride and oxidized konjac glucomannan (DAK).

These cross linkers prevent burst release of the medicaments. Hydrogels of gelatin has been

prepared with DAK. Some researchers have reported in situ hydrogel formation by incorporating

lactose along with sodium azide that results in formation of azide groups along with amino groups

in polymers like chitosan and thus a photocrosslinkable chitosan (Az-Ch-LA) is formed which has

desired integrity [13,14].

Use of water and critical conditions of drying

Aerogels of carbon have been prepared by super critically controlling the drying conditions.

Aerogels of resorcinol formaldehyde hydrogels have also been prepared by using water as solvent

and sodium carbonate as pH regulator. The final texture of hydrogel is governed by molar ratio of

resorcinol to sodium carbonate. This method of preparation leads to porous hydrogels with no

shrinkage during drying process. The method is expensive but leads to formation of xerogels with

sufficient mechanical strength [15].

Use of nucleophilic substitution reaction

Hydrogels of N-2-dimethylamino ethyl-methacryalmide (DMAEMA), a pH and temperature

sensitive hydrogel has been prepared by nucleophilic substitution reaction between methacyloyl




chloride and 2-dimethylamino ethylamine. The synthesized hydrogel was characterized for its

swelling behaviour [16].

Use of gelling agents

Gelling agents like glycophosphate, 1-2 propanediol, glycerol, trehalose, mannitol, etc, have been

used in formation of hydrogels. Usually the problem of turbidity and presence of negative charged

moieties which are associated with this method pose problem of interaction with the drug [16].

Use of irradiation and freeze thawing

Hydrogels prepared by chemical methods (i.e. use of crosslinkers, gelling agents or reaction

initiators) are having problems of removal of residue or unnecessary charged moieties present.

Irradiation method is suitable and convenient but the processing is costly. The mechanical

strength of such hydrogels is less. However with freeze thawing method, the hydrogels so formed

have sufficient mechanical strength and stability but are opaque in appearance with a little

swelling capacity. However, hydrogels prepared by microwave irradiation are more porous than

conventional methods [11].

Natural polymers and synthetic monomers used in hydrogel

Table 2: Natural polymers and synthetic monomers used in hydrogel fabrication

Natural polymers Synthetic monomers/polymers

Chitosan Hydroxyethylmethacryate (HEMA)

Alginate N-(2-Hydroxy propyl)methacrylate (HPMA)

Fibrin N-Vinyl-2-pyrrolidone (NVP)

Collagen N-Isopropylacrylamide (NIPAMM)

Gelatin Vinyl acctate (VAc)

Hyaluronic acid Acryolic acid (AA)

Dextran

Methacrylic acid (MAA)

Polyethylene glycol acrylate/methacrylate (IPEGA/PEGMA)

Polyethylene glycol diacrylate/dimethacrylate (PEGDA/PEGDMA)

Applications of hydrogels

Certain important properties of hydrogels for their applications as biomaterials can be tabulated as

follows:

Superior biocompatibility

Good oxygen permeability

Low protein adsorption and cell adhesion

Aqueous surface environment to protect cells and therapeutic drugs (peptides, proteins,

oligonucleotides, DNA)




Minimal frictional irritation within the surrounding tissues upon implantation

Soft and tissue-like physical properties

Micro-porous structure for additional transport channels

Ease of surface modification with specific biomolecules

Can be injected in vivo as a solution that gels at body temperature

These properties of hydrogels made them ideal biomaterials for applications in drug delivery

system, cell encapsulation, contact lenses, scaffolds for tissue engineering, biosensors, intelligent

cell culture substrates, wound dressing, soft tissue replacement and many more.

Hydrogels in drug delivery

Well-designed drug delivery systems must control solute release over time. Various biomaterials

have been investigated to control drug release; however, among them, hydrogels show two

distinct advantages. (i) Drugs can easily diffuse out through the hydrogels. The rate of drug

release can be controlled in many ways such as by changing the crosslinking density, preparing

the hydrogel with monomers of controlled hydrophilicity and/or controlling the ratio of

hydrophilic to hydrophobic monomers. (ii) Compared with hydrophobic materials, hydrogels may

interact less strongly with drugs; consequently, a larger fraction of active molecules of drug,

especially proteins and peptides, can be released through hydrogel carriers [17].

Bioresponsive hydrogels in drug delivery systems

Bioresponsive hydrogels, which undergo structural and/or morphological changes in response to a

biological stimulus, have been investigated for numerous applications in drug delivery, tissue

regeneration, and biomimetic systems. Much work on bioresponsive hydrogels for drug delivery

relates to the release of insulin in response to raised blood sugar levels as a potential autonomous

treatment of insulin-dependent diabetes. Glucose oxidase molecules are immobilized onto a basic

polymeric carrier. Following the enzyme reaction glucose is converted to gluconic acid and

therefore the pH of the hydrogel is temporarily lowered. In this situation the basic groups on the

polymer are protonated and induced swelling of the gel which enhancing the release profile of

insulin. This system works as a feedback loop: upon release of insulin the sugar levels drop,

resulting in a pH increase that stops the release of further insulin.

Bioresponsive hydrogels can be designed in a degradable form in response to external stimuli

such as enzymes. Such systems deliver physically entrapped guest molecules, held freely within

the carrier, and do not require chemical modification for targeted delivery [18].




Fig.6: Schematic representation of the glucose-sensitive hydrogel membrane consisting of a

poly (amine) and glucose-oxidase-loaded membrane [20].

Polyvinyl Alcohol-Hydrogels (PVA-H) as an artificial cartilage for orthopedic implants

PVA-H has excellent biocompatibility; experiments were performed using animals [19]. This

PVA-H was implanted into various sites in rabbits and dogs, subcutaneously, intramuscularly, etc.

and follow-up after surgery confirmed superior biocompatibility. In order to make certain in vivo

immune-reactions against PVA-H, fine particles of PVA-H and ultra-high molecular weight

polyethylene (UHMWPE), which is a common material for artificial joints, were injected into the

bilateral knee joints, respectively, in the same rabbit and compared. The PVA-H used was fine

particles with a diameter of 100 μm, with UHMWPE particles as control. This is a histological

photograph of tissue observed three months after injection. In the periphery of the UHMWPE

particles, accumulated macrophages and foreign-body giant cells, and remarkable foreign-body

reactions were observed, while, almost no reactions were seen around PVA gel particles on the

opposite side.

Fig.7: Histological appearance of the implant material particles and the surrounding tissue

in rabbit’s knee joint. (×100) (a) UHMWPE particle: many macrophage and giant cells are

surrounding particle due to intense foreign-body reactions. (b) PVA-H particle: foreign-

body reactions were hardly observed




Hydrogels for cell encapsulation

Cell encapsulation technology provides a promising therapeutic modality for diabetes,

hemophilia, cancer and renal failure [21].

The selection of a suitable biomaterial as a membrane for encapsulating cells is the major

challenge towards the success of cell encapsulation therapy. Biocompatibility, microporous

structure and minimal surface irritation within the surrounding tissues of hydrogels attracted them

for this application. They can be designed with required porosity that resists any entrance of

immune cells and allows stimuli, oxygen, nutrients and/or waste transfer through the pores.

Genetically modified alginates and polyethylene oxide based hydrogels [22] have been studied as

cell encapsulation systems.

Hydrogels in tissue engineering

Tissue engineering (TE) is a multidisciplinary approach and involves the expertise of materials

science, medical science and biological science for the development of biological substitutes

(tissue/ organ). It is emerging as an important field in regenerative medicine.

It has got three basic components namely, cells/tissues, scaffolds and implantation and/or

grafting. The principles of TE have been used extensively to restore the function of a traumatized/

malfunctioning tissues or organs. In practice, the patient’s cells are generally combined with a

scaffold for generating new tissue. A scaffold can be made up of either ceramic or polymer, which

can be either permanent or resorbable. The pore size of the scaffolds should be >80 μm [23].

This is necessary for the cell migration into the core of the scaffolds, angiogenesis, and supply of

nutrients to the cells and to take away the metabolic products away from the cells. The scaffolds

made up of polymers are generally hydrogels.

Every year thousands of people are victims of tissue loss and organ failure caused either due to

disease or trauma. Also, there is a shortage of organ donors because of the religious beliefs and/or

medical complications. Recently the use of resorbable hydrogels in TE has gained much

importance because (a) it is easy to process the polymers; (b) the properties of the hydrogels can

be tailored very easily; and (c) resorbable polymers like polylactic acid (PLA), polyglycolic acid

(PGA), and their co-polymers (PLA-co-PGA; PLGA) are being used for biomedical application.

Sterilization of the hydrogels is very tricky, which may alter the characteristics of the scaffold.

Hence, due consideration on the sterilization method should be given before selecting a particular

sterilization method [24].




Fig.8: Schematic diagram showing multidisciplinary approach of tissue engineering

Hydrogels for contact lens application

The cornea of the eye is a precisely formed transparent structure of protein fibers containing about

80% water and 20% formed materials making it a natural hydrogel. Synthetic hydrogels have

found to be suitable in contact lens applications when the refractive power of cornea is

compromised. In addition to their biocompatibility and softness, inter-connected microstructures

of hydrogels help oxygen diffusitivity to the epithelial layer of the cornea. Certain hydrogels

possess high refractive index, modulus, and transparency, required to fit for this application. Since

no single hydrophilic polymer structure provides all required properties, copolymers developed

from a group of hydrophilic monomers like dimethylacrylamide, N-vinyl pyrrolidone and

methacrylic acid and hydrophobic monomers like perfluoro polyethers, methyl methacrylate and

silicon-containing monomers are utilized to design contact lenses [25].

Hydrogels in wound healing

Hydrogel is a crosslinked polymer matrix which has the ability to absorb and hold water in its

network structure. Hydrogels act as a moist wound dressing material and have the ability to

absorb and retain the wound exudates along with the foreign bodies, such as bacteria, within its

network structure. In addition to this, hydrogels have been found to promote fibroblast

proliferation by reducing the fluid loss from the wound surface and protect the wound from

external noxae necessary for rapid wound healing. Hydrogels help in maintaining a micro-climate

for biosynthetic reactions on the wound surface necessary for cellular activities. Fibroblast

proliferation is necessary for complete epithelialisation of the wound, which starts from the edge

of the wound. Since hydrogels help to keep the wound moist, keratinocytes can migrate on the

surface.




Hydrogels may be transparent, depending on the nature of the polymers, and provide cushioning

and cooling/soothing effects to the wound surface. The main advantage of the transparent

hydrogels includes monitoring of the wound healing without removing the wound dressing. The

process of angiogenesis can be initiated by using semi-occlusive hydrogel dressings, which is

initiated due to temporary hypoxia. Angiogenesis of the wound ensures the growth of granulation

tissue by maintaining adequate supply of oxygen and nutrients to the wound surface. Hydrogel

sheets are generally applied over the wound surface with backing of fabric or polymer film and

are secured at the wound surface with adhesives or with bandages [4].

Fig.9: Hydrogels in burn treatment

Medical application of hydrogels

Hydrogels have also been designed for augmenting vocal cords, prevention of scar formation after

surgery and as coverings for perforated ear drums and rhinoplasty. These applications were the

driving force that initiated a detailed study on the relationship between the structure of cross-

linked hydrophilic polymers and their biocompatibility [26]. These results were translated into

clinical applications: one of the successful examples was the use of HEMA-based hydrogels in

rhinoplasty, which produced long-term biocompatibility and excellent cosmetic results [27].

Fig.10: Use of hydrogels (copolymers of HEMA with EDMA) in rhinoplasty:

(a) patient before surgery; (b) patient after surgery [28]




Growing new body parts

The technology is still a long way off, but scientists are hopeful that some time in the future it will

be possible to grow replacement body parts in hydrogels. Cells of the required tissue will be

added to the hydrogel and injected into the body where they are needed. The hydrogel will take

the place of the damaged tissue and also allow nutrients to pass through it to the cells inside. Over

time, the cells will grow and the hydrogel be degraded by the body until new tissue is in place to

repair the damage.

Hydrogels are still a long way from being used in hospitals and whole organs grown on hydrogels

are even further away, but researchers in the USA recently managed to grow lung tissue in a

hydrogel which demonstrated that this idea has potential.

Drier babies, wetter plants

Disposable nappies make use of the ability of hydrogels to take up and retain water, even under

pressure. They contain small crystals (about 1 mm in diameter) of hydrogel in the fluff at the core

of the nappy. They absorb the urine and swell up. Because they do not easily give the water back,

the child stays dry.

Plant water storage crystals are similar. They absorb water and swell up. If they are put in with

plants in tubs or hanging baskets, they will slowly release the water as the soil dries up and extend

the amount of time required between waterings, for example when you go on holiday.




CONCLUSION

During past decades, hydrogels have played a very essential role in biomedical applications. New

synthetic methods have been used to prepare homo- and co-polymeric hydrogels for a wide range

of drugs, peptides, and protein delivery applications. Recent enhancements in the field of polymer

science and technology have led to the development of various stimuli sensitive hydrogels. Either

pH-sensitive and/or temperature-sensitive hydrogels can be used for site-specific controlled drug

delivery. Hydrogels that are responsive to specific molecules, such as glucose or antigens, can be

used as biosensors as well as drug delivery systems. Polymer solutions in water (sol phase) that

transform into a gel phase on changing the temperature (thermo-gelation) offer a very exciting

field of research. Recent advances in the development of novel hydrogels for drug delivery

applications have focused on several aspects of their synthesis, characterization and behaviour.

Obviously, drug release from hydrogel networks is controlled by a complex combination of

different mechanisms, such as matrix swelling, drug dissolution/diffusion and hydrogel erosion.

Successful design of drug delivery systems relies not only on proper network design but also on

precise description of hydrogel behaviour as well as mathematical modelling of drug release

profiles. As more advanced release devices, such as in-situ forming hydrogels are developed more

rigorous mathematical modeling approaches are needed to describe the complete mechanisms

governing drug release from these systems.

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