Hydrogel nanoparticles(3)

of immunogen/pathogen moieties,they do offer various advanta-geous properties such as being usually non-toxic,biocompatibility,and showing a number of remarkable physicochemical properties that make them suitable for different applications in drug delivery systems [49,51].In comparison,the well-de ?ned structure of synthetic polymers may lead to hydrogels with well-de ?ned and ?ne-tunnable degradation kinetic as well as mechanical properties.

As mentioned,water content plays an important role in determin-ing the overall characteristic of a polymeric network.Accordingly,hydrophilic hydrogels with high amounts of water in their structures show distinctive properties compared to hydrophobic polymeric networks.Furthermore,hydrogels have signi ?cantly milder condi-tions for preparation with gel formation occurring at ambient temperatures and organic solvents are rarely required [51].Hydrogels,particularly those intended for applications in drug delivery and biomedical purposes,are required to have acceptable biodegradability and biocompatibility which necessitates the development of novel synthesis and crosslinking methods to design the desired products.In this way,a great variety of crosslinking approaches have been developed to prepare desired hydrogels for each particular application [54].These crosslinkling methods routinely used for preparation of hydrogels are listed in Fig.2.Moreover,the characteristics and potential applications of hydrogels of different structures,rely not only on the preparation methods but also on the monomers used in the synthesis of hydrogel polymeric networks.A summary of monomers most commonly used in the fabrication of hydrogel structures of pharmaceutical interest is shown in Table 2[53].2.2.Release mechanism from hydrogel matrices

Since the most common mechanism of drug release from hydrogels is passive diffusion,molecules of different sizes and characteristics would freely diffuse into/out of hydrogel matrix during the loading and storage periods.The hydrophilic nature of a hydrogel makes it highly different from non-hydrophilic polymer matrices with respect to the release behavior of the incorporated agents.From various modelistic studies on the possible release mechanisms of an active compound from a hydrogel device,focused on the rate-limiting step of the release phenomena,drug release mechanisms from hydrogels can be categor-ized as:i)diffusion-controlled,ii)swelling-controlled,and iii)chemi-

cally-controlled.According to Fick's ?rst law of diffusion (with constant or variable diffusion coef ?cients),the diffusion-controlled behavior is the most dominantly applicable mechanism to describe the drug release from hydrogels [55].The drug diffusion out of a hydrogel matrix is primarily dependent on the mesh sizes within the matrix of the gel [56],which,in turn,is affected by several parameters,including,mainly,the degree of crosslinking,chemical structure of the composing monomers,and,when applicable,type as well as intensity of the external stimuli.Meanwhile,mechanical strength,degradability,diffusivity,and other physical properties of a hydrogel network are greatly dependent on its mesh size [55–57].Typical mesh sizes reported for biomedical hydrogels range from 5to 100nm (in their swollen state)[57,58],which are much larger than most small-molecule drugs.As a result,diffusion of these drugs is not considerably retarded in swollen state,whereas macro-molecules like oligonucleotides,peptides,and proteins,due to their hydrodynamic radii,will have a sustained release unless the structure and mesh size of the swollen hydrogels are designed appropriately to obtain desired rates of macromolecular diffusion [59].In the case of the swelling-controlled mechanism,when diffusion of a drug is signi ?

cantly

Fig.2.Novel crosslinking methods used in hydrogels.

Table 2

Monomers commonly used in synthesis of synthetic hydrogels for pharmaceutical application

Monomer chemical name

Monomer abbreviation Hydroxyethyl methacrylate

HEMA Hydroxyethoxyethyl methacrylate HEEMA Hydroxydiethoxyethyl methacrylate HDEEMA Methoxyethyl methacrylate

MEMA Methoxyethoxyethyl methacrylate MEEMA Methoxydiethoxyethyl methacrylate MDEEMA Ethylene glycol dimethacrylate EGDMA N -vinyl-2-pyrrolidone NVP N -isopropyl Aam NIPAAm Vinyl acetate VAc Aacrylic acid AA Methacrylic acid

MAA N -(2-hydroxypropyl)methacrylamide HPMA

EG

Ethylene glycol PEG acrylate

PEGA PEG methacrylate PEGMA PEG diacrylate

PEGDA PEG dimethacrylate

PEGDMA

1640M.Hamidi et al./Advanced Drug Delivery Reviews 60(2008)1638–1649

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