Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5394_Библиотеки_им_академика_М_И_Перельмана

Hydrogels are three-dimensional network of polymer chains containing water within the network. The network can be either physically or chemically cross-linked (a covalent bonding) structures between polymer chains. Water content of hydro­gels can be adjusted by modulating the composition and conformation of polymers, such as hydrophilic/hydrophobic balance of polymer chains and pendant groups, and degree of cross-linking. Hydrogels can swell and shrink in response to external stimuli, such as changes in temperature, pH, solvent, electric current, magnetic field, and ultrasound, and are called stimuli-responsive hydrogels. Hydrogels can also respond to changes of some biomolecules, such as glucose and single-stranded DNA (Murakami and Maeda 2005). Due to their attractive swelling and responsive properties and resemblance to biological tissues (Serra et al. 2006), hydrogels have been extensively studied for potential drug delivery, tissue engineering, and medical device applications (Hoffman 2002).

Hydrogels can control release of all type of therapeutic agents, hydrophobic and hydrophilic, and small and big molecules. Moreover, the aqueous environment of hydrogels has advantages in protecting peptide, protein, oligonucleotide, and DNA types of therapeutics from degradation and denaturation. Kinetics of drug release from hydrogels can be controlled via three important mechanisms: diffusion of drugs, swelling of hydrogels, and degradation of hydrogels. The chemical composition (hydrophilic/hydrophobic balance), ratios of monomers/macromers and solvents, and cross-linking density (porosity) of hydrogels play important roles in controlling swelling of hydrogels, and subsequent diffusion and release of drugs from hydrogels. Drug release kinetics can also be tuned by controlling the degradation rate of the hydrolytically (carbonate, ester, polyphosphate, and phosphazene) or enzymatically degradable bonds of the hydrogels, and changing external stimuli of stimuli-respon­sive hydrogels. Finally, drug release kinetics from hydrogels is also affected by the nature of drugs. While hydrogels have been used for controlled release of drugs for

Alginate, starch, collagen, chitosan, gelatin, and hyaluronate are most widely used natural polymers for hydrogel fabrication because of their intrinsic biocompat­ibility (Liu et al. 2006; Gilhotra and Mishra 2008; Al-Kassas and El-Khatib 2009; Wadhwa et al. 2009; Gorle and Gattani 2010; Lai et al. 2010; Tanaka et al. 2010). Enzymes, such as alginase, amylase, collagenase, dextranase, and protease can degrade alginate, starch, collagen, dextran, and amide-bond containing hydrogels (Moriyama and Yui 1996; Dai et al. 2005). The most commonly used synthetic polymer- based hydrogels are based on poly(2-hydroxyethyl methacrylate), poly(ethylene glycol), poly(acrylamide), poly(N-isopropylacrylamide), and poly(acrylic acid) (Eljarrat-Binstock et al. 2008a, b; Kang and Mieler 2008; Swindle-Reilly et al. 2009; Singh et al. 2010). These synthetic hydrogels can be chemically cross-linked hydro- gels obtained by radical polymerization of monomers in the presence of cross­linkers, reaction of functional side groups of polymers with themselves or other functional cross-linkers. One example is thermoresponsive hydrogels based on poly(isopropylacrylamide), which become attractive biomaterials for ocular drug delivery in recent years (Kang Derwent and Mieler 2008; Misra et al. 2009). These hydrogels have been made by polymerizing N-isopropylacrylamide with macromer cross-linkers including dextran-lactate 2-hydroxyetheyl methacrylate (dextran­lactate HEMA) (Misra et al. 2009) and poly(ethylene glycol) diacrylate (PEGDA) (Kang Derwent and Mieler 2008). These macromers can control the pore size, and/ or the hydrophobicity/hydrophilicity, and/or the degradation of the hydrogel net­works, and thus subsequent drug release kinetics. Polymers bearing carboxylic, or hydroxyl, or amino side groups, such as poly(acrylic acid), poly(ethylene glycol), chitosan, can be incorporated to enhance the mucoadhesive property of the hydro­gels (Park and Robinson 1987; Huang et al. 2000; Peppas et al. 2000; 2009; Ludwig

2009). The physical geometry of the chemically cross-linked hydrogels also strongly

depends on the sites (tissue biology and physiology) of the administration if in situ gelation is performed. In situ chemical gelation can be initiated by ultraviolet and visible light polymerization, and oxidation of thiol groups of polymer chains and then formation of disulfide bonds (Swindle-Reilly et al. 2009). After hydrogels are synthesized and optimized, purification with repeated washing is next important step to remove traces of un-reacted components of chemically cross-linked hydrogels to avoid ocular toxicity.

Physically cross-linked hydrogels are obtained through hydrogen bonding, hydrophobic interaction, electrostatic interaction, or stereo-complex formation. Thermogelation is a physically cross-linking process when liquid polymer solutions turn into hydrogels due to hydrophobic interactions among polymer chains as tem­perature is elevated (Kumar et al. 1994; Nanjawade et al. 2007; Mundada and Avari

After hydrogels are formed, confirmation of the chemical structures, character­ization of the physical properties, and evaluation of the biological properties of the hydrogels are the next important and necessary steps before the hydrogels can be used for controlled ocular drug delivery clinically. Attenuated total reflection Fourier transform infrared spectroscope (ATR-FTIR), nuclear magnetic resonance (NMR) spectroscopy, and mass spectroscopy are common instruments to characterize the chemical structures and degradation properties of hydrogels (Huang et

resonance microscopy (Mishra et al. 2007). Defect in hydrogels can be detected using scanning laser acoustic microscopy (Luprano et al. 1997). The mechanical properties of hydrogels including storage, loss and compression moduli, tensile strength, and viscoelastic behaviors can be measured by rheometer and dynamic mechanical ana­lyzer (Liu et al. 2006; Schuetz et al. 2008; Zhou et al. 2008; Swindle-Reilly et al.

Although intravitreally implantable/injectable hydrogels can efficiently deliver drugs to the retina and choroid, the implantation/injection process is invasive and can cause complications. Cataract formation, glaucoma, vitreous hemorrhage, chor­oidal detachment, retinal detachment, hypotony, vitreous loss, exacerbation of intraocular inflammation and wound dehiscence, and endophthalmitis are also asso­ciated with the implants (Prasad et implants/injections need to be replaced requiring multiple clinic visits and surgical procedures.

Because of invasive nature and associated complications of intravitreal treatments, interest in subconjunctival retinal drug delivery is growing (Kompella et al. 2003; Gukasyan et al. 2007; Mac Gabhann et al. 2007). This route is well-suited for retinal delivery since the internal limiting membrane that separates the retina from the vitreous limits diffusion to the vitreous (Mac Gabhann et al. 2007). The subconjunctival space offers the possibility of delivering multiple types of sustained-release formulations

sensation. This limits the use of the iontophoretic technique for sustained drug delivery. Nevertheless, short-term delivery of anti-inflammatory drugs such as methylprednisolone, dexamethasone, and methotrexate to the retina of rabbits has been successfully achieved by Eljarrat-Binstock et al. using drug-loaded hydrogels made of hydroxyethyl methacrylate cross-linked with ethylenglycol dimethacry­late that were mounted on a portable iontophoretic device (Eljarrat-Binstock et al.