Novel porphyrin-incorporated hydrogels for photoactive intraocular lens biomaterials

Novel surface-modified hydrogel materials have been prepared by binding charged porphyrins TMPyP (tetrakis(4-N-methylpyridyl)porphyrin) and TPPS (tetrakis(4-sulfonatophenyl)porphyrin) to copolymers of HEMA (2-hydroxyethyl methacrylate) with either MAA (methacrylic acid) or DEAEMA (2-(diethylamino)ethyl methacrylate). The charged hydrogels display strong electrostatic interactions with the appropriate cationic or anionic porphyrins to give materials which are intended to be used to generate cytotoxic singlet oxygen (1O2) on photoexcitation and can therefore be used to reduce postoperative infection of the intraocular hydrogel-based replacement lenses that are used in cataract surgery. The UV/vis spectra of TMPyP in MAA:HEMA copolymers showed a small shift in the Soret band and a change from single exponential (161 micros) triplet decay lifetime in solution to a decay that could be fitted to a biexponential fit with two approximately equal components with tau = 350 and 1300 micros. O2 bubbling reduced the decay to a dominant (90%) component with a much reduced lifetime of 3 micros and a minor, longer lived (20 micros) component. With D2O solvent the 1O2 lifetime was measured by 1270 nm fluorescence as 35 micros in MAA:HEMA, compared to 67 mus in solution, although absorbance-matched samples showed similar yield of 1O2 in the polymers and in aqueous solution. In contrast to the minor perturbation in photophysical properties caused by binding TMPyP to MAA:HEMA, TPPS binding to DEAEMA:HEMA copolymers profoundly changed the 1O2 generating ability of the TPPS. In N2-bubbled samples, the polymer-bound TPPS behaved in a similar manner to TMPyP in its copolymer host; however, O2 bubbling had only a very small effect on the triplet lifetime and no 1O2 generation could be detected. The difference in behavior may be linked to differences in binding in the two systems. With TMPyP in MAA:HEMA, confocal fluorescence microscopy showed significant penetration of the porphyrin into the core of the polymer film samples (>150 microm). However, for TPPS in DEAEMA:HEMA copolymers, although the porphyrin bound much more readily to the polymer, it remained localized in the first 20 microm, even in heavily loaded samples. It is possible that the resulting high concentration of TPPS may have cross-linked the hydrogels to such an extent that it significantly reduced the solubility and/or diffusion rate of oxygen into the doped polymers. This effect is significant since it demonstrates that even simple electrostatic binding of charged porphyrins to hydrogels can have an unexpectedly large effect on the properties of the system as a whole. In this case it makes the apparently promising TPPS/DEAEMA:HEMA system a poor candidate for clinical application as a postoperative antibacterial treatment for intraocular lenses while the apparently equivalent cationic system TMPyP/MAA:HEMA displays all the required properties.     

Copolymers of N-alkylacrylamides as thermosensitive hydrogels

Many of the N-alkyl substituted acrylamide polymers can manifest a lower critical solution temperature (LCST) in aqueous solutions. The LCST of such polymers can be easily varied by a free radical copolymerization of the appropriate comonomers. Natural compounds such as bile acids can be introduced into such polymers to modify the LCST and aggregation behavior and to render the material both thermo- and pH-sensitivity.     

Hydroxyapatite/polyurethane composites as promising biomaterials

The biomaterials are intended to augment or replace the function of tissues or organs in human body. Every year millions of people require soft- or hard-tissue regeneration worldwide. Polymers and their composites are a large class of biomaterials appreciated for tissue regeneration. Polyurethane (PUR) is an organic synthetic multifunctional polymer with established biomedical applications. The hydroxyapatite (HA) is one of the biocompatible ceramic materials similar to natural bone material. The amalgamation of hydroxyapatite with polyurethane enhances the bioactivity of final product along with the combination of individual properties. Here, we review the synthesis, characterization, and applications studies of HA/PUR-based biomaterials. We initiate this review with a brief and representative compilation of the chemical composition and methods of preparation for HA/PUR biomaterials. Then, moving ahead, first, we review the simple HA/PUR biomaterials and use of PUR templates. Second, we review the significance of modified HA and PUR in these biomaterials. Third, we discuss the potential of bio-based PUR and inclusion of third constituent in the HA/PUR biomaterials. Then, we appraise the involvement of trace nutrient in deposition of HA on PUR scaffolds. Finally, we consider the other expedient applications of HA/PUR composites such as drug delivery system and sorbent of pollutants.     

Injectable hydrogels as unique biomedical materials

A concentrated fish soup could be gelled in the winter and re-solled upon heating. In contrast, some synthetic copolymers exhibit an inverse sol-gel transition with spontaneous physical gelation upon heating instead of cooling. If the transition in water takes place below the body temperature and the chemicals are biocompatible and biodegradable, such gelling behavior makes the associated physical gels injectable biomaterials with unique applications in drug delivery and tissue engineering etc. Various therapeutic agents or cells can be entrapped in situ and form a depot merely by a syringe injection of their aqueous solutions at target sites with minimal invasiveness and pain. This tutorial review summarizes and comments on this soft matter, especially thermogelling poly(ethylene glycol)-(biodegradable polyester) block copolymers. The main types of injectable hydrogels are also briefly introduced, including both physical gels and chemical gels.     

Potential applications of fluorhydroxyapatite as biomaterials in medicine

The present work was undertaken to investigate the bioactivity and cytotoxicity of fluorhydroxyapatite ceramics. The bioactivity was evaluated by in vitro testing in simulated body fluid (SBF), in which ion concentrations are almost identical with inorganic ion concentrations of human blood plasma. Pellets of FA, HA and FHA were immersed in SBF for 48 hours, 1 week and 4 weeks at 36.5°C. Changes of the surface microstructure of the samples were observed by scanning electron microscopy (SEM). 48 hours and one week immersion in SBF did not result in any substantial progress in bioactivity. After 4 weeks in SBF a new biologically active layer was created on the surface of the biomaterials. In addition, the embryonal mouse fibroblast cell line NIH-3T3 was used for a comparative study of basal cytotoxicity of FHA, HA and FA discs. The sensitivity of these cells for tested biomaterials was evaluated on the basis of two cytotoxic end points: cell proliferation and cell morphology. The basal cytotoxicity of FHA, FA and HA discs was measured by a direct contact method. After 24, 48 and 72 hours, the cell growth was evaluated by direct counting of non-affected cells and cells treated by biomaterials. After 72 hours of biomaterials treatment, about 25% inhibition of cell number and unchanged morphology was found.      

Polyacrylamide hydrogels as substrates for studying bacteria

Polyacrylamide hydrogels can be used as chemically and physically defined substrates for bacterial cell culture, and enable studies of the influence of surfaces on cell growth and behaviour.     

Glycosyl-nucleoside fluorinated amphiphiles as components of nanostructured hydrogels

The synthesis of two novel glycosyl-nucleoside fluorinated amphiphiles (GNFs) derived from the 2H,2H,3H,3H-perfluoro-undecanoyl hydrophobic chain is described. The GNF amphiphiles, which feature either β-d-glucopyranosyl or β-d-lactopyranosyl moieties linked to a thymine base via a 1,2,3 triazole linker, were prepared using a ‘double click’ chemistry route. Surface tension measurements, gelation properties, and TEM studies show that GNFs spontaneously assemble into supramolecular structures. Similarly to their hydrocarbon analogues (GNLs), the GNFs have unique gelation properties in water. A minimum hydrogelation concentration of 0.1% (w/w), was determined in the case of the β-d-glucopyranosyl derivative. Cell viability studies indicate that fluorocarbon GNF 5 was not toxic for human cells (Huh7), whereas hydrocarbon analogue GNL is toxic above 100 μm.     

Polymeric materials as biomaterials under particular consideration of biodegradable polymers

Biomaterials may be defined as artificial materials which fulfill the mechanical requirements and interact with the biosystem they are in contact with in same way as a natural material would react in the same place. While the requirements of mechanical properties can be reached by suitable organo-polymeric and inorganic materials the interfacial biocompatiblity is neither understood in all its complexity nor can be fulfilled by any of the applied materials. Surface modification and characterization with greatest scrutiny and the observation of the answer of selected parameters of the biosystem are a subject of utmost interest. A few examples will be presented. In the long range, however, it has to be considered that any material is degraded and hence should present continuously a renewable biocompatible surface. On the other hand, materials are desired which deliberately are biodegradable. Presently available materials are polylactides and copolymers. An alternative could be presented by polydepsipeptides because of two reasons, (i) the local concentration of acid formed upon degradation would be reduced as compared to polylactides which in certain cases might be advantageous and (ii) the aminoacid units could carry side groups with bioactive molecules attached. Therefore, a new method of acylation of an aminoacid with a hydroxyacid is presented as well as the cyclisation to result in the cyclic depsipeptide and the polymerisation to yield the polydepsipeptide. The microstructure of the polymers, the thermal properties and the degradation behaviour is presented.     

Use of hydrogels as corneal inlays for refractive surgery

A novel hydrogel has been used for intracorneal implantation, in order to correct refractive errors of the eye. Our hydrogel is a polyanionic copolymer of acrylonitrile and sodium methallylsulfonate material (AN 69, made by HOSPAL, France). We describe here its formation, chemico-physical and biological properties (in vitro and in vivo), and its biomechanical behaviour when implanted into the cornea.     

Dendritic macromers as in situ polymerizing biomaterials for securing cataract incisions

Dendritic macromers are attractive macromolecules for hydrogel formation since high cross-linking densities at low polymer concentration can be obtained, varied physical properties can be observed based on the macromer structure, and low viscous aqueous solutions can be injected in an in vivo site of irregular shaped to form a well-integrated polymer network. A peptide dendron possessing terminal cysteine residues was synthesized and characterized. When this peptide dendron was mixed with poly(ethylene glycol dialdehyde) in aqueous solution at pH = 7.4, a hydrogel spontaneously formed as a consequence of thiazolidine linkages between the macromers. Such in situ polymerized hydrogels are of interest for tissue engineering and wound-repair applications. To evaluate the potential use of this hydrogel sealant in ophthalmic surgeries, a 3-mm clear corneal incision (i.e., the wounds created during a typical cataract surgery) was successfully sealed.     

Designed rubbery biomaterials

Research on novel implantable rubbery polyisobutylene‐based biomaterials carried out at the University of Akron during the past ∼15 years is outlined. Specific attention is paid to recent investigations focusing on the synthesis of semipermeable amphiphilic networks designed to be used as immunoisolatory membranes. The membranes envelop insulin‐producing living pig beta cells. They are biocompatible to the host (human) and the guest (beta cells) and remain permeable for many months in vivo. They are rubbery slippery, robust, sterilizable, optically transparent, with controlled pore dimensions that allow the in‐diffusion of glucose and nutrients, out‐diffusion of insulin and wastes, but they do not allow the entry of immunoproteins (IgG). The pores remain permeable for many months in vivo. The membranes are made by copolymerizig/crosslinking hydrophilic (meth)acrylates with methacrylate‐telechelic polyisobutylenes. Controlling the molecular weights of the constituent segments controls the pore sizes of the membranes. Immunoisolated pig beta cells enveloped in our membranes and implanted subcutaneously in a rat have corrected severe hyperglycemia.     

Crosslinked Alginate Films as Rate Controlling Membranes for Transdermal Drug Delivery Application

The present investigation was undertaken to prepare and evaluate the crosslinked sodium alginate (SA) films as rate controlling membranes (RCM) for transdermal drug delivery application. The drug free films of SA were prepared by mercury substrate method and evaluated for thickness uniformity, tensile strength and water vapor permeation (WVP). The films were characterized by scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). Drug diffusion characteristics of the films were studied using diclofenac diethylamine as a model drug. The prepared membranes were thin, flexible and smooth. Tensile strength measurement and DSC analysis suggested that as the crosslink density increases, the tougher membranes were formed. The WVP and drug diffusion were dependent upon the crosslink density and thickness of the films. The permeability was decreased with increasing crosslink density and thickness of the films. The molar mass between the crosslinks and crosslink density were calculated using empirical equations. The primary skin irritation study indicated that the prepared membranes were less irritant and safe for transdermal application.     

Elastomeric polypeptide-based biomaterials

Elastomeric proteins are characterized by their large extensibility before rupture, reversible deformation without loss of energy, and high resilience upon stretching. Motivated by their unique mechanical properties, there has been tremendous research in understanding and manipulating elastomeric polypeptides, with most work conducted on the elastins but more recent work on an expanded set of polypeptide elastomers. Facilitated by biosynthetic strategies, it has been possible to manipulate the physical properties, conformation, and mechanical properties of these materials. Detailed understanding of the roles and organization of the natural structural proteins has permitted the design of elastomeric materials with engineered properties, and has thus expanded the scope of applications from elucidation of the mechanisms of elasticity to the development of advanced drug delivery systems and tissue engineering substrates.     

Templating hydrogels

Templating processes for creating polymerized hydrogels are reviewed. The use of contact photonic crystals and of non-contact colloidal crystalline arrays as templates are described and applications to chemical sensing and device fabrication are illustrated. Emulsion templating is illustrated in the formation of microporous membranes, and templating on reverse emulsions and double emulsions is described. Templating in solutions of macromolecules and micelles is discussed and then various applications of hydrogel templating on surfactant liquid crystalline mesophases are illustrated, including a nanoscale analogue of colloidal crystalline array templating, except that the bead array in this case is a cubic array of nonionic micelles. The use of particles as templates in making core-shell and hollow microgel beads is described, as is the use of membrane pores as another illustration of confinement templating.     

Synthesis of biocompatible nanocomposite hydrogels as a local drug delivery system

Nanocomposite biocompatible hydrogels (NCHG) were synthesised as model systems for in situ cured potentially local drug delivery devices for curing periodontal infections. The composite consists of the following components: nanoparticles (NPs), matrix gel, and chlorhexidine (CHX) as antibacterial drug. The NPs were obtained by free radical initiated copolymerization of the monomers, 2-hydroxyethyl methacrylate (HEMA) and polyethyleneglycol dimethacrylate (PEGDMA), in aqueous solution. The same monomers were used to prepare crosslinked matrices by photopolymerization. NCHGs were obtained by mixing NPs, monomers, and drug in an aqueous solution then crosslinked by photopolymerization. Mechanical properties, swelling behavior, and the kinetics of drug release have been investigated. It was found that compression strength values increased with increasing ratio of the crosslinker PEGDMA. Incorporation of NPs into the matrix resulted similar compression strength as the matrix hydrogel. The hydrated NCHGs swelled more slowly but admitted more water. The drug was incorporated in NPs by swelling in CHX aqueous solution or added to the solution of monomer mixture followed by photopolymerization. Studies of release kinetics revealed that on average 60% of the loaded drug was released. The most rapid release was observed over a 24 h period for matrix gels with low crosslinking density. For NCHGs, the release period exceeded 48 h. An unexpected result was observed for NCHGs without drug in the NPs. In this case, increasing release was observed for the first 24 h. Thereafter, however, the apparent quantity of detectable drug decreased dramatically.     

Sugar acrylate‐based polymers as chiral molecularly imprintable hydrogels

New polymeric hydrogels with molecular imprinting properties were prepared from enzymically generated sugar acrylates. These so called MIPs (molecularly imprinted polymers) were used as chiral stationary phases for the resolution of the D ‐ and L ‐isomers of CBz–Asp in polar organic eluants. In the presence of 25% (mol/mol) methyl‐α‐D ‐glucopyranoside‐6‐acrylate [the balance consisting of N,N′‐methylenebisacrylamide (BIS)], a separation factor of nearly 2.5 is achieved. The effectiveness of separation was dependent on the nature of the solvent used as eluant and the sugar incorporated into the MIP. Molecular modeling revealed that hydrogen bonding between the sugar and CBz–Asp strongly influences chiral resolution. The broad array of sugars available and their ability to be modified selectively with the use of biocatalysts in both aqueous and organic media may provide a wide range of new imprinted materials for use in separations, sensing, and catalysis. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 1665–1671, 1999