Hydrogels for an Accommodating Intraocular Lens. An Explorative Study

Biomacromolecules 2003, 4, 608-616

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Hydrogels for an Accommodating Intraocular Lens. An Explorative Study Jacqueline H. de Groot,†,‡ Coenraad J. Spaans,§,| Ralph V. van Calck,§ Folkert J. van Beijma,†,§ Sverker Norrby,† and Albert J. Pennings*,‡,§ Pharmacia Groningen BV, Van Swietenlaan 5, 9728 NX Groningen, The Netherlands, and Department of Polymer Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands Received October 21, 2002; Revised Manuscript Received February 11, 2003

In this study it was investigated whether hydrogels could be used for an accommodating lens. The requirements of such a hydrogels are a low modulus, high refractive index, transparency, and strength. Since conventional hydrogels do not possess this combination of properties, a novel preparation method and new polymers are introduced. As starting materials poly(1-hydroxy-1,3-propanediyl), poly(ethylene-co-vinyl alcohol), poly(vinyl alcohol), and poly(allyl alcohol) were used. The first three were cross-linked with a number of diisocyanate compounds. Network formation was performed at low concentrations in a good solvent. Mixing of the polymer solution and cross-linker appeared to be crucial for transparency. Poly(1-hydroxy-1,3propanediyl), cross-linked with a slow reacting diisocyanate block, shows the most promising properties with respect to refractive index, transparency, tensile strength, and modulus. Poly(allyl alcohol) hydrogel was made by compression molding. The hydrogel was transparent and had a high refractive index and low modulus. It was concluded that hydrogels could be used as accommodating lens material. Introduction The natural lens is a precisely formed structure of fiber cells containing about 65% water and 35% organic material, chiefly structural proteins. The proteins are responsible for the relatively high refractive index (1.42) of the lens and are structured in such a way that there are negligible local variations in their density, resulting in a transparent lens.1 The lens has the ability to rapidly change its shape so that objects at different viewing distances can be imaged clearly on the retina. The lens is enclosed in a capsule, which is connected to the ciliary body by zonular fibers. By contraction and relaxation of the ciliary muscle, zonular fibers are respectively relaxed and stressed. In this so-called accommodation process, the lens itself plays a passive role. Due to the softness of the lens, this results respectively in a more round and a more flat lens as is shown in Figure 1. The Young’s modulus of the natural lens is less than 1 kPa. Koenig et al.2 found that lens proteins appear as compact globular proteins of 1350 kDa (cortical) and 1700 kDa (nuclear) and they behave as aggregates g50000 kDa at concentrations present in the lens. Apparently the forces that keep the proteins in a globular aggregate conformation and the interaction between aggregates are very weak, to obtain a very low modulus. The accommodation amplitude decreases with age and is completely gone at the age of 50-55.3 The lack of accom* To whom correspondence may be addressed. E-mail: apennings@ orteq.com. † Pharmacia Groningen BV. ‡ Current address: Orteq BV, Kamerlingheplein 16, 9712 TR Groningen, The Netherlands. § University of Groningen. | Current address: Corus RD&T, PO Box 10000, 1970 CA IJmuiden, The Netherlands.

Figure 1. Accommodation of the lens: (top) far vision; (bottom) near vision.

modation of older lenses has mainly been attributed to gradual stiffening of the lens over the years. There are indications that the rest of the accommodation mechanism still works.4 Fisher showed that the Young’s modulus of the lens increased from less than 1 kPa at the age of 20 to more than 2 kPa at ages higher than 50.5 Newer research by Eckert et al. has indicated an even 10-fold increase from 20 to 60 years of age.6 The insufficient accommodation amplitude for clear vision at short distances is called presbyopia and is the most common ocular affliction in the world. Although presbyopia can be corrected by bifocal or reading spectacles, this correction is not ideal and is troubling people in everyday life. Therefore, it would be useful to restore accommodation, to improve the quality of life, by replacing the natural lens with soft biomaterials inside the capsular bag. Hydrogels are a class of materials that are interesting for this application. The natural lens itself is a hydrogel. Hydrogels have been found to be biocompatible and are used in numerous applications in medical technology. Additionally, hydrogels have the potential to be very soft, due to the presence of water. To function as a natural lens, the properties

10.1021/bm0257053 CCC: $25.00 © 2003 American Chemical Society Published on Web 03/27/2003

Hydrogels as Accommodating Lens Material

of the hydrogel should be comparable to the natural lens with respect to refractive index, modulus, and transparency which are respectively, 1.42, 1.5 kPa, and more than 60% in the visible light range. In addition, the hydrogel lens should be foldable in the dry or wet state, so that the eye surgeon can implant it through a small incision. This requires strength of both the dry and the swollen polymer network. There are, however, no hydrogels available with a combination of these properties. For an accommodating hydrogel lens material, it is important that the swelling pressure in the eye is zero. According to the Flory-Rehner theory, the swelling pressure of a polymer gel may be expressed as:7 $ ) -{(RΤ/V)[ln(1 - φ) + φ + χφ2 + wφ3]} - G where G is the elastic modulus of the swollen network, V is the molar volume of the solvent, φ is the volume fraction of the polymer, and χ and w are the second- and third-order interaction parameters, respectively. Since the first term on the right-hand side refers to a mixing term, the osmotic component, the swelling pressure can be also expressed as:8 $ ) Πmix - G In equilibrium with water (eye fluid), the swelling pressure of the hydrogel lens is zero when the mixing pressure is balanced by the elastic response of the network, the elastic modulus. Since the modulus of the hydrogel is restricted to 1.5 kPa, Πmix is also restricted to be 1.5 kPa. It is known that hydrogels based on water-soluble polymers have high Πmix due to the good interaction between polymer and water. Hecht et al. determined Πmix of poly(vinyl alcohol) (PVA) hydrogels as a function of polymer concentration.9 Even though water is known to be nearly a θ solvent for PVA,10 at 25 wt %, Πmix was found to be 100 kPa and is exponentially increasing with concentration. At concentrations needed for the required refractive index, 3050 wt %, Πmix will be in the megapascals and thus be much too high for this application. For this reason researchers who tried to use hydrogels based on water-soluble polymers as an accommodating lens were not successful. They had to lower the polymer concentration below 10 wt % to reduce Πmix.11-13 However, the low concentration resulted in a low refractive index. The only possibility to maintain a high polymer concentration in hydrogels based on water-soluble polymers is to cross-link them densely.14 It is obvious that this results in high modulus hydrogels. Another option to reduce Πmix is to use a polymer with a reduced interaction with water, a water-swellable polymer. This is also how nature is achieving a high protein concentration in the lens. At concentrations above 15 wt %, the lens proteins form aggregates with a molecular weight of more than 50 million.15 The proteins have a globular, collapsed conformation due to the reduced interaction between polymer and water.16 However, a material comparable to the natural lens cannot be transferred due to the low strength of the material. Poly(HEMA) is an example of a synthetic water-swellable polymer. The polymer has to be chemically cross-linked to

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Figure 2. Molecular weight between entanglements.

obtain reasonable mechanical properties. However, conventional poly(HEMA) networks swollen in water are very weak (0.5 MPa) and have a high modulus. Since the pioneering work of Wichterle and Lim,17 who invented poly(HEMA) networks in 1960, a great deal of research has been concentrated on hydrogels to improve their properties. This has mainly been done by introducing hydrophobic monomer in the network. Due to the reduced water content, the refractive index and modulus of these hydrogels are too high.18 It can be concluded that conventional hydrogels cannot be used as accommodating lens material. To develop such a material, a novel approach as well as novel polymers are needed. To obtain a low modulus, low cross-link densities are needed. Cross-links can either be covalent or be physical. Physical cross-links are formed when interaction takes place between the polymer chains, for instance, due to hydrogen bonding. This might even lead to crystallization. Strong polymer-polymer interactions should, therefore, be prevented. Trapped entanglements are also physical cross-links and will, thus, also increase the modulus. The molecular weight between entanglements of a gel (Figure 2) increases strongly upon dilution as indicated by one of the scaling laws of de Gennes19 Mgel ) Mmelt φp-R where Mmelt is the molecular weight between entanglements of polymer melt, φp is the polymer volume fraction, and R is an exponent, the value of which depends on the solvent quality, being 1.25 for a good and 2 for a poor solvent. To limit the amount of entanglements, cross-linking should, therefore, be performed in a good solvent at low concentrations. To obtain strong hydrogels, the structural defects of the network should be limited. The main source of flaws arises from dangling ends in the network, which do not contribute to the transmission of stress. Other flaws are trapped entanglements and loops formed by intramolecular crosslinking. The network defects shown in Figure 3 where first indicated by Flory.20 In addition to the mechanical properties, they will also affect the transparency since they cause networks to be inhomogeneous. From tensile strength measurements of rubber fractions cross-linked to the same cross-linking density, Flory derived the following correction for the fraction of the network, which is active, Sa Sa ) φp{1 - 2Mc/(M + Mc)}21 where φp is the polymer volume fraction in the swollen network, Mc is the molecular weight between cross-links,

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Figure 3. Network defects indicated by Flory.

and M is the molecular weight of the polymer prior to crosslinking. Sa is linearly proportional to the tensile strength. This equation indicates that high strength values are attained when the molecular weight prior to cross-linking as well as the molecular weight between cross-links is high. In this case the number of dangling ends is minimized. A possible way to prepare strong, transparent, soft hydrogels with a high refractive index is to cross-link high molecular weight, water-swellable polymers in a good solvent. In this study four high molecular weight waterswellable polyalcohols are used: poly(1-hydroxy-1,3-propanediyl), poly(vinyl alcohol-co-ethylene), poly(vinyl alcohol), and poly(allyl alcohol). Poly(1-hydroxy-1,3-propanediyl), poly(vinyl alcohol-co-ethylene), and poly(vinyl alcohol) were cross-linked with different diisocyanates in a good solvent at 5 wt %. After drying, the networks were swollen in water. Poly(allyl alcohol) hydrogels were made by compression molding. The appearance, transmission, equilibrium water content, and mechanical properties were determined, and the hydrogels were evaluated on their suitability to be used for an accommodating lens. Experimental Section Material and Methods. All reactions were performed under an inert atmosphere of nitrogen gas in flame-dried glassware. Poly(vinyl alcohol) (PVA, 99+% hydrolyzed, Mn > 200000 g/mol) was synthesized from high molecular weight poly(vinyl acetate) (PVAc, Aldrich Chemical Co. Inc.) according to literature procedures.22 Poly(allyl alcohol) (PAA) was obtained by reduction of high molecular weight polymethylacrylate (PMA) (received from the University of Groningen, Mw 730000, Mn 260000) with lithium aluminum hydride following literature procedures.23 Poly(vinyl alcohol-co-ethylene) (73/27) (EVA, Aldrich Chemical Co. Inc.) was used as received. Poly(1-hydroxy-1,3-propanediyl) (PHP) was synthesized from polyketone (Carilon, LVN [η] ) 6.7 dL/g, Mv ∼ 450000 g/mol, Akzo-Nobel, Dobbs Ferry) according to the procedure of Lommerts et al.24 However, three additional purification steps were included. The crude polyalcohol was dissolved in N-methylpyrrolidone (NMP, Acros) (1% w/w) at 60 °C. After cooling to room temperature, the solution was filtered and precipitated in diethyl ether (Acros or Aldrich). The resulting polyalcohol was dried under reduced pressure at 50 °C. This procedure was repeated. The purified

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polyalcohol had an intrinsic viscosity of 5.5 dL/g in m-cresol (Acros) at 25 °C. n-Butylisocyanate (BI) and the cross-linkers 1,4-butanediisocyanate (BDI, DSM) and 1,12-dodecyldiisocyanate (DDI, Aldrich) were distilled under reduced nitrogen prior to use. The block cross-linker, BDI-BDO-BDI, which is 1,4-butanediol (BDO) endcapped with BDI was synthesized following the procedure of the de Groot et al.25 All solvents (Acros or Aldrich) were purified and dried according to literature procedures. Network Formation. The networks were synthesized using a variety of polyalcohols and solvents. PHP was dissolved in NMP, PVA in DMSO, and poly(vinyl alcohol)co-ethylene in NMP to a concentration of 5 wt % at 80 °C. The solution was cooled to 60 °C. In some cases PHB and PVA were first reacted with butylisocyanate (5 or 10 mol % of the OH groups were converted). Mixing was performed at 60 °C and reaction at 80 °C for 3 h by addition of butylisocyanate in a small amount of solvent. Butylated PVA turned out to be soluble in NMP, and thus cross-linking was carried out in that solvent. The solution was cooled to 60 °C and mixed with the cross-linker that was dissolved in a small amount of solvent. The reaction mixture was homogenized for 3 min and poured onto a glass plate with a Teflon ring. A second glass plate was used to close the cell in such a way that no gass bubbles were included. The cell with the reaction mixture was placed in an oven at 80 °C for 40 h. Subsequently, the upper glass plate was removed and the solvent was allowed to evaporate at 80 °C. The resulting networks were stored at 50 °C under reduced pressure. Films were placed in water for at least 1 week. Compression Molding of Poly(allyl alcohol). Poly(allyl alcohol) was dissolved in methanol/2 N HCl (1:1). The solutions was then spray-dried. The powder was then compression molded at 150 °C for 10 min. A mold with a diameter of 2 cm and a thickness of 1.5 mm was used. A force of 300 kN was applied using a Pasadena Hydraulics, Inc., hydraulic press. Network Characterization. Dry and wet networks were characterized. IR spectrophotometry (Perkin-Elmer, Spectrum One) was used to determine the degree of hydrolysis of poly(vinyl acetate). Differential scanning calorimetry (DSC) was carried out using a Perkin-Elmer DSC-7 on sample weights of 5-10 mg with a heating rate of 10 °C/min over the temperature range of -100 to 250 °C. Tensile testing was performed on dry and wet rectangularshaped specimens (40 × 1.0 × 0.35 mm), cut from thin films at room temperature using an Instron (4301) tensile tester, equipped with a 100 N load cell and an extension rate of 10 mm/min. The length between clamps was 25 mm. For the determination of the permanent set, a hydrogel was deformed to 100% strain two times. After 3 min the third cycle was recorded. For determination of the permanent set, a 10 N load cell was used. Shear modulus was determined with a stress-controlled rheometer (Bohlin, CVOR)


Figure 4. Polyalcohols used for network formation.

Optical transmissions were determined using a SLM Aminco 3000 Array Milton Roy spectrophotometer in the range of λ ) 200-800 nm. After the network films were immersed in water at the appropriate temperature, equilibrium water contents (EWCs) were determined using the following formula EWC (%) ) (Psw - Pd)/Psw × 100 In which Psw refers to the mass of the swollen network and Pd to the mass of the network in the dry state. The refractive index of the dry polymer networks was determined with a Bellingham & Stanley 60/ED refractometer. The refractive index of the hydrogels was calculated from the weight fraction water and polymer of the hydrogel. Results and Discussion Polymers. Poly(vinyl alcohol-co-ethylene), 73/27 (EVA), was obtained commercially. Poly(1-hydroxy-1,3-propanediyl), poly(vinyl alcohol), and poly(allyl alcohol) were synthesized. The chemical structures of the used polymers are presented in Figure 4. Poly(1-hydroxy-1,3-propanediyl) (PHP) was synthesized from polyketone, being a stereoregular perfectly alternating copolymer of ethylene and carbon monoxide. The reduction was carried out in a 50/50 (v/v) mixture of ethanol and water using sodium boron hydride as reducing agent.24 Although polyketone is only slightly soluble in mixtures of ethanol and water, the reduction can be carried out in this solvent system because the resulting polyalcohol is soluble in it. Solvation of the resulting polyalcohol is thus the driving force for the completion of the reaction. For high molecular weight samples, long reaction times (24 h.) were needed in order to obtain complete conversion, which was monitored with IR spectroscopy. It also turned out to be crucial to use finely powdered polyketone in order to create a large surface area. Powdering was performed at liquid nitrogen temperatures. The resulting PHP was extensively purified by subsequent filtration and precipitation. To ensure complete transparency of the polymer solution, this procedure was repeated three times. High molecular weight poly(vinyl alcohol) (PVA) was synthesized by following the procedure of Sakurada et al.22 High molecular weight poly(vinyl acetate) was hydrolyzed using methanol in combination with aqueous NaOH. The resulting polymer precipitated from the solution and was purified by washing with methanol.


Figure 5. Hydrogel formation. A high molecular weight waterswellable polymer is cross-linked at low concentration in a good solvent. After that the network is dried and swollen in water.

High molecular weight polyallyl alcohol (PAA) was synthesized by reduction of high molecular weight polymethylacrylate with a 4-fold excess of lithium aluminum hydride according to the procedure of Schultz et al.23 The reaction was carried out in THF. The polymer, however, is insoluble in organic solvents. It is known that only when Pn < 350 the polymer is soluble in organic solvents. For high molecular weights, only combinations of organic solvents and aqueous acid can be used, e.g., methanol/2 M hydrochloric acid (1/1) or THF/2 M hydrochlorid acid (1/1). Network Formation. The choice of the cross-linker might be crucial for transparency because the water-swellable polymers are obviously close to phase separation in water. By reduction of the number of conformations of the polymer at cross-linking, a water-swellable polymer might easy phase separate. Diisocyanates are chosen as cross-linkers for several reasons. Interesting work has been done by Gnanou, Hild, and Rempp.26 They synthesized hydrophilic polyurethane networks by cross-linking poly(ethylene oxide) precursor polymer with triisocyanate yielding optically perfectly transparent hydrogels. In addition, in our earlier research27 we synthesized densely cross-linked polyurethane networks, which were implanted in the eye of rabbits and were well tolerated and did not induce posterior opacification within a year of implantation. Polyurethane-based hydrogels, are, therefore, also expected to be tolerated as well. Finally, compared with conventional diacrylate cross-linkers, the main difference is that acrylate cross-linking occurs in an uncontrolled, radical reaction whereas isocyanates react in a step reaction, resulting in more homogeneous networks28 and probably more transparent hydrogels. As a representative for a short cross-linker, 1,4-butanediisocyanate has been used. 1,12-Dodecyldiisocyanate has been used as longer cross-linker. The hydrogel formation procedure is shown in Figure 5. PHP, EVA, and PVA were dissolved at a concentration of 5 wt % at 80 °C in methylpyrrolidone (NMP) or DMSO and the cross-linker was added in a small amount of solvent. The high temperature was used to decrease the viscosity of the polymer solution to enable mixing. In some cases the polymer was modified with n-butylisocyanate before cross-linking. After homogenization, the solution was transferred to a glass plate with a Teflon ring on it. A second glass plate and a clamp were used to close the cell, and all the air was excluded. After reaction, the upper glass plate was removed and the solvent was evaporated. With this technique, the volume during

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Table 1. Appearance of Hydrogels Based on Poly(hydroxy-1,3-propanediyl) (PHP), Poly(ethylene-co-vinyl alcohol) (EVA), and Poly(vinyl alcohol) (PVA) (Modified with Butylisocyanate), Cross-Linked in N-Methylpyrrolidone at Cross-Link Percentages of 0.5-20% with Different Cross-Linkers polymer

solvent

cross-linker

appearance

PHP PHP PHP EVA (27/73) EVA (27/73) PVAf

NMPa NMP NMP NMP NMP NMP

BDIb DDIc BDI-BDO-BDId BDI BDI-BDO-BDI BDI-BDO-BDI

opaque opaque transparente transparent transparent opaque

a N-Methylpyrrolidone. b 1,4-Butanediisocyanate. c 1,12-Dodecyldiisocyanate. d Diisocyanate block.25 e Very susceptible to environmental changes. f Modified with 5 mol % n-butylisocyanate.

cross-linking is kept constant. This has several implications for the structure of the resulting network. Due to the good solvent and the low concentration, the amount of entanglements in the polymer solution has been minimized. After cross-linking, this results in networks wherein a minimal amount of entanglements is trapped. Furthermore, it can be expected that cross-linking has occurred under homogeneous conditions. It appeared to be very difficult to mix the polymer solution with 1,4-butanediisocyanate and 1,12-dodecyldiisocyanate homogeneously. Due to the high reactivity of the diisocyanates, a gel was formed 3 min after addition of the crosslinker. Sometimes this was not enough to get a proper mixing. Even at lower concentrations (2.5 wt %) at room temperature, this appeared to be a problem. It is therefore, essential to use a less reactive diisocyanate. In a previous study we have developed a diisocyanate block.25 It was made by end-capping butanediol (BDO) with butanediisocyanate (BDI). The diisocyanate block was used to chain extend poly(lactide-co--caprolactone) prepolymers to make polyurethanes. We have found that the diisocyanate block was less reactive than 1,4-butanediisocyanate. Since the high reactivity of both butanediisocyanate and dodecyldiisocyanate appeared to be a problem, it was decided to use this diisocyanate block also for cross-linking the water-swellable polymers. With this, diisocyanate mixing could be performed over a much longer time, so it is expected that cross-linking occurred under homogeneous conditions. Characterization. A series of networks was made varying in cross-link percentage from 0.5 to 20 mol %. The different series and their appearances are summarized in Table 1. PVA was modified with 5 mol % n-butylisocyanate to reduce the polymer-polymer interaction and crystallinity of the polymer. All PHP hydrogels obtained by cross-linking with 1,4butanediisocyanate and 1,12-dodecyldiisocyanate were opaque. This is likely a result of the high reactivity of the diisocyanate giving rise to inhomogeneous reaction. Furthermore the more polar nature of 1,12-dodecyldiisocyanate may give rise to a phase-separated morphology. The BDI-BDO-BDI crosslinker has a lower reactivity than the other cross-linkers and is rather polar. The networks were transparent but turned out to be rather unstable with respect to phase separation. A sudden increase or decrease in temperature often resulted in opaqueness or even a complete loss of transparency. Sudden

Figure 6. Equilibrium water content as a function of cross-link density (mol %) for (b) poly(1-hydroxy-1,3-propanediyl) and (O) poly(vinyl alcohol-co-ethylene) 73/27 based networks (BDI-BDO-BDI crosslinker) at 25 °C.

change in environment, such as removal of the water surrounding, had the same result. This process was not reversible. These effects have also been observed by Shibayama et al.29 and are also observed for the natural lens.1 Apparently these hydrogels are very close to phase separation. EVA cross-linked with either 1,4-butanediisocyanate or 1,12-dodecyldiisocyanate was transparent. At this moment we do not have an explanation for this. All the PVA hydrogels were initially transparent, but after 3 days in water they all became opaque. This was also observed for PVA hydrogels that were modified with ethylisocyanate and phenylisocyanate. At cross-link percentages >4 mol %, syneresis was observed for EVA- and PVA-based hydrogels indicating that in these cases elastic forces play an important role at high cross-link percentages. The poly(1-hydroxy-1,3-propanediyl)based networks generally did not show this effect. This can be explained by the decreased interactions between crosslinker and the polymer chain compared to the EVA and PVA systems. Furthermore, NMP may be a better solvent for PHP than it is for EVA polymer and that DMSO is for PVA. Since the PVA hydrogels were all opaque, it was decided not to further explore this polymer for the application. In Figure 6 the equilibrium water contents (EWC) of the transparent PHP and EVA hydrogels, cross-linked with the BDI-BDO-BDI block, as a function of cross-link percentage is shown. The EWC of the PHP hydrogels decreases from 54% at a cross-link density of 1 mol % to 37% at a cross-link density of 10 mol %. This corresponds to a respective refractive index of 1.41-1.44, respectively. The EWC content of the EVA hydrogels is nearly constant and lies around 17%, which corresponds to a refractive index of 1.46. The EWC is rather low, although the composition in terms of hydrogen, oxygen, and carbon content is comparable to PHP. This may be caused by the blockiness of the copolymer or branching, resulting in an altered morphology. With respect to the refractive index and the modulus, a hydrogel with a higher water content is needed. EVA polymers with higher poly(vinyl alcohol) content (>90%) would be interesting. Since they are not available, it was decided to continue the study with PHP. The tensile strengths of the PHP hydrogels cross-linked with BDI and BDI-BDO-BDI as a function of mole



Table 2. Appearance of Hydrogels Based on Poly(hydroxy-1,3-propanediyl) (PHP), Modified with n-Butylisocyanate and Cross-Linked at Cross-Link Percentages of 0.5 mol % polymer

cross-linker

PHP PHP PHP PHP

BDI-BDO-BDIa

a

BDI-BDO-BDI BDI-BDO-BDI BDI-BDO-BDI

Diisocyanate block.25

b

n-butyl isocyanate (mol %)

appearance

0 5 10 25

transparentb transparent transparent transparent

Very susceptible to environmental changes.

Figure 7. Tensile strength as a function of cross-link density (mol %) for water-swollen, BDI-based poly(1-hydroxy-1,3-propanediyl) network. The tensile strengths are not corrected for the amount of polymer in the cross section.

Figure 9. Equilibrium water content as a function of n-butylisocyanate percentage (mol %) in poly(1-hydroxy-1,3-propanediyl) systems.

Figure 8. Tensile strength as a function of cross-link density (mol %) for both a dry and a swollen BDI-BDO-BDI based poly(1hydroxy-1,3-propanediyl) network: (b) dry networks; (0) hydrogels, the tensile strengths are corrected for the amount of polymer in the cross section; (9) hydrogel, the tensile strengths are not corrected.

percentage of cross-linker is shown in Figures 7 and 8, respectively. In addition, the tensile strength of dry PHP, BDI-BDO-BDI cross-linked network as a function of cross-link density is also shown in Figure 8. As can be seen, all curves show a maximum in the tensile strength. The hydrogel data in Figure 8 have also been corrected for the amount of polymer in the cross section, since the amount of water does not contribute to the strength, and shows a more pronounced maximum. This behavior has been seen before30 and was predicted by Flory.21 The first part of the curve can be explained by the decreasing amount of dangling ends with increasing cross-link density. The second part of the curve, where the tensile strength decreases with increasing crosslink density, is explained in terms of polydispersity of the molecular weight between cross-links. In addition, the decreased ability of the PHP chains to crystallize under strain with increasing cross-link density will also have an effect. The maximal tensile strength of the hydrogel is about 10 MPa, which is extremely high for hydrogels with such high water content. The Young’s moduli of the hydrogels generally vary between 1.5 and 4.0 MPa, which is too high for the application. Since BDI-BDO-BDI cross-linked hydrogels were transparent, we focused on these hydrogels. The high modulus and the unstability of the hydrogels is probably

the result of the high polymer-polymer interaction, which may lead to the formation of crystallites. It is known that PHP crystallizes under strain.24 It is, therefore, very likely that small crystallites are present although no melting point is observed in the DSC. To reduce crystallization, PHP was modified with 5 mol % butylisocyanate. To keep the EWC and the modulus low, we have chosen to use a small amount of cross-linker in further studies. The networks that have been synthesized are summarized in Table 2. Modified hydrogels were much more stable to environmental changes than the unmodified hydrogels. The most likely explanation for this effect is that homogeneity of the unmodified system is disturbed, resulting in a phase-separated morphology in which concentrated polymer phases are present as well as dilute polymer phases. In the concentrated phases crystallization may take place. n-Butylisocyanate apparently avoids phase separation and possibly crystallization. In Figure 9 the EWC as a function of n-butylisocyanate percentage is shown. The EWC decreases with increasing n-butylisocyanate content to about 10%. After that the EWC does not decrease any further. The EWC can thus be influenced both by the addition of side groups and by the cross-link density. Especially for application in the body, it is essential to know the dependence of the EWC on the temperature. In Figure 10 the equilibrium water content of modified and unmodified PHP hydrogels cross-linked with BDI-BDOBDI as a function of temperature is shown. Both hydrogels show a lower critical solution temperature (LCST) effect. Higher temperatures resulted in more polymer-polymer interactions and thus a decreased hydrophilicity. Due to the less hydrophilic nature of the n-butylurethane moiety compared to the hydroxyl group, the equilibrium water content of the modified hydrogel has decreased over the complete

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Figure 10. Equilibrium water content as a function of temperature for 0.5% cross-linked poly(1-hydroxy-1,3-propanediyl) hydrogels: (b) unmodified; (O) modified with 5% n-butylisocyanate. Figure 12. Stress-strain curves of dry (1-hydroxy-1,3-propanediyl) networks: (s) 5% n-butylisocyanate; (‚ ‚ ‚) 10% n-butylisocyanate; (- ‚ -) 25% n-butyl isocyanate groups at 25 °C. The extension rate was 10 mm/min.

Figure 11. Dependence of the Tg on the percentage of side groups.

temperature range. At each temperature the hydrogels were transparent. At 37 °C the equilibrium water content of unmodified PHP and modified PHP hydrogels is 50 and 32 wt % respectively, which correspond to a refractive index of 1.41 and 1.44. A further experiment that has been performed is determination of the EWC of the modified PHP hydrogel in saline. At 37 °C, a small increase from 32% to 36% EWC was observed. In view of transparency and mechanical properties, the thermal behavior of the network is of great importance. Polymers with a Tg below room temperature allow folding. On the other hand if the Tg of the polymer is above room temperature, the Tg can be lowered by the addition of some water. The dependence of the Tg of the dry PHP networks with 0.5% cross-links on the percentage of n-butyl functionalization is shown in Figure 11. The Tg is strongly affected by the amount of side groups and in decreasing with increasing functionality. This is due to the fact that functionalization reduces the interaction between polymer chains.31 PHP networks with 0-5% side groups look most promising for the application. Their Tg is low enough, and their EWC are in the good range. The optical transmission of the hydrogel with 5% n-butylisocyanate at λ ) 480 nm was found to be >90%. The stress-strain curves of dry poly(1-hydroxy-1,3propanediyl) networks with different amounts of n-butylisocyanate groups are shown in Figure 12. Two effects can be observed. In the case of 5% side groups, the Tg was observed at room temperature resulting in materials with a rather high modulus. When 10% of n-butylisocyanate is

Figure 13. Stress-strain curves of water-swollen (1-hydroxy-1,3propanediyl) networks with (s) 0% n-butylisocyanate, (- - -) 5% n-butylisocyanate, (‚ ‚ ‚) 10% n-butylisocyanate, and (- ‚ -) 25% n-butyl isocyanate groups at 25 °C. The equilibrium water content is 55, 40, 25, and 30 wt %, respectively. The extension rate was 10 mm/min.

added, the Tg decreases to 18 °C (Figure 11) and the modulus decreases dramatically. At the end of the curve, an upturn effect is observed indicating oriented crystallization. When the amount of side groups is increased to 25%, oriented crystallization is suppressed and the upturn effect is negligible. The polymer with 5% side groups has the highest tensile strength. This is because around the Tg the viscoelastic contributions are most pronounced. The stress-strain curves of the 0, 5, 10, and 25% modified PHP hydrogels are shown in Figure 13. The equilibrium water contents are 55, 40, 25, and 30 wt %, respectively. The Young’s moduli and moduli at 50-125% strain are shown in Table 3. The Young’s modulus seems to increase with the degree of modification. One has to be careful in drawing conclusions because different effects determine the Young’s modulus in this case. On one hand it is expected that that the crystallinity decreases with the increasing degree of modification, resulting in an increase in modulus with the degree of modification. On the other hand the EWC decreases with increasing degree of modification, so it can be expected that the Young’s modulus is increasing with


Hydrogels as Accommodating Lens Material Table 3. Young’s Moduli and Moduli at 50-125% Strain for PHP 0.5% Cross-Linked Hydrogels with 0, 5, 10, and 15% Modification modification (%) 0 5 10 25 a

EWC

Young’s modulus (MPa)

modulus at 50-125% strain (MPa)

55 40 25 30

3 4 6 6

a 0.20 0.60 0.60

Approaching zero.

increasing degree of modification. In addition, the Young’s modulus might also be a result of a skin-core effect because the skin tends to contain less water due to evaporation. This effect is most pronounced at very low strains. All hydrogels show a very low modulus between 50 and 125% strain. This low modulus is caused by the absence of entanglements, allowing the polymer chains to rearrange freely on increasing strain. This is also the reason for the high strain at break, which is above 300% in all cases. The modulus in this region is increasing with increasing modification due to the reduction of the water content. The modulus of the unmodified hydrogel was so low that it could not be determined accurately since it is approaching zero. At higher strains, the network with 0 and 5% side groups shows a considerable upturn effect indicating oriented crystallization. It is known that PHP is able to crystallize under stress.24 In the case of 10 and 25% side groups, the upturn effect is less because crystallization is prevented by a large amount of side groups. The tensile strength of the unmodified and 5% modified PHP hydrogels, which is 14.5 and 7.5 MPa, respectively, is most impressive since their respective equilibrium water content is 40 and 55 wt %, respectively. It can be concluded that hydrogels based on PHP modified with less than 0-5% look most promising for the application because they poses high strength and the right refractive index and the modulus is very low. The crystallinity might be responsible for the high Young’s modulus and could be decreased with a less hydrophobic modifier such as ethylisocyanate. Furthermore, it would be interesting to measure the stress-strain behavior under water to prevent evaporation of water out of the hydrogel. When the hydrogel is implanted in the wet state, it is important to determine the permanent deformation of the water-swollen networks because the hydrogel has to undergo large stresses during implantation. The gel was deformed two times to 100% strain. After 3 min, a third cycle was recorded. The first and third cycle are shown in Figure 14. As can be seen, the permanent deformation is approximately 5%. This is rather low since only 3 min was allowed before the third cycle was recorded. The waiting time was so short due to the evaporation of the water. A hysteresis loop is observed indicating nonideal rubber behavior. Permanent deformation and the hystersis loops clearly indicate that small crystallites are present thoughout. The network is, however, clear, indicating that the crystallites are smaller than the wavelength of light. In the third cycle, the Young’s modulus has increased from 6 to 9 MPa, while the modulus at 100% strain is not influenced. It can be

Figure 14. Determination of the permanent deformation of polyalcohol: (s) first cycle; (- - -) third cycle. The cylcles were recorded at 10 mm/min. After the second cylce, 3 min was allowed before the third cycle was recorded.

concluded that drying of the sample has some effect but cannot be fully responsible for the high initial Young’s modulus, which is measured at short time where evaporation is neglectible. The high initial Young’s modulus should be explained in terms of the disruption of small crystallites. However, the drying of the sample is likely to have a great influence on the hysteresis of the hydrogels. To determine the permanent set of hydrogels more properly, the tests should be performed in 100% humidity. Compression Molding of Poly(allyl alcohol). Since high molecular weight poly(allyl alcohol) is insoluble in organic solvents, the polymer was processed by compression molding at 150 °C. The DSC thermogram showed a Tg at 52 °C and no crystallinity. The brittle and transparent polymer was swollen in water at 25 °C to give a transparent hydrogel with an EWC of 45%, which corresponds to a refractive index of 1.42. The shear modulus of the polymer is 40 kPa. This corresponds to a Young’s modulus of 120 kPa. Since the polymer has been compression molded in the melt, it can be expected that it contains a considerable amount of entanglements. Even though, the Young’s modulus of the hydrogel was very low. In addition, the skin-core effect due to drying out of the surface is less pronounced in this hydrogel because the hydrogel was 10 times thicker than the PHP hydrogels. By reducing the amounts of entanglements, it should be possible to reduce the modulus to the level comparable to the natural lens modulus. Obviously some chemical crosslinks should be introduced to prevent permanent deformation. An interesting possibility may be swelling of small polymer particles in a cross-linker solution, followed by removal of the solvent and then compression molding the polymer below the melting temperature of the polymer so that no extra entanglements are introduced. It is known that during formation of small particles by precipitation from low concentration solution, no extra entanglements are introduced.16 By this method32 a homogeneous polymer-crosslinker mixture can be obtained resulting in homogeneous polymer networks after cross-linking.

616


Conclusions New hydrogels based on high molecular weight polyalcohols have been prepared by two different techniques. Three candidate materials, poly(1-hydroxy-1,3-propanediyl), poly(ethylene-co-vinyl alcohol), and poly(vinyl alcohol) were cross-linked with diisocyantes. Poly(1-hydroxy-1,3-propanediyl) shows the most promising properties with respect to refractive index, transparency, modulus, and tensile strength. Proper mixing of the polymer solution and crosslinker appeared to be crucial to obtain transparent hydrogels. Cross-linking with a diisocyanate block of low reactivity results in the most homogeneous and transparent networks. The resulting materials show a low modulus and look promising with respect to the application as accommodating lens. This results from the fact that cross-linking was performed in a good solvent at low concentration, thus minimizing the amount of trapped entanglements. In all cases, a maximum in tensile strength was observed as a function of cross-link density. Equilibrium water contents and thus the refractive index can be adjusted by modification of the polymer with more hydrophobic monoisocyanates. In the case of low cross-link densities, stabilization of the systems with respect to phase separation is required, e.g., by addition of monoisocyanate. The optimal amount of monoisocyanate is 0-5%. Low modification degrees are needed to keep the water content high and the modulus low. Some degree of modification is needed to stabilize the system. An alternative method would be to modify the polymer with a less hydrophibic monoisocyanate. In that case more modification is possible to decrease crystallinity, without decreasing the water content too much, which will decrease the Young’s modulus of the hydrogels. Poly(allyl alcohol) has been processed by compression molding. Even though entanglements are surely present, this material had a very low modulus. Homogeneous crosslinking of small polymer particles could also result in materials suitable for the application. It can be concluded that hydrogels could be used as accommodating lens materials. Requirements that have to be fulfilled are homogeneous cross-linking, weak polymerpolymer interactions in water, limited amount of trapped entanglements, and dangling ends. In addition, the hydrogels should be evaluated in a humid surrounding. Acknowledgment. The authors thank Dr. John Juijn (Acordis, Arnhem) and Ing. Gert Alberda van Ekenstein (University of Groningen) for providing polyketone and polymethylacrylate, respectively.

de Groot et al.

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BM0257053

Hydrogels for an Accommodating Intraocular Lens. An Explorative Study

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