Synthesis of Soft Polysiloxane-urea Elastomers for Intraocular Lens Application

This study describes synthetic routes for aminopropyl-terminated polydimethylsiloxanes and polydimethyl-methyl-phenyl-siloxane-block copolymers and for soft polysiloxane-based urea (PSU) elastomers. It presents the application of PSUs as accommodating an intraocular lens. An evaluation method for in vitro cytotoxicity is also described.

Transcript

The methods demonstrated in this video show a convenient way to synthesize amino-terminated polysiloxanes and soft polysiloxane-based polyureas which are suitable for the application as accommodating intraocular lens. The main advantage of these techniques is that synthesis and analysis of the polymers can be performed easily according to standard methods without any complicated experimental setup. The implication of this technology extend toward cataract therapy because most commercially available intraocular lens materials are based on acrylic polymers which are too stiff to allow for sufficient accommodation.

Although this method was optimized to provide materials of very soft characteristics, of very high transparency, the method can easily be adopted to provide materials of completely different performance characteristics, materials that could also be applicable for example as coatings. Visual demonstration of the methods is critical as some of the synthesis and analysis steps are difficult to describe because they include experimental details that are important for successful performance. First, add 19.5 grams of degassed D4 and 0.9 grams of APTMDS to a 100 milliliter three neck round bottom flask equipped with a PTFE coated centrifugal stirrer and nitrogen inlet and outlet.

Add approximately 26 milligrams of previously prepared catalyst and stir the reaction mixture for 30 minutes at 80 degrees Celsius under a continuous nitrogen flow. Using a dropping funnel, add 45.5 grams of D4 drop wise to the reaction mixture within two to three hours and further stir at 80 degrees Celsius for 24 hours under a continuous nitrogen flow. Following this, exchange the centrifugal stirrer with a large oval magnetic stir bar and seal the three neck round bottom flask with two glass stoppers.

Use an adapter with a valve and slowly heat the PDMS to 150 degrees Celsius under a vacuum of 0.1 millibar to distill off the cyclic side products using a Schlenk line. Next, add one and a half to two grams of polysiloxane to a 250 milliliter conical flask containing a magnetic stir bar and dissolve the polysiloxane in 50 milliliters of THF under continuous stirring. Titrate the amino groups with 0.1 molar hydrochloric acid using bromophenol blue until a color change from blue to yellow is observed.

Repeat the titration with three samples to calculate the number average molecular weight. Add 2.939 grams of H12 MDI to a 250 milliliter four neck round bottom reaction flask equipped with a centrifugal stirrer, dropping funnel, and nitrogen inlet and outlet. Dissolve the H12 MDI in 40 to 50 milliliters of THF.

Next, dissolve 45 grams of degassed PDMS in 100 milliliters of THF in a beaker. Add the PDMS solution drop wise to the H12 MDI solution via a dropping funnel under continuous stirring and a nitrogen flow at room temperature. Then rinse the beaker and dropping funnel with 50 milliliters of THF and add this solution to the reaction mixer.

Add portions of the stoichiometric amount of the chain extender APTMDS to the pre-polymer solution. First, add 80%of the calculated stoichiometric amount of the dissolved chain extender APTMDS to the reaction mixture. Add the last portion of the chain extender to the reaction mixture and check the disappearance of the isocyanate absorption band in the FTIR spectrum.

To obtain non-cytotoxic polysiloxane-based polyurea elastomers with high molecular weights, it is important that the last portion of the chain extender is weighed out precisely and added to the polymer solution at a balanced stoichiometric ratio. Pour the resulting polysiloxane-based urea or PSU solution into a PTFE foil covered glass Petri dish and evaporate the solvent overnight in the fume hood. Combine seven to eight grams of small PSU pieces and 200 to 250 milliliters of chloroform in a 250 to 300 milliliter conical flask.

Add a magnetic stir bar and loosely seal the flask with a glass stopper and stir the mixture for at least 24 hours. On the following day, add the homogenous solution to a glass Petri dish and cover it with perforated aluminum foil. Ensure that the Petri dish is in a well ventilated area to allow the solvents to evaporate.

After drying the film, carefully remove it from the glass surface of the Petri dish using a small thin spatula and store it in a transparent envelope for mechanical characterization. To prepare di-cut dog bone shaped specimens from the PSU films, place the film under a punching knife unit. Push the lever down to punch out the test specimen and store it for at least 72 hours at ambient temperature.

Next, push the power on button on a tensile testing machine and click the button go to starting position in the main window of the software. After removing the transparent envelope, inspect the test specimen under a cross polarizer to exclude any internal stress. Measure the thickness and width of the test specimen using a caliper.

Then insert the values for thickness and width into the corresponding fields in the main window of the software. Now fix the test specimen between the upper clamping jaws of the testing machine. Click the button zero force in the main window of the software.

Then fix the bottom end of the test specimen between the bottom clamping jaws of the testing machine. Click the start measurement button to start the hysteresis measurement. For the tensile test, repeat the previous steps.

Add previously sterilized samples of PSU and 0.7 grams of Pellethane as a reference to 15 milliliter conical centrifuge tubes. Extract the samples with DMEM without FBS for 72 plus or minus two hours at 37 degrees Celsius and 5%carbon dioxide at an extraction ratio of 0.1 gram per milliliter. Prepare blind samples by adding DMEM without FBS into 50 milliliter conical centrifuge tubes and perform the same extraction.

Next, pipette 200 microliters of each PSU extract into six wells of a 96-well microplate containing HaCat cells. Next, pipette 200 microliters of the blind sample into six wells. For the negative control, pipette 200 microliters of fresh DMEM supplemented with 10%FBS into six wells.

For the positive control, pipette 200 microliters of DMEM supplemented with 10%FBS and 1%SDS into six wells. After incubating the cells for 24 hours at 37 degrees Celsius and 5%carbon dioxide, remove the extracts, blind samples, and controls. Then pipette 120 microliters of a previously prepared MTS stock solution into each well including the six wells without cells to determine the background.

After incubating the cells in the MTS solution for four hours, measure the absorbance of each well at 492 nanometers using a microplate reader. The ring chain equilibration of D4 and methylphenyl D4 with APTMDS yielded aminopropyl-terminated polydimethylsiloxanes and polydimethyl methylphenlysiloxane copolymers respectively. Aminopropyl-terminated polydimethylsiloxanes were synthesized with molecular weights between 3, 000 and 33, 000.

The copolymerization of the cyclic siloxane with pendant phenyl groups methylphenyl D4 was successful with a refractive index increasing from 1.401 to 1.4356. In line FTIR spectroscopy of the PSU elastomers confirmed the extremely rapid reaction of the isocyanate groups with the amino groups from the PDMS and APTMDS. Transparent PSU elastomer films exhibited a transmittance of greater than 90%up to a MDS molecular weight of 18, 000.

At higher PDMS molecular weights, the PSU films became increasingly opaque. With an increase in the PDMS molecular weight, soft PSU elastomers could be prepared. The Young's Modulus of PSU elastomers decreased from 5.5 to 0.6 megapascal.

Mechanical hysteresis was reduced for the PSU elastomers when they were prepared from high molecular weight PDMS. The hysteresis values were the first cycle at a 100%strain decreased from 54 to 6%The applied synthetic method permitted the preparation of PSU elastomers that do not release cytotoxic residuals as shown in cell viability tests performed with extracts of PSU elastomers on HaCat cells. While performing the synthesis of amino-terminated polysiloxanes, it's important to precisely weigh in the calculated amount of silane-based because this largely determines the final molecular weight of the polysiloxane.

Following this procedure, polyureas or polysiloxanes may be prepared that contain different pendant groups such as silanes. Silanes would have the advantage to produce cross linking materials. Such cross linking materials will open up new potential applications like drug eluting dressings, biofunctionalized materials or soft gels.

Don't forget that working with the isocynates and tetramethyl ammonium hydroxide can be hazardous and precautions such as safety glasses and hand gloves should always be taken while performing this procedure.

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Journal (Chemistry)

Journal (Chemistry)

Synthesis of Soft Polysiloxane-urea Elastomers for Intraocular Lens Application

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