The antimicrobial properties of silver (Ag) nanoparticles (NP) have been investigated in depth during the last decades.[1] For cataract treatment minimal invasive surgery has become state-of-the-art. The physicians are still fighting against postoperative inflammations, such as endophthalmitis.[2] We present a novel approach to reduce these postoperative complications by equipping the hydrophilic intraocular lenses (IOL) with a Ag NP depot. As the Ag NP are completely entrapped inside the polymeric IOL no direct contact of the nanoparticles with epithelial cells may occur. Using 1-hydroxybenzotriazole (HOBt) or 7-hydroxycumarine (7HOCum) as photo reduction mediators (PRM) the formation of the Ag NP is accomplished in situ. PRM and Ag nitrate are diffused into the ready made IOL. By means of two-photon-absorption (TPA) photochemistry at λTPA = 532 nm the Ag NP generation is precisely controlled to occur inside the IOL only. At no point NP are directly exposed to the surface.[3] Interesting dependencies between the used PRM and the resulting particle size distribution or the effectiveness of the silver ion reduction inside the polymer matrix are reported. The Ag NP were prepared in the outer area of the IOL not to affect the optical properties of the ophthalmic implant. The amount of Ag ions released was determined and found to be sufficient to effectively reduce the counts of airborne germs. Besides HOBt and 7HOCum we also investigated the photo reductive properties of several other organic reagents, such as benzophenone (BP) and 4-hydroxybenzophenone (4HOBP) for the ability to produce even three-dimensional nanoparticle structures inside a polymer matrix.
Intraocular lens (IOL) implantation is the standard technique to treat cataract. Despite recent progress in surgical
procedures, posterior capsule opacification is one of the sill remaining postoperative complications of cataract surgery.
We present a novel strategy to reduce the incidence of posterior capsule opacification. A drug delivery polymer suitable
for manufacturing intraocular lenses has been developed which enables repeated drug release in a non-invasive and
controlled manner. The therapeutic molecules are attached through a UV light sensitive linkage to the polymer backbone
which is mainly responsible for the optical properties of the intraocular lenses. However, UV light can not trigger the
release of drug from the polymer due to the high absorption of the cornea. We developed linkers which enable drug
release by two-photon absorption induced cleavage of the linker structure. Since the two-photon absorption requires high
photon densities, this does not occur in ambient light conditions in daily life, but is easily triggered by focused laser
beams from a pulsed laser. In this proof-of-principle study we have employed a cyclobutane type linker and investigated
the properties of the therapeutic system with the approved drugs 5-fluorouracil and chlorambucil. The controlled drug
delivery was successfully demonstrated in vitro and additional cell tests confirmed that the device itself shows no
cytotoxicity until photochemical activation. This presented concept can provide a powerful method in ophthalmic drug
delivery.
Typical postoperative complications in cataract surgery are that refractive power and curvature of the implanted
intraocular lens (IOL) do not have optimum values, requiring the patient to wear viewing aids. This is mainly
because biometric data relevant for calculation of the IOL's shape cannot be determined with the required
precision. Hence, there is a need for methods to tune the focal length postoperatively in a non-invasive manner.
We have developed polymers where we can induce a change in refractive index by linking or cleaving bonds
between a su.ciently large number of side groups of the polymer main chain in a photoinduced cycloaddition
or cycloreversion reaction, respectively. These photoreactions lead to a change in refractive index great enough
to be interesting for the concept of in vivo tunable IOL's. The photochemical reaction can be triggered by a
two-photon process (TPA) using a pulsed laser system, i.e. the energy required for bond breaking is provided
by two photons in the visible range. This is important because light in the UV cannot induce undesired changes
of the refractive index owing to the strong UV-absorption of the cornea. Undesired changes due to light in the
visible range of the spectrum are unlikely to happen because photon density of sun light is much too low for
TPA. Due to the excellent spatial resolution that can be achieved with two-photon processes one cannot only
modify the refractive index of the entire lens but also selectively in well defined areas enabling to correct for
aberrations such as astigmatism.
Here, we present new polymers that do not only exhibit a photo induced change of refractive index great
enough to induce a change of focal length of more than two diopters in a standard IOL. These new polymers
have also significantly improved material properties with respect to the fabrication of the IOL and the TPA-sensitivities
and the light energy required to induce the refractive index change.
Tens of millions of cataract surgeries are done every year and the number is increasing heavily. Posterior capsule opacification is the major postoperative complication with an incidence of 10 to 50% within 5 years, depending on the age of the patient. We present a novel approach for secondary cataract treatment in a noninvasive manner. Photochemically triggered drug release from a polymer enables repeated drug applications for cataract treatment years after implantation of the intraocular lens, just when needed. However, light in the visible spectral range must pass through the lens but must not induce drug release. We demonstrate that two-photon absorption photochemistry is a powerful tool to overcome this problem. With wavelengths in the visible regime, a photochemical reaction that requires energies in the UV is triggered. The high intensities needed for this process never occur in any lighting condition in daily lives, but may be easily obtained with focused laser beams routinely used in ophthalmology. The properties of the therapeutic system are specified and the function is demonstrated by in-vitro cell tests. Noninvasive multidose photochemically triggered drug release from implanted intraocular lenses carrying a drug depot may be a therapeutic as well as an economic choice to established treatments of secondary cataracts.
Before an intraocular lens (IOL) is implanted during cataract surgery, biometric data of the patient's eye have to be determined to calculate the thickness and shape of the IOL. In particular the postoperative anterior chamber depth is an important parameter to predict the correct shape of the IOL. This value, however, cannot be measured without significant uncertainities. We present a solution to this problem, describe novel polymers suitable for IOLs which refractive indices can be changed non-invasively in a photo-induced process. The focal length can be modified by about 2 D, which is sufficient to achive ideal acuteness of vision for almost all patients with implanted IOLs. The change in refractive index is accomplished by linking or cleaving bonds between a sufficiently large number of side groups of the polymer main chain in a photoinduced cyloaddition or cycloreversion, respectively. The photochemical reaction can also be triggered by a two-photon process (TPA) using a pulsed laser system, i.e. the energy required for bond breaking is provided by two photons in the visible range. Light in the UV as well as the visible range of the spectrum cannot induce undesired changes of the refractive index owing to the strong UV-absorption of the cornea and photon densities much too low for TPA, respectively. Due to the excellent spatial resolution that can be achieved with two-photon processes not only modification of the refractive index of the entire lens but also selectively in well defined areas is possible enabling the correction for aberrations such as astigmatism.
One of the major complications of cataract surgery is posterior capsule opacification caused by proliferation and migration of residual lens epithelial cells into the visual axis. In this study we present a novel approach to treat posterior capsule opacification in a non-invasive manner. A polymer-drug conjugate has been developed which is suitable for manufacturing functional intraocular lenses equipped with a drug delivery system. The therapeutic molecules, 5-fluorouracil, were attached through a photolabile linkage to the acrylic polymer backbone of the intraocular lens material. The controlled release of 5-fluorouracil is accomplished by two-photon induced cleavage of the linkage which is stable in ordinary conditions. The properties of the therapeutic system are characterized and the function is demonstrated in in vitro tests. The utilization of two-photon-absorption processes in drug delivery may provide a powerful tool to prevent posterior capsule opacification.
Although phototriggered cleavage of chemical bonds induced by single-photon or two-photon-absorption provides attractive tools for controlled drug delivery, the choice of drugs is still limited by the linker system to which the therapeutic molecules need to be bound covalently. The use of a multifunctional linker system suitable for coupling a broad spectrum of drugs to the polymeric carrier will open a new field for drug delivery. We have developed a novel photocleavable multifunctional linker system based on coumarin dimers, whose unique photochemical behavior are well characterized. As a first example, an acrylic polymer-drug conjugate with antimetabolites is explored. The cleavage of the link between the drug and the polymer backbone is triggered by both single- as well as two-photon absorption. The release of the drug is investigated. It is possible to manufacture a polymeric drug delivery device with several drugs in different areas. In particular the two-photon-absorption induced process offers the possibility to address the drug of interest owing to the superior spatial resolution. The key to such devices is a versatile linker-system which can be adopted to work with various drug compounds.
Novel polymeric materials carrying a drug depot have been developed which are suitable for fabrication of
photochemically modulated drug delivery devices. In order to avoid uncontrolled drug release the drug is covalently
attached to the polymer backbone using a photo-active linker. Controlled drug release from the polymer can be
accomplished either via single-photon excitation or by two-photon absorption (TPA). In particular the second possibility
is of interest for applications where exposure to day light or UV light may not be omitted. One example are polymeric
intraocular lenses (IOL), which are implanted instead of the opaque natural lens during cataract surgery. Secondary
cataract formation is quite often observed after implantation of polymeric IOLs. In this study the well known cell toxic
agent 5-fluorouracil (5FU) attached to a methylmethacrylate-based polymer was investigated as an IOL which can upon
photochemical excitation release 5FU in order to treat or to prevent secondary cataract formation. The photochemical
cleavage of the linker molecule was analyzed with single- and two-photon excitation. UV/VIS spectroscopy and HPLC
analysis confirmed the release of 5FU form the polymer backbone. The diffusion of the drug precursor out from the
polymer as well as the hydrolysis of the drug precursor which leads to 5FU formation were investigated in vitro.
Photochemically controlled drug release systems require quite special linker systems for the photocleavable attachment
of a drug to a polymer backbone. Such linkers must be photochemically cleavable exactly at that point where a detachment
of the drug molecule is possible without any added chemical groups in order not to influence its therapeutic
properties. The need for such special linker systems is a bottleneck. The photochemical cleavage of chemical bonds
requires energies in the UV and may be accomplished either by single-photon or two-photon absorption. We found that
dimers of drugs like 5-fuorouracil (5-FU) show significant changes in their physico-chemical properties like solubility in
polymer matrices compared to their monomers. Due to this differences they may be used as drug depot forms without the
need of any linker system at all. Upon photochemical cleavage of the dimer, either by single-photon or two-photon
absorption, the active monomer form of the drug is released without any residual groups attached. Synthesis, chemical
and photochemical characterization of dimeric 5-FU is reported and potential applications in polymer systems for
medical applications are outlined.
Secondary cataracts are quite often observed after implantation of polymeric intraocular lenses. The reason for this complication is that lens epithelial cells remain in the capsular bag when the natural lens is removed. They begin proliferation and cause secondary cataracts. It is not desireable to add cell toxic agents at the time of the implantation because wound healing is negatively affected. We have developed polymeric intraocular lenses which are equipped with a drug depot which may be released non-invasively through photochemical treatment. In the example presented the drug is 5-fluoruracil (5FU) which is covalently bound to the polymer. Deliberation of 5FU from the polymer is done photochemically. Since light is transmitted permanently through the artificial intraocular lens and wearing of special glasses by the patient should be omitted conventional photochemistry is not a suitable tool for the drug release. The polymer-5FU linkage is designed in a way that it has a high two-photon absorption cross-section. Two-photon absorption is used to selectively release 5FU from the lens. The one-photon reaction is blocked since the cornea does absorb UV light. The principle shown here is not limited to 5FU but may be applied to other drugs also.
Access to the requested content is limited to institutions that have purchased or subscribe to SPIE eBooks.
You are receiving this notice because your organization may not have SPIE eBooks access.*
*Shibboleth/Open Athens users─please
sign in
to access your institution's subscriptions.
To obtain this item, you may purchase the complete book in print or electronic format on
SPIE.org.
INSTITUTIONAL Select your institution to access the SPIE Digital Library.
PERSONAL Sign in with your SPIE account to access your personal subscriptions or to use specific features such as save to my library, sign up for alerts, save searches, etc.