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In this paper we propose a new and cost-effective fabrication scheme for porous polymer optical fibers. Different porous polymer fibers made from polycarbonate (PC) and poly(methyl methacrylate) (PMMA) using this method have been thermally drawn and characterized. Porosity in the fiber cladding is introduced by the absorbed water in one layer of the polymer fiber preforms under heat treatment and/or thermal drawing, and can be controlled by adjusting the water concentration. In addition, we have shown that the fabricated porous polymer fibers have the potential application in localized drug delivery for cancer treatment.
© 2017 Optical Society of America
1. Introduction
Optical fibers have been successfully made from different materials including fused silica [1], fluoride glass [2], chalcogenide glass [3], sapphire [4], polymers [5] and more. Among them, silica optical fibers have the lowest attenuation and the largest commercial availability, therefore they are widely utilized in optical communications, fiber optic sensors, and optical imaging applications [6–8]. On the other hand, polymer optical fibers (POF) have gained an increasing interest from researchers due to their high flexibility, ease of fabrication, biocompatibility and mechanical robustness [9, 10]. In the biomedical field, polymer materials have been traditionally adopted in applications including biodegradable scaffolds, drug delivery and photomedicine [11–13]. With the recent development of the microstructured POFs, novel biomedical sensors and microfluidic devices have been implemented with the use of polymer optical fibers [14, 15].
One type of cancer treatments is the photodynamic therapy which uses special photosensitizing substance along with light to elicit cell death [16]. It offers temporal and spatial control of the treatment by locally delivering light to the region of interest to activate the photosensitizer [17]. One limitation is that when the drug is given intravenously, the patient sometimes needs to avoid being exposed to bright light and direct sunlight between the time of administration and the local activation of the drug to avoid systemic toxicity. Also, traditional photodynamic therapy systems use separate apparatus for drug delivery and light activation. Special optical fibers with holey structure can overcome the two limitations and provide a solution for the integration of local drug releasing and light triggering in deep tissue. Active photosensitizers can be loaded onto the implanted fiber beforehand and subsequently released in vivo, followed by light activation through the same fiber. Despite of comprehensive discussion on the fabrication and applications of the microstructured silica and polymer optical fibers [18, 19], limited researches have focused on fibers with random pore distribution [20–24].
In this work, we have proposed and validated a cost-effective scheme to fabricate porous polymer optical fibers. The porosity in the fiber cladding is introduced by the absorbed water in one layer of the polymer fiber preforms under heat treatment and/or thermal drawing. As far as we know, this fabrication method has not been reported before. The ability of the porous cladding to absorb liquid through capillary force facilitates promising applications in the biomedical field. Experimental results have demonstrated the potential usage of these porous polymer fibers in localized drug delivery.
In the following section we will discuss the material properties of the two polymers, polycarbonate (PC) and poly(methyl methacrylate) (PMMA) pertinent to water absorption and pore generation as understanding the material properties is the first step toward successful fiber drawing. Details about the porous polymer fiber fabrication scheme will be presented in Section 3 followed by the characterization of the thermally-drawn fibers. The results of drug release demonstrations are included in Section 4. Conclusion is given in the last section.
2. Material properties
Various polymers have been used to make high quality, low optical loss polymer optical fibers after they were first introduced in the 1960s. Common materials include PC, PMMA, polystyrene (PS), cyclic olefin copolymer (COC) and fluoropolymers such as CYTOP [5]. Certain polymers have a tendency to absorb and retain water [25–27], and the residual moisture in polymer, if not removed, has been observed to induce pores in the structure when heated at elevated temperatures. This is generally undesirable during thermal drawing of polymer fibers as the pores are defect sites causing geometric deformation and additional optical loss. However, we believe that controlled and localized pore generation in the cladding region can be beneficial if the amount of the absorbed water in the polymer and the thermal drawing conditions are optimized. PC (McMaster-Carr) and extruded PMMA (US Plastics) have been chosen for our experiments to verify the assumption.
To estimate the residual moisture of the materials purchased from the vendors, the weight of 1 inch diameter PC and PMMA rods were measured before and after being dried in a vacuum oven at 80 °C for an extended time. Although batches of materials may have different moisture level, the results suggest that there are about 0.09% and 0.18% w/w water in PC and PMMA, respectively. Vacuum-dried 1 inch diameter PC and PMMA rods were immersed in deionized water at 60 °C and their weight was monitored daily. Figure 1(a) depicts the weight change in a month and the results suggest that the water saturation limit for PC is 0.5% w/w. Despite having absorbed more water, PMMA didn’t reach equilibrium for the duration of time which is consistent with results from previous publications reporting ~2% w/w water absorption [25]. Visible changes to the PMMA rods can be observed during the water bath immersion as the clear material becomes slightly milky over time, as shown in the inset photo of Fig. 1(a). To determine the onset temperature for pore formation, PC and PMMA after being immersed in 60 °C water for three days (containing ~0.3% and ~0.7% w/w respectively), were heated in an oven separately for 30 minutes at different temperatures under atmospheric pressure and vacuum respectively. Figure 1(b) and 1(c) are the results from different pressure and temperature conditions (In each figure, front row: in vacuum, back row: in air; from left to right: 160 °C, 180 °C and 200 °C). As shown in the figures below, pressure did not affect the pore generation yet temperature played a crucial role in this process. At 160 °C neither material showed significant pore formation, yet at 180 °C and 200 °C, all samples were filled with pores. We concluded that the critical temperature for the generation of porosity is around 180 °C. The difference between the two materials can be observed as pores inside the PC rods are smaller and more uniform compared to those inside the PMMA rods. The deformation of PMMA at elevated temperatures can be explained by its lower glass transition temperature (~105 °C for PMMA and ~150 °C for PC [28]).
Fig. 1 (a) The weight increase from water absorption of PC and PMMA during the 60 °C water bath (inset: PMMA before (left) and after one-month water bath (right)). (b) PC tubes (OD 0.75 inch, ID 0.25 inch) heated in an oven for 30 minutes. (c) 1 inch diameter PMMA rods heated in an oven for 30 minutes. (In (b) and (c) front row: in vacuum, back row: in air; from left to right: 160 °C, 180 °C and 200 °C).
3. Porous fiber fabrication and characterization
Thermal drawing is the most common method for polymer fiber fabrication [5, 19]. A polymer fiber preform resembling the final fiber geometry is fed into a furnace where it is heated. The polymer gradually softens, allowing it to be pulled into a continuous fiber whose diameter is controlled by the preform down fed rate, the fiber capstan rate and the furnace temperature. Figure 2(a) is an illustration of the thermal drawing process. Our proposed method to thermally draw porous polymer optical fiber utilizes the pore-generation property of PC and PMMA.
Fig. 2 (a) Thermal drawing of polymer fibers. (b) and (c) PC preform after consolidation at 180 °C in vacuum for 30 minutes (core diameter: 0.25 inch; cladding tube OD: 0.75 inch, ID: 0.25 inch; outer tube OD: 1 inch, ID: 0.75 inch).
One inch diameter PC and PMMA rods were first drawn after a three-day 60 °C water bath, and the resulting fibers had pores elongated along the axial direction. A fiber draw-down ratio of greater than 50 can stretch the original submillimeter pores to several meters’ long. To limit the pore generation in the fiber cladding, vacuum-dried polymer rods were inserted into the water-bathed tubes which would result in a solid-core, porous-cladding fiber. An outer layer made from a vacuum-dried tube or tightly wrapped polymer film layers (vacuum-dried 75-μm-thick PC films (McMaster-Carr)) were added to provide additional support for the porous cladding in the drawn fiber. Thirty minutes of consolidation of the preforms in a vacuum oven at 140 °C for PMMA and 180 °C for PC eliminates possible air gaps at the interfaces. Water-induced pores can be readily observed in the PC preforms after consolidation as shown in Figs. 2(b) and 2(c) as the pore formation starts at 180 °C. Besides the water absorbance method, additional fabrication scheme was also proposed to mitigate the issue of irregular pore-generation in PMMA. Vacuum-dried tubes were first drawn into capillary tubes with diameters between 500 μm and 1000 μm. Those capillary tubes were placed between a vacuum-dried core rod and an outer tube to form the cladding region. Consolidation was conducted under atmospheric pressure instead of vacuum to minimize capillary tube collapsing before the preform can be readily drawn into a fiber.
Different designs of fiber geometry and drawing conditions have been tested, and Table 1 lists the preform fabrication and drawing parameters of four fibers. Corresponding micrographs of the cross sections of the fibers were taken with a LEO 1550 field-emission SEM (Zeiss) and are shown in Fig. 3. Fiber A and B were made from PC and the difference in their porosity resulted from the water concentration in the cladding region of the preform (0.09% vs. 0.3% w/w). Fiber A showed a more uniform distribution of pores. By comparing the two fibers, we concluded that the size and location of the pores are randomly distributed in the porous cladding region but the average porosity is related to the starting water concentration. Higher water concentration in the preform has generated larger and more interconnected pores within the fiber. Fibers with similar porosity can be drawn repeatedly when the water concentration, drawing temperature and tension are kept the same. Fiber C was made from PMMA following the same fabrication scheme. The preform was left in the oven at 80 °C for three days after consolidation to reduce its water concentration in the cladding region in order to minimize the generation of large pores which would deform the fiber geometry. The pores in the fiber cladding were partially blocked by the resin from sample preparation for SEM imaging. Fiber D was drawn from a PMMA preform whose cladding region was filled with capillary tubes. The higher drawing temperature has caused some capillaries to collapse during the drawing. This alternative method has resulted in a less random distribution of pores yet the capillaries would not interconnect with each other.
Table 1. Preform geometry and fiber drawing parameters
Fig. 3 (a) - (d) SEM images of the cross sections of porous optical fibers A-D, scale bar: 100 μm. Fibers shown in (c) and (d) were embedded in resin before SEM imaging; red dash lines circle the porous cladding area and black dash lines circle the fiber boundary.
Standard cutback measurement was performed at 532 nm and 633 nm to evaluate their optical transmission loss. The starting length of Fiber A and B made from PC was around 40 cm and that of Fiber C and D made from PMMA was around 1 m. The results of the four fibers are given in Table 2. The intrinsic optical loss of optical grade PC and PMMA at these wavelengths is well below 1 dB/m, and the reason for the large loss compared to commercial polymer fiber is mainly due to material quality as both PC and PMMA purchased were not optical grade. The PC material we have used has worse optical transmission property compared to the PMMA, thus the first two PC fibers have higher loss than the other two PMMA fibers. It is anticipated that the optical loss from material absorption and scattering will be greatly reduced if high-quality polymer is used for making the polymer fiber preforms.
Table 2. Optical transmission loss of fibers A-D
Porous cladding fiber with a lower average refractive index in the cladding region has been shown to exhibit confinement of optical power [21]. Hybrid structure using both PC and PMMA can enhance light confinement. Figure 4 shows images of a hybrid porous polymer fiber consisting of four concentric layers: a PC core, the first PMMA cladding, the second porous PC cladding and one outer PC layer. The majority of the light propagates in the core due to the refractive index difference between the PC core and PMMA cladding (1.59 and 1.49 for PC and PMMA, respectively), while porosity in the second PC cladding can be used for drug delivery. The SEM image in Fig. 4 (a) shows the four-layer structure with the porous cladding between the two red circles. The PC tube used in the perform for the porous cladding has ~0.09% water therefore didn’t generate significant amount of pores. Figure 4(b) is the fiber cross section taken by an optical microscope when light was injected to the fiber core from the other end of the 20 cm fiber segment. The core being the brightest part of the fiber has confirmed its good light guiding property.
Fig. 4 (a) SEM image of the cross sections of porous optical fiber made from PC and PMMA, (b) optical microscopic image of the porous optical fiber with light injected to the core from the other end, scale bar: 100 μm. Red dash lines circle the porous cladding area and black dash lines circle the boundary of the core.
4. Preliminary ex vivo drug release study
Since the porous structure has the capability of absorbing liquid into the capillaries, drugs for cancer treatment can be loaded into the porous polymer fibers that can be implanted into tissues with minimal invasiveness and long-term biocompatibility. This can facilitate the localized drug delivery in which drug is released in a controlled manner and activated by light on demand. To simulate the drug release process through fibers, 4% agarose gels were used as the tissue phantom and a dye solution (2 mg/mL rhodamine in deionized water) was chosen as the indicator. The fluorescent rhodamine emits red light (~620 nm) when excited by green light (~570 nm). Three different 2 cm fiber segments (the porous-cladding PC fiber, the porous-cladding PMMA fiber and the capillary tube-cladding PMMA fiber) were dipped into the rhodamine solution for five minutes and subsequently dried overnight. The fibers were then inserted into the agarose gel blocks (~2 × 2 × 1 cm) immersed in phosphate-buffered saline (PBS) at 37 °C, as shown in Fig. 5(a). Fluorescent images were taken by an IVIS imaging system after two days (Fig. 5(b)) and the results confirmed that the dye has diffused from fibers into the phantom in all cases. Ex vivo experiments were conducted to further verify the validity of the proposed concept. The same fibers loaded with the dye solution were inserted in murine 4T1 mammary tumors placed in Opti-MEMTM culture media at 37 °C for three days. The results confirmed the release of the dye from all fibers (Figs. 5(c) and 5(d)).
Fig. 5 (a) Bright field image of agarose gel phantoms with rhodamine-loaded fibers inserted. (b) Fluorescent image of rhodamine release in gels in (a) in PBS at 37 °C after 2 days. (c) Bright field image of murine 4T1 tumors. (d) Fluorescent image of dye released in tumors in (c) at 37 °C after 3 days. The color in (b) & (d) is presented as the radiant efficiency. In all figures, from left to right test subjects were inserted with the porous-cladding PC fiber, the capillary tube-cladding PMMA fiber and the porous-cladding PMMA fiber.
Polymer materials have been widely used for drug delivery. Implantable devices made from polymer materials can be fabricated by lithography, rapid prototyping, laser micromachining, electrospinning, etc [12, 29]. While those technologies provide flexibility in material selection and control over drug release characteristics, scaffolds and films are the commonly fabricated structures and they are not designed to guide light. Porous polymer fiber capable of transmitting light and locally deliver drug are particularly useful for photodynamic therapy where the released drug requires light activation. The preliminary results from the three fibers are qualitative and their release profiles can be monitored to compare the performance in future experiments. Sustained and controlled drug release could be achieved by loading drug-doped biodegradable polymers, such as Poloxamer 407, into the porosity. Demonstration of simultaneous drug deliver and activation experiment will also be carried out after optimization of the fiber structure.
5. Conclusion
This work presents a new porous polymer fiber fabrication scheme and the possible biomedical application for the porous fibers. Following the proposed scheme, porosity in the fiber cladding is introduced by thermally drawing polymers with controlled water concentration. Additional porous fiber fabrication method has been demonstrated through thermal drawing of capillaries-filled preforms. PC-based fibers with <1 dB/cm transmission loss and PMMA-based fibers with <0.2 dB/cm transmission loss have been fabricated. Both types of porous polymer allow liquid to be drawn into the cladding and released into tissue phantoms and murine tumors, which demonstrates their proof-of-principle drug delivery capability. With their intrinsic flexibility and biocompatibility, these porous polymer optical fibers can be used for localized drug delivery and activation in cancer treatment.
Acknowledgments
The authors would like to thank Kemaya Nguyen, Shan Jiang, and Maryam Tousi from the Electrical and Computer Engineering Department, Virginia Tech for the productive discussion about fiber fabrication, agarose gel preparation, SEM sample preparation and image acquisition. Yongliang Zhong from the Chemical Engineering Department, Virginia Tech for the help with the IVIS system.
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