Laser-responsive shape memory device to program the stepwise control of intraocular pressure in glaucoma

Laser-responsive shape memory device to program the stepwise control of intraocular pressure in glaucoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Laser-responsive shape memory device to program the stepwise control of intraocular pressure in glaucoma Hak-Joon Sung, Kyubae Lee, Wungrak Choi, Si Young Kim, Won Take Oh, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1829962/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Clinical laser systems enable user-specified control of the energy level, focus, and frequency by minimizing untargeted influences, which has never been applied to implantable shape memory polymers (SMPs). The glaucoma clinic possesses multi-decade issues to control progressive fluctuations in intraocular pressure (IOP) with tissue fibrosis upon implantation of silicone drainage devices. As a translatable device, we applied a laser-responsive SMP to develop i) a tube with intimal gel coating to release anti-fibrotic drugs and ii) safety lock ring. When the SMP tube was inserted into a silicone tube with wrapping externally by the ring, intimal gel degradation and argon laser-triggered diameter increase enabled three-step IOP control. Sustained drug release of the intimal gel suppressed tissue fibrosis, and the ring prevented late hypotonic IOP by externally squeezing the silicone tube. The unprecedented design and functions were validated using computational, in vitro, and rabbit glaucoma models by determining clinic-friendly argon laser parameters. laser-responsive shape memory polymer computational fluid dynamics modeling anti-fibrotic drug release glaucoma clinician-specified control of intraocular pressure Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Main The paradigm of implantable medical devices has evolved to promote patient-specific precision 1 , 2 , 3 . Although patient status changes over time and depends on lesions, the fixed function, property, and size of devices limit clinician-specified controls by considering the situation and disease progress. Controls are urgently required when dealing with dynamic body parameters such as pressure 4 , flow 5 , and heat 6 . Uncontrolled body parameters upon device implantation progressively exacerbate the prognosis, increasing mortality and morbidity. Silicone has long been used in a wide range of implantable medical devices owing to its durability, controllable properties, and easy fabrication 7 , 8 . However, the inability to handle dynamic body conditions such as structural changes represents a critical limitation in moving towards the next paradigm. In addition, its surface property promotes bacterial growth with biofilm formation 9 , which further limits its evolution as a leading medical material. Hence, cross-disciplinary material function and device design are required to help clinicians control device functions to deal with unpredictable changes in pathological parameters. In particular, pinpoint control of target lesions has emerged as a current paradigm in clinics along with recent advances in laser systems to minimize untargeted influences 10 , 11 . This paradigm is suggested to promote clinician-specified remote control of device functions by integrating with state-of-the-art imaging and laser systems. Glaucoma occurs because of the overfilling of eye water and consequent increase in intraocular pressure (IOP) 12 , 13 . Hence, for the past decades, silicone devices have been implanted into glaucomatous eyes to drain the fluid and control the IOP over time 14 , 15 , 16 . Regardless of the device type, the fixed diameter of the drainage tube and silicone material has been considered as common factors that generate critical issues. The first issue starts within two weeks of device implantation because the fixed diameter of the silicone tube generates a relatively large negative pressure. The consequent over-drainage of the flow results in a hypotonic IOP drop (< 6 mmHg) 17 , 18 , 19 . If this situation aggravates, choroidal detachment occurs with blindness, which underscores the need for a smaller diameter to suppress the IOP drop during the early phase of device implantation. A month after implantation, the second issue arises as the hypotonic IOP elevates to fluctuate mostly into the hypertensive (> 20 mmHg) or hypotonic range, because the elevation speed and period are patient-specific 20 , 21 . Hence, patient-specific control to increase the tube diameter in a stepwise fashion is necessary owing to the pattern of IOP fluctuation. Third, this uncontrollable change in IOP is strongly associated with fibrotic tissue formation, primarily owing to the nature of the silicone material that promotes biofilm formation, suggesting the need for anti-fibrotic function for tube implantation 22 , 23 , 24 , 25 . Lastly, several months after device implantation, some patients exhibit a sudden drop in the IOP that induces choroidal detachment and blindness upon severe progression, which indicates the need for a safety lock to suppress the abnormal IOP drop as needed 26 . Hence, these issues should be addressed by upgrading the device function and material properties to enable the clinician-specified control of IOP. As a breakthrough solution for the pinpoint control of device function, a laser-responsive shape memory polymer (SMP) was used to program a three-step increase in tube diameter (D) with the release of anti-fibrotic drugs. An SMP tube was designed to be inserted into a silicone tube for application in current silicone drainage devices, regardless of the type. Shape programing enabled the recovery of large D tubes (inner diameter, ID = 250 µm) from medium D (ID = 200 µm) via argon laser shots by shrinking the tube length (3 → 1.5 mm) based on Poisson’s ratio (2.0) of the SMP. The lumen of the medium D tube was coated with drug-loaded hydrogel to produce a small D (ID = 50 µm). The hydrogel was designed to degrade within two weeks to become medium D and release anti-fibrotic drugs in a sustained manner. A safety lock ring was produced to suppress the sudden drop in IOP by squeezing a silicone tube as an external wrap during the late phase of implantation. The SMP was blended with polycaprolactone (PCL) to enhance the squeezing force by increasing the melting temperature (T m ). This prevents unexpected ring action owing to insufficient energy transfer by laser shots to the SMP tube. This study suggests the next generation of biotechnology concepts for designing implantable medical devices based on the cross-disciplinary needs of clinics. Results Clinical justification for programing SMP tube functions. Glaucoma occurs owing to the blockage of ocular flow drainage and consequent increase in IOP with optic nerve damage (Fig. 1 a). The implantation of the drainage device into the glaucomatous eye induces the flow of intraocular fluid through the silicone tube thereby reducing the IOP ( Supplementary Fig. 1a ). The 12-month examination of glaucoma patients (n = 127) after device implantation justifies the need for stepwise IOP control (Fig. 1 b): i) the fixed diameter of the drainage tube induced hypotonic IOP drops owing to the over-drainage of eye flow by generating excess negative pressure. ii) The IOP rapidly increased to the normal range within two weeks with unstable IOP fluctuations to the hypertensive range until three months. iii) Despite the remaining predominantly in the normal range afterwards, some deviated to the pathological hypertensive range until 12 months. Early hypotonic IOP induced anterior chamber shrinkage compared with the normal case ( Supplementary Fig. 1b ), followed by choroidal detachment and blindness in severe cases (Fig. 1 c). The properties of the silicone device often caused tissue fibrosis associated with late hypertensive IOP (Fig. 1 d). Glaucoma progression induced a gradual loss of vision of 41% compared to 100% in normal eyes. Five months after implantation of the drainage device, vision loss worsened (~ 33% of the visual area) because of the hypertensive IOP caused by tissue fibrosis ( Supplementary Fig. 1c ). A laser-responsive SMP tube is proposed to address these issues as the pin-point delivery of light energy increases the diameter by minimizing untargeted influences (Fig. 1 e -top ). Gelatin was conjugated with methacrylic anhydride (GelMA) followed by conjugation with a complex of β-cyclodextrin (β-CD) and chloroacetic acid to produce GelMA-β-CD ( Supplementary Fig. 2a ), as confirmed by proton nuclear magnetic resonance ( 1 H-NMR) ( Supplementary Fig. 2b-d ) and Fourier transform infrared (FTIR) spectroscopy ( Supplementary Fig. 2e,f ). Consequently, the three steps of IOP control proceed from: i) the small diameter (D) by GelMA coating onto the intima to release the anti-fibrotic drug, ii) medium D after GelMA degradation with drug release, and iii) large D after diameter increase (shape recovery) upon argon laser shots (Fig. 1 e -bottom ). Three step IOP control and drug release by SMP tube. Computational fluid dynamics (CFD) modeling was used to simulate the diameter (D), pressure, and velocity profiles and determine the length of the SMP tube for shape programing. The profiles were modeled after inserting the SMP tube into the silicone tube (length = 10 mm; inner D = 305 µm) of the glaucoma drainage device ( Supplementary Fig. 3a ). When the length of the SMP was set to 30 mm for insertion into the silicone tube, the post-recovery length was 15 mm. Consequently, D was changed from 50 µm (small D) to 200 µm (medium D) before and after GelMA degradation, respectively, followed by a further increase to 250 µm (large D) upon shape recovery using argon laser shots. Accordingly, the CFD velocity increased markedly upon the insertion of the SMP tube and decreased to a level similar to that of the silicone tube only following the increased D, indicating stepwise control of the drainage flow rate and IOP. Consequently, CFD modeling verified the three-step control of IOP by the SMP because the pressure difference (ΔP) that indicated IOP drop resistance increased from 0.015 (silicone D w/o SMP tube) to 6.352 mmHg (small D) to prevent hypotonic drop (Fig. 2 a). Then, ΔP decreased to 0.036 (medium D) and 0.018 mmHg (large D) to control hypertensive shifts in IOP in a user-specified manner by stepwise increases in tube diameter. Shape programing of the SMP tube was conducted following the shape memory cycle ( Supplementary Fig. 3b ), as visualized by scanning electron microscopy (SEM), to perform stepwise increases in tube diameter from 50 µm (small D) to 200 µm (medium D) before and after the degradation of drug-loaded GelMA, respectively, followed by a further increase to 250 µm (large D) upon shape recovery (Fig. 2 b). The progressive changes in D were validated in vivo from 21-day implantation into the eyes as GelMA degraded until day 14 (before laser), and argon laser shots at day 14 increased D as programmed, which was confirmed at day 21 (after laser) ( Supplementary Fig. 3c ). A custom-built system was operated under a constant flow rate (25 µL/min) using a silicone drainage tube, with and without the SMP tube (Fig. 2 c). The resistance to pressure drops increased markedly from without the SMP tube to a small D over time, followed by a stepwise decrease to a medium D and further to a large D after 700 s (Fig. 2 d). β-CD was conjugated to GelMA (GelMA-β-CD) to increase the loading capacity of the anti-fibrotic drug (5-FU; 5-Fluorouracil) (Fig. 2 e), as confirmed by 1 H-NMR (Fig. 2 f), which increased the loading by almost 10 times compared to GelMA only (Fig. 2 g). As the concentration of GelMA-β-CD increased (5, 7, and 10% w/v), the in vitro degradation slowed down for 14 days at 37°C (Fig. 2 h), suggesting an effective means to control the speed of IOP drop and drug release. β-CD conjugation to GelMA (5% w/v) enabled the sustained release of 5-FU for 14 days in vitro, in contrast to the burst release by GelMA only (Fig. 2 i). Clinic-friendly setting of SMP tube operation. During shape programing, the 1.5 mm long tube (recovery shape) was elongated at 55°C and frozen to fix at 0°C so that the diameter decreased, followed by cutting to a 3 mm long tube (insertion shape) based on Poisson’s ratio ( v = 0.2) of the SMP (Fig. 3 a). The SMP tube was painted black to promote laser absorption, and argon laser shots in the clinical room induced the expansion of the tube diameter by decreasing its length (Fig. 3 b). Warm water can also be used, although it spreads into the neighboring areas 27 . However, calculations confirmed the superior energy efficiency (approximately 66 times) of the argon laser (energy density: approximately 4,286 J/cm 3 ) through pinpoint shot delivery when compared to the water heat energy (Q water : approximately 65 J/cm 3 at 50°C) (Fig. 3 c and Supplementary Fig. 4 ), indicating another advantage in minimizing unexpected influences on neighboring tissues 28 . The efficiency of the argon laser E was tuned in the following two steps to determine the maximum E of a single shot within the clinical safety range (Fig. 3 d,e). This minimized the number of laser shots so that the pin-point laser focusing remained undisturbed. First, as the low-E shot resulted in non-linear shape recovery (e.g., bending), the minimum E of a single shot for linear recovery within the clinically safe range (max. 70 mJ) was determined to be 40 mJ (Fig. 3 d and Movie S1 ). Next, the critical E of a single shot for shape recovery was determined as 60 mJ to minimize the number of laser shots because the shape recovery ratio did not improve significantly between 60 ~ 70 mJ (safety limit) (Fig. 3 e). Rescue of rabbit glaucoma eyes by SMP tube. A n SMP tube was inserted into a silicone tube with external wrapping by the SMP + PCL ring (SMP: black), which was implanted into glaucomatous eyes in a rabbit model (Fig. 4 a). The SMP device suppressed the near hypotonic drop of IOP (w/o SMP tube) for 10 days by changing from small D to medium D owing to GelMA degradation with the release of the anti-fibrotic drug (Fig. 4 b). Then, the change from medium D to large D of the SMP tube by argon laser shots lowered the hypertensive IOP (w/o SMP tube) to the normal range until 42 days ( Movie S2 ). The beneficial effect of changing from medium D to large D by argon laser shots suppressed the incremental IOP (- laser) until 21 days, although the incremental levels remained lower than those without the SMP (Fig. 4 c). Moreover, the groups with saline treatment at 25°C and 50°C were compared to induce shape recovery upon intra- versus extraocular implantation of the SMP tube ( Supplementary Fig. 5 ). The saline at 50°C could not induce shape recovery in the intraocular position, but succeeded in the extraocular position, as demonstrated by the shortened tube length ( Movie S3 ). It indicates the limitation of water heat owing to insufficient energy transfer to the intraocular position as further supported by no shape change by the saline treatment at 25°C. The release of the anti-fibrotic drug (5-FU) from GelMA in the SMP tube (small D) suppressed inflammatory cell invasion (hematoxylin and eosin, H&E) and consequent fibrotic tissue formation (Masson’s trichrome) (Fig. 4 d). When bacterial adhesion was tested on SMP silicone films for two days post-seeding of Pseudomonas aeruginosa , the superior antibiofilm effect of SMP was demonstrated by fewer crystal violet signals with fewer bacteria ( Supplementary Fig. 6 ). Safety lock ring to suppress late hypotonic IOP. The clinical data indicated a late IOP drop (> 4 months) to the hypotonic range in some sudden cases post implantation of the glaucoma device (Fig. 5 a). In the late hypotonic case, some patients appeared to suffer choroidal detachment and vision loss under prolonged severity, clearly underscoring the need for safely alleviating this condition (Fig. 5 b). The SMP + PCL ring was designed to squeeze the silicone tube as an external wrap upon laser shots (Fig. 5 c and Movie S4 ), thereby significantly decreasing the silicone tube diameter and reducing hypotonic fluid drainage (Fig. 5 d,e). The ring was painted black to promote laser absorption. When the device was implanted in a normal rabbit eye, the IOP dropped continuously owing to the large diameter of the silicone tube until day 7 (Fig. 5 f). Immediately after the argon laser treatment, the IOP drop stopped upon the squeezing shape recovery of the SMP + PCL ring ( Movie S4 ). This was followed by the recovery of IOP to the normal range until day 13. The SMP was blended with PCL to increase the modulus and promote the squeezing force, in contrast to the relatively more elastic property of SMP (Fig. 5 g). The blending of SMP with PCL provided another advantage to users because the increase in T m by 10°C could prevent unexpected squeezing by the ring when the argon laser shot to the SMP tube was misfocused or transferred the heat to the ring (Fig. 5 h). Discussion Unmet clinical needs have served as one of the most potent driving forces guiding continuous advances in implantable medical devices 29 , 30 , 31 . This study is clearly aligned with this paradigm; thus, the results suggest the next generation of device design and function considering the following salient points. First, the clinical argon laser system was used to induce shape recovery of the SMP tube because the pinpoint delivery of laser E enabled site-specific control of the diameter increase with minimal influences on neighboring tissues. This control option is a powerful feature aligned with the concepts of user-specified remote control, which has been applied to the current development of diagnostic and drug delivery systems. Second, GelMA coating of the lumen of the tube provided the double benefit of increasing the diameter within two weeks of implantation and releasing anti-fibrotic drugs, thereby addressing the multi-decade problem observed in silicone drainage devices 32 , 33 , 34 . Third, the SMP + PCL ring was attached to the silicone device as a safety lock to reverse the one-way function of the SMP tube upon laser shots. Despite the rarity of the late hypotonic case 35 , 36 , saving even one patient using the ring function provides an unprecedented basis for guiding future medical devices. Other important factors of this study are summarized as follows. i) The design and function of the SMP devices were justified by tracking the clinical IOP profile of 127 glaucoma patients for one year. Therefore, this study suggests an unprecedented solution to address unmet clinical needs. ii) The three diameters were simulated by computational modeling of the flow and pressure. Hence, the detailed structural parameters before and after shape recovery were determined more precisely than the previous empirical and textbook-based methods, suggesting an advanced guideline to upgrade other implantable medical devices. iii) The laser parameters were tuned in two steps to maximize the efficiency of the pinpoint control within a clinic-friendly range. The use of a clinical laser system is meaningful because this first trial can influence the application of existing diagnostic and treatment machines for remotely operating implantable devices. iv) The hydrogel was designed to promote the drug loading capacity and enable sustained release. This fine-tuned the double benefits of diameter increase and anti-fibrotic drug release to fulfil the scope of clinical need more efficiently 37 , 38 . v) The anti-biofilm property of the SMP surface was validated, supporting the effect of anti-fibrotic drugs, which can be applied to other implantable devices such as bile duct stents 39 , 40 , nasolacrimal duct stents 41 , and dental devices 42 . vi) The concept of SMP functions was validated using a customized in vitro pressure system and a new model for rabbit glaucoma. In particular, the rabbit model exhibited the clinical pattern of IOP fluctuation when a drainage tube was implanted and clearly demonstrated the advantages of the SMP tube, expanding its broad impact and leadership. In future studies, the surface properties of SMP for suppressing bacterial adhesion should be further elucidated. The surface E and crystalline phase pattern of the SMP surface were identified as potential players because variations in these factors altered the effects on protein adsorption with microbial and mammalian cell attachment 43 , 44 . However, current analytical systems have limitations in interpreting the dynamic changes in the surface parameters at the nanoscale upon controlling the external energy absorption. The interpretation becomes more difficult when biological players are introduced because of the heterogeneous behaviors of material and biological parameters depending on temperature, type, and duration. Moreover, because the SMP was painted black to help pinpoint laser absorption, the appearance of eyes should be considered further, especially for the population in related jobs. Methods Shape memory polymer (SMP) synthesis : All chemicals were purchased from Sigma-Aldrich (St. Louis, MO, USA). SMP was synthesized by ring-opening polymerization of ε-caprolactone (CL) and glycidyl methacrylate (GMA) monomers using an established protocol 45 . Briefly, CL (20.82 mL), 1,6-hexanediol (118.2 mg) initiator, and hydroquinone (132.14 mg, 1:10 molar ratio of hydroquinone to GMA) as auto-crosslinking inhibitor were reacted in a three-necked round bottom flask under stirring at 110 °C for 10 min, followed by the reaction of GMA (1.6 mL) with the mixture for 10 min. Subsequently, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD; 278.4 mg) was dissolved in acetonitrile solvent (2 mL), which was reacted at 110 °C for 6 h under a nitrogen atmosphere. The reaction mixture was dissolved in chloroform (30 mL) after cooling to room temperature (25 °C) and then, a white precipitate was formed in cold diethyl ether (800 mL, 4 °C). The final SMP product was obtained via vacuum drying (OV4-30, Jeio Tech, Daejeon, Republic of Korea) at room temperature. Gelatin methacryloyl (GelMA) synthesis : Photopolymerizable GelMA was synthesized by reacting methacrylate groups with the amine groups of gelatin molecules 46 . Briefly, gelatin powder from porcine skin (5 g, gel strength 300, type A, Sigma-Aldrich, St. Louis, MO, USA) was completely dissolved in phosphate buffer saline (PBS; 1X, pH 7.4, Welgene, Gyeongsangbuk-do, Republic of Korea) at 40 °C to prepare 10% (w/v) gelatin solution. Next, methacrylic anhydride (MA; 0.25 mL, Sigma-Aldrich, St. Louis, MO, USA) was added dropwise to the gelatin solution (50 mL) at a rate of 0.5 mL/min under vigorous stirring for reaction at 50 °C for 3 h in the dark. Finally, the reaction was stopped by adding five-fold warm (40 °C) PBS to the reaction mixture. The unreacted MA and salts were then dialyzed in warm distilled water (40 °C) using a dialysis tube (molecular weight cut-off (MWCO): 12-14 kDa, Spectrum Laboratories Inc., New Brunswick, NJ, USA) for 5 days in the dark. The dialyzed solution was lyophilized to obtain a white porous foam of GelMA and stored at -30 °C until use. β-cyclodextrin (β-CD) conjugated GelMA (GelMA-β-CD) synthesis : GelMA-β-CD was synthesized to enhance the drug loading capacity using modifications of a previous report 47 . First, the GelMA backbone was conjugated with β-CD by introducing a carboxymethyl (CM) group into β-CD through the following steps. A mixture of β-CD (10 g, Sigma-Aldrich, St. Louis, MO, USA) and sodium hydroxide (NaOH; 9.3 g, Sigma-Aldrich, St. Louis, MO, USA) was dissolved in distilled water (37 mL) and reacted with a 16.3% (v/v) monochloroacetic acid solution (27 mL, Sigma-Aldrich, St. Louis, MO, USA) at 50 °C for 5 h. Then, the product was cooled to room temperature (25 °C), and the pH was adjusted to 6-7 using hydrochloric acid (HCl; Duksan, Gyeonggi-do, Republic of Korea) solution, followed by pouring into methanol to obtain a white precipitate. Finally, carboxymethylated β-CD (CM-β-CD) was obtained by vacuum-drying the solid precipitate. Next, GelMA (1 g) was completely dissolved in PBS (10% w/v, 10 ml) at 40 °C, and CM-β-CD (2 g) was added to 2-(N-morpholino)ethanesulfonic acid (MES; 0.1M, pH 6, Bio Solution Co., Ltd., Seoul, Republic of Korea) buffer solution (10 mL). The carboxyl groups of CM-β-CD were activated by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC; 120 mmol/L, Sigma-Aldrich, St. Louis, MO, USA) and N-hydroxysuccinimide (NHS; 60 mmol/L, Sigma-Aldrich, St. Louis, MO, USA) for 30 min. The GelMA solution (10 mL) was added to the CM-β-CD solution (10 mL) by adjusting the pH to 8-9 using NaOH (Duksan, Gyeonggi-do, Republic of Korea) solution. The reaction was continued for 12 h under vigorous stirring at 40 °C. Finally, the unreacted CM-β-CD and other impurities were dialyzed in warm distilled water (40 °C) using a dialysis tube (MWCO: 12-14 kDa) for 5 d under dark conditions. Material characterization : Successful conjugation and synthesis were confirmed by proton nuclear magnetic resonance ( 1 H-NMR; Avance III 400-MHz, Bruker Biospin, Billerica, MA, USA) spectroscopy, Fourier transform infrared (FTIR; Vertex 70, Bruker Biospin, Billerica, MA, USA) spectroscopy, dynamic mechanical analysis (DMA; Discovery DMA850, TA Instruments, New Castle, DE, USA), and differential scanning calorimetry (DSC; Discovery DSC25, TA Instruments, New Castle, DE, USA). The structure and molar composition were determined by 1 H-NMR spectroscopy using a single z-axis gradient inverse probe at a frequency of 400 MHz. SMP and other materials were dissolved in chloroform-d (CDCl 3 ; Sigma-Aldrich, St. Louis, MO, USA) and dimethyl sulfoxide-d 6 (DMSO-d 6 ; Sigma-Aldrich, St. Louis, MO, USA). The results were further confirmed by FTIR spectroscopy using the KBr pellet method. The mechanical properties were characterized by analyzing the stress-strain curve using DMA at a controlled strain rate of 5 mm/min. The samples were prepared in the form of rectangles (8 (length) × 5 (width) × 0.25 (thickness) mm thick). Heat-flow-related thermal transitions were examined using DSC. The samples were heated to 150 °C, and then cooled to -80 °C for two cycles at a heating rate of 5 °C /min under a nitrogen atmosphere. The glass transition temperature ( T g ), melting temperature ( T m ), crystallization temperature ( T c ), melting enthalpy (∆ H m ), and crystallization enthalpy (∆ H c ) were determined using the DSC thermograms. Anti-fibrotic drug loading : Anti-fibrotic 5-Fluorouracil (5-FU) was loaded into the GelMA-β-CD hydrogel via hydrophobic interactions of β-CD to include 5-FU in a complex form. A GelMA-β-CD solution (5% w/v, 10 mL) and 5-FU powder (10 mg, Sigma-Aldrich, St. Louis, MO, USA) were mixed for 30 min under vigorous stirring to form the complex, which is also known as a host-guest interaction. The cavity of β-CD (host) accommodated 5-FU (guest) via hydrophobic interactions (GelMA-β-CD/5-FU), as confirmed by 1 H-NMR. The CH proton peak of 5-FU appeared at δ = 7.6 ppm. The capacity of GelMA-β-CD to load 5-FU was evaluated (n = 3) by centrifuging the complex solution at 12,000 rpm for 10 min. The amount of free 5-FU in the supernatant was determined using an ultraviolet-visible (UV-Vis) spectrophotometer (Lambda25, PerkinElmer, Waltham, MA, USA) (absorbance: 269 nm), thereby performing reverse calculations for the amount of GelMA-β-CD/5-FU complex. GelMA (n = 3) without β-CD conjugation was used as the control. The degree of drug loading capacity for 5-FU was calculated using the following equation: Drug loading capacity for 5-FU drug (%) = 100% × (A – B) / A A: Total amount of 5-FU that reacts with GelMA or GelMA-β-CD B: Excluded amount of 5-FU that forms the complex in the supernatant The GelMA-β-CD/5-FU complex solution was lyophilized and stored at -30 °C until use. Computational fluid dynamics (CFD) modeling : CFD modeling was conducted to theoretically calculate the pressure difference (∆ P) and velocity between the inlet and outlet of the silicone drainage tube, with or without SMP tube insertion. Because clinical implantation of a glaucoma drainage tube often causes early hypotonic intraocular pressure (IOP) owing to its large diameter, the insertion of an SMP tube with a smaller diameter in the middle part of the drainage tube was expected to address this issue. The inner diameter of the SMP tube was adjusted according to the clinical ∆ P (> 6 mm Hg) while the silicone tube diameter was fixed. The clinical definition of hypotonic IOP is less than 6 mmHg; thus, the initial inner diameter (50 µm) of the inserted SMP tube was determined to generate more than 6 mmHg. All CFD calculations were performed using the fluid flow (Fluent) mode in ANSYS (ANSYS workbench 2021 R2, Canonsburg, PA, USA). Since the Reynolds number (NRe) of the intraocular fluid was estimated to be less than approximately 2,000 (turbulent flow: NRe > 2,000), a laminar flow condition was used to calculate ∆ P and velocity upon SMP tube insertion, where a constant flow rate (Q = 2.5 µL/min) and open boundary condition were applied. The obtained results were compared with the Hagen-Poiseuille law ( ∆ P = , where , , , and are the fluid rate, viscosity, length, and radius, respectively). SMP device production : The length and diameter of the anti-fibrotic drug-loaded SMP tubes were determined by CFD modeling, and SMP tube was fabricated as follows. SMP (1 g) was fully dissolved in N-Methyl-2-pyrrolidone (NMP; 1 mL, Sigma-Aldrich, St. Louis, MO, USA) at 37 °C and mixed with a photoinitiator, 2-hydroxy-1-(4-(hydroxyethoxy)phenyl)-2-methyl-1-propanone (Irgacure 2959; 5 mg, Sigma-Aldrich, St. Louis, MO, USA). Next, a poly(vinyl alcohol) (PVA; Raise3D, Irvine, CA, USA) wire was produced using a three-dimensional (3D) printer (Raised3D Pro2, Raise3D, Irvine, CA, USA) and used as a sacrificial material to generate the inner diameter of the SMP. A glass capillary tube (Paul Marienfeld GmbH & Co., KG, Lauda-Königshofen, Germany) was used as the outer mold. The PVA wire (outer diameter: 260 µm) was inserted into the glass capillary tube (inner diameter: 560 µm), followed by the injection of the SMP solution between the two layers. The SMP solution in the glass capillary tube was polymerized by UV irradiation (365 nm, 265 mJ/cm 2 ) for 100 s using a UV crosslinker (CL-3000L UV Crosslinker, Analytik Jena, Jena, Germany), and then, PVA was dissolved in distilled water for 3 days at 25 °C. The SMP tube was separated from the glass capillary tube and air dried. The SMP tube underwent shape-programming as follows: (i) The original length of the SMP tube was doubled in hot water at 55 °C ( T > T m ), as the double length was determined considering the Poisson’s ratio ( v = 0.2) of SMP tube. (ii) The elongated SMP tube was immersed in cold water ( T < T m ) to fix the temporary shape, and (iii) the temporary shape of the SMP tube was cut to a length of 3 mm, as determined by CFD modeling. Next, an anti-fibrotic drug (5-FU)-loaded GelMA hydrogel (GelMA-β-CD/5-FU hydrogel) was coated onto the intimal layer of the SMP tube to facilitate its release into the intraocular fluid. GelMA-β-CD/5-FU solution (5% w/v) containing 0.5% (w/v) Irgacure 2959 was prepared in PBS at 37 °C. Then, a tungsten wire (outer diameter =50 µm, GoodFellow, Delson, QC, Canada) was inserted into the temporary shape of the SMP tube as the outer mold (inner diameter: 200 µm), followed by the injection of the hydrogel solution in between the SMP tube and tungsten wire. The whole set was exposed to UV light for crosslinking GelMA by polymerization under the previously described conditions, and the tungsten wire was removed to create the inner diameter of the SMP tube. The SMP tube was painted black to promote laser absorption. To produce the SMP+PCL ring, SMP was blended with PCL (10% w/v, MW ~80,000, Sigma-Aldrich, St. Louis, MO, USA) with SMP to improve its mechanical properties, as determined by DMA. An SMP+PCL tube was produced following the same process used to make the SMP tube using a glass capillary tube as an outer mold (inner diameter: 800 µm) with intraluminal insertion of a PVA wire (outer diameter: 360 µm). The diameter of the SMP+PCL tube was enlarged by inserting a taper-shaped polylactic acid (PLA; Raise 3D, Irvine, CA, USA) mold with an incremental outer diameter of 200~1000 µm into the SMP+PCL tube. The tube position was adjusted to the targeted outer diameter range of the tapered PLA mold in hot water at 55 °C so that the inner diameter of SMP+PC tube increased from 200 to 1000 µm. Subsequently, the shape was fixed in cold water (0 °C). The SMP+PCL tube was cut into 1 mm long SMP+PCL rings. The ring diameter was examined using SEM (MERLIN, Zeiss Merlin, Oberkochen, BW, Germany) with image analysis. The ring was painted black to promote laser absorption. Pressure measurement system : The drainage pressure of the silicone tube, with or without SMP tube insertion, was measured as previously described (n = 3) 27 . The measurement system was customized to be equipped with a pressure transmitter (PNS, Nuritech, Incheon, Republic of Korea), pressure indicator (PD1, Nuritech, Incheon, Republic of Korea), three-way stopcock, silicone tube [2 (inner diameter) × 4 (outer diameter) mm, Korea Ace Scientific Co., Seoul, Republic of Korea], syringe, 30-gauge needle (Korea vaccine Co., LTD., Gyeonggi-do, Republic of Korea), and syringe pump (Standard PHD ULTRA™ CP Syringe Pump, Harvard Apparatus, Holliston, MA, USA). A silicone tube with small D, medium D, large D, or without SMP tube insertion was connected to the needle, and distilled water was injected into the test tube at a constant flow rate (25 µL/min) using the syringe pump. The pressure changes (mmHg) were recorded using a digital pressure indicator. GelMA - β -CD degradation : A consistent rod shape (4 mm diameter and 1 mm height) of GelMA-β-CD hydrogel with different concentrations (5, 7, and 10% (w/v)) was produced by crosslinking in a cylindrical UV system (n = 3). In vitro degradation was examined in PBS containing type I collagenase (1 unit/mL, Gibco, Waltham, MA, USA) at 37 °C on a rocking shaker (50 rpm, RK-1D, Daihan Scientific, Kangwon-do, Republic of Korea), followed by replacing PBS every 2 days. Non-degraded hydrogels were collected each time, washed twice with distilled water, and lyophilized to measure their weight. The weight (%) of the non-degraded hydrogels was calculated using the following equation: Weight (W %) of non-degradation= ( W each time point / W starting point ) × 100 The hydrogel with the most rapid degradation was used in the rest of the experiments. In vivo degradation of the GelMA-β-CD hydrogel upon insertion into an SMP tube was determined during 14 day-implantation into rabbit eyes by analyzing SEM images at each time point. Anti-fibrotic drug release : In vitro release of 5-FU from the hydrogel with the most rapid degradation was determined by analyzing each cumulative profile with and without β-CD conjugation on GelMA (n = 3). The test samples were incubated under the same conditions as described above for hydrogel degradation. The test solution containing 5-FU post-release from each hydrogel was collected at each time point, followed by replenishing the same amount of PBS. The amount of 5-FU released was determined using a UV-Vis spectrophotometer at 265 nm and a calibration plot. Anti-bacterial adhesion : In vitro bacterial adhesion was determined to confirm the superior anti-biofilm effect of SMP over silicone as reported previously 41 . Briefly, Pseudomonas ( P. ) aeruginosa (ATCC 9027, Seoul, Republic of Korea) was cultured in a tryptic soy agar (Sigma-Aldrich, St. Louis, MO, USA) at 37 °C until their growth reached the mid-exponential phase, 0.55 optical density of as indicated by an optical density of 0.55 obtained using a microplate spectrophotometer (600 nm, Infinite M Nano, Tecan, Männedorf, Switzerland). Sample films (1.5 × 1.5 cm) were prepared and incubated with P. aeruginosa at 37 °C for 48 h, followed by washing with distilled water to remove non-adhering bacteria. The samples were then air-dried for 40 min and stained with crystal violet (0.1%, Sigma-Aldrich, St. Louis, MO, USA) for 15 min for imaging by inverted optical microscopy (Leica DMi8, Leica Microsystems, Wetzlar, Germany) and SEM. For quantitative analysis, crystal violet dye was extracted from the bacteria using 95% (w/v) ethanol (Sigma-Aldrich, St. Louis, MO, USA), and the absorbance was measured at 600 nm using a microplate spectrophotometer. Shape memory function : Since argon laser irradiation (Topcon PASCAL Streamline 532 nm Green Laser, Topcon Medical Laser Systems, Santa Clara, CA, USA) was used to induce the shape recovery of SMP tube, the energy density per unit surface area of tube was determined using the laser power and exposure time: Energy density (m J/cm 2 ) = A / B A: Laser energy (Power (mW) × Exposure time (ms)) B: Surface area ( cm 2 ) Owing to the fixed laser irradiation (surface) area, the energy density was adjusted by varying the laser power (0 ~70mJ). The shape recovery efficiency of the SMP tube was determined by changing a bent tube to a linear tube shape as sufficient laser energy per single shot was delivered. Next, the energy density was further examined to induce complete shape recovery in the range of 40~70 mJ by calculating the shape recovery ratio per single laser shot (%) (n = 3) as follows: Shape recovery ratio per single laser shot (%) = [B / A] ×100% A: Length of original shape B: Length of recovered shape after single laser shot The shape-recovery efficiency of the SMP+PCL ring was determined by analyzing the squeezed lumen area of the silicone tube using SEM images before and after argon laser irradiation (n = 3). The superior effect of the argon laser over water heat on shape recovery was examined by implanting tube samples into rabbit eyes. Two water samples at 25 °C and 50 °C were compared because the temperatures were below and above T m , respectively, and proteins begin to denature above 50 °C. After the SMP tubes were inserted into silicone tubes, one was implanted into the intraocular position of the anterior chamber, while the other was positioned in an extraocular position on the cornea (control). The change in the length of the SMP tube at each position was analyzed upon water treatment. The energy density (E Laser ) of the argon laser was compared to the heat energy (Q Water ) of water to determine its superior efficiency (%). The surface temperature of the rabbit cornea was measured using a thermal imaging camera (HT-18; Hti, Guangdong, China). The SMP tube and ring were painted black to promote laser absorption. Clinical data analysis : Long-term IOP profiles were analyzed post implantation of silicone drainage devices (Model FP-7, New World Medical, Inc., Rancho Cucamonga, CA, USA) in glaucoma patients (n=127 between January 2015 and December 2016) at the Severance Hospital of the Yonsei University College of Medicine. Clinical IOP data were collected before and during the 12-month implantation. The hypotony and hypertensive phases were defined as IOP less than 6 mmHg and > 20 mmHg, respectively. The hypotony phase was diagnosed by i) fundus examination of choroidal detachment using an Optos Daytona (Queensferry House, Carnegie Campus, Dunfermline, Scotland, United Kingdom) and ii) imaging of the anterior chamber using anterior segment optical coherence tomography (AS-OCT; TOMEY GmbH, Wiesbadener Strasse, Nuremberg, Germany). The hypertension phase was diagnosed by considering the visual field index to analyze the rate of glaucoma progression using a Humphrey visual field analyzer (ZEISS Humphrey Field Analyzer 3, Carl Zeiss Meditec, Inc., Dublin, CA). The visual area of the eye was calculated as the percentage of the visible area (white) to the total area, including the blind part (black). Rabbit study : Rabbit experiments were approved by the Institutional Animal Care and Use Committee and conducted following the Use of Animals in Ophthalmic and Vision Research, as provided by the Association for Research in Vision and Ophthalmology Statement. New Zealand white rabbits (weight:2.5-3 kg) were used to develop the glaucoma model by inserting dental composite resins (resin; BEAUTIFIL Flow, SHOFU DENTAL CORPORATION, San Marcos, CA, USA) into the anterior chamber to clog the drainage channel. This blocked the outflow of intraocular fluid and the IOP was elevated. Briefly, the rabbits were anesthetized by intramuscular injection of tiletamine-zolazepam (Zoletil 50; 10 mg/kg, Virbac Lab, Carros, France) and xylazine hydrochloride (Rompun; 2%, 5 mg/kg, Bayer Korea, Seoul, South Korea). Topical anesthesia was administered (proparacaine eye drops, Alcaine; Alcon, Fort Worth, Tex., USA) to control the pain. Paracentesis (0.05 mL) was performed using a 31-gauge needle (Korea Vaccine Co. Ltd., Gyeonggi-do, Republic of Korea). The resin (0.05 mL) was inserted into the anterior chamber, and 25% of the drainage channel was blocked by fixing the resin using a light-emitting diode (LED.H Curing light, Woodpecker, Wroclaw, Dolnoslaskie, Poland). The IOP was measured thrice per eye preoperatively and postoperatively on days 1, 3, and 7 to confirm the increase in IOP up to approximately 60% as an indication of successful glaucoma modeling. A silicone drainage tube with or without SMP tube insertion was implanted into the glaucomatous eyes of rabbits under the same anesthesia conditions as described above (n = 5). Corneal traction was first performed by placing a 7-0 Vicryl suture from the anterior to the limbus, resulting in the downward rotation of the eye. Conjunctival resection was then performed in the supra-temporal region, followed by posterior dissection to separate Tenon’s capsule from the sclera. A 23-gauge needle (Korea Vaccine Co., LTD., Gyeonggi-do, Republic of Korea) was inserted into the anterior chamber at a position 0.25 mm posterior to the limbus, followed by the insertion of sample tubes into the anterior chamber with the beveling side up through the needle tract. The sample tubes were anchored to the sclera using a 10-0 nylon suture, the conjunctiva was secured to the limbus using an interrupted 10-0 nylon suture, and ofloxacin ointment was applied to the eye. IOP was measured thrice under topical anesthesia at predetermined intervals for each eye using a tonometer (Tono-Pen AVIA®, Reichert Technologies, Depew, USA). An argon laser was used to expand the inner diameter of the SMP tube and increase the drainage of intraocular fluid 14 days post implantation. IOP measurements were continued for 42 days after implantation. The synergistic effect between the diameter expansion and release of anti-fibrotic drugs by hydrogel degradation on IOP control was demonstrated in the late postoperative period. As a sham control, eyes with normal pressure were subjected to tube implantation. The three test groups were SMP tube insertion i) with and ii) without argon laser irradiation, and iii) no SMP tube insertion (n = 3). The effect of laser-induced diameter expansion on IOP reduction was validated by comparing the SMP tube insertion groups with and without argon laser irradiation. The anti-fibrotic effect of drug release on IOP control was confirmed by comparing the SMP tube insertion group without argon laser irradiation and the group without SMP tube insertion. The IOP profiles between days 14 and 21 were compared. Because of the sudden IOP drop that often occurs for unknown reasons during the late postoperative period in glaucoma patients after tube implantation, the SMP+PCL ring was developed to decrease the drainage amount of intraocular fluid by shape recovery to squeeze the silicone tube as an external wrap. Normal eyes were implanted with a silicone drainage tube (w/o SMP tube insertion) with the SMP+PCL ring, while normal eyes without any implantation served as a control (n = 6). The SMP+PCL ring was irradiated by an argon laser 7 days after implantation, followed by IOP measurement for the next 13 days. Histological analysis : Fibrotic tissue formation around the drainage tube was examined using tissues obtained after sacrificing the rabbits and then carefully excising the eyes to minimize disturbance of the bleb and implant. The tissues were fixed with 4% paraformaldehyde (CellNest, Gyeonggi-do, Republic of Korea) for 24 h, and the eyes were dissected with incisions passing through the middle of the bleb. After embedding the eye tissues in paraffin wax, the paraffin blocks were sectioned for hematoxylin and eosin (H&E) and Masson’s trichrome staining. The fibrous tissue area was determined from four different photographs of Masson’s trichrome staining, followed by quantitative image analyses using ImageJ (Fiji, National Institute of Health, MD, USA) as the fibrous tissue was indicated by blue color-positive collagen fibers. Statistical analysis : All experiments were performed with at least three replicates per condition. Statistical analyses were performed using one-way analysis of variance (ANOVA) with Tukey’s post-hoc test to perform multiple pairwise comparisons between groups. All experimental data are presented as mean ± standard deviation, where n denotes the number of samples obtained from independent experiments or with dots and whisker plots, in which dots and whiskers are shown as average and minimum/maximum, respectively. Each experimental condition is mentioned in the corresponding figure legend. Differences were considered statistically significant when p < 0.05 (* p < 0.05, ** p < 0.01, and *** p < 0.001). All statistical analyses were conducted with the following software programs: Excel, KyPlot 6.0 software (Kyenslab, Tokyo, Japan), Origin 2018 (OriginLab, Northampton, MA, USA), and SigmaPlot V.12.0 (Systat Software Inc., San Jose, CA, USA). Declarations Acknowledgments This study was financially supported by i) the National Research Foundation of Korea (NRF) funded by the Korean government (MSIT) (2019R1A2C2010802, 2022R1I1A1A01071919, and 2019R1A2C1091089); ii) the Korea Medical Device Development Fund Grant funded by the Ministry of Science and ICT, Ministry of Trade, Industry and Energy, Ministry of Health & Welfare, and Ministry of Food and Drug Safety (1711138302, KMDF_PR_20200901_0152). Competing interests The authors declare no competing interests. Author contributions Kyubae Lee and Wungrak Choi contributed equally to this work as co-first authors. Chan Yun Kim and Hak-Joon Sung (lead) are listed as co-corresponding authors, considering their significant contributions to the technical and clinical aspects, respectively. Hak-Joon Sung designed and directed the study in collaboration with Chan Yun Kim. Kyubae Lee and Wungrak Choi conducted the experiments, analyzed the data, and prepared the figures and supplementary movies. Wungrak Choi and Hyoung Won Bae oversaw the clinical aspects of the study and assisted with animal studies. Si Young Kim, Won Take Oh, Jeongeun Park, and Chan Hee Lee collaborated on the in vitro studies, and Dong-Su Jang assisted in the graphical design under the guidance of Chan Yun Kim. Hak-Joon Sung wrote the manuscript with the assistance of Kyubae Lee and Wungrak Choi. References Araci, I. E. et al. An implantable microfluidic device for self-monitoring of intraocular pressure. Nat. Med. 20 , 1074-1078 (2014). Choi, Y. S. et al. Fully implantable and bioresorbable cardiac pacemakers without leads or batteries. Nat. Biotechnol. 39 , 1228-1238 (2021). Sonmezoglu, S. et al. Monitoring deep-tissue oxygenation with a millimeter-scale ultrasonic implant. Nat. Biotechnol. 39 , 855-864 (2021). Jonas, J. B. et al. Glaucoma. Lancet 390 , 2183-2193 (2017). Liu, W.-T. et al. Interstitial fluid behavior and diseases. Adv. Sci. 9 , 2100617 (2022). Scheffer, M. et al. Quantifying resilience of humans and other animals. Proc. Natl. Acad. Sci. U.S.A. 115 , 201810630 (2018). Nguyen, P. Q. et al. Wearable materials with embedded synthetic biology sensors for biomolecule detection. Nat. Biotechnol. 39 , 1366-1374 (2021). Kathe, C. et al. Wireless closed-loop optogenetics across the entire dorsoventral spinal cord in mice. Nat. Biotechnol. 40 , 198-208 (2022). Zhu, Y. et al. Lab-on-a-contact lens: recent advances and future opportunities in diagnostics and therapeutics. Adv. Mater. 34 , e2108389 (2022). Chen, R. et al. Deep brain optogenetics without intracranial surgery. Nat. Biotechnol. 39 , 161-164 (2021). Hua, D. et al. Bubble forming films for spatial selective cell killing. Adv. Mater. 33 , 2008379 (2021). Wang, N. et al. Activation of a tissue-specific stress response in the aqueous outflow pathway of the eye defines the glaucoma disease phenotype. Nat. Med. 7 , 304-309 (2001). Weinreb, R. N. et al. Primary open-angle glaucoma. Nat. Rev. Dis. Prim. 2 , 16067 (2016). Lim, K. S. et al. Glaucoma drainage devices; past, present, and future. Br. J. Ophthalmol. 82 , 1083-1089 (1998). Schwartz, K. S. et al. Glaucoma drainage implants: a critical comparison of types. Curr. Opin. Ophthalmol. 17 , 181-189 (2006). Pereira, I. C. F. et al. Conventional glaucoma implants and the new MIGS devices: a comprehensive review of current options and future directions. Eye . 35 , 3202-3221 (2021). Suñer, I. J. et al. Hypotony maculopathy after filtering surgery with mitomycin C. Incidence and treatment. Ophthalmology. 104 , 207-215 (1997). Christakis, P. G. et al. Five-year pooled data analysis of the Ahmed Baerveldt comparison study and the Ahmed versus Baerveldt study. Am. J. Ophthalmol. 176 , 118-126 (2017). Megevand, G. S. and Bron A. M. Personalising surgical treatments for glaucoma patients. Prog. Retin. Eye Res. 81 , 100879 (2021). Ayyala, R. S. et al. A clinical study of the Ahmed glaucoma valve implant in advanced glaucoma. Ophthalmology. 105 , 1968-1976 (1998). Nouri-Mahdavi, K. et al. Evaluation of the hypertensive phase after insertion of the Ahmed glaucoma valve. Am. J. Ophthalmol. 136 , 1001-1008 (2003). Jacob, J. T. et al. Slow release of the antimetabolite 5-fluorouracil (5-FU) from modified Baerveldt glaucoma drains to prolong drain function. Biomaterials. 22 , 3329-3335 (2001). Wronska, M. A. et al. Adding functions to biomaterial surfaces through protein incorporation. Adv. Mater. 28 , 5485-5508 (2016). Doloff, J. C. et al. The surface topography of silicone breast implants mediates the foreign body response in mice, rabbits and humans. Nat. Biomed. Eng. 5 , 1115-1130 (2021). Horejs, Christine. Preventing fibrotic encapsulation. Nat. Rev. Mater. 6 , 554 (2021). Rosentreter, A. et al. Previous cyclodestruction is a risk factor for late-onset hypotony and suprachoroidal haemorrhage after glaucoma drainage device surgery. Br. J. Ophthalmol. 97 , 715-719 (2013). Oh, W. T. et al. Shape memory tube plug for fine-control of intraocular pressure by glaucoma devices. ACS Biomater. Sci. Eng. 6 , 3784-3790 (2020). Xia, Y. et al. A review of shape memory polymers and composites: mechanisms, materials, and applications. Adv. Mater. 33 , e2000713 (2021). Patel, S. R. and Lieber, C. M. Precision electronic medicine in the brain. Nat. Biotechnol. 37 , 1007-1012 (2019). Li, C. et al. Design of biodegradable, implantable devices towards clinical translation. Nat. Rev. Mater. 5 , 61-81 (2020). Lee, G. -H. et al. Multifunctional materials for implantable and wearable photonic healthcare devices. Nat. Rev. Mater. 5 , 149-165 (2020). Hill, R. A. et al. Molteno implantation for glaucoma in young patients. Ophthalmology. 98 , 1042-1046 (1991). Lloyd, M. A. et al. Clinical experience with the single-plate molteno implant in complicated glaucomas. Update of a pilot study. Ophthalmology. 99 , 679-687 (1992). Siegner, S. W. et al. Clinical experience with the Baerveldt glaucoma drainage implant. Ophthalmology. 102 , 1298-1307 (1995). Burney, E. N. et al. Hypotony and choroidal detachment as late complications of trabeculectomy. Am. J. Ophthalmol. 103 , 685-688 (1987). Francis, B. A. et al. Changes in axial length following trabeculectomy and glaucoma drainage device surgery. Br. J. Ophthalmol. 89 , 17-20 (2005). Tagalakis, A. D. et al. In vitro and in vivo delivery of a sustained release nanocarrier-based formulation of an MRTF/SRF inhibitor in conjunctival fibrosis. J. Nanobiotechnology. 16 , 97 (2018). Dong, A. et al. Glaucoma drainage device coated with mitomycin C loaded opal shale microparticles to inhibit bleb fibrosis. ACS Appl. Mater. Interfaces. 11 , 10244-10253 (2019). Ballinger, A. B. et al. Persistent systemic inflammatory response after stent insertion in patients with malignant bile duct obstruction. Gut. 42 , 555-559 (1998). Swidsinski, A. et al. Bacterial biofilm within diseased pancreatic and biliary tracts. Gut. 54 , 388-395 (2005). Park, J. Y. et al. Nasolacrimal stent with shape memory as an advanced alternative to silicone products. Acta Biomater. 101 , 273-284 (2020). Arciola, C. R. et al. Implant infections: adhesion, biofilm formation and immune evasion. Nat. Rev. Microbiol. 16 , 397-409 (2018). Chen, H. et al. Biocompatible polymer materials: Role of protein–surface interactions. Prog. Polym. Sci. 33 , 1059-1087 (2008). Nel, A. E. et al. Understanding biophysicochemical interactions at the nano–bio interface. Nat. Mater. 8 , 543-557 (2009). Shin, Y. C. et al. Development of a shape-memory tube to prevent vascular stenosis. Adv. Mater. 31 , 1904476 (2019). Lee, K. et al. Osteogenic and adipogenic differentiation of mesenchymal stem cells in gelatin solutions of different viscosities. Adv. Healthc. Mater. 9 , 2000617 (2020). Zhou, X. et al. Biodegradable β-cyclodextrin conjugated gelatin methacryloyl microneedle for delivery of water-insoluble drug. Adv. Healthc. Mater. 9 , 2000527 (2020). Additional Declarations There is NO Competing Interest. Supplementary Files LaserTubeSupplementaryfiguressubmit.docx Supplementaryvideo1.mp4 Supplementary video 1 Supplementaryvideo2.mp4 Supplementary video 2 Supplementaryvideo3.mp4 Supplementary video 3 Supplementaryvideo4.mp4 Supplementary video 4 NCOMMS2236652TFlatRS.pdf Reporting Summary Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1829962","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":136855578,"identity":"79f70faf-f4fc-4b8d-a5de-b582353913ba","order_by":0,"name":"Hak-Joon 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\u003cstrong\u003eb\u003c/strong\u003e, The data from a 12-month examination of glaucoma patients (n = 127) justifies the clinical need for the stepwise control of IOP using an SMP tube: i) When the drainage device was implanted, the fixed diameter of tube lowered the high IOP to the hypotonic range by over-draining eye water. ii) The IOP remained in the hypotony range for one week and then rapidly increased to the normal range within the next week, resulting in unstable IOP fluctuations in several patients to the hypertensive range until three months. iii) Despite remaining dominantly in the normal range afterwards, some deviated to the pathological hypertensive range until 12 months. \u003cstrong\u003ec\u003c/strong\u003e, The early hypotonic IOP induced anterior chamber shrinkage and choroidal detachment, followed by blindness in severe cases. \u003cstrong\u003ed\u003c/strong\u003e, The properties of the silicone device often caused tissue fibrosis (dashed yellow line) during interaction with body fluid wastes, causing the late hypertensive IOP by incremental drainage blockage and tissue fibrosis. \u003cstrong\u003ee\u003c/strong\u003e, The laser-responsive shape memory tube was proposed to address the issues as the pin-point delivery of light energy promotes the fine control of diameter increase (shape recovery) by minimizing unexpected influences on neighboring tissues. The three steps of IOP control proceed from i) the small D by GelMA coating onto the intima to release anti-fibrotic drug, to ii) the medium D after GelMA degradation with drug release, and finally, to iii) the large D post diameter increase (shape recovery) upon pin-point exposure to the argon laser.\u003c/p\u003e","description":"","filename":"floatimage1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1829962/v1/efe046f63706da107b462ac1.jpg"},{"id":26671521,"identity":"f289338e-2619-466d-8ac4-39765835f220","added_by":"auto","created_at":"2022-09-19 20:32:37","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":284086,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eVerification of three step IOP control and anti-fibrotic drug release by the SMP tube using computational and analytical experiments. a\u003c/strong\u003e, CFD simulations verified the three-step control of IOP by SMP because ΔP, that indicated the IOP drop resistance, increased from 0.015 (silicone D w/o SMP tube) to 6.352 mmHg (small D) to prevent the hypotonic drop. Then, ΔP decreased to 0.036 (medium D) and 0.018 mmHg (large D) to control hypertensive shifts of IOP in a user-specified manner via stepwise increases of the tube diameter. \u003cstrong\u003eb\u003c/strong\u003e, SEM visualized the stepwise increases of tube diameter from 50 µm (small D) to 200 µm (medium D) before and after the degradation of drug-loaded GelMA, respectively, followed by a further increase to 250 µm (large D) upon shape recovery. \u003cstrong\u003ec\u003c/strong\u003e, A pressure measurement system under a constant flow rate (25 µL/min) was custom-built using a silicone drainage tube with and without the insertion of the SMP tube. \u003cstrong\u003ed\u003c/strong\u003e, This system confirmed the SMP tube function as the pressure drop resistance increased significantly from the value without the SMP tube to that for small D over time, followed by stepwise decreases to medium D and further to large D at the end of 700 seconds (s). \u003cstrong\u003ee\u003c/strong\u003e, β-cyclodextrin (CD) was conjugated to GelMA (GelMA-β-CD) to increase the loading capacity of the anti-fibrotic drug (5-FU).\u003cstrong\u003e f\u003c/strong\u003e, The successful production of GelMA-β-CD with 5-FU loading was confirmed by proton nuclear magnetic resonance (1H-NMR) spectroscopy. \u003cstrong\u003eg\u003c/strong\u003e, β-CD conjugation to GelMA increased the loading capacity of 5-FU by almost 10 times compared to GelMA only. \u003cstrong\u003eh\u003c/strong\u003e, As the concentration of GelMA-β-CD increased (5, 7, and 10% w/v), the in vitro degradation slowed down for 14 days at 37 °C, suggesting its effectiveness in controlling the speeds of IOP drop and drug release. \u003cstrong\u003ei\u003c/strong\u003e, β-CD conjugation to GelMA (5% w/v) enabled the sustained release of 5-FU drugfor 14 days in vitro in contrast to the burst release by GelMA only. Data = mean ± standard deviation (n = 3). ** p \u0026lt; 0.01; *** p \u0026lt; 0.001 between lined groups or versus day 0 from one-way ANOVA with Tukey’s post hoc test.\u003c/p\u003e","description":"","filename":"floatimage2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1829962/v1/69f8a3850caf12d9145d8209.jpg"},{"id":26669523,"identity":"0cbef857-227b-42a8-9708-b1da876fc044","added_by":"auto","created_at":"2022-09-19 20:22:37","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":230589,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eShape programing of the SMP tube by tuning the clinic-friendly laser parameter. a\u003c/strong\u003e, During the shape programing process, the 1.5 mm long tube (recovery shape) was elongated at 50 °Cand frozen to fix at 0 °Cto reduce the diameter, followed by cutting to a 3 mm long tube (temporary shape) based on the Poisson’s ratio (\u003cem\u003ev\u003c/em\u003e = 0.2) of the SMP. The SMP tube was painted black to promote laser absorption. \u003cstrong\u003eb\u003c/strong\u003e, After argon laser shots in the clinical room, the shape recovery was tested to validate the expansion of tube diameter by decreasing the length. \u003cstrong\u003ec, \u003c/strong\u003eThe pin-point shot delivery of laser energy (E) was more efficient (approximately 66 times) compared to hot water (50 °C), indicating its advantage in minimizing untargeted influences. \u003cstrong\u003ed-e\u003c/strong\u003e, Two-step characterization of laser E efficiency was performed to determine the maximum E of a single shot within the clinical safety range and minimize the shot number to maintain the pin-point laser focusing. \u003cstrong\u003ed\u003c/strong\u003e, First, because the low E shot resulted in non-linear shape recovery (e.g., bending), the minimum E of a single shot for linear recovery within the clinical safety range (max. 70 mJ) was determined as 40 mJ. \u003cstrong\u003ee\u003c/strong\u003e, Next, the critical E of a single shot for shape recovery was determined as 60 mJ to minimize the number of laser shots because the shape recovery ratio between 60~70 mJ (safety limit) was not significantly improved. Data = mean ± standard deviation (n= 3). * p \u0026lt; 0.05; ** p \u0026lt; 0.01; *** p \u0026lt; 0.001 versus 40 mJ from one-way ANOVA with Tukey’s post hoc test (N.S.: not significant).\u003c/p\u003e","description":"","filename":"floatimage3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1829962/v1/d132b96c46ae0740cfe6a3e5.jpg"},{"id":26670608,"identity":"754e80ca-e8f5-4e68-bef5-f7f6b8725795","added_by":"auto","created_at":"2022-09-19 20:27:37","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":374683,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTreatment of rabbit glaucoma eyes using the SMP tube with stepwise diameter recovery and anti-fibrotic drug release. a\u003c/strong\u003e, The SMP device was produced by inserting the SMP tube into a silicone tube (part of glaucoma device) with external wrapping by SMP+PCL ring as a safety lock to prevent late hypotonic IOP (See Fig. 5 for details). The SMP device was implanted into glaucomatous eyes in a rabbit model and tested to validate the diameter increase by decreasing the length using argon laser shots. \u003cstrong\u003eb\u003c/strong\u003e, In the rabbit glaucoma model, the implantation of the SMP device suppressed the near hypotonic IOP drop (w/o SMP tube) for 10 days by changing from small D to medium D SMP tube owing to the complete degradation of GelMA with complete release of the anti-fibrotic drug. Then, the change from medium D to large D SMP tube by argon laser shots lowered the hypertensive IOP (w/o SMP tube) to the normal range until 42 days (n = 5 rabbits). \u003cstrong\u003ec\u003c/strong\u003e, The beneficial effect of the change from medium D to large D by argon laser shots suppressed the incremental IOP (- laser) until 21 days in the rabbit glaucoma model although the incremental levels were still lower than those of w/o SMP group. (n = 3 rabbits). \u003cstrong\u003ed\u003c/strong\u003e, The silicone property of glaucoma device induced fibrotic tissue formation owing to infection with inflammatory responses. The release of anti-fibrotic drug (5-FU) from GelMA in the SMP tube (small D) suppressed the inflammatory cell invasion (H\u0026amp;E) and consequent fibrotic tissue formation (Masson’s trichrome) as confirmed by quantitative image analysis (n=4 rabbits). Data = mean ± standard deviation.* p \u0026lt; 0.05; *** p \u0026lt; 0.001 between lined groups from one-way ANOVA with Tukey’s post hoc test.\u003c/p\u003e","description":"","filename":"floatimage4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1829962/v1/135e563cce30e05c2a01b5ea.jpg"},{"id":26669525,"identity":"c5fac010-1db6-4552-af64-27609385bb54","added_by":"auto","created_at":"2022-09-19 20:22:37","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":193121,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSMP+PCL ring as a safety lock to suppress late hypotonic IOP by externally squeezing a silicone tube.\u003c/strong\u003e \u003cstrong\u003ea\u003c/strong\u003e, The clinical data indicates a sudden late IOP drop (\u0026gt; 4 months) to the hypotonic range in some cases after the implantation of the glaucoma device. \u003cstrong\u003eb\u003c/strong\u003e, In this late hypotonic case, some patients appeared to develop choroidal detachment and vision loss under prolonged severity, indicating the necessity of safeguards to remedy this condition. \u003cstrong\u003ec\u003c/strong\u003e, The SMP+PCL ring was developed to address this issue as argon laser shots induced shape recovery of the ring by squeezing the silicone tube in the form of an external wrap. Consequently, the diameter of the silicone tube decreased significantly to reduce hypotonic fluid drainage \u003cstrong\u003ed\u003c/strong\u003e, in SEM imaging \u003cstrong\u003ee\u003c/strong\u003e, with quantitative Image analysis (n = 3). The ring was painted black to promote laser absorption. \u003cstrong\u003ef\u003c/strong\u003e, When the device was implanted in a normal rabbit eye, the IOP dropped continuously owing to the large diameter of silicone tube until day 7. Immediately after the argon laser shots, the IOP drop stopped upon the squeezing shape recovery of the SMP+PCL ring with the decrease in diameter of the silicone tube. Next, the IOP recovered to normal levels afterwards until day 13 (n = 6 rabbits). \u003cstrong\u003eg\u003c/strong\u003e, SMP was blended with PCL because the modulus increased to promote the squeezing force in contrast to the relatively more elastic property of SMP only, as analyzed by a dynamic mechanical analyzer (DMA). \u003cstrong\u003eh\u003c/strong\u003e, The blending of SMP with PCL provided another user advantage because the increase in Tmby 10 °C could prevent unexpected squeezing by the ring when the argon laser shots to the SMP tube were misfocused or transferred the heat to the ring, as analyzed by differential scanning calorimetry (DSC).\u003cstrong\u003e g\u003c/strong\u003e, Data = mean ± standard deviation.*** p \u0026lt; 0.001 between lined groups from one-way ANOVA with Tukey’s post hoc test.\u003c/p\u003e","description":"","filename":"floatimage5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1829962/v1/99746815b5a97afb7f727c1a.jpg"},{"id":28448470,"identity":"edf6d493-eb63-49d4-940a-352cda52e2eb","added_by":"auto","created_at":"2022-10-31 10:47:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1639815,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1829962/v1/5ce84104-2815-4068-93a0-8bf88aad1e84.pdf"},{"id":26670611,"identity":"88c8759d-095e-4b82-914e-ebedb3bf2f47","added_by":"auto","created_at":"2022-09-19 20:27:37","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2579809,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"LaserTubeSupplementaryfiguressubmit.docx","url":"https://assets-eu.researchsquare.com/files/rs-1829962/v1/1a290d37dd1e4c81ccbdc730.docx"},{"id":26669526,"identity":"15b340a3-b1a9-4968-8b64-676ea62fc5ae","added_by":"auto","created_at":"2022-09-19 20:22:37","extension":"mp4","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":19899038,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary video 1\u003c/p\u003e","description":"","filename":"Supplementaryvideo1.mp4","url":"https://assets-eu.researchsquare.com/files/rs-1829962/v1/3b741d486bb56aaf4ca5ea51.mp4"},{"id":26669528,"identity":"899677c7-a586-4373-8412-88492dcb78bc","added_by":"auto","created_at":"2022-09-19 20:22:37","extension":"mp4","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":21999232,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary video 2\u003c/p\u003e","description":"","filename":"Supplementaryvideo2.mp4","url":"https://assets-eu.researchsquare.com/files/rs-1829962/v1/d0c9e3daf91fb85670a860de.mp4"},{"id":26669529,"identity":"8cc68ca9-860c-4990-9613-cd233edc2c02","added_by":"auto","created_at":"2022-09-19 20:22:37","extension":"mp4","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":23007029,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary video 3\u003c/p\u003e","description":"","filename":"Supplementaryvideo3.mp4","url":"https://assets-eu.researchsquare.com/files/rs-1829962/v1/8182aad3284d214bfa52b498.mp4"},{"id":26669530,"identity":"4265231a-447b-44ea-801c-14eff6b369d1","added_by":"auto","created_at":"2022-09-19 20:22:37","extension":"mp4","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":38999590,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary video 4\u003c/p\u003e","description":"","filename":"Supplementaryvideo4.mp4","url":"https://assets-eu.researchsquare.com/files/rs-1829962/v1/2753d1ae8e925c80b04d8f11.mp4"},{"id":26670610,"identity":"16249b13-b775-4d86-a3fb-80fa9891e4d5","added_by":"auto","created_at":"2022-09-19 20:27:37","extension":"pdf","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":323591,"visible":true,"origin":"","legend":"\u003cp\u003eReporting Summary\u003c/p\u003e","description":"","filename":"NCOMMS2236652TFlatRS.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1829962/v1/6df427867db1d39e21f07351.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Laser-responsive shape memory device to program the stepwise control of intraocular pressure in glaucoma","fulltext":[{"header":"Main","content":"\u003cp\u003eThe paradigm of implantable medical devices has evolved to promote patient-specific precision\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Although patient status changes over time and depends on lesions, the fixed function, property, and size of devices limit clinician-specified controls by considering the situation and disease progress. Controls are urgently required when dealing with dynamic body parameters such as pressure\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e, flow\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, and heat\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Uncontrolled body parameters upon device implantation progressively exacerbate the prognosis, increasing mortality and morbidity. Silicone has long been used in a wide range of implantable medical devices owing to its durability, controllable properties, and easy fabrication\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. However, the inability to handle dynamic body conditions such as structural changes represents a critical limitation in moving towards the next paradigm. In addition, its surface property promotes bacterial growth with biofilm formation\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, which further limits its evolution as a leading medical material. Hence, cross-disciplinary material function and device design are required to help clinicians control device functions to deal with unpredictable changes in pathological parameters. In particular, pinpoint control of target lesions has emerged as a current paradigm in clinics along with recent advances in laser systems to minimize untargeted influences\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. This paradigm is suggested to promote clinician-specified remote control of device functions by integrating with state-of-the-art imaging and laser systems.\u003c/p\u003e \u003cp\u003eGlaucoma occurs because of the overfilling of eye water and consequent increase in intraocular pressure (IOP)\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Hence, for the past decades, silicone devices have been implanted into glaucomatous eyes to drain the fluid and control the IOP over time\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Regardless of the device type, the fixed diameter of the drainage tube and silicone material has been considered as common factors that generate critical issues. The first issue starts within two weeks of device implantation because the fixed diameter of the silicone tube generates a relatively large negative pressure. The consequent over-drainage of the flow results in a hypotonic IOP drop (\u0026lt;\u0026thinsp;6 mmHg)\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. If this situation aggravates, choroidal detachment occurs with blindness, which underscores the need for a smaller diameter to suppress the IOP drop during the early phase of device implantation. A month after implantation, the second issue arises as the hypotonic IOP elevates to fluctuate mostly into the hypertensive (\u0026gt;\u0026thinsp;20 mmHg) or hypotonic range, because the elevation speed and period are patient-specific\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Hence, patient-specific control to increase the tube diameter in a stepwise fashion is necessary owing to the pattern of IOP fluctuation. Third, this uncontrollable change in IOP is strongly associated with fibrotic tissue formation, primarily owing to the nature of the silicone material that promotes biofilm formation, suggesting the need for anti-fibrotic function for tube implantation\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Lastly, several months after device implantation, some patients exhibit a sudden drop in the IOP that induces choroidal detachment and blindness upon severe progression, which indicates the need for a safety lock to suppress the abnormal IOP drop as needed\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Hence, these issues should be addressed by upgrading the device function and material properties to enable the clinician-specified control of IOP.\u003c/p\u003e \u003cp\u003eAs a breakthrough solution for the pinpoint control of device function, a laser-responsive shape memory polymer (SMP) was used to program a three-step increase in tube diameter (D) with the release of anti-fibrotic drugs. An SMP tube was designed to be inserted into a silicone tube for application in current silicone drainage devices, regardless of the type. Shape programing enabled the recovery of large D tubes (inner diameter, ID\u0026thinsp;=\u0026thinsp;250 \u0026micro;m) from medium D (ID\u0026thinsp;=\u0026thinsp;200 \u0026micro;m) via argon laser shots by shrinking the tube length (3 \u0026rarr; 1.5 mm) based on Poisson\u0026rsquo;s ratio (2.0) of the SMP. The lumen of the medium D tube was coated with drug-loaded hydrogel to produce a small D (ID\u0026thinsp;=\u0026thinsp;50 \u0026micro;m). The hydrogel was designed to degrade within two weeks to become medium D and release anti-fibrotic drugs in a sustained manner. A safety lock ring was produced to suppress the sudden drop in IOP by squeezing a silicone tube as an external wrap during the late phase of implantation. The SMP was blended with polycaprolactone (PCL) to enhance the squeezing force by increasing the melting temperature (T\u003csub\u003em\u003c/sub\u003e). This prevents unexpected ring action owing to insufficient energy transfer by laser shots to the SMP tube. This study suggests the next generation of biotechnology concepts for designing implantable medical devices based on the cross-disciplinary needs of clinics.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cb\u003eClinical justification for programing SMP tube functions.\u003c/b\u003e Glaucoma occurs owing to the blockage of ocular flow drainage and consequent increase in IOP with optic nerve damage (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). The implantation of the drainage device into the glaucomatous eye induces the flow of intraocular fluid through the silicone tube thereby reducing the IOP (\u003cb\u003eSupplementary Fig.\u0026nbsp;1a\u003c/b\u003e). The 12-month examination of glaucoma patients (n\u0026thinsp;=\u0026thinsp;127) after device implantation justifies the need for stepwise IOP control (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb): i) the fixed diameter of the drainage tube induced hypotonic IOP drops owing to the over-drainage of eye flow by generating excess negative pressure. ii) The IOP rapidly increased to the normal range within two weeks with unstable IOP fluctuations to the hypertensive range until three months. iii) Despite the remaining predominantly in the normal range afterwards, some deviated to the pathological hypertensive range until 12 months. Early hypotonic IOP induced anterior chamber shrinkage compared with the normal case (\u003cb\u003eSupplementary Fig.\u0026nbsp;1b\u003c/b\u003e), followed by choroidal detachment and blindness in severe cases (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). The properties of the silicone device often caused tissue fibrosis associated with late hypertensive IOP (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed). Glaucoma progression induced a gradual loss of vision of 41% compared to 100% in normal eyes. Five months after implantation of the drainage device, vision loss worsened (~\u0026thinsp;33% of the visual area) because of the hypertensive IOP caused by tissue fibrosis (\u003cb\u003eSupplementary Fig.\u0026nbsp;1c\u003c/b\u003e). A laser-responsive SMP tube is proposed to address these issues as the pin-point delivery of light energy increases the diameter by minimizing untargeted influences (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ee\u003cb\u003e-top\u003c/b\u003e). Gelatin was conjugated with methacrylic anhydride (GelMA) followed by conjugation with a complex of β-cyclodextrin (β-CD) and chloroacetic acid to produce GelMA-β-CD (\u003cb\u003eSupplementary Fig.\u0026nbsp;2a\u003c/b\u003e), as confirmed by proton nuclear magnetic resonance (\u003csup\u003e1\u003c/sup\u003eH-NMR) (\u003cb\u003eSupplementary Fig.\u0026nbsp;2b-d\u003c/b\u003e) and Fourier transform infrared (FTIR) spectroscopy (\u003cb\u003eSupplementary Fig.\u0026nbsp;2e,f\u003c/b\u003e). Consequently, the three steps of IOP control proceed from: i) the small diameter (D) by GelMA coating onto the intima to release the anti-fibrotic drug, ii) medium D after GelMA degradation with drug release, and iii) large D after diameter increase (shape recovery) upon argon laser shots (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ee\u003cb\u003e-bottom\u003c/b\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eThree step IOP control and drug release by SMP tube.\u003c/b\u003e Computational fluid dynamics (CFD) modeling was used to simulate the diameter (D), pressure, and velocity profiles and determine the length of the SMP tube for shape programing. The profiles were modeled after inserting the SMP tube into the silicone tube (length\u0026thinsp;=\u0026thinsp;10 mm; inner D\u0026thinsp;=\u0026thinsp;305 \u0026micro;m) of the glaucoma drainage device (\u003cb\u003eSupplementary Fig.\u0026nbsp;3a\u003c/b\u003e). When the length of the SMP was set to 30 mm for insertion into the silicone tube, the post-recovery length was 15 mm. Consequently, D was changed from 50 \u0026micro;m (small D) to 200 \u0026micro;m (medium D) before and after GelMA degradation, respectively, followed by a further increase to 250 \u0026micro;m (large D) upon shape recovery using argon laser shots. Accordingly, the CFD velocity increased markedly upon the insertion of the SMP tube and decreased to a level similar to that of the silicone tube only following the increased D, indicating stepwise control of the drainage flow rate and IOP. Consequently, CFD modeling verified the three-step control of IOP by the SMP because the pressure difference (ΔP) that indicated IOP drop resistance increased from 0.015 (silicone D w/o SMP tube) to 6.352 mmHg (small D) to prevent hypotonic drop (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). Then, ΔP decreased to 0.036 (medium D) and 0.018 mmHg (large D) to control hypertensive shifts in IOP in a user-specified manner by stepwise increases in tube diameter.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eShape programing of the SMP tube was conducted following the shape memory cycle (\u003cb\u003eSupplementary Fig.\u0026nbsp;3b\u003c/b\u003e), as visualized by scanning electron microscopy (SEM), to perform stepwise increases in tube diameter from 50 \u0026micro;m (small D) to 200 \u0026micro;m (medium D) before and after the degradation of drug-loaded GelMA, respectively, followed by a further increase to 250 \u0026micro;m (large D) upon shape recovery (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). The progressive changes in D were validated in vivo from 21-day implantation into the eyes as GelMA degraded until day 14 (before laser), and argon laser shots at day 14 increased D as programmed, which was confirmed at day 21 (after laser) (\u003cb\u003eSupplementary Fig.\u0026nbsp;3c\u003c/b\u003e). A custom-built system was operated under a constant flow rate (25 \u0026micro;L/min) using a silicone drainage tube, with and without the SMP tube (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). The resistance to pressure drops increased markedly from without the SMP tube to a small D over time, followed by a stepwise decrease to a medium D and further to a large D after 700 s (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed). β-CD was conjugated to GelMA (GelMA-β-CD) to increase the loading capacity of the anti-fibrotic drug (5-FU; 5-Fluorouracil) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ee), as confirmed by \u003csup\u003e1\u003c/sup\u003eH-NMR (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ef), which increased the loading by almost 10 times compared to GelMA only (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eg). As the concentration of GelMA-β-CD increased (5, 7, and 10% w/v), the in vitro degradation slowed down for 14 days at 37\u0026deg;C (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eh), suggesting an effective means to control the speed of IOP drop and drug release. β-CD conjugation to GelMA (5% w/v) enabled the sustained release of 5-FU for 14 days in vitro, in contrast to the burst release by GelMA only (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ei).\u003c/p\u003e \u003cp\u003e \u003cb\u003eClinic-friendly setting of SMP tube operation.\u003c/b\u003e During shape programing, the 1.5 mm long tube (recovery shape) was elongated at 55\u0026deg;C and frozen to fix at 0\u0026deg;C so that the diameter decreased, followed by cutting to a 3 mm long tube (insertion shape) based on Poisson\u0026rsquo;s ratio (\u003cem\u003ev\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.2) of the SMP (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea). The SMP tube was painted black to promote laser absorption, and argon laser shots in the clinical room induced the expansion of the tube diameter by decreasing its length (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). Warm water can also be used, although it spreads into the neighboring areas\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. However, calculations confirmed the superior energy efficiency (approximately 66 times) of the argon laser (energy density: approximately 4,286 J/cm\u003csup\u003e3\u003c/sup\u003e) through pinpoint shot delivery when compared to the water heat energy (Q\u003csub\u003ewater\u003c/sub\u003e: approximately 65 J/cm\u003csup\u003e3\u003c/sup\u003e at 50\u0026deg;C) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec \u003cb\u003eand Supplementary Fig.\u0026nbsp;4\u003c/b\u003e), indicating another advantage in minimizing unexpected influences on neighboring tissues\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. The efficiency of the argon laser E was tuned in the following two steps to determine the maximum E of a single shot within the clinical safety range (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed,e). This minimized the number of laser shots so that the pin-point laser focusing remained undisturbed. First, as the low-E shot resulted in non-linear shape recovery (e.g., bending), the minimum E of a single shot for linear recovery within the clinically safe range (max. 70 mJ) was determined to be 40 mJ (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed \u003cb\u003eand Movie S1\u003c/b\u003e). Next, the critical E of a single shot for shape recovery was determined as 60 mJ to minimize the number of laser shots because the shape recovery ratio did not improve significantly between 60\u0026thinsp;~\u0026thinsp;70 mJ (safety limit) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ee).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eRescue of rabbit glaucoma eyes by SMP tube.\u003c/b\u003e A\u003cb\u003en\u003c/b\u003e SMP tube was inserted into a silicone tube with external wrapping by the SMP\u0026thinsp;+\u0026thinsp;PCL ring (SMP: black), which was implanted into glaucomatous eyes in a rabbit model (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea). The SMP device suppressed the near hypotonic drop of IOP (w/o SMP tube) for 10 days by changing from small D to medium D owing to GelMA degradation with the release of the anti-fibrotic drug (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb). Then, the change from medium D to large D of the SMP tube by argon laser shots lowered the hypertensive IOP (w/o SMP tube) to the normal range until 42 days (\u003cb\u003eMovie S2\u003c/b\u003e). The beneficial effect of changing from medium D to large D by argon laser shots suppressed the incremental IOP (- laser) until 21 days, although the incremental levels remained lower than those without the SMP (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ec). Moreover, the groups with saline treatment at 25\u0026deg;C and 50\u0026deg;C were compared to induce shape recovery upon intra- versus extraocular implantation of the SMP tube (\u003cb\u003eSupplementary Fig.\u0026nbsp;5\u003c/b\u003e). The saline at 50\u0026deg;C could not induce shape recovery in the intraocular position, but succeeded in the extraocular position, as demonstrated by the shortened tube length (\u003cb\u003eMovie S3\u003c/b\u003e). It indicates the limitation of water heat owing to insufficient energy transfer to the intraocular position as further supported by no shape change by the saline treatment at 25\u0026deg;C. The release of the anti-fibrotic drug (5-FU) from GelMA in the SMP tube (small D) suppressed inflammatory cell invasion (hematoxylin and eosin, H\u0026amp;E) and consequent fibrotic tissue formation (Masson\u0026rsquo;s trichrome) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ed). When bacterial adhesion was tested on SMP silicone films for two days post-seeding of \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e, the superior antibiofilm effect of SMP was demonstrated by fewer crystal violet signals with fewer bacteria (\u003cb\u003eSupplementary Fig.\u0026nbsp;6\u003c/b\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eSafety lock ring to suppress late hypotonic IOP.\u003c/b\u003e The clinical data indicated a late IOP drop (\u0026gt;\u0026thinsp;4 months) to the hypotonic range in some sudden cases post implantation of the glaucoma device (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea). In the late hypotonic case, some patients appeared to suffer choroidal detachment and vision loss under prolonged severity, clearly underscoring the need for safely alleviating this condition (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eb). The SMP\u0026thinsp;+\u0026thinsp;PCL ring was designed to squeeze the silicone tube as an external wrap upon laser shots (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ec \u003cb\u003eand Movie S4\u003c/b\u003e), thereby significantly decreasing the silicone tube diameter and reducing hypotonic fluid drainage (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ed,e). The ring was painted black to promote laser absorption. When the device was implanted in a normal rabbit eye, the IOP dropped continuously owing to the large diameter of the silicone tube until day 7 (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ef). Immediately after the argon laser treatment, the IOP drop stopped upon the squeezing shape recovery of the SMP\u0026thinsp;+\u0026thinsp;PCL ring (\u003cb\u003eMovie S4\u003c/b\u003e). This was followed by the recovery of IOP to the normal range until day 13. The SMP was blended with PCL to increase the modulus and promote the squeezing force, in contrast to the relatively more elastic property of SMP (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eg). The blending of SMP with PCL provided another advantage to users because the increase in T\u003csub\u003em\u003c/sub\u003e by 10\u0026deg;C could prevent unexpected squeezing by the ring when the argon laser shot to the SMP tube was misfocused or transferred the heat to the ring (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eh).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eUnmet clinical needs have served as one of the most potent driving forces guiding continuous advances in implantable medical devices\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. This study is clearly aligned with this paradigm; thus, the results suggest the next generation of device design and function considering the following salient points. First, the clinical argon laser system was used to induce shape recovery of the SMP tube because the pinpoint delivery of laser E enabled site-specific control of the diameter increase with minimal influences on neighboring tissues. This control option is a powerful feature aligned with the concepts of user-specified remote control, which has been applied to the current development of diagnostic and drug delivery systems. Second, GelMA coating of the lumen of the tube provided the double benefit of increasing the diameter within two weeks of implantation and releasing anti-fibrotic drugs, thereby addressing the multi-decade problem observed in silicone drainage devices\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Third, the SMP\u0026thinsp;+\u0026thinsp;PCL ring was attached to the silicone device as a safety lock to reverse the one-way function of the SMP tube upon laser shots. Despite the rarity of the late hypotonic case\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e, saving even one patient using the ring function provides an unprecedented basis for guiding future medical devices.\u003c/p\u003e \u003cp\u003eOther important factors of this study are summarized as follows. i) The design and function of the SMP devices were justified by tracking the clinical IOP profile of 127 glaucoma patients for one year. Therefore, this study suggests an unprecedented solution to address unmet clinical needs. ii) The three diameters were simulated by computational modeling of the flow and pressure. Hence, the detailed structural parameters before and after shape recovery were determined more precisely than the previous empirical and textbook-based methods, suggesting an advanced guideline to upgrade other implantable medical devices. iii) The laser parameters were tuned in two steps to maximize the efficiency of the pinpoint control within a clinic-friendly range. The use of a clinical laser system is meaningful because this first trial can influence the application of existing diagnostic and treatment machines for remotely operating implantable devices. iv) The hydrogel was designed to promote the drug loading capacity and enable sustained release. This fine-tuned the double benefits of diameter increase and anti-fibrotic drug release to fulfil the scope of clinical need more efficiently\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. v) The anti-biofilm property of the SMP surface was validated, supporting the effect of anti-fibrotic drugs, which can be applied to other implantable devices such as bile duct stents\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e, nasolacrimal duct stents\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, and dental devices\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. vi) The concept of SMP functions was validated using a customized in vitro pressure system and a new model for rabbit glaucoma. In particular, the rabbit model exhibited the clinical pattern of IOP fluctuation when a drainage tube was implanted and clearly demonstrated the advantages of the SMP tube, expanding its broad impact and leadership.\u003c/p\u003e \u003cp\u003eIn future studies, the surface properties of SMP for suppressing bacterial adhesion should be further elucidated. The surface E and crystalline phase pattern of the SMP surface were identified as potential players because variations in these factors altered the effects on protein adsorption with microbial and mammalian cell attachment\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. However, current analytical systems have limitations in interpreting the dynamic changes in the surface parameters at the nanoscale upon controlling the external energy absorption. The interpretation becomes more difficult when biological players are introduced because of the heterogeneous behaviors of material and biological parameters depending on temperature, type, and duration. Moreover, because the SMP was painted black to help pinpoint laser absorption, the appearance of eyes should be considered further, especially for the population in related jobs.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eShape memory polymer (SMP) synthesis\u003c/em\u003e\u003c/strong\u003e: All chemicals were purchased from Sigma-Aldrich (St. Louis, MO, USA). SMP was synthesized by ring-opening polymerization of \u0026epsilon;-caprolactone (CL) and glycidyl methacrylate (GMA) monomers using an established protocol\u003csup\u003e45\u003c/sup\u003e. Briefly, CL (20.82 mL), 1,6-hexanediol (118.2 mg) initiator, and hydroquinone (132.14 mg, 1:10 molar ratio of hydroquinone to GMA) as auto-crosslinking inhibitor were reacted in a three-necked round bottom flask under stirring at 110 \u0026deg;C for 10 min, followed by the reaction of GMA (1.6 mL) with the mixture for 10 min. Subsequently, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD; 278.4 mg)\u0026nbsp;was dissolved in acetonitrile solvent (2 mL), which was reacted at 110 \u0026deg;C for 6 h under a nitrogen atmosphere. The reaction mixture was dissolved in chloroform (30 mL) after cooling to room\u0026nbsp;temperature (25 \u0026deg;C) and then, a white precipitate was formed in cold diethyl ether (800 mL, 4 \u0026deg;C). The final SMP product was obtained via vacuum drying (OV4-30, Jeio Tech, Daejeon, Republic of Korea) at room temperature.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eGelatin methacryloyl (GelMA) synthesis\u003c/em\u003e\u003c/strong\u003e: Photopolymerizable GelMA was synthesized by reacting\u0026nbsp;methacrylate\u0026nbsp;groups with the amine groups of gelatin molecules\u003csup\u003e46\u003c/sup\u003e. Briefly, gelatin powder from porcine skin (5 g, gel strength 300, type A, Sigma-Aldrich, St. Louis, MO, USA) was completely dissolved in phosphate buffer saline (PBS; 1X, pH 7.4, Welgene, Gyeongsangbuk-do, Republic of Korea) at 40 \u0026deg;C to prepare 10% (w/v) gelatin solution. Next, methacrylic anhydride (MA; 0.25 mL, Sigma-Aldrich, St. Louis, MO, USA) was added dropwise to the gelatin solution (50 mL) at a rate of 0.5 mL/min under vigorous stirring for reaction at 50 \u0026deg;C for 3 h in the dark. Finally, the reaction was stopped by adding five-fold warm (40 \u0026deg;C) PBS to the reaction mixture. The unreacted MA and salts were then dialyzed in warm distilled water (40 \u0026deg;C) using a dialysis tube (molecular weight cut-off (MWCO): 12-14 kDa, Spectrum Laboratories Inc., New Brunswick, NJ, USA) for 5 days in the dark. The dialyzed solution was lyophilized to obtain a white porous foam of GelMA and stored at -30\u0026nbsp;\u0026deg;C\u0026nbsp;until use.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026beta;-cyclodextrin (\u0026beta;-CD) conjugated GelMA (GelMA-\u0026beta;-CD) synthesis\u003c/em\u003e\u003c/strong\u003e: GelMA-\u0026beta;-CD was synthesized to enhance the drug loading capacity using modifications of a previous report\u003csup\u003e47\u003c/sup\u003e. First, the GelMA backbone was conjugated with \u0026beta;-CD by introducing a carboxymethyl (CM) group into \u0026beta;-CD through the following steps. A mixture of \u0026beta;-CD (10 g,\u0026nbsp;Sigma-Aldrich, St. Louis, MO, USA) and sodium hydroxide (NaOH; 9.3 g,\u0026nbsp;Sigma-Aldrich, St. Louis, MO, USA) was dissolved in distilled water (37 mL) and reacted with a 16.3% (v/v) monochloroacetic acid solution (27 mL,\u0026nbsp;Sigma-Aldrich, St. Louis, MO, USA) at\u0026nbsp;50 \u0026deg;C for 5 h. Then, the product was cooled to room temperature (25 \u0026deg;C), and the pH was adjusted to 6-7 using hydrochloric acid (HCl; Duksan, Gyeonggi-do, Republic of Korea) solution, followed by pouring into methanol to obtain a white precipitate. Finally, carboxymethylated\u0026nbsp;\u0026beta;-CD\u0026nbsp;(CM-\u0026beta;-CD) was obtained by vacuum-drying the solid precipitate. Next, GelMA (1 g) was completely dissolved in PBS (10% w/v, 10 ml) at 40 \u0026deg;C, and CM-\u0026beta;-CD (2 g) was added to 2-(N-morpholino)ethanesulfonic acid (MES; 0.1M, pH 6, Bio Solution Co., Ltd., Seoul, Republic of Korea) buffer solution (10 mL). The carboxyl groups of CM-\u0026beta;-CD\u0026nbsp;were activated by N-(3-Dimethylaminopropyl)-N\u0026prime;-ethylcarbodiimide hydrochloride (EDC; 120 mmol/L, Sigma-Aldrich, St. Louis, MO, USA)\u0026nbsp;and N-hydroxysuccinimide (NHS; 60 mmol/L, Sigma-Aldrich, St. Louis, MO, USA) for 30 min. The GelMA solution (10 mL) was added to the\u0026nbsp;CM-\u0026beta;-CD\u0026nbsp;solution (10 mL) by adjusting the pH to 8-9 using NaOH (Duksan, Gyeonggi-do, Republic of Korea) solution. The reaction was continued for 12 h under vigorous stirring at 40 \u0026deg;C. Finally, the unreacted CM-\u0026beta;-CD\u0026nbsp;and other impurities were dialyzed in warm distilled water (40 \u0026deg;C) using a dialysis tube (MWCO: 12-14 kDa) for 5 d under dark conditions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eMaterial characterization\u003c/em\u003e\u003c/strong\u003e: Successful conjugation and synthesis were confirmed by\u0026nbsp;proton nuclear magnetic resonance (\u003csup\u003e1\u003c/sup\u003eH-NMR; Avance III 400-MHz, Bruker Biospin, Billerica, MA, USA) spectroscopy, Fourier transform infrared (FTIR; Vertex 70, Bruker Biospin, Billerica, MA, USA) spectroscopy, dynamic mechanical analysis (DMA; Discovery DMA850, TA Instruments, New Castle, DE, USA), and differential scanning calorimetry (DSC; Discovery DSC25, TA Instruments, New Castle, DE, USA). The structure and molar composition were determined by \u003csup\u003e1\u003c/sup\u003eH-NMR spectroscopy using a single z-axis gradient inverse probe at a frequency of 400 MHz. SMP and other materials were dissolved in chloroform-d (CDCl\u003csub\u003e3\u003c/sub\u003e; Sigma-Aldrich, St. Louis, MO, USA) and dimethyl sulfoxide-d\u003csub\u003e6\u003c/sub\u003e (DMSO-d\u003csub\u003e6\u003c/sub\u003e; Sigma-Aldrich, St. Louis, MO, USA). The results were further confirmed by FTIR\u0026nbsp;spectroscopy\u0026nbsp;using the KBr pellet method. The mechanical properties were characterized by analyzing the stress-strain curve using DMA at a controlled strain rate of 5 mm/min. The samples were prepared in the form of rectangles (8 (length) \u0026times; 5 (width) \u0026times; 0.25 (thickness) mm\u0026nbsp;thick).\u0026nbsp;Heat-flow-related thermal transitions were examined using DSC. The samples were heated to 150 \u0026deg;C, and then cooled to -80 \u0026deg;C for two cycles at a heating rate of 5 \u0026deg;C /min under a nitrogen atmosphere. The glass transition temperature (\u003cem\u003eT\u003c/em\u003e\u003csub\u003eg\u003c/sub\u003e), melting temperature (\u003cem\u003eT\u003c/em\u003e\u003csub\u003em\u003c/sub\u003e), crystallization temperature (\u003cem\u003eT\u003c/em\u003e\u003csub\u003ec\u003c/sub\u003e), melting enthalpy (∆\u003cem\u003eH\u003c/em\u003e\u003csub\u003em\u003c/sub\u003e), and crystallization enthalpy (∆\u003cem\u003eH\u003c/em\u003e\u003csub\u003ec\u003c/sub\u003e) were determined using the DSC thermograms.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAnti-fibrotic drug loading\u003c/em\u003e\u003c/strong\u003e: Anti-fibrotic 5-Fluorouracil (5-FU) was loaded into the GelMA-\u0026beta;-CD\u0026nbsp;hydrogel\u0026nbsp;via hydrophobic interactions\u0026nbsp;of\u0026nbsp;\u0026beta;-CD to include 5-FU in a complex form. A GelMA-\u0026beta;-CD solution (5% w/v, 10 mL) and 5-FU powder (10 mg, Sigma-Aldrich, St. Louis, MO, USA) were mixed for 30 min\u0026nbsp;under vigorous stirring to form the complex, which is also known as a host-guest interaction. The cavity of\u0026nbsp;\u0026beta;-CD (host) accommodated 5-FU (guest) via hydrophobic interactions (GelMA-\u0026beta;-CD/5-FU), as confirmed by\u0026nbsp;\u003csup\u003e1\u003c/sup\u003eH-NMR. The CH proton peak of 5-FU appeared at \u0026delta; = 7.6 ppm. The capacity of GelMA-\u0026beta;-CD to load 5-FU was evaluated (n = 3) by centrifuging the complex solution at 12,000 rpm for 10 min. The amount of free 5-FU in the supernatant was determined using an ultraviolet-visible (UV-Vis) spectrophotometer (Lambda25, PerkinElmer, Waltham, MA, USA) (absorbance: 269 nm), thereby performing reverse calculations for the amount of GelMA-\u0026beta;-CD/5-FU complex. GelMA (n = 3) without\u0026nbsp;\u0026beta;-CD conjugation was used as the control. The degree of drug loading capacity for 5-FU was calculated using the following equation:\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDrug loading capacity for 5-FU drug (%) =\u0026nbsp;\u003c/em\u003e\u003cem\u003e100% \u0026times; (A \u0026ndash; B) / A\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eA: Total amount of 5-FU that reacts with GelMA or GelMA-\u0026beta;-CD\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eB: Excluded amount of 5-FU that forms the complex in the supernatant\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe GelMA-\u0026beta;-CD/5-FU complex solution was lyophilized and stored at -30 \u0026deg;C until use.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eComputational fluid dynamics (CFD) modeling\u003c/em\u003e\u003c/strong\u003e: CFD modeling was conducted to theoretically calculate the pressure difference (∆ P) and velocity between the inlet and outlet of\u0026nbsp;the silicone drainage tube, with\u0026nbsp;or without SMP tube insertion. Because clinical implantation of a glaucoma drainage tube often causes early hypotonic intraocular pressure (IOP) owing to its large diameter, the insertion of\u0026nbsp;an SMP tube with a smaller diameter in the middle\u0026nbsp;part of\u0026nbsp;the drainage tube\u0026nbsp;was expected to address this issue. The inner diameter of\u0026nbsp;the SMP tube\u0026nbsp;was adjusted according to the clinical ∆ P (\u0026gt; 6 mm\u0026nbsp;Hg) while the silicone tube\u0026nbsp;diameter was fixed. The clinical definition of hypotonic IOP is less than 6 mmHg; thus, the initial inner diameter (50\u0026nbsp;\u0026micro;m) of\u0026nbsp;the inserted SMP tube was determined to\u0026nbsp;generate more than 6 mmHg. All CFD calculations were performed using the fluid flow (Fluent) mode in ANSYS (ANSYS workbench 2021 R2, Canonsburg, PA, USA). Since the \u003cem\u003eReynolds number (NRe)\u003c/em\u003e of the intraocular fluid was estimated to be less than approximately 2,000 (turbulent flow: \u003cem\u003eNRe\u003c/em\u003e \u0026gt; 2,000), a laminar flow condition was used to calculate ∆ P and velocity upon SMP tube insertion, where a constant flow rate (Q = 2.5\u0026nbsp;\u0026micro;L/min) and open boundary condition were applied. The obtained results were compared with the \u003cem\u003eHagen-Poiseuille law\u003c/em\u003e (\u003cem\u003e∆ P =\u0026nbsp;\u003c/em\u003e, where\u0026nbsp;,\u0026nbsp;,\u0026nbsp;, and\u0026nbsp;\u0026nbsp;are the fluid rate, viscosity, length, and radius, respectively).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSMP device production\u003c/em\u003e\u003c/strong\u003e: The length and diameter of\u0026nbsp;the anti-fibrotic drug-loaded SMP tubes were determined by CFD modeling, and SMP tube was fabricated as follows.\u0026nbsp;SMP (1 g) was fully dissolved in N-Methyl-2-pyrrolidone (NMP; 1 mL, Sigma-Aldrich, St. Louis, MO, USA) at 37 \u0026deg;C and mixed with a photoinitiator, 2-hydroxy-1-(4-(hydroxyethoxy)phenyl)-2-methyl-1-propanone (Irgacure 2959; 5 mg, Sigma-Aldrich, St. Louis, MO, USA). Next,\u0026nbsp;a\u0026nbsp;poly(vinyl alcohol) (PVA; Raise3D,\u0026nbsp;Irvine, CA, USA) wire was produced using a three-dimensional (3D) printer (Raised3D Pro2, Raise3D,\u0026nbsp;Irvine, CA, USA) and used as a sacrificial material to generate the inner diameter of\u0026nbsp;the SMP. A glass capillary tube (Paul Marienfeld GmbH \u0026amp; Co., KG, Lauda-K\u0026ouml;nigshofen, Germany)\u0026nbsp;was used as the outer mold. The PVA wire (outer diameter: 260\u0026nbsp;\u0026micro;m) was inserted into the glass capillary tube (inner diameter: 560\u0026nbsp;\u0026micro;m), followed by\u0026nbsp;the injection of\u0026nbsp;the SMP solution between the two layers. The SMP solution in the glass capillary tube was polymerized by UV irradiation (365 nm, 265 mJ/cm\u003csup\u003e2\u003c/sup\u003e) for 100 s using a UV crosslinker (CL-3000L UV Crosslinker, Analytik Jena, Jena, Germany), and then, PVA was dissolved in distilled water for 3 days at 25 \u0026deg;C. The SMP tube was separated from the glass capillary tube and air dried.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe SMP tube underwent shape-programming as follows: (i) The original length of the SMP tube was doubled in hot water at 55 \u0026deg;C (\u003cem\u003eT\u003c/em\u003e \u0026gt; \u003cem\u003eT\u003c/em\u003e\u003csub\u003em\u003c/sub\u003e),\u0026nbsp;as the double length was determined considering the\u0026nbsp;Poisson\u0026rsquo;s ratio (\u003cem\u003ev\u003c/em\u003e = 0.2) of SMP tube. (ii) The elongated SMP tube was immersed in cold water (\u003cem\u003eT\u003c/em\u003e \u0026lt; \u003cem\u003eT\u003c/em\u003e\u003csub\u003em\u003c/sub\u003e) to fix the temporary shape, and\u0026nbsp;(iii) the temporary shape of\u0026nbsp;the SMP tube was cut to a length of\u0026nbsp;3 mm,\u0026nbsp;as determined by CFD modeling. Next,\u0026nbsp;an anti-fibrotic drug (5-FU)-loaded GelMA hydrogel (GelMA-\u0026beta;-CD/5-FU hydrogel) was coated onto the intimal layer of the SMP tube to facilitate\u0026nbsp;its\u0026nbsp;release into the intraocular fluid. GelMA-\u0026beta;-CD/5-FU solution (5% w/v) containing\u0026nbsp;0.5% (w/v) Irgacure 2959\u0026nbsp;was prepared in PBS at 37\u0026nbsp;\u0026deg;C. Then, a tungsten wire (outer diameter =50\u0026nbsp;\u0026micro;m, GoodFellow, Delson, QC, Canada) was inserted into the temporary shape of\u0026nbsp;the SMP tube as the outer mold (inner diameter:\u0026nbsp;200\u0026nbsp;\u0026micro;m), followed by\u0026nbsp;the injection of the hydrogel\u0026nbsp;solution in between the SMP tube and tungsten wire. The whole set was exposed to UV\u0026nbsp;light\u0026nbsp;for crosslinking GelMA by polymerization under the previously described conditions, and the tungsten wire was removed to create the inner diameter of the SMP tube. The SMP tube was painted black to promote\u0026nbsp;laser absorption.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo produce the SMP+PCL ring, SMP was blended with PCL (10% w/v, MW ~80,000, Sigma-Aldrich, St. Louis, MO, USA) with SMP to improve its mechanical properties, as determined by DMA. An\u0026nbsp;SMP+PCL tube was produced following the same process used to make the SMP tube using a\u0026nbsp;glass capillary tube as an outer mold (inner diameter: 800\u0026nbsp;\u0026micro;m) with intraluminal insertion of\u0026nbsp;a PVA wire (outer diameter:\u0026nbsp;360\u0026nbsp;\u0026micro;m). The diameter of\u0026nbsp;the\u0026nbsp;SMP+PCL tube was enlarged by inserting a taper-shaped polylactic acid (PLA; Raise 3D,\u0026nbsp;Irvine, CA, USA) mold with\u0026nbsp;an incremental\u0026nbsp;outer diameter of 200~1000\u0026nbsp;\u0026micro;m into the SMP+PCL tube. The tube position was adjusted to the targeted outer diameter range of the tapered PLA mold\u0026nbsp;in hot water at 55 \u0026deg;C so that the inner diameter of SMP+PC tube increased from 200 to 1000\u0026nbsp;\u0026micro;m. Subsequently, the shape was fixed in cold water (0 \u0026deg;C). The SMP+PCL tube was cut into\u0026nbsp;1 mm long SMP+PCL rings. The ring diameter was examined using SEM (MERLIN, Zeiss Merlin, Oberkochen, BW, Germany) with image analysis.\u0026nbsp;The ring was painted black to promote\u0026nbsp;laser absorption.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePressure measurement system\u003c/em\u003e\u003c/strong\u003e: The drainage pressure of\u0026nbsp;the silicone tube, with\u0026nbsp;or without SMP tube insertion, was measured as previously described\u0026nbsp;(n = 3)\u003csup\u003e27\u003c/sup\u003e. The measurement system was customized to\u0026nbsp;be equipped with\u0026nbsp;a pressure transmitter (PNS, Nuritech, Incheon,\u0026nbsp;Republic of Korea), pressure indicator (PD1, Nuritech, Incheon,\u0026nbsp;Republic of Korea), three-way stopcock, silicone tube [2 (inner diameter)\u0026nbsp;\u0026times; 4 (outer diameter) mm,\u0026nbsp;Korea Ace Scientific Co., Seoul, Republic of Korea], syringe, 30-gauge needle (Korea vaccine Co., LTD., Gyeonggi-do, Republic of Korea), and syringe pump (Standard PHD ULTRA\u0026trade; CP Syringe Pump, Harvard Apparatus, Holliston, MA, USA). A silicone tube with small D, medium D, large D, or without SMP tube insertion was connected to the needle, and distilled water was injected into the test tube at a constant flow rate (25\u0026nbsp;\u0026micro;L/min)\u0026nbsp;using the syringe pump. The pressure changes (mmHg) were recorded using a digital pressure indicator.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eGelMA\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e-\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026beta;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e-CD degradation\u003c/em\u003e\u003c/strong\u003e: A consistent rod shape (4 mm diameter and 1 mm height) of GelMA-\u0026beta;-CD hydrogel with different concentrations (5, 7, and 10% (w/v)) was produced by crosslinking in a cylindrical UV system (n = 3). \u003cem\u003eIn vitro\u003c/em\u003e degradation was examined in PBS containing type I collagenase (1 unit/mL, Gibco, Waltham, MA, USA) at 37\u0026nbsp;\u0026deg;C on a rocking shaker (50 rpm, RK-1D, Daihan Scientific, Kangwon-do, Republic of Korea), followed by replacing PBS every 2 days. Non-degraded hydrogels were collected each time, washed twice with distilled water, and lyophilized to measure their\u0026nbsp;weight. The weight (%) of\u0026nbsp;the non-degraded hydrogels\u0026nbsp;was calculated using the following equation:\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eWeight (W %) of non-degradation= (\u003c/em\u003e\u003cem\u003eW \u003csub\u003eeach\u0026nbsp;\u003c/sub\u003e\u003c/em\u003e\u003cem\u003e\u003csub\u003etime point\u0026nbsp;\u003c/sub\u003e\u003c/em\u003e\u003cem\u003e/\u0026nbsp;\u003c/em\u003e\u003cem\u003eW \u003csub\u003estarting\u0026nbsp;\u003c/sub\u003e\u003c/em\u003e\u003cem\u003e\u003csub\u003epoint\u003c/sub\u003e\u003c/em\u003e\u003cem\u003e) \u0026times; 100\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe hydrogel with\u0026nbsp;the most rapid\u0026nbsp;degradation was used in the rest of\u0026nbsp;the experiments.\u0026nbsp;\u003cem\u003eIn vivo\u003c/em\u003e degradation of\u0026nbsp;the GelMA-\u0026beta;-CD hydrogel upon insertion into an\u0026nbsp;SMP tube was determined during 14 day-implantation into rabbit eyes by analyzing SEM images at each time point.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAnti-fibrotic drug release\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e \u003cem\u003eIn vitro\u003c/em\u003e release of 5-FU from the hydrogel with\u0026nbsp;the most rapid degradation was\u0026nbsp;determined by analyzing each cumulative profile\u0026nbsp;with and without\u0026nbsp;\u0026beta;-CD conjugation on GelMA\u0026nbsp;(n = 3). The\u0026nbsp;test samples were incubated under the same conditions as described above\u0026nbsp;for hydrogel degradation. The test\u0026nbsp;solution containing 5-FU post-release from each hydrogel was collected at each time point, followed by replenishing the same amount of PBS. The amount of 5-FU\u0026nbsp;released was\u0026nbsp;determined using a UV-Vis spectrophotometer at 265 nm and a calibration plot.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAnti-bacterial adhesion\u003c/em\u003e\u003c/strong\u003e: \u003cem\u003eIn vitro\u003c/em\u003e bacterial adhesion was determined to confirm the superior anti-biofilm effect of SMP over silicone as reported previously\u003csup\u003e41\u003c/sup\u003e. Briefly, \u003cem\u003ePseudomonas\u0026nbsp;\u003c/em\u003e(\u003cem\u003eP.\u003c/em\u003e)\u003cem\u003e\u0026nbsp;aeruginosa\u003c/em\u003e (ATCC 9027, Seoul, Republic of Korea) was cultured in a tryptic soy agar (Sigma-Aldrich, St. Louis, MO, USA) at 37 \u0026deg;C until their growth reached the mid-exponential phase,\u0026nbsp;0.55 optical density of\u0026nbsp;as indicated by an optical density of 0.55 obtained using a microplate spectrophotometer\u0026nbsp;(600 nm,\u0026nbsp;Infinite M Nano, Tecan, M\u0026auml;nnedorf,\u0026nbsp;Switzerland). Sample films (1.5\u0026nbsp;\u0026times;\u0026nbsp;1.5 cm) were prepared and incubated with\u0026nbsp;\u003cem\u003eP. aeruginosa\u003c/em\u003e at 37 \u0026deg;C for 48 h, followed by washing with distilled water to remove non-adhering bacteria. The samples were then air-dried for 40 min and stained with crystal violet (0.1%, Sigma-Aldrich, St. Louis, MO, USA) for 15 min for imaging by inverted optical microscopy (Leica DMi8, Leica Microsystems, Wetzlar, Germany) and SEM. For quantitative analysis, crystal violet dye was extracted from the bacteria using 95% (w/v) ethanol (Sigma-Aldrich, St. Louis, MO, USA), and the absorbance was measured\u0026nbsp;at 600 nm using\u0026nbsp;a microplate spectrophotometer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eShape memory function\u003c/em\u003e\u003c/strong\u003e: Since argon laser irradiation (Topcon PASCAL Streamline 532\u0026nbsp;nm Green Laser, Topcon Medical Laser Systems, Santa Clara, CA, USA) was used to induce the shape recovery of SMP tube, the\u0026nbsp;energy density\u0026nbsp;per unit surface area of tube was determined using the laser power and exposure time:\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEnergy density (m\u003c/em\u003e\u003cem\u003eJ/cm\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e\u003cem\u003e) = A / B\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eA: Laser energy (Power (mW) \u0026times; Exposure time (ms))\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eB: Surface area (\u003c/em\u003e\u003cem\u003ecm\u003csup\u003e2\u003c/sup\u003e)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOwing to the fixed laser irradiation (surface) area, the energy density was adjusted by varying the laser power (0 ~70mJ). The shape recovery efficiency of\u0026nbsp;the SMP tube was determined by changing a bent tube to\u0026nbsp;a linear\u0026nbsp;tube shape as sufficient\u0026nbsp;laser energy per single shot\u0026nbsp;was delivered. Next, the energy density was further examined to induce complete shape recovery in the range of 40~70 mJ by calculating the shape recovery ratio per single laser shot (%) (n = 3) as follows:\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eShape recovery ratio per single laser shot\u003c/em\u003e\u003cem\u003e\u0026nbsp;(%) =\u003c/em\u003e \u003cem\u003e[B / A] \u0026times;100%\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eA: Length of original shape\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eB: Length of recovered shape after single laser shot\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe shape-recovery efficiency of\u0026nbsp;the SMP+PCL ring was\u0026nbsp;determined by analyzing the squeezed lumen area of\u0026nbsp;the silicone tube\u0026nbsp;using SEM images before and after argon laser irradiation (n = 3). The superior effect of\u0026nbsp;the argon laser over water\u0026nbsp;heat on shape recovery was examined by implanting tube samples into rabbit eyes. Two water samples at 25\u0026nbsp;\u0026deg;C\u0026nbsp;and\u0026nbsp;50\u0026nbsp;\u0026deg;C\u0026nbsp;were compared because the temperatures were below and above T\u003csub\u003em\u003c/sub\u003e, respectively, and proteins begin to denature above\u0026nbsp;50\u0026nbsp;\u0026deg;C. After\u0026nbsp;the SMP tubes were inserted into silicone tubes, one was implanted into\u0026nbsp;the intraocular position of\u0026nbsp;the\u0026nbsp;anterior chamber,\u0026nbsp;while the other was positioned in an extraocular position on the cornea (control).\u0026nbsp;The\u0026nbsp;change in the\u0026nbsp;length of\u0026nbsp;the SMP tube\u0026nbsp;at each position was analyzed upon water treatment. The energy density (E\u003csub\u003eLaser\u003c/sub\u003e) of the argon laser was compared to the heat energy (Q\u003csub\u003eWater\u003c/sub\u003e) of water to determine its superior efficiency (%).\u0026nbsp;The surface temperature of\u0026nbsp;the\u0026nbsp;rabbit cornea was measured using a thermal imaging camera (HT-18; Hti, Guangdong, China).\u0026nbsp;The SMP tube and ring were painted black to promote\u0026nbsp;laser absorption.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eClinical data analysis\u003c/em\u003e\u003c/strong\u003e: Long-term IOP\u0026nbsp;profiles\u0026nbsp;were analyzed post implantation of silicone drainage devices (Model FP-7, New World Medical, Inc., Rancho Cucamonga, CA, USA) in\u0026nbsp;glaucoma patients (n=127 between January 2015 and December 2016) at the Severance Hospital of the Yonsei University College of Medicine. Clinical IOP data were collected before and during\u0026nbsp;the\u0026nbsp;12-month implantation. The hypotony and hypertensive phases were defined as IOP less than 6 mmHg and \u0026gt; 20 mmHg, respectively. The hypotony phase was diagnosed by i) fundus examination of choroidal detachment using an Optos Daytona (Queensferry House, Carnegie Campus, Dunfermline, Scotland, United Kingdom) and ii) imaging of the anterior chamber using anterior segment optical coherence tomography (AS-OCT; TOMEY GmbH, Wiesbadener Strasse, Nuremberg, Germany). The hypertension phase was diagnosed by considering the\u0026nbsp;visual field index to analyze the rate of glaucoma progression using a Humphrey visual field analyzer (ZEISS Humphrey Field Analyzer 3, Carl Zeiss Meditec, Inc., Dublin, CA). The visual area of\u0026nbsp;the eye was calculated as\u0026nbsp;the\u0026nbsp;percentage of the visible area (white) to the total area, including the blind part (black).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eRabbit study\u003c/em\u003e\u003c/strong\u003e: Rabbit experiments\u0026nbsp;were approved by the Institutional Animal Care and Use Committee and conducted following the Use of Animals in Ophthalmic and Vision Research,\u0026nbsp;as provided by the Association for Research in Vision and Ophthalmology Statement. New Zealand white rabbits (weight:2.5-3 kg) were used to develop the glaucoma model by inserting dental composite\u0026nbsp;resins (resin; BEAUTIFIL Flow, SHOFU DENTAL CORPORATION, San Marcos, CA, USA) into the anterior chamber to clog the drainage channel. This blocked the outflow of intraocular fluid and the IOP was elevated. Briefly,\u0026nbsp;the rabbits were anesthetized by intramuscular injection of tiletamine-zolazepam (Zoletil 50; 10 mg/kg, Virbac Lab, Carros, France) and xylazine hydrochloride (Rompun; 2%, 5 mg/kg, Bayer Korea, Seoul, South Korea). Topical anesthesia was administered (proparacaine eye\u0026nbsp;drops, Alcaine; Alcon, Fort Worth, Tex., USA) to control the pain. Paracentesis (0.05 mL) was performed using\u0026nbsp;a 31-gauge needle (Korea\u0026nbsp;Vaccine Co. Ltd., Gyeonggi-do, Republic of Korea). The resin (0.05 mL) was inserted\u0026nbsp;into the anterior chamber, and 25% of the drainage channel was blocked\u0026nbsp;by fixing the resin using\u0026nbsp;a light-emitting diode (LED.H Curing light, Woodpecker, Wroclaw, Dolnoslaskie, Poland). The IOP was measured thrice per eye preoperatively and postoperatively on days 1, 3, and 7 to\u0026nbsp;confirm the increase in IOP up to approximately 60% as an indication of successful glaucoma modeling.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA silicone drainage tube with or without SMP tube insertion was implanted into the glaucomatous\u0026nbsp;eyes of rabbits under the same anesthesia conditions\u0026nbsp;as described above (n = 5). Corneal traction was first performed by placing\u0026nbsp;a 7-0 Vicryl suture\u0026nbsp;from the anterior to the limbus, resulting in the downward rotation of the eye. Conjunctival resection was then performed in the supra-temporal\u0026nbsp;region, followed by posterior dissection to separate Tenon\u0026rsquo;s capsule from\u0026nbsp;the sclera. A 23-gauge needle\u0026nbsp;(Korea Vaccine Co., LTD., Gyeonggi-do, Republic of Korea)\u0026nbsp;was inserted into the anterior chamber at a position 0.25 mm posterior to the limbus, followed by the insertion of sample tubes into the anterior chamber with the beveling side up through the needle tract. The sample tubes were anchored to the sclera using a 10-0 nylon suture, the conjunctiva was secured to the limbus using an interrupted 10-0 nylon suture, and ofloxacin ointment was applied to the eye. IOP was measured\u0026nbsp;thrice under topical anesthesia at predetermined intervals\u0026nbsp;for each eye using a tonometer (Tono-Pen AVIA\u0026reg;, Reichert Technologies, Depew, USA). An argon laser was used to\u0026nbsp;expand the inner diameter of the SMP tube and increase the drainage of intraocular fluid 14 days post implantation. IOP measurements were continued for 42 days after implantation.\u0026nbsp;The synergistic effect between the diameter expansion and release of anti-fibrotic drugs by\u0026nbsp;hydrogel degradation on IOP control was demonstrated in the late postoperative period. As a sham control, eyes with\u0026nbsp;normal pressure were subjected to tube implantation. The three test groups were SMP tube insertion i) with and ii) without argon laser irradiation, and iii) no SMP tube insertion (n = 3). The effect of laser-induced diameter expansion on IOP reduction was validated by comparing\u0026nbsp;the\u0026nbsp;SMP tube insertion groups with\u0026nbsp;and without argon laser irradiation. The anti-fibrotic effect of drug release on IOP control was confirmed by comparing the SMP tube insertion group without argon laser irradiation and the group without SMP tube insertion. The IOP profiles between\u0026nbsp;days 14 and 21\u0026nbsp;were compared.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBecause of the sudden IOP drop that often occurs for unknown reasons during the late postoperative period in glaucoma patients after tube implantation, the SMP+PCL ring was developed to decrease the drainage amount of intraocular fluid by shape recovery to squeeze the silicone tube as an external wrap. Normal eyes were\u0026nbsp;implanted with\u0026nbsp;a\u0026nbsp;silicone drainage tube\u0026nbsp;(w/o SMP tube insertion) with\u0026nbsp;the\u0026nbsp;SMP+PCL ring,\u0026nbsp;while normal eyes without any implantation served as a control (n = 6). The SMP+PCL ring was irradiated by an argon laser 7 days after implantation, followed by IOP measurement for the next 13 days.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHistological analysis\u003c/em\u003e\u003c/strong\u003e: Fibrotic\u0026nbsp;tissue formation\u0026nbsp;around the drainage tube was examined using tissues obtained after sacrificing\u0026nbsp;the\u0026nbsp;rabbits and then carefully excising the eyes to minimize disturbance of the bleb and implant. The tissues were fixed with 4% paraformaldehyde (CellNest, Gyeonggi-do, Republic of Korea) for 24 h, and the eyes\u0026nbsp;were dissected with incisions passing through the middle of the bleb. After\u0026nbsp;embedding the eye tissues in paraffin wax,\u0026nbsp;the paraffin blocks were sectioned for hematoxylin and eosin (H\u0026amp;E) and Masson\u0026rsquo;s trichrome staining. The fibrous tissue area was determined from four different photographs of Masson\u0026rsquo;s trichrome staining, followed by quantitative image analyses using ImageJ (Fiji, National Institute of Health, MD, USA) as the fibrous tissue was indicated by blue color-positive collagen fibers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/strong\u003e: All experiments were performed with at least three replicates per condition. Statistical analyses were performed using one-way analysis of variance (ANOVA) with Tukey\u0026rsquo;s post-hoc test to perform multiple pairwise comparisons between groups. All experimental data are presented as mean \u0026plusmn; standard deviation, where n denotes the number of samples obtained from independent experiments or with dots and whisker plots, in which dots and whiskers are shown as average and minimum/maximum, respectively. Each experimental condition is mentioned in the corresponding figure legend. Differences were considered statistically significant when p \u0026lt; 0.05 (* p \u0026lt; 0.05, ** p \u0026lt; 0.01, and *** p \u0026lt; 0.001). All statistical analyses were conducted with the following software programs: Excel, KyPlot 6.0 software (Kyenslab, Tokyo, Japan), Origin 2018 (OriginLab, Northampton, MA, USA), and SigmaPlot V.12.0 (Systat Software Inc., San Jose, CA, USA).\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was financially supported by i) the National Research Foundation of Korea (NRF) funded by the Korean government (MSIT) (2019R1A2C2010802, 2022R1I1A1A01071919, and 2019R1A2C1091089); ii) the Korea Medical Device Development Fund Grant funded by the Ministry of Science and ICT, Ministry of Trade, Industry and Energy, Ministry of Health \u0026amp; Welfare, and Ministry of Food and Drug Safety (1711138302, KMDF_PR_20200901_0152).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKyubae Lee and Wungrak Choi contributed equally to this work as co-first authors. Chan Yun Kim and Hak-Joon Sung (lead) are listed as co-corresponding authors, considering their significant contributions to the technical and clinical aspects, respectively. Hak-Joon Sung designed and directed the study in collaboration with Chan Yun Kim. Kyubae Lee and Wungrak Choi conducted the experiments, analyzed the data, and prepared the figures and supplementary movies. Wungrak Choi and Hyoung Won Bae oversaw the clinical aspects of the study and assisted with animal studies. Si Young Kim, Won Take Oh, Jeongeun Park, and Chan Hee Lee collaborated on the in vitro studies, and Dong-Su Jang assisted in the graphical design under the guidance of Chan Yun Kim. Hak-Joon Sung wrote the manuscript with the assistance of Kyubae Lee and Wungrak Choi.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eAraci, I. E. et al. An implantable microfluidic device for self-monitoring of intraocular pressure. \u003cem\u003eNat. Med.\u003c/em\u003e \u003cstrong\u003e20\u003c/strong\u003e, 1074-1078 (2014).\u003c/li\u003e\n \u003cli\u003eChoi, Y. S. et al. Fully implantable and bioresorbable cardiac pacemakers without leads or batteries. \u003cem\u003eNat. Biotechnol.\u003c/em\u003e \u003cstrong\u003e39\u003c/strong\u003e, 1228-1238 (2021).\u003c/li\u003e\n \u003cli\u003eSonmezoglu, S. et al. Monitoring deep-tissue oxygenation with a millimeter-scale ultrasonic implant. \u003cem\u003eNat. Biotechnol.\u003c/em\u003e \u003cstrong\u003e39\u003c/strong\u003e, 855-864 (2021).\u003c/li\u003e\n \u003cli\u003eJonas, J. B. et al. Glaucoma. \u003cem\u003eLancet\u003c/em\u003e \u003cstrong\u003e390\u003c/strong\u003e, 2183-2193 (2017).\u003c/li\u003e\n \u003cli\u003eLiu, W.-T. et al. Interstitial fluid behavior and diseases. \u003cem\u003eAdv. Sci.\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, 2100617 (2022).\u003c/li\u003e\n \u003cli\u003eScheffer, M. et al. Quantifying resilience of humans and other animals. \u003cem\u003eProc. Natl. Acad. Sci. U.S.A.\u003c/em\u003e \u003cstrong\u003e115\u003c/strong\u003e, 201810630 (2018).\u003c/li\u003e\n \u003cli\u003eNguyen, P. Q. et al. Wearable materials with embedded synthetic biology sensors for biomolecule detection. \u003cem\u003eNat. Biotechnol.\u003c/em\u003e \u003cstrong\u003e39\u003c/strong\u003e, 1366-1374 (2021).\u003c/li\u003e\n \u003cli\u003eKathe, C. et al. Wireless closed-loop optogenetics across the entire dorsoventral spinal cord in mice. \u003cem\u003eNat. Biotechnol.\u003c/em\u003e \u003cstrong\u003e40\u003c/strong\u003e, 198-208 (2022).\u003c/li\u003e\n \u003cli\u003eZhu, Y. et al. Lab-on-a-contact lens: recent advances and future opportunities in diagnostics and therapeutics. \u003cem\u003eAdv. Mater.\u003c/em\u003e \u003cstrong\u003e34\u003c/strong\u003e, e2108389 (2022).\u003c/li\u003e\n \u003cli\u003eChen, R. et al. Deep brain optogenetics without intracranial surgery. \u003cem\u003eNat. Biotechnol.\u003c/em\u003e \u003cstrong\u003e39\u003c/strong\u003e, 161-164 (2021).\u003c/li\u003e\n \u003cli\u003eHua, D. et al. Bubble forming films for spatial selective cell killing. \u003cem\u003eAdv. Mater.\u003c/em\u003e \u003cstrong\u003e33\u003c/strong\u003e, 2008379 (2021).\u003c/li\u003e\n \u003cli\u003eWang, N. et al. Activation of a tissue-specific stress response in the aqueous outflow pathway of the eye defines the glaucoma disease phenotype. \u003cem\u003eNat. Med.\u003c/em\u003e \u003cstrong\u003e7\u003c/strong\u003e, 304-309 (2001).\u003c/li\u003e\n \u003cli\u003eWeinreb, R. N. et al. Primary open-angle glaucoma. \u003cem\u003eNat. Rev. Dis. Prim.\u003c/em\u003e \u003cstrong\u003e2\u003c/strong\u003e, 16067 (2016).\u003c/li\u003e\n \u003cli\u003eLim, K. S. et al. Glaucoma drainage devices; past, present, and future. \u003cem\u003eBr. J. Ophthalmol.\u003c/em\u003e \u003cstrong\u003e82\u003c/strong\u003e, 1083-1089 (1998).\u003c/li\u003e\n \u003cli\u003eSchwartz, K. S. et al. Glaucoma drainage implants: a critical comparison of types. \u003cem\u003eCurr. Opin. Ophthalmol.\u003c/em\u003e \u003cstrong\u003e17\u003c/strong\u003e, 181-189 (2006).\u003c/li\u003e\n \u003cli\u003ePereira, I. C. F. et al. Conventional glaucoma implants and the new MIGS devices: a comprehensive review of current options and future directions. \u003cem\u003eEye\u003c/em\u003e. \u003cstrong\u003e35\u003c/strong\u003e, 3202-3221 (2021).\u003c/li\u003e\n \u003cli\u003eSu\u0026ntilde;er, I. J. et al. Hypotony maculopathy after filtering surgery with mitomycin C. Incidence and treatment. \u003cem\u003eOphthalmology.\u003c/em\u003e \u003cstrong\u003e104\u003c/strong\u003e, 207-215 (1997).\u003c/li\u003e\n \u003cli\u003eChristakis, P. G. et al. Five-year pooled data analysis of the Ahmed Baerveldt comparison study and the Ahmed versus Baerveldt study. \u003cem\u003eAm. J. Ophthalmol.\u003c/em\u003e \u003cstrong\u003e176\u003c/strong\u003e, 118-126 (2017).\u003c/li\u003e\n \u003cli\u003eMegevand, G. S. and Bron A. M. Personalising surgical treatments for glaucoma patients. \u003cem\u003eProg.\u003c/em\u003e \u003cem\u003eRetin. Eye Res.\u003c/em\u003e \u003cstrong\u003e81\u003c/strong\u003e, 100879 (2021).\u003c/li\u003e\n \u003cli\u003eAyyala, R. S. et al. A clinical study of the Ahmed glaucoma valve implant in advanced glaucoma. \u003cem\u003eOphthalmology.\u003c/em\u003e \u003cstrong\u003e105\u003c/strong\u003e, 1968-1976 (1998).\u003c/li\u003e\n \u003cli\u003eNouri-Mahdavi, K. et al. Evaluation of the hypertensive phase after insertion of the Ahmed glaucoma valve. \u003cem\u003eAm. J. Ophthalmol.\u003c/em\u003e \u003cstrong\u003e136\u003c/strong\u003e, 1001-1008 (2003).\u003c/li\u003e\n \u003cli\u003eJacob, J. T. et al. Slow release of the antimetabolite 5-fluorouracil (5-FU) from modified Baerveldt glaucoma drains to prolong drain function. \u003cem\u003eBiomaterials.\u003c/em\u003e \u003cstrong\u003e22\u003c/strong\u003e, 3329-3335 (2001).\u003c/li\u003e\n \u003cli\u003eWronska, M. A. et al. Adding functions to biomaterial surfaces through protein incorporation. \u003cem\u003eAdv. Mater.\u003c/em\u003e \u003cstrong\u003e28\u003c/strong\u003e, 5485-5508 (2016).\u003c/li\u003e\n \u003cli\u003eDoloff, J. C. et al. The surface topography of silicone breast implants mediates the foreign body response in mice, rabbits and humans. \u003cem\u003eNat. Biomed. Eng.\u003c/em\u003e \u003cstrong\u003e5\u003c/strong\u003e, 1115-1130 (2021).\u003c/li\u003e\n \u003cli\u003eHorejs, Christine. Preventing fibrotic encapsulation. \u003cem\u003eNat. Rev. Mater.\u003c/em\u003e \u003cstrong\u003e6\u003c/strong\u003e, 554 (2021).\u003c/li\u003e\n \u003cli\u003eRosentreter, A. et al. Previous cyclodestruction is a risk factor for late-onset hypotony and suprachoroidal haemorrhage after glaucoma drainage device surgery. \u003cem\u003eBr. J. Ophthalmol.\u003c/em\u003e \u003cstrong\u003e97\u003c/strong\u003e, 715-719 (2013).\u003c/li\u003e\n \u003cli\u003eOh, W. T. et al. Shape memory tube plug for fine-control of intraocular pressure by glaucoma devices. \u003cem\u003eACS Biomater. Sci. Eng.\u003c/em\u003e \u003cstrong\u003e6\u003c/strong\u003e, 3784-3790 (2020).\u003c/li\u003e\n \u003cli\u003eXia, Y. et al. A review of shape memory polymers and composites: mechanisms, materials, and applications. \u003cem\u003eAdv. Mater.\u003c/em\u003e \u003cstrong\u003e33\u003c/strong\u003e, e2000713 (2021).\u003c/li\u003e\n \u003cli\u003ePatel, S. R. and Lieber, C. M. Precision electronic medicine in the brain. \u003cem\u003eNat. Biotechnol.\u003c/em\u003e \u003cstrong\u003e37\u003c/strong\u003e, 1007-1012 (2019).\u003c/li\u003e\n \u003cli\u003eLi, C. et al. Design of biodegradable, implantable devices towards clinical translation. \u003cem\u003eNat. Rev. Mater.\u003c/em\u003e \u003cstrong\u003e5\u003c/strong\u003e, 61-81 (2020).\u003c/li\u003e\n \u003cli\u003eLee, G. -H. et al. Multifunctional materials for implantable and wearable photonic healthcare devices. \u003cem\u003eNat. Rev. Mater.\u003c/em\u003e \u003cstrong\u003e5\u003c/strong\u003e, 149-165 (2020).\u003c/li\u003e\n \u003cli\u003eHill, R. A. et al. Molteno implantation for glaucoma in young patients.\u003cem\u003e\u0026nbsp;Ophthalmology.\u003c/em\u003e \u003cstrong\u003e98\u003c/strong\u003e, 1042-1046 (1991).\u003c/li\u003e\n \u003cli\u003eLloyd, M. A. et al. Clinical experience with the single-plate molteno implant in complicated glaucomas. Update of a pilot study.\u003cem\u003e\u0026nbsp;Ophthalmology.\u003c/em\u003e \u003cstrong\u003e99\u003c/strong\u003e, 679-687 (1992).\u003c/li\u003e\n \u003cli\u003eSiegner, S. W. et al. Clinical experience with the Baerveldt glaucoma drainage implant. \u003cem\u003eOphthalmology.\u003c/em\u003e \u003cstrong\u003e102\u003c/strong\u003e, 1298-1307 (1995).\u003c/li\u003e\n \u003cli\u003eBurney, E. N. et al. Hypotony and choroidal detachment as late complications of trabeculectomy. \u003cem\u003eAm. J. Ophthalmol.\u003c/em\u003e \u003cstrong\u003e103\u003c/strong\u003e, 685-688 (1987).\u003c/li\u003e\n \u003cli\u003eFrancis, B. A. et al. Changes in axial length following trabeculectomy and glaucoma drainage device surgery. \u003cem\u003eBr. J. Ophthalmol.\u003c/em\u003e \u003cstrong\u003e89\u003c/strong\u003e, 17-20 (2005).\u003c/li\u003e\n \u003cli\u003eTagalakis, A. D. et al. In vitro and in vivo delivery of a sustained release nanocarrier-based formulation of an MRTF/SRF inhibitor in conjunctival fibrosis. \u003cem\u003eJ. Nanobiotechnology.\u003c/em\u003e \u003cstrong\u003e16\u003c/strong\u003e, 97 (2018).\u003c/li\u003e\n \u003cli\u003eDong, A. et al. Glaucoma drainage device coated with mitomycin C loaded opal shale microparticles to inhibit bleb fibrosis. \u003cem\u003eACS Appl. Mater. Interfaces.\u003c/em\u003e \u003cstrong\u003e11\u003c/strong\u003e, 10244-10253 (2019).\u003c/li\u003e\n \u003cli\u003eBallinger, A. B. et al. Persistent systemic inflammatory response after stent insertion in patients with malignant bile duct obstruction. \u003cem\u003eGut.\u003c/em\u003e \u003cstrong\u003e42\u003c/strong\u003e, 555-559 (1998).\u003c/li\u003e\n \u003cli\u003eSwidsinski, A. et al. Bacterial biofilm within diseased pancreatic and biliary tracts. \u003cem\u003eGut.\u003c/em\u003e \u003cstrong\u003e54\u003c/strong\u003e, 388-395 (2005).\u003c/li\u003e\n \u003cli\u003ePark, J. Y. et al. Nasolacrimal stent with shape memory as an advanced alternative to silicone products. \u003cem\u003eActa Biomater.\u003c/em\u003e \u003cstrong\u003e101\u003c/strong\u003e, 273-284 (2020).\u003c/li\u003e\n \u003cli\u003eArciola, C. R. et al. Implant infections: adhesion, biofilm formation and immune evasion. \u003cem\u003eNat. Rev. Microbiol.\u003c/em\u003e \u003cstrong\u003e16\u003c/strong\u003e, 397-409 (2018).\u003c/li\u003e\n \u003cli\u003eChen, H. et al. Biocompatible polymer materials: Role of protein\u0026ndash;surface interactions. \u003cem\u003eProg. Polym. Sci.\u003c/em\u003e \u003cstrong\u003e33\u003c/strong\u003e, 1059-1087 (2008).\u003c/li\u003e\n \u003cli\u003eNel, A. E. et al. Understanding biophysicochemical interactions at the nano\u0026ndash;bio interface. \u003cem\u003eNat. Mater.\u003c/em\u003e \u003cstrong\u003e8\u003c/strong\u003e, 543-557 (2009).\u003c/li\u003e\n \u003cli\u003eShin, Y. C. et al. Development of a shape-memory tube to prevent vascular stenosis. \u003cem\u003eAdv. Mater.\u003c/em\u003e \u003cstrong\u003e31\u003c/strong\u003e, 1904476 (2019).\u003c/li\u003e\n \u003cli\u003eLee, K. et al. Osteogenic and adipogenic differentiation of mesenchymal stem cells in gelatin solutions of different viscosities. \u003cem\u003eAdv. Healthc. Mater.\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, 2000617 (2020).\u003c/li\u003e\n \u003cli\u003eZhou, X. et al. Biodegradable\u0026nbsp;\u0026beta;-cyclodextrin conjugated gelatin methacryloyl microneedle for delivery of water-insoluble drug. \u003cem\u003eAdv. Healthc. Mater.\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, 2000527 (2020).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"laser-responsive shape memory polymer, computational fluid dynamics modeling, anti-fibrotic drug release, glaucoma, clinician-specified control of intraocular pressure","lastPublishedDoi":"10.21203/rs.3.rs-1829962/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1829962/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eClinical laser systems enable user-specified control of the energy level, focus, and frequency by minimizing untargeted influences, which has never been applied to implantable shape memory polymers (SMPs). The glaucoma clinic possesses multi-decade issues to control progressive fluctuations in intraocular pressure (IOP) with tissue fibrosis upon implantation of silicone drainage devices. As a translatable device, we applied a laser-responsive SMP to develop i) a tube with intimal gel coating to release anti-fibrotic drugs and ii) safety lock ring. When the SMP tube was inserted into a silicone tube with wrapping externally by the ring, intimal gel degradation and argon laser-triggered diameter increase enabled three-step IOP control. Sustained drug release of the intimal gel suppressed tissue fibrosis, and the ring prevented late hypotonic IOP by externally squeezing the silicone tube. The unprecedented design and functions were validated using computational, in vitro, and rabbit glaucoma models by determining clinic-friendly argon laser parameters.\u003c/p\u003e","manuscriptTitle":"Laser-responsive shape memory device to program the stepwise control of intraocular pressure in glaucoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-09-19 20:22:35","doi":"10.21203/rs.3.rs-1829962/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d7a6e764-31ae-40a3-a1d5-66de390807e8","owner":[],"postedDate":"September 19th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-10-31T10:47:08+00:00","versionOfRecord":[],"versionCreatedAt":"2022-09-19 20:22:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1829962","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1829962","identity":"rs-1829962","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}