Developing Implants for Ophthalmic Drug Delivery and Flow Modulation

Glaucoma is the leading cause of irreversible blindness worldwide. Surgical interventions are frequently necessary to lower the intraocular pressure (IOP) and do so by creating a new channel for aqueous humour to drain into the subconjunctival space. This channel can be formed by performing a glaucoma filtration surgery (GFS) or by implanting a glaucoma drainage device (GDD). However, excessive scarring at the surgical site blocks aqueous outflow, elevates IOP, and results in treatment failure. Drugs injected locally to control scarring rapidly clear from the subconjunctiva, and current implants are susceptible to a foreign body response. This work investigated strategies that could improve the outcomes of these current glaucoma interventions. First, drug-eluting spacers were formulated using established biocompatible materials to prolong drug release in conditions representing the subconjunctival space post-GFS or GDD implantation. Of these formulations, the spacer containing non-ionic surfactant, Brij 98, at a concentration of 1.25% w/v was able to prolong the release of dexamethasone from poly(2-hydroxyethyl methacrylate) pHEMA hydrogels significantly longer (>30 days) than hydrogels containing no surfactant (<7 days) at therapeutically relevant drug concentrations in vitro. Next, engineering principles were applied to inflated elastomeric membranes, which provided novel insights into considerations needed to design a novel ophthalmic drug delivery pump. Pocket geometry and material properties had a significant impact on internal pressure and subsequent pump function. Modelling data supports the feasibility of elastomeric pumps for prolonged subconjunctival drug delivery. Finally, an alternative mechanism of IOP control was investigated. Novel and established hydrogel formulations were evaluated for aqueous permeability and mechanical integrity. Despite evidence to suggest the feasibility of hydrogels to modulate aqueous flow, the in vitro permeability of hydrogel candidates was determined to be too low to maintain optimal IOP. Furthermore, hydrogel permeability tended to negate its mechanical integrity, making them unsuitable candidate materials for GDD development

Doctor of Philosophy

dissertationBiocompatibility is a key aspect in determining the success of a biomedical device. In this work the development, manufacture, designs, and biocompatibility of two devices are discussed. As protein adsorption to a material surface is the first step in the host wound healing and inflammatory response this phenomenon was additionally examined. The capsule drug ring (CDR) is a reservoir and delivery agent which is designed to be placed within the capsular bag during cataract surgery. Prototypes were manufactured by hot melt extrusion of Bionate® II (DSM), a polycarbonate urethane. The devices have been optimized using Avastin® as the drug of interest. In vitro biocompatibility was assessed with human lens epithelial cell (B-3), mouse macrophage (J774A.1), and mouse fibroblast (L-929) cell lines. Cell migration and proliferation were assessed after in vitro culture. Proinflammatory cytokines (i.e., MIP-1β, MIP-1α, MCP-1, IL-1β, TNF, and TGF-β1) were quantified using cytometric bead array (CBA). Preliminary in vivo biocompatibility and pharmacokinetics testing has been performed in rabbits. Cataract extraction uses ultrasound energy and vacuum to liquefy, emulsify, and aspirate the cloudy lens. During phacoemulsification, thermal energy and fluidic currents within the eye can damage the postmitotic corneal endothelium. This results in corneal edema, compromised vision, and a potential need for corneal transplantation. Viscoelastics are used to stabilize the anterior chamber, to maintain the eye pressurization, and to help absorb and dissipate thermal energy. However, the fragile corneal endothelium is often damaged despite the use of viscoelastics. This work discusses the development of a foldable 100 micron transparent shield for use during phacoemulsification. This endo-contact lens is designed to float in the anterior chamber to allow for surgical access, and to absorb and deflect thermal energy to protect the fragile corneal endothelium

Contact lens platforms for ocular health monitoring

As of today, the World Health Organization (WHO) counts millions of cases of preventable blindness every year in high income countries, attributed to the lack of early-stage ophthalmic screening technologies. Contemporary methods rely on bulky and costly equipment exclusively operated by specialized clinicians, resulting in a medical approach based on reaction over prevention. A possible approach results from a literature survey on the tear fluid properties, which revealed its potential to be used as a diagnostic medium. However, existing tear sampling technologies lack practicality, and introduce a high contamination risk of tear samples

In vivo evaluation of a novel donut-shaped minitablet for intraocular implantation

PhD, Faculty of Health Sciences, University of the Witwatersrand, 200

Preclinical Animal Modeling in Medicine

The results of preclinical animal research have been successfully implemented in various medical and biological practices. The use of animals in medicine is based on significant anatomical, physiological, and molecular similarities between humans and animals. Particularly, mammals that have vast biological commonalities with humans represent not only a valuable model to explore the mechanisms of varied human diseases, but also to define new diagnostic and treatment strategies. This book covers broad but important aspects of animal modeling for scientific medicine as well as for translational systems and biological sciences. Alternative methods such as cell culture and in vitro experiments that do not require the sacrifice of an animal are encouraged for scientific and medical studies

Advances in Ophthalmology

This book focuses on the different aspects of ophthalmology - the medical science of diagnosis and treatment of eye disorders. Ophthalmology is divided into various clinical subspecialties, such as cornea, cataract, glaucoma, uveitis, retina, neuro-ophthalmology, pediatric ophthalmology, oncology, pathology, and oculoplastics. This book incorporates new developments as well as future perspectives in ophthalmology and is a balanced product between covering a wide range of diseases and expedited publication. It is intended to be the appetizer for other books to follow. Ophthalmologists, researchers, specialists, trainees, and general practitioners with an interest in ophthalmology will find this book interesting and useful

액정폴리머를 기반의 소형, 안구밀착형, 장기안정적인 인공망막장치

학위논문 (박사)-- 서울대학교 대학원 : 전기·컴퓨터공학부, 2015. 8. 김성준.A novel retinal prosthetic device was developed using liquid crystal polymer (LCP) to address the problems associated with conventional metal- and polymer-based devices: the hermetic metal package is bulky, heavy and labor-intensive, whereas a thin, flexible and MEMS-compatible polymer-based system is not durable enough for chronic implantation. Exploiting the advantageous properties of LCP such as a low moisture absorption rate, thermo-bonding and thermo-forming, a small, light-weight, long-term reliable retinal prosthesis was fabricated that can be conformally attached on the eye-surface. A LCP fabrication process using monolithic integration and conformal deformation was established enabling miniaturization and a batch manufacturing process as well as eliminating the need for feed-through technology. The fabricated 16-channels LCP-based retinal implant had 14 mm-diameter with the maximum thickness of 1.4 mm and weight of 0.4 g and could be operated wirelessly up to 16 mm of distance in the air. The long-term reliability of the all-LCP retinal device was evaluated in vitro as well as in vivo. Because an all-polymer implant introduces intrinsic gas permeation for which the traditional helium leak test for metallic packages was not designed to quantify, a new set of reliability tests were designed and carried out specifically for all-polymer implants. Moisture ingress through various pathways were classified into polymer surface, polymer-polymer and polymer-metal adhesions each of which were quantitatively investigated by analytic calculation, in vitro aging test of electrode part and package part, respectively. The functionality and long-term implantation stability of the device was verified through in vivo animal experiments by measuring the cortical potential and monitoring implanted dummy devices for more than a year, respectively. Samples of the LCP electrodes array failed after 114 days in 87°C salin as a result of water penetration through the LCP-metal interface. An eye-confirmable LCP package survived more than 35 days in an accelerated condition at 87°C. The in vivo results confirmed that no adverse effects around the retina were observed after implantation of the device for more than a year.ABSTRACT i Contents iv List of Figures xi List of Tables xxi Chapter 1 : Introduction 1 1.1. Neuroprosthetic devices 1 1.2. Retinal prosthesis 2 1.2.1. Concept 2 1.2.2. Three approaches 3 1.2.3. Camera vs. Photodiode 4 1.3. Conventional devices 5 1.4. Liquid Crystal Polymer (LCP) 7 1.4.1. Low moisture absorption and permeability 9 1.4.2. Thermoplastic property 9 1.4.3. Compatibility with MEMS technologies 10 1.4.4. RF characteristics 10 1.5. LCP-based retinal prosthesis 11 1.6. Long-term reliability 12 1.7. Dissertation outline 14 Chapter 2: Methods 16 2.1. System Overview 16 2.2. Microfabrication on LCP 18 2.2.1. Limitations of the previous microfabrication technique on LCP 19 2.2.2. Improved LCP-based microfabrication 22 2.2.2.1. Electroplated micro-patterning 23 2.2.2.2. Laser-thinning for higher flexibility 24 2.2.2.3. Laser-ablation for site opening 25 2.3. All-LCP Monolithic Fabrication 26 2.3.1. Multilayered integration 29 2.3.1.1. Electrical components 29 2.3.1.2. Thermal lamination 32 2.3.1.3. Layer configuration 34 2.3.2. Thermal deformation 35 2.3.2.1. Deformation process 35 2.3.2.2. Wavy lines for stretchability 36 2.3.2.3. Electrical properties of the deformed coil 40 2.3.3. Circuit Assembly 40 2.3.3.1. Stimulation ASIC 40 2.3.3.2. Surrounding circuitries 41 2.3.4. Packaging 43 2.3.5. Laser Machining 44 2.4. Device characterization 44 2.4.1. Transmitter Circuit and Wireless Operation 45 2.4.1.1. Transmitter circuit 45 2.4.1.2. Transmitter coil 46 2.4.1.3. Wireless operation test 46 2.4.2. Electrochemical measurements 48 2.5. Long-term reliability tests in vitro 49 2.5.1. Failure mechanisms of an all-LCP device 49 2.5.2. Analytic calculation 51 2.5.3. Long-term reliability tests in accelerated environment 55 2.5.3.1. Long-term reliability of electrode array 55 2.5.3.2. Long-term reliability of package 57 2.5.3.3. Long-term reliability of complete device 58 2.5.4. Long-term electrochemical stability 59 2.6. Acute and Chronic Evaluation in vivo 60 2.6.1. Surgical implantation 60 2.6.2. Acute functionality test 62 2.6.3. Long-term implantation stability 63 Chapter 3: Results 64 3.1. Microfabrication on LCP 64 3.1.1. Electroplated micro-patterning 64 3.1.2. Laser-ablation for site opening 67 3.1.3. Laser-thinning for higher flexibility 69 3.2. All-LCP Monolithic fabrication 71 3.2.1. Multilayered integration 71 3.2.2. Thermal deformation 73 3.2.2.1. Deformation results 73 3.2.2.2. Wavy lines for stretchability 74 3.2.2.3. Effect on the electrical properties 74 3.2.3. Circuit assembly 76 3.2.4. Packaging 77 3.2.5. Laser machining 79 3.3. Device Characterization 80 3.3.1. General specifications 81 3.3.2. Transmitter circuit and coil 83 3.3.3. Wireless operation 83 3.3.4. Electrochemical measurements 84 3.4. Long-term reliability tests in vitro 86 3.4.1. Analytic calculation 87 3.4.2. Long-term reliability tests in accelerated condition 90 3.4.2.1. Long-term reliability of electrode arrays 90 3.4.2.2. Long-term reliability of package 92 3.4.2.3. Long-term reliability of complete device 93 3.4.3. Long-term Electrochemical stability 93 3.5. Acute and chronic evaluation in vivo 95 3.5.1. Surgical implantation 95 3.5.2. Acute functionality test 96 3.5.3. Long-term implantation stability 97 Chapter 4: Discussion 100 4.1. Comparison with conventional devices 100 4.2. Potential applications 102 4.3. Opportunities for further improvements 102 4.4. Long-term reliability 104 Chapter 5: Conclusion 108 Reference 110 국문초록 118 감사의 글 121Docto