1047 GR Ondrugdelivery Issue 48 Opthalmic Mar 14.Indd

Micro Engineering Solutions

MICRO OPHTHALMIC OCULAR IMPLANTS

More often than not, the smallest component in a medical or pharmaceutical implant or device is the enabling component. Micro manufacturing (micro injection molding, micro machining, and micro automation) has blazed the trail for many new developments, implants, micro surgery, and robotic surgeries today. This article, by Donna Bibber, Plastics Engineer & Chief Executive Officer of Micro-Engineering Solutions, explores one such market segment in which micro manufacturing has played and will continue to play a significant role in worldwide growth in the next five years … ophthalmic devices.

Age-related eye diseases such as cataracts, • Daiichi Pharmaceutical Co Ltd diabetic retinopathy, glaucoma and macular • Genentech Inc degeneration (to name only a few) continue • Inspire Pharmaceuticals Inc to cause loss of vision either significantly or • ISTA Pharmaceuticals Inc completely. Driven by a baby boomer aging • Johnson & Johnson (Vistakon population, technology innovations and vast, Pharmaceuticals LLC) rapidly emerging markets in China and India, • Merck & Co Inc the ophthalmic devices sector is expected to • Pfizer Inc attain a double-digit growth. Ophthalmic • Santen Pharmaceutical Co Ltd. and intraocular implants are largely made up of many micro sized and highly precise com- Major players in the surgical ophthalmic ponents and assemblies. This market sector space include: continues to remain one of the largest and • Abbott Medical Optics fastest growing micro medical and pharma • Alcon micro device sectors, globally. • Bausch + Lomb Inc.

MARKET DATA CONDITIONS AND TREATMENT

The global ophthalmic device market was The eye is a complex and sensitive organ. valued at $10 billion (£6 billion) in 2008 There are many structures and targets, locat- with the US market comprising $5.5 billion ed closely together and sometimes, in terms of this. Driven by growth in the vision care of targets for treatment, these structures are and cataract surgery market categories, the conflicting with one another in their proxim- market is forecast to grow by 8.5% annu- ity. Existing in the eye are significant defense ally during 2008-2015 to reach $15 billion mechanisms, such as the tear film and the Ms Donna Bibber worldwide ($9.8 billion in the US). cornea, which present challenges for medica- Chief Executive Officer On the downside, due to reduced con- tion to enter. Specifically, the vitreous fluid is T: +1 774 230 3459 sumer discretionary spending in the US, the difficult for injected medication to traverse to F: +1 508 434 0281 market continues to grapple with growth reach the posterior of the eye. E: donnabibber decline in refractive surgery. On the upside, A number of conditions of varying seri- @microengineeringsolutions.com the treatments for other conditions are ousness and interest are: the major factors for the vastly emerging 1. Glaucoma Micro Engineering Solutions, LLC growth markets worldwide. 2. Cataracts 102 City Depot Road Major players in the ophthalmic phar- 3. Diabetic retinopathy PO Box 952 maceutical space include: 4. Age-related macular degeneration Charlton City MA 01508 • Alcon (now part of Novartis) 5. Dry eye syndrome United States • Allergan Inc 6. Uveitis • Bausch & Lomb Inc 7. Retinal detachment www.microengineeringsolutions.com

8. Advanced age and lifestyle diseases; still an extremely high level of unmet need 9. Others of lesser importance can be treated / managed with eye glasses, OTC medication, antibiotics, and specific hygiene protocols and, in limited instances, with surgery.

Treatment often requires contributions from two or more parts of an inseparable Figure 1: A micro-injection moulded glaucoma drain (shunt). therapeutic triad: • Ophthalmic pharmacology • Surgery of the visual tract For example, glaucoma, the “sneak thief Shunts are mostly tubular, however this • Implantable ophthalmic medical devices. of sight”, affects many elderly, African one is shaped and designed for placement Americans, and those with a family his- in the sclera (side of the eye). It is designed Highly innovative specialist companies tory. Considered the second leading cause of to act like a venturi system which uses the dominate pharmacological development. blindness (after cataracts), glaucoma is prin- pressure of the eye to push the discharge Innovative companies on the drug delivery cipally caused by elevated intraocular pres- from glaucoma to behind the eye where it side are equally important. Industry develop- sure within the eye. Micro surgical devices can drain. In addition to the 250 μm entry ment occurs through a large number of high- and intraocular implants are used if eye orifice, there are 4 suture holes of 250 μm ly-focused, research driven specialist compa- drops are not an effective treatment. Micro diameter (2x a human hair) moulded into nies, often very small and funded through components and surgical treatments include: the top of the implant. These suture holes innovation-support funding programs. Such • Trabeculectomy (laser surgery) is most also must be free and clear of particulate or companies can need to be able to easily find common approach; creates a hole in sclera flash to prevent sutures from cutting during a large marketing partner as big pharma is to allow fluid to drain into the outer cyst implantation or after surgery. often funding this development externally in • Conventional surgery can also be used to Age-related macular degeneration (AMD) lieu of doing it themselves in-house. create a drainage hole in the white part of is the leading cause of permanent impairment Highly innovative specialty companies the eye if laser surgery is unsuccessful of reading ability and loss of fine detail for define and epitomise the requirement for • Implant surgery positions a device to aid those over age 65 years. The macula is the treatments for these conditions that comprise micro sized and ultra-precision components and assemblies. Anyone who has ever worn corrective contacts and/or been on the bad “Successful creation of a device that is both paper thin and end of a windy day near an outdoor fire pit, strong is an engineering challenge that requires the skill you have probably noticed that the smallest speck in your eye can cause you severe pain. and expertise that only micro moulding and nano surface The reasons for intraocular implants specialty companies can understand and implement” being micro sized then are to provide the eye an extreme level of comfort with the least invasive, yet compliant implants in the human body. The thin and delicate struc- the drainage; estimated that several thou- central portion of the retina used for seeing tures of the eye require paper thin and flex- sand are performed each year in the US fine detail and can be destroyed in one of two ible components that are nonetheless strong • Canaloplasty places a microcatheter into ways beginning at age 60. enough to withstand extreme fluid pressures Canal of Schlemm to enlarge the natural In 2004, 1.5% of adults over age 40 in and behind the eye. The successful creation drainage channel for healthy eyes. experienced advanced AMD and 6.1% had of a device that is both paper thin and strong Figure 1 shows a glaucoma drain, com- intermediate AMD (1.8 and 7.3 million is an engineering challenge that requires the monly known as a shunt. This shunt is adults, respectively). The dry form is most skill and expertise that only micro moulding injection moulded, spherically shaped with common form of AMD but it can become and nano surface specialty companies can a wedge-shaped radial side action in the tool wet form which is more destructive. In dry understand and implement. Let us explore that creates the drain geometry. At the end AMD light sensitive cells in macula break this micro requirement specifically for some of the side action travel is a 250 μm orifice down. Dry AMD is treated by oral ingestion of the more common conditions/treatments. whereby no moulding flash can be tolerated. of high dose of anti-oxidants and zinc.

Punctal plugs

Meibomian glands

Figure 3: Punctal plugs placed in drainage channels of the upper and lower eyelids (Source: allaboutvision.com).

Figure 2: Macular degeneration laser guide.

Wet AMD is characterised by growth of necessary and also require OEM testing even properly (balancing the dropper over the abnormal blood vessels behind retina. Laser if they are shown to be Class VI compliant. eye and making sure it all gets into the eye) surgery is used in small proportion of patients Dry eye is one of the most common reasons defeats the purpose and wastes consumer to destroy these vessels but the treatment for an appointment with an ophthalmologist. and healthcare costs. Much effort is put also damages the retina. Another treatment Dry eye condition is defined as an irritation of into micro pumping and micro administer- approach involved intravenous injection of a the eye due to an inability to produce or main- ing of these fluids with aspirators, implant- photo-activated drug (into the arm). When tain/retain enough tears on the surface of the able pumps, and slow release polymers that exposed to light in the eye the drug is activated eye. It can result in damage to the front sur- release the drug in timed increments. and it destroys the unwanted new blood ves- face of the eye and impair vision. The causes sels. Injections into the eye to block growth of vary from specific diseases (such as Sjögren’s DESIGN CONSIDERATIONS abnormal new blood vessels are also available. syndrome or lacrimal and meibomian gland Prior to 2007, medicine was not avail- dysfunction) to other causes including age, Many drug delivery devices are now man- able to treat AMD; in 2007 the market was gender (women are more susceptible), medi- ufactured in non-traditional ways such as sili- estimated to represent more than $1.2 bil- cations, certain medical conditions, environ- con wafer technology, MEMS, and ground- lion in sales. mental conditions such as exposure to smoke, up manufacturing methods. These methods Figure 2 shows an AMD guidance device wind, or dry climates, and other factors such are then matched to more traditional top- used in laser surgery. The spherical radius sits as prolonged use of contact lenses or refractive down methods to provide medical and phar- on the cornea and the lens underside must eye surgeries (LASIK). maceutical companies with differentiated and be free of flash, mould parting lines, and Treatment, may require micro compo- strategic value. These processing techniques surface imperfections. The 300 μm laser hole nents (approximately a quarter of the size of are typically developed using “conventional” shuts off on the spherical radius and blend- a grain of rice) including punctal plugs (see single micron level positional accuracy using ing these geometries three-dimensionally in Figure 3) whereby a plug is surgically placed current work holding devices. These meth- steel to produce the polymer micro injection in both the top and lower eyelid to prevent ods are inadequate in preventing cross con- moulded component is very challenging. fluid in the eye from draining, thereby keep- tamination of actives in capillaries and other In this case, material selection was also a ing the eye hydrated. microscopic microfluidic assemblies. Nanometre-positional accuracy was not available to the mainstream even 2-3 years ago. Even today, traditional pallet-holders “New methods combine traditional top-down methods coupled with automatic X, Y, Z probing with futuristic bottom-up methods to provide medical and can barely guarantee a one micron positional accuracy. It is also strange to think pharmaceutical device companies with enabling products this isn’t good enough for the eye, but the to treat the likes of glaucoma, macular degeneration, surface finish is absolutely necessary, orders cataracts, dry eye, and even diabetes around the world” of magnitude tighter tolerances than seen in conventional or macro manufacturing. So it is evident that developing ophthalmic and intraocular implants requires thinking at key factor in providing the rigidity required Additional treatments use OTC eye the scale on which the human body operates, to hold the guide in place during laser deploy- drops or prescription lubricants and anti- and the human body operates at the scale of ment. USP Class VI materials (they have inflammatories. These medications are nanometres. White and Red blood cells on previously been used in medical products) are extremely costly and if not administered average range from 8-100 μm in diameter and

“Top Down” Methods “Bottom Up” Methods

Laser Machining Genetic Code

EDM-WEDM Complexity Theory

Ultrasonic Machining Self-assembly

Ion Machining Biological Cell

Grinding Proteins

CNC Machining DNA and RNA

Chemical Milling LIGA

Photochemical Milling 3D Printing Figure 5: Google’s smart contact lens Electrochemical Machining (Source: Google Inc).

Figure 4: Summary of Micro-Engineering Solutions’ micro and nano manufacturing methods used today and in the future.

DNA can be as small as 2-3 nm. In between Google said the lens comprises “chips and these two range a great deal of discovery and sensors so small they look like bits of glitter, science that we cannot begin to understand and an antenna thinner than a human hair”. without simulation outside the body, for exam- The chip and sensor are embedded between ple mimicking strands of DNA and blood cells two layers of soft contact lens material. A working together. It is for this reason that tiny pinhole in the lens allows tear fluid from ophthalmic, intraocular, drug delivery and the surface of the eye to seep into the glucose pharmaceutical device companies are look- sensor. The prototypes currently being tested ing for help from manufacturers to push the can take glucose level readings every second. boundaries of what is possible to achieve fea- The project was co-founded by Brian Otis tures and tolerances in the nanometre range. and Babak Parviz who worked together at the Figure 6: Retinal implant As shown in Figure 4, what we have University of Washington (Seattle, WA, US) (Source: Institute for Ophthalmic discovered in the micron range has certainly before moving to Google. Research at the University of Tübingen). helped us to learn some top down meth- One can’t help imagining that, beyond ods that didn’t work, and some bottom diagnostics, completely encased electronics ways to cross the elusive blood-retinal bar- up methods that worked but needed some placed onto the cornea may one day bring rier, micro-electronics and eyes controlling refinement using a combined top-down/ vision, gaming, web browsing, and social the brain to control prosthetics, and even bottom-up method. interaction to a completely new level. controlling motion for paraplegics. Imagine Growing structures (i.e. bottom-up meth- Alternative methods are coupling neu- a technology allowing people to see…… ods) to create geometry was also not main- roscience with ophthalmic science as seen people they haven’t seen in years, objects in stream until 2-3 years ago. A good rule of in Figure 6, which shows a retinal implant a room, light in a sky, food on a plate, and thumb is that material and process marrying embedded in the eye that restores vision to to recognise a smile. We are fortunate to be will force a top down methodology until we the vision impaired or the visionless. well positioned in micro and nano manu- can mill, grind, edm (electrical discharge Non-traditional methods for manufacturing to play a part in enabling these machine), diamond turn, and etch no more. facturing such as nanometre positional treatments and products that contribute to We have already used LIGA (German acro- accuracy and dust-specked sized injection worldwide health. nym meaning lithography, electroplating, moulded, machined, and assembled compo- and moulding) for many years as a bottom- nents are spawning technological advances ABOUT THE AUTHOR up method. However, with the emergence in ophthalmic intraocular implants and of 3D printing, at some point in the near intraocular drug delivery devices. These Donna Bibber is a Plastics Engineer future, we will be looking that technology new methods combine traditional top-down and CEO of Micro Engineering Solutions, to create geometry, surfaces, and – when methods with futuristic bottom-up meth- a micro-focused design and manufactur- the materials are available and 3D printable ods to provide medical and pharmaceutical ing company providing micro moulding – even human organs. This will push micro device companies with enabling products and micro automation/assembly services manufacturers and macro manufacturers to treat the likes of glaucoma, macular to start-up and Fortune 500 companies beyond our current capabilities in top-down degeneration, cataracts, dry eye, and even alike. Ms Bibber has published and lec- methods, or there might be a “marriage diabetes around the world. tured on hundreds of technical papers on made in heaven” employing both methods. Areas unknown can be explored with micro moulding medical and pharmaceuti- For example, in the area of diabetes, micro manufacturing – restoring lost vision, cal devices, and associated topics worldwide Google is developing a smart contact lens enhancing vision, hydrating eyes in harsh and was voted onto the MD+DI List of 100 for measuring glucose in tears (see Figure 5). conditions, gaining less invasive, viable Notable People in Medical Devices in 2008.