IMPLANTABLE MEMS DRUG DELIVERY SYSTEMS FOR ADMINISTRATION OF UNALTEREDTHERAPEUTIC AGENTS
Ellis Meng, Ph.D.1& Mark S. Humayun, M.D., Ph.D.2 1University of Southern California, Viterbi Schoolof Engineering, Department of Biomedical Engineering, Los Angeles, CA 90089 & 2University ofSouthern California, Keck School of Medicine/Doheny Eye Institute, Departments of Ophthalmology,
Biomedical Engineering, and Cell and Neurobiology, Los Angeles, CA 90033
We have developed the first implantable intraocular microelectromechanical systems (MEMS) drugdelivery device capable of being refilled for targeted intraocular delivery of therapeutic compounds intheir unaltered format. In particular, this approach enables a practical drug delivery vehicle for treating
difficult-to-reach diseases affecting the posterior segment of the eye.
Drug therapy intervention plays a major role in the management of many ocular diseases. However,precise delivery of pharmaceutical solutions to a specified target within the body is an ongoingchallenge in many areas of drug delivery. Current routes of ocular treatment (topical, systemic orintraocular injections) have limited efficacy due to physiological barriers, potential side effects, andoccasional patient compliance. Thus, a new paradigm for treatment ocular diseases using
micromachined drug delivery devices is explored as an optimal means of pharmacologic management.
Our intraocular MEMS drug delivery devices are refillable for chronic use and capable of controlled
delivery of unaltered therapeutic agents. Only a single surgical intervention is required to implant thedevice following which long term operation with potentially fewer side effects is possible.
Manually and electrically-controlled device prototypes have been designed, fabricated, and tested(benchtop, ex vivo, and in vivo). Both systems share a common layout, containing a refillable drug
reservoir and a transscleral cannula. The reservoir is implanted subconjunctivally, while the cannula isinserted through an incision into either the anterior or posterior segment. Placement of the tip of thecannula is determined by the desired site of therapy. A specific dose of medication is electronicallydispensed from the device reservoir, directed into the eye via the cannula, and is released from thecannula tip. Once the drug is depleted, the reservoir can be refilled by injection using a 30 G noncoring needle with the same or alternate medication. Needles no larger than 25 G eliminate the needfor sutures as the tissue is able to reseal following puncture. Repeated refillability is a key feature andenables prolonged use of the device up to several years.
The manually-controlled device also includes a check valve that prevents backflow of fluids into thedrug reservoir. Drugs are dispensed through the pressure-sensitive valve into the eye when thereservoir is gently depressed by the patient. The simple manual format offers convenient rapid
prototyping of functional drug delivery systems as surgical models for developing the surgical techniqueand assessment of biocompatibility. The electrically-controlled device includes an electrolysis pumpthat utilizes gas generation associated with electrolysis for intraocular drug delivery.
Reliability of the drug reservoir following multiple refills was confirmed in benchtop experiments andrepeated refills were performed ex vivo (porcine eyes) and in vivo (rabbits). Bolus delivery wasdemonstrated in benchtop experiments and enucleated porcine eyes with the manually-controlled
surgical models. Bolus and continuous dispensation (pL/min-μL/min), with a fixed or variable rate, werealso demonstrated with the electronically-controlled device. Flow rate was conveniently adjusted byvarying the applied current (μA-mA). In both systems, delivery of 25 μL of phenylephrine solution(1.5%) was performed in rabbit eyes and resulted in a real-time physiological response (pupil dilation).
Electrically-controlled devices were used only in acute experiments, however, the surgical models arebeing followed for a total of 6 months with periodic examination, color photography and fluoresceinangiography. This is the first demonstration of physiological response to MEMS-based drug delivery.
A new generation of drug delivery implants are currently being developed for treatment of glaucoma
and retinitis pigmentosa.