Declining availability of human eye tissues for research.

Research in modern investigative ophthalmology and vision science has two fundamental uses for human tissues: laboratory studies of anatomy, physiology, biochemistry, pathology, genomics, and proteomics, and ophthalmic device research and development. Because population aging focuses attention on chronic diseases such as age-related maculopathy (ARM), glaucoma, and diabetic retinopathy, it is instructive to note the experience of research in other age-related diseases. Thirty years after cholesterol-enriched lesions in coronary artery disease were characterized, 20 years after -protein from Alzheimer brain was isolated, and even the current widespread availability of animal models and in vitro systems for both diseases, high-impact studies using human tissues still appear regularly in atherosclerosis and Alzheimer research. There will be a continuing need to examine well-characterized human tissues in light of new information from animal models resulting from gene-based investigations. For reference, the cardiovascular literature, with a century of animal models, periodically compares models to human disease. Because of the unique anatomy of the macula and the aqueous outflow tract in humans, human tissue will be a mainstay of ARM and glaucoma research for the foreseeable future. From this perspective, eye research using human tissues is an important component of the power grid that energizes clinical ophthalmology by providing relevance. There are three basic strategies for finding eyes with chronic diseases, all of which rely on the harvesting of eyes from deceased donors by eye banks. These include a registry (obtaining donor pledges in advance of donor death), systematic harvesting (gleaning all available tissues from deceased donors at a single source to find tissues meeting specific criteria), and a clearinghouse (matching investigators in one city specific protocols with tissues meeting those criteria in another city). A well-known clearinghouse is National Disease Research Interchange (NDRI, Philadelphia, PA), with 125 active eye protocols, 113 sources (eye banks, tissue banks, organ procurement organizations, and hospitals), and 25 years of support from the National Eye Institute. Figure 1 shows a trend that is slow, yet pervasive, and potentially of great significance for clinical ophthalmology: the number of research tissues from human donor eyes provided by U.S. eye banks declined 28% from 21,766 in 1997 to 15,780 in 2004. This trend shows no signs of reversal. What underlies this development? Should it concern us? What should ARVO members do in response? This article presents the results of a membership survey, the mechanics of how eye banks procure research tissues, eye banking developments that underlie this unpropitious trend, and shortand medium-term recommendations from the Research Tissue Acquisition Working Group (RTAWG) for ARVO members and eye banks in the United States. A recent web-based survey of 240 U.S. ARVO members (6% of the U.S. membership) indicates continued demand for human tissues for research. The local eye bank ranked first among respondents as a tissue source, but in reality most investigators use multiple tissue sources, including remote eye banks. The major prohibitory factors in the use of human tissues are cost, nonavailability of tissue meeting stringent criteria, and lack of clinical documentation. Regarding costs, examining tissue from 10 ARM donors and 10 age-matched controls can cost $8000 to $10,000 and can take 1 year just to acquire the tissue. However, many investigators indicated they could bear higher costs if tissue were collected within a short death-to-preservation interval. Tissue quality is an increasingly controlling consideration due to the high sensitivity of current assays. The percentage of investigator requests to NDRI specifying deathto-delivery time of less than 24 hours was 26% in 1993 and 61% in 2003. However, due to the time spent complying with more regulations (see below), postmortem processing time has risen from 3.9 hours to 6.8 hours over the same interval. Although experiments involving histology, anterior chamber perfusions, proteomics, and cell isolations have different degrees of tolerance for postmortem delay, all uses benefit from tissues in which death-to-preservation time is minimized. The most stringent requirements apply to mRNA preservation for gene expression studies. Direct comparisons between donor eyes and simulated eye bank conditions indicate that a 5-hour postmortem upper limit for intact RPE mRNA can be extended to 24 hours by using specialized media (e.g., RNAlater; Ambinon, Auston, TX). Regarding availability, much eye research requires tissues that do not meet transplant criteria (e.g., fetal tissue, older donors, i.e., 80 yr), thus requiring special effort from cooperating eye banks. Further, local eye bank practices affect research tissue availability. For example, in some states a medical examiner (ME) law does not permit whole eye enucleation in cases of violent or suspicious causes of death typically referred to the ME. Thus, tissues from younger individuals dying of these causes are off-limits, and accordingly, the average age of whole eye donors to NDRI has stabilized at 65 years. New rules requiring personal medical history interviews with someone acquainted with the deceased donors, will depress this already small source of young donors further. Other problems impacting tissue availability include lack of conformity with acceptance criteria, cornea-only donations, and family willingness to consent to eye donation for transplant but not for research. Regarding clinical history, 71% of respondents required clinical documentation for their work, and nearly as many (61%) indicated willingness to pay more for that service, which is noteworthy, because ophthalmic medical history for eye donors is not required of eye banks by regulatory agencies. From the Department of Ophthalmology, University of Alabama School of Medicine, Birmingham, Alabama. Members of the Research Tissue Acquisition Working Group are listed in the Appendix. Presented, in part, at Special Interest groups at the annual meetings of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Florida, May 2003 and May 2004. Submitted for publication July 26, 2005; revised November 8 and 26, 2005; accepted May 10, 2006. Disclosure: C.A. Curcio, None Corresponding author: Christine A. Curcio, Department of Ophthalmology, University of Alabama School of Medicine, 700 South 18th Street, Room H020, Callahan Eye Foundation Hospital, Birmingham AL 35294-0009; [email protected].