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1From the Department of Ophthalmology, University of Alabama School of Medicine, Birmingham, Alabama.
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.1 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 short- and medium-term recommendations from the Research Tissue Acquisition Working Group (RTAWG) for ARVO members and eye banks in the United States.
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To acquaint investigators with the mechanics of eye donation, we review the three R’s: referral, recovery, and regulation. Referral: Donor identification proceeds from patient death, which, if in a hospital, must be reported to an organ procurement organization (OPO), followed by OPO triage to eye bank. Eye banks and OPOs negotiate the extent of initial information sharing and responsibility. (Note that sources, such as hospice, law enforcement agencies, funeral directors, and non-Medicare/Medicaid participating hospitals do not need to comply with the OPO notice rule.) Criteria for eye donation, including those for research, must be constantly updated and communicated to eye bank, OPO, and hospital staffs. The eye bank, OPO, or both in concert may screen and obtain consent and detailed medical/social history. Research criteria pertaining to brain death, family history, or permission for later contact must be well known to staff to capture most viable research candidates at this stage. Donors potentially suitable for corneal transplants take precedence over research donors, based on revenue-generating potential and primary mission. Eye banks differ as to whether they rely on designated requesters among hospital staff (who must be regularly trained and motivated) or in-house staff to obtain consent. Recovery: large eye banks maintain technical staff around the clock for recovery operations and tissue delivery to a central location for evaluation, processing, and distribution. Recordkeeping at this phase includes review of consent form, review and possibly copying of donor’s medical chart, completion of a hemodilution algorithm to ensure blood sample suitability for serology testing, and microscopic review of corneal tissue for viability markers. Support services include human resources, accounting, information technology for donor database, supplies and equipment stocking and maintenance, administrative and nontechnical support staff, physical plant costs, and insurance (liability, health). Regulation: Eye banks are accredited by the Eye Bank Association of America (EBAA) based on review of standard operating procedures compliant with EBAA Medical Standards developed by its Medical Advisory Board (successor to the Eye Bank Committee of the American Academy of Ophthalmology) and of procedures compliant with the EBAA Policy Statement on Research Tissue; U.S. Food and Drug Administration (FDA); state law; U.S. Department of Health and Human Services—Centers for Medicare and Medicaid; Offices of the U.S. Inspector General and Attorney General; and the Occupational Health and Safety Administration. Site inspections by EBAA include review of policy and procedures manuals, donor records, laboratory procedures and maintenance, technical staff, Quality Assurance, and the Medical and Executive Directors. Site inspections by the FDA include review of donor records, factors pertaining to transmissible disease, donor suitability, and Good Tissue Practices. Finally, it should be noted that although the cornea is nonvascular, many regulatory details more appropriate to the greater risk for disease transmission associated with vascularized tissues spill over to eye banks.
Numerous factors in the eye bank system during the past three decades converge toward the current climate of a smaller research tissue pool. Although in situ excision of the cornea was first reported in 1975,3 corneas were previously obtained largely from whole globes enucleated from deceased donors until hypothermic preservation media became available in the 1980s. In addition to the cornea, other eye parts had medical uses (e.g., sclera fashioned to cover drainage implant tubes in Molteno shunt procedures for glaucoma or to wrap hydroxyapatite prosthetic eyes). Regarding finances, all tissue was historically provided gratis to recipients due to the philanthropic support that funded all eye bank operations. A typical eye bank in 1975 may have received seed money from the estimable Lions Club, and generous Lions Club members donated time and effort. Funeral directors may have volunteered to perform enucleations across a state. Space may have been provided in a hospital (sometimes in return for abated tissue costs for surgeons), utilities donated, and supplies purchased through hospital stores. Processing fees for transplant corneal tissue did not become common until the late 1980s after the introduction of corneal storage media, EBAA Medical Standards, and serologic testing requirements. After 1990, pericardium, dura, and artificial biomaterials became feasible substitutes for sclera, thus drastically reducing demand for harvested sclera, and in turn, harvested whole globes. Concomitantly, in situ corneal excision, requiring more surgical skill, became the method of choice for obtaining transplantable corneas. This transition rendered impractical adequate training and quality assurance for occasional procurers such as funeral directors. On the logistic side, local Lions Clubs financial and programmatic support dwindled, requiring eye banks to self-support through processing fees. Hospitals can no longer afford to donate services and time. The Conditions of Participation (the required referral law promulgated by Centers for Medicare and Medicaid Services) requiring audits of all deaths imposed the need for a labor-intensive 24-7 call center. Heightened awareness of factors associated with transmissible disease, including the appearance of new diseases (SARS, West Nile virus) and continued concern about neurodegenerative diseases of uncertain etiology (Alzheimer’s) led to more extensive serology testing and increased scrutiny of all donors to avoid transmission of infectious agents. These shifts in toto demand more time and money for public education, human resource management, legislative issues, salaries, and less for investment and infrastructure upgrades. The net result is a contracted national eye bank apparatus (106 U.S. eye banks in 1997 vs. 88 in 2003), as smaller eye banks merge with others to survive or disappear outright.
It should now be clear that although freely given, donor eye tissues for research are not harvested, processed, and delivered for free. Yet until the mid-1990s, most eye banks received little ($25–$100) or no reimbursement for research tissue. A recent cost analysis for a typical eye bank identifies operational and nonoperational costs. Operational costs include direct contributions to tissue production (storage media) and indirect contributions (facilities, clerical support, and quality assurance). Nonoperational costs include hospital staff education, public education, and marketing. Further, harvesting a research donation requires two thirds to three fourths of the technician time required for a transplant donation (depending on circumstances of the individual eye bank) and benefits from all the equipment, supplies, public education, and marketing infrastructure established for transplant donations. These considerations have elicited more realistic cost estimates of $400 to $900 per single donor eye ($800–$1800 per donor) for research (once again, depending on circumstances of the individual eye bank).
It is indisputable that eye banks, due to a revised financial model, have evolved over the past decade into true nonprofit organizations that rely on processing fees to pay their operating costs. As a result, the cost of research tissue acquisition can no longer be absorbed by an eye bank and investigators must pay more. Fortunately, some eye banks established special programs/protocols to meet researchers’ needs, and as long as this situation persists, investigators willing to reimburse for procurement costs will continue to obtain the tissues they require. The RTAWG therefore offers the following short-term recommendations for U.S. ARVO members:
The RTAWG also offers the following medium-term considerations for U.S. ARVO members and eye banks:
From the RTAWG’s perspective, then, the decline in human research tissues may be reversed in small steps as individual investigators work with their providers to acquire valuable resources for continued progress in understanding chronic eye diseases.
For further information about human donor eyes for research contact, Eye Bank Association of America (http://www.restoresight.org/), National Disease Resource Interchange (http://www.ndriresource.org/index.html), or VisionShare (http://www.visionshare.org/).
Appendix 1
Research Tissue Acquisition Working Group
Alan Marmorstein, Chair, University of Arizona, Tucson, AZ; John J. Requard, Vision Share, Raleigh, NC; Patricia Aiken-O’Neill, Eye Bank Association of America, Washington, DC; W. Daniel Stamer, University of Arizona, Tucson, AZ; Chris McGahan, North Carolina State University, Raleigh, NC; David Linker, National Disease Research Interchange, Philadelphia, PA; Jon Lonsdale, National Disease Research Interchange, Philadelphia, PA; and Lori Methia, ARVO, Rockville, MD. Additional material was provided by Barbara Crow, Lions Eye Bank of Oregon, Portland, OR; Scott Howard, Alabama Eye Bank, Birmingham, AL; Firmon Hardenbergh, Alabama Eye Bank, Birmingham, AL; Monty Montoya, Northwest Lions Eye Bank, Seattle, WA; Marcy McLain, Cleveland Eye Bank, Cleveland, OH; and Paul Volek, National Disease Research Interchange, Philadelphia, PA.
Footnotes
2 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.
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; curcio{at}uab.edu.
References
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