And Transplantation

Regulatory Aspects. Treatment of type 1 diabetes by transplanting human allogeneic islets is an investigational procedure. It is ensconced by layers of quality and regulatory oversight to safeguard public health and monitor the development of the new procedure. In the United States, transplantable allogeneic pancreatic islets meet the definition of a "drug" in the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 USC 321(g), and are subject to certain requirements of the FD&C Act. Therefore, before the initiation of any studies in humans of allogeneic islet transplantation, an investigational new drug (IND) application must be approved by the FDA (Regulations for Biological Products Title 21, Code of Federal Regulations Part 312—Investigational New Drugs). Appendix 1 lists the pertinent documents published by the FDA concerning the regulation of cellular and tissue-based products intended for transplantation, including allogeneic islets. The basis for this regulatory order is to ensure that a safe, quality product is used for transplantation.

For biological products, safety is ensured by control of the "manufacturing" process. This requires methodology to adequately characterize and demonstrate that the final therapeutic product can be "manufactured" consistently. To successfully obtain islet preparations that are safe to implant and of high quality, each stage of the production process is defined by standard operating procedures and quality control checks implemented during the course of the isolation and purification procedure. The "manufacturing" process of islets begins at the time of organ procurement.

Pancreas Donor Criteria, Procurement and Preservation. An ideal donor will have a favorable medical, sexual, and social history; pass the physical examination requirements; and clear all standard laboratory tests used in multiorgan donor workups to show low risk of disease transmission. The impact of pancreas donor criteria on the results of islet isolation and purification has been studied retrospectively by a number of groups.35-38 Older donor age, a local procurement team, and high body mass index are positively correlated with successful islet isolations. Hyperglycemia, increased duration of cardiac arrest, and increased duration of cold storage are negatively correlated.

The surgical technique for pancreas recovery for islet transplantation follows the principles established for immediately vascularized, whole-organ pancreas transplantation.39,40 The competence and commitment of the surgical team procuring a pancreas for islet transplantation is just as crucial for success of the islet transplant as it is in ensuring successful whole pancreas transplantation. One particularly important consideration of pancreas procurement for islet transplantation concerns the care in maintaining the integrity of the pancreas capsule. Since distention of the pancreas by intraductal injection of collagenase represents a crucial step in subsequent islet isolation, any breach of the pancreatic capsule will compromise this aspect of the isolation procedure. A moderately firm, hard, edematous, or fatty pancreas is not a contraindication to procurement for islet transplantation. In fact, the visual criteria to rule-in a pancreas for islet transplantation are more liberal than for whole pancreas transplantation.

Adequate perfusion of the pancreas with cold preservation solution is accomplished by aortic cannulation and flush through the splenic and superior mesenteric arteries. Venous hypertension in the pancreas should be avoided during in situ flush. If the cannula for in situ portal perfusion is located and secured in the portal vein, the pancreatic portion of the portal vein must be transected to allow continuous drainage of pancreatic fluid outflow. Thus, excessive perfusion pressure or restriction of venous outflow of the pancreas is avoided.

Continuous and effective surface cooling of the pancreas is of paramount importance: warm ischemia is detrimental to subsequent islet isolation.41 Topical cooling is accomplished by widely opening the lesser sac after dividing the gastro-colic omentum and placing ice slush on the anterior aspect of the pancreas immediately after aortic crossclamping and vascular flush. The pancreas is kept cool while liver procurement occurs. Next the pancreas is procured and stored in cold preservation solution. Finally the kidneys are procured.

Pancreata to be processed for islet isolation are less tolerant of cold ischemia than those used in whole pancreas transplantation. Cold preservation time should be kept less than 9 hours to improve islet isolation yield and function. Simple cold storage in University of Wisconsin (UW) solution has been the standard

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