Organ transplantation remains the only solution to many diseases, including organ failure. Approximately 110,000 patients are currently on the organ waiting list in the US alone. Most will perish while waiting for a donor organ. Despite the apparent shortage, the number of donors available for organ recovery is in the hundreds of thousands. The problem is that most of these organs are suboptimal, and without treatment must be precluded from transplantation. Our group aims to develop novel approaches to render these organs transplantable and ultimately eliminate the donor organ shortage. Our research focuses on the development of an organ culture platform, the basis of which is extracorporeal machine perfusion enabling multiple dynamic preservation modalities.
Representative project descriptions are provided below.
- We have demonstrated the first successful resuscitation and transplantation of cadaveric (1hr warm ischemic) rat livers after recovery with room temperature perfusion. This approach is directly translatable to clinical application and is functionally superior to current hypothermic preservation (static or perfusion) by enabling tissue repair and avoiding cold-induced damage. Future efforts on this front include the identification of specific mechanisms of recovery of multiple disease states including ischemic and steatotic organs; the development of mathematical models for dynamic computer-aided optimization of the protocol and perfusion media for pathology-specific targeted treatments; development of a quantitative index of organ viability; scale-up to porcine models, and implementation in human systems.
- We have further modified machine perfusion to enhance the recovery of cells from organs that are extensively injured beyond recovery for transplantation. Of particular interest is the isolation of hepatocytes, which are the key element in a number of novel cell-based alternative therapies to orthotopic transplantation, such as bioartificial liver devices, cell transplantation and tissue engineered constructs. In all cases, the lack of a reliable, abundant source of healthy human hepatocytes is a major bottleneck in translation from bench to bedside. In the recent past, we have been able to improve cell yields from these organs by 26-fold, with cells that are of equal or comparable in function to hepatocytes from fresh livers.
- In organ preservation, we are pursuing a new, enhanced approach: subzero nonfreezing for extended storage durations, with the intent to ultimately bank organs. While classic organ preservation keeps organs on ice, we are developing a perfusion protocol that enables storage at temperatures below 0°C without any freezing of the organ, suspending metabolism significantly. So far, we have stably achieved storage at -10°C with cells, and we have successfully transplanted livers stored for 24 hours at -7°C.
- In a complementary effort, we are developing perfusion methods to decellularize non-salvageable cadaveric organs to create whole-organ scaffolds for tissue engineering. The rationale here is to utilize the nature-made vascular bedding in these scaffolds, which has proven impossible to mimic with synthetic biomaterials. To date, we have been able to create reengineered livers from cadaveric rat livers that function in vitro and are transplantable in vivo.
- Uygun BE, Soto-Gutierrez A, Yagi H, Izamis ML, Guzzardi MA, Shulman CJ, Milwid J, Tilles A, Kobayashi N, Berthiaume F, Hertl M, Nahmias Y, Yarmush ML, Uygun K. Organ Re-Engineering: Development of a Transplantable Recellularized Liver Graft using Decellularized Liver Matrix. Nature Medicine 2010; 16: 814-820.
- Izamis ML, Sharma N, Uygun BE, Yarmush ML, Uygun K, Berthiaume F. In vivo Metabolic Flux Analysis: Effects of Burn Injury in Rats. Biotech Bioeng 2011; 108: 839-52.
- Nagrath D, Avila-Elchiver M, Berthiaume F, Tilles AW, Messac A, Yarmush ML. Soft constraints-based multiobjective framework for flux balance analysis. Metabol Eng 2010; 12: 429–445.
- Yagi H, Parekkadan B, Suganuma K, Soto-Gutierrez A, Tompkins RG, Tilles AW, Yarmush ML. Long term superior performance of a stem cell/hepatocyte device for the treatment of acute liver failure. Tissue Eng Part A. 2009; 15: 3377-88.
- Kidambi S, Yarmush RS, Novik E, Chao P, Yarmush ML, Nahmias Y. Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression and drug clearance. Proc Nat’l Acad Sci 2009; 106: 15714-15719.
- Tolboom H, Pouw RE, Izamis ML, Milwid JM, Soto-Gutierrez A, Nahmias Y, Uygun K, Berthiaume F, Yarmush ML, Recovery of warm ischemic livers by ex vivo normothermic perfusion. Transplantation, 87:170-7, 2009.
- Nagrath D, Xu H, Tanimura Y, Zuo R, Berthiaume F, and Yarmush ML. Metabolic preconditioning of donor organs: defatting fatty livers by normothermic perfusion ex vivo. Metabol Eng 2009; 11: 274-283.
- Cho CH, Parashurama N, Nahmias Y, Park J, Tilles AW, Yarmush ML. Homogeneous differentiation of hepatocyte-like cells from embryonic stem cells. FASEB J 2008; 22: 898-909.
- Nagrath D, Avila-Elchiver M, Berthiaume F, Tilles AW, Messac A, Yarmush ML. Integrated energy and flux balance based multiobjective framework for large-scale metabolic networks. Ann Biomed Eng 2007; 35: 863-885.
- a Tolboom H, Pouw R, Uygun K, Tanimura Y, Izamis ML, Berthiaume F, Yarmush ML. A model for normothermic preservation of the rat liver. Tissue Eng 2007; 13: 2143-2151.
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