A study of seriously ill patients on kidney dialysis who were the first to receive tissue grafts engineered from their own adult cells has delivered promising results. The long-awaited findings are reported in an Article published in this week's edition of The Lancet, written by Dr Todd N McAllister, Cytograft Tissue Engineering, Novato, California, USA, and colleagues.
Currently about half of all dialysis patients have their blood filtered three times weekly via a plastic tube that creates a 'shunt' or bypass between the arterial and venous circulation. These tubes are prone to significantly higher failure rates than those created from the patient's own vein segment — however only around half of patients have vein segments suitable for making a shunt, meaning the other half need plastic tubes. In this regenerative medicine study, patients lacking suitable vein segments had an engineered blood vessel grown from cells harvested from their own skin (an autologous graft). In a departure from most regenerative medicine approaches, the blood vessels were built exclusively from the patient's cells, without the inclusion of synthetic scaffolds or exogenous biomaterials (such as pieces of plastic to act as support). The mechanical strength usually provided by such synthetic materials was in this study provided by the grafts themselves. The authors propose that this is key to maintaining graft viability in the long-term.
This pioneering study looked at 10 patients from centres in Buenos Aires, Argentina, and Katowice, Poland, enrolled between 2004 and 2007. All were older than 21 years and had either had a previous graft failure, or were candidates for a plastic tube graft — but instead received a graft made from their own cells. The grafts were grown1, and implanted as arteriovenous shunts. Grafts were then assessed for both mechanical stability during the safety phase (0-3 months) and effectiveness after haemodialysis was started.
The researchers found that three grafts failed within the safety phase, which is consistent with failure rates expected for this high-risk patient population. One patient was withdrawn from the study because of severe gastrointestinal bleeding shortly before implantation, and another died of unrelated causes during the safety period with a functioning graft. The remaining five patients had grafts functioning for haemodialysis for between six and 20 months after implantation, giving a total of 68 patient-months of patency2. In these five patients, only one intervention (surgical correction) was needed to maintain secondary patency. Overall, primary patency was maintained in seven (78%) of the surviving nine patients one month after implantation, and five (over 60%) of the surviving eight patients six months after implantation. These figures are close to the objectives of the Dialysis Outcomes Quality Initiative3 of about 76% three months after implantation.
The authors explain that they chose an arteriovenous kidney shunt over, for example, a leg bypass shunt for their work because frequent haemodialysis visits allowed excellent graft surveillance and provided an opportunity for early intervention if the graft showed signs of failure. Also, in these patients graft failures are rarely threatening to life or limb, with several clinical options available for urgent haemodialysis.
The authors say*: "This study demonstrated that we can provide the requisite mechanical strength in a tissue engineered construct without relying upon synthetic biomaterials. The exclusion of these foreign materials may have critical advantages for long term efficacy by reducing the inflammatory or rejection responses typically associated with synthetics. The fact that our long-term intervention rate was so low, even with this high risk group, offers hope to patients suffering from end stage renal disease, and is an encouraging sign from a cost-effectiveness perspective."
In an accompanying Comment, Dr Vladimir Mironov, Medical University of South Carolina, Charleston, SC, USA, and Professor Vladimir Kasyanov, Riga Stradins University, Riga, Latvia, discuss that the potential high cost of tissue-engineered grafts is a concern. They conclude: "Further optimisation and simplification of the original cell-sheet technology4 and the use of rapid biofabrication processes could eventually lead to a clinically and commercially successful product. The successful clinical testing of the first commercial tissue-engineered vascular graft is a revolutionary milestone, manifesting the emergence of clinical vascular tissue engineering."
Dr Todd N McAllister, Cytograft Tissue Engineering, Novato, California, USA T) +1 415-506-0240 / +1 415-299-7793 E) todd@cytograft.com
Dr Vladimir Mironov, Medical University of South Carolina, Charleston, SC, USA T) +1 843-792-7630 E) mironovv@musc.edu
For full Article and Comment see: http://press.thelancet.com/kidneytissuegraftfinal.pdf
Also see http://press.thelancet.com/vesselpic.JPG for a picture of the vessel prior to implantation, with the blue 'suture' thread used to attach it to the patient's circulation. You may use this picture in your publications/broadcasts, please credit Cytograft Tissue Engineering
Notes to editors:
1 for full detailed of graft production, see p2, full Article: Procedures.
2 patency is a term to express the viability of the graft. A graft is considered patent if it there is considered to be sufficient blood flowing through it, and it does not have a significant blockage (stenosis).
3 This is an initiative organised by the US National Kidney Foundation to improve dialysis outcome
4 cell-sheet technology: the exact technology used in this study is called sheet-based tissue engineering. In SBTE, cells from the skin are cultured in the lab in conditions that promote production of proteins such as collagen. The cells become embedded in the proteins they secrete, and, after a few weeks, a sheet of collagen/cells is produced. This can then be peeled from the vessel/flask and rolled or stacked to form more complex 3D tissues with high mechanical strength.
*Quote direct from authors and cannot be found in the text of the Article
Journal
The Lancet