Bioengineering blood vessels

Stephanie Smith, Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD

The fast-growing field of tissue engineering provides an interesting application of stem-cell technology to the generation of biological tissues. In recent years, we have begun to see the emergence of these techniques in a clinical context for tissue transplantation. In 2008, there was widespread interest as a patient with end-stage bronchomalacia received the first bioengineered trachea transplant (1). In this groundbreaking procedure, a donor trachea was decellularised to create a structural scaffold, seeded with the patient’s stem cells and then transplanted back into the patient. Whilst more complex than standard allograft procedures, utilising tissue engineering techniques in this way has the significant advantage tissue rejection avoidance – and thereby reducing the requirement for immunosuppressant drugs.

Blood vessels, much like the trachea, have a relatively simplistic, cylindrical structural basis (compared to the intrinsic complexity of solid organs, such as the liver) - therefore making them an attractive target for the next wave of research in this field. Moreover, synthetic vascular replacement attempts using materials such as polyethylene terephthalate and expanded polytetrafluoroethylene have not been entirely successful, with poor vessel patency being an issue in some cases (2). In a paper published in June’s issue of the Lancet (3), Olausson et al. present proof-of-concept results that bring promise for clinical transplantation of bioengineered blood vessels, providing a 21st century twist on the well-established principle of vascular bypass surgery.

Up to 80% of children with extra-hepatic portal vein obstruction will suffer from potentially fatal upper gastro-intestinal haemorrhagic complications during their lifetime as a complication arising from portal hypertension (4), presenting a significant clinical challenge. Surgical guidelines recommend bypass procedure using an autologous vein (known as the meso Rex bypass) to restore portal blood flow (5). However, the procedure is not always successful, in which case allograft vessels may be required for the bypass – requiring immunosuppressant drugs to avoid tissue rejection. The findings of Olausson et al. suggest using tissue engineering may provide a safer alternative to allograft procedures in patients where standard autologous transplantation is unsuccessful.

A 9cm iliac vein segment was obtained from an organ donor and decellularised. Following this, the vessel was recelluarised with autologous endothelial and smooth muscle cells derived from patient stem cells (obtained from the bone marrow of the patient). The recellularised vessel was then transplanted into the patient to perform a “meso Rex” bypass. The patient in the case report was a 10 year old girl diagnosed with extrahepatic portal vein obstruction (3).

The graft successfully provided a functional blood supply in the portal vein, with the patient having normal laboratory values for 9 months. It is believed that the improved patency of the recellularised engineered vessel compared to synthetic materials is due to the presence of a functional endothelium and the myriad of regulatory factors that it produces. Of particular note, as predicted, the patient did not mount an immune response to the graft as assessed by the presence of anti-donor HLA antibodies. The patient gained an improved quality of life as a result of the procedure (3), demonstrating improved exercise tolerance and cognitive improvements (more articulate speech and increased concentration).

It should be noted that the results described by Olausson et al, whilst promising, are based on the case of a single patient – future clinical trials will be required to provide a more meaningful evaluation of the procedure. In addition, some argue that the procedure is currently too slow and expensive to be implemented on a practical level in the clinic. However, reductions in the number of steps in the preparatory process are already happening, particularly with regard to decellularisation protocols (2) – perhaps if the trend continues, this may translate to eventual success in the health-care market. The direct application of tissue-engineered vascular transplantation presented in the study is the treatment of extrahepatic portal vein obstruction. Other applications of the technique could provide elegant surgical solutions to numerous vascular problems, from coronary artery disease through to diabetic vascular deficit. Despite its limitations, the work of Olausson et al. presents more than simply a tissue engineering breakthrough - the study provides one more step forward along the path toward personalised medicine.

References: 

1. Macchiarini P, Jungebluth P, Go T, Asnaghi MA, Rees LE, Cogan TA, Dodson A, Martorell J, Bellini S, Parnigotto PP, Dickinson SC, Hollander AP, Mantero S, Conconi MT, Birchall MA. Clinical transplantation of a tissue-engineered airway. Lancet. 2008 Dec 13;372(9655):2023-30.
10.1016/S0140-6736(08)61598-6 r
10.1016/S0140-6736(08)61598-6

2. Birchall M, Hamilton G. Tissue-engineered vascular replacements for children. Lancet. 2012 [Epub ahead of print] doi:10.1016/S0140-6736(12)60817-4

3. Olausson M, Patil PB, Kuna VK, Chougule P, Hernandez N, Methe K, Kullberg-Lindh C, Borg H, Ejnell H, Sumitran-Holgersson S. Transplantation of an allogeneic vein bioengineered with autologous stem cells: a proof-of-concept study. Lancet. 2012 Jun 13. [Epub ahead of print]
doi:10.1016/S0140-6736(12)60633-3

4. Mack CL, Zelko FA, Lokar J, Superina R, Alonso EM, Blei AT, Whitington PF. Surgically restoring portal blood flow to the liver in children with primary extrahepatic portal vein thrombosis improves fluid neurocognitive ability. Pediatrics. 2006 Mar;117(3):e405-12. 10.1542/peds.2005-1177

5. Superina R, Shneider B, Emre S, Sarin S, de Ville de Goyet J. Surgical guidelines for the management of extra-hepatic portal vein obstruction. Pediatr Transplant. 2006 Dec;10(8):908-13. 10.1111/j.1399-3046.2006.00598.x

Story image (human bone marrow derived mesenchymal stem cells) taken from Wikimedia Commons