Tissue engineering for the treatment of intracranial aneurysms

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By Alim Mitha and David Kallmes

Endovascular coiling has made a huge impact on the treatment of intracranial aneurysms. Since the advent of the GDC coil 25 years ago, there has been growing body of evidence that support its use over surgical clipping in subarachnoid haemorrhage, and consequently its popularity has grown in the treatment of unruptured aneurysms as well. Now, more aneurysms than ever before are being coiled and volumes will increase further as coil and catheter technology continues to improve.

The major drawbacks of endovascular coiling, however, are the high recurrence and retreatment rates for treated aneurysms. Recurrence tends to be associated with size of the aneurysm, rupture status, packing density, as well as whether a remnant of the aneurysm remains after the procedure. Hand in hand with the recurrence risk associated with coiling is the requirement for lifelong imaging in these patients and possibly retreatment procedures, as well as the financial cost associated with them. Recent studies have demonstrated retreatment rates on the order of 20 to 30%.3,8 For the patient, this results in an emotional burden of living with the knowledge that their aneurysm has recurred and the uncertainty that this brings. Modifications to coils have attempted to address these high recurrence rates, such as PGLA or expandable hydrogel coatings, but have not proved successful.

The key to successfully addressing these high recurrence rates lies within the growing body of knowledge on the pathogenesis of aneurysm formation. We have learned in recent years that aneurysm formation likely begins with a haemodynamically triggered dysfunction of the endothelial layer; inflammation ensues, along with degradation of the extracellular matrix, reduced collagen synthesis, and thinning of the medial layer, eventually resulting in apoptosis and loss of cellular components of the blood vessel wall.2 The cells most affected by this process include the endothelium, fibroblasts (responsible for fibrin and collagen production), and vascular smooth muscle cells (which provide structural support to the wall). Although endovascular coiling helps to recover some of the deficient cell types through intra-aneurysmal thrombosis and healing, clearly the process is incomplete. Therefore, addressing these high recurrence rates may require coil modifications that “boost” a specific component of the healing response leading to more complete replenishment of cell types that are present in the healthy vessel wall.        

Tissue engineering is a process whereby cells are harvested, modified in some way outside the body, and then re-introduced to the site of disease typically on a scaffold. We are fortunate to be able to work with devices everyday, such as stents and coils that can act as scaffolds for the delivery of cells to the site of the aneurysm. Other forms of tissue engineering include surface modifications of these coils and stents to attract certain cell types in larger numbers than would typically be found during the physiologic healing process. Delivery of cells is also not limited to scaffolds, but can be done intra-arterially, intrathecally, or even intravenously. Cells used for tissue engineering can be from xenogeneic, allogeneic, or autologous sources; from a regulatory perspective, however, allogeneic or autologous cells that do not require immunosuppression are clearly more desirable.  

The concept of tissue engineering to augment the healing of intracranial aneurysms is not a new one. Coils containing viable synovial fibroblasts have previously been injected into experimental aneurysms in a rabbit model, demonstrating increased presence of fibroblasts in the pericoil histology compared with no nucleated cells seen in control animals treated with bare platinum coils.7 Vascular smooth muscle cells have also been tried, but with only modest success.6,9 Endothelial cells or their precursors are also possible candidates since experimental aneurysms injected with these cells have shown improved neointima formation, which may reduce aneurysm recurrence.1,4,5 More recently, mesenchymal stem cells, which are known to have tremendous regenerative potential, have been evaluated as a possible therapy for intracranial aneurysms.10 Further research studies, however, are needed to more clearly determine whether one of these cell types is clearly a better candidate than the others, or whether a combination of cells may be required to improve aneurysm healing.

There are obvious practical questions that need to be answered prior to considering tissue engineering as a viable option for preventing aneurysm recurrence. What is the safety profile of using allogeneic or autologous cells? How will these cells be best delivered to the aneurysm to achieve a beneficial therapeutic effect? How will these cells be stored and handled prior to implantation, and will these storage and handling requirements preclude their use in cases of ruptured aneurysms? Perhaps most importantly, does it have the potential to be a cost-effective solution for preventing aneurysm recurrence? Some of these questions, such as the safety issues, may be addressed as tissue engineering becomes progressively more popular for the treatment of other diseases as well.

In summary, the growing knowledge of the pathogenesis of intracranial aneurysms will be crucial to our understanding of how best to provide a durable endovascular treatment. The concept of using tissue engineering to replenish deficient cell types and, in turn, to help reduce recurrence and retreatment rates of coiled aneurysms is clearly in its infancy, and may be one way to achieve this. As clinicians we can agree that endovascular coiling today is an excellent way to treat aneurysms; as investigators, however, we should remain committed to the idea that we can always do better for our patients.


Alim P Mitha is Cerebrovascular and Endovascular Neurosurgeon at the Foothills Medical Centre in Calgary, Canada. David F Kallmes is an Interventional Neuroradiologist at the Mayo Clinic in Rochester, Minnesota, USA. Both have research interests in tissue engineering techniques for intracranial aneurysms.


References

Aronson JP and Mitha AP et al, A novel tissue engineering approach using an endothelial progenitor cell-seeded biopolymer to treat intracranial saccular aneurysms. J Neurosurg 2012;117:546–554. 

Chalouhi N et al, Biology of intracranial aneurysms: role of inflammation. J Cereb Blood Flow Metab 2012;32:1659–1676.

Dorfer C et al, Management of residual and recurrent aneurysms after initial endovascular treatment. Neurosurgery 2012;70:537–553.

Fang X et al, Bone marrow-derived endothelial progenitor cells are involved in aneurysm repair in rabbits. J Clin Neurosci 2012;19:1283–1286.

Li Z-F et al, Endothelial progenitor cells contribute to neointima formation in rabbit elastase-induced aneurysm after flow diverter treatment. CNS Neurosci Ther 2013;19:352–357.

Marbacher S et al, Intraluminal Cell Transplantation Prevents Growth and Rupture in a Model of Rupture-Prone Saccular Aneurysms. Stroke 2014;45:3684–3690.

Marx WF et al, Endovascular treatment of experimental aneurysms by use of biologically modified embolic devices: Coil-mediated intraaneurysmal delivery of fibroblast tissue allografts. Am J Neuroradiol 2001;22:323–333.

Ogilvy CS et al, Validation of a System to Predict Recanalization After Endovascular Treatment of Intracranial Aneurysms. Neurosurgery 2015;77:168–173.

Raymond J et al, Fibrinogen and vascular smooth muscle cell grafts promote healing of experimental aneurysms treated by embolization. Stroke 1999;30:1657–1664.

Rouchaud A et al, Autologous mesenchymal stem cell endografting in experimental cerebrovascular aneurysms. Neuroradiology 2013;55:741–749.