Engineered Blood Vessels
Patents with Abstracts
“Surgical treatment of vascular disease has become common, creating the need for a readily available, small-diameter vascular graft. Many patients who are in need of bypass surgery do not possess sufficient veins to act as replacements for their diseased arteries. Such medical realities have propagated efforts to engineer biological replacements for such arteries. The characteristics proposed for an "ideal" engineered small diameter artery include the following: it should be biocompatible, that is, non-thrombogenic and non-immunogenic, be able to simulate the physical attributes of arteries, i.e. elasticity, contractility, compliance (viscoelasticity), adequate strength, physiological transport properties (i.e. appropriate permeability to solutes and cells), and be resistant to infection as well (Mayer, J. E. et al, 2001; Conte, M. S., 1998; Niklason, L. E., 1999; Nerem, R. M., 2000). All of these characteristics are associated with a confluent, non-activated endothelium. Moreover, these characteristics ultimately result in an acceptable wound healing response without fibrosis.
Weinberg and Bell pioneered the first attempt at building blood vessels by demonstrating the feasibility of creating an adventitia-like layer made from fibroblasts and collagen, a media-like layer made from smooth muscle cells ("SMCs") and collagen, and an intima-like endothelial cell ("EC") layer constructed into a tubular configuration. In order to withstand physiological pressures, these constructs required support sleeves made from Dacron.TM., a synthetic material (Weinberg, C. B. and Bell, E., 1986) having biocompatibility issues.
Other approaches are currently being investigated, several of which do not involve the use of synthetic materials. One such approach is acellular, based on implanting decellularized tissues treated to enhance biocompatibility, strength, and cell adhesion/invasion leading to cellularization with host cells (Huynh, T. et al, 1999). It has yet to be elucidated whether these acellular grafts will elicit an inflammatory response in humans, and whether they will develop the host EC layer. Badylak and coworkers also attempted to use an implanted noncellular construct consisting of a rolled small intestinal submucosa (SIS) as a small diameter vascular graft, which serves to recruit cells from surrounding host tissue (Badylak, S. et al, 1999). However, as with other acellular studies, this study suffered from a lack of non-thrombogenic EC lining on the lumen of the graft.
Other approaches involve implantation of constructs possessing some degree of cellularity. The most recent of these is based on the concept of "self-assembly" wherein SMCs are grown to overconfluence on tissue culture plastic in medium inducing high extracellular matrix (ECM) synthesis (L'Heureux, N. et al, 1998; L'Heureux, N. et al, 2001). This leads to sheets of "neo-tissue" which are subsequently processed into multi-layer tubular form resembling the medial layer. The tube is cultured to maturity over a time span of 8 weeks. During maturation, the cells assumed a circumferential orientation and produced large amounts of ECM. While these artificial vessels could withstand impressive pressure stress, displaying rupture strengths comparable to those of native human coronary arteries, when grafted into a dog transplant model, the vessels displayed a 50% thrombosis rate after one week of implantation. This may be attributed to xenograft rejection.
Other approaches rely on a polymeric scaffold. One is based on forming a tube of a synthetic biodegradable polyglycolic acid polymer mesh and then seeding aortic SMCs and culturing it for a period of time, relying on active cell invasion or an applied pulsatile force to achieve cellularity (Shinoka, T. et al, 1998; Niklason, L. E. et al, 1999; Shinoka, T. et al, 2001; Niklason, L. E. et al, 2001). The other is based on a tube of a biopolymer formed with and compacted by tissue cells, where an appropriately applied mechanical constraint to the compaction yields circumferential alignment of fibrils and cells characteristic of the arterial medial layer (L'Heureux, N. et al, 1993; Barocas, V. H. et al, 1998; Seliktar, D. et al, 2000). However, the constructs lacked burst strength.”
[Tranquillo, Ross and Reyes, US Patent 8,192,288 (6/5/2012)]
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Roger D. Corneliussen
Maro Polymer Links
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Copyright 2012 by Roger D. Corneliussen.
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* Date of latest addition; date of first entry is 6/18/2012.