Tissue Engineering of the Microvasculature The ECM Holds the

One of the greatest current challenges in biomedical science is to refine and apply tissue-engineering technologies to correct a variety of human diseases. Among the most significant limitations to generating tissue equivalents are the difficulties inherent in endowing such implants with suitable vasculatures. Although much progress has been made in the arena of large-diameter vascular conduits, technologies to develop the microvasculature are in their infancy. However, the necessity of the microvasculature is evidenced by the observation that most cells must be within @ 100 mm or so from a capillary, and in some cases (e.g., those tissues with high metabolic rates such as skeletal or cardiac muscle myocytes), may require even greater proximity (e.g., @ 50 mm). Difficulties in engineering of the microvasculature include its complex arrangement, diminutive size, and fragility. For example, the smallest module of the microvasculature is the capillary bed, which typically consists of a thoroughfare channel that passes between an arteriole and a venule, but which also feeds a fine honeycomb-like arrangement of capillary tubes. Depending on the metabolic needs of the tissue, precapillary sphincters, arranged at the junctures between the arterioles and the capillary network, may control the flow into the capillaries. The diameters of these vessels range from @ 50 mm for arterioles (Figure 1) down to 5 or less mm for true capillaries, which do not contain associated smooth muscle cells or pericytes.

Examination of the microvasculature of even relatively modest-sized tissues (e.g., the wing of the little brown bat Myotis lucifigus) reveals a remarkably complex structure, containing more than 2,500 distinct blood vessels ranging anywhere from @ 4 to 75 mm in diameter. To fashion such a vasculature within an engineered tissue in a directed way seems daunting, and it would be of great advantage to tissue engineers if the assumption that the development of the vascular bed is dictated by the parenchymal tissues that surround it proves to be correct. In other words, if a tissue equivalent is seeded with the proper parenchymal and supportive cells (i.e., vascular cells and others such as fibrob-lasts), the capability can be created to sort and undergo morphogenesis into the proper tissue arrangement. For instance, mixtures of EC and fibroblasts cultured on cross-linked mats of chitosan-chondroitin sulfate-collagen form dermis-like tissues, complete with what appeared to be microvessels, which developed in the vicinity of fibroblast-and ECM-rich regions. However, it is currently unclear if such tissues are endowed with native-type microvascula-tures. Moreover, if such a tissue equivalent were transplanted into a host animal, it is uncertain whether the vasculature of the implant would be capable of anastomosing with that of the host. As with this latter example, to date, attempts to engineer the microvasculature have largely involved use of the ECM-binding growth factors and/or ECM scaffolds as key tools.

A predominant approach toward engineering the microvasculature involves attempting to stimulate vascular regeneration by promoting the growth or regeneration of the endogenous vasculature in ischemic tissues. Such methods have mainly involved delivering angiogenic growth factors, such as FGF-2 or VEGF, to tissues either by injection or sustained polymer-based release; as mentioned earlier, these factors work in concert with extracellular or cell surface proteoglycans to exert their activities. The current literature demonstrates that such approaches hold much promise in promoting microvascular regeneration in ischemic tissues, and many reviews discuss these findings, so this topic will not be further discussed.

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