Principals of neovascularization for tissue engineering

doi:10.1016/S0098-2997(02)00008-0

Molecular Aspects of Medicine

Volume 23, Issue 6, December 2002, Pages 463-483

https://doi.org/10.1016/S0098-2997(02)00008-0 Get rights and content

Abstract

The goals in tissue engineering include the replacement of damaged, injured or missing body tissues with biological compatible substitutes such as bioengineered tissues. However, due to an initial mass loss after implantation, improved vascularization of the regenerated tissue is essential. Recent advances in understanding the process of blood vessel growth has offered significant tools for therapeutic neovascularization. Several angiogenic growth factors including vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor (bFGF) were used for vascularization of ischemic tissues. Three approaches have been used for vascularization of bioengineered tissue: incorporation of angiogenic factors in the bioengineered tissue, seeding endothelial cells with other cell types and prevascularization of matrices prior to cell seeding. This paper reviews the process of blood vessel growth and tissue vascularization, and discuss strategies for efficient vascularization of engineered tissues.

Introduction

Organ or tissue transplantation is the common therapy for failure or loss of organs or tissues. Because of a shortage in organ donors, synthetic materials such as Teflon and silicone were introduced for the replacement or reconstruction of tissues. However, functional replacement of organs with artificial materials is limited. In the 1960s, researchers formed a new field called “Tissue engineering” in order to combine the fields of materials science with cell biology (Atala and Nyberg, 2000). The term “Tissue engineering” was introduced into the medical research for the development of biological substitutes to maintain, restore and improve functions of lost organs and tissues (Schultheiss et al., 2000; Skalak and Fox, 1988). Significant progress has been made in culturing large amounts of cells in vitro, and in the design and usage of support materials to deliver the cells in vivo (Fontaine et al., 1995). However, these were usually “single cell type” cultures and attempts to reconstruct tissues with more than one cell type were unsuccessful. A critical obstacle in tissue engineering is the ability to maintain large masses of living cells, upon transfer from the in vitro culture conditions into the host, in vivo (Mooney and Mikos, 1999). To achieve the goals of engineering large complex tissues, and possibly internal organs, vascularization of the regenerating tissue is essential. A tissue with more than a few millimeters in volume can not survive by diffusion and requires formation of new blood capillaries to supply essential nutrients and oxygen (Mooney and Mikos, 1999). Studies initiated by Judah Folkman and his colleagues in the last two decades have indicated that growing tumors, usually consisting of “single cell type”, follow the same rules. Tumors do not grow beyond a few millimeters unless they become vascularized by directing an ingrowth of capillaries from adjacent blood vessels (Folkman, 2001; Folkman and D’Amore, 1996). In addition, it was recently discovered that normal embryonic development of organs such as liver and spleen is dependent on the presence of endothelial cells (EC) and blood vessels (Lammert et al., 2001; Matsumoto et al., 2001). These studies resulted in better understanding of how the new capillaries are formed from existing vessels, a process known as angiogenesis, and the angiogenic factors that control and guide them (Folkman and Shing, 1992; Hanahan and Folkman, 1996; Risau, 1997). An alternative mode of neovascularization is the formation of new vessels from EC, and their progenitors (angioblasts). This process, called vasculogenesis, takes place mainly during embryogenesis in developing organs (Drake et al., 1998; Risau and Flamme, 1995).

This paper reviews the process of blood vessel growth and tissue vascularization and their regulation by angiogenic factors. Strategies employed for therapeutic vascularization of ischemic and bioengineered tissues will be discussed.

Section snippets

Formation of new blood vessels

Blood vessels are constructed by two processes, angiogenesis, the sprouting of capillaries from preexisting blood vessels and vasculogenesis, the in situ assembly of capillaries from undifferentiated EC. The formation of the first capillaries takes place mostly during the early stages of embryogenesis (Folkman and D’Amore, 1996; Yancopoulos et al., 1998). Early vascular plexus in the yolk sac originates from the mesoderm by differentiation of angioblasts, which subsequently generate primitive

Angiogenic growth factors

In the adult, the EC of the large vessels are usually in a quiescent stage due to cell–cell contact and inhibition of proliferation. When converting into the angiogenic phase, EC will capture new properties that facilitate tissue neovascularization (Hanahan and Folkman, 1996). Conversion of EC to the angiogenic phenotype is stimulated under special conditions, such as low oxygen levels (hypoxia), and is accompanied by: (a) changes in cell shape, which facilitate migration; (b) enhanced

Therapeutic neovascularization of ischemic tissues

The recent advances in the understanding of the angiogenic process and the isolation of potent and specific angiogenic growth factors prompted their therapeutic usage (Henry, 1999; Isner and Asahara, 1998). Angiogenic factors have been used as pharmacological agents. Earlier studies using bFGF protein showed augmentation of collateral vessel formation in a rabbit ischemic hindlimb model (Baffour et al., 1992) or in infarcted myocardium (Yanagisawa-Miwa et al., 1992). Treatment with bFGF

Neovascularization of engineered tissues

The requirements for ischemic tissue revascularization and for “de-novo” vascularization of engineered tissues share many similarities. However, while angiogenic processes taking place in ischemic limbs or infarcted myocardium have been studied extensively, studies on bioengineered tissue vascularization have not been performed until recently. Efforts have been aimed at incorporating the knowledge acquired in angiogenesis of ischemic tissues into practical approaches to vascularize

Bioengineered blood vessels

Over 400,000 coronary artery bypass grafts (CABG) and 50,000 peripheral bypass grafts are performed annually (Sayers et al., 1998). However, up to 30% of the patients who require arterial bypass surgery do not possess suitable or sufficient saphenous veins of the leg, which remains the standard conduit for coronary bypass surgery (Tu et al., 1997). Synthetic grafts are currently been used for peripheral vascular repair and the most commonly employed are polytetrafluoroethylene or Dacron

Conclusions and practical aspects

Despite the successes in bioengineering tissues consisting of thin layers of cells such as skin, a major challenge for tissue engineering in the future is the production of larger organs with more complex structures like the kidney. Tissues with a large mass of cells will require a vascular network of arteries, veins and capillaries to deliver nutrients to each cell. The development of efficient methods to vascularize bioengineered tissues is critical for a successful outcome. Three approaches

Acknowledgements

We thank Kadi Udompanyanan and James Yoo for their technical assistance in the muscle regeneration study and preparation of the figures.

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Principals of neovascularization for tissue engineering

Abstract

Introduction

Section snippets

Formation of new blood vessels

Angiogenic growth factors

Therapeutic neovascularization of ischemic tissues

Neovascularization of engineered tissues

Bioengineered blood vessels

Conclusions and practical aspects

Acknowledgements

Am. J. Ophthalmol.

J. Vasc. Surg.

Adv. Cancer Res.

J. Vasc. Surg.

Biomaterials

Semin. Oncol.

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

J. Biol. Chem.

Am. J. Cardiol.

Lancet

J. Biol. Chem.

Endocrinol. Metab Clin. North Am.

Cell

Curr. Biol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

Biochem. Biophys. Res. Commun.

Biomaterials

Prog. Growth Factor Res.

Am. J. Pathol.

Lab. Invest.

Cytokine Growth Factor Rev

Nucleotide sequence of a bovine clone encoding the angiogenic protein, basic fibroblast growth factor

Science

Establishment of heterotropic liver tissue mass with direct link to the host liver following implantation of hepatocytes transfected with vascular endothelial growth factor gene in mice

Tissue Eng.

Accelerated restitution of endothelial integrity and endothelium-dependent function after phVEGF165 gene transfer

Circulation

Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization

Circ. Res.

Isolation of putative progenitor endothelial cells for angiogenesis

Science

VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells

EMBO J.

Tissue engineering

World J. Urol.

Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects

J. Mol. Med.

Biological roles of fibroblast growth factor-2

Endocr. Rev.

Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation

Development

Structural evidence that endothelial cell growth factor beta is the precursor of both endothelial cell growth factor alpha and acidic fibroblast growth factor

Proc. Natl. Acad. Sci. USA

Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth

J. Cell Biol.

Developmental biology. One cell two fates

Nature

Growing better blood vessels

Nat. Biotechnol.

Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele

Nature

Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188

Nat. Med.

Blood vessel maturation: vascular development comes of age

J. Clin. Invest.

The angiopoietins: Yin and Yang in angiogenesis

Curr. Top Microbiol. Immunol.

The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor

Science

Morphogenesis of the first blood vessels

Ann. NY Acad. Sci.

Vascular permeability factor/vascular endothelial growth factor: an important mediator of angiogenesis in malignancy and inflammation