Integrated approaches to spatiotemporally directing angiogenesis in host and engineered tissues

Abstract

The field of tissue engineering has turned towards biomimicry to solve the problem of tissue oxygenation and nutrient/waste exchange through the development of vasculature. Induction of angiogenesis and subsequent development of a vascular bed in engineered tissues is actively being pursued through combinations of physical and chemical cues, notably through the presentation of topographies and growth factors. Presenting angiogenic signals in a spatiotemporal fashion is beginning to generate improved vascular networks, which will allow for the creation of large and dense engineered tissues. This review provides a brief background on the cells, mechanisms, and molecules driving vascular development (including angiogenesis), followed by how biomaterials and growth factors can be used to direct vessel formation and maturation. Techniques to accomplish spatiotemporal control of vascularization include incorporation or encapsulation of growth factors, topographical engineering, and 3D bioprinting. The vascularization of engineered tissues and their application in angiogenic therapy in vivo is reviewed herein with an emphasis on the most densely vascularized tissue of the human body - the heart.

Statement of significance: Vascularization is vital to wound healing and tissue regeneration, and development of hierarchical networks enables efficient nutrient transfer. In tissue engineering, vascularization is necessary to support physiologically dense engineered tissues, and thus the field seeks to induce vascular formation using biomaterials and chemical signals to provide appropriate, pro-angiogenic signals for cells. This review critically examines the materials and techniques used to generate scaffolds with spatiotemporal cues to direct vascularization in engineered and host tissues in vitro and in vivo. Assessment of the field's progress is intended to inspire vascular applications across all forms of tissue engineering with a specific focus on highlighting the nuances of cardiac tissue engineering for the greater regenerative medicine community.

Keywords: Angiogenesis; Biomaterials; Cardiac tissue; Growth factors; Tissue engineering; Vascularization.

Figure 1

Temporally controlled, overlapping, parallel, and repetitive signaling events (abridged) in angiogenesis and its role in the wound healing response. Examples of activated factors are listed below each stage of wound healing. Ang: Angiopoietin; bFGF: Basic fibroblast growth factor; EGF: Epidermal growth factor; bFGF: Basic fibroblastic growth factor; IL-1: Interleukin-1; MMPs: Matrix metalloproteinases; PDGF: Platelet-derived growth factor; SHH: Sonic hedgehog; TGF-ß: Transforming growth factor beta; TNF: Tumor necrosis factor; VEGF: Vascular endothelial growth factor.

Figure 2

Spatiotemporal control of angiogenesis can be achieved through the presentation of chemical and physical cues. This can be categorized into four distinct categories, which is further differentiated by the techniques utilized to present spatiotemporal cues within each category. Combinations of these techniques are often utilized to precisely engineer vessel network formation using chemical and physical cues integrated in one system. Of interest to note is the similarity in techniques used to present chemical cues in the matrix incorporation and encapsulation methods, the distinction being one related to material choice and design.