Mimicking the physical cues of the ECM in angiogenic biomaterials

Abstract

A functional microvascular system is imperative to build and maintain healthy tissue. Impaired microvasculature results in ischemia, thereby limiting the tissue's intrinsic regeneration capacity. Therefore, the ability to regenerate microvascular networks is key to the development of effective cardiovascular therapies. To stimulate the formation of new microvasculature, researchers have focused on fabricating materials that mimic the angiogenic properties of the native extracellular matrix (ECM). Here, we will review biomaterials that seek to imitate the physical cues that are natively provided by the ECM to encourage the formation of microvasculature in engineered constructs and ischemic tissue in the body.

Keywords: angiogenesis; biomaterial–cell interaction; materials signal; vascular.

Figure 1.

ECs in the native ECM respond to physical cues that are transduced through the architecture of fibrous structural proteins and receptor-binding peptides contained within the ECM. These physical cues should be incorporated into natural and synthetic matrices to create better angiogenic biomaterials and thereby maximize microvascular recovery

Figure 2.

An intermediate concentration of ECM proteins is essential for robust microvascular regeneration. (A) Increasing collagen density abolished the growth of microvessels in both an experimental setup (microvessels are labeled with isolectin IB4-Alexa 488) and a computational model (microvessels are outlined in red). Reprinted from [26] with permission. (B) Increasing diffusivity encourages the transport of pro-angiogenic molecules, stimulating sprouting angiogenesis. Reprinted from [23] with permission from Cell Press

Figure 3.

Modeling in vitro sprouting angiogenesis using EC-coated spheroids embedded in hydrogels of varying stiffness reveals conflicting behavior. (A) ECs in glycated collagen hydrogels show increased sprouting and maintain a larger projected area in stiffer hydrogels. (B) ECs in calcium-crosslinked collagen/alginate hybrid hydrogels show a decreased angiogenic response in stiffer hydrogels; this trend holds irrespective of ECM density. Reprinted from [42] and [45], respectively, with permission from Elsevier

Figure 4.

Materials with viscoelastic properties better recapitulate the mechanical milieu of the native ECM. (A) Alginate crosslinked covalently with adipic acid dihydrazide remained mostly elastic. In contrast, alginate crosslinked via calcium dissipated more than half of the absorbed stress within minutes. Reprinted from [66] with permission from Elsevier. (B) By introducing lower molecular weight alginate and PEG spacers, Chaudhuri et al. were able to create biomaterials that more closely mimicked the natural viscoelastic properties of the ECM. Reprinted from [67] with permission from Nature Publishing Group. (C) An IPN of collagen and hydrazone-bonded hyaluronic acid promoted cell spreading and fiber remodeling. Reprinted from [69] with permission from Elsevier

Figure 5.

The degradability of the ECM regulates vascular morphogenesis. (A) Decreasing the degradability of methacrylated dextran hydrogels by reducing their susceptibility to MMP-mediated degradation increased the number of multicellular sprouts (cyan highlights F-actin expression). Stiffness remained constant at ∼1 kPa. Reprinted from [83] with permission. (B) Aprotinin, a small molecule commonly used to stabilize fibrin hydrogels, slowed degradation and impaired the ability of mCherry-HUVECs to form vascular networks. Reprinted with permission from [84]

Figure 6.

Controlling cell-integrin interactions regulates EC morphogenesis. (A) cRGD peptide and anti-$\mathrm{\alpha }$5 antibodies block the initiation of vasculogenesis in fibrin hydrogels. Reprinted from [94] with permission from Elsevier. (B) GFOGER-modified PEG hydrogels implanted in a radial bone defect showed significantly increased vascularization when compared to RGD-modified PEG hydrogels, even in the absence of growth factors. Reprinted from [96] with permission from John Wiley and Sons. (C) ${\mathrm{\alpha }}_3/{\mathrm{\alpha }}_5{\mathrm{\beta }}_1$- and ${\mathrm{\alpha }}_{\mathrm{v}}{\mathrm{\beta }}_3$-specific hyaluronic acid-based matrices implanted in a murine Matrigel plug assay differentially regulate the topology of Isolectin-AF488 labeled neovessels. Reprinted by permission from Springer Nature [99]