Table 3 Methods to develop vascularization, their advantages and disadvantages

Scaffold Functionalization

Growth factor delivery system (VEGF, bFGF, PDGF, TGF, Angiopoietin-1 and 2)

Most basic and simple method is to load or coat the growth factor of interest to the scaffold

Pre encapsulation method ensured a prolonged release of growth factors providing high degree of vascularization

Short effective half-life due to their poor stability or fast blood clearance

[49, 50]

Protein Modification techniques

High concentration use can induce cancer development

Pre-encapsulation of growth factors in dual drug delivery systems of micro or nanospheres before embedding into a scaffold

Engineered scaffold designing

Channeled scaffold prepared by incorporating phosphate based glass fibers into collagen scaffolds or by laser cutting technique

Oxygen diffusion rate, cell alignment and angiogenesis may be controlled

-

[49]

Micro patterning and molecular gradients

Improved cell viability

Cell Based Techniques

Endothelial cell co-culture

Endothelial cells introduced in the tissue via 3D multicellular spheroids or simple mixing of cultures (co-culturing)

Lumenized capillary like network develop

Functional anastomosis into host vasculature remain unsolved

[49]

Growth factor producing cells (Mesenchymal Stem Cells)

Growth factors like VEGF secreted in vivo models

Improve angiogenesis

Heterogeneity nature of MSCs and individual to individual variance major limitation that delay clinical translation of MSCs

[49, 51]

Transfection of human MSCs with VEGF-plasmid coated scaffolds

iPSCs

Co culture of hiPSC-endothelial cells and hiPSC-derived pericytes/MSCs led to development of tube like structure

Un-exhaustible cell source to form pre-vascularized systems

High chances of tumor formation due to the ‘unsafe’ iPSC lines and residual undifferentiated iPSCs in final product

[51]

Pre-vascularization

Scaffold vessel formation

Cells (generally endothelial cells) are seeded in the scaffold to form vessel like structure before implantation

Therapeutic angiogenesis can occur in a very short period of time

Endothelial cells lack high proliferative turnover in-vitro so cannot always be cultured in therapeutic quantities

[50]

Cell sheet technology

Cells seeded on a smart cell culture substrate (example—temperature responsive substrate) to produce a 2D sheet of pre vascularized tissue

No requirement of a preexisting scaffold

-

[50, 52]

Rapid wound healing

In vivo bioreactor system

A scaffold implanted subcutaneously for a period of time to allow neovascularization. Flap technique and AV-loop are two important techniques for in-vivo pre-vascularization

Increased cell survival, proliferation, and vascular infiltration

Inappropriate porous microstructure

[50]