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Cellular Based Strategies for Microvascular Engineering

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Abstract

Vascularization is a major hurdle in complex tissue and organ engineering. Tissues greater than 200 μm in diameter cannot rely on simple diffusion to obtain nutrients and remove waste. Therefore, an integrated vascular network is required for clinical translation of engineered tissues. Microvessels have been described as <150 μm in diameter, but clinically they are defined as <1 mm. With new advances in super microsurgery, vessels less than 1 mm can be anastomosed to the recipient circulation. However, this technical advancement still relies on the creation of a stable engineered microcirculation that is amenable to surgical manipulation and is readily perfusable. Microvascular engineering lays on the crossroads of microfabrication, microfluidics, and tissue engineering strategies that utilize various cellular constituents. Early research focused on vascularization by co-culture and cellular interactions, with the addition of angiogenic growth factors to promote vascular growth. Since then, multiple strategies have been utilized taking advantage of innovations in additive manufacturing, biomaterials, and cell biology. However, the anatomy and dynamics of native blood vessels has not been consistently replicated. Inconsistent results can be partially attributed to cell sourcing which remains an enigma for microvascular engineering. Variations of endothelial cells, endothelial progenitor cells, and stem cells have all been used for microvascular network fabrication along with various mural cells. As each source offers advantages and disadvantages, there continues to be a lack of consensus. Furthermore, discord may be attributed to incomplete understanding about cell isolation and characterization without considering the microvascular architecture of the desired tissue/organ.

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Abbreviations

AdEPC:

Adipose derived EPC

ANG:

Angiopoietin

AVL:

Arteriovenous loop

bFGF:

Basic fibroblast growth factor

BM:

Bone marrow

Dll4:

Delta-like 4

DMVEC:

Dermal microvascular endothelial cell

EB:

Embryoid body

EC:

Endothelial cell

ECFC:

Endothelial colony forming cell

ECM:

Extracellular membrane

eNOS:

Endothelial nitric oxide synthase

EPC:

Endothelial progenitor cell

ESC:

Embryonic stem cell

FGF:

Fibroblast growth factor

FLK-1:

Fetal liver kinase-1

HA:

Hydroxyapatite

HGF:

Hepatocyte growth factor

HIF:

Hypoxia-inducible factor

HUVEC:

Human umbilical vein umbilical cell

iPSC:

Induced pluripotent stem cell

MC:

Methylcellulose

MF:

Microvessel fragment

MMP:

Matrix metalloproteinase

MSC:

Mesenchymal stem cell

NHLF:

Normal human lung fibroblast

PCL:

Polycaprolactone

PDMS:

Polydimethylsiloxane

PECAM:

Platelet endothelial cell adhesion molecule

PEG:

Poly ethylene glycol

PLGA:

Poly(lactide-co-glycolide)

PNIPAAm:

Poly n-isopropyl acrylamide

SMA:

Smooth muscle actin

SVF:

Stromal vascular fraction

TCP:

Tri-calcium phosphate

TGF:

Transforming growth factor

TIMP:

Tissue inhibitor of metalloproteinase

VE:

Vascular endothelial

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

vWF:

von Willebrand factor

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Acknowledgements

This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under BIRCWH award # K12HD055882 “Career Development Program in Women’s Health Research at Penn State”, the American Association of Plastic Surgeons Research Scholar Award, and a Penn State Junior Faculty Research Scholar Award (PA Tobacco Settlement Fund).

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Authors and Affiliations

  1. Irvin S. Zubar Plastic Surgery Research Laboratory, Penn State College of Medicine, Hershey, PA 17033, USA

    Srinivas V. Koduru, Ashley N. Leberfinger, Denis Pasic & Dino J. Ravnic

  2. Department of Surgery, Division of Plastic Surgery, Penn State Health Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA, 17033, USA

    Srinivas V. Koduru, Ashley N. Leberfinger, Denis Pasic, Shane Lince & Dino J. Ravnic

  3. Department of Biomedical Engineering, Materials Research Institute, The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA, USA

    Anoosha Forghani, Daniel J. Hayes & Ibrahim T. Ozbolat

  4. Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, PA, USA

    Ibrahim T. Ozbolat

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Koduru, S.V., Leberfinger, A.N., Pasic, D. et al. Cellular Based Strategies for Microvascular Engineering. Stem Cell Rev and Rep 15, 218–240 (2019). https://doi.org/10.1007/s12015-019-09877-4

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