Elsevier

Acta Biomaterialia

Volume 41, 1 September 2016, Pages 17-26
Acta Biomaterialia

Review article
Vascularization of three-dimensional engineered tissues for regenerative medicine applications

https://doi.org/10.1016/j.actbio.2016.06.001Get rights and content

Abstract

Engineering of three-dimensional (3D) tissues is a promising approach for restoring diseased or dysfunctional myocardium with a functional replacement. However, a major bottleneck in this field is the lack of efficient vascularization strategies, because tissue constructs produced in vitro require a constant flow of oxygen and nutrients to maintain viability and functionality. Compared to angiogenic cell therapy and growth factor treatment, bioengineering approaches such as spatial micropatterning, integration of sacrificial materials, tissue decellularization, and 3D bioprinting enable the generation of more precisely controllable neovessel formation. In this review, we summarize the state-of-the-art approaches to develop 3D tissue engineered constructs with vasculature, and demonstrate how some of these techniques have been applied towards regenerative medicine for treatment of heart failure.

Statement of Significance

Tissue engineering is a promising approach to replace or restore dysfunctional tissues/organs, but a major bottleneck in realizing its potential is the challenge of creating scalable 3D tissues. Since most 3D engineered tissues require a constant supply of nutrients, it is necessary to integrate functional vasculature within the tissues in order to facilitate the transport of nutrients. To address these needs, researchers are employing biomaterial engineering and design strategies to foster vessel formation within 3D tissues. This review highlights the state-of-the-art bioengineering tools and technologies to create vascularized 3D tissues for clinical applications in regenerative medicine, highlighting the application of these technologies to engineer vascularized cardiac patches for treatment of heart failure.

Introduction

In the United States, congestive heart failure accounts for over 300,000 deaths in the US annually and $39 billion in total hospital burden [1]. With the increasing demand for heart transplantation [2], meeting this demand with current heart transplantation approaches is becoming increasingly difficult. To address this limitation, the field of tissue engineering has made notable progress towards regenerative medical approaches to repair damaged or diseased myocardium using a combination of biocompatible materials and patient-specific cells grown in the laboratory [3], [4]. However, the biggest hurdle for the clinical translation of three-dimensional (3D) tissue engineered constructs is their functional vascularization. 3D engineered myocardial tissues require a constant supply of oxygen and nutrients, as well as a route to remove wastes that are generated in the tissue, in order to maintain long-term survival and functionality. In vivo, living cells must be within 100–200 μm from a blood capillary in order to survive and function [5], due to the diffusion limit of oxygen through biological tissues [6]. Thus, when designing 3D myocardial tissue in vitro, it is critical to consider this requirement in order to prevent significant cell death and promote optimal cell function. Furthermore, the strategy to induce vascularization should be compatible with integration into the host’s circulatory system.

The realization of efficient, robust and reproducible methods to provide relatively large tissue-engineered constructs with functional vasculature will facilitate the mass production and widespread adoption of such constructs for clinical applications. As such, much financial and intellectual investment on this front continues to be made [7]. This review will highlight the latest progress and most promising vascularization strategies in tissue engineering to date, highlighting the application of these strategies towards engineering vascularized cardiac tissue.

Section snippets

Development: vasculogenesis to angiogenesis

Physiologically, human vasculature is composed of several cell types that function concurrently to provide specific mechanical and chemical microenvironments for the optimal transport of blood and nutrients throughout the body [8]. Successful in vitro vascularization strategies are dependent on their ability to most closely mimic in vivo physiology. Thus, it is crucial to comprehensively understand the biological properties of native blood vessels when designing vascularization approaches in

Biomaterials used in vascularization approaches

It is well-recognized that interactions between endothelial cells and biomaterials play an important role in modulating neovessel formation in engineered tissues [30]. Early vascularization engineering efforts utilized non-biodegradable materials (i.e. silicon) mainly by employing soft lithography and photolithography approaches [31], [32]. Although these early efforts led to important discoveries [33], [34], [35], clinical translation was limited by the inability of those engineered constructs

Towards in vivo application

The ultimate goal of all tissue engineering efforts is to translate in vitro engineered tissues or organs to human patients as a therapeutic treatment. Since it is critical for tissue patches to integrate with the host’s vasculature to optimally restore function to the damaged area, vascularization has remained a critical area of interest. Owing to the experimental progress of engineering vascularized tissue constructs in vitro, many engineered tissues have progressed into pre-clinical testing

Conclusions and future remarks

Tissues and organs produced in vitro need a constant supply of oxygen and nutrients to maintain viability and functionality. Tissue engineering has continued to progress forward with new chemical/biochemical discoveries combining compatible mixtures of natural and synthetic components. However, the lack of efficiently designed vasculature in vitro has stunted its exponential growth. Currently, some of the major roadblocks of vascularization approaches include (1) inefficient network

Acknowledgements

This work was supported in part by Grants to NFH from the US National Institutes of Health (HL098688, HL127113, and EB020235), a Merit Review Award (1I01BX002310) from the Department of Veterans Affairs Biomedical Laboratory Research and Development service, the Stanford Chemistry Engineering & Medicine for Human Health, the Stanford Cardiovascular Institute, and a McCormick Gabilan fellowship.

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