Review articleVascularization of three-dimensional engineered tissues for regenerative medicine applications
Graphical abstract
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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