Elsevier

Acta Biomaterialia

Volume 95, 1 September 2019, Pages 112-130
Acta Biomaterialia

Review article
Upgrading prevascularization in tissue engineering: A review of strategies for promoting highly organized microvascular network formation

https://doi.org/10.1016/j.actbio.2019.03.016Get rights and content

Abstract

Functional and perfusable vascular network formation is critical to ensure the long-term survival and functionality of engineered tissues after their transplantation. Although several vascularization strategies have been reviewed in past, the significance of microvessel organization in three-dimensional (3D) scaffolds has been largely ignored. Advances in high-resolution microscopy and image processing have revealed that the majority of tissues including cardiac, skeletal muscle, bone, and skin contain highly organized microvessels that orient themselves to align with tissue architecture for optimum molecular exchange and functional performance. Here, we review strategies to develop highly organized and mature vascular networks in engineered tissues, with a focus on electromechanical stimulation, surface topography, micro scaffolding, surface-patterning, microfluidics and 3D printing. This review will provide researchers with state of the art approaches to engineer vascularized functional tissues for diverse applications.

Statement of significance

Vascularization is one of the critical challenges facing tissue engineering. Recent technological advances have enabled researchers to develop microvascular networks in engineered tissues. Although far from translational applications, current vascularization strategies have shown promising outcomes. This review emphasizes the most recent technological advances and future challenges for developing organized microvascular networks in vitro. The next critical step is to achieve highly perfusable, dense, mature and organized microvascular networks representative of native tissues.

Introduction

Development of highly perfusable and mature vascular networks in vitro holds great potential to revolutionize transplantable tissue technologies to satisfy the therapeutic needs of disease conditions that lack effective treatment options. In vitro fabrication of a large three-dimensional (3D) graft normally requires a system (eg. a perfusion bioreactor) that can provide nutrients and oxygen to all cells within the living construct. Unfortunately, post in vivo transplantation, the rate of host vessel invasion is limited to several tenths of a micron per day, leading to necrosis in the central area of the graft [1], [2], [3], [4]. Thus, a tissue engineered graft with wall thickness greater than the diffusion limit of gases and nutrients (∼150–200 μm) requires a pre-formed vascular network. This network must be able to rapidly anastomose to host vasculature in order to promote optimum graft survival [5]. Development of perfusable and functional engineered tissues may reduce mortality following myocardial ischemia (MI), limit the development of chronic ulcers, prevent bone and cartilage damage and reduce alcoholic hepatitis, among many other benefits. The Food and Drug Administration (FDA)-approved tissue engineered products developed in the past (particularly for wound healing), mostly serve as a natural reservoir of growth factors, cytokines and extracellular (ECM) proteins, but lack crucial pre-formed vasculature [6], [7], [8]. As a result, they fail to integrate with the host, and eventually undergo necrosis.

Although an extensive amount of research has been conducted to develop small diameter vascular grafts [9], major technological advances are still required for development of functional and perfusable microvascular networks that can be integrated into engineered tissues. Several vascularization strategies have been reviewed to date, mostly with a focus on single vessel or vascular network formation in engineered scaffolds using co-culture of various cell types [10], [11], external growth factor provision [12], 3D bio-printing [13], use of microfabrication [14] and microfluidic techniques [15]. However, the significance of the microvessel structure and organization has been largely ignored. This review exclusively discusses current advances and challenges associated with in vitro development of highly organized and tissue architecture oriented microvacular networks. These strategies are categorized in five subsections including (1) electromechanical stimulation, (2) topographical stimulation, (3) microfabrication, (4) micro-patterning and (5) 3D bioprinting. Engineered structured vessels not only facilitate functional tissue regeneration post-implantation, but also augment fabrication of in vitro vascular disease models to understand pathogenesis of atherosclerosis, hypertension, cardiac arrest, stroke and cancer. In order to develop tissue architecture oriented microvessels in vitro, it is important to understand their physiological organization in native tissues.

Section snippets

Microvascular network formation in native tissues: Insights from developmental process

Vascular networks, categorized as the blood vascular and lymphatic systems, are a crucial component of biological tissue. While blood vascular networks mediate the exchange of gases, nutrients and metabolic byproducts, the lymphatic system optimizes nutrient transport between blood and tissue [16]. Hierarchically organized blood vascular networks contain a multitude of vessels with vast differences in their diameters, ranging from 3 cm to a few micrometers [17]. In this hierarchy of different

Cellular and acellular components of microvascular networks: Mimicking the physiological apparatus

Capillary structure incorporates ECs as the vessel lumen with surrounding perivascular cells, as illustrated in Fig. 1A. ECs maintain blood homeostasis, interact with immune cells and maintain molecular exchange with blood. In addition, ECs are elongated in the direction of blood flow and can increase their surface area by cell spreading to regulate shear stress generated by the flow [41]. Moreover, ECs regulate the expression of an assortment of surface molecules that can elicit a wide

Strategies to promote a structured microvascular network formation in engineered tissues

Primitive microvascular network formation by mono or co-culture of ECs and perivascular cells isolated from several sources have been extensively studied in vitro and in vivo [11]. Besides selecting appropriate cell types, external growth factors [47], [48] and/or protein stimulation [49] have also been targeted to develop microvacular networks in vitro. Provision of angiogenic growth factors regulate several stages of angiogenesis including EC migration [50], vessel sprouting, perivascular

Conclusion remarks and future perspective

An enormous amount of research data associated with the understanding of angiogenic and vasculogenic processes is currently being translated into tissue engineering applications to further develop perfusable and functional vascular networks that can re-vascularize ischemic tissues. Controlled delivery of angiogenic growth factors or appropriate cell types can promote re-vascularization in ischemic tissues via therapeutic angiogenesis. Although phase I and II human clinical trials involving

Acknowledgements

This study was supported by the National Institutes of Health (1R15CA202656 and 1R15HL115521-01A1) and the National Science Foundation (1703570) to FZ.

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