Engineering blood vessels and vascularized tissues: technology trends and potential clinical applications.
Chandra Prafulla,Atala Anthony
Clinical science (London, England : 1979)
Vascular tissue engineering has the potential to make a significant impact on the treatment of a wide variety of medical conditions, including providing generated vascularized tissue and organ constructs for transplantation. Since the first report on the construction of a biological blood vessel, significant research and technological advances have led to the generation of clinically relevant large and small diameter tissue engineered vascular grafts (TEVGs). However, developing a biocompatible blood-contacting surface is still a major challenge. Researchers are using biomimicry to generate functional vascular grafts and vascular networks. A multi-disciplinary approach is being used that includes biomaterials, cells, pro-angiogenic factors and microfabrication technologies. Techniques to achieve spatiotemporal control of vascularization include use of topographical engineering and controlled-release of growth/pro-angiogenic factors. Use of decellularized natural scaffolds has gained popularity for engineering complex vascularized organs for potential clinical use. Pre-vascularization of constructs prior to implantation has also been shown to enhance its anastomosis after implantation. Host-implant anastomosis is a phenomenon that is still not fully understood. However, it will be a critical factor in determining the success of a TEVGs or bioengineered organ. Many clinical studies have been conducted using TEVGs, but vascularized tissue/organ constructs are still in the research & development stage. In addition to technical challenges, there are commercialization and regulatory challenges that need to be addressed. In this review we examine recent advances in the field of vascular tissue engineering, with a focus on technology trends, challenges and potential clinical applications.
10.1042/CS20180155
In vitro fabrication of functional three-dimensional tissues with perfusable blood vessels.
Sekine Hidekazu,Shimizu Tatsuya,Sakaguchi Katsuhisa,Dobashi Izumi,Wada Masanori,Yamato Masayuki,Kobayashi Eiji,Umezu Mitsuo,Okano Teruo
Nature communications
In vitro fabrication of functional vascularized three-dimensional tissues has been a long-standing objective in the field of tissue engineering. Here we report a technique to engineer cardiac tissues with perfusable blood vessels in vitro. Using resected tissue with a connectable artery and vein as a vascular bed, we overlay triple-layer cardiac cell sheets produced from coculture with endothelial cells, and support the tissue construct with media perfused in a bioreactor. We show that endothelial cells connect to capillaries in the vascular bed and form tubular lumens, creating in vitro perfusable blood vessels in the cardiac cell sheets. Thicker engineered tissues can be produced in vitro by overlaying additional triple-layer cell sheets. The vascularized cardiac tissues beat and can be transplanted with blood vessel anastomoses. This technique may create new opportunities for in vitro tissue engineering and has potential therapeutic applications.
10.1038/ncomms2406
A Vascular Endothelial Growth Factor-Dependent Sprouting Angiogenesis Assay Based on an In Vitro Human Blood Vessel Model for the Study of Anti-Angiogenic Drugs.
EBioMedicine
Angiogenesis is the formation of new capillaries from pre-existing blood vessels and participates in proper vasculature development. In pathological conditions such as cancer, abnormal angiogenesis takes place. Angiogenesis is primarily carried out by endothelial cells, the innermost layer of blood vessels. The vascular endothelial growth factor-A (VEGF-A) and its receptor-2 (VEGFR-2) trigger most of the mechanisms activating and regulating angiogenesis, and have been the targets for the development of drugs. However, most experimental assays assessing angiogenesis rely on animal models. We report an in vitro model using a microvessel-on-a-chip. It mimics an effective endothelial sprouting angiogenesis event triggered from an initial microvessel using a single angiogenic factor, VEGF-A. The angiogenic sprouting in this model is depends on the Notch signaling, as observed in vivo. This model enables the study of anti-angiogenic drugs which target a specific factor/receptor pathway, as demonstrated by the use of the clinically approved sorafenib and sunitinib for targeting the VEGF-A/VEGFR-2 pathway. Furthermore, this model allows testing simultaneously angiogenesis and permeability. It demonstrates that sorafenib impairs the endothelial barrier function, while sunitinib does not. Such in vitro human model provides a significant complimentary approach to animal models for the development of effective therapies.
10.1016/j.ebiom.2017.12.014
Dual layer collagen-GAG conduit that mimic vascular scaffold and promote blood vessel cells adhesion, proliferation and elongation.
Zhou Juan,Ying Huiyan,Wang Mingyu,Su Dandan,Lu Guozhong,Chen Jinghua
Materials science & engineering. C, Materials for biological applications
A dual layer conduit, which consists of collagen I-hyaluronic acid (Col-HA, external layer) and collagen I-heparin (Col-HP, inner layer), has been developed. This conduit not only meets the structural requirement of nature blood vessel, but also presents favourable mechanical performance after crosslinking via EDC. In addition, its biological properties are evaluated through culturing with fibroblast cell (Cos-7) on Col-HA surface and vascular endothelial cell (HMEC) on Col-HP layer. Results demonstrate that the conduit can support Cos-7 and HMEC adhesion, proliferation and elongation on respective side. This dual layer conduit would be a new choice of artificial vascular scaffold and improve blood vessel regeneration for tissue engineering.
10.1016/j.msec.2018.06.072
Facilitating tumor spheroid-based bioassays and in vitro blood vessel modeling via bioinspired self-formation microstructure devices.
Kuo Ching-Te,Lu Siang-Rong,Chen Wei-Min,Wang Jong-Yueh,Lee Si-Chen,Chang Hsiu-Hao,Wo Andrew M,Chen Benjamin P C,Lee Hsinyu
Lab on a chip
Non-planar microstructure-based tissue culture devices have emerged as powerful tools to mimic in vivo physiological microenvironments in a wide range of medical applications. Here we report a spontaneous aqueous molding approach - inspired by Stenocara gracilipes beetles - to rapidly fabricate non-planar microstructure devices for facilitating tissue-based bioassays. The device fabrication is determined from the self-assembled liquid morphology, which is induced by condensation or guided by surface tension. Through experiments and modeling, we reveal that the molding mainly comprises two typical circular and striped domains, highlighting versatile applications for bioengineering. In addition, the molding characteristic is dependent on the geometry of the patterned wetting surfaces, the working volume of the liquid, and the interaction between the liquid and the substrate. The theoretical model, based on the geometry of the patterned liquid, is highly consistent with experimental data. We also demonstrate that our approach can facilitate the culturing of tumor spheroids incorporated with biomimic nano-cilia, rapid high-throughput drug screening, tumor spheroid migration assay, and in vitro modeling of blood vessels. Remarkably, the delivery of multiple concentrations of drugs and their associate mixtures (a total of 25 test spots in one device) can be carried out simultaneously within seconds. Taken together, these insights may offer new opportunities to tailor non-planar microstructures, and our proposed methodology can be applicable for the emerging needs in tumor cell biology and tissue engineering.
10.1039/c8lc00423d
Design considerations for engineering 3D models to study vascular pathologies in vitro.
Acta biomaterialia
Many cardiovascular diseases (CVD) are driven by pathological remodelling of blood vessels, which can lead to aneurysms, myocardial infarction, ischaemia and strokes. Aberrant remodelling is driven by changes in vascular cell behaviours combined with degradation, modification, or abnormal deposition of extracellular matrix (ECM) proteins. The underlying mechanisms that drive the pathological remodelling of blood vessels are multifaceted and disease specific; however, unravelling them may be key to developing therapies. Reductionist models of blood vessels created in vitro that combine cells with biomaterial scaffolds may serve as useful analogues to study vascular disease progression in a controlled environment. This review presents the main considerations for developing such in vitro models. We discuss how the design of blood vessel models impacts experimental readouts, with a particular focus on the maintenance of normal cellular phenotypes, strategies that mimic normal cell-ECM interactions, and approaches that foster intercellular communication between vascular cell types. We also highlight how choice of biomaterials, cellular arrangements and the inclusion of mechanical stimulation using fluidic devices together impact the ability of blood vessel models to mimic in vivo conditions. In the future, by combining advances in materials science, cell biology, fluidics and modelling, it may be possible to create blood vessel models that are patient-specific and can be used to develop and test therapies. STATEMENT OF SIGNIFICANCE: Simplified models of blood vessels created in vitro are powerful tools for studying cardiovascular diseases and understanding the mechanisms driving their progression. Here, we highlight the key structural and cellular components of effective models and discuss how including mechanical stimuli allows researchers to mimic native vessel behaviour in health and disease. We discuss the primary methods used to form blood vessel models and their limitations and conclude with an outlook on how blood vessel models that incorporate patient-specific cells and flows can be used in the future for personalised disease modelling.
10.1016/j.actbio.2021.02.031