Curated Papers > High-Impact Authoritative "Organoid" Literature

Engineering Organoid Vascularization.

Literature Information

DOI	10.3389/fbioe.2019.00039
PMID	30941347
Journal	Frontiers in bioengineering and biotechnology
Impact Factor	4.8
JCR Quartile	Q1
Publication Year	2019
Times Cited	160
Keywords	bioengineering, biofabrication, biomaterials, organoid, vascularization
Literature Type	Journal Article, Review
ISSN	2296-4185
Pages	39
Issue	7()
Authors	Sergei Grebenyuk, Adrian Ranga

TL;DR

This paper reviews advancements in developing in vitro vascular structures to enhance the functional complexity and scalability of organoids for drug discovery and regenerative medicine. By integrating vascular networks, which are crucial for nutrient exchange and tissue organization, the research aims to address current limitations in achieving in vivo-like functionality in engineered tissues.

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bioengineering · biofabrication · biomaterials · organoid · vascularization

Abstract

The development of increasingly biomimetic human tissue analogs has been a long-standing goal in two important biomedical applications: drug discovery and regenerative medicine. In seeking to understand the safety and effectiveness of newly developed pharmacological therapies and replacement tissues for severely injured non-regenerating tissues and organs, there remains a tremendous unmet need in generating tissues with both functional complexity and scale. Over the last decade, the advent of organoids has demonstrated that cells have the ability to reorganize into complex tissue-specific structures given minimal inductive factors. However, a major limitation in achieving truly in vivo-like functionality has been the lack of structured organization and reasonable tissue size. In vivo, developing tissues are interpenetrated by and interact with a complex network of vasculature which allows not only oxygen, nutrient and waste exchange, but also provide for inductive biochemical exchange and a structural template for growth. Conversely, in vitro, this aspect of organoid development has remained largely missing, suggesting that these may be the critical cues required for large-scale and more reproducible tissue organization. Here, we review recent technical progress in generating in vitro vasculature, and seek to provide a framework for understanding how such technologies, together with theoretical and developmentally inspired insights, can be harnessed to enhance next generation organoid development.

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Primary Questions Addressed

1. What specific techniques have shown the most promise in enhancing vascularization within organoids?
2. How do the structural characteristics of in vivo vasculature influence the functional outcomes of engineered organoids?
3. What are the potential applications of vascularized organoids in drug discovery and regenerative medicine?
4. How can theoretical models of vascular development inform the engineering of more complex organoid systems?
5. What challenges remain in scaling up vascularized organoid systems for clinical applications?

Key Findings

Research Background and Purpose

The development of increasingly biomimetic human tissue analogs is crucial for drug discovery and regenerative medicine. Organoids, derived from pluripotent or progenitor stem cells, can self-organize into complex tissue structures. However, their functionality is limited by the absence of vascularization, which is essential for nutrient and oxygen exchange, as well as structural support. This review discusses recent advancements in engineering vascularization in organoids and proposes a framework for integrating these technologies to enhance organoid development.

Main Methods/Materials/Experimental Design

The authors explore various techniques for creating vascular networks in organoids, highlighting the following approaches:

1. Bioprinting Techniques: Methods like fused deposition modeling (FDM) and droplet-based printing are employed to create vascular structures by layering bioinks containing cells.
2. Microfluidics: These systems allow for precise control of the microenvironment and facilitate the integration of vascular networks with organoids.
3. Sacrificial Networks: This approach involves embedding a sacrificial material within a hydrogel, which is later removed to create perfusable channels.
4. Laser Ablation: Utilizing focused laser light to create channels within hydrogels, enhancing the integration of vascular structures.
5. 2-Photon Polymerization: A high-resolution technique for creating complex vascular networks at the microscale.
6. Pro-Angiogenic Matrices: Engineering extracellular matrices that promote vascularization alongside organoid growth.
7. In Vivo Transplantation: Transplanting organoids into host animals to integrate with the native vasculature.

Key Results and Findings

• Vascularized organoids exhibit improved functionality, as demonstrated by successful integration with host vasculature in vivo.
• Techniques like bioprinting and microfluidics have shown promise in creating perfusable vascular networks.
• The use of modular and controllable extracellular matrices enhances organoid growth and vascularization.
• The interplay between organoid and vascular development is critical for achieving physiological functionality.

Main Conclusions/Significance/Innovation

The review emphasizes that effective vascularization is essential for the development of functional organoids that can serve as reliable models for drug discovery and regenerative medicine. The integration of advanced bioprinting techniques, microfluidics, and engineered extracellular matrices can lead to more biomimetic tissue models. The findings underscore the importance of a multi-faceted approach that combines structural and molecular strategies to create vascularized organoids.

Research Limitations and Future Directions

Despite significant progress, challenges remain in achieving the desired scale and complexity of vascular networks. Current techniques often fall short of replicating the intricate architecture of natural vasculature. Future research should focus on:

• Developing materials that can dynamically respond to the growth of organoids.
• Exploring the role of various cell types in promoting vascularization.
• Optimizing fabrication techniques to achieve finer control over vascular network design and integration with organoids.

The potential for organoids in personalized medicine and drug screening continues to grow, necessitating further exploration of vascularization strategies to enhance their applicability in clinical settings.

References

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Literatures Citing This Work

1. An Air Bubble-Isolating Rotating Wall Vessel Bioreactor for Improved Spheroid/Organoid Formation. - Michael A Phelan;Anthony L Gianforcaro;Jonathan A Gerstenhaber;Peter I Lelkes - Tissue engineering. Part C, Methods (2019)
2. In vitro and in silico Models to Study Mosquito-Borne Flavivirus Neuropathogenesis, Prevention, and Treatment. - Megan Chesnut;Laura S Muñoz;Georgina Harris;Dana Freeman;Lucio Gama;Carlos A Pardo;David Pamies - Frontiers in cellular and infection microbiology (2019)
3. Past, Present, and Future of Brain Organoid Technology. - Bonsang Koo;Baekgyu Choi;Hoewon Park;Ki-Jun Yoon - Molecules and cells (2019)
4. Cerebral Organoid Models for Neurotropic Viruses. - Jenna Antonucci;Lee Gehrke - ACS infectious diseases (2019)
5. Reverse engineering human brain evolution using organoid models. - Mohammed A Mostajo-Radji;Matthew T Schmitz;Sebastian Torres Montoya;Alex A Pollen - Brain research (2020)
6. Uncovering cell biology in the third dimension. - Gabriella L Robertson;Alejandra I Romero-Morales;Ethan S Lippmann;Vivian Gama - Molecular biology of the cell (2020)
7. Integrated On-Chip 3D Vascular Network Culture under Hypoxia. - Miguel Ángel Olmedo-Suárez;Tomohiro Sekiguchi;Atsushi Takano;Maria Del Pilar Cañizares-Macías;Nobuyuki Futai - Micromachines (2020)
8. The endothelium, a key actor in organ development and hPSC-derived organoid vascularization. - Alejandra Vargas-Valderrama;Antonietta Messina;Maria Teresa Mitjavila-Garcia;Hind Guenou - Journal of biomedical science (2020)
9. Links between Nutrition, Infectious Diseases, and Microbiota: Emerging Technologies and Opportunities for Human-Focused Research. - Manuela Cassotta;Tamara Yuliett Forbes-Hernández;Ruben Calderón Iglesias;Roberto Ruiz;Maria Elexpuru Zabaleta;Francesca Giampieri;Maurizio Battino - Nutrients (2020)
10. Exploiting CRISPR Cas9 in Three-Dimensional Stem Cell Cultures to Model Disease. - Sneha Gopal;André Lopes Rodrigues;Jonathan S Dordick - Frontiers in bioengineering and biotechnology (2020)

... (150 more literatures)

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