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Vascularized organoids on a chip: strategies for engineering organoids with functional vasculature.
Literature Information
| DOI | 10.1039/d0lc01186j |
|---|---|
| PMID | 33480945 |
| Journal | Lab on a chip |
| Impact Factor | 5.4 |
| JCR Quartile | Q1 |
| Publication Year | 2021 |
| Times Cited | 126 |
| Keywords | vascularized organoids, microfluidic platform, functional vasculature |
| Literature Type | Journal Article, Review |
| ISSN | 1473-0189 |
| Pages | 473-488 |
| Issue | 21(3) |
| Authors | Shun Zhang, Zhengpeng Wan, Roger D Kamm |
TL;DR
This paper highlights the limitations of current human organoid models, particularly their lack of functional vasculature, which hinders structural maturity and leads to necrosis in core regions due to insufficient nutrient supply. It reviews recent advancements in vascularizing organoids and proposes strategies for integrating perfused capillary networks into microfluidic platforms, aiming to enhance organoid growth and functionality beyond early developmental stages.
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vascularized organoids · microfluidic platform · functional vasculature
Abstract
Human organoids, self-organized and differentiated from homogenous pluripotent stem cells (PSC), replicate the key structural and functional characteristics of their in vivo counterparts. Despite the rapid advancement of organoid technology and its diverse applications, major limitations in achieving truly in vivo like functionality have been the lack of matured structural organization and constraints on tissue size, both of which are direct consequences of lacking a functional vasculature. In the absence of perfusable vessels, a core region within organoids quickly becomes necrotic during development due to increased metabolic demands that cannot be met by diffusion alone. Thus, incorporating functional vasculature in organoid models is indispensable for their growth in excess of several hundred microns and maturaturation beyond the embryonic and fetal phase. Here, we review recent advancements in vascularizing organoids and engineering in vitro capillary beds, and further explore strategies to integrate them on a microfluidic based platform, aiming for establishing perfused vasculature throughout organoids in vitro.
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Primary Questions Addressed
- What are the current challenges in scaling up vascularized organoids for larger tissue engineering applications?
- How do different methods of vascularization impact the functional properties of organoids?
- What are the implications of integrating microfluidic systems with vascularized organoids for drug testing and disease modeling?
- In what ways can the study of vascularized organoids contribute to understanding diseases related to vascular dysfunction?
- What future technologies might enhance the efficiency of creating functional vasculature within organoids on a chip?
Key Findings
Background and Purpose
Organoids are three-dimensional (3D) cell aggregates derived from pluripotent stem cells (PSCs) that replicate key structural and functional characteristics of in vivo organs. Despite advancements in organoid technology, achieving in vivo-like functionality remains challenging due to the absence of a functional vasculature. This review focuses on recent strategies to engineer vascularized organoids, emphasizing the integration of perfusable vascular networks within organoid models using microfluidic platforms.
Main Methods/Materials/Experimental Design
The authors categorize techniques for vascularizing organoids into two main approaches: self-organizing (emergent) and pre-patterned (top-down engineered).
Methodology Overview
| Methodology | Description |
|---|---|
| Co-culture with ECs | Mixing endothelial cells (ECs) with organoid progenitor cells to promote vascularization. |
| Co-differentiation | Inducing mesodermal progenitor cells to differentiate into ECs during organoid development. |
| Mechanical Stimulation | Applying shear stress through flow in microfluidic devices to enhance vascularization and maturation. |
| Self-organizing Networks | Using microfluidic devices to allow ECs to self-organize into vascular networks within hydrogels. |
| Pre-patterning | Creating predefined vascular structures using techniques like 3D printing and sacrificial molds. |
Mermaid Flowchart
Key Results and Findings
- Co-culture with ECs: This method showed varying degrees of success across different organoid types, with enhanced vascularization observed in liver and brain organoids when ECs were incorporated.
- Co-differentiation: Endothelial cells derived from mesodermal progenitors were successfully integrated into kidney and liver organoids, promoting vascular network formation.
- Mechanical Stimulation: Kidney organoids cultured under flow conditions demonstrated improved vascularization and maturation compared to static cultures.
- Self-organizing Networks: Microfluidic devices enabled ECs to form functional capillary networks, mimicking in vivo vasculature in terms of structure and function.
- Pre-patterning: Techniques such as 3D bioprinting allowed for the creation of complex vascular structures, though challenges remain in achieving capillary-scale diameters.
Main Conclusions/Significance/Innovation
The incorporation of functional vasculature within organoids is crucial for their maturation and physiological relevance. This review highlights the need for integrated approaches combining various methodologies to create fully vascularized organoids. The development of in vitro platforms with functional vasculature can significantly enhance the utility of organoids in disease modeling, drug screening, and regenerative medicine.
Research Limitations and Future Directions
- Limitations: Current methods often do not achieve full perfusion within organoids without in vivo transplantation, and there is a lack of detailed comparative studies on different vascularization protocols.
- Future Directions: Further research should focus on optimizing culture conditions for both organoids and vascular beds, understanding the interactions between different cell types, and developing standardized protocols for vascularization. Advances in bioprinting and synthetic hydrogels may pave the way for more sophisticated vascularized organoid models.
In conclusion, while significant progress has been made in engineering vascularized organoids, achieving a fully functional in vitro system remains a key challenge for future research.
References
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Literatures Citing This Work
- Organoid research in digestive system tumors. - Xiaoxiao Yang;Xuewen Xu;Haitao Zhu;Ming Wang;Dongqing Wang - Oncology letters (2021)
- Tubular human brain organoids to model microglia-mediated neuroinflammation. - Zheng Ao;Hongwei Cai;Zhuhao Wu;Sunghwa Song;Hande Karahan;Byungwook Kim;Hui-Chen Lu;Jungsu Kim;Ken Mackie;Feng Guo - Lab on a chip (2021)
- Generation and validation of APOE knockout human iPSC-derived cerebral organoids. - Yuka A Martens;Siming Xu;Richard Tait;Gary Li;Xinping C Zhao;Wenyan Lu;Chia-Chen Liu;Takahisa Kanekiyo;Guojun Bu;Jing Zhao - STAR protocols (2021)
- Operationalizing the Use of Biofabricated Tissue Models as Preclinical Screening Platforms for Drug Discovery and Development. - Olive Jung;Min Jae Song;Marc Ferrer - SLAS discovery : advancing life sciences R & D (2021)
- A robust vasculogenic microfluidic model using human immortalized endothelial cells and Thy1 positive fibroblasts. - Zhengpeng Wan;Shun Zhang;Amy X Zhong;Sarah E Shelton;Marco Campisi;Shriram K Sundararaman;Giovanni S Offeddu;Eunkyung Ko;Lina Ibrahim;Mark F Coughlin;Tiankun Liu;Jing Bai;David A Barbie;Roger D Kamm - Biomaterials (2021)
- In Vitro Strategies to Vascularize 3D Physiologically Relevant Models. - Alessandra Dellaquila;Chau Le Bao;Didier Letourneur;Teresa Simon-Yarza - Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2021)
- Organoids: a novel modality in disease modeling. - Zahra Heydari;Farideh Moeinvaziri;Tarun Agarwal;Paria Pooyan;Anastasia Shpichka;Tapas K Maiti;Peter Timashev;Hossein Baharvand;Massoud Vosough - Bio-design and manufacturing (2021)
- The vascular niche in next generation microphysiological systems. - Makena L Ewald;Yu-Hsi Chen;Abraham P Lee;Christopher C W Hughes - Lab on a chip (2021)
- Prevascularized Micro-/Nano-Sized Spheroid/Bead Aggregates for Vascular Tissue Engineering. - Maedeh Rahimnejad;Narges Nasrollahi Boroujeni;Sepideh Jahangiri;Navid Rabiee;Mohammad Rabiee;Pooyan Makvandi;Omid Akhavan;Rajender S Varma - Nano-micro letters (2021)
- Pericytes: Intrinsic Transportation Engineers of the CNS Microcirculation. - Ahmed M Eltanahy;Yara A Koluib;Albert Gonzales - Frontiers in physiology (2021)
... (116 more literatures)
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