Vascularizing Organoids to Promote Long-Term Organogenesis on a Chip

Round 1

Reviewer 1 Report

This review article provides a comprehensive summary of studies focused on vascularizing organoids, drawing from a wide array of prior research across various types of organoids. It introduces the fundamental concept of vascular formation using growth factors. While the review encompasses a significant breadth of studies, further inclusion of additional aspects of vascularization would fortify its scope. Here are suggestions for improvement:

1.     The utilization of microfluidic devices represents a major approach in enhancing organoid vascularization. Although these studies are effectively summarized, a more in-depth explanation of the mechanistic insights could be beneficial. For instance, the crucial role of mechanosensing signals in vascular development is presumed, yet this aspect is currently absent in the manuscript.

2.     Beyond promoting long-term organogenesis, the vascularization of organoids offers additional advantages. For instance, it has led to the development of more accurate disease models using perfusion chips (e.g., PMID: 36129975). Incorporating these studies would augment the value of vascularization research and enrich this review.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Vascularizing organoids to promote long-term organogenesis on a chip

The challenges of the expanding field of complex organoid culture systems are when organoid sizes increase, vascularization is needed to allow efficient oxygen and nutrient transport and prevent necrotic cores from formation. The authors nicely discussed and summarized the recent methods for initiating and maintaining vascularization in organoids, achieved through endothelial cells or the secretion of vascular growth factors. The review concludes by mentioning the potential of vascularized organoids in improving understanding of organ development and proposing avenues for organoid-on-a-chip applications in disease modeling.

Overall, it was a well-written review which was nicely organized and easy to read. I only suggest one minor comment here:

One reason for incorporation of vasculature into the organoids is, as the authors mentioned, to allow efficient oxygen and nutrient transport, however, the authors probably also want to include some results on the fact that endothelial cells have also been reported to secret angiocrine factors, which are necessary for development, maintaining tissue homeostasis and injury repair. This would be another good reason for incorporating vasculature into the organ-on-chip system. There are lots of relevant references from Shahin Rafi’s Lab, including:

 https://pubmed.ncbi.nlm.nih.gov/21068842/

https://pubmed.ncbi.nlm.nih.gov/22036563/

Also, reference like:

https://pubmed.ncbi.nlm.nih.gov/24485453/ might also be helpful.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf