Biomanufacturing of organ-specific tissues with high cellular density and embedded vascular channels

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Abstract

We report a biomanufacturing method for creating perfusable human tissues composed of stem cell–derived organ building blocks.

Abstract

Engineering organ-specific tissues for therapeutic applications is a grand challenge, requiring the fabrication and maintenance of densely cellular constructs composed of ~10 ⁸ cells/ml. Organ building blocks (OBBs) composed of patient-specific–induced pluripotent stem cell–derived organoids offer a pathway to achieving tissues with the requisite cellular density, microarchitecture, and function. However, to date, scant attention has been devoted to their assembly into 3D tissue constructs. Here, we report a biomanufacturing method for assembling hundreds of thousands of these OBBs into living matrices with high cellular density into which perfusable vascular channels are introduced via embedded three-dimensional bioprinting. The OBB matrices exhibit the desired self-healing, viscoplastic behavior required for sacrificial writing into functional tissue (SWIFT). As an exemplar, we created a perfusable cardiac tissue that fuses and beats synchronously over a 7-day period. Our SWIFT biomanufacturing method enables the rapid assembly of perfusable patient- and organ-specific tissues at therapeutic scales.

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Most cited references 16

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An integrated design and fabrication strategy for entirely soft, autonomous robots.

Michael Wehner, Ryan Truby, Daniel J Fitzgerald … (2016)

Soft robots possess many attributes that are difficult, if not impossible, to achieve with conventional robots composed of rigid materials. Yet, despite recent advances, soft robots must still be tethered to hard robotic control systems and power sources. New strategies for creating completely soft robots, including soft analogues of these crucial components, are needed to realize their full potential. Here we report the untethered operation of a robot composed solely of soft materials. The robot is controlled with microfluidic logic that autonomously regulates fluid flow and, hence, catalytic decomposition of an on-board monopropellant fuel supply. Gas generated from the fuel decomposition inflates fluidic networks downstream of the reaction sites, resulting in actuation. The body and microfluidic logic of the robot are fabricated using moulding and soft lithography, respectively, and the pneumatic actuator networks, on-board fuel reservoirs and catalytic reaction chambers needed for movement are patterned within the body via a multi-material, embedded 3D printing technique. The fluidic and elastomeric architectures required for function span several orders of magnitude from the microscale to the macroscale. Our integrated design and rapid fabrication approach enables the programmable assembly of multiple materials within this architecture, laying the foundation for completely soft, autonomous robots.

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Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis.

Minoru Takasato, Pei X Er, Han S Chiu … (2015)

The human kidney contains up to 2 million epithelial nephrons responsible for blood filtration. Regenerating the kidney requires the induction of the more than 20 distinct cell types required for excretion and the regulation of pH, and electrolyte and fluid balance. We have previously described the simultaneous induction of progenitors for both collecting duct and nephrons via the directed differentiation of human pluripotent stem cells. Paradoxically, although both are of intermediate mesoderm in origin, collecting duct and nephrons have distinct temporospatial origins. Here we identify the developmental mechanism regulating the preferential induction of collecting duct versus kidney mesenchyme progenitors. Using this knowledge, we have generated kidney organoids that contain nephrons associated with a collecting duct network surrounded by renal interstitium and endothelial cells. Within these organoids, individual nephrons segment into distal and proximal tubules, early loops of Henle, and glomeruli containing podocytes elaborating foot processes and undergoing vascularization. When transcription profiles of kidney organoids were compared to human fetal tissues, they showed highest congruence with first trimester human kidney. Furthermore, the proximal tubules endocytose dextran and differentially apoptose in response to cisplatin, a nephrotoxicant. Such kidney organoids represent powerful models of the human organ for future applications, including nephrotoxicity screening, disease modelling and as a source of cells for therapy.

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Three-dimensional bioprinting of thick vascularized tissues.

David B Kolesky, Kimberly A Homan, Mark A Skylar-Scott … (2016)

The advancement of tissue and, ultimately, organ engineering requires the ability to pattern human tissues composed of cells, extracellular matrix, and vasculature with controlled microenvironments that can be sustained over prolonged time periods. To date, bioprinting methods have yielded thin tissues that only survive for short durations. To improve their physiological relevance, we report a method for bioprinting 3D cell-laden, vascularized tissues that exceed 1 cm in thickness and can be perfused on chip for long time periods (>6 wk). Specifically, we integrate parenchyma, stroma, and endothelium into a single thick tissue by coprinting multiple inks composed of human mesenchymal stem cells (hMSCs) and human neonatal dermal fibroblasts (hNDFs) within a customized extracellular matrix alongside embedded vasculature, which is subsequently lined with human umbilical vein endothelial cells (HUVECs). These thick vascularized tissues are actively perfused with growth factors to differentiate hMSCs toward an osteogenic lineage in situ. This longitudinal study of emergent biological phenomena in complex microenvironments represents a foundational step in human tissue generation.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): SciAdv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: September 2019

Publication date (Electronic): 06 September 2019

Volume: 5

Issue: 9

Electronic Location Identifier: eaaw2459

Affiliations

[1 ]Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138, USA.

[2 ]John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA.

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[*]

These authors contributed equally to this work.

[† ]Corresponding author. Email: jalewis@ 123456seas.harvard.edu

Author information

Mark A. Skylar-Scott http://orcid.org/0000-0003-3496-7124

Ryan L. Truby http://orcid.org/0000-0002-1313-6463

Jennifer A. Lewis http://orcid.org/0000-0002-0280-2774

Article

Publisher ID: aaw2459

DOI: 10.1126/sciadv.aaw2459

PMC ID: 6731072

PubMed ID: 31523707

SO-VID: 486804a8-4efe-4f4d-9827-2d5be3147306

Copyright © Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 01 December 2018

Date accepted : 02 August 2019

Funding

Funded by: doi http://dx.doi.org/10.13039/100000006, Office of Naval Research;

Award ID: N000141612823

Funded by: doi http://dx.doi.org/10.13039/100000051, National Human Genome Research Institute;

Award ID: RM1HG008525

Funded by: GETTYLAB;

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Copyeditor Sam Ardiente

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Biomanufacturing of organ-specific tissues with high cellular density and embedded vascular channels

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Vascular Biology

Most cited references 16

An integrated design and fabrication strategy for entirely soft, autonomous robots.

Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis.

Three-dimensional bioprinting of thick vascularized tissues.

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