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Biomimetic models of the glomerulus

Nature Reviews Nephrology volume 18, pages 241–257 (2022)Cite this article

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Abstract

The use of biomimetic models of the glomerulus has the potential to improve our understanding of the pathogenesis of kidney diseases and to enable progress in therapeutics. Current in vitro models comprise organ-on-a-chip, scaffold-based and organoid approaches. Glomerulus-on-a-chip designs mimic components of glomerular microfluidic flow but lack the inherent complexity of the glomerular filtration barrier. Scaffold-based 3D culture systems and organoids provide greater microenvironmental complexity but do not replicate fluid flows and dynamic responses to fluidic stimuli. As the available models do not accurately model the structure or filtration function of the glomerulus, their applications are limited. An optimal approach to glomerular modelling is yet to be developed, but the field will probably benefit from advances in biofabrication techniques. In particular, 3D bioprinting technologies could enable the fabrication of constructs that recapitulate the complex structure of the glomerulus and the glomerular filtration barrier. The next generation of in vitro glomerular models must be suitable for high(er)-content or/and high(er)-throughput screening to enable continuous and systematic monitoring. Moreover, coupling of glomerular or kidney models with those of other organs is a promising approach to enable modelling of partial or full-body responses to drugs and prediction of therapeutic outcomes.

Key points

  • The prevalence of kidney failure is increasing worldwide, and glomerulopathy is often a causal or contributing factor.

  • The available in vitro models of the glomerulus are suboptimal, which limits their use for interrogation of pathological mechanisms and testing of drugs.

  • The complexity of the renal corpuscle results in a fragile balance of constituents that can be easily disturbed in pathological situations, leading to irreparable damage.

  • Initiatives for improving current in vitro biomimetic models of the glomerulus focus on replication of the 3D microenvironment using on-a-chip technology, scaffolds and organoids containing glomerular tissue.

  • The suitability of emerging biofabrication techniques, such as 3D bioprinting, for glomerular modelling is yet to be fully assessed.

  • Larger-scale applications of glomerular models will rely on their standardization and effective utility for high(er)-throughput and/or high(er)-content screening.

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Fig. 1: The glomerulus in health and disease.
Fig. 2: On a chip models of the glomerulus.
Fig. 3: Membranes and 3D scaffolds for glomerular modelling.
Fig. 4: Glomerular tissue organoids with improved maturation and vascularization.
Fig. 5: 3D bioprinting and multi-photon ablation techniques that could be used to build glomerular models.

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Acknowledgements

The authors gratefully acknowledge research funding from the National Institutes of Health (R00CA201603, R21EB025270, R21EB026175, R21EB030257, R01EB028143, R01HL153857, R01DK72381, R03EB027984, R37DK39773 and UH3TR002155), the National Science Foundation (CBET-EBMS-1936105), the Brigham Research Institute, the Hofvijverkring Visiting Scientist Program, the Dutch Kidney Foundation (18KVP01), Utrecht Institute for Pharmaceutical Sciences and European Union’s Horizon 2020 research and innovation programme WIDESPREAD-05-2018-TWINNING Remodel.

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Authors and Affiliations

  1. Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA

    Marta G. Valverde, Luis S. Mille, Kianti P. Figler, Ernesto Cervantes, Vanessa Y. Li, Joseph V. Bonventre & Yu Shrike Zhang

  2. Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Department of Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands

    Marta G. Valverde & Rosalinde Masereeuw

  3. Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Joseph V. Bonventre

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  1. Marta G. Valverde
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Contributions

M.G.V. and L.S.M. researched the data and wrote most of the text. K.P.F., E.C. and V.Y.L. researched the data and contributed to discussion of the content. M.G.V., L.S.M. and K.P.F. created the submitted figures. J.V.B., R.M. and Y.S.Z. contributed substantially to discussion of the content throughout. Y.S.Z. participated in researching the data and writing of the initial draft. M.G.V., L.S.M., J.V.B., R.M. and Y.S.Z. reviewed/edited the manuscript.

Corresponding authors

Correspondence to Joseph V. Bonventre, Rosalinde Masereeuw or Yu Shrike Zhang.

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Competing interests

Y.S.Z. sits on the Advisory Board of Allevi, Inc., which however, did not support this work. J.V.B. is co-founder and holds equity in Goldfinch Bio. The interests of Y.S.Z. and J.V.B. were reviewed and are managed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflict of interest policies. The other authors declare no competing interests.

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Nature Reviews Nephrology thanks the anonymous reviewers for their contribution to the peer review of this work.

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Glossary

Drug disposition

In pharmacology, drug disposition refers to the processes of drug distribution and elimination of a drug once it has entered the body.

Microfluidics

The technology used to manufacture devices containing chambers and tunnels in the microscale through which fluids flow or are confined. These devices, commonly known as microfluidic chips, permit fluids to be precisely directed, mixed, separated or manipulated to attain multiplexing, automation and high-throughput systems.

Oxygen plasma treatment

A surface treatment in which oxygen plasma is used to remove impurities and contaminants, as well as to create functional groups to increase hydrophilicity and enhance bonding properties.

Thermoplastics

A group of polymers that melt at high temperatures and harden upon cooling. They can be melted and recast almost indefinitely so are highly recyclable.

Soft lithography

A group of techniques that use elastomeric stamps and moulds to shape materials with micrometre or nanometre resolution.

Vat polymerization 3D printing

A 3D printing technique in which each layer of the construct is created by projecting a different image onto a liquid resin contained in a vat to start the crosslinking reaction.

Hydrogel

Highly crosslinked hydrophilic polymer network that is heavily swollen with water and can be used as a dynamic, tunable, degradable material for growing cells and tissues.

Electrospinning

A manufacturing technique based on the creation of small diameter fibres (nanometres to micrometres) by exposing a polymeric solution to a high-power electric field during its ejection.

Bioinks

Solutions of natural and/or synthetic biomaterials used to create tissue constructs by bioprinting; bioinks usually encapsulate cells.

Extrusion bioprinting

A technique used to create organized tissue constructs by continuously dispensing or extruding a bioink through a nozzle, resulting in 3D structures.

Inkjet bioprinting

A technique used to create organized tissue constructs by rapidly dispensing small droplets in the picolitre volume range.

Feature resolution

The smallest feature size upon which a structure can be built.

Two-photon lithography

A light-assisted bioprinting technique in which excitation for the polymerization of the material is achieved by a femtosecond pulsed near-infrared laser. This technology typically creates high-resolution features with sizes of ~50–100 nm.

Breadboard

In the microfluidic context, a breadboard is a piece of hardware containing built-in microfluidic channels and valves that enable modular assembly of microfluidic chips and fluid routing.

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Valverde, M.G., Mille, L.S., Figler, K.P. et al. Biomimetic models of the glomerulus. Nat Rev Nephrol 18, 241–257 (2022). https://doi.org/10.1038/s41581-021-00528-x

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