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Synthetic alternatives to Matrigel. ​

Literature Information ​

DOI10.1038/s41578-020-0199-8
PMID32953138
JournalNature reviews. Materials
Impact Factor86.2
JCR QuartileQ1
Publication Year2020
Times Cited401
KeywordsSynthetic scaffolds, Matrigel, Cell culture, Regenerative medicine, Organoid assembly
Literature TypeJournal Article
ISSN2058-8437
Pages539-551
Issue5(7)
AuthorsElizabeth A Aisenbrey, William L Murphy

TL;DR ​

This review evaluates the limitations of Matrigel, a widely used basement-membrane matrix in cell culture, due to its variable composition and lack of reproducibility, which hinder its application in cellular biology and drug discovery. It highlights the advances in synthetic scaffolds that offer chemically defined, tunable, and reproducible alternatives, while discussing the challenges to their widespread adoption and future directions for improving cell culture methodologies.

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Synthetic scaffolds · Matrigel · Cell culture · Regenerative medicine · Organoid assembly

Abstract ​

Matrigel, a basement-membrane matrix extracted from Engelbreth-Holm-Swarm mouse sarcomas, has been used for more than four decades for a myriad of cell culture applications. However, Matrigel is limited in its applicability to cellular biology, therapeutic cell manufacturing and drug discovery owing to its complex, ill-defined and variable composition. Variations in the mechanical and biochemical properties within a single batch of Matrigel - and between batches - have led to uncertainty in cell culture experiments and a lack of reproducibility. Moreover, Matrigel is not conducive to physical or biochemical manipulation, making it difficult to fine-tune the matrix to promote intended cell behaviours and achieve specific biological outcomes. Recent advances in synthetic scaffolds have led to the development of xenogenic-free, chemically defined, highly tunable and reproducible alternatives. In this Review, we assess the applications of Matrigel in cell culture, regenerative medicine and organoid assembly, detailing the limitations of Matrigel and highlighting synthetic scaffold alternatives that have shown equivalent or superior results. Additionally, we discuss the hurdles that are limiting a full transition from Matrigel to synthetic scaffolds and provide a brief perspective on the future directions of synthetic scaffolds for cell culture applications.

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Primary Questions Addressed ​

  1. What specific synthetic alternatives to Matrigel have shown the most promise in cell culture applications?
  2. How do the mechanical and biochemical properties of synthetic scaffolds compare to those of Matrigel in promoting cell growth?
  3. What challenges do researchers face when transitioning from Matrigel to synthetic alternatives in therapeutic cell manufacturing?
  4. In what ways can synthetic scaffolds be tailored to enhance specific cellular behaviors compared to Matrigel?
  5. What future advancements in synthetic scaffold technology could further improve their efficacy in regenerative medicine and organoid assembly?

Key Findings ​

Research Background and Purpose ​

Matrigel, a complex extracellular matrix derived from mouse tumors, has been a staple in cell culture for over 40 years. However, its undefined composition and batch variability hinder reproducibility in experiments, particularly in cellular biology and regenerative medicine. This review evaluates the limitations of Matrigel and explores synthetic alternatives that offer defined, tunable, and reproducible scaffolds for cell culture applications.

Main Methods/Materials/Experimental Design ​

The review compares Matrigel with various synthetic scaffolds, focusing on their applications in stem-cell culture, regenerative medicine, and organoid assembly. The following key methodologies are employed:

  1. Assessment of Matrigel Limitations:

    • Variability in biochemical and mechanical properties.
    • Presence of xenogenic contaminants.
    • Difficulty in controlling matrix properties.

  2. Comparison with Synthetic Scaffolds:

    • Synthetic materials are engineered to have defined compositions, allowing for better control over mechanical and biochemical properties.
    • Examples include polyacrylamide (PAM) and polyethylene glycol (PEG) hydrogels, which can be functionalized with peptides to enhance cell interactions.

  3. Evaluation of Performance:

    • Synthetic scaffolds are tested against Matrigel in terms of their ability to support stem cell maintenance, differentiation, and organoid formation.
Mermaid diagram

Key Results and Findings ​

  • Matrigel Limitations:

    • High batch-to-batch variability in composition and properties.
    • Potential contamination affecting cell behavior and experimental outcomes.

  • Synthetic Alternatives:

    • Scaffolds such as PMEDSAH and PEG hydrogels have shown to support stem cell culture and differentiation at levels comparable to or exceeding Matrigel.
    • Synthetic scaffolds provide a xenogenic-free environment, enhancing safety for clinical applications.

  • Organoid Assembly:

    • Synthetic scaffolds allow for more controlled organoid formation, reducing variability and improving reproducibility compared to Matrigel.

Main Conclusions/Significance/Innovation ​

The review emphasizes that synthetic scaffolds represent a significant advancement over Matrigel for cell culture applications. They provide a controlled environment that can be tailored to specific cellular behaviors, which is crucial for applications in regenerative medicine and drug discovery. The findings suggest a paradigm shift towards the adoption of synthetic materials in research and clinical settings, enhancing reproducibility and safety.

Research Limitations and Future Directions ​

While synthetic scaffolds show promise, challenges remain, including:

  • The need for optimization to meet specific cellular requirements for different applications.
  • The cost of synthetic peptides and growth factors required for effective cell culture.
  • User-friendly scaffold preparation methods to encourage widespread adoption.

Future research should focus on:

  • Developing cost-effective synthetic scaffolds.
  • Creating versatile scaffolds that can adapt to various cell types and applications.
  • Establishing standardized protocols for scaffold use in clinical settings to ensure consistency and reliability.

References ​

  1. Synthetic hydrogels for human intestinal organoid generation and colonic wound repair. - Ricardo Cruz-Acuña;Miguel Quirós;Attila E Farkas;Priya H Dedhia;Sha Huang;Dorothée Siuda;Vicky García-Hernández;Alyssa J Miller;Jason R Spence;Asma Nusrat;Andrés J García - Nature cell biology (2017)
  2. Identification of endothelial cell binding sites on the laminin gamma 1 chain. - M L Ponce;M Nomizu;M C Delgado;Y Kuratomi;M P Hoffman;S Powell;Y Yamada;H K Kleinman;K M Malinda - Circulation research (1999)
  3. Heparin-based hydrogels induce human renal tubulogenesis in vitro. - Heather M Weber;Mikhail V Tsurkan;Valentina Magno;Uwe Freudenberg;Carsten Werner - Acta biomaterialia (2017)
  4. Human pluripotent stem cell culture: considerations for maintenance, expansion, and therapeutics. - Kevin G Chen;Barbara S Mallon;Ronald D G McKay;Pamela G Robey - Cell stem cell (2014)
  5. Immobilization of Cell-Adhesive Laminin Peptides in Degradable PEGDA Hydrogels Influences Endothelial Cell Tubulogenesis. - Saniya Ali;Jennifer E Saik;Dan J Gould;Mary E Dickinson;Jennifer L West - BioResearch open access (2013)
  6. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. - J Gray Camp;Farhath Badsha;Marta Florio;Sabina Kanton;Tobias Gerber;Michaela Wilsch-Bräuninger;Eric Lewitus;Alex Sykes;Wulf Hevers;Madeline Lancaster;Juergen A Knoblich;Robert Lachmann;Svante Pääbo;Wieland B Huttner;Barbara Treutlein - Proceedings of the National Academy of Sciences of the United States of America (2015)
  7. Perlecan--a multifunctional extracellular proteoglycan scaffold. - Mary C Farach-Carson;Daniel D Carson - Glycobiology (2007)
  8. Single-cell PCR analysis of murine embryonic stem cells cultured on different substrates highlights heterogeneous expression of stem cell markers. - Chiara Franzin;Martina Piccoli;Elena Serena;Enrica Bertin;Luca Urbani;Camilla Luni;Valerie Pasqualetto;Simon Eaton;Nicola Elvassore;Paolo De Coppi;Michela Pozzobon - Biology of the cell (2013)
  9. The elastic modulus of Matrigel as determined by atomic force microscopy. - Shauheen S Soofi;Julie A Last;Sara J Liliensiek;Paul F Nealey;Christopher J Murphy - Journal of structural biology (2009)
  10. PEG hydrogels for the controlled release of biomolecules in regenerative medicine. - Chien-Chi Lin;Kristi S Anseth - Pharmaceutical research (2009)

Literatures Citing This Work ​

  1. Translating Embryogenesis to Generate Organoids: Novel Approaches to Personalized Medicine. - Sounak Sahu;Shyam K Sharan - iScience (2020)
  2. Engineered tissues and strategies to overcome challenges in drug development. - Andrew S Khalil;Rudolf Jaenisch;David J Mooney - Advanced drug delivery reviews (2020)
  3. Screening method to identify hydrogel formulations that facilitate myotube formation from encapsulated primary myoblasts. - Dhananjay V Deshmukh;Nils Pasquero;Gajraj Rathore;Joel Zvick;Ori Bar-Nur;Jurg Dual;Mark W Tibbitt - Bioengineering & translational medicine (2020)
  4. A materials-science perspective on tackling COVID-19. - Zhongmin Tang;Na Kong;Xingcai Zhang;Yuan Liu;Ping Hu;Shan Mou;Peter Liljeström;Jianlin Shi;Weihong Tan;Jong Seung Kim;Yihai Cao;Robert Langer;Kam W Leong;Omid C Farokhzad;Wei Tao - Nature reviews. Materials (2020)
  5. Optimal, Large-Scale Propagation of Mouse Mammary Tumor Organoids. - Emma D Wrenn;Breanna M Moore;Erin Greenwood;Margaux McBirney;Kevin J Cheung - Journal of mammary gland biology and neoplasia (2020)
  6. Developmentally-Inspired Biomimetic Culture Models to Produce Functional Islet-Like Cells From Pluripotent Precursors. - Raymond Tran;Christopher Moraes;Corinne A Hoesli - Frontiers in bioengineering and biotechnology (2020)
  7. Natural and Synthetic Biomaterials for Engineering Multicellular Tumor Spheroids. - Advika Kamatar;Gokhan Gunay;Handan Acar - Polymers (2020)
  8. From 2D to 3D Cancer Cell Models-The Enigmas of Drug Delivery Research. - Indra Van Zundert;Beatrice Fortuni;Susana Rocha - Nanomaterials (Basel, Switzerland) (2020)
  9. Intestinal Morphogenesis in Development, Regeneration, and Disease: The Potential Utility of Intestinal Organoids for Studying Compartmentalization of the Crypt-Villus Structure. - Ohman Kwon;Tae-Su Han;Mi-Young Son - Frontiers in cell and developmental biology (2020)
  10. Engineering a Chemically Defined Hydrogel Bioink for Direct Bioprinting of Microvasculature. - Ryan W Barrs;Jia Jia;Michael Ward;Dylan J Richards;Hai Yao;Michael J Yost;Ying Mei - Biomacromolecules (2021)

... (391 more literatures)

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