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Dynamic matrices with DNA-encoded viscoelasticity for cell and organoid culture.
Literature Information
| DOI | 10.1038/s41565-023-01483-3 |
|---|---|
| PMID | 37550574 |
| Journal | Nature nanotechnology |
| Impact Factor | 34.9 |
| JCR Quartile | Q1 |
| Publication Year | 2023 |
| Times Cited | 28 |
| Keywords | DNA-crosslinked matrix, viscoelasticity, cell culture, tissue engineering, self-healing |
| Literature Type | Journal Article |
| ISSN | 1748-3387 |
| Pages | 1463-1473 |
| Issue | 18(12) |
| Authors | Yu-Hsuan Peng, Syuan-Ku Hsiao, Krishna Gupta, André Ruland, Günter K Auernhammer, Manfred F Maitz, Susanne Boye, Johanna Lattner, Claudia Gerri, Alf Honigmann, Carsten Werner, Elisha Krieg |
TL;DR
This study introduces DyNAtrix, a fully synthetic hydrogel that self-assembles using DNA libraries to create a dynamic, programmable matrix with tunable viscoelastic properties, mimicking the mechanical characteristics of living tissues. The ability to control cell-instructive properties and maintain high cell viability and proliferation highlights DyNAtrix's potential as a versatile platform for advancements in biomechanics, biophysics, and tissue engineering.
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DNA-crosslinked matrix · viscoelasticity · cell culture · tissue engineering · self-healing
Abstract
Three-dimensional cell and organoid cultures rely on the mechanical support of viscoelastic matrices. However, commonly used matrix materials lack control over key cell-instructive properties. Here we report on fully synthetic hydrogels based on DNA libraries that self-assemble with ultrahigh-molecular-weight polymers, forming a dynamic DNA-crosslinked matrix (DyNAtrix). DyNAtrix enables computationally predictable and systematic control over its viscoelasticity, thermodynamic and kinetic parameters by changing DNA sequence information. Adjustable heat activation allows homogeneous embedding of mammalian cells. Intriguingly, stress-relaxation times can be tuned over four orders of magnitude, recapitulating mechanical characteristics of living tissues. DyNAtrix is self-healing, printable, exhibits high stability, cyto- and haemocompatibility, and controllable degradation. DyNAtrix-based cultures of human mesenchymal stromal cells, pluripotent stem cells, canine kidney cysts and human trophoblast organoids show high viability, proliferation and morphogenesis. DyNAtrix thus represents a programmable and versatile precision matrix for advanced approaches to biomechanics, biophysics and tissue engineering.
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Primary Questions Addressed
- How can the tunable viscoelastic properties of DyNAtrix be optimized for specific cell types or applications in tissue engineering?
- What are the potential implications of using DNA-encoded matrices in regenerative medicine and how do they compare to traditional materials?
- In what ways could the self-healing properties of DyNAtrix enhance the longevity and functionality of organoid cultures in vitro?
- How does the incorporation of ultrahigh-molecular-weight polymers influence the mechanical stability and degradation rates of the DyNAtrix?
- What future research directions could explore the integration of DyNAtrix with other biomaterials or technologies for enhanced tissue engineering outcomes?
Key Findings
Research Background and Objectives
Three-dimensional (3D) cell and organoid cultures are essential for studying biological processes and developing therapies. Traditional viscoelastic matrices used for these cultures, such as animal-derived Matrigel, present challenges including batch variability and limited tunability of mechanical properties. This study introduces a novel fully synthetic hydrogel called DyNAtrix, which utilizes DNA libraries to create a dynamic, programmable matrix with enhanced control over its mechanical properties.
Main Methods/Materials/Experimental Design
The study employed a DNA-crosslinked hydrogel, DyNAtrix, made from a DNA-functionalized ultrahigh-molecular-weight (UHMW) polymer. The gelation process involved using combinatorial crosslinker libraries (CCLs) to enhance crosslinking efficiency at low DNA concentrations.
Key Steps in the Experimental Design
- Synthesis of DNA-functionalized UHMW Polymer: A polymer backbone was created with attached DNA strands to serve as anchor sites.
- Preparation of Combinatorial Crosslinker Libraries: Dual-splint designs were utilized to create libraries that enhanced crosslinking efficiency and tunability.
- Gelation of DyNAtrix: Gelation was achieved at low DNA concentrations, allowing for a stable matrix.
- Characterization of Mechanical Properties: The viscoelastic properties were assessed through rheological measurements, demonstrating the tunability of stress relaxation times.
- Cell Culture Experiments: Human mesenchymal stromal cells, pluripotent stem cells, and organoids were embedded in DyNAtrix to evaluate its suitability for 3D culture.
- Assessment of Cell Viability and Morphogenesis: Cell viability, proliferation, and morphological development were analyzed to determine the effectiveness of DyNAtrix as a culture matrix.
Key Results and Findings
- Mechanical Properties: DyNAtrix exhibited tunable viscoelasticity with stress relaxation times adjustable over four orders of magnitude, mimicking the mechanical characteristics of living tissues.
- Cell Viability: High viability (91-99%) of human mesenchymal stromal cells was observed over a week, outperforming traditional matrices.
- Organoid Development: DyNAtrix supported the growth of various organoids, including human trophoblast organoids, with similar outcomes to those grown in Matrigel.
- Self-healing and Printability: The hydrogel demonstrated self-healing properties and was suitable for bioprinting, allowing for the fabrication of complex 3D structures.
Main Conclusions/Significance/Innovativeness
DyNAtrix represents a significant advancement in the field of tissue engineering and regenerative medicine by providing a programmable, cost-effective, and biocompatible hydrogel that can be tailored to specific research needs. Its ability to mimic the mechanical properties of biological tissues while being fully synthetic addresses many limitations of current culture systems, paving the way for improved reproducibility and regulatory compliance in biomedical applications.
Research Limitations and Future Directions
- Limitations: The reliance on DNA crosslinkers, which may induce immunogenic responses, and the potential degradation of the hydrogel in biological environments are concerns that need addressing.
- Future Directions: Further research is needed to optimize the material for in vivo applications, including testing its performance in long-term studies and integrating additional functionalities such as bioactive molecules for enhanced cell signaling and interaction.
Summary Table of Key Features
| Feature | DyNAtrix | Traditional Matrigel |
|---|---|---|
| Source | Fully synthetic | Animal-derived |
| Tunability | High | Low |
| Cell Viability | 91-99% | Variable |
| Mechanical Mimicry | Excellent | Moderate |
| Self-healing | Yes | No |
| Printability | Yes | No |
This structured summary captures the essential elements of the study, highlighting the innovative aspects of DyNAtrix and its potential applications in biomedical research.
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Literatures Citing This Work
- Programmable and Reversible Integrin-Mediated Cell Adhesion Reveals Hysteresis in Actin Kinetics that Alters Subsequent Mechanotransduction. - Zheng Zhang;Hongyuan Zhu;Guoqing Zhao;Yunyi Miao;Lingzhu Zhao;Jinteng Feng;Huan Zhang;Run Miao;Lin Sun;Bin Gao;Wencheng Zhang;Zheng Wang;Jianfang Zhang;Ying Zhang;Hui Guo;Feng Xu;Tian Jian Lu;Guy M Genin;Min Lin - Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2023)
- Boosting cartilage repair with silk fibroin-DNA hydrogel-based cartilage organoid precursor. - Congyi Shen;Jian Wang;Guangfeng Li;Shuyue Hao;Yan Wu;Peiran Song;Yafei Han;Mengmeng Li;Guangchao Wang;Ke Xu;Hao Zhang;Xiaoxiang Ren;Yingying Jing;Ru Yang;Zhen Geng;Jiacan Su - Bioactive materials (2024)
- Unraveling the Dual-Stretch-Mode Impact on Tension Gauge Tethers' Mechanical Stability. - Jingzhun Liu;Jie Yan - Journal of the American Chemical Society (2024)
- Advancing Synthetic Hydrogels through Nature-Inspired Materials Chemistry. - Bram G Soliman;Ashley K Nguyen;J Justin Gooding;Kristopher A Kilian - Advanced materials (Deerfield Beach, Fla.) (2024)
- The Role of Biophysical Factors in Organ Development: Insights from Current Organoid Models. - Yofiel Wyle;Nathan Lu;Jason Hepfer;Rahul Sayal;Taylor Martinez;Aijun Wang - Bioengineering (Basel, Switzerland) (2024)
- Y-switch: a spring-loaded synthetic gene switch for robust DNA/RNA signal amplification and detection. - Krishna Gupta;Elisha Krieg - Nucleic acids research (2024)
- DNA microbeads for spatio-temporally controlled morphogen release within organoids. - Cassian Afting;Tobias Walther;Oliver M Drozdowski;Christina Schlagheck;Ulrich S Schwarz;Joachim Wittbrodt;Kerstin Göpfrich - Nature nanotechnology (2024)
- ECM-mimicking composite hydrogel for accelerated vascularized bone regeneration. - Guanglong Li;Fei Gao;Donglei Yang;Lu Lin;Weijun Yu;Jiaqi Tang;Ruhan Yang;Min Jin;Yuting Gu;Pengfei Wang;Eryi Lu - Bioactive materials (2024)
- Recent Development of Fibrous Hydrogels: Properties, Applications and Perspectives. - Wen Luo;Liujiao Ren;Bin Hu;Huali Zhang;Zhe Yang;Lin Jin;Di Zhang - Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2025)
- Acoustic virtual 3D scaffold for direct-interacting tumor organoid-immune cell coculture systems. - Han Shan;Maike Chen;Shuang Zhao;Xiongwei Wei;Mingde Zheng;Yixin Li;Qibo Lin;Zixi Jiang;Ziyan Chen;Chunlong Fei;Zhaoxi Li;Zeyu Chen;Xiang Chen - Science advances (2024)
... (18 more literatures)
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