Laura Rijns

All Publications

• Mimicking the extracellular world: from natural to fully synthetic matrices utilizing supramolecular biomaterials. Nanoscale Rijns, L., Rutten, M. G., Vrehen, A. F., Aldana, A. A., Baker, M. B., Dankers, P. Y. 2024

  Abstract

  The extracellular matrix (ECM) has evolved around complex covalent and non-covalent interactions to create impressive function-from cellular signaling to constant remodeling. A major challenge in the biomedical field is the de novo design and control of synthetic ECMs for applications ranging from tissue engineering to neuromodulation to bioelectronics. As we move towards recreating the ECM's complexity in hydrogels, the field has taken several approaches to recapitulate the main important features of the native ECM (i.e. mechanical, bioactive and dynamic properties). In this review, we first describe the wide variety of hydrogel systems that are currently used, ranging from fully natural to completely synthetic to hybrid versions, highlighting the advantages and limitations of each class. Then, we shift towards supramolecular hydrogels that show great potential for their use as ECM mimics due to their biomimetic hierarchical structure, inherent (controllable) dynamic properties and their modular design, allowing for precise control over their mechanical and biochemical properties. In order to make the next step in the complexity of synthetic ECM-mimetic hydrogels, we must leverage the supramolecular self-assembly seen in the native ECM; we therefore propose to use supramolecular monomers to create larger, hierarchical, co-assembled hydrogels with complex and synergistic mechanical, bioactive and dynamic features.

  View details for DOI 10.1039/d4nr02088j

  View details for PubMedID 39161293

• Co-Assembled Supramolecular Hydrogelators Enhance Glomerulogenesis in Kidney Organoids Through Cell-Adhesive Motifs ADVANCED FUNCTIONAL MATERIALS van Sprang, J. F., Aarts, J. M., Rutten, M. A., Rijns, L., Tiemeijer, B. M., Schotman, M. G., Dankers, P. W. 2024; 34 (42)

  View details for DOI 10.1002/adfm.202404786

  View details for Web of Science ID 001287714700001

• Molecularly Engineered Supramolecular Thermoresponsive Hydrogels with Tunable Mechanical and Dynamic Properties. Biomacromolecules Rijns, L., Duijs, H., Lafleur, R. P., Cardinaels, R., Palmans, A. R., Dankers, P. Y., Su, L. 2024

  Abstract

  Synthetic supramolecular polymers and hydrogels in water are emerging as promising biomaterials due to their modularity and intrinsic dynamics. Here, we introduce temperature sensitivity into the nonfunctionalized benzene-1,3,5-tricarboxamide (BTA-EG4) supramolecular system by incorporating a poly(N-isopropylacrylamide)-functionalized (BTA-PNIPAM) moiety, enabling 3D cell encapsulation applications. The viscous and structural properties in the solution state as well as the mechanical and dynamic features in the gel state of BTA-PNIPAM/BTA-EG4 mixtures were investigated and modulated. In the dilute state (c ∼μM), BTA-PNIPAM acted as a chain capper below the cloud point temperature (Tcp = 24 °C) but served as a cross-linker above Tcp. At higher concentrations (c ∼mM), weak or stiff hydrogels were obtained, depending on the BTA-PNIPAM/BTA-EG4 ratio. The mixture with the highest BTA-PNIPAM ratio was ∼100 times stiffer and ∼10 times less dynamic than BTA-EG4 hydrogel. Facile cell encapsulation in 3D was realized by leveraging the temperature-sensitive sol-gel transition, opening opportunities for utilizing this hydrogel as an extracellular matrix mimic.

  View details for DOI 10.1021/acs.biomac.3c01357

  View details for PubMedID 39059106

• Using Chemistry To Recreate the Complexity of the Extracellular Matrix: Guidelines for Supramolecular Hydrogel-Cell Interactions. Journal of the American Chemical Society Rijns, L., Baker, M. B., Dankers, P. Y. 2024

  Abstract

  Hydrogels have emerged as a promising class of extracellular matrix (ECM)-mimicking materials in regenerative medicine. Here, we briefly describe current state-of-the-art of ECM-mimicking hydrogels, ranging from natural to hybrid to completely synthetic versions, giving the prelude to the importance of supramolecular interactions to make true ECM mimics. The potential of supramolecular interactions to create ECM mimics for cell culture is illustrated through a focus on two different supramolecular hydrogel systems, both developed in our laboratories. We use some recent, significant findings to present important design principles underlying the cell-material interaction. To achieve cell spreading, we propose that slow molecular dynamics (monomer exchange within fibers) is crucial to ensure the robust incorporation of cell adhesion ligands within supramolecular fibers. Slow bulk dynamics (stress-relaxation─fiber rearrangements, τ1/2 ≈ 1000 s) is required to achieve cell spreading in soft gels (<1 kPa), while gel stiffness overrules dynamics in stiffer gels. Importantly, this resonates with the findings of others which specialize in different material types: cell spreading is impaired in case substrate relaxation occurs faster than clutch binding and focal adhesion lifetime. We conclude with discussing considerations and limitations of the supramolecular approach as well as provide a forward thinking perspective to further understand supramolecular hydrogel-cell interactions. Future work may utilize the presented guidelines underlying cell-material interactions to not only arrive at the next generation of ECM-mimicking hydrogels but also advance other fields, such as bioelectronics, opening up new opportunities for innovative applications.

  View details for DOI 10.1021/jacs.4c02980

  View details for PubMedID 38888174

• BALANCING SCAFFOLD DEGRADATION AND NEO-TISSUE FORMATION IN IN-SITU TISSUE ENGINEERED VASCULAR GRAFTS. Tissue engineering. Part A Uiterwijk, M., Coolen, B., Rijswijk van, J. W., Söntjens, S., van Houtem, M., Szymczyk, W., Rijns, L., Janssen, H., Wal van der, A., Mol de, B., Bouten, C., Strijkers, G., Dankers, P., Kluin, J. 2024

  Abstract

  An essential aspect of cardiovascular in situ tissue engineering (TE) is to ensure balance between scaffold degradation and neo-tissue formation. We evaluated the degradation velocity and neo-tissue formation of three electrospun supramolecular bisurea-based biodegradable scaffolds that differ in their soft-block backbone compositions only. Scaffolds were implanted as interposition grafts in the abdominal aorta in rats, and evaluated at different time points (t = 1, 6, 12, 24 and 40 weeks) on function, tissue formation, strength and scaffold degradation. The fully carbonate-based biomaterial showed minor degradation after 40 weeks in vivo, while the other two ester-containing biomaterials showed (near) complete degradation within 6 to 12 weeks. Local dilatation was only observed in these faster degrading scaffolds. All materials showed to some extent calcifications, at early as well as late time points. Histological evaluation showed equal and non-native like neo-tissue formation after total degradation. The fully carbonate based scaffolds lagged in neo-tissue formation, presumably as its degradation was (far from) complete at 40 weeks. A significant difference in vessel wall contrast enhancement was observed by MRI between grafts with total compared to minimal degraded scaffolds.

  View details for DOI 10.1089/ten.TEA.2023.0019

  View details for PubMedID 38420632

• Bisurea-Based Supramolecular Polymers for Tunable Biomaterials. Chemistry (Weinheim an der Bergstrasse, Germany) Vleugels, M., Bosman, R., da Camino, P., Wijker, S., Fehér, B., Spiering, J., Rijns, L., Bellan, R., Dankers, P., Palmans, A. R. 2023: e202303361

  Abstract

  Water-soluble supramolecular polymers show great potential to develop dynamic biomaterials with tailored properties. Here, we elucidate the morphology, stability and dynamicity of supramolecular polymers derived from bisurea-based monomers. An accessible synthetic approach from 2,4-toluene diisocyanate (TDI) as the starting material is developed. TDI has two isocyanates that differ in intrinsic reactivity, which allows to obtain functional, desymmetrized monomers in a one-step procedure. We explore how the hydrophobic/hydrophilic ratio affects the properties of the formed supramolecular polymers by increasing the number of methylene units from 10 to 12 keeping the hydrophilic hexa(ethylene glycol) constant. All bisurea-based monomers form long, fibrous structures with 3-5 monomers in the cross-section in water, indicating a proper hydrophobic\hydrophilic balance. The stability of the supramolecular polymers increases with an increasing amount of methylene units, whereas the dynamic nature of the monomers decreases. The introduction of one Cy3 dye affords modified supramolecular monomers, which co-assemble with the unmodified monomers into fibrous structures. All systems show excellent water-compatibility and no toxicity for different cell-lines. Importantly, in cell culture media, the fibrous structures remain present, highlighting the stability of these supramolecular polymers in physiological conditions. The results obtained here motivate further investigation of these bisurea-based building blocks as dynamic biomaterial.

  View details for DOI 10.1002/chem.202303361

  View details for PubMedID 38032693

• Importance of Molecular and Bulk Dynamics in Supramolecular Hydrogels in Dictating Cellular Spreading CHEMISTRY OF MATERIALS Rijns, L., Peeters, J. W., Hendrikse, S. S., Vleugels, M. J., Lou, X., Janssen, H. M., Meijer, E. W., Dankers, P. W. 2023; 35 (19): 8203-8217

  View details for DOI 10.1021/acs.chemmater.3c01676

  View details for Web of Science ID 001069987200001

• Controlled, supramolecular polymer formulation to engineer hydrogels with tunable mechanical and dynamic properties JOURNAL OF POLYMER SCIENCE Rutten, M. A., Rijns, L., Dankers, P. W. 2023

  View details for DOI 10.1002/pol.20230283

  View details for Web of Science ID 001072556800001

• The Importance of Effective Ligand Concentration to Direct Epithelial Cell Polarity in Dynamic Hydrogels. Advanced materials (Deerfield Beach, Fla.) Rijns, L., Hagelaars, M. J., van der Tol, J. J., Loerakker, S., Bouten, C. V., Dankers, P. Y. 2023: e2300873

  Abstract

  Epithelial cysts and organoids are multicellular hollow structures formed by correctly polarized epithelial cells. Important in steering these cysts from single cells is the dynamic regulation of extracellular matrix presented ligands, and matrix dynamics. Here, control over the effective ligand concentration is introduced, decoupled from bulk and local mechanical properties, in synthetic dynamic supramolecular hydrogels formed through noncovalent crosslinking of supramolecular fibers. Control over the effective ligand concentration is realized by 1) keeping the ligand concentration constant, but changing the concentration of nonfunctionalized molecules or by 2) varying the ligand concentration, while keeping the concentration of non-functionalized molecules constant. The results show that in 2D, the effective ligand concentration within the supramolecular fibers rather than gel stiffness (from 0.1 to 8 kPa) regulates epithelial polarity. In 3D, increasing the effective ligand concentration from 0.5 × 10-3 to 2 × 10-3 m strengthens the effect of increased gel stiffness from 0.1 to 2 kPa, to synergistically yield more correctly polarized cysts. Through integrin manipulation, it is shown that epithelial polarity is regulated by tension-based homeostasis between cells and matrix. The results reveal the effective ligand concentration as influential factor in regulating epithelial polarity and provide insights on engineering of synthetic biomaterials for cell and organoid culture.

  View details for DOI 10.1002/adma.202300873

  View details for PubMedID 37264535

• Engineering Strategies to Move from Understanding to Steering Renal Tubulogenesis. Tissue engineering. Part B, Reviews Hagelaars, M. J., Rijns, L., Dankers, P. Y., Loerakker, S., Bouten, C. V. 2023; 29 (3): 203-216

  Abstract

  Rebuilding the kidney in the context of tissue engineering offers a major challenge as the organ is structurally complex and has a high variety of specific functions. Recreation of kidney function is inherently connected to the formation of tubules since the functional subunit of the kidney, the nephron, is based on tubular structures. In vivo, tubulogenesis culminates in a perfectly shaped, patterned, and functional renal tubule via different morphogenic processes that depend on delicately orchestrated chemical, physical, and mechanical interactions between cells and between cells and their microenvironment. This review summarizes the current understanding of the role of the microenvironment in the morphogenic processes involved in in vivo renal tubulogenesis. We highlight the current state-of-the-art of renal tubular engineering and provide a view on the design elements that can be extracted from these studies. Next, we discuss how computational modeling can aid in specifying and identifying design parameters and provide directions on how these design parameters can be incorporated in biomaterials for the purpose of engineering renal tubulogenesis. Finally, we propose that a step-by-step reciprocal interaction between understanding and engineering is necessary to effectively guide renal tubulogenesis. Impact statement Tubular tissue engineering lies at the foundation of regenerating kidney tissue function, as the functional subunit of the kidney, the nephron, is based on tubular structures. Guiding renal tubulogenesis toward functional renal tubules requires in-depth knowledge of the developmental processes that lead to the formation of native tubules as well as engineering approaches to steer these processes. In this study, we review the role of the microenvironment in the developmental processes that lead to functional renal tubules and give directions how this knowledge can be harnessed for biomaterial-based tubular engineering using computational models.

  View details for DOI 10.1089/ten.TEB.2022.0120

  View details for PubMedID 36173101

• Introducing carbohydrate patterning in mannose-decorated supramolecular assemblies and hydrogels. Chemical communications (Cambridge, England) Rijns, L., Su, L., Maxeiner, K., Morgese, G., Ng, D. Y., Weil, T., Dankers, P. Y. 2023; 59 (15): 2090-2093

  Abstract

  Benzene-1,3,5-tricarboxamide (BTA) glyco-monomers containing one, two or three mannose units are synthesized and formulated into differently patterned supramolecular glycopolymers through homo-assembly or co-assembly with non-functionalized BTAs. Unfortunately, no cellular activity could be detected. Excitingly, these glyco-BTA monomers could be formulated into hydrogels, paving the way for (immune) cell culture.

  View details for DOI 10.1039/d2cc06064g

  View details for PubMedID 36723198

  View details for PubMedCentralID PMC9933453

• Engineered hydrogels for mechanobiology NATURE REVIEWS METHODS PRIMERS Blache, U., Ford, E. M., Ha, B., Rijns, L., Chaudhuri, O., Dankers, P. W., Kloxin, A. M., Snedeker, J. G., Gentleman, E. 2022; 2 (1)

  View details for DOI 10.1038/s43586-022-00179-7

  View details for Web of Science ID 000899042600002

• Towards understanding the messengers of extracellular space: Computational models of outside-in integrin reaction networks. Computational and structural biotechnology journal Karagöz, Z., Rijns, L., Dankers, P. Y., van Griensven, M., Carlier, A. 2021; 19: 303-314

  Abstract

  The interactions between cells and their extracellular matrix (ECM) are critically important for homeostatic control of cell growth, proliferation, differentiation and apoptosis. Transmembrane integrin molecules facilitate the communication between ECM and the cell. Since the characterization of integrins in the late 1980s, there has been great advancement in understanding the function of integrins at different subcellular levels. However, the versatility in molecular pathways integrins are involved in, the high diversity in their interaction partners both outside and inside the cell as well as on the cell membrane and the short lifetime of events happening at the cell-ECM interface make it difficult to elucidate all the details regarding integrin function experimentally. To overcome the experimental challenges and advance the understanding of integrin biology, computational modeling tools have been used extensively. In this review, we summarize the computational models of integrin signaling while we explain the function of integrins at three main subcellular levels (outside the cell, cell membrane, cytosol). We also discuss how these computational modeling efforts can be helpful in other disciplines such as biomaterial design. As such, this review is a didactic modeling summary for biomaterial researchers interested in complementing their experimental work with computational tools or for seasoned computational scientists that would like to advance current in silico integrin models.

  View details for DOI 10.1016/j.csbj.2020.12.025

  View details for PubMedID 33425258

  View details for PubMedCentralID PMC7779863