Abstract
The need for improved prediction of clinical response is driving the development of cancer models with enhanced physiological relevance. A new concept of ‘precision biomaterials’ is emerging, encompassing patient-mimetic biomaterial models that seek to accurately detect, treat and model cancer by faithfully recapitulating key microenvironmental characteristics. Despite recent advances allowing tissue-mimetic stiffness and molecular composition to be replicated in vitro, approaches for reproducing the 3D fibre architectures found in tumour extracellular matrix (ECM) remain relatively unexplored. Although the precise influences of patient-specific fibre architecture are unclear, we summarize the known roles of tumour fibre architecture, underlining their implications in cell–matrix interactions and ultimately clinical outcome. We then explore the challenges in reproducing tissue-specific 3D fibre architecture(s) in vitro, highlighting relevant biomaterial fabrication techniques and their benefits and limitations. Finally, we discuss imaging and image analysis techniques (focussing on collagen I-optimized approaches) that could hold the key to mapping tumour-specific ECM into high-fidelity biomaterial models. We anticipate that an interdisciplinary approach, combining materials science, cancer research and image analysis, will elucidate the role of 3D fibre architecture in tumour development, leading to the next generation of patient-mimetic models for mechanistic studies and drug discovery.
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References
Theocharis, A. D., Manou, D. & Karamanos, N. K. The extracellular matrix as a multitasking player in disease. FEBS J. 286, 2830–2869 (2019).
Pickup, M. W., Mouw, J. K. & Weaver, V. M. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 15, 1243–1253 (2014).
Cox, T. R. & Erler, J. T. Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis. Models Mech. 4, 165–178 (2011).
Daley, W. P., Peters, S. B. & Larsen, M. Extracellular matrix dynamics in development and regenerative medicine. J. Cell Sci. 121, 255–264 (2008).
Naba, A. et al. The matrisome: in silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices. Mol. Cell. Proteom. 11, M111.014647 (2012). This paper details proteomic strategies to characterize normal and tumour extracellular matrix composition to facilitate broader application of these methods for studying disease.
Chen, S. et al. Cancer-associated fibroblasts suppress SOX2-induced dysplasia in a lung squamous cancer coculture. Proc. Natl Acad. Sci. USA 115, E11671–E11680 (2018).
Fischbach, C. et al. Engineering tumors with 3D scaffolds. Nat. Methods 4, 855–860 (2007).
Riedl, A. et al. Comparison of cancer cells in 2D vs 3D culture reveals differences in AKT-mTOR-S6K signaling and drug responses. J. Cell Sci. 130, 203–218 (2017).
Yamada, K. M. & Cukierman, E. Modeling tissue morphogenesis and cancer in 3D. Cell 130, 601–610 (2007).
Baker, B. M. & Chen, C. S. Deconstructing the third dimension: how 3D culture microenvironments alter cellular cues. J. Cell Sci. 125, 3015–3024 (2012).
Caballero, D. et al. Precision biomaterials in cancer theranostics and modelling. Biomaterials 280, 121299 (2022).
Curvello, R., Kast, V., Ordóñez-Morán, P., Mata, A. & Loessner, D. Biomaterial-based platforms for tumour tissue engineering. Nat. Rev. Mater. 8, 314–330 (2023).
Sievers, J., Mahajan, V., Welzel, P. B., Werner, C. & Taubenberger, A. Precision hydrogels for the study of cancer cell mechanobiology. Adv. Healthc. Mater. 12, e2202514 (2023).
Mullard, A. R&D re-balancing act. Nat. Rev. Drug Discov. 22, 258 (2023).
Brancato, V., Oliveira, J. M., Correlo, V. M., Reis, R. L. & Kundu, S. C. Could 3D models of cancer enhance drug screening? Biomaterials 232, 119744 (2020).
Rodenhizer, D., Dean, T., D’Arcangelo, E. & McGuigan, A. P. The current landscape of 3D in vitro tumor models: what cancer hallmarks are accessible for drug discovery? Adv. Healthc. Mater. 7, e1701174 (2018).
Ashworth, J. C. et al. Peptide gels of fully-defined composition and mechanics for probing cell-cell and cell-matrix interactions in vitro. Matrix Biol. 85–86, 15–33 (2020).
Gjorevski, N. et al. Designer matrices for intestinal stem cell and organoid culture. Nature 539, 560–564 (2016).
Micalet, A., Moeendarbary, E. & Cheema, U. 3D in vitro models for investigating the role of stiffness in cancer invasion. ACS Biomater. Sci. Eng. 9, 3729–3741 (2023).
Sokol, E. S. et al. Growth of human breast tissues from patient cells in 3D hydrogel scaffolds. Breast Cancer Res. 18, 19 (2016).
Bonnans, C., Chou, J. & Werb, Z. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol. 15, 786–801 (2014).
Winkler, J., Abisoye-Ogunniyan, A., Metcalf, K. J. & Werb, Z. Concepts of extracellular matrix remodelling in tumour progression and metastasis. Nat. Commun. 11, 5120 (2020).
Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20, 174–186 (2020).
Malik, R., Lelkes, P. I. & Cukierman, E. Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer. Trends Biotechnol. 33, 230–236 (2015).
Lee, S. et al. Differentially expressed genes regulating the progression of ductal carcinoma in situ to invasive breast cancer. Cancer Res. 72, 4574–4586 (2012).
Naba, A., Clauser, K. R., Lamar, J. M., Carr, S. A. & Hynes, R. O. Extracellular matrix signatures of human mammary carcinoma identify novel metastasis promoters. eLife 3, e01308 (2014).
Tian, C. et al. Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells. Proc. Natl Acad. Sci. USA 116, 19609–19618 (2019). This research demonstrates that individual matrisome proteins derived from pancreatic cancer stromal cells or from cancer cells differentially correlate with patient outcome.
Tian, C. et al. Cancer cell-derived matrisome proteins promote metastasis in pancreatic ductal adenocarcinoma. Cancer Res. 80, 1461–1474 (2020).
Ting, D. T. et al. Single-cell RNA sequencing identifies extracellular matrix gene expression by pancreatic circulating tumor cells. Cell Rep. 8, 1905–1918 (2014).
Vargas, A. C. et al. Gene expression profiling of tumour epithelial and stromal compartments during breast cancer progression. Breast Cancer Res. Treat. 135, 153–165 (2012).
Chitty, J. L. et al. A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer. Nat. Cancer 4, 1326–1344 (2023).
Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009). This article demonstrates that collagen crosslinking and stiffening underpins breast tumorigenesis, highlighting how collagen architecture influences breast cancer malignancy.
Liu, D. & Hornsby, P. J. Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res. 67, 3117–3126 (2007).
Mangala, L. S., Fok, J. Y., Zorrilla-Calancha, I. R., Verma, A. & Mehta, K. Tissue transglutaminase expression promotes cell attachment, invasion and survival in breast cancer cells. Oncogene 26, 2459–2470 (2007).
Shinde, A. et al. Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche. Oncogenesis 9, 16 (2020).
Acerbi, I. et al. Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr. Biol. 7, 1120–1134 (2015).
Goetz, J. G. et al. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 146, 148–163 (2011).
Provenzano, P. P., Inman, D. R., Eliceiri, K. W., Trier, S. M. & Keely, P. J. Contact guidance mediated three-dimensional cell migration is regulated by Rho/ROCK-dependent matrix reorganization. Biophys. J. 95, 5374–5384 (2008).
Conklin, M. W. et al. Collagen alignment as a predictor of recurrence after ductal carcinoma in situ. Cancer Epidemiol. Biomark. Prev. 27, 138–145 (2018).
Piersma, B., Hayward, M.-K. & Weaver, V. M. Fibrosis and cancer: a strained relationship. Biochim. Biophys. Acta Rev. Cancer 1873, 188356 (2020).
Brauchle, E. et al. Biomechanical and biomolecular characterization of extracellular matrix structures in human colon carcinomas. Matrix Biol. 68–69, 180–193 (2018).
Bredfeldt, J. S. et al. Computational segmentation of collagen fibers from second-harmonic generation images of breast cancer. J. Biomed. Opt. 19, 16007 (2014).
Guo, Y. P. et al. Growth factors and stromal matrix proteins associated with mammographic densities. Cancer Epidemiol. Biomark. Prev. 10, 243–248 (2001).
McCormack, V. A. & dos Santos Silva, I. Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol. Biomark. Prev. 15, 1159–1169 (2006).
McConnell, J. C. et al. Increased peri-ductal collagen micro-organization may contribute to raised mammographic density. Breast Cancer Res. 18, 5 (2016).
Provenzano, P. P. et al. Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med. 4, 38 (2006). This is a landmark paper defining the three TACS that have since been shown to be diagnostic and prognostic of disease progression and outcome.
Conklin, M. W. et al. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am. J. Pathol. 178, 1221–1232 (2011).
Xi, G. et al. Large-scale tumor-associated collagen signatures identify high-risk breast cancer patients. Theranostics 11, 3229–3243 (2021).
Ray, A. et al. Stromal architecture directs early dissemination in pancreatic ductal adenocarcinoma. JCI Insight 7, e150330 (2022).
Kirkpatrick, N. D., Brewer, M. A. & Utzinger, U. Endogenous optical biomarkers of ovarian cancer evaluated with multiphoton microscopy. Cancer Epidemiol. Biomark. Prev. 16, 2048–2057 (2007).
Wen, B. et al. 3D texture analysis for classification of second harmonic generation images of human ovarian cancer. Sci. Rep. 6, 35734 (2016).
Sendín-Martín, M. et al. Quantitative collagen analysis using second harmonic generation images for the detection of basal cell carcinoma with ex vivo multiphoton microscopy. Exp. Dermatol. 32, 392–402 (2023).
Laklai, H. et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat. Med. 22, 497–505 (2016).
Almici, E. et al. Quantitative image analysis of fibrillar collagens reveals novel diagnostic and prognostic biomarkers and histotype-dependent aberrant mechanobiology in lung cancer. Mod. Pathol. 36, 100155 (2023).
Ikuta, D. et al. Fibrosis in metastatic lymph nodes is clinically correlated to poor prognosis in colorectal cancer. Oncotarget 9, 29574–29586 (2018).
Pearce, O. M. T. et al. Deconstruction of a metastatic tumor microenvironment reveals a common matrix response in human cancers. Cancer Discov. 8, 304–319 (2018). This study demonstrates that multi-omics characterization of the evolving human metastatic microenvironment from patient samples can be used to define matrisome signatures distinguishing patients with a shorter overall survival in ovarian and 12 other primary solid cancers.
Zhang, C. et al. Fibrotic microenvironment promotes the metastatic seeding of tumor cells via activating the fibronectin 1/secreted phosphoprotein 1-integrin signaling. Oncotarget 7, 45702–45714 (2016).
Erler, J. T. et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15, 35–44 (2009).
Cox, T. R. et al. LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res. 73, 1721–1732 (2013).
Afasizheva, A. et al. Mitogen-activated protein kinase signaling causes malignant melanoma cells to differentially alter extracellular matrix biosynthesis to promote cell survival. BMC Cancer 16, 186 (2016).
Farmer, P. et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat. Med. 15, 68–74 (2009).
Principe, D. R. et al. Long-term gemcitabine treatment reshapes the pancreatic tumor microenvironment and sensitizes murine carcinoma to combination immunotherapy. Cancer Res. 80, 3101–3115 (2020).
Shen, C. J. et al. Ionizing radiation induces tumor cell lysyl oxidase secretion. BMC Cancer 14, 532 (2014).
Barker, H. E., Paget, J. T. E., Khan, A. A. & Harrington, K. J. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat. Rev. Cancer 15, 409–425 (2015).
Mancini, M. L. & Sonis, S. T. Mechanisms of cellular fibrosis associated with cancer regimen-related toxicities. Front. Pharmacol. 5, 51 (2014).
Berestjuk, I. et al. Targeting discoidin domain receptors DDR1 and DDR2 overcomes matrix-mediated tumor cell adaptation and tolerance to BRAF-targeted therapy in melanoma. EMBO Mol. Med. 14, e11814 (2022).
Cuzick, J., Warwick, J., Pinney, E., Warren, R. M. L. & Duffy, S. W. Tamoxifen and breast density in women at increased risk of breast cancer. J. Natl Cancer Inst. 96, 621–628 (2004).
Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014).
Maller, O. et al. Collagen architecture in pregnancy-induced protection from breast cancer. J. Cell Sci. 126, 4108–4110 (2013).
Chandler, C., Liu, T., Buckanovich, R. & Coffman, L. G. The double edge sword of fibrosis in cancer. Transl. Res. 209, 55–67 (2019).
Dibus, M., Joshi, O. & Ivaska, J. Novel tools to study cell-ECM interactions, cell adhesion dynamics and migration. Curr. Opin. Cell Biol. 88, 102355 (2024).
Humphries, J. D., Byron, A. & Humphries, M. J. Integrin ligands at a glance. J. Cell Sci. 119, 3901–3903 (2006).
Ray, A. & Provenzano, P. P. Aligned forces: origins and mechanisms of cancer dissemination guided by extracellular matrix architecture. Curr. Opin. Cell Biol. 72, 63–71 (2021).
Friedl, P. & Wolf, K. Plasticity of cell migration: a multiscale tuning model. J. Cell Biol. 188, 11–19 (2010).
Hayen, W., Goebeler, M., Kumar, S., Riessen, R. & Nehls, V. Hyaluronan stimulates tumor cell migration by modulating the fibrin fiber architecture. J. Cell Sci. 112, 2241–2251 (1999).
Murphy, C. M. & O’Brien, F. J. Understanding the effect of mean pore size on cell activity in collagen-glycosaminoglycan scaffolds. Cell Adhes. Migr. 4, 377–381 (2010).
Paul, C. D., Mistriotis, P. & Konstantopoulos, K. Cancer cell motility: lessons from migration in confined spaces. Nat. Rev. Cancer 17, 131–140 (2017).
Short, B. Testing the limits of cell migration. J. Cell Biol. 201, 965 (2013).
Wolf, K. et al. Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force. J. Cell Biol. 201, 1069–1084 (2013). This study describes the relationship between tumour fibre architecture and cell migration by identifying critical pore sizes at which migration is inhibited.
Fischer, R. S. et al. Contractility, focal adhesion orientation, and stress fiber orientation drive cancer cell polarity and migration along wavy ECM substrates. Proc. Natl Acad. Sci. USA 118, e2021135118 (2021).
Zanotelli, M. R. et al. Regulation of ATP utilization during metastatic cell migration by collagen architecture. Mol. Biol. Cell 29, 1–9 (2018).
Madamanchi, A., Zijlstra, A. & Zutter, M. M. Flipping the switch: integrin switching provides metastatic competence. Sci. Signal. 7, pe9 (2014).
Samaržija, I. et al. Integrin crosstalk contributes to the complexity of signalling and unpredictable cancer cell fates. Cancers 12, 1910 (2020).
Di Martino, J. et al. The microenvironment controls invadosome plasticity. J. Cell Sci. 129, 1759–1768 (2016).
Panková, K., Rösel, D., Novotný, M. & Brábek, J. The molecular mechanisms of transition between mesenchymal and amoeboid invasiveness in tumor cells. Cell. Mol. Life Sci. 67, 63–71 (2010).
Haeger, A., Krause, M., Wolf, K. & Friedl, P. Cell jamming: collective invasion of mesenchymal tumor cells imposed by tissue confinement. Biochim. Biophys. Acta 1840, 2386–2395 (2014).
Weigelin, B., Bakker, G.-J. & Friedl, P. Intravital third harmonic generation microscopy of collective melanoma cell invasion. Intravital 1, 32–43 (2012).
Ilina, O. et al. Cell-cell adhesion and 3D matrix confinement determine jamming transitions in breast cancer invasion. Nat. Cell Biol. 22, 1103–1115 (2020).
Khalil, A. A. et al. Collective invasion in ductal and lobular breast cancer associates with distant metastasis. Clin. Exp. Metastasis 34, 421–429 (2017).
Provenzano, P. P. et al. Collagen density promotes mammary tumor initiation and progression. BMC Med. 6, 11 (2008).
Gaggioli, C. et al. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat. Cell Biol. 9, 1392–1400 (2007).
Du, W., Xia, X., Hu, F. & Yu, J. Extracellular matrix remodeling in the tumor immunity. Front. Immunol. 14, 1340634 (2023).
Yuan, Z. et al. Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments. Mol. Cancer 22, 48 (2023).
Kuczek, D. E. et al. Collagen density regulates the activity of tumor-infiltrating T cells. J. Immunother. Cancer 7, 68 (2019).
Salmon, H. et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J. Clin. Invest. 122, 899–910 (2012).
Byers, C. et al. Tertiary lymphoid structures accompanied by fibrillary matrix morphology impact anti-tumor immunity in basal cell carcinomas. Front. Med. 9, 981074 (2022).
Netti, P. A., Berk, D. A., Swartz, M. A., Grodzinsky, A. J. & Jain, R. K. Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res. 60, 2497–2503 (2000).
Reyes-Ramos, A. M. et al. Collagen I fibrous substrates modulate the proliferation and secretome of estrogen receptor-positive breast tumor cells in a hormone-restricted microenvironment. ACS Biomater. Sci. Eng. 7, 2430–2443 (2021).
Gomez, D., Natan, S., Shokef, Y. & Lesman, A. Mechanical interaction between cells facilitates molecular transport. Adv. Biosys. 3, e1900192 (2019).
Wijeratne, P. A., Hipwell, J. H., Hawkes, D. J., Stylianopoulos, T. & Vavourakis, V. Multiscale biphasic modelling of peritumoural collagen microstructure: the effect of tumour growth on permeability and fluid flow. PLoS ONE 12, e0184511 (2017).
Jana, A., Ladner, K., Lou, E. & Nain, A. S. Tunneling nanotubes between cells migrating in ECM mimicking fibrous environments. Cancers 14, 1989 (2022).
Rustom, A., Saffrich, R., Markovic, I., Walther, P. & Gerdes, H.-H. Nanotubular highways for intercellular organelle transport. Science 303, 1007–1010 (2004).
Mierke, C. T. Viscoelasticity, like forces, plays a role in mechanotransduction. Front. Cell Dev. Biol. 10, 789841 (2022).
Chaudhuri, O., Cooper-White, J., Janmey, P. A., Mooney, D. J. & Shenoy, V. B. Effects of extracellular matrix viscoelasticity on cellular behaviour. Nature 584, 535–546 (2020).
Wang, H., Abhilash, A. S., Chen, C. S., Wells, R. G. & Shenoy, V. B. Long-range force transmission in fibrous matrices enabled by tension-driven alignment of fibers. Biophys. J. 107, 2592–2603 (2014).
Seo, B. R. et al. Collagen microarchitecture mechanically controls myofibroblast differentiation. Proc. Natl Acad. Sci. USA 117, 11387–11398 (2020).
Fattet, L. et al. Matrix rigidity controls epithelial-mesenchymal plasticity and tumor metastasis via a mechanoresponsive EPHA2/LYN complex. Dev. Cell 54, 302–316.e7 (2020).
Su, C.-Y. et al. Tumor stromal topography promotes chemoresistance in migrating breast cancer cell clusters. Biomaterials 298, 122128 (2023).
Pradhan, S., Hassani, I., Clary, J. M. & Lipke, E. A. Polymeric biomaterials for in vitro cancer tissue engineering and drug testing applications. Tissue Eng. B Rev. 22, 470–484 (2016).
Caliari, S. R. & Burdick, J. A. A practical guide to hydrogels for cell culture. Nat. Methods 13, 405–414 (2016).
Unnikrishnan, K., Thomas, L. V. & Ram Kumar, R. M. Advancement of scaffold-based 3D cellular models in cancer tissue engineering: an update. Front. Oncol. 11, 733652 (2021).
Passaniti, A., Kleinman, H. K. & Martin, G. R. Matrigel: history/background, uses, and future applications. J. Cell Commun. Signal. 16, 621–626 (2022).
Sachs, N. et al. A living biobank of breast cancer organoids captures disease heterogeneity. Cell 172, 373–386.e10 (2018).
Kaur, S., Kaur, I., Rawal, P., Tripathi, D. M. & Vasudevan, A. Non-Matrigel scaffolds for organoid cultures. Cancer Lett. 504, 58–66 (2021).
Curtis, K. J. et al. Mechanical stimuli and matrix properties modulate cancer spheroid growth in three-dimensional gelatin culture. J. R. Soc. Interface 17, 20200568 (2020).
Linke, F. et al. 3D hydrogels reveal medulloblastoma subgroup differences and identify extracellular matrix subtypes that predict patient outcome. J. Pathol. 253, 326–338 (2021).
Qiao, S.-P. et al. An alginate-based platform for cancer stem cell research. Acta Biomater. 37, 83–92 (2016).
Vining, K. H., Stafford, A. & Mooney, D. J. Sequential modes of crosslinking tune viscoelasticity of cell-instructive hydrogels. Biomaterials 188, 187–197 (2019).
Nam, S., Hu, K. H., Butte, M. J. & Chaudhuri, O. Strain-enhanced stress relaxation impacts nonlinear elasticity in collagen gels. Proc. Natl Acad. Sci. USA 113, 5492–5497 (2016).
Tse, J. R. & Engler, A. J. Preparation of hydrogel substrates with tunable mechanical properties. Curr. Protoc. Cell Biol. https://doi.org/10.1002/0471143030.cb1016s47 (2010).
Levental, I., Georges, P. C. & Janmey, P. A. Soft biological materials and their impact on cell function. Soft Matter 3, 299–306 (2007).
Ashworth, J. C. et al. Preparation of a user-defined peptide gel for controlled 3D culture models of cancer and disease. J. Vis. Exp. https://doi.org/10.3791/61710 (2020).
Gjorevski, N. & Lutolf, M. P. Synthesis and characterization of well-defined hydrogel matrices and their application to intestinal stem cell and organoid culture. Nat. Protoc. 12, 2263–2274 (2017).
Richardson, T. et al. Engineered peptide modified hydrogel platform for propagation of human pluripotent stem cells. Acta Biomater. 113, 228–239 (2020).
Rekad, Z., Izzi, V., Lamba, R., Ciais, D. & Van Obberghen-Schilling, E. The alternative matrisome: alternative splicing of ECM proteins in development, homeostasis and tumor progression. Matrix Biol. 111, 26–52 (2022).
Mredha, M. T. I. et al. A facile method to fabricate anisotropic hydrogels with perfectly aligned hierarchical fibrous structures. Adv. Mater. https://doi.org/10.1002/adma.201704937 (2018).
Prince, E., Chen, Z., Khuu, N. & Kumacheva, E. Nanofibrillar hydrogel recapitulates changes occurring in the fibrotic extracellular matrix. Biomacromolecules 22, 2352–2362 (2021).
McCoy, M. G., Seo, B. R., Choi, S. & Fischbach, C. Collagen I hydrogel microstructure and composition conjointly regulate vascular network formation. Acta Biomater. 44, 200–208 (2016).
Oh, S., Nguyen, Q. D., Chung, K.-H. & Lee, H. Bundling of collagen fibrils using sodium sulfate for biomimetic cell culturing. ACS Omega 5, 3444–3452 (2020).
Feng, C., Cheng, Y. & Chao, P. G. The influence and interactions of substrate thickness, organization and dimensionality on cell morphology and migration. Acta Biomater. 9, 5502–5510 (2013).
Nerger, B. A., Brun, P. T. & Nelson, C. M. Marangoni flows drive the alignment of fibrillar cell-laden hydrogels. Sci. Adv. 6, eaaz7748 (2020).
Mredha, M. T. I. et al. Anisotropic tough double network hydrogel from fish collagen and its spontaneous in vivo bonding to bone. Biomaterials 132, 85–95 (2017).
Wallace, M., Cardoso, A. Z., Frith, W. J., Iggo, J. A. & Adams, D. J. Magnetically aligned supramolecular hydrogels. Chem. Eur. J. 20, 16484–16487 (2014).
Abalymov, A., Pinchasik, B.-E., Akasov, R. A., Lomova, M. & Parakhonskiy, B. V. Strategies for anisotropic fibrillar hydrogels: design, cell alignment, and applications in tissue engineering. Biomacromolecules 24, 4532–4552 (2023).
Taufalele, P. V., VanderBurgh, J. A., Muñoz, A., Zanotelli, M. R. & Reinhart-King, C. A. Fiber alignment drives changes in architectural and mechanical features in collagen matrices. PLoS ONE 14, e0216537 (2019).
Sapudom, J. et al. The phenotype of cancer cell invasion controlled by fibril diameter and pore size of 3D collagen networks. Biomaterials 52, 367–375 (2015).
Riching, K. M. et al. 3D collagen alignment limits protrusions to enhance breast cancer cell persistence. Biophys. J. 107, 2546–2558 (2014).
Su, C.-Y. et al. Engineering a 3D collective cancer invasion model with control over collagen fiber alignment. Biomaterials 275, 120922 (2021).
Vader, D., Kabla, A., Weitz, D. & Mahadevan, L. Strain-induced alignment in collagen gels. PLoS ONE 4, e5902 (2009).
Liu, C. et al. Self-assembly of mesoscale collagen architectures and applications in 3D cell migration. Acta Biomater. 155, 167–181 (2023).
Gong, X., Kulwatno, J. & Mills, K. L. Rapid fabrication of collagen bundles mimicking tumor-associated collagen architectures. Acta Biomater. 108, 128–141 (2020).
Dewavrin, J.-Y., Hamzavi, N., Shim, V. P. W. & Raghunath, M. Tuning the architecture of three-dimensional collagen hydrogels by physiological macromolecular crowding. Acta Biomater. 10, 4351–4359 (2014).
Saiani, A. et al. Self-assembly and gelation properties of α-helix versus β-sheet forming peptides. Soft Matter 5, 193–202 (2009).
Xie, J., Bao, M., Bruekers, S. M. C. & Huck, W. T. S. Collagen gels with different fibrillar microarchitectures elicit different cellular responses. ACS Appl. Mater. Interfaces 9, 19630–19637 (2017).
Plou, J. et al. From individual to collective 3D cancer dissemination: roles of collagen concentration and TGF-β. Sci. Rep. 8, 12723 (2018).
Berger, A. J., Linsmeier, K. M., Kreeger, P. K. & Masters, K. S. Decoupling the effects of stiffness and fiber density on cellular behaviors via an interpenetrating network of gelatin-methacrylate and collagen. Biomaterials 141, 125–135 (2017).
Velez, D. O. et al. 3D collagen architecture induces a conserved migratory and transcriptional response linked to vasculogenic mimicry. Nat. Commun. 8, 1651 (2017). This article demonstrates the application of molecular crowding to achieve independent control over fibre architecture and collagen hydrogel stiffness, to show that matrix architecture (pore size and fibre length) regulates β1-integrin signalling and cancer cell motility.
Ranamukhaarachchi, S. K. et al. Macromolecular crowding tunes 3D collagen architecture and cell morphogenesis. Biomater. Sci. 7, 618–633 (2019).
Cavo, M. et al. Electrospun nanofibers in cancer research: from engineering of in vitro 3D cancer models to therapy. Biomater. Sci. 8, 4887–4905 (2020).
Fong, E. L. S. et al. Modeling Ewing sarcoma tumors in vitro with 3D scaffolds. Proc. Natl Acad. Sci. USA 110, 6500–6505 (2013).
Ameer, J. M., Pr, A. K. & Kasoju, N. Strategies to tune electrospun scaffold porosity for effective cell response in tissue engineering. J. Funct. Biomater. 10, 30 (2019).
Saha, S. et al. Electrospun fibrous scaffolds promote breast cancer cell alignment and epithelial-mesenchymal transition. Langmuir 28, 2028–2034 (2012).
Wang, K. et al. Creation of macropores in electrospun silk fibroin scaffolds using sacrificial PEO-microparticles to enhance cellular infiltration. J. Biomed. Mater. Res. A 101, 3474–3481 (2013).
Yucheng, Y., Glubay, S., Stirling, R., Ma, Q. & McKenzie, J. Improved fiber control through ohmic/convective flow behavior. J. Mater. Sci. 57, 10457–10469 (2022).
Wang, M. et al. Regulating mechanotransduction in three dimensions using sub‐cellular scale, crosslinkable fibers of controlled diameter, stiffness, and alignment. Adv. Funct. Mater. https://doi.org/10.1002/adfm.201808967 (2019).
Hoogenkamp, H. R. et al. Directing collagen fibers using counter-rotating cone extrusion. Acta Biomater. 12, 113–121 (2015).
Yang, S. et al. Oriented collagen fiber membranes formed through counter-rotating extrusion and their application in tendon regeneration. Biomaterials 207, 61–75 (2019).
Hong, J., Yeo, M., Yang, G. H. & Kim, G. Cell-electrospinning and its application for tissue engineering. Int. J. Mol. Sci. 20, 6208 (2019).
Grossman, M. et al. Tumor cell invasion can be blocked by modulators of collagen fibril alignment that control assembly of the extracellular matrix. Cancer Res. 76, 4249–4258 (2016).
Visser, D. et al. Electrospinning of collagen: enzymatic and spectroscopic analyses reveal solvent-independent disruption of the triple-helical structure. J. Mater. Chem. B Mater. Biol. Med. 11, 2207–2218 (2023).
Prieto, E. I., Mojares, E. B. A., Cortez, J. J. M. & Vasquez, M. R. Electrospun nanofiber scaffolds for the propagation and analysis of breast cancer stem cells in vitro. Biomed. Mater. 16, 035004 (2021).
Zeugolis, D. I. et al. Electro-spinning of pure collagen nano-fibres — just an expensive way to make gelatin? Biomaterials 29, 2293–2305 (2008). This is a key study that demonstrates the difficulty in electrospinning natural materials, showing for the first time the loss of the collagen triple helix in electrospun constructs.
Jordahl, S. et al. Engineered fibrillar fibronectin networks as three-dimensional tissue scaffolds. Adv. Mater. 31, e1904580 (2019).
Hiraki, H. L. et al. Magnetic alignment of electrospun fiber segments within a hydrogel composite guides cell spreading and migration phenotype switching. Front. Bioeng. Biotechnol. 9, 679165 (2021).
Sundararaghavan, H. G., Saunders, R. L., Hammer, D. A. & Burdick, J. A. Fiber alignment directs cell motility over chemotactic gradients. Biotechnol. Bioeng. 110, 1249–1254 (2013).
Yang, F., Han, L.-H. & Tong, X. Dynamic macropore formation using multiple porogens. Patent number US20140161843A1 (2014).
Ricci, C. et al. Interfacing polymeric scaffolds with primary pancreatic ductal adenocarcinoma cells to develop 3D cancer models. Biomatter 4, e955386 (2014).
Du, L. et al. Hierarchical macro/micro-porous silk fibroin scaffolds for tissue engineering. Mater. Lett. 236, 1–4 (2019).
Tammaro, D., Villone, M. M., D’Avino, G. & Maffettone, P. L. An experimental and numerical investigation on bubble growth in polymeric foams. Entropy 24, 183 (2022).
Chen, G., Ushida, T. & Tateishi, T. Scaffold design for tissue engineering. Macromol. Biosci. 2, 67–77 (2002).
Loh, Q. L. & Choong, C. Three-dimensional scaffolds for tissue engineering applications: role of porosity and pore size. Tissue Eng. B Rev. 19, 485–502 (2013).
Annabi, N. et al. Controlling the porosity and microarchitecture of hydrogels for tissue engineering. Tissue Eng. B Rev. 16, 371–383 (2010).
Ma, P. X. Scaffolds for tissue fabrication. Mater. Today 7, 30–40 (2004).
Lin, A. S. P., Barrows, T. H., Cartmell, S. H. & Guldberg, R. E. Microarchitectural and mechanical characterization of oriented porous polymer scaffolds. Biomaterials 24, 481–489 (2003).
Woo, K. M., Chen, V. J. & Ma, P. X. Nano-fibrous scaffolding architecture selectively enhances protein adsorption contributing to cell attachment. J. Biomed. Mater. Res. A 67, 531–537 (2003).
Aguado, B. A. et al. Extracellular matrix mediators of metastatic cell colonization characterized using scaffold mimics of the pre-metastatic niche. Acta Biomater. 33, 13–24 (2016).
Schoof, H., Apel, J., Heschel, I. & Rau, G. Control of pore structure and size in freeze-dried collagen sponges. J. Biomed. Mater. Res. 58, 352–357 (2001).
Schoof, H., Bruns, L., Fischer, A., Heschel, I. & Rau, G. Dendritic ice morphology in unidirectionally solidified collagen suspensions. J. Cryst. Growth 209, 122–129 (2000).
Kang, H. W., Tabata, Y. & Ikada, Y. Fabrication of porous gelatin scaffolds for tissue engineering. Biomaterials 20, 1339–1344 (1999).
Davidenko, N. et al. Biomimetic collagen scaffolds with anisotropic pore architecture. Acta Biomater. 8, 667–676 (2012).
Faraj, K. A., van Kuppevelt, T. H. & Daamen, W. F. Construction of collagen scaffolds that mimic the three-dimensional architecture of specific tissues. Tissue Eng. 13, 2387–2394 (2007).
Shepherd, J. H. et al. Structurally graduated collagen scaffolds applied to the ex vivo generation of platelets from human pluripotent stem cell-derived megakaryocytes: enhancing production and purity. Biomaterials 182, 135–144 (2018).
Campbell, J. J., Husmann, A., Hume, R. D., Watson, C. J. & Cameron, R. E. Development of three-dimensional collagen scaffolds with controlled architecture for cell migration studies using breast cancer cell lines. Biomaterials 114, 34–43 (2017).
Hume, R. D. et al. Tumour cell invasiveness and response to chemotherapeutics in adipocyte invested 3D engineered anisotropic collagen scaffolds. Sci. Rep. 8, 12658 (2018).
Yannas, I. V., Lee, E., Orgill, D. P., Skrabut, E. M. & Murphy, G. F. Synthesis and characterization of a model extracellular matrix that induces partial regeneration of adult mammalian skin. Proc. Natl Acad. Sci. USA 86, 933–937 (1989).
Hofmann, S. et al. Control of in vitro tissue-engineered bone-like structures using human mesenchymal stem cells and porous silk scaffolds. Biomaterials 28, 1152–1162 (2007).
Lu, H., Ko, Y.-G., Kawazoe, N. & Chen, G. Cartilage tissue engineering using funnel-like collagen sponges prepared with embossing ice particulate templates. Biomaterials 31, 5825–5835 (2010).
Wolf, K. et al. Collagen-based cell migration models in vitro and in vivo. Semin. Cell Dev. Biol. 20, 931–941 (2009).
Cyr, J. A., Husmann, A., Best, S. M. & Cameron, R. E. Complex architectural control of ice-templated collagen scaffolds using a predictive model. Acta Biomater. 153, 260–272 (2022). This study demonstrates application of multi-directional temperature gradients and finite element modelling to control and predict complex fibre architectures in ice-templated collagen scaffolds.
Pawelec, K. M., Husmann, A., Best, S. M. & Cameron, R. E. A design protocol for tailoring ice-templated scaffold structure. J. R. Soc. Interface 11, 20130958 (2014).
Song, X., Philpott, M. A., Best, S. M. & Cameron, R. E. Controlling the architecture of freeze-dried collagen scaffolds with ultrasound-induced nucleation. Polymers 16, 213 (2024).
Buttafoco, L. et al. First steps towards tissue engineering of small-diameter blood vessels: preparation of flat scaffolds of collagen and elastin by means of freeze drying. J. Biomed. Mater. Res. B Appl. Biomater. 77, 357–368 (2006).
Yang, F. et al. Manufacturing and morphology structure of polylactide-type microtubules orientation-structured scaffolds. Biomaterials 27, 4923–4933 (2006).
Ashworth, J. C., Mehr, M., Buxton, P. G., Best, S. M. & Cameron, R. E. Cell invasion in collagen scaffold architectures characterized by percolation theory. Adv. Healthc. Mater. 4, 1317–1321 (2015).
Caliari, S. R. et al. Collagen scaffold arrays for combinatorial screening of biophysical and biochemical regulators of cell behavior. Adv. Healthc. Mater. 4, 58–64 (2015).
Mayorca-Guiliani, A. E. et al. ISDoT: in situ decellularization of tissues for high-resolution imaging and proteomic analysis of native extracellular matrix. Nat. Med. 23, 890–898 (2017). Here, Mayorca-Guiliani et al. develop a new tissue decellularization platform for high-resolution characterization of the 3D tumour matrix, including high-resolution mapping of collagen architecture.
Jamaluddin, M. F. B. et al. Bovine and human endometrium-derived hydrogels support organoid culture from healthy and cancerous tissues. Proc. Natl Acad. Sci. USA 119, e2208040119 (2022).
Sensi, F. et al. Establishment of a human 3D pancreatic adenocarcinoma model based on a patient-derived extracellular matrix scaffold. Transl. Res. 253, 57–67 (2023).
Tian, X. et al. Organ-specific metastases obtained by culturing colorectal cancer cells on tissue-specific decellularized scaffolds. Nat. Biomed. Eng. 2, 443–452 (2018).
Fitzpatrick, L. E. & McDevitt, T. C. Cell-derived matrices for tissue engineering and regenerative medicine applications. Biomater. Sci. 3, 12–24 (2015).
Ragelle, H. et al. Comprehensive proteomic characterization of stem cell-derived extracellular matrices. Biomaterials 128, 147–159 (2017).
Rubí-Sans, G. et al. Development of cell-derived matrices for three-dimensional in vitro cancer cell models. ACS Appl. Mater. Interfaces 13, 44108–44123 (2021).
Almici, E., Caballero, D., Montero Boronat, J. & Samitier Martí, J. Engineering cell-derived matrices with controlled 3D architectures for pathophysiological studies. Methods Cell Biol. 156, 161–183 (2020).
Saldin, L. T., Cramer, M. C., Velankar, S. S., White, L. J. & Badylak, S. F. Extracellular matrix hydrogels from decellularized tissues: structure and function. Acta Biomater. 49, 1–15 (2017).
Caballero, D. & Samitier, J. Topological control of extracellular matrix growth: a native-like model for cell morphodynamics studies. ACS Appl. Mater. Interfaces 9, 4159–4170 (2017).
Caballero, D., Palacios, L., Freitas, P. P. & Samitier, J. An interplay between matrix anisotropy and actomyosin contractility regulates 3D‐directed cell migration. Adv. Funct. Mater. 27, 1702322 (2017). Cell-derived matrices, aligned using physical templates, are used in this study to demonstrate that fibre anisotropy dictates the directionality but not distance of cell migration.
Casale, C., Imparato, G., Mazio, C., Netti, P. A. & Urciuolo, F. Geometrical confinement controls cell, ECM and vascular network alignment during the morphogenesis of 3D bioengineered human connective tissues. Acta Biomater. 131, 341���354 (2021).
Wilks, B. T. et al. Quantifying cell-derived changes in collagen synthesis, alignment, and mechanics in a 3D connective tissue model. Adv. Sci. 9, e2103939 (2022).
Huang, G. et al. Functional and biomimetic materials for engineering of the three-dimensional cell microenvironment. Chem. Rev. 117, 12764–12850 (2017).
Franco-Barraza, J., Beacham, D. A., Amatangelo, M. D. & Cukierman, E. Preparation of extracellular matrices produced by cultured and primary fibroblasts. Curr. Protoc. Cell Biol. 71, 10.9.1–10.9.34 (2016).
Murphy, K. J. et al. Cell-derived matrix assays to assess extracellular matrix architecture and track cell movement. Bio. Protoc. 12, e4570 (2022).
Chan, W. W. et al. Towards biomanufacturing of cell-derived matrices. Int. J. Mol. Sci. 22, 11929 (2021).
Jones, S. et al. Application of a 3D hydrogel-based model to replace use of animals for passaging patient-derived xenografts. In Vitro Models 2, 99–111 (2023).
Conway, J. R. W. et al. Three-dimensional organotypic matrices from alternative collagen sources as pre-clinical models for cell biology. Sci. Rep. 7, 16887 (2017).
Ye, Z., Wandall, H. H. & Dabelsteen, S. Phosphoproteomic analysis and organotypic cultures for the study of signaling pathways. Bio Protoc. 14, e4941 (2024).
Yuan, H. et al. Synthetic fibrous hydrogels as a platform to decipher cell-matrix mechanical interactions. Proc. Natl Acad. Sci. USA 120, e2216934120 (2023).
Baker, B. M. et al. Cell-mediated fibre recruitment drives extracellular matrix mechanosensing in engineered fibrillar microenvironments. Nat. Mater. 14, 1262–1268 (2015). This study on cell response to microenvironmental stiffness in native-like extracellular matrices uses engineered synthetic fibrous materials mimicking collagen matrices.
Lim, K. S. et al. Fundamentals and applications of photo-cross-linking in bioprinting. Chem. Rev. 120, 10662–10694 (2020).
ISO/ASTM International. ISO/ASTM 52900: Additive Manufacturing — General Principles — Fundamentals and Vocabulary 2nd edn (ISO, 2021).
Shapira, A. & Dvir, T. 3D tissue and organ printing-hope and reality. Adv. Sci. 8, 2003751 (2021).
Spagnolo, B. et al. Three-dimensional cage-like microscaffolds for cell invasion studies. Sci. Rep. 5, 10531 (2015).
Tayalia, P., Mendonca, C. R., Baldacchini, T., Mooney, D. J. & Mazur, E. 3D cell-migration studies using two-photon engineered polymer scaffolds. Adv. Mater. 20, 4494–4498 (2008).
Alkmin, S. et al. Migration dynamics of ovarian epithelial cells on micro-fabricated image-based models of normal and malignant stroma. Acta Biomater. 100, 92–104 (2019). This study combines SHG imaging of ovarian tissue with multiphoton polymerization to reproduce image data representing normal and tumour tissue, applying these constructs to study the role of fibre structure in migration dynamics.
Zandrini, T., Florczak, S., Levato, R. & Ovsianikov, A. Breaking the resolution limits of 3D bioprinting: future opportunities and present challenges. Trends Biotechnol. 41, 604–614 (2023).
Castilho, M. et al. Hydrogel-based bioinks for cell electrowriting of well-organized living structures with micrometer-scale resolution. Biomacromolecules 22, 855–866 (2021).
Zandrini, T. et al. Multi-foci laser microfabrication of 3D polymeric scaffolds for stem cell expansion in regenerative medicine. Sci. Rep. 9, 11761 (2019).
Atry, F. et al. Parallel multiphoton excited fabrication of tissue engineering scaffolds using a diffractive optical element. Opt. Express 28, 2744–2757 (2020).
Ouyang, W. et al. Ultrafast 3D nanofabrication via digital holography. Nat. Commun. 14, 1716 (2023).
Saha, S. K. et al. Scalable submicrometer additive manufacturing. Science 366, 105–109 (2019).
Dobos, A. et al. Thiol-gelatin-norbornene bioink for laser-based high-definition bioprinting. Adv. Healthc. Mater. 9, e1900752 (2020). This paper describes the development of a new bioink allowing rapid bioprinting of cell-containing materials by two-photon polymerization.
Puiggalí-Jou, A. et al. FLight biofabrication supports maturation of articular cartilage with anisotropic properties. Adv. Healthc. Mater. 13, e2302179 (2023).
Liu, H. et al. Filamented light (FLight) biofabrication of highly aligned tissue-engineered constructs. Adv. Mater. 34, e2204301 (2022).
Nerger, B. A., Brun, P. T. & Nelson, C. M. Microextrusion printing cell-laden networks of type I collagen with patterned fiber alignment and geometry. Soft Matter 15, 5728–5738 (2019).
Huang, Y., Agrawal, B., Sun, D., Kuo, J. S. & Williams, J. C. Microfluidics-based devices: new tools for studying cancer and cancer stem cell migration. Biomicrofluidics 5, 13412 (2011).
Sontheimer-Phelps, A., Hassell, B. A. & Ingber, D. E. Modelling cancer in microfluidic human organs-on-chips. Nat. Rev. Cancer 19, 65–81 (2019).
Davidson, P. M., Sliz, J., Isermann, P., Denais, C. & Lammerding, J. Design of a microfluidic device to quantify dynamic intra-nuclear deformation during cell migration through confining environments. Integr. Biol. 7, 1534–1546 (2015).
Lee, P., Lin, R., Moon, J. & Lee, L. P. Microfluidic alignment of collagen fibers for in vitro cell culture. Biomed. Microdevices 8, 35–41 (2006).
Drifka, C. R. et al. Comparison of picrosirius red staining with second harmonic generation imaging for the quantification of clinically relevant collagen fiber features in histopathology samples. J. Histochem. Cytochem. 64, 519–529 (2016).
Marcos-Garcés, V., Harvat, M., Molina Aguilar, P., Ferrández Izquierdo, A. & Ruiz-Saurí, A. Comparative measurement of collagen bundle orientation by Fourier analysis and semiquantitative evaluation: reliability and agreement in Masson’s trichrome, picrosirius red and confocal microscopy techniques. J. Microsc. 267, 130–142 (2017).
Abd-Elgaliel, W. R. & Tung, C.-H. Exploring the structural requirements of collagen-binding peptides. Biopolymers 100, 167–173 (2013).
Haddad, T. S. et al. Tutorial: methods for three-dimensional visualization of archival tissue material. Nat. Protoc. 16, 4945–4962 (2021).
Yu, T., Zhu, J., Li, D. & Zhu, D. Physical and chemical mechanisms of tissue optical clearing. iScience 24, 102178 (2021).
Vielreicher, M. et al. Taking a deep look: modern microscopy technologies to optimize the design and functionality of biocompatible scaffolds for tissue engineering in regenerative medicine. J. R. Soc. Interface 10, 20130263 (2013).
Katsamenis, O. L. et al. X-ray micro-computed tomography for nondestructive three-dimensional (3D) X-ray histology. Am. J. Pathol. 189, 1608–1620 (2019).
Ouni, E. et al. A blueprint of the topology and mechanics of the human ovary for next-generation bioengineering and diagnosis. Nat. Commun. 12, 5603 (2021).
Bushby, A. J. et al. Imaging three-dimensional tissue architectures by focused ion beam scanning electron microscopy. Nat. Protoc. 6, 845–858 (2011).
Cicchi, R. et al. From molecular structure to tissue architecture: collagen organization probed by SHG microscopy. J. Biophotonics 6, 129–142 (2013).
Keikhosravi, A. et al. Quantification of collagen organization in histopathology samples using liquid crystal based polarization microscopy. Biomed. Opt. Express 8, 4243–4256 (2017).
Freudiger, C. W. et al. Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy. Science 322, 1857–1861 (2008). This paper describes stimulated Raman scattering microscopy for label-free in situ visualization of 3D structures in living tissues.
Becker, L. et al. Raman microspectroscopy identifies fibrotic tissues in collagen-related disorders via deconvoluted collagen type I spectra. Acta Biomater. 162, 278–291 (2023).
Butler, H. J. et al. Using Raman spectroscopy to characterize biological materials. Nat. Protoc. 11, 664–687 (2016).
Kreiss, L. et al. Label-free analysis of inflammatory tissue remodeling in murine lung tissue based on multiphoton microscopy, Raman spectroscopy and machine learning. J. Biophotonics 15, e202200073 (2022).
Eekhoff, J. D. & Lake, S. P. Three-dimensional computation of fibre orientation, diameter and branching in segmented image stacks of fibrous networks. J. R. Soc. Interface 17, 20200371 (2020).
Liu, Z. et al. Rapid three-dimensional quantification of voxel-wise collagen fiber orientation. Biomed. Opt. Express 6, 2294–2310 (2015).
Wershof, E. et al. A FIJI macro for quantifying pattern in extracellular matrix. Life Sci. Alliance 4, e202000880 (2021).
Devlin, M.-J. et al. The tumor microenvironment of clear-cell ovarian cancer. Cancer Immunol. Res. 10, 1326–1339 (2022).
Liu, Y. et al. Fibrillar collagen quantification with curvelet transform based computational methods. Front. Bioeng. Biotechnol. 8, 198 (2020).
Sorelli, M. et al. Fiber enhancement and 3D orientation analysis in label-free two-photon fluorescence microscopy. Sci. Rep. 13, 4160 (2023).
Bumgarner, J. R. & Nelson, R. J. Open-source analysis and visualization of segmented vasculature datasets with VesselVio. Cell Rep. Methods 2, 100189 (2022).
Spangenberg, P. et al. Rapid and fully automated blood vasculature analysis in 3D light-sheet image volumes of different organs. Cell Rep. Methods 3, 100436 (2023).
Sapudom, J. et al. Collagen fibril orientation instructs fibroblast differentiation via cell contractility. Adv. Sci. 10, e2301353 (2023).
Joukhdar, H. et al. Imparting multi‐scalar architectural control into silk materials using a simple multi‐functional ice‐templating fabrication platform. Adv. Mater. Technol. https://doi.org/10.1002/admt.202201642 (2023).
Joshi, I. M. et al. Microengineering 3D collagen matrices with tumor-mimetic gradients in fiber alignment. Adv. Funct. Mater. https://doi.org/10.1002/adfm.202308071 (2023).
Osuna de la Peña, D. et al. Bioengineered 3D models of human pancreatic cancer recapitulate in vivo tumour biology. Nat. Commun. 12, 5623 (2021).
Vega, S. L. et al. Combinatorial hydrogels with biochemical gradients for screening 3D cellular microenvironments. Nat. Commun. 9, 614 (2018).
Yang, Y., Motte, S. & Kaufman, L. J. Pore size variable type I collagen gels and their interaction with glioma cells. Biomaterials 31, 5678–5688 (2010).
Acknowledgements
T.R.C. is supported by the National Health and Medical Research Council (NHMRC) of Australia and Cancer Council NSW (CCNSW). J.C.A. is funded by the University of Nottingham (Anne McLaren fellowship).
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J.C.A. is a co-founder, shareholder and scientific advisory board member of Peptimatrix Ltd. T.R.C. declares no competing interest.
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Glossary
- Additive manufacturing
-
The process of building an object based on 3D data, usually layer by layer, encompassing methods that directly deposit materials using a print head or similar (commonly grouped together as ‘3D printing’), as well as other techniques such as light-activated polymerization.
- Amorphous collagen
-
Collagen molecules that are not organized into fibrous or fibrillar structures.
- Anastomosis
-
A connection between two passageways, such as where two previously independent, discrete blood vessels subsequently join.
- Atomic force microscopy
-
A technique used for mapping the atomic-scale topography of a surface by means of the repulsive electronic forces between the surface and the tip of a microscope probe moving above the surface.
- Basement membrane
-
Structure visible by light microscopy and, in addition to the basal lamina, that consist of layers that are typically secreted by cells from underlying connective tissue; many basement membranes are rich in fibronectin.
- Cell jamming
-
A collective cell behaviour observed in densely packed groups of cells such as tumours, wherein they exhibit solid-like properties akin to jammed granular materials.
- Collective invasion
-
A mode of migration in which groups of cells move together as a cohesive unit through the surrounding extracellular matrix.
- Extrusion
-
A printing approach in which a continuous strand of material is deposited.
- Fibrillar
-
Indicates that a molecule or substance has formed, or is intrinsically capable of forming, elongated units, that is, fibres, which in the ECM are often hierarchical, containing structure on multiple length scales.
- Integrin switching
-
A process in which cells dynamically alter integrin expression, engagement and/or activation. For example, during cancer metastasis, tumour cells may undergo integrin switching to acquire a more invasive phenotype, enabling them to detach from the primary tumour and invade surrounding tissues.
- Interstitial matrix
-
The space that exits between cells within a tissue or organ, and generally contains a high level of structural proteins, wherein collagen I and fibronectin are the main components in many tissues.
- Light-responsive biomaterial
-
A biomaterial that can undergo reversible or irreversible changes in its properties or functions upon exposure to light.
- Micro-CT
-
A non-destructive imaging technique that uses X-rays and computed tomography (CT) to produce detailed three-dimensional images of objects at a microscopic scale.
- Microtracks
-
Narrow, often microscopic-scale pathways or channels within the 3D matrix structure that can guide the movement or alignment of cells.
- Scanning electron microscopy
-
(SEM). A high-resolution imaging technique that deploys a focused beam of electrons to scan the surface of the sample.
- Shear stress
-
A type of stress, defined as force per unit area, caused by forces acting parallel to a surface, leading to a deformation or displacement.
- Tunnelling nanotubes
-
(TNTs). Actin-based membrane protrusions that form cell–cell contacts.
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Ashworth, J.C., Cox, T.R. The importance of 3D fibre architecture in cancer and implications for biomaterial model design. Nat Rev Cancer 24, 461–479 (2024). https://doi.org/10.1038/s41568-024-00704-8
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DOI: https://doi.org/10.1038/s41568-024-00704-8
