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Dense Nanofibrillar Collagen–Silica Hybrids with High Strength and ECM‐Mimetic Tissue Integration
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Macromolecular Chemistry.ORCID iD: 0000-0002-0932-0161
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Macromolecular Chemistry.ORCID iD: 0000-0002-6175-2682
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Electrical Engineering, Solid-State Electronics.ORCID iD: 0000-0002-3555-5503
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science and Engineering, Applied Material Science.
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2026 (English)In: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 36, no 36, article id e26318Article in journal (Refereed) Published
Abstract [en]

Collagen, the primary structural protein of the extracellular matrix (ECM), is widely used in biomaterials for tissue engineering and repair. However, its limited mechanical properties constrain its use in load-bearing applications. Here, we present a strategy to fabricate dense collagen–silica hybrid hydrogels (16 wt.% collagen) that have high mechanical strength, flexibility, printability, and biofunctionality. Using borate-mediated templating, we synchronize the formation of nanostructured silica networks with collagen fibrillogenesis, and subsequently covalently bind the two phases. This approach yields a compressive modulus ∼1.5 MPa for the hybrid hydrogels with a water content as high as 85%. Characterization confirms that borates act transiently during processing, allowing network formation without being retained in the final material. The hybrid hydrogels support high cell viability, elongation, and alignment in 3D cultures, while in vivo, initially cell-free scaffolds, implanted subcutaneously display minimal inflammation, vascularized tissue integration, and controlled, cell-mediated degradation. Taken together, this work establishes a robust framework for creating printable, ECM-mimetic collagen–silica hybrids with nanoscale reinforcement, offering new opportunities in regenerative medicine and scaffold fabrication.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2026. Vol. 36, no 36, article id e26318
Keywords [en]
collagen–silica hybrid, ECM-mimetic scaffold, nanostructured reinforcement, printable biomaterial, tissue integration
National Category
Medical Materials
Identifiers
URN: urn:nbn:se:uu:diva-582593DOI: 10.1002/adfm.202526318ISI: 001694494500001Scopus ID: 2-s2.0-105030674368OAI: oai:DiVA.org:uu-582593DiVA, id: diva2:2047066
Part of project
Biomimetic Materials for Personalised Bone Regeneration, Swedish Research Council
Funder
Swedish Research Council, 2020‐04977Available from: 2026-03-19 Created: 2026-03-19 Last updated: 2026-05-28Bibliographically approved
In thesis
1. Engineering Dense Collagen for Tissue Regeneration
Open this publication in new window or tab >>Engineering Dense Collagen for Tissue Regeneration
2026 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Tissue engineering aims to develop materials that help the body repair damaged tissues. Collagen is attractive for this purpose because it is a major component of the extracellular matrix, but conventional collagen hydrogels are mechanically weak, while dense collagen is more difficult to process and shape. This thesis investigated how collagen could be engineered into stable, printable and biologically accessible scaffolds.

Study I examined three-dimensional printing of conventional collagen using a support-bath technique. The method enabled controlled scaffold architecture, but the resulting collagen remained mechanically soft. The study showed that geometry could be imposed on collagen, while also revealing the need for greater structural function within the material itself.

Study II therefore focused on developing a dense collagen–silica hybrid, DCSi. A concentrated acidic collagen precursor containing hydrolyzed silanes remained processable before fabrication and was subsequently matured in alkaline borate. The maturation environment strongly influenced collagen organization, silica distribution and mechanical behavior. Borate produced a dense fibrillar collagen structure with finely distributed silica and substantially improved structural stability. DCSi could also be printed into multilayer structures when extrusion and stabilization were controlled together. Importantly, cells colonized the material in vitro, while host cells and blood vessels entered the scaffold after implantation.

Study III adapted DCSi for bone repair by introducing a calcium-phosphate mineral phase. Mineralized DCSi retained its collagen-rich structure and flexibility while providing a bone-specific inorganic component. After implantation in a rat femoral defect, mineralized DCSi produced more new bone than non-mineralized DCSi after six weeks.

Study IV examined DCSi as a printed patch for uterine tissue repair. The patches were designed as thin and flexible structures and were evaluated with or without mesenchymal stromal cells. Both supported tissue ingrowth and vascularization, while the cell-free patches showed more consistent structural regeneration under the conditions tested.

Together, these studies show that dense collagen can be engineered into a versatile scaffold platform by controlling how structure develops during processing. This provides a route towards collagen-based materials that are not only biologically relevant, but also structurally functional, manufacturable and adaptable to different regenerative applications.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2026. p. 85
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 2658
National Category
Biomaterials Science
Research subject
Chemistry with specialization in Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-583414 (URN)978-91-513-2800-3 (ISBN)
Public defence
2026-09-28, Sonja Lyttkens (101121), Ångström, Regementsvägen 10, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2026-09-08 Created: 2026-03-29 Last updated: 2026-09-11

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Norein, NoreinTavakoli, ShimaWolf, Philipp M.Xie, LingLeifer, KlausHulsart Billström, GryHilborn, Jöns

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