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Collagen Hydrogels for Regenerative Medicine
Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The need for regenerative therapies to repair damaged or deteriorated organs and tissues, such as heart, skin, and cornea, is rising due to donor shortage and aging of the world’s population. Many proposed regenerative therapeutic approaches include a combination of cells, bioactive compounds, and hydrogels. Although collagen hydrogels have shown a lot of promise in regenerative medicine research, there are still challenges in their design and application strategies. Therefore, this thesis describes the development of novel collagen hydrogel designs for improved use in tissue bonding, cell delivery, and myocardial infarction therapy applications.

Firstly, a visible-light crosslinked collagen hydrogel for tissue photobonding was developed. Methacrylated collagen hydrogel was crosslinked using the photoinitiator rose Bengal and visible light. The properties of the resulting hydrogel were tunable by changing the hydrogel composition. Biomimetic and ex vivo skin models were used to demonstrate the ability of the hydrogel to bond tissues whose edges are separated. Additionally, using the hydrogel led to less scarring compared to traditional sutures in a mouse skin incision model.

Secondly, collagen was modified with thiol groups to design a hydrogel crosslinked using the thiol-Michael addition click reaction for cell encapsulation and delivery. The hydrogels demonstrated excellent shear-thinning and self-healing properties, allowing for injection after the crosslinking was complete. Additionally, the hydrogels showed minimal swelling and maintained their shape in an aqueous buffer for a prolonged period. Cell encapsulation and delivery using the hydrogels was demonstrated in vitro with mesenchymal stromal cells and endothelial cells.

Thirdly, recombinant human collagen III hydrogels were prepared by crosslinking the collagen with EDC and NHS. The hydrogels contained either 1% or 2% collagen. Therapeutic strategies for these hydrogels were investigated, including the timing and dosage of the treatment, in a mouse MI model. Comparing 1% hydrogel injection at a single early time point (3 h) and three time points (3 h, 7 and 14 days) post-MI revealed improved cardiac function, reduced scar size and inflammation, and increased vascularization in the single injection group. Additionally, increasing the collagen III dose to 2% in the hydrogel at a single early time point (3 h) injection did not confer any additional functional improvement compared to 1% and resulted in scar size and vascular density comparable to control (PBS injection). In summary, this work contributes to the development of collagen hydrogel therapies for regenerative medicine by presenting a visible-light crosslinked collagen hydrogel for tissue bonding, a novel click-crosslinked collagen hydrogel with excellent shear-thinning properties for cell delivery, and the use of a recombinant human collagen III hydrogel in post-MI therapy, highlighting the importance of optimizing the timing and dosage of biomaterial therapies.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2020. , p. 83
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1725
National Category
Biomaterials Science
Identifiers
URN: urn:nbn:se:liu:diva-164541ISBN: 9789179299330 (print)OAI: oai:DiVA.org:liu-164541DiVA, id: diva2:1416220
Supervisors
Available from: 2020-03-23 Created: 2020-03-23 Last updated: 2020-03-23Bibliographically approved
List of papers
1. Collagen-Based Photoactive Agent for Tissue Bonding
Open this publication in new window or tab >>Collagen-Based Photoactive Agent for Tissue Bonding
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2017 (English)In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 9, no 11, p. 9265-9270Article in journal (Refereed) Published
Abstract [en]

Using a combination of methacrylated, collagen and the photosensitizer rose Bengal, a new light-activated biomimetic material for tissue sutureless bonding was developed. This formulation was cross-linked using green light. In vivo tests in mice demonstrate the suitability of the material for sutureless wound closure.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2017
Keywords
tissue photobonding; rose Bengal; collagen; wound healing; cross-linking
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:liu:diva-136583 (URN)10.1021/acsami.7b01984 (DOI)000397478100010 ()28282110 (PubMedID)
Note

Funding Agencies|Natural Sciences and Engineering Research Council (NSERC) [RGPIN- 2015-0632, 342107]; AFA Forsakring, Sweden; UOHI start-up grant [1255]; Burroughs Wellcome Fund

Available from: 2017-04-21 Created: 2017-04-21 Last updated: 2020-03-23
2. Injectable Shape-Holding Collagen Hydrogel for Cell Encapsulation and Delivery Cross-linked Using Thiol-Michael Addition Click Reaction
Open this publication in new window or tab >>Injectable Shape-Holding Collagen Hydrogel for Cell Encapsulation and Delivery Cross-linked Using Thiol-Michael Addition Click Reaction
2019 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 20, no 9, p. 3475-3484Article in journal (Refereed) Published
Abstract [en]

Injectable hydrogels based on extracellular matrix-derived polymers show much promise in the field of tissue engineering and regenerative medicine. However, the hydrogels reported to date have at least one characteristic that limits their potential for clinical use, such as excessive swelling, complicated and potentially toxic cross-linking process, or lack of shear thinning and self-healing properties. We hypothesized that a collagen hydrogel cross-linked using thiol-Michael addition click reaction would be able to overcome these limitations. To this end, collagen was modified to introduce thiol groups, and hydrogels were prepared by cross-linking with 8-arm polyethylene glycol-maleimide. Rheological measurements on the hydrogels revealed excellent shear-thinning and self-healing properties. Additionally, only minimal swelling (6%) was observed over a period of 1 month in an aqueous buffer solution. Finally, tests using mesenchymal stromal cells and endothelial cells showed that the hydrogels are cell-compatible and suitable for cell encapsulation and delivery. Thus, the reported thiolated-collagen hydrogel cross-linked using thiol-Michael addition click reaction overcomes most of the challenges in the injectable hydrogel design and is an excellent candidate for cell delivery in regenerative medicine and tissue engineering applications. The hydrogel reported here is the first example of a self-healing hydrogel containing covalent cross-links.

Place, publisher, year, edition, pages
American Chemical Society, 2019
National Category
Biomaterials Science
Identifiers
urn:nbn:se:liu:diva-164539 (URN)10.1021/acs.biomac.9b00769 (DOI)
Available from: 2020-03-23 Created: 2020-03-23 Last updated: 2020-03-23Bibliographically approved

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