Topically-applied collagen-binding serum albumin-fused interleukin-4 modulates wound microenvironment in non-healing wounds
Abstract Non-healing wounds have a negative impact on quality of life and account for many cases of amputation and even early death among patients. Diabetic patients are the predominate population affected by these non-healing wounds. Despite the significant clinical demand, treatment with biologics...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | npj Regenerative Medicine |
| Online Access: | https://doi.org/10.1038/s41536-023-00326-y |
| _version_ | 1827635332359651328 |
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| author | Abigail L. Lauterbach Rachel P. Wallace Aaron T. Alpar Kirsten C. Refvik Joseph W. Reda Ako Ishihara Taryn N. Beckman Anna J. Slezak Yukari Mizukami Aslan Mansurov Suzana Gomes Jun Ishihara Jeffrey A. Hubbell |
| author_facet | Abigail L. Lauterbach Rachel P. Wallace Aaron T. Alpar Kirsten C. Refvik Joseph W. Reda Ako Ishihara Taryn N. Beckman Anna J. Slezak Yukari Mizukami Aslan Mansurov Suzana Gomes Jun Ishihara Jeffrey A. Hubbell |
| author_sort | Abigail L. Lauterbach |
| collection | DOAJ |
| description | Abstract Non-healing wounds have a negative impact on quality of life and account for many cases of amputation and even early death among patients. Diabetic patients are the predominate population affected by these non-healing wounds. Despite the significant clinical demand, treatment with biologics has not broadly impacted clinical care. Interleukin-4 (IL-4) is a potent modulator of the immune system, capable of skewing macrophages towards a pro-regeneration phenotype (M2) and promoting angiogenesis, but can be toxic after frequent administration and is limited by its short half-life and low bioavailability. Here, we demonstrate the design and characterization of an engineered recombinant interleukin-4 construct. We utilize this collagen-binding, serum albumin-fused IL-4 variant (CBD-SA-IL-4) delivered in a hyaluronic acid (HA)-based gel for localized application of IL-4 to dermal wounds in a type 2 diabetic mouse model known for poor healing as proof-of-concept for improved tissue repair. Our studies indicate that CBD-SA-IL-4 is retained within the wound and can modulate the wound microenvironment through induction of M2 macrophages and angiogenesis. CBD-SA-IL-4 treatment significantly accelerated wound healing compared to native IL-4 and HA vehicle treatment without inducing systemic side effects. This CBD-SA-IL-4 construct can address the underlying immune dysfunction present in the non-healing wound, leading to more effective tissue healing in the clinic. |
| first_indexed | 2024-03-09T15:25:18Z |
| format | Article |
| id | doaj.art-601c46ab07994fd8abb735c9a63a3160 |
| institution | Directory Open Access Journal |
| issn | 2057-3995 |
| language | English |
| last_indexed | 2024-03-09T15:25:18Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Regenerative Medicine |
| spelling | doaj.art-601c46ab07994fd8abb735c9a63a31602023-11-26T12:34:01ZengNature Portfolionpj Regenerative Medicine2057-39952023-09-018111310.1038/s41536-023-00326-yTopically-applied collagen-binding serum albumin-fused interleukin-4 modulates wound microenvironment in non-healing woundsAbigail L. Lauterbach0Rachel P. Wallace1Aaron T. Alpar2Kirsten C. Refvik3Joseph W. Reda4Ako Ishihara5Taryn N. Beckman6Anna J. Slezak7Yukari Mizukami8Aslan Mansurov9Suzana Gomes10Jun Ishihara11Jeffrey A. Hubbell12Pritzker School of Molecular Engineering, University of ChicagoPritzker School of Molecular Engineering, University of ChicagoPritzker School of Molecular Engineering, University of ChicagoPritzker School of Molecular Engineering, University of ChicagoPritzker School of Molecular Engineering, University of ChicagoPritzker School of Molecular Engineering, University of ChicagoCommittee on Molecular Metabolism and Nutrition, University of ChicagoPritzker School of Molecular Engineering, University of ChicagoDepartment of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto UniversityPritzker School of Molecular Engineering, University of ChicagoPritzker School of Molecular Engineering, University of ChicagoPritzker School of Molecular Engineering, University of ChicagoPritzker School of Molecular Engineering, University of ChicagoAbstract Non-healing wounds have a negative impact on quality of life and account for many cases of amputation and even early death among patients. Diabetic patients are the predominate population affected by these non-healing wounds. Despite the significant clinical demand, treatment with biologics has not broadly impacted clinical care. Interleukin-4 (IL-4) is a potent modulator of the immune system, capable of skewing macrophages towards a pro-regeneration phenotype (M2) and promoting angiogenesis, but can be toxic after frequent administration and is limited by its short half-life and low bioavailability. Here, we demonstrate the design and characterization of an engineered recombinant interleukin-4 construct. We utilize this collagen-binding, serum albumin-fused IL-4 variant (CBD-SA-IL-4) delivered in a hyaluronic acid (HA)-based gel for localized application of IL-4 to dermal wounds in a type 2 diabetic mouse model known for poor healing as proof-of-concept for improved tissue repair. Our studies indicate that CBD-SA-IL-4 is retained within the wound and can modulate the wound microenvironment through induction of M2 macrophages and angiogenesis. CBD-SA-IL-4 treatment significantly accelerated wound healing compared to native IL-4 and HA vehicle treatment without inducing systemic side effects. This CBD-SA-IL-4 construct can address the underlying immune dysfunction present in the non-healing wound, leading to more effective tissue healing in the clinic.https://doi.org/10.1038/s41536-023-00326-y |
| spellingShingle | Abigail L. Lauterbach Rachel P. Wallace Aaron T. Alpar Kirsten C. Refvik Joseph W. Reda Ako Ishihara Taryn N. Beckman Anna J. Slezak Yukari Mizukami Aslan Mansurov Suzana Gomes Jun Ishihara Jeffrey A. Hubbell Topically-applied collagen-binding serum albumin-fused interleukin-4 modulates wound microenvironment in non-healing wounds npj Regenerative Medicine |
| title | Topically-applied collagen-binding serum albumin-fused interleukin-4 modulates wound microenvironment in non-healing wounds |
| title_full | Topically-applied collagen-binding serum albumin-fused interleukin-4 modulates wound microenvironment in non-healing wounds |
| title_fullStr | Topically-applied collagen-binding serum albumin-fused interleukin-4 modulates wound microenvironment in non-healing wounds |
| title_full_unstemmed | Topically-applied collagen-binding serum albumin-fused interleukin-4 modulates wound microenvironment in non-healing wounds |
| title_short | Topically-applied collagen-binding serum albumin-fused interleukin-4 modulates wound microenvironment in non-healing wounds |
| title_sort | topically applied collagen binding serum albumin fused interleukin 4 modulates wound microenvironment in non healing wounds |
| url | https://doi.org/10.1038/s41536-023-00326-y |
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