Balance of Macrophage Activation by a Complex Coacervate-Based Adhesive Drug Carrier Facilitates Diabetic Wound Healing
Uncontrolled and sustained inflammation disrupts the wound-healing process and produces excessive reactive oxygen species, resulting in chronic or impaired wound closure. Natural antioxidants such as plant-based extracts and natural polysaccharides have a long history in wound care. However, they ar...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/12/2351 |
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| author | Ching-Shuen Wang Shen-Dean Luo Shihai Jia Wilfred Wu Shwu-Fen Chang Sheng-Wei Feng Chieh-Hsiang Yang Jiann-Her Lin Yinshen Wee |
| author_facet | Ching-Shuen Wang Shen-Dean Luo Shihai Jia Wilfred Wu Shwu-Fen Chang Sheng-Wei Feng Chieh-Hsiang Yang Jiann-Her Lin Yinshen Wee |
| author_sort | Ching-Shuen Wang |
| collection | DOAJ |
| description | Uncontrolled and sustained inflammation disrupts the wound-healing process and produces excessive reactive oxygen species, resulting in chronic or impaired wound closure. Natural antioxidants such as plant-based extracts and natural polysaccharides have a long history in wound care. However, they are hard to apply to wound beds due to high levels of exudate or anatomical sites to which securing a dressing is difficult. Therefore, we developed a complex coacervate-based drug carrier with underwater adhesive properties that circumvents these challenges by enabling wet adhesion and controlling inflammatory responses. This resulted in significantly accelerated wound healing through balancing the pro- and anti-inflammatory responses in macrophages. In brief, we designed a complex coacervate-based drug carrier (ADC) comprising oligochitosan and inositol hexaphosphate to entrap and release antioxidant proanthocyanins (PA) in a sustained way. The results from in vitro experiments demonstrated that ADC is able to reduce LPS-stimulated pro-inflammatory responses in macrophages. The ability of ADC to reduce LPS-stimulated pro-inflammatory responses in macrophages is even more promising when ADC is encapsulated with PA (ADC-PA). Our results indicate that ADC-PA is able to polarize macrophages into an M2 tissue-healing phenotype via up-regulation of anti-inflammatory and resolution of inflammatory responses. Treatment with ADC-PA around the wound beds fine-tunes the balance between the numbers of inducible nitric oxide synthase-positive (iNOS+) and mannose receptor-negative (CD206-) M1 and iNOS-CD206+ M2 macrophages in the wound microenvironment compared to controls. Achieving such a balance between the numbers of iNOS+CD206- M1 and iNOS-CD206+ M2 macrophages in the wound microenvironment has led to significantly improved wound closure in mouse models of diabetes, which exhibit severe impairments in wound healing. Together, our results demonstrate for the first time the use of a complex coacervate-based drug delivery system to promote timely resolution of the inflammatory responses for diabetic wound healing by fine-tuning the functions of macrophages. |
| first_indexed | 2024-03-09T17:24:31Z |
| format | Article |
| id | doaj.art-e37c0ba23bc04504b3531cecd6ebda1f |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T17:24:31Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-e37c0ba23bc04504b3531cecd6ebda1f2023-11-24T12:56:34ZengMDPI AGAntioxidants2076-39212022-11-011112235110.3390/antiox11122351Balance of Macrophage Activation by a Complex Coacervate-Based Adhesive Drug Carrier Facilitates Diabetic Wound HealingChing-Shuen Wang0Shen-Dean Luo1Shihai Jia2Wilfred Wu3Shwu-Fen Chang4Sheng-Wei Feng5Chieh-Hsiang Yang6Jiann-Her Lin7Yinshen Wee8School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 110, TaiwanDepartment of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung 833, TaiwanDepartment of Neurobiology, University of Utah, Salt Lake City, UT 84112, USADepartment of Genetics and Genome Sciences, School of Medicine, Case Western University, Cleveland, OH 44106, USAGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, TaiwanSchool of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 110, TaiwanDepartment of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USADepartment of Neurosurgery, Taipei Medical University Hospital, Taipei 110, TaiwanDepartment of Pathology, University of Utah, Salt Lake City, UT 84112, USAUncontrolled and sustained inflammation disrupts the wound-healing process and produces excessive reactive oxygen species, resulting in chronic or impaired wound closure. Natural antioxidants such as plant-based extracts and natural polysaccharides have a long history in wound care. However, they are hard to apply to wound beds due to high levels of exudate or anatomical sites to which securing a dressing is difficult. Therefore, we developed a complex coacervate-based drug carrier with underwater adhesive properties that circumvents these challenges by enabling wet adhesion and controlling inflammatory responses. This resulted in significantly accelerated wound healing through balancing the pro- and anti-inflammatory responses in macrophages. In brief, we designed a complex coacervate-based drug carrier (ADC) comprising oligochitosan and inositol hexaphosphate to entrap and release antioxidant proanthocyanins (PA) in a sustained way. The results from in vitro experiments demonstrated that ADC is able to reduce LPS-stimulated pro-inflammatory responses in macrophages. The ability of ADC to reduce LPS-stimulated pro-inflammatory responses in macrophages is even more promising when ADC is encapsulated with PA (ADC-PA). Our results indicate that ADC-PA is able to polarize macrophages into an M2 tissue-healing phenotype via up-regulation of anti-inflammatory and resolution of inflammatory responses. Treatment with ADC-PA around the wound beds fine-tunes the balance between the numbers of inducible nitric oxide synthase-positive (iNOS+) and mannose receptor-negative (CD206-) M1 and iNOS-CD206+ M2 macrophages in the wound microenvironment compared to controls. Achieving such a balance between the numbers of iNOS+CD206- M1 and iNOS-CD206+ M2 macrophages in the wound microenvironment has led to significantly improved wound closure in mouse models of diabetes, which exhibit severe impairments in wound healing. Together, our results demonstrate for the first time the use of a complex coacervate-based drug delivery system to promote timely resolution of the inflammatory responses for diabetic wound healing by fine-tuning the functions of macrophages.https://www.mdpi.com/2076-3921/11/12/2351complex coacervatesoligochitosanphytic acidantioxidantsreactive oxygen speciessustained release |
| spellingShingle | Ching-Shuen Wang Shen-Dean Luo Shihai Jia Wilfred Wu Shwu-Fen Chang Sheng-Wei Feng Chieh-Hsiang Yang Jiann-Her Lin Yinshen Wee Balance of Macrophage Activation by a Complex Coacervate-Based Adhesive Drug Carrier Facilitates Diabetic Wound Healing Antioxidants complex coacervates oligochitosan phytic acid antioxidants reactive oxygen species sustained release |
| title | Balance of Macrophage Activation by a Complex Coacervate-Based Adhesive Drug Carrier Facilitates Diabetic Wound Healing |
| title_full | Balance of Macrophage Activation by a Complex Coacervate-Based Adhesive Drug Carrier Facilitates Diabetic Wound Healing |
| title_fullStr | Balance of Macrophage Activation by a Complex Coacervate-Based Adhesive Drug Carrier Facilitates Diabetic Wound Healing |
| title_full_unstemmed | Balance of Macrophage Activation by a Complex Coacervate-Based Adhesive Drug Carrier Facilitates Diabetic Wound Healing |
| title_short | Balance of Macrophage Activation by a Complex Coacervate-Based Adhesive Drug Carrier Facilitates Diabetic Wound Healing |
| title_sort | balance of macrophage activation by a complex coacervate based adhesive drug carrier facilitates diabetic wound healing |
| topic | complex coacervates oligochitosan phytic acid antioxidants reactive oxygen species sustained release |
| url | https://www.mdpi.com/2076-3921/11/12/2351 |
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