Initial Assessment of a Dual-Bioactive Hydrogel Incorporating Phagocytosis-Stimulating and Tissue-Regenerative Proteins for Enhanced Wound Healing
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Keywords:
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Wound Healing, Phagocytosis Activating Protein, Thrombospondin, Hydrogel
Abstract
Wound healing is a complex process that can be impaired by various factors. Hydrogel is a recommended choice for keeping the skin moist and enhancing wound healing. Hydrogel can contain bioactive compounds to improve wound healing effectiveness further. Phagocytosis activating protein (PAP) and thrombospondin (TSP) can stimulate macrophage and promote cell proliferation. They had the potential to enhance wound healing when incorporated into a hydrogel. This study aims to evaluate the effect of PAP and TSP hydrogel on irritation and wound healing efficacy in a rat model. This experiment is conducted using a full-thickness wounds model in rats. The hydrogel formulations with PAP and/or TSP were applied to the wounds for 21 days. The wound contraction, histology, and TGF-β1 expression were measured. The results showed that low-dose PAP hydrogel had the best wound healing performance among all groups, with high TGF-β1 levels in the early phase and low levels in the late phase. Low-dose TSP hydrogel had similar but weaker effects than low-dose PAP hydrogel. There was no sign of skin irritation for all formulations. Hydrogel containing a low dose of PAP or TSP is a promising formula for further developing new wound dressing materials. It also opens an opportunity to cure some challenging to-treat wounds, such as diabetic and burn wounds.
References
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Chen, L.-s., B.-w. Zheng, C.-y. Zhao, C.-c. He, and X.-H. Gao (2026). The Role of Thrombospondin-1 in Dermatological Conditions. Frontiers in Medicine, 13; 1724955
DaCosta, M. L., M. C. Regan, M. Al Sader, M. Leader, and D. Bouchier-Hayes (1998). Diphenylhydantoin Sodium Promotes Early and Marked Angiogenesis and Results in Increased Collagen Deposition and Tensile Strength in Healing Wounds. Surgery, 123(3); 287–293
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Grellner, W., S. Vieler, and B. Madea (2005). Transforming Growth Factors (TGF-α and TGF-β1) in the Determination of Vitality and Wound Age: Immunohistochemical Study on Human Skin Wounds. Forensic Science International, 153(2); 174–180
Guo, S. and L. A. DiPietro (2010). Factors Affecting Wound Healing. Journal of Dental Research, 89(3); 219–229
He, X., W. Wu, Y. Hu, M. Wu, H. Li, L. Ding, S. Huang, and Y. Fan (2024). Visualizing the Global Trends of Peptides in Wound Healing through an In-Depth Bibliometric Analysis. International Wound Journal, 21(4); e14575
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Huang, L. and L. Fu (2015). Mechanisms of Resistance to EGFR Tyrosine Kinase Inhibitors. Acta Pharmaceutica Sinica B, 5(5); 390–401
Kamlungmak, S., J. Dechraksa, A. R. Padmavathi, S. Sawatdee, K. Tinpun, T. Nakpheng, and T. Srichana (2019). Lamellar Phase Behavior and Molecular Interaction of a Thermoresponsive Poloxamer and Crosslinked Poly(Vinyl Alcohol) Hydrogel. Materials Today Communications, 20; 100542
Berikut adalah daftar referensi yang telah dirapikan. Nama jurnal atau buku telah dicetak miring (italic) sesuai standar penulisan akademis, dan terdapat spasi di antara masing-masing entri agar Anda dapat langsung menyalinnya dengan mudah:
Daftar Referensi
Acciaretti, F., S. Vesentini, and L. Cipolla (2022). Fabrication Strategies Towards Hydrogels for Biomedical Application: Chemical and Mechanical Insights. Chemistry–An Asian Journal, 17(22); e202200797
Altuntas, S., H. K. Dhaliwal, A. Eid Radwan, M. Amiji, and F. Buyukserin (2022). Local Epidermal Growth Factor Delivery Using Nanopillared Chitosan–Gelatin Films for Melanogenesis and Wound Healing. Biomaterials Science, 11(1); 181–194
Aramwit, P. and A. Sangcakul (2007). The Effects of Sericin Cream on Wound Healing in Rats. Bioscience, Biotechnology, and Biochemistry, 71(10); 2473–2477
Bogadi, S., M. E. Uddin, M. H. Rahman, V. V. S. R. Karri, R. Begum, and S. E. Udeabor (2025). Wound Healing in the Modern Era: Emerging Research, Biomedical Advances, and Transformative Clinical Approaches. Journal of Drug Delivery Science and Technology, 110; 107058
Bonnici, L., S. Suleiman, P. Schembri-Wismayer, and A. Cassar (2024). Targeting Signalling Pathways in Chronic Wound Healing. International Journal of Molecular Sciences, 25(1); 50
Chen, H., F. Liang, C. Fu, Z. Wang, and Z. Zhang (2023). Valproic Acid Accelerates Skin Wound Healing in Mice Via Its Anti-Inflammatory and Apoptotic Cell Clearance-Promoting Effects. Journal of International Medical Research, 51(6); 03000605231184038
Chen, L.-s., B.-w. Zheng, C.-y. Zhao, C.-c. He, and X.-H. Gao (2026). The Role of Thrombospondin-1 in Dermatological Conditions. Frontiers in Medicine, 13; 1724955
DaCosta, M. L., M. C. Regan, M. Al Sader, M. Leader, and D. Bouchier-Hayes (1998). Diphenylhydantoin Sodium Promotes Early and Marked Angiogenesis and Results in Increased Collagen Deposition and Tensile Strength in Healing Wounds. Surgery, 123(3); 287–293
Deachamag, P., U. Intaraphad, A. Phongdara, and W. Chotigeat (2006). Expression of a Phagocytosis Activating Protein (PAP) Gene in Immunized Black Tiger Shrimp. Aquaculture, 255(1–4); 165–172
Franz, M. G. (2015). Wound Healing. In G. M. Doherty, editor, CURRENT Diagnosis & Treatment: Surgery. McGraw-Hill Education, New York, NY, 14 edition
Grellner, W., S. Vieler, and B. Madea (2005). Transforming Growth Factors (TGF-α and TGF-β1) in the Determination of Vitality and Wound Age: Immunohistochemical Study on Human Skin Wounds. Forensic Science International, 153(2); 174–180
Guo, S. and L. A. DiPietro (2010). Factors Affecting Wound Healing. Journal of Dental Research, 89(3); 219–229
He, X., W. Wu, Y. Hu, M. Wu, H. Li, L. Ding, S. Huang, and Y. Fan (2024). Visualizing the Global Trends of Peptides in Wound Healing through an In-Depth Bibliometric Analysis. International Wound Journal, 21(4); e14575
He, Y., J. Hu, A. Ma, P. Du, M. Yang, X. Xiong, and Y. Deng (2026). The Crosstalk Between Efferocytosis and Macrophage Polarization in Diabetic Wounds: A Comprehensive Review. Journal of Inflammation Research; 566523
Huang, L. and L. Fu (2015). Mechanisms of Resistance to EGFR Tyrosine Kinase Inhibitors. Acta Pharmaceutica Sinica B, 5(5); 390–401
Kamlungmak, S., J. Dechraksa, A. R. Padmavathi, S. Sawatdee, K. Tinpun, T. Nakpheng, and T. Srichana (2019). Lamellar Phase Behavior and Molecular Interaction of a Thermoresponsive Poloxamer and Crosslinked Poly(Vinyl Alcohol) Hydrogel. Materials Today Communications, 20; 100542
Kamlungmak, S., T. Nakpheng, S. Kaewpaiboon, M. A. K. M. Bintang, S. Prom-In, C. Chunhachaichana, and T. Srichana (2021). Safety and Biocompatibility of Mupirocin Nanoparticle-Loaded Hydrogel on Burn Wound in Rat Model. Biological and Pharmaceutical Bulletin, 44(11); 1707–1716
Khimmakthong, U., P. Deachamag, A. Phongdara, and W. Chotigeat (2011). Stimulating the Immune Response of Litopenaeus vannamei Using the Phagocytosis Activating Protein (PAP) Gene. Fish & Shellfish Immunology, 31(3); 415–422
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Aramwit, P. and A. Sangcakul (2007). The Effects of Sericin Cream on Wound Healing in Rats. Bioscience, Biotechnology, and Biochemistry, 71(10); 2473–2477
Bogadi, S., M. E. Uddin, M. H. Rahman, V. V. S. R. Karri, R. Begum, and S. E. Udeabor (2025). Wound Healing in the Modern Era: Emerging Research, Biomedical Advances, and Transformative Clinical Approaches. Journal of Drug Delivery Science and Technology, 110; 107058
Bonnici, L., S. Suleiman, P. Schembri-Wismayer, and A. Cassar (2024). Targeting Signalling Pathways in Chronic Wound Healing. International Journal of Molecular Sciences, 25(1); 50
Chen, H., F. Liang, C. Fu, Z. Wang, and Z. Zhang (2023). Valproic Acid Accelerates Skin Wound Healing in Mice Via Its Anti-Inflammatory and Apoptotic Cell Clearance-Promoting Effects. Journal of International Medical Research, 51(6); 03000605231184038
Chen, L.-s., B.-w. Zheng, C.-y. Zhao, C.-c. He, and X.-H. Gao (2026). The Role of Thrombospondin-1 in Dermatological Conditions. Frontiers in Medicine, 13; 1724955
DaCosta, M. L., M. C. Regan, M. Al Sader, M. Leader, and D. Bouchier-Hayes (1998). Diphenylhydantoin Sodium Promotes Early and Marked Angiogenesis and Results in Increased Collagen Deposition and Tensile Strength in Healing Wounds. Surgery, 123(3); 287–293
Deachamag, P., U. Intaraphad, A. Phongdara, and W. Chotigeat (2006). Expression of a Phagocytosis Activating Protein (PAP) Gene in Immunized Black Tiger Shrimp. Aquaculture, 255(1–4); 165–172
Franz, M. G. (2015). Wound Healing. In G. M. Doherty, editor, CURRENT Diagnosis & Treatment: Surgery. McGraw-Hill Education, New York, NY, 14 edition
Grellner, W., S. Vieler, and B. Madea (2005). Transforming Growth Factors (TGF-α and TGF-β1) in the Determination of Vitality and Wound Age: Immunohistochemical Study on Human Skin Wounds. Forensic Science International, 153(2); 174–180
Guo, S. and L. A. DiPietro (2010). Factors Affecting Wound Healing. Journal of Dental Research, 89(3); 219–229
He, X., W. Wu, Y. Hu, M. Wu, H. Li, L. Ding, S. Huang, and Y. Fan (2024). Visualizing the Global Trends of Peptides in Wound Healing through an In-Depth Bibliometric Analysis. International Wound Journal, 21(4); e14575
He, Y., J. Hu, A. Ma, P. Du, M. Yang, X. Xiong, and Y. Deng (2026). The Crosstalk Between Efferocytosis and Macrophage Polarization in Diabetic Wounds: A Comprehensive Review. Journal of Inflammation Research; 566523
Huang, L. and L. Fu (2015). Mechanisms of Resistance to EGFR Tyrosine Kinase Inhibitors. Acta Pharmaceutica Sinica B, 5(5); 390–401
Kamlungmak, S., J. Dechraksa, A. R. Padmavathi, S. Sawatdee, K. Tinpun, T. Nakpheng, and T. Srichana (2019). Lamellar Phase Behavior and Molecular Interaction of a Thermoresponsive Poloxamer and Crosslinked Poly(Vinyl Alcohol) Hydrogel. Materials Today Communications, 20; 100542
Berikut adalah daftar referensi yang telah dirapikan. Nama jurnal atau buku telah dicetak miring (italic) sesuai standar penulisan akademis, dan terdapat spasi di antara masing-masing entri agar Anda dapat langsung menyalinnya dengan mudah:
Daftar Referensi
Acciaretti, F., S. Vesentini, and L. Cipolla (2022). Fabrication Strategies Towards Hydrogels for Biomedical Application: Chemical and Mechanical Insights. Chemistry–An Asian Journal, 17(22); e202200797
Altuntas, S., H. K. Dhaliwal, A. Eid Radwan, M. Amiji, and F. Buyukserin (2022). Local Epidermal Growth Factor Delivery Using Nanopillared Chitosan–Gelatin Films for Melanogenesis and Wound Healing. Biomaterials Science, 11(1); 181–194
Aramwit, P. and A. Sangcakul (2007). The Effects of Sericin Cream on Wound Healing in Rats. Bioscience, Biotechnology, and Biochemistry, 71(10); 2473–2477
Bogadi, S., M. E. Uddin, M. H. Rahman, V. V. S. R. Karri, R. Begum, and S. E. Udeabor (2025). Wound Healing in the Modern Era: Emerging Research, Biomedical Advances, and Transformative Clinical Approaches. Journal of Drug Delivery Science and Technology, 110; 107058
Bonnici, L., S. Suleiman, P. Schembri-Wismayer, and A. Cassar (2024). Targeting Signalling Pathways in Chronic Wound Healing. International Journal of Molecular Sciences, 25(1); 50
Chen, H., F. Liang, C. Fu, Z. Wang, and Z. Zhang (2023). Valproic Acid Accelerates Skin Wound Healing in Mice Via Its Anti-Inflammatory and Apoptotic Cell Clearance-Promoting Effects. Journal of International Medical Research, 51(6); 03000605231184038
Chen, L.-s., B.-w. Zheng, C.-y. Zhao, C.-c. He, and X.-H. Gao (2026). The Role of Thrombospondin-1 in Dermatological Conditions. Frontiers in Medicine, 13; 1724955
DaCosta, M. L., M. C. Regan, M. Al Sader, M. Leader, and D. Bouchier-Hayes (1998). Diphenylhydantoin Sodium Promotes Early and Marked Angiogenesis and Results in Increased Collagen Deposition and Tensile Strength in Healing Wounds. Surgery, 123(3); 287–293
Deachamag, P., U. Intaraphad, A. Phongdara, and W. Chotigeat (2006). Expression of a Phagocytosis Activating Protein (PAP) Gene in Immunized Black Tiger Shrimp. Aquaculture, 255(1–4); 165–172
Franz, M. G. (2015). Wound Healing. In G. M. Doherty, editor, CURRENT Diagnosis & Treatment: Surgery. McGraw-Hill Education, New York, NY, 14 edition
Grellner, W., S. Vieler, and B. Madea (2005). Transforming Growth Factors (TGF-α and TGF-β1) in the Determination of Vitality and Wound Age: Immunohistochemical Study on Human Skin Wounds. Forensic Science International, 153(2); 174–180
Guo, S. and L. A. DiPietro (2010). Factors Affecting Wound Healing. Journal of Dental Research, 89(3); 219–229
He, X., W. Wu, Y. Hu, M. Wu, H. Li, L. Ding, S. Huang, and Y. Fan (2024). Visualizing the Global Trends of Peptides in Wound Healing through an In-Depth Bibliometric Analysis. International Wound Journal, 21(4); e14575
He, Y., J. Hu, A. Ma, P. Du, M. Yang, X. Xiong, and Y. Deng (2026). The Crosstalk Between Efferocytosis and Macrophage Polarization in Diabetic Wounds: A Comprehensive Review. Journal of Inflammation Research; 566523
Huang, L. and L. Fu (2015). Mechanisms of Resistance to EGFR Tyrosine Kinase Inhibitors. Acta Pharmaceutica Sinica B, 5(5); 390–401
Kamlungmak, S., J. Dechraksa, A. R. Padmavathi, S. Sawatdee, K. Tinpun, T. Nakpheng, and T. Srichana (2019). Lamellar Phase Behavior and Molecular Interaction of a Thermoresponsive Poloxamer and Crosslinked Poly(Vinyl Alcohol) Hydrogel. Materials Today Communications, 20; 100542
Kamlungmak, S., T. Nakpheng, S. Kaewpaiboon, M. A. K. M. Bintang, S. Prom-In, C. Chunhachaichana, and T. Srichana (2021). Safety and Biocompatibility of Mupirocin Nanoparticle-Loaded Hydrogel on Burn Wound in Rat Model. Biological and Pharmaceutical Bulletin, 44(11); 1707–1716
Khimmakthong, U., P. Deachamag, A. Phongdara, and W. Chotigeat (2011). Stimulating the Immune Response of Litopenaeus vannamei Using the Phagocytosis Activating Protein (PAP) Gene. Fish & Shellfish Immunology, 31(3); 415–422
Koh, T. J. and L. A. DiPietro (2011). Inflammation and Wound Healing: The Role of the Macrophage. Expert Reviews in Molecular Medicine, 13; e23
Kohyama, K., H. Kato, H. Okada, T. Ishihara, Y. Yasue, R. Kamidani, K. Suzuki, T. Miyake, H. Okuda, H. Shibata, et al. (2024). Concomitant Heparin Use Promotes Skin Graft Donor Site Healing by Basic Fibroblast Growth Factor: A Pilot Prospective Randomized Controlled Study. Contemporary Clinical Trials Communications, 42; 101375
Larouche, J., S. Sheoran, K. Maruyama, and M. M. Martino (2018). Immune Regulation of Skin Wound Healing: Mechanisms and Novel Therapeutic Targets. Advances in Wound Care, 7(7); 209–231
Liu, A., P. Garg, S. Yang, P. Gong, M. A. Pallero, D. S. Annis, J. E. Murphy-Ullrich, and S. E. Goldblum (2009). Epidermal Growth Factor-Like Repeats of Thrombospondins Activate Phospholipase Cγ and Increase Epithelial Cell Migration Through Indirect Epidermal Growth Factor Receptor Activation. Journal of Biological Chemistry, 284(10); 6389–6402
Liu, Z., L. Chen, B. Hao, Y. Hou, C. Lv, Y. Zhu, and C. Han (2025). SHP099-Containing Multi-Targeting Hydrogel Promotes Rapid Skin Reconstruction Through Modulating a Variety of Cells. Frontiers in Bioengineering and Biotechnology, 13; 1564827
Lowe, J. M., D. Menendez, and M. B. Fessler (2014). A New Inflammatory Role for p53 in Human Macrophages. Cell Cycle, 13(19); 2983–2984
Mârza, S. M., A. M. Dăescu, R. C. Purdoiu, M. Dragomir, M. Tătaru, I. Melega, and I. Papuc (2024). Healing of Skin Wounds in Rats Using Creams Based on Symphytum officinale Extract. International Journal of Molecular Sciences, 25(6); 3099
Miyazono, K. (2000). Positive and Negative Regulation of TGF-β Signaling. Journal of Cell Science, 113(7); 1101–1109
Muñoz-Torres, J. R., I. Garza-Veloz, P. Velasco-Elizondo, and M. L. Martinez-Fierro (2025). HEALS-A and GRADES: Novel Histological and Clinical Scales for Assessing Skin Regeneration in Murine Wound Healing Models. Diagnostics, 15(3); 387
Ozgok Kangal, M. K. and N. L. Kopitnik (2026). Physiology, Wound Healing. In StatPearls. StatPearls Publishing, Treasure Island, FL
Pakyari, M., A. Farrokhi, M. K. Maharlooei, and A. Ghahary (2013). Critical Role of Transforming Growth Factor Beta in Different Phases of Wound Healing. Advances in Wound Care, 2(5); 215–224
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Authors
Changklang, P., Suwandecha, T., Sriwiriyajan, S., Nopparat, J., Balekar, N., & Srichana, T. (2026). Initial Assessment of a Dual-Bioactive Hydrogel Incorporating Phagocytosis-Stimulating and Tissue-Regenerative Proteins for Enhanced Wound Healing. Science and Technology Indonesia, 11(3), 1127–1137. https://doi.org/10.26554/sti.2026.11.3.1127-1137
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