Near-infrared light-activated collagen-based hydrogel with oriented microchannel structure promoting fibroblast infiltration and inflammatory resolution‌

Abstract

Tissue repair is challenged by inefficient cellular infiltration and prolonged inflammation. Herein, the mesoporous polydopamine nanoparticles were loaded with spermidine and then encapsulated in agarose, which were incorporated into the oxidized hyaluronic acid crosslinked collagen matrix to fabricate NIR-activated hydrogel (DOCH@P) by the directional freeze-thaw process. DOCH@P hydrogel had obvious oriented microchannel structure due to the extrusion of directional ice crystals and the chemical crosslinking during the directional freeze-thaw process, besides enhanced mechanical properties, viscoelasticity and favorable tissue adhesive strength. DOCH@P hydrogel with photothermal performance promoted the melting of the agarose in the shell of nanoparticles under NIR-activation, thus achieving NIR-responsive spermidine release behavior. NIR-activated DOCH@P hydrogel exhibited significantly robust broad-spectrum antibacterial activity and antioxidative activity. Significantly, DOCH@P hydrogel demonstrated superior capabilities in inducing directional migration and infiltration of fibroblasts through the synergistic integration of the oriented microchannels physical contact guidance and spermidine bioactivity. Based on the multi-layered spermidine-mediated immunoregulation, NIR-activated DOCH@P hydrogel ultimately drove macrophages towards anti-inflammatory M2 phenotype to alleviate excessive inflammation and remold immune homeostasis. Overall, the NIR-activated collagen-based hydrogel with oriented microchannel structure provides a promising scaffold foundation for guiding tissue regeneration through physical contact-guided cellular infiltration and anti-inflammation.

Graphical Abstract

Keywords

Hydrogel scaffold / Spermidine / Photothermal performance / Antibacterial activity / Anti-inflammation / Directional freeze-thaw technology

References

[1] Liu Z, Li N, Li W, Xu S, Yao L, Xiao J. Molecular weight-controllable oral yak skin collagen for enhanced healing of photoaged skin. Collagen Leather, 2025, 7(124

[2] Dickinson LE, Gerecht S. Engineered biopolymeric scaffolds for chronic wound healing. Front Physiol, 2016, 7: 341

[3] Savitri C, Ha SS, Kwon JW, Kim SH, Kim Y-M, Park HM, et al.. Human fibroblast-derived matrix hydrogel accelerates regenerative wound remodeling through the interactions with macrophages. Adv Sci, 2024, 11(18): 2305852

[4] Cañedo-Dorantes L, Cañedo-Ayala M. Skin acute wound healing: a comprehensive review. Int J Inflamm, 2019, 20191: 3706315

[5] Zhang X, Wu Y, Gong H, Xiong Y, Chen Y, Li L, et al.. A multifunctional herb-derived glycopeptide hydrogel for chronic wound healing. Small, 2024, 20(36): 2400516

[6] Dong C, Lv Y. Application of collagen scaffold in tissue engineering: recent advances and new perspectives. Polymers, 2016, 8(2): 42

[7] Lin X, Yang X, Li P, Xu Z, Zhao L, Mu C, et al.. Antibacterial conductive collagen-based hydrogels for accelerated full-thickness wound healing. ACS Appl Mater Interfaces, 2023, 15(19): 22817-29

[8] Lu P, Ruan D, Huang M, Tian M, Zhu K, Gan Z, et al.. Harnessing the potential of hydrogels for advanced therapeutic applications: current achievements and future directions. Signal Transduct Target Therapy, 2024, 9(1): 166

[9] Zhang Q, Dou M, Su X, Yu Z, Wei B, Zhu L, et al.. Collagen-based biomaterials: recent advances on regulating cell migration and correlated biomedical applications. Collagen Leather, 2025, 7(1): 17

[10] He C, Bi S, Zhang R, Chen C, Liu R, Zhao X, et al.. A hyaluronic acid hydrogel as a mild photothermal antibacterial, antioxidant, and nitric oxide release platform for diabetic wound healing. J Controlled Release, 2024, 370: 543-55

[11] Liu J, Chen F, Tian L, Wu J, Liu K, Wan Q, et al.. Therapeutic potential of gelatine methacrylate hydrogels loaded with macrophage-derived exosomes for accelerating angiogenesis and cutaneous wound healing. Collagen Leather, 2024, 6(1): 13

[12] Tu Z, Chen M, Wang M, Shao Z, Jiang X, Wang K, et al.. Engineering bioactive M2 macrophage-polarized anti-inflammatory, antioxidant, and antibacterial scaffolds for rapid angiogenesis and diabetic wound repair. Adv Funct Mater, 2021, 31(30): 2100924

[13] Wang J, Ding Y, Liu J, Chen Y, Wang Y, Zhao A. Oxidative stress-responsive hydrogen sulfide-releasing composite hydrogel for refractory diabetic wounds repair. Appl Mater Today, 2024, 40: 102387

[14] Sarig-Nadir O, Livnat N, Zajdman R, Shoham S, Seliktar D. Laser photoablation of guidance microchannels into hydrogels directs cell growth in three dimensions. Biophys J, 2009, 96(11): 4743-52

[15] Chen K, Chen Q, Zong T, Liu S, Yang X, Luo Y, et al.. Effect of directional stretching on properties of PVA-HA-PAA composite hydrogel. J Bionic Eng, 2021, 18(5): 1202-14

[16] Xue Y, Li J, Jiang T, Han Q, Jing Y, Bai S, et al.. Biomimetic conductive hydrogel scaffolds with anisotropy and electrical stimulation for in vivo skeletal muscle reconstruction. Adv Healthc Mater, 2021, 13(4): 2302180

[17] Luo Z, Tang G, Ravanbakhsh H, Li W, Wang M, Kuang X, et al.. Vertical extrusion Cryo(bio)printing for anisotropic tissue manufacturing. Adv Mater, 2022, 34(12): 2108931

[18] Chi J, Wang M, Chen J, Hu L, Chen Z, Backman LJ, et al.. Topographic orientation of scaffolds for tissue regeneration: recent advances in biomaterial design and applications. Biomimetics, 2022, 7(3): 131

[19] Xu S, Tang X, Wang M, Wang Z, Zhan R, Chen J. Stimuli-responsive hydrogels composed of modified cellulose nanocrystal and gelatin with oriented channels for guiding axonal myelination. Carbohydr Polym, 2025, 356: 123402

[20] Wegst UGK, Kamm PH, Yin K, García-Moreno F. Freeze casting. Nat Reviews Methods Primers, 2024, 4(1): 28

[21] Shao G, Hanaor DAH, Shen X, Gurlo A. Freeze casting: from low-dimensional building blocks to aligned porous structures—a review of novel materials, methods, and applications. Adv Mater, 2020, 32(17): 1907176

[22] Qiao J, Lan X, Gan Y, Dong F, Xiong Y. Mechanical enhancement mechanism and synergistic antibacterial/wound-healing properties of ZIF-8/chitosan quaternary ammonium salt-modified bi-directional hydrogel wound dressings. Colloids Surf A, 2026, 730: 138962

[23] Liu S, Zhou X, Nie L, Wang Y, Hu Z, Okoro OV, et al.. Anisotropic PLGA microsphere/PVA hydrogel composite with aligned macroporous structures for directed cell adhesion and proliferation. Int J Polym Mater Polym Biomaterials, 2023, 72(5): 397-406

[24] Hu C, Liu W, Wang J, Hua C, Long L, Yang X, et al.. Injectable hydrogels with tailored recombinant humanized collagen type I for the repair of damaged hearts by remodeling the myocardial microenvironment. Collagen Leather, 2025, 7(1): 38

[25] Wu Q, Yang R, Fan W, Wang L, Zhan J, Cao T, et al.. Spermidine-functionalized injectable hydrogel reduces inflammation and enhances healing of acute and diabetic wounds in situ. Adv Sci, 2024, 11(22): 2310162

[26] Wang D, Lu K, Zou G, Wu D, Cheng Y, Sun Y. Attenuating intervertebral disc degeneration through spermidine-delivery nanoplatform based on polydopamine for persistent regulation of oxidative stress. Int J Biol Macromol, 2024, 274: 132881

[27] Bagheri A, Arandiyan H, Boyer C, Lim M. Lanthanide-doped upconversion nanoparticles: emerging intelligent light-activated drug delivery systems. Adv Sci, 2016, 3(7): 1500437

[28] Mayer G, Heckel A. Biologically active molecules with a light switch. Angew Chem Int Ed, 2006, 45(30): 4900-21

[29] Carling C-J, Nourmohammadian F, Boyer J-C, Branda NR. Remote-control photorelease of caged compounds using near-infrared light and upconverting nanoparticles. Angew Chem Int Ed, 2010, 49(22): 3782-5

[30] Luo X, Zhang L, Luo Y, Cai Z, Zeng H, Wang T, et al.. Charge-driven self-assembled microspheres hydrogel scaffolds for combined drug delivery and photothermal therapy of diabetic wounds. Adv Funct Mater, 2023, 33(26): 2214036

[31] Pan W-Y, Huang C-C, Lin T-T, Hu H-Y, Lin W-C, Li M-J, et al.. Synergistic antibacterial effects of localized heat and oxidative stress caused by hydroxyl radicals mediated by graphene/iron oxide-based nanocomposites. Nanomed Nanotechnol Biol Med, 2016, 12(2): 431-8

[32] Chen Q, Li S, Zhao W, Zhao C. A rapid-triggered approach towards antibacterial hydrogel wound dressing with synergic photothermal and sterilization profiles. Biomaterials Adv, 2022, 138: 212873

[33] Tan W, Long T, Wan Y, Li B, Xu Z, Zhao L, et al.. Dual-drug loaded polysaccharide-based self-healing hydrogels with multifunctionality for promoting diabetic wound healing. Carbohydr Polym, 2023, 312: 120824

[34] Mu C, Li D, Lin W, Ding Y, Zhang G. Temperature Induced Denaturation of Collagen in Acidic Solution. Biopolymers, 2007, 86: 282-7

[35] Reščič J, Kovačević D, Tomšič M, Jamnik A, Ahualli S, Bohinc K. Experimental and theoretical study of the silica particle interactions in the presence of multivalent rod-like ions. Langmuir, 2014, 30(32): 9717-25

[36] Zhao P, Zhang Y, Chen X, Xu C, Guo J, Deng M, et al.. Versatile hydrogel dressing with skin adaptiveness and mild photothermal antibacterial activity for methicillin-resistant staphylococcus aureus-infected dynamic wound healing. Adv Sci, 2022, 10(11): 2206585

[37] Liu Y, Ai K, Lu L. Polydopamine and its derivative materials: synthesis and promising applications in energy, environmental, and biomedical fields. Chem Rev, 2014, 114(9): 5057-115

[38] Askarizadeh M, Esfandiari N, Honarvar B, Sajadian SA, Azdarpour A. Kinetic modeling to explain the release of medicine from drug delivery systems. ChemBioEng Reviews, 2023, 10(6): 1006-49

[39] Guaccio A, Borselli C, Oliviero O, Netti PA. Oxygen consumption of chondrocytes in agarose and collagen gels: a comparative analysis. Biomaterials, 2008, 29(10): 1484-93

[40] Zhang S, Su H, Li L, Ma J, Wang Z, Hu F, et al.. Ultrasound-assisted directional freezing enables high-performance hydrogel evaporators with tunable microchannels for solar desalination. J Mater Chem A, 2025, 13(44): 38276-89

[41] Fan X, Liu H, Wang J, Tang K. Investigation of double network hydrogel with controllable swelling behavior by response surface methodology. J Appl Polym Sci, 2020, 137(24): 48805

[42] Ye Z, Chi T, Evans CJ, Liu D, Addonizio CJ, Su B, et al.. Implications of supramolecular crosslinking on hydrogel toughening by directional freeze-casting and salting-out. Adv Funct Mater, 2024, 34(38): 2402613

[43] Yi X, Xu Z, Liu Q, Zhou H, Yuan L, Li D, et al.. Matrix metalloproteinase-responsive collagen-oxidized hyaluronic acid injectable hydrogels for osteoarthritic therapy. Biomaterials Adv, 2022, 137: 212804

[44] Lan X, Yang H, Xiong Y, Zeng G, Dong F. Polyvinyl alcohol/chitosan quaternary ammonium salt composite hydrogel with directional macroporous structure for photothermal synergistic antibacterial and wound healing promotion. Int J Biol Macromol, 2024, 267: 131549

[45] Li Z, Huang J, Jiang Y, Liu Y, Qu G, Chen K, et al.. Novel temperature-sensitive hydrogel promotes wound healing through YAP and MEK-mediated mechanosensitivity. Adv Healthc Mater, 2022, 11(23): 2201878

[46] Ma P, Liu Y, Yang C-y, Yang J, Cao Z, Ren B, et al.. A multifunctional bilayer hydrogel patch with photothermal-driven directional contraction and bioregulation for enhanced wound healing. Mater Today, 2025, 90: 297-313

[47] Han Q, Wang A, Song W, Zhang M, Wang S, Ren P, et al.. Fabrication of conductive, adhesive, and stretchable agarose-based hydrogels for a wearable biosensor. ACS Appl Bio Mater, 2021, 4(8): 6148-56

[48] Overchuk M, Weersink RA, Wilson BC, Zheng G. Photodynamic and photothermal therapies: synergy opportunities for nanomedicine. ACS Nano, 2023, 17(9): 7979-8003

[49] Liu Z, Zhao X, Yu B, Zhao N, Zhang C, Xu F-J. Rough carbon–iron oxide nanohybrids for near-infrared-ii light-responsive synergistic antibacterial therapy. ACS Nano, 2021, 15(4): 7482-90

[50] Zhang H, Zou Y, Lu K, Wu Y, Lin Y, Cheng J, et al.. A nanoplatform with oxygen self-supplying and heat-sensitizing capabilities enhances the efficacy of photodynamic therapy in eradicating multidrug-resistant biofilms. J Mater Sci Technol, 2024, 169: 209-19

[51] Su H, Liu Z, Zhang Z, Jing X, Meng L. Development of a deep eutectic solvent-assisted kaempferol hydrogel: a promising therapeutic approach for psoriasis-like skin inflammation. Mol Pharm, 2023, 20(12): 6319-29

[52] Yang C, Zhang Y, Zhang X, Tang P, Zheng T, Ran R, et al.. An injectable, self-healing, and antioxidant collagen- and hyaluronic acid-based hydrogel mediated with gallic acid and dopamine for wound repair. Carbohydr Polym, 2023, 320: 121231

[53] Wang T, Wang Y, Zhang Y, Fang Z, Li S, Gu Z, et al.. Drug-loaded mesoporous polydopamine nanoparticles in chitosan hydrogels enable myocardial infarction repair through ros scavenging and inhibition of apoptosis. ACS Appl Mater Interfaces, 2024, 16(45): 61551-64

[54] Cui H, Deng Y, An B, Ning Q, Sun X, Wang M, et al.. situ spermidine-integrated dynamic hyaluronic acid-based hydrogels platforms for anti-inflammation and anti-fibrosis in subconjunctival injuries. Carbohydr Polym, 2026, 374: 124509

[55] Li S, Dan X, Chen H, Li T, Liu B, Ju Y, et al.. Developing fibrin-based biomaterials/scaffolds in tissue engineering. Bioactive Mater, 2024, 40: 597-623

[56] Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and disease. Science, 2018, 359(6374): eaan2788

[57] Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, et al.. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med, 2016, 22(12): 1428-38

[58] Kim G, Kim M, Kim M, Park C, Yoon Y, Lim D-H, et al.. Spermidine-induced recovery of human dermal structure and barrier function by skin microbiome. Commun Biology, 2021, 4(1): 231

[59] Minois N. Molecular basis of the ‘anti-aging’ effect of spermidine and other natural polyamines—a mini-review. Gerontology, 2014, 60(4): 319-26

[60] Wang L, Zhong Y, Wu Q, Wang Y, Tang R, Zhou S, et al.. Spermidine-functionalized biomaterials to modulate implant-induced immune response and enhance wound healing. Chem Eng J, 2023, 476: 146416

[61] Ye Z, Wang S, Zhang C, Zhao Y. Coordinated modulation of energy metabolism and inflammation by branched-chain amino acids and fatty acids. Front Endocrinology‌, 2020, 11: 617

[62] Wang Y-F, Lee G-L, Huang Y-H, Kuo C-C. sn-1,2-diacylglycerols protect against lethal endotoxemia by controlling systemic inflammation. Immunobiology, 2016, 221(11): 1309-18

Funding

the National Natural Science Foundation of China(22305164)

the “Hong Yuan Youth Development Fund” of School of Chemical Engineering, Sichuan University(the “Hong Yuan Youth Development Fund” of School of Chemical Engineering, Sichuan University)

Sichuan Province's “Biomanufacturing” Major Science and Technology Special Project(2024ZDZX0053)

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