Journal of Zhejiang University

Journal of Zhejiang University SCIENCE A

Accepted manuscript available online (unedited version)

3D printing of wet-bonded multilayer scaffolds for skin wound repair

Author(s): Kangning SHEN, Jingyi GU, Ximin YUAN, Nian LIU, Yinglin WANG, Jiabin CAI, Yang SHI, Kaiyang WANG, Xinghua YE, Minghao YANG, Zhiyong MA, Zhijian XIE
Affiliation(s): Zhejiang Key Laboratory of Industrial Solid Waste Thermal Hydrolysis Technology and Intelligent Equipment, Huzhou University, Huzhou 313000, China; more
Corresponding email(s): 02641@zjhu.edu.cn, xzj66@zju.edu.cn
Key Words: 3D printing; Biomimetic skin; Wet adhesive; Polycaprolactone (PCL) modification; Genipin

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Kangning SHEN, Jingyi GU, Ximin YUAN, Nian LIU, Yinglin WANG, Jiabin CAI, Yang SHI, Kaiyang WANG, Xinghua YE, Minghao YANG, Zhiyong MA, Zhijian XIE. 3D printing of wet-bonded multilayer scaffolds for skin wound repair[J]. Journal of Zhejiang University Science A,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.A2500653

@article{title="3D printing of wet-bonded multilayer scaffolds for skin wound repair",
author="Kangning SHEN, Jingyi GU, Ximin YUAN, Nian LIU, Yinglin WANG, Jiabin CAI, Yang SHI, Kaiyang WANG, Xinghua YE, Minghao YANG, Zhiyong MA, Zhijian XIE",
journal="Journal of Zhejiang University Science A",
year="in press",
publisher="Zhejiang University Press & Springer",
doi="https://doi.org/10.1631/jzus.A2500653"
}

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%T 3D printing of wet-bonded multilayer scaffolds for skin wound repair
%A Kangning SHEN
%A Jingyi GU
%A Ximin YUAN
%A Nian LIU
%A Yinglin WANG
%A Jiabin CAI
%A Yang SHI
%A Kaiyang WANG
%A Xinghua YE
%A Minghao YANG
%A Zhiyong MA
%A Zhijian XIE
%J Journal of Zhejiang University SCIENCE A
%P 625-639
%@ 1673-565X
%D in press
%I Zhejiang University Press & Springer
doi="https://doi.org/10.1631/jzus.A2500653"

TY - JOUR
T1 - 3D printing of wet-bonded multilayer scaffolds for skin wound repair
A1 - Kangning SHEN
A1 - Jingyi GU
A1 - Ximin YUAN
A1 - Nian LIU
A1 - Yinglin WANG
A1 - Jiabin CAI
A1 - Yang SHI
A1 - Kaiyang WANG
A1 - Xinghua YE
A1 - Minghao YANG
A1 - Zhiyong MA
A1 - Zhijian XIE
J0 - Journal of Zhejiang University Science A
SP - 625
EP - 639
%@ 1673-565X
Y1 - in press
PB - Zhejiang University Press & Springer
ER -
doi="https://doi.org/10.1631/jzus.A2500653"

Abstract
Chinese Summary
Academic Network
Reviewer Comment

Abstract: The skin repair process is significantly influenced by the regulation of a dynamic mechanical microenvironment. However, traditional single-layer scaffolds face limitations, including poor mechanical compatibility and weak interfacial adhesion. These drawbacks stem from their inability to mimic the multilayer heterogeneous structure and functional synergy of natural skin. In this paper, a biomimetic skin extracellular matrix (ECM) scaffold with a layered structure bio-polycaprolactone (PCL) skin (BPS) is proposed, consisting of three layers: a surface layer (SL), a support layer (PL), and a base layer (BL). The SL consists of a 3D-printed microporous PCL structure, which simulates the epidermal barrier’s antibacterial and breathable properties. The PL, a surface-modified multilayer PCL scaffold, mimics the dermal layer and provides essential mechanical support and elasticity. The BL, a hydrogel coated onto the surface of the PL, provides excellent biological properties. Genipin serves as a crosslinker, and ethylenediamine is used for amination treatment of the PCL scaffold surface. This chemical crosslinking strengthens interlayer connections, enhancing functional synergy and tripling the anti-swelling properties of the hydrogel. Additionally, it improves the wet adhesion of the scaffold to skin tissue, ensuring stable adherence to the wound surface. Compared to traditional scaffolds, this multilayer structure effectively integrates biological functions with mechanical performance, providing sustained protection and support during wound healing.

3D打印用于皮肤伤口修复的湿粘合多层支架

作者：沈槺柠^1,2，顾静怡³，原禧敏⁴，刘念⁴，王胤霖³，蔡嘉宾^1,2，史洋³，王恺阳⁴，叶兴华²，杨铭浩²，马志勇^1,2，谢志坚³
机构：¹湖州师范学院，浙江省工业固体废物热解技术与智能装备重点实验室，中国湖州，313000；²湖州师范学院，工程学院，中国湖州，313000；³浙江大学医学院附属口腔医院，口腔医学院，浙江省口腔疾病临床研究中心，浙江省口腔生物医学研究重点实验室，浙江大学癌症中心，中国杭州，310016;⁴浙江大学，机械工程学院，流体动力基础件与机电系统全国重点实验室，中国杭州，310058
目的：传统单层支架无法模拟天然皮肤的多层异质结构和功能协同，导致机械兼容性差、界面粘附弱。本文旨在构建一种具有分层结构的仿生皮肤细胞外基质（ECM）支架（BPS），并通过三层设计（表面层（SL）、支撑层（PL）和基底层（BL））实现抗菌透气、力学支撑和生物活性的集成，以提高皮肤伤口修复效果。
创新点：1.提出利用熔融电写（MEW）工艺制备的三层仿生皮肤ECM支架和通过聚己内酯（PCL）表面氨基化处理和京尼平交联实现层间水凝胶与纤维的共价键结合，显著增强纤维凝胶界面稳定性并提供湿粘附性能；2.利用盐离子屏蔽效应调控明胶分子链缠结，实现水凝胶降解速率的可调控以及与皮肤再生周期的匹配；3.通过水凝胶缠结、各向异性网格拓扑结构和共价结合，有效抑制水凝胶水平膨胀，保证支架在潮湿环境下的力学稳定性。
方法：1.通过MEW技术制备微孔SL和PL拓卜结构，并采用NaOH刻蚀和乙二胺（EDA）胺化处理在PCL表面引入氨基；2.制备京尼平交联的明胶水凝胶基层，添加甘油和柠檬酸钠调控力学性能和降解行为，并利用SEM、FT-IR、XPS、XRD等表征化学结构与微观形貌；3.建立大鼠全层皮肤缺损模型，评估修复效果，并评价生物相容性与基因表达。
结论：1.BPS支架具有优异的力学性能和湿粘附性能，与人体皮肤力学特性匹配；其通过PCL表面胺化与京尼平交联，提高了界面韧性，从而实现了优异的抗溶胀稳定性。2. BPS支架无细胞毒性，SL微孔结构提供透气性的同时有效阻隔大肠杆菌和金黄色葡萄球菌。3.BPS组大鼠全层皮肤缺损模型中，14天愈合率达92.5%，胶原沉积为对照组的1.6倍且有序，并且血管密度和VCL表达最高。总之，多层仿生设计克服了单层材料功能单一的局限，为复杂皮肤缺损修复提供了一种集力学适配、生物活性和湿粘附于一体的多功能修复支架。

关键词组：3D打印；仿生皮肤；湿性粘；聚己内酯改性；京尼平

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]AgrawalA, RahbarN, CalvertPD, 2013. Strong fiber-reinforced hydrogel. Acta Biomaterialia, 9(2):5313-5318.

[2]AQSIQ (General Administration of Quality Supervision, Inspection and Quarantine of the People’s Republic of China), 2006. Plastics–Determination of Tensile Properties–Part 3: Test Conditions for Films and Sheets, GB/T 1040.3-2006. National Standards of the People’s Republic of China(in Chinese).

[3]ArifZU, KhalidMY, NorooziR, et al., 2022. Recent advances in 3D-printed polylactide and polycaprolactone-based biomaterials for tissue engineering applications. International Journal of Biological Macromolecules, 218:930-968.

[4]ASTM (American Society for Testing and Materials), 2016. Standard Test Method for in vitro Degradation Testing of Hydrolytically Degradable Polymer Resins and Fabricated Forms for Surgical Implants, ASTM F1635-16. ASTM International, West Conshohocken, USA.

[5]ASTM (American Society for Testing and Materials), 2024. Standard Test Method for Strength Properties of Tissue Adhesives in T-Peel by Tension Loading, ASTM F2256-24. ASTM International, West Conshohocken, USA.

[6]BarbuA, NeamtuB, ZăhanM, et al., 2021. Current trends in advanced alginate-based wound dressings for chronic wounds. Journal of Personalized Medicine, 11(9):890.

[7]Barros AlmeidaI, Garcez Barretto TeixeiraL, Oliveira de CarvalhoF, et al., 2021. Smart dressings for wound healing: a review. Advances in Skin & Wound Care, 34(2):1-8.

[8]BoatengJ, CatanzanoO, 2015. Advanced therapeutic dressings for effective wound healing—a review. Journal of Pharmaceutical Sciences, 104(11):3653-3680.

[9]BrohemCA, da Silva CardealLB, TiagoM, et al., 2011. Artificial skin in perspective: concepts and applications. Pigment Cell & Melanoma Research, 24(1):35-50.

[10]ChenY, MaYZ, FuJZ, et al., 2025. Design and fabrication of biomimetic four-region drug-loaded cartilage scaffolds with porous hollow fibers. Journal of Zhejiang University-SCIENCE A, 26(11):1070-1082.

[11]ChenYW, FuT, ZouZF, et al., 2025. Biological reinforced concrete for cartilage repair with 3D printing. Advanced Science, 12(16):2416734.

[12]DhandayuthapaniB, YoshidaY, MaekawaT, et al., 2011. Polymeric scaffolds in tissue engineering application: a review. International Journal of Polymer, 2011:290602.

[13]DoillonCJ, DunnMG, BenderE, et al., 1985. Collagen fiber formation in repair tissue: development of strength and toughness. Collagen and Related Research, 5(6):481-492.

[14]DrobnikJ, StebelA, 2017. Tangled history of the European uses of Sphagnum moss and sphagnol. Journal of Ethnopharmacology, 209:41-49.

[15]GronbeckC, FengH, 2023. Distribution of intermediate and complex skin repairs performed by dermatologists following updated 2020 coding guidelines. Journal of the American Academy of Dermatology, 88(4):954-956.

[16]GuarinoRD, ChaneyBN, Liebmann-VinsonA, et al., 2007. Peptides for Enhanced Cell Attachment and Growth. US Patent 7157275.

[17]GuoLZ, ZhangL, WangZM, et al., 2023. Direct construction of strong, tough, conductive, and adhesive hydrogel bioelectronics enabled by salt-dissolved cellulose. Materials Today Communications, 37:107002.

[18]HanL, LiuZX, LiM, et al., 2025. 3D bioprinting of a dermal scaffold for full-thickness skin tissue regeneration. Bio-Design and Manufacturing, 8:68-84.

[19]Hunter-FeatherstoneE, YoungN, ChamberlainK, et al., 2021. Culturing keratinocytes on biomimetic substrates facilitates improved epidermal assembly in vitro. Cells, 10(5):1177.

[20]HuoXS, WangJL, CongZH, et al., 2025. Strong and tough eutectogels with broad-range tunable mechanical properties via the hydrogen bond network-specific effect. Advanced Functional Materials, 35(27):2422464.

[21]LiXY, GongJP, 2024. Design principles for strong and tough hydrogels. Nature Reviews Materials, 9(6):380-398.

[22]LiuJ, WangSY, XuK, et al., 2020. Fabrication of double crosslinked chitosan/gelatin membranes with Na⁺ and pH dual-responsive controlled permeability. Carbohydrate Polymers, 236:115963.

[23]LiuN, ShiY, LiJY, et al., 2025. Morphology-guided cellular behavior modulation with 3D-printed engineered ECM. Cell Biomaterials, 1(6):100090.

[24]Maaz ArifM, KhanSM, GullN, et al., 2021. Polymer-based biomaterials for chronic wound management: promises and challenges. International Journal of Pharmaceutics, 598:120270.

[25]MengQ, ShenC, 2018. Construction of low contracted 3D skin equivalents by genipin cross-linking. Experimental Dermatology, 27(10):1098-1103.

[26]NianGD, KimJ, BaoXY, et al., 2022. Making highly elastic and tough hydrogels from doughs. Advanced Materials, 34(50):2206577.

[27]ObagiZ, DamianiG, GradaA, et al., 2019. Principles of wound dressings: a review. Surgical Technology International, 35:50-57.

[28]O’BrienFJ, 2011. Biomaterials & scaffolds for tissue engineering. Materials Today, 14(3):88-95.

[29]OomensCWJ, van VijvenM, PetersGWM, 2017. Skin mechanics. In: Payan Y, Ohayon J (Eds.), Biomechanics of Living Organs. Academic Press, London, UK, p.347-357.

[30]PanP, HuC, LiangAH, et al., 2023. Preparation and properties of antibacterial silk fibroin scaffolds. Polymers, 15(23):4581.

[31]ParkJ, KimTY, KimY, et al., 2023. A mechanically resilient and tissue-conformable hydrogel with hemostatic and antibacterial capabilities for wound care. Advanced Science, 10(30):2303651.

[32]PatelAK, MichaudP, PetitE, et al., 2013. Development of a chitosan-based adhesive. Application to wood bonding. Journal of Applied Polymer Science, 127(6):5014-5021.

[33]PengW, LiD, DaiKL, et al., 2022. Recent progress of collagen, chitosan, alginate and other hydrogels in skin repair and wound dressing applications. International Journal of Biological Macromolecules, 208:400-408.

[34]RobinsonTM, HutmacherDW, DaltonPD, 2019. The next frontier in melt electrospinning: taming the jet. Advanced Functional Materials, 29(44):1904664.

[35]SingerAJ, ClarkRAF, 1999. Cutaneous wound healing. New England Journal of Medicine, 341(10):738-746.

[36]TangP, SongP, PengZY, et al., 2021. Chondrocyte-laden GelMA hydrogel combined with 3D printed PLA scaffolds for auricle regeneration. Materials Science and Engineering: C, 130:112423.

[37]TrichetL, Le DigabelJ, HawkinsRJ, et al., 2012. Evidence of a large-scale mechanosensing mechanism for cellular adaptation to substrate stiffness. Proceedings of the National Academy of Sciences, 109(18):6933-6938.

[38]van den BoschE, GielensC, 2003. Gelatin degradation at elevated temperature. International Journal of Biological Macromolecules, 32(3-5):129-138.

[39]WuSJ, WuJJ, KaserSJ, et al., 2024. A 3D printable tissue adhesive. Nature Communications, 15(1):1215.

[40]YangYT, LiM, PanGY, et al., 2023. Multiple stimuli-responsive nanozyme-based cryogels with controlled NO release as self-adaptive wound dressing for infected wound healing. Advanced Functional Materials, 33(31):2214089.

[41]YaoK, LvS, ZhangXJ, et al., 2025. 3D printing of multiscale biomimetic scaffold for tendon regeneration. Advanced Functional Materials, 35(4):2413970.

[42]YazdiSJM, BaqersadJ, 2022. Mechanical modeling and characterization of human skin: a review. Journal of Biomechanics, 130:110864.

[43]YuYB, XuS, LiSM, et al., 2021. Genipin-cross-linked hydrogels based on biomaterials for drug delivery: a review. Biomaterials Science, 9(5):1583-1597.

[44]ZhangL, WangSH, WangZM, et al., 2023. A sweat-pH-enabled strongly adhesive hydrogel for self-powered e-skin applications. Materials Horizons, 10(6):2271-2280.

[45]ZhaoWX, HuCX, WangYN, et al., 2025. Optimization-based conformal path planning for in situ bioprinting during complex skin defect repair. Bio-Design and Manufacturing, 8:1-19.

[46]ZhouY, ZhuoRX, LiuZL, 2005. Synthesis and characterization of novel aliphatic poly(carbonate-ester)s with functional pendent groups. Macromolecular Rapid Communications, 26(16):1309-1314.

[47]ZussmanE, ChagantiSR, VenugopalJR, et al., 2018. Fiber-Reinforced Hydrogel Composites and Methods of Forming Fiber-Reinforced Hydrogel Composites. US Patent 9950093.

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