Collagen-Inspired 3D Printing Electrospinning Biomimetic Patch for Abdominal Wall Defect Regeneration

Abstract

Repairing abdominal wall defects presents significant challenges, due to the high infection risk, poor biocompatibility, and insufficient mechanical strength associated with synthetic materials. To overcome these limitations, we developed a bioinspired multifunctional 3DPF patch by integrating 3D printing and electrospinning technologies. The core material of the patch is 4arm-PLGA-GPO (4A-GPO), synthesized by conjugating the Gly-Pro-Hyp (GPO) peptide sequence with 4arm-PLGA(4A), which significantly enhances bioactivity and mechanical properties. Additionally, the patch encapsulates basic fibroblast growth factor (bFGF) to stimulate cell proliferation and migration, while an antibacterial layer composes of emodin (EMO) and tobramycin to prevent infection. In vivo studies demonstrate the 3DPF patch effectively accelerates tissue repair by reducing fibrosis and adhesions, promoting angiogenesis and collagen deposition, and modulating the immune response. Transcriptomic analysis reveals that the patch downregulates IL-17 mediated inflammatory pathways while upregulating cell adhesion molecule-related pathways, synergistically facilitating microenvironment reconstruction. Furthermore, molecular docking studies suggest the patch interacts with key molecules such as VEGF and COL3, enhancing angiogenesis and matrix remodeling. In summary, this biomimetic patch, composed of bioactive materials with well-defined chemical compositions, integrates mechanical support, immune modulation, and antibacterial protection. by offering a comprehensive solution for abdominal wall repair, it holds significant potential for clinical translation in complex tissue engineering applications.

Keywords

Biomimetic patch / 3D printing / Electrospinning / Abdominal wall defect / Inflammation / Tissue remodeling

References

[1] ChristmanKL. Biomaterials for tissue repair. Science, 2019, 363340

[2] StuartK, PaderiJ, SnyderPW, FreemanL, PanitchA. Collagen-binding peptidoglycans inhibit MMP mediated collagen degradation and reduce dermal scarring. PLoS ONE, 2011, 6e22139

[3] EmingSA, WynnTA, MartinP. Inflammation and metabolism in tissue repair and regeneration. Science, 2017, 3561026

[4] LvY, CaiF, ZhaoX, ZhuX, WeiF, ZhengY, ShiX, YangJ. Bioinspired microstructured janus bioadhesive for the prevention of abdominal and intrauterine adhesions. Adv Func Mater, 2024, 342314402

[5] UberoiA, McCready-VangiA, GriceEA. The wound microbiota: microbial mechanisms of impaired wound healing and infection. Nat Rev Microbiol, 2024, 22507

[6] ZhangQ, YangY, SuoD, ZhaoS, CheungJCW, LeungPHM, ZhaoX. A biomimetic adhesive and robust janus patch with anti-oxidative anti-inflammatory and anti-bacterial activities for tendon repair. ACS Nano., 2023, 1716798

[7] WhitakerR, Hernaez-EstradaB, HernandezRM, Santos-VizcainoE, SpillerKL. Immunomodulatory biomaterials for tissue repair. Chem Rev, 2021, 12111305

[8] YinXY, HaoYP, LuY, ZhangDJ, ZhaoYD, MeiL, SuiKY, ZhouQH, HuJL. Bio-multifunctional hydrogel patches for repairing full-thickness abdominal wall defect. Adv Func Mater, 2021, 3113

[9] KarinM, CleversH. Reparative inflammation takes charge of tissue regeneration. Nature, 2016, 529307

[10] GaoR, KongPX, YangCF, LiuX, WangJR, OuyangWB, HuangPS, ZhangCNA, FengZJ, WangWW. Gelatinized PLCL electrospun membrane for the prevention of postoperative abdominal adhesion through fibrinolysis activation. Adv Mater Interfaces., 2022, 92200063

[11] LiangWW, HeWY, HuangRK, TangYC, LiSM, ZhengBN, LinYY, LuYH, WangH, WuDC. Peritoneum-inspired janus porous hydrogel with anti-deformation, anti-adhesion, and pro-healing characteristics for abdominal wall defect treatment. Adv Mater., 2022, 342108992

[12] CuiT, YuJ, LiQ, WangC-F, ChenS, LiW, WangG. Large-scale fabrication of robust artificial skins from a biodegradable sealant-loaded nanofiber scaffold to skin tissue via microfluidic blow-spinning. Adv Mater, 2020, 322000982

[13] ShigemuraY, AkabaS, KawashimaE, ParkEY, NakamuraY, SatoK. Identification of a novel food-derived collagen peptide, hydroxyprolyl-glycine, in human peripheral blood by pre-column derivatisation with phenyl isothiocyanate. Food Chem, 2011, 1291019

[14] ZitnayJL, JungGS, LinAH, QinZ, LiY, YuSM, BuehlerMJ, WeissJA. Accumulation of collagen molecular unfolding is the mechanism of cyclic fatigue damage and failure in collagenous tissues. Sci Adv., 2020, 6eaba2795

[15] SuzukiH, MahapatraD, BoardAJ, SteelPJ, DyerJM, GerrardJA, DobsonRCJ, ValéryC. Sub-Ångstrom structure of collagen model peptide (GPO)10 shows a hydrated triple helix with pitch variation and two proline ring conformations. Food Chem., 2020.

[16] YamamotoS, DeguchiK, OnumaM, NumataN, SakaiY. Absorption and urinary excretion of peptides after collagen tripeptide ingestion in humans. Biol Pharm Bull, 2016, 39428

[17] PersikovAV, RamshawJAM, KirkpatrickA, BrodskyB. Triple-helix propensity of hydroxyproline and fluoroproline: comparison of host−guest and repeating tripeptide collagen models. J Am Chem Soc, 2003, 12511500

[18] WonJ, KangJ, NohK, ChungHC, KangW. Pharmacokinetics of collagen dipeptides (Gly–Pro and Pro–Hyp) and tripeptides (Gly–Pro–Hyp) in rats. J Food Sci, 2023, 89701

[19] MaY, KleinbeckK, KaoWJ. Extracellular matrix-derived tripeptide proline-glycine-proline inhibits keratinocyte proliferation and migration. Wound Repair Regen, 2011, 19718

[20] KwonYW, HeoSC, LeeTW, ParkGT, YoonJW, JangIH, KimSC, KoHC, RyuY, KangH, HaCM, LeeSC, KimJH. N-Acetylated proline-glycine-proline accelerates cutaneous wound healing and neovascularization by human endothelial progenitor cells. Sci Rep, 2017, 743057

[21] SarkerB, HumJ, NazhatSN, BoccacciniAR. Combining collagen and bioactive glasses for bone tissue engineering: a review. Adv Healthc Mater, 2015, 4176

[22] NuneM, SubramanianA, KrishnanUM, KaimalSS, SethuramanS. Self-assembling peptide nanostructures on aligned poly(lactide-co-glycolide) nanofibers for the functional regeneration of sciatic nerve. Nanomedicine (Lond), 2017, 12219

[23] ShenY, TuT, YiB, WangX, TangH, LiuW, ZhangY. Electrospun acid-neutralizing fibers for the amelioration of inflammatory response. Acta Biomater, 2019, 97200

[24] YaoK, LvS, ZhangX, ShenK, ChenY, MaZ, HeY. 3D Printing of multiscale biomimetic scaffold for tendon regeneration. Adv Funct Mater., 2024, 352413970

[25] ZhouX, QianY, ChenL, LiT, SunX, MaX, WangJ, HeC. Flowerbed-inspired biomimetic scaffold with rapid internal tissue infiltration and vascularization capacity for bone repair. ACS Nano, 2023, 175140

[26] AnsariV, CaloreA, ZonderlandJ, HaringsJAW, MoroniL, BernaertsKV. Additive manufacturing of alpha-amino acid based poly(ester amide)s for biomedical applications. Biomacromol, 2022, 231083

[27] ShinCS, CabreraFJ, LeeR, KimJ, Ammassam VeettilR, ZaheerM, AdumbumkulathA, MhatreK, AjayanPM, CurleySA, ScottBG, AcharyaG. 3D-bioprinted inflammation modulating polymer scaffolds for soft tissue repair. Adv Mater, 2021, 332003778

[28] BianS, HuX, ZhuH, DuW, WangC, WangL, HaoL, XiangY, MengF, HuC, WuZ, WangJ, PanX, GuanM, LuWW, ZhaoX. 3D Bioprinting of artificial skin substitute with improved mechanical property and regulated cell behavior through integrating patterned nanofibrous films. ACS Nano, 2024, 1818503

[29] ZielińskiPS, GudetiPKR, RikmanspoelT, Włodarczyk-BiegunMK. 3D printing of bio-instructive materials: toward directing the cell. Bioact Mater, 2023, 19292

[30] TianH, HuY, WuJ, WangR, WangJ, CaiX, ChenX, HeY, WangS. Crystal transduction 3D printing of bio-hydrogels with high fidelity and order micro pores. Adv Funct Mater., 2024, 352415799

[31] LiuS, WangZ, ChenX, HanM, XuJ, LiT, YuL, QinM, LongM, LiM, ZhangH, LiY, WangL, HuangW, WuY. Multiscale anisotropic scaffold integrating 3D printing and electrospinning techniques as a heart-on-a-chip platform for evaluating drug-induced cardiotoxicity. Adv Healthc Mater., 2023, 122300719

[32] ChenX, WangJ, AnQ, LiD, LiuP, ZhuW, MoX. Electrospun poly(l-lactic acid-co-ɛ-caprolactone) fibers loaded with heparin and vascular endothelial growth factor to improve blood compatibility and endothelial progenitor cell proliferation. Colloids Surf, B, 2015, 128106

[33] WangC, HouW, GuoX, LiJ, HuT, QiuM, LiuS, MoX, LiuX. Two-phase electrospinning to incorporate growth factors loaded chitosan nanoparticles into electrospun fibrous scaffolds for bioactivity retention and cartilage regeneration. Mater Sci Eng C Mater Biol Appl, 2017, 79507

[34] SaidSS, O'NeilC, YinH, NongZ, PickeringJG, MequanintK. Concurrent and sustained delivery of FGF2 and FGF9 from Electrospun Poly(ester amide) fibrous mats for therapeutic angiogenesis. Tissue Eng Part A, 2016, 22584

[35] CheS, YangY, LiZ, SuZ, ZhangS. Integration of Zn(2+), ATP, and bFGF to nanodressing with core-shell structure fabricated by emulsion electrospinning for wound healing. ACS Appl Bio Mater, 2024, 73316

[36] RandhawaA, DuttaSD, GangulyK, PatilTV, LimKT. Manufacturing 3D biomimetic tissue: a strategy involving the integration of electrospun nanofibers with a 3D-printed framework for enhanced tissue regeneration. Small., 2024, 202309269

[37] HeW, LiC, ZhaoS, LiZ, WuJ, LiJ, ZhouH, YangY, XuY, XiaH. Integrating coaxial electrospinning and 3D printing technologies for the development of biphasic porous scaffolds enabling spatiotemporal control in tumor ablation and osteochondral regeneration. Bioact Mater, 2024, 34338

[38] NuneM, SubramanianA, KrishnanUM, SethuramanS. Peptide nanostructures on nanofibers for peripheral nerve regeneration. J Tissue Eng Regen Med., 2019, 131059

[39] MengZ, MuX, HeJ, ZhangJ, LingR, LiD. Embedding aligned nanofibrous architectures within 3D-printed polycaprolactone scaffolds for directed cellular infiltration and tissue regeneration. Int J Extrem Manuf., 2023, 5025001

[40] TaoY, JiaoG, ZhaoX, TanX, QiaoL, ShengR, WeiD, ZhangT. Amino acid-crosslinked 4arm-PLGA Janus patch with anti-adhesive and anti-bacterial properties for hernia repair. Colloids Surf, B, 2024, 243114126

[41] NguyenLTH, AhnS-H, ShinH-M, YangI-J. Anti-psoriatic effect of Rheum palmatum L. and its underlying molecular mechanisms. Int J Mole Sci., 2022, 2316000

[42] KimH, WangSY, KwakG, YangY, KwonIC, KimSH. Exosome-guided phenotypic switch of M1 to M2 macrophages for cutaneous wound healing. Adv Sci (Weinh), 2019, 61900513

[43] PehP, LimNSJ, BlockiA, CheeSML, ParkHC, LiaoS, ChanC, RaghunathM. Simultaneous delivery of highly diverse bioactive compounds from blend electrospun fibers for skin wound healing. Bioconjug Chem, 2015, 261348

[44] HuJ, TianL, PrabhakaranMP, DingX, RamakrishnaS. Fabrication of nerve growth factor encapsulated aligned poly(ε-Caprolactone) nanofibers and their assessment as a potential neural tissue engineering scaffold. Polymers, 2016, 854

[45] WuB, YangX, KongN, LiangJ, LiS, WangH. Engineering modular peptide nanoparticles for ferroptosis-enhanced tumor immunotherapy. Angewandte Chemie Int Ed., 2025, 64e202421703

[46] XingQ, ZhangJ, XieY, WangY, QiW, RaoH, SuR, HeZ. Aromatic motifs dictate nanohelix handedness of tripeptides. ACS Nano, 2018, 1212305

[47] YangX, LuH, TaoY, ZhouL, WangH. Spatiotemporal control over chemical assembly in living cells by integration of acid-catalyzed hydrolysis and enzymatic reactions. Angew Chem Int Ed, 2021, 6023797

[48] ChoiJS, LeongKW, YooHS. In vivo wound healing of diabetic ulcers using electrospun nanofibers immobilized with human epidermal growth factor (EGF). Biomaterials, 2008, 29587

[49] ZhengY, ChenX, ZhangQ, YangL, ChenQ, ChenZ, WangY, WuD. Evaluation of reactive oxygen species scavenging of polydopamine with different nanostructures. Adv Healthc Mater., 2024.

[50] BokhariN, AliA, YasmeenA, KhanR, HaiderS, SharifF. Fabrication of bioactive silk composite meshes for hernia repair and guided soft tissue remodeling: In silico, in vitro and in vivo models. Appl Mater Today., 2024.

[51] TanX, ShengR, LiuZ, LiW, YuanR, TaoY, YangN, GeL. Assembly of metal-phenolic networks onto microbubbles for one-step generation of functional microcapsules. Small., 2023.

[52] QianH, LeiT, HuaL, ZhangY, WangD, NanJ, LiuW, SunY, HuY, LeiP. Fabrication, bacteriostasis and osteointegration properties researches of the additively-manufactured porous tantalum scaffolds loading vancomycin. Bioact Mater, 2023, 24450

[53] MartinP, Pardo-PastorC, JenkinsRG, RosenblattJ. Imperfect wound healing sets the stage for chronic diseases. Science., 2024.

[54] Boada-RomeroE, MartinezJ, HeckmannBL, GreenDR. The clearance of dead cells by efferocytosis. Nat Rev Mol Cell Biol, 2020, 21398

[55] SmithTD, NagallaRR, ChenEY, LiuWF. Harnessing macrophage plasticity for tissue regeneration. Adv Drug Deliv Rev, 2017, 114193

[56] GuanF, WangR, YiZ, LuoP, LiuW, XieY, LiuZ, XiaZ, ZhangH, ChengQ. Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets. Signal Transduct Target Ther, 2025, 1093

[57] SharmaN, AkkoyunluM, RabinRL. Macrophages-common culprit in obesity and asthma. Allergy, 2018, 731196

[58] PérezS, Rius-PérezS. Macrophage polarization and reprogramming in acute inflammation: a redox perspective. Antioxidants (Basel)., 2022.

[59] TangF, MiaoD, HuangR, ZhengB, YuY, MaP, PengB, LiY, WangH, WuD. Double-layer asymmetric porous mesh with dynamic mechanical support properties enables efficient single-stage repair of contaminated abdominal wall defect. Adv Mater., 2024.

[60] ZhaoY, SunW, WuX, GaoX, SongF, DuanB, LuA, YangH, HuangC. Janus membrane with intrafibrillarly strontium-apatite-mineralized collagen for guided bone regeneration. ACS Nano, 2024, 187204

[61] NieswandtB, WatsonSP. Platelet-collagen interaction: is GPVI the central receptor?. Blood, 2003, 102449

[62] MeyaardL. The inhibitory collagen receptor LAIR-1 (CD305). J Leukoc Biol, 2007, 83799

[63] ElangoJ, HouC, BaoB, WangS, de Maté Sánchez ValJE, WenhuiW. The molecular interaction of collagen with cell receptors for biological function. Polymers (Basel)., 2022.

[64] AbbasiB, ShamsasenjanK, AhmadiM, BeheshtiSA, SalehM. Mesenchymal stem cells and natural killer cells interaction mechanisms and potential clinical applications. Stem Cell Res Ther, 2022, 1397

[65] ZhaoC, LiX, HanX, LiZ, BianS, ZengW, DingM, LiangJ, JiangQ, ZhouZ, FanY, ZhangX, SunY. Molecular co-assembled strategy tuning protein conformation for cartilage regeneration. Nat Commun., 2024, 151488

[66] KellyB, PearceEL. Amino assests: how amino acids support immunity. Cell Metab, 2020, 32154

Funding

the Postgraduate Research &Practice Innovation Program of Jiangsu Province(SJCX23-0056)

Suzhou Science and Technology Plan Project(SYG202343)

Research Fund from Advanced Ocean Institute of Southeast University(GP202410)

RIGHTS & PERMISSIONS

Donghua University, Shanghai, China