A Dual-Crosslinked Metallo-elastomer Platform for Architecture-Directed Vascular Remodeling

Abstract

The engineering of durable small-diameter vascular grafts remains constrained by the challenge of simultaneously achieving mechanical robustness, controlled degradation, and instructive scaffold architecture. Here, we report a programmable dual-crosslinked metallo-elastomer platform, poly(1,3-propylene itaconate-co-2,2′-bipyridine-5,5′-dicarboxylate-co-succinate-co-sebacate) (M-PBIS), that integrates dynamic metal–ligand coordination with covalent crosslinking to enable orthogonal control over network mechanics, time-dependent viscoelastic behavior, and processability. PBIS polymers were synthesized by modular step-growth polyesterification, allowing independent tuning of backbone composition, bipyridine ligand density for metal coordination, and alkene (C = C) content for covalent crosslinking. This multidimensional design space allowed systematic tuning of tensile elastic modulus (0.06–3.2 MPa), extensibility (53%–491%), toughness (66–1339 kJ m⁻³), creep resistance, and self-healing behavior, while maintaining controlled hydrolytic degradation and low physiological swelling (< 7%). Rheological analysis established a processing window supportive of conventional melt- and flow-based fabrication methods. To elucidate the role of scaffold architecture in vascular remodeling, M-PBIS was fabricated into small-diameter grafts using either poly(methyl methacrylate) (PMMA)-templated porous structures or electrowritten circumferentially-biased, helically wound fibers. In a rat carotid artery interposition model, electrowritten Zn-PBIS grafts maintained patency and dimensional stability through 21 weeks, supporting organized endothelialization, circumferential smooth muscle alignment, and structured extracellular matrix deposition. In contrast, PMMA-templated porous grafts underwent progressive dilation and structural instability during remodeling. These results demonstrate that dual-crosslinked metallo-elastomers combined with biomimetic circumferentially-biased fiber architecture enable mechanically resilient, biologically adaptive vascular grafts and establish M-PBIS as a manufacturable platform for resorbable small-diameter arterial reconstruction and other load-bearing soft-tissue applications.

Graphical abstract

Keywords

Dual-crosslinked metallo-elastomers / Electrowriting / Circumferentially-biased helically wound fiber alignment / Resorbable vascular graft / In situ vascular remodeling

References

[1] Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, Barengo NC, Beaton AZ, Benjamin EJ, Benziger CP. Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD 2019 study. J Am Coll Cardiol, 2020, 76: 2982

[2] De Vries MR, Simons KH, Jukema JW, Braun J, Quax PH. Vein graft failure: from pathophysiology to clinical outcomes. Nat Rev Cardiol, 2016, 13: 451

[3] Leal BB, Wakabayashi N, Oyama K, Kamiya H, Braghirolli DI, Pranke P. Vascular tissue engineering: polymers and methodologies for small caliber vascular grafts. Front Cardiovasc Med, 2021, 7 592361

[4] Obiweluozor FO, Emechebe GA, Kim D-W, Cho H-J, Park CH, Kim CS, Jeong IS. Considerations in the development of small-diameter vascular graft as an alternative for bypass and reconstructive surgeries: a review. Cardiovasc Eng Technol, 2020, 11: 495

[5] Xue L, Greisler HP. Biomaterials in the development and future of vascular grafts. J Vasc Surg, 2003, 37: 472

[6] Stowell CE, Wang Y. Quickening: translational design of resorbable synthetic vascular grafts. Biomaterials, 2018, 173: 71

[7] Kurobe H, Maxfield MW, Tara S, Rocco KA, Bagi PS, Yi T, Udelsman B, Zhuang ZW, Cleary M, Iwakiri Y. Development of small diameter nanofiber tissue engineered arterial grafts. PLoS ONE, 2015, 10 e0120328

[8] Wang Y, Ameer GA, Sheppard BJ, Langer R. A tough biodegradable elastomer. Nat Biotechnol, 2002, 20: 602

[9] Lee K-W, Gade PS, Dong L, Zhang Z, Aral AM, Gao J, Ding X, Stowell CE, Nisar MU, Kim K. A biodegradable synthetic graft for small arteries matches the performance of autologous vein in rat carotid arteries. Biomaterials, 2018, 181: 67

[10] Stowell CE, Li X, Matsunaga MH, Cockreham CB, Kelly KM, Cheetham J, Tzeng E, Wang Y. Resorbable vascular grafts show rapid cellularization and degradation in the ovine carotid. J Tissue Eng Regen Med, 2020, 14: 1673

[11] Chen Y, Miller PG, Ding X, Stowell CE, Kelly KM, Wang Y. Chelation crosslinking of biodegradable elastomers. Adv Mater, 2020, 32: 2003761

[12] Chen YG, Dombaxe C, D’Amato AR, Van Herck S, Welch H, Fu Q, Zhang S, Wang Y. Transformation of metallo-elastomer grafts in a carotid artery interposition model over a year. Biomaterials, 2024, 309 122598

[13] Fertier L, Koleilat H, Stemmelen M, Giani O, Joly-Duhamel C, Lapinte V, Robin J-J. The use of renewable feedstock in UV-curable materials-a new age for polymers and green chemistry. Prog Polym Sci, 2013, 38: 932

[14] Guo W, Shen Z, Guo B, Zhang L, Jia D. Synthesis of bio-based copolyester and its reinforcement with zinc diacrylate for shape memory application. Polymer, 2014, 55: 4324

[15] Hoon-Khosla M, Fawcett WR, Goddard JD, Tian W-Q, Lipkowski J. Reflection FTIR studies of the conformation of 2,2′-bipyridine adsorbed at the Au(111) electrode/electrolyte interface. Langmuir, 2000, 16: 2356

[16] Constable EC, Housecroft CE. The early years of 2,2′-bipyridine—A ligand in its own lifetime. Molecules, 2019, 24: 3951

[17] Hadjiivanov KI, Panayotov DA, Mihaylov MY, Ivanova EZ, Chakarova KK, Andonova SM, Drenchev NL. Power of infrared and Raman spectroscopies to characterize metal-organic frameworks and investigate their interaction with guest molecules. Chem Rev, 2020, 121: 1286

[18] Yang L-J, Liu Q-L, Wang M-X, Gu L-S, Luo Y-H, Sun B-W. Complexation of different transition metals with 4,4′-dimethyl-2,2′-bipyridine: crystal structure, UV spectra and Hirshfeld surfaces. Spectrochim Acta A Mol Biomol Spectrosc, 2016, 166: 1

[19] McCusker JK. Femtosecond absorption spectroscopy of transition metal charge-transfer complexes. Acc Chem Res, 2003, 36: 876

[20] Schubert US, Hofmeier H, Newkome GR. Modern terpyridine chemistry, 2006, Weinheim, Wiley-VCH

[21] Sperling LH. Introduction to physical polymer science, 2015, Hoboken, John Wiley & Sons

[22] Guo B, Chen Y, Lei Y, Zhang L, Zhou WY, Rabie ABM, Zhao J. Biobased poly(propylene sebacate) as shape memory polymer with tunable switching temperature for potential biomedical applications. Biomacromol, 2011, 12: 1312

[23] Klapwijk AR, Simone E, Nagy ZK, Wilson CC. Tuning crystal morphology of succinic acid using a polymer additive. Cryst Growth Des, 2016, 16: 4349

[24] Liu M, Bai J, Kong L, Bai Z, He C, Li W. The correlation between coal char structure and reactivity at rapid heating condition in TGA and heating stage microscope. Fuel, 2020, 260: 116318

[25] Stempfle F, Ortmann P, Mecking S. Long-chain aliphatic polymers to bridge the gap between semicrystalline polyolefins and traditional polycondensates. Chem Rev, 2016, 116: 4597

[26] Khusnutdinova JR, Milstein D. Metal-ligand cooperation. Angew Chem Int Ed, 2015, 54: 12236

[27] Liu X, Allais F, Fadlallah S. Itaconic acid as a platform chemical for bio-based polymers: from green polymerization strategies to structure-driven applications. Green Chem, 2026, 28: 3371

[28] Fetters L, Lohse D, Colby R. Mark JE. Chain dimensions and entanglement spacings. Physical properties of polymers handbook, 2007, New York, Springer: 447-454

[29] Ding X, Gantumur N, Lee BP, Chen YG. Photocurable and 3D printable functional polyesters to engineer elastomeric scaffolds for biomedical applications. Macromol Biosci, 2025, 25(10): e00189

[30] Webber MJ, Tibbitt MW. Dynamic and reconfigurable materials from reversible network interactions. Nat Rev Mater, 2022, 7: 541

[31] Li L, Chen X, Jin K, Rusayyis MB, Torkelson JM. Arresting elevated-temperature creep and achieving full cross-link density recovery in reprocessable polymer networks and network composites via nitroxide-mediated dynamic chemistry. Macromolecules, 2021, 54: 1452

[32] Lehnert N, Kim E, Dong HT, Harland JB, Hunt AP, Manickas EC, Oakley KM, Pham J, Reed GC, Alfaro VS. The biologically relevant coordination chemistry of iron and nitric oxide: electronic structure and reactivity. Chem Rev, 2021, 121: 14682

[33] Sun X, Wang H, Ding Y, Yao Y, Liu Y, Tang J. Fe³⁺-coordination mediated synergistic dual-network conductive hydrogel as a sensitive and highly-stretchable strain sensor with adjustable mechanical properties. J Mater Chem B, 2022, 10: 1442

[34] Yang C, Gao Y, Ma T, Bai M, He C, Ren X, Luo X, Wu C, Li S, Cheng C. Metal alloys-structured electrocatalysts: metal-metal interactions, coordination microenvironments, and structural property-reactivity relationships. Adv Mater, 2023, 35: 2301836

[35] Ma W, Ding X, Chen Y, Wang Y. Synthesis and characterization of alkyne-functionalized photo-cross-linkable polyesters. ACS Omega, 2022, 7: 15540

[36] Zhang W, Wu B, Sun S, Wu P. Skin-like mechanoresponsive self-healing ionic elastomer from supramolecular zwitterionic network. Nat Commun, 2021, 12: 4082

[37] Zheng N, Xu Y, Zhao Q, Xie T. Dynamic covalent polymer networks: a molecular platform for designing functions beyond chemical recycling and self-healing. Chem Rev, 2021, 121: 1716

[38] Cao L, Gong Z, Liu C, Fan J, Chen Y. Design and fabrication of mechanically strong and self-healing rubbers via metal-ligand coordination bonds as dynamic crosslinks. Compos Sci Technol, 2021, 207: 108750

[39] Shao C, Chang H, Wang M, Xu F, Yang J. High-strength, tough, and self-healing nanocomposite physical hydrogels based on the synergistic effects of dynamic hydrogen bond and dual coordination bonds. ACS Appl Mater Interfaces, 2017, 9: 28305

[40] Singh G, Chanda A. Mechanical properties of whole-body soft human tissues: a review. Biomed Mater, 2021, 16: 062004

[41] Khare E, Holten-Andersen N, Buehler MJ. Transition-metal coordinate bonds for bioinspired macromolecules with tunable mechanical properties. Nat Rev Mater, 2021, 6: 421

[42] Rodin M, Li J, Kuckling D. Dually cross-linked single networks: structures and applications. Chem Soc Rev, 2021, 50: 8147

[43] Soetrisno DD, Martínez Narváez CD, Sharma V, Conrad JC. Concentration regimes for extensional relaxation times of unentangled polymer solutions. Macromolecules, 2023, 56: 4919

[44] Trindade MA, Benjeddou A, Ohayon R. Modeling of frequency-dependent viscoelastic materials for active-passive vibration damping. J Vib Acoust, 2000, 122: 169

[45] Vlachopoulos J, Strutt D. Polymer processing. Mater Sci Technol, 2003, 19: 1161

[46] Pielichowski K, Njuguna J, Majka TM. Thermal degradation of polymeric materials. Thermal degradation of polymeric materials, 2022, Amsterdam, Elsevier

[47] Mullins L. Softening of rubber by deformation. Rubber Chem Technol, 1969, 42: 339

[48] Jennings R, Rogers J, West T. Factors influencing mobility control by polymer solutions. J Petrol Technol, 1971, 23: 391

[49] Zhang W, Chen J, Zeng H. Narain R. Polymer processing and rheology. Polymer science and nanotechnology, 2020, Amsterdam, Elsevier: 149-178

[50] Odian G. Principles of polymerization, 2004, Hoboken, John Wiley & Sons

[51] Bowman CN, Kloxin CJ. Toward an enhanced understanding and implementation of photopolymerization reactions. AIChE J, 2008, 54: 2775

[52] Boyce MC, Arruda EM. Swelling and mechanical stretching of elastomeric materials. Math Mech Solids, 2001, 6: 641

[53] Zilla P, Bezuidenhout D, Human P. Prosthetic vascular grafts: wrong models, wrong questions and no healing. Biomaterials, 2007, 28: 5009

[54] Papenburg BJ, Rodrigues ED, Wessling M, Stamatialis D. Insights into the role of material surface topography and wettability on cell-material interactions. Soft Matter, 2010, 6: 4377

[55] Bosch-Rué E, Díez-Tercero L, Rodríguez-González R, Bosch-Canals BM, Perez RA. Assessing the potential role of copper and cobalt in stimulating angiogenesis for tissue regeneration. PLoS ONE, 2021, 16 e0259125

[56] Sena CM, Leandro A, Azul L, Seiça R, Perry G. Vascular oxidative stress: impact and therapeutic approaches. Front Physiol, 2018, 9: 1668

[57] Michalczyk K, Cymbaluk-Płoska A. The role of zinc and copper in gynecological malignancies. Nutrients, 2020, 12: 3732

[58] Zhu Y, Guo S, Ravichandran D, Ramanathan A, Sobczak MT, Sacco AF, Patil D, Thummalapalli SV, Pulido TV, Lancaster JN. 3D-printed polymeric biomaterials for health applications. Adv Healthc Mater, 2025, 14: 2402571

[59] D’Amato AR, Ding X, Wang Y. Using solution electrowriting to control the properties of tubular fibrous conduits. ACS Biomater Sci Eng, 2021, 7: 400

[60] Lee K-W, Johnson NR, Gao J, Wang Y. Human progenitor cell recruitment via SDF-1α coacervate-laden PGS vascular grafts. Biomaterials, 2013, 34: 9877

[61] Madani M, Golts E. Caplan MJ. Cardiovascular anatomy. Reference module in biomedical sciences, 2014, Amsterdam, Elsevier

[62] Batinac T, Batičić L, Kršek A, Knežević D, Marcucci E, Sotošek V, Ćurko-Cofek B. Endothelial dysfunction and cardiovascular disease: hyperbaric oxygen therapy as an emerging therapeutic modality. Journal of Cardiovascular Development and Disease, 2024, 11: 408

[63] Wang Z, Cui Y, Wang J, Yang X, Wu Y, Wang K, Gao X, Li D, Li Y, Zheng X-L. The effect of thick fibers and large pores of electrospun poly(ε-caprolactone) vascular grafts on macrophage polarization and arterial regeneration. Biomaterials, 2014, 35: 5700

[64] Wagenseil JE, Mecham RP. Vascular extracellular matrix and arterial mechanics. Physiol Rev, 2009, 89: 957

[65] Li Q, Ding X, Chen C, Zhang K, Dong R. An overview of small diameter vascular grafts: from materials to fabrication. Mater Adv, 2025, 6: 6221

[66] Discher D, Dong C, Fredberg JJ, Guilak F, Ingber D, Janmey P, Kamm RD, Schmid-Schönbein GW, Weinbaum S. Biomechanics: cell research and applications for the next decade. Ann Biomed Eng, 2009, 37: 847

[67] Ma J, Zhao N, Zhu D. Endothelial cellular responses to biodegradable metal zinc. ACS Biomater Sci Eng, 2015, 1: 1174

Funding

American Heart Association(26AIREA1570555)

New Jersey Health Foundation(PC74-26)

Rowan University

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