Immobilization of a Metal–Organic Framework on a Nanofiber Membrane as Artificial Platelets for Efficient Hemostasis

Abstract

Medical hemostatic gauze is one of the most common agents for bleeding management used in pre-hospital care and clinical treatment. An ideal hemostat requires the features including fast coagulation ability, high biocompatibility and low cost, which is difficult to be achieved simultaneously. Herein, we reported a chemical immobilization method to uniformly anchor the zeolitic imidazolate framework (ZIF-8) nanoparticles on polyvinyl alcohol (PVA) membrane, which dramatically accelerated the in vivo conversion process of prothrombin to thrombin, achieving a short hemostasis time around 60 s with a low amount of blood loss of 23 mg. Later, the hemostatic mechanism was unveiled by two pathways involving the activation of platelets and the conversion of prothrombin, indicating that this ZIF-8-based membrane works in a similar way to natural platelet-based physiological processes. More importantly, the convenient manufacturing and excellent biocompatibility of ZIF-8-based membrane provide a practical candidate hemostat for clinical bleeding management.

Keywords

Noncompressible hemostasis / Immobilization of metal–organic frameworks / Artificial platelets / Nanofiber membrane

References

[1] Bao GY, Gao QM, Cau M, Ali-Mohamad N, Strong M, Jiang SB, Yang Z, Valiei A, Ma ZW, Amabili M, Gao ZH, Mongeau L, Kastrup C, Li JY. Liquid-infused microstructured bioadhesives halt non-compressible hemorrhage. Nat Commun, 2022, 13: 5035,

[2] Gao Y, Sarode A, Kokoroskos N, Ukidve A, Zhao Z, Guo S, Flaumenhaft R, Gupta AS, Saillant N, Mitragotri S. A polymer-based systemic hemostatic agent. Sci Adv, 2020, 6: eaba0588,

[3] Hickman DA, Pawlowski CL, Sekhon UDS, Marks J, Gupta AS. Biomaterials and advanced technologies for hemostatic management of bleeding. Adv Mater, 2018, 30: 1700859,

[4] Luc NF, Rohner N, Girish A, Sekhon UDS, Neal MD, Sen GA. Bioinspired artificial platelets: past, present and future. Platelets, 2022, 33: 35,

[5] Yang PP, Zhang K, He PP, Fan Y, Gao XJJ, Gao XF, Chen ZM, Hou DY, Li Y, Yi Y, Cheng DB, Zhang JP, Shi LQ, Zhang XZ, Wang L, Wang H. A biomimetic platelet based on assembling peptides initiates artificial coagulation. Sci Adv, 2020, 6: eaaz4107,

[6] Krishnaswamy S. The transition of prothrombin to thrombin. J Thromb Haemostasis, 2013, 11: 265,

[7] Bu Y, Zhang L, Sun G, Sun F, Liu J, Yang F, Tang P, Wu D. Tetra-PEG based hydrogel sealants for in vivo visceral hemostasis. Adv Mater, 2019, 31: 1901580,

[8] Wang HF, Cheng JY, Sun FF, Dou XY, Liu JH, Wang YR, Li M, Gao JP, Liu X, Wang X, Yang F, Zhu ZR, Shen H, Zhang LC, Tang PF, Wu DC. A super tough, rapidly biodegradable, ultrafast hemostatic bioglue. Adv Mater, 2023, 35: 2208622,

[9] Li N, Zhang GQ, Liu Y, Sun LL, Zhao X, Ding LQ, Liu YN, Wang M, Ren XL. A natural self-assembled gel-sponge with hierarchical porous structure for rapid hemostasis and antibacterial. Adv Healthc Mater, 2023, 12: 2301465,

[10] Zhang KW, Xian YW, Li M, Pan Z, Zhu ZR, Yang Y, Wang HF, Zhang LC, Zhang C, Wu DC. Gelable and adhesive powder for lethal non-compressible hemorrhage control. Adv Funct Mater, 2023, 33: 2305222,

[11] Pourshahrestani S, Zeimaran E, Djordjevic I, Kadri NA, Towler MR. Inorganic hemostats: the state-of-the-art and recent advances. Mater Sci Eng C Mater Biol Appl, 2016, 58: 1255,

[12] He HY, Zhou WK, Gao J, Wang F, Wang SB, Fang Y, Gao Y, Chen W, Zhang W, Weng YX, Wang ZC, Liu HQ. Efficient, biosafe and tissue adhesive hemostatic cotton gauze with controlled balance of hydrophilicity and hydrophobicity. Nat Commun, 2022, 13: 552,

[13] Peng HT. Hemostatic agents for prehospital hemorrhage control: a narrative review. Mil Med Res, 2020, 7: 13

[14] Yu LS, Shang XQ, Chen H, Xiao LP, Zhu YH, Fan J. A tightly-bonded and flexible mesoporous zeolite-cotton hybrid hemostat. Nat Commun, 1932, 2019: 10

[15] He HY, Sun CX, Weng YX, Huang HJ, Ni P, Fang Y, Xu RF, Wang ZC, Liu HQ. Catechol modification of non-woven chitosan gauze for enhanced hemostatic efficacy. Carbohydr Polym, 2022, 286,

[16] Cui Y, Huang ZW, Lei L, Li QL, Jiang JL, Zeng QH, Tang AD, Yang HM, Zhang Y. Robust hemostatic bandages based on nanoclay electrospun membranes. Nat Commun, 2021, 12: 5922,

[17] Montazerian H, Davoodi E, Baidya A, Baghdasarian S, Sarikhani E, Meyer CE, Haghniaz R, Badv M, Annabi N, Khademhosseini A, Weiss PS. Engineered hemostatic biomaterials for sealing wounds. Chem Rev, 2022, 122: 12864,

[18] Gogoi RK, Raidongia K. Strategic shuffling of clay layers to imbue them with responsiveness. Adv Mater, 2017, 29: 1701164,

[19] Feng Y, He YQ, Lin XY, Xie MY, Liu MX, Lvov YR. Assembly of clay nanotubes on cotton fibers mediated by biopolymer for robust and high-performance hemostatic dressing. Adv Healthc Mater, 2023, 12: 2202265,

[20] Wu M-X, Yang Y-W. Metal-organic framework (MOF)-based drug/cargo delivery and cancer therapy. Adv Mater, 2017, 29: 1606134,

[21] Luo ZD, Fan SR, Gu CY, Liu WC, Chen JX, Li BH, Liu JA. Metal-organic framework (MOF)-based nanomaterials for biomedical applications. Curr Med Chem, 2019, 26: 3341,

[22] Meng ZY, Qiu ZM, Shi YX, Wang SX, Zhang GX, Pi YC, Pang H. Micro/nano metal-organic frameworks meet energy chemistry: A review of materials synthesis and applications. eScience, 2023, 3: 100092,

[23] Xie Y, Wu XY, Shi YX, Peng Y, Zhou HJ, Wu XH, Ma J, Jin JC, Pi YC, Pang H. Recent progress in 2D metal-organic framework-related materials. Small, 2024, 20: 2305548,

[24] Li SC, Hu BC, Shang LM, Ma T, Li C, Liang HW, Yu SH. General synthesis and solution processing of metal-organic framework nanofibers. Adv Mater, 2022, 34: 2202504,

[25] Zhang B, Chen HW, Hu QH, Jiang LM, Shen YQ, Zhao D, Zhou ZX. CelluMOFs: green, facile, and flexible metal-organic frameworks for versatile applications. Adv Funct Mater, 2021, 31: 2105395,

[26] Zhang S, Ding F, Liu Y, Ren X. Glucose-responsive biomimetic nanoreactor in bacterial cellulose hydrogel for antibacterial and hemostatic therapies. Carbohydr Polym, 2022, 292,

[27] Lamei E, Hasanzadeh M. Fabrication of chitosan nanofibrous scaffolds based on tannic acid and metal-organic frameworks for hemostatic wound dressing applications. Int J Biol Macromol, 2022, 208: 409,

[28] Xiong Y, Feng Q, Lu L, Qiu XA, Knoedler S, Panayi AC, Jiang DS, Rinkevich Y, Lin Z, Mi BB, Liu GH, Zhao YL. Metal-organic frameworks and their composites for chronic wound healing: from bench to bedside. Adv Mater, 2024, 36: 2302587,

[29] He YP, Xu J, Sun X, Ren XH, Maharjan A, York P, Su Y, Li HY, Zhang JW. Cuboidal tethered cyclodextrin frameworks tailored for hemostasis and injured vessel targeting. Theranostics, 2019, 9: 2489,

[30] Lefrançais E, Ortiz-Muñoz G, Caudrillier A, Mallavia B, Liu F, Sayah DM, Thornton EE, Headley MB, David T, Coughlin SR, Krummel MF, Leavitt AD, Passegué E, Looney MR. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature, 2017, 544: 105,

[31] Shang XQ, Chen H, Castagnola V, Liu K, Boselli L, Petseva V, Yu LS, Xiao LP, He M, Wang FJ, Dawson KA, Fan J. Unusual zymogen activation patterns in the protein corona of Ca-zeolites. Nat Catal, 2021, 4: 607,

[32] Hamedi H, Moradi S, Hudson SM, Tonelli AE, King MW. Chitosan based bioadhesives for biomedical applications: a review. Carbohydr Polym, 2022, 282,

[33] Kheirabadi BS, Mace JE, Terrazas IB, Fedyk CG, Estep JS, Dubick MA, Blackbourne LH. Safety evaluation of new hemostatic agents, smectite granules, and kaolin-coated gauze in a vascular injury wound model in swine. J Trauma Acute Care Surg, 2010, 68: 269,

[34] Gaharwar AK, Avery RK, Assmann A, Paul A, McKinley GH, Khademhosseini A, Olsen BD. Shear-thinning nanocomposite hydrogels for the treatment of hemorrhage. ACS Nano, 2014, 8: 9833,

[35] Liang YP, Xu CC, Li GF, Liu TC, Liang JF, Wang X. Graphene-kaolin composite sponge for rapid and riskless hemostasis. Colloids Surf B, 2018, 169: 168,

[36] Liu CK, Liu C, Shi Z, Lu W, Liu ZY, Liu SH, Wang XJ, Wang XQ, Huang F. Sprayable surface-adaptive biocompatible membranes for efficient hemostasis via assembly of chitosan and polyphosphate. Carbohydr Polym, 2023, 302,

[37] Hui C, Ding LQ, Sun TC, Liu Z, Ramakrishna S, Long YZ, Zhang J. Collocalia birds inspired Janus-structured bandage with strong wet tissue adhesion for rapid hemostasis and wound healing. Chem Eng J, 2023, 464,

[38] Neurath H. Evolution of proteolytic enzymes. Science, 1984, 224: 350,

[39] Neurath H, Walsh KA. Role of proteolytic enzymes in biological regulation (a review). Proc Natl Acad Sci U S A, 1976, 73: 3825,

[40] Crawley JTB, Zanardelli S, Chion CKNK, Lane DA. The central role of thrombin in hemostasis. J Thromb Haemost, 2007, 5: 95,

[41] Allen GA, Wolberg AS, Oliver JA, Hoffman M, Roberts HR, Monroe DM. Impact of procoagulant concentration on rate, peak and total thrombin generation in a model system. J Thromb Haemost, 2004, 2: 402,

[42] Wilkens M. Endogenous thrombin potential in practical use. Hamostaseologie, 2011, 31: 88

[43] Brodin E, Seljeflot I, Arnesen H, Hurlen M, Appelbom H, Hansen JB. Endogenous thrombin potential (ETP) in plasma from patients with AMI during antithrombotic treatment. Thromb Res, 2009, 123: 573,

Funding

National Natural Science Foundation of China(22201223); Chutian Scholar Foundation of Hubei Province; Natural Science Foundation of Hubei Province(2022CFA023)