Microchannelled alkylated chitosan sponge to treat noncompressible hemorrhages and facilitate wound healing
Xinchen Du, Le Wu, Hongyu Yan, Zhuyan Jiang, Shilin Li, Wen Li, Yanli Bai, Hongjun Wang, Zhaojun Cheng, Deling Kong, Lianyong Wang, Meifeng Zhu, Xinchen Du, Le Wu, Hongyu Yan, Zhuyan Jiang, Shilin Li, Wen Li, Yanli Bai, Hongjun Wang, Zhaojun Cheng, Deling Kong, Lianyong Wang, Meifeng Zhu
Abstract
Developing an anti-infective shape-memory hemostatic sponge able to guide in situ tissue regeneration for noncompressible hemorrhages in civilian and battlefield settings remains a challenge. Here we engineer hemostatic chitosan sponges with highly interconnective microchannels by combining 3D printed microfiber leaching, freeze-drying, and superficial active modification. We demonstrate that the microchannelled alkylated chitosan sponge (MACS) exhibits the capacity for water and blood absorption, as well as rapid shape recovery. We show that compared to clinically used gauze, gelatin sponge, CELOX™, and CELOX™-gauze, the MACS provides higher pro-coagulant and hemostatic capacities in lethally normal and heparinized rat and pig liver perforation wound models. We demonstrate its anti-infective activity against S. aureus and E. coli and its promotion of liver parenchymal cell infiltration, vascularization, and tissue integration in a rat liver defect model. Overall, the MACS demonstrates promising clinical translational potential in treating lethal noncompressible hemorrhage and facilitating wound healing.
Conflict of interest statement
The authors declare no competing interests.
© 2021. The Author(s).
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References
- Hickman DA, Pawlowski CL, Sekhon UDS, Marks J, Gupta AS. Biomaterials and advanced technologies for hemostatic management of bleeding. Adv. Mater. 2018;30:1700859. doi: 10.1002/adma.201700859.
- Gao Y, et al. A polymer-based systemic hemostatic agent. Sci. Adv. 2020;6:0588.
- Johnson D, et al. The effects of QuikClot Combat Gauze on hemorrhage control in the presence of hemodilution and hypothermia. Ann. Med. Surg. 2014;3:21–25. doi: 10.1016/j.amsu.2014.03.001.
- Boerman MA, et al. Next generation hemostatic materials based on NHS-ester functionalized poly(2-oxazoline)s. Biomacromolecules. 2017;18:2529–2538. doi: 10.1021/acs.biomac.7b00683.
- Yang X, et al. Peptide-immobilized starch/PEG sponge with rapid shape recovery and dual-function for both uncontrolled and noncompressible hemorrhage. Acta Biomater. 2019;99:220–235. doi: 10.1016/j.actbio.2019.08.039.
- Zhao X, Guo B, Wu H, Liang Y, Ma PX. Injectable antibacterial conductive nanocomposite cryogels with rapid shape recovery for noncompressible hemorrhage and wound healing. Nat. Commun. 2018;9:2784. doi: 10.1038/s41467-018-04998-9.
- Bu Y, et al. Synthesis and properties of hemostatic and bacteria-responsive in situ hydrogels for emergency treatment in critical situations. ACS Appl. Mater. Interfaces. 2016;8:12674–12683. doi: 10.1021/acsami.6b03235.
- Landsman TL, et al. A shape memory foam composite with enhanced fluid uptake and bactericidal properties as a hemostatic agent. Acta Biomater. 2017;47:91–99. doi: 10.1016/j.actbio.2016.10.008.
- Yang X, et al. Design and development of polysaccharide hemostatic materials and their hemostatic mechanism. Biomater. Sci. 2017;5:2357–2368. doi: 10.1039/C7BM00554G.
- Chen S, Carlson MA, Zhang YS, Hu Y, Xie J. Fabrication of injectable and superelastic nanofiber rectangle matrices (“peanuts”) and their potential applications in hemostasis. Biomaterials. 2018;179:46–59. doi: 10.1016/j.biomaterials.2018.06.031.
- Mueller GR, et al. A novel sponge-based wound stasis dressing to treat lethal noncompressible hemorrhage. J. Trauma Acute Care Surg. 2012;73:S134–S139. doi: 10.1097/TA.0b013e3182617c3c.
- Rodriguez JN, et al. Opacification of shape memory polymer foam designed for treatment of intracranial aneurysms. Ann. Biomed. Eng. 2012;40:883–897. doi: 10.1007/s10439-011-0468-1.
- Rodriguez JN, et al. In vivo response to an implanted shape memory polyurethane foam in a porcine aneurysm model. J. Biomed. Mater. Res. A. 2014;102:1231–1242. doi: 10.1002/jbm.a.34782.
- Huang Y, et al. Degradable gelatin-based IPN cryogel hemostat for rapidly stopping deep noncompressible hemorrhage and simultaneously improving wound healing. Chem. Mater. 2020;32:6595–6610. doi: 10.1021/acs.chemmater.0c02030.
- Li M, Zhang Z, Liang Y, He J, Guo B. Multifunctional tissue-adhesive cryogel wound dressing for rapid nonpressing surface hemorrhage and wound repair. ACS Appl. Mater. Interfaces. 2020;12:35856–35872. doi: 10.1021/acsami.0c08285.
- Xu C, Dai G, Hong Y. Recent advances in high-strength and elastic hydrogels for 3D printing in biomedical applications. Acta Biomater. 2019;95:50–59. doi: 10.1016/j.actbio.2019.05.032.
- Daly AC, Pitacco P, Nulty J, Cunniffe GM, Kelly DJ. 3D printed microchannel networks to direct vascularisation during endochondral bone repair. Biomaterials. 2018;162:34–46. doi: 10.1016/j.biomaterials.2018.01.057.
- Rnjak-Kovacina J, Wray LS, Golinski JM, Kaplan DL. Arrayed hollow channels in silk-based scaffolds provide functional outcomes for engineering critically-sized tissue constructs. Adv. Funct. Mater. 2014;24:2188–2196. doi: 10.1002/adfm.201302901.
- Zhu M, et al. In vivo engineered extracellular matrix scaffolds with instructive niches for oriented tissue regeneration. Nat. Commun. 2019;10:4620. doi: 10.1038/s41467-019-12545-3.
- Zhang L, Yang G, Johnson BN, Jia X. Three-dimensional (3D) printed scaffold and material selection for bone repair. Acta Biomater. 2019;84:16–33. doi: 10.1016/j.actbio.2018.11.039.
- Zhao Y, et al. Synthetic poly(vinyl alcohol)-chitosan as a new type of highly efficient hemostatic sponge with blood-triggered swelling and high biocompatibility. J. Mater. Chem. B. 2019;7:1855–1866. doi: 10.1039/C8TB03181A.
- Leonhardt EE, Kang N, Hamad MA, Wooley KL, Elsabahy M. Absorbable hemostatic hydrogels comprising composites of sacrificial templates and honeycomb-like nanofibrous mats of chitosan. Nat. Commun. 2019;10:2307. doi: 10.1038/s41467-019-10290-1.
- Du X, et al. Injectable hydrogel composed of hydrophobically modified chitosan/oxidized-dextran for wound healing. Mater. Sci. Eng. C. 2019;104:109930. doi: 10.1016/j.msec.2019.109930.
- Du X, et al. Anti-infective and pro-coagulant chitosan-based hydrogel tissue adhesive for sutureless wound closure. Biomacromolecules. 2020;21:1243–1253. doi: 10.1021/acs.biomac.9b01707.
- Dowling MB, et al. A self-assembling hydrophobically modified chitosan capable of reversible hemostatic action. Biomaterials. 2011;32:3351–3357. doi: 10.1016/j.biomaterials.2010.12.033.
- Chen G, et al. Wound healing: Bioinspired multifunctional hybrid hydrogel promotes wound healing. Adv. Funct. Mater. 2018;28:1870233. doi: 10.1002/adfm.201870233.
- Fang Y, et al. 3D porous chitin sponge with high absorbency, rapid shape recovery, and excellent antibacterial activities for noncompressible wound. Chem. Eng. J. 2020;388:124169. doi: 10.1016/j.cej.2020.124169.
- Gupta D, Singh AK, Dravid A, Bellare J. Multiscale porosity in compressible cryogenically 3D printed gels for bone tissue engineering. ACS Appl. Mater. Interfaces. 2019;11:20437–20452. doi: 10.1021/acsami.9b05460.
- Wang C, et al. Bioinspired, injectable, quaternized hydroxyethyl cellulose composite hydrogel coordinated by mesocellular silica foam for rapid, noncompressible hemostasis and wound healing. ACS Appl. Mater. Interfaces. 2019;11:34595–34608. doi: 10.1021/acsami.9b08799.
- Zhao X, et al. Injectable dry cryogels with excellent blood-sucking expansion and blood clotting to cease hemorrhage for lethal deep-wounds, coagulopathy and tissue regeneration. Chem. Eng. J. 2021;403:126329. doi: 10.1016/j.cej.2020.126329.
- Benesch J, Tengvall P. Blood protein adsorption onto chitosan. Biomaterials. 2002;23:2561–2568. doi: 10.1016/S0142-9612(01)00391-X.
- Chan LW, et al. PolySTAT-modified chitosan gauzes for improved hemostasis in external hemorrhage. Acta Biomater. 2016;31:178–185. doi: 10.1016/j.actbio.2015.11.017.
- Cui C, et al. Water-triggered hyperbranched polymer universal adhesives: from strong underwater adhesion to rapid sealing hemostasis. Adv. Mater. 2019;31:1905761. doi: 10.1002/adma.201905761.
- Bu Y, et al. Tetra-PEG based hydrogel sealants for in vivo visceral hemostasis. Adv. Mater. 2019;31:1901580. doi: 10.1002/adma.201901580.
- Liu C, et al. A highly efficient, in situ wet-adhesive dextran derivative sponge for rapid hemostasis. Biomaterials. 2019;205:23–37. doi: 10.1016/j.biomaterials.2019.03.016.
- Wang X, et al. Exploration of blood coagulation of N-alkyl chitosan nanofiber membrane in vitro. Biomacromolecules. 2018;19:731–739. doi: 10.1021/acs.biomac.7b01492.
- Yang X, et al. Fabricating antimicrobial peptide-immobilized starch sponges for hemorrhage control and antibacterial treatment. Carbohyd. Polym. 2019;222:115012. doi: 10.1016/j.carbpol.2019.115012.
- Vo D, Lee CK. Antimicrobial sponge prepared by hydrophobically modified chitosan for bacteria removal. Carbohyd. Polym. 2018;187:1–7. doi: 10.1016/j.carbpol.2018.01.082.
- H J, et al. A smart aminoglycoside hydrogel with tunable gel degradation, on-demand drug release, and high antibacterial activity. J. Control. Release. 2017;247:145–152. doi: 10.1016/j.jconrel.2017.01.003.
- Wang X, Meier RJ, Wolfbeis OS. Fluorescent pH-sensitive nanoparticles in an agarose matrix for imaging of bacterial growth and metabolism. Angew. Chem. Int. Ed. 2013;52:406–409. doi: 10.1002/anie.201205715.
- Dutta PK, Tripathi S, Mehrotra GK, Dutta J. Perspectives for chitosan based antimicrobial films in food applications. Food Chem. 2009;114:1173–1182. doi: 10.1016/j.foodchem.2008.11.047.
- Xi Y, Ge J, Guo Y, Lei B, Ma PX. Biomimetic elastomeric polypeptide-based nanofibrous matrix for overcoming multidrug-resistant bacteria and enhancing full-thickness wound healing/skin regeneration. ACS Nano. 2018;12:10772–10784. doi: 10.1021/acsnano.8b01152.
- Wu P, et al. Construction of vascular graft with circumferentially oriented microchannels for improving artery regeneration. Biomaterials. 2020;242:119922. doi: 10.1016/j.biomaterials.2020.119922.
- Li W, et al. Subcutaneously engineered autologous extracellular matrix scaffolds with aligned microchannels for enhanced tendon regeneration: aligned microchannel scaffolds for tendon repair. Biomaterials. 2019;224:119488. doi: 10.1016/j.biomaterials.2019.119488.
- Cao L, et al. Construction of multicellular aggregate by E-cadherin coated microparticles enhancing the hepatic specific differentiation of mesenchymal stem cells. Acta Biomater. 2019;95:382–394. doi: 10.1016/j.actbio.2019.01.030.
- Zhang Z, et al. Sandwich-like fibers/sponge composite combining chemotherapy and hemostasis for efficient postoperative prevention of tumor recurrence and metastasis. Adv. Mater. 2018;30:1803217. doi: 10.1002/adma.201803217.
Source: PubMed