Introduction of PVA can improve the compliance of bacterial nano-cellulose hydrogel, which has been suggested as a promising biomaterial for artificial blood vessels especially for small-caliber vessels.
Background
Hemostasis and repair are two essential processes in wound healing, yet early hemostasis and following vascularization are challenging to address in an integrated manner.
Results
In this study, we constructed a hemostatic sponge OBNC-DFO by fermentation of Komagataeibacterxylinus combined with TEMPO oxidation to obtain oxidized bacterial nanocellulose (OBNC). Then angiogenetic drug desferrioxamine (DFO) was grafted through an amide bond, and it promoted clot formation and activated coagulation reaction by rapid blood absorption due to the high total pore area (approximately 42.429 m2/g measured by BET). The further release of DFO stimulated the secretion of HIF-1α and the reconstruction of blood flow, thus achieving rapid hemostasis and vascularization in damaged tissue. This new hemostatic sponge can absorb water at a rate of approximate 1.70 g/s, rapidly enhancing clot formation in the early stage of hemostasis. In vitro and in vivo coagulation experiments (in rat tail amputation model and liver trauma model) demonstrated superior pro-coagulation effects of OBNC and OBNC-DFO to clinically used collagen hemostatic sponges (COL). They promoted aggregation and activation of red blood cells and platelets with shorter whole blood clotting time, more robust activation of endogenous coagulation pathways and less blood loss. In vitro cellular assays showed that OBNC-DFO prevailed over OBNC by promoting the proliferation of human umbilical vein endothelial cells (HUVECs). In addition, the release of DFO enhanced the secretion of HIF-1α, further strengthening vascularization in damaged skin. In the rat skin injury model, 28 days after being treated with OBNC-DFO, skin appendages (e.g., hair follicles) became more intact, indicating the achievement of structural and functional regeneration of the skin.
Conclusion
This hemostatic and vascularization-promoting oxidized bacterial nanocellulose hemostatic sponge, which rapidly activates coagulation pathways and enables skin regeneration, is a highly promising hemostatic and pro-regenerative repair biomaterial.
Graphical Abstract
Bacterial
nanocellulose (BNC) is a promising material for small-caliber
artificial blood vessels, although promoting its anticoagulant properties
with more rapid endothelialization would improve long-term patency.
Silk fibroin nanoparticles (SFNP) were introduced into the luminal
wall surface of BNC conduits both with and without heparin (Hep) through
pressurization followed by fixation. Hep was introduced in two ways:
(1) embedded within SF nanoparticles to form SF-HepNPs for construction
of the BNC-SF-HepNP conduit and (2) chemically grafted onto BNC and
BNC-SFNP to form BNC-Hep and BNC-SFNP-Hep conduits. Fourier transform
infrared spectroscopy confirmed the formation of SF-HepNPs, although
they did not incorporate into the fibrillar network due to their large
size. Hep was successfully grafted onto BNC and BNC-SFNP, verified
by toluidine blue staining. The hemocompatibility and cytocompatibility
of the five samples (BNC, BNC-SFNP, BNC-SF-HepNP, BNC-Hep, and BNC-SFNP-Hep
conduits) were compared in vitro. The heparinized
BNC-Hep and BNC-SFNP-Hep conduits improved the anticoagulant properties,
and BNC-SFNP-Hep promoted human umbilical vein endothelial cell proliferation
but also controlled excessive human arterial smooth muscle cell proliferation,
assisting rapid endothelialization and improving lumen patency. No
significant inflammatory reaction or material degradation was observed
after subcutaneous implantation for 4 weeks. Autogenous tissues were
observed around the conduits, and cells infiltrated into the edges
of all samples, the BNC-SFNP conduit causing the deepest infiltration,
providing an appropriate microenvironment for angiogenesis when used
in small-caliber blood vessel applications. Few inflammatory cells
were found around the BNC-Hep and BNC-SFNP-Hep conduits. Thus, the
anticoagulant properties of the BNC-SFNP-Hep conduit and its stimulation
of endothelialization suggest that it has great potential in clinical
applications as a small-caliber artificial blood vessel.
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