The Balance between the Hemostatic Effect and Immune Response of Hyaluronan Conjugated with Different Chain Lengths of Inorganic Polyphosphate

Inorganic polyphosphate (PolyP) is a potential hemostatic material. However, the effect of PolyP chain length on the immune response and hemostatic function remains to be established. We have developed PolyP-conjugated hyaluronans (HA-PolyPs) with three different short-chain PolyPs (n = 13, 40, and 100 phosphate units). All short-chain PolyPs showed biocompatibility in the cell viability and inflammatory cytokine secretion test in vitro and in vivo, wherein shorter PolyPs showed milder responses in some cases. We then produced HA-PolyP hydrogels (HAX-PolyPs) with three different short-chain PolyPs as hemostats. Interestingly, the in vivo biocompatibility and hemostatic activity of HAX-PolyP were not significantly affected by the length of conjugated PolyPs. HAX-PolyP with all chain lengths significantly decreased the amount of bleeding in a novel mouse liver bleeding model. These results indicated that the shortest PolyP (n = 13) induced milder acute inflammation and had an efficient hemostatic effect when conjugated to hyaluronic acid. The present study provides key insights into the design of PolyP-based biomaterials and bioconjugates, which are expected to grow in importance for various medical applications.