Syntheses and characterization of anti-thrombotic and anti-oxidative Gastrodin-modified polyurethane for vascular tissue engineering

Abstract

Vascular grafts must avoid negative inflammatory responses and thrombogenesis to prohibit fibrotic deposition immediately upon implantation and promote the regeneration of small diameter blood vessels (<6 mm inner diameter). Here, polyurethane (PU) elastomers incorporating anti-coagulative and anti-inflammatory Gastrodin were fabricated. The films had inter-connected pores with porosities equal to or greater than 86% and pore sizes ranging from 250 to 400 μm. Incorporation of Gastrodin into PU films resulted in desirable mechanical properties, hydrophilicity, swelling ratios and degradation rates without collapse. The released Gastrodin maintained bioactivity over 21 days as assessed by its anti-oxidative capability. The Gastrodin/PU had better anti-coagulation response (less observable BSA, fibrinogen and platelet adhesion/activation and suppressed clotting in whole blood). Red blood cell compatibility, measured by hemolysis, was greatly improved with 2Gastrodin/PU compared to other Gastrodin/PU groups. Notably, Gastrodin/PU upregulated anti-oxidant factors Nrf2 and HO-1 expression in H 2 O 2 treated HUVECs, correlated with decreasing pro-inflammatory cytokines TNF-α and IL-1β in RAW 264.7 cells. Upon implantation in a subcutaneous pocket, PU was encapsulated by an obvious fibrous capsule, concurrent with a large amount of inflammatory cell infiltration, while Gastrodin/PU induced a thinner fibrous capsule, especially 2Gastrodin/PU. Further, enhanced adhesion and proliferation of HUVECs seeded onto films in vitro demonstrated that 2Gastrodin/PU could help cell recruitment, as evidenced by rapid host cell infiltration and substantial blood vessel formation in vivo . These results indicate that 2Gastrodin/PU has the potential to facilitate blood vessel regeneration, thus providing new insight into the development of clinically effective vascular grafts.

Sequential gastrodin release PU/n-HA composite scaffolds reprogram macrophages for improved osteogenesis and angiogenesis

“…The peaks at 1723 cm −1 and 1529 cm −1 were ascribed to C = O and –NH stretching of the urethane group (OCONH) of PU, respectively. The characteristic peak at 3372 cm −1 for gastrodin was significantly reduced in PU, indicating its role in cross-link polymerization, as demonstrated in our previous report [ 51 ]. The broad peaks at 1092 cm −1 and 1034 cm −1 corresponded to the vibration of a phosphate group (PO 4 ), suggesting that n-HA was composited into the scaffolds.…”

“…Huang et al also showed that gastrodin can protect hBMSCs and RAW 264.7 cells from oxidative stress, ameliorate trabecular micro-architecture, and inhibit osteoclastogenesis in ovariectomized rats (OVX) [ 44 ]. However, as gastrodin is easily metabolized in vivo , we considered that gastrodin combined with PU could achieve sequential release of gastrodin, thereby reducing the inflammatory response (i.e., TNF-α and IL-1β levels) in RAW 264.7 cells [ 51 ]. Thus, we designed a gastrodin-delivery composite scaffold and explored its immunomodulatory effects on vascular bone regeneration.…”

“…Of note, polyurethane (PU) has binding sites at chain segments and been widely used to deliver drugs to augment healing outcomes [ 45 , 46 ], holding great promise as a superior functional material in tissue engineering [ [47] , [48] , [49] , [50] ]. Thus, gastrodin bound to PU not only enhances mechanical properties as a cross-linker, but also increases hydrophilicity to facilitate cell adhesion [ 51 ]. These attractive features encourage us to synthesize anti-inflammatory gastrondin/PU for vascular tissue engineering in previous report [ 52 ].…”

Challenges and strategies for in situ endothelialization and long-term lumen patency of vascular grafts

“…Furthermore, Gastrodin, which is applied in cardiovascular diseases, can lower blood viscosity and regulate inflammation reactions. Zheng et al [ 25 ] fabricated Gastrodin-loaded PU scaffolds, and found that the Gastrodin modified grafts showed greater potential in preventing thrombogenesis and inflammations.…”

“…For long-term patency, thrombogenesis is the key factor leading to vascular occlusion. Vascular grafts, as the foreigner directly exposed to blood flux in vasculature, are easy to cause protein deposition and provoke thrombogenesis [ 24 , 25 ]. The aggregation of insoluble fibrin, platelet, and red cells induces the coagulation cascades and results in thrombus formation [ [26] , [27] , [28] ].…”