Double crosslinking decellularized bovine pericardium of dialdehyde chondroitin sulfate and zwitterionic copolymer for bioprosthetic heart valves with enhanced antithrombogenic, anti-inflammatory and anti-calcification properties.

Due to the increasing aging population and the advancements in transcatheter aortic valve replacement (TAVR), the use of bioprosthetic heart valves (BHVs) in patients diagnosed with valvular disease has increased substantially. Commercially available glutaraldehyde (GA) cross-linked biological valves suffer from reduced durability due to a combination of factors, including the high cell toxicity of GA, subacute thrombus, inflammation and calcification. In this study, oxidized chondroitin sulfate (OCS), a natural polysaccharide derivative, was used to replace GA to cross-link decellularized bovine pericardium (DBP), carrying out the first crosslinking of DBP to obtain OCS-BP. Subsequently, the zwitterion radical copolymerization system was introduced in situ to perform double cross-linking to obtain double crosslinked BHVs with biomimetic modification (P(APM/MPC)-OCS-BP). P(APM/MPC)-OCS-BP presented enhanced mechanical properties, collagen stability and enzymatic degradation resistance due to double crosslinking. The ex vivo AV-shunt assay and coagulation factors test suggested that P(APM/MPC)-OCS-BP exhibited excellent anticoagulant and antithrombotic properties due to the introduction of P(APM/MPC). P(APM/MPC)-OCS-BP also showed good HUVEC-cytocompatibility due to the substantial reduction of its residual aldehyde group. The subcutaneous implantation also demonstrated that P(APM/MPC)-OCS-BP showed a weak inflammatory response due to the anti-inflammatory effect of OCS. Finally, in vivo and in vitro results revealed that P(APM/MPC)-OCS-BP exhibited an excellent anti-calcification property. In a word, this simple cooperative crosslinking strategy provides a novel solution to obtain BHVs with good mechanical properties, and HUVEC-cytocompatibility, anti-coagulation, anti-inflammatory and anti-calcification properties. It might be a promising alternative to GA-fixed BP and exhibited good prospects in clinical applications.

A photocrosslinked methacrylated carboxymethyl chitosan/oxidized locust bean gum double network hydrogel for cartilage repair.

Repairing articular cartilage defects is a great challenge due to the poor self-regenerative capability of cartilage. Inspired by active substances found in the natural cartilage extracellular matrix, we used methacrylated carboxymethyl chitosan (MA-CMCS) and oxidized locust bean gum (OLBG) as the hydrogel backbone, and prepared a photocrosslinked dual network hydrogel containing allicin and decellularized cartilage powder (DCP). The rheological, swelling and water retention capacities of MA-CMCS@OLBG-Allicin/DCP (MCOAC) hydrogels were investigated to confirm the successful preparation of hydrogels suitable for cartilage repair. The MCOAC hydrogels showed good antibacterial ability to kill S. aureus and E. coli and anti-inflammatory properties due to the introduction of allicin. Furthermore, MA-CMCS@OLBG-Allicin/DCP hydrogels presented good cytocompatibility due to the addition of DCP, which could promote chondrocyte proliferation and promote the differentiation of BMSCs to chondrocytes. Further studies in vivo demonstrated that the DCP-contained MCOAC hydrogel exhibited superior performance in promoting cartilage tissue growth and wound healing in articular cartilage defects. Thus, the MCOAC hydrogel is a promising cartilage repair hydrogel with potential for clinical use.

A synergistic strategy of dual-crosslinking and loading intelligent nanogels for enhancing anti-coagulation, pro-endothelialization and anti-calcification properties in bioprosthetic heart valves.

Currently, glutaraldehyde (GA)-crosslinked bioprosthetic heart valves (BHVs) still do not guarantee good biocompatibility and long-term effective durability for clinical application due to their subacute thrombus, inflammation, calcification, tearing and limited durability. In this study, double-modified xanthan gum (oxidized/vinylated xanthan gum (O2CXG)) was acquired from xanthan gum for subsequent double crosslinking and modification platform construction. Sulfonic acid groups with anticoagulant properties were also introduced through the free radical polymerization of vinyl sulfonate (VS) and vinyl on O2CXG. Taking advantage of the drug-loading function of xanthan gum, the treated pericardium was further loaded with inflammation-triggered dual drug-loaded nanogel (heparin (Hep) and atorvastatin (Ator)). Mechanical properties of O2CXG-crosslinked porcine pericardium (O2CXG-PP) were significantly improved via the first network formed by Schiff base bonds and the second C-C bonds network. Due to the presence of sulfonic acid groups as well as the dual drug release from nanogels under the stimulation of H2O2, the hemocompatibility, anti-inflammatory, pro-endothelialization and anti-calcification properties of the crosslinked pericardium modified with nanogels loaded with Hep and Ator (O2CXG+VS+(Hep+Ator) nanogel-PP) was significantly better than that of GA-crosslinked PP (GA-PP). The collaborative strategy of double crosslinking and sequential release of anticoagulant/endothelium-promoting drugs triggered by inflammation could effectively meet the requirement of enhanced multiple performance and long-term durability of bioprosthetic heart valves and provide a valuable pattern for multi-functionalization of blood contacting materials. STATEMENT OF SIGNIFICANCE: Currently, glutaraldehyde-crosslinked bioprosthetic heart valves (BHVs) are subject to subacute thrombus, inflammation, calcification and tearing, which would not guarantee good biocompatibility and long-term effective durability. We developed a cooperative strategy of double crosslinking and surface modification in which double-modified xanthan gum plays a cornerstone. The mechanical properties of this BHV were significantly improved via the first network formed by Schiff base bonds and the second C-C bonds network. Inflammation-triggered combination delivery of heparin and atorvastatin has been demonstrated to enhance anticoagulation, anti-inflammatory and pro-endothelialization of BHVs by utilizing local inflammatory response. The collaborative strategy could effectively meet the requirement of enhanced multiple performance and long-term durability of BHVs and provide a valuable pattern for the multi-functionalization of blood-contacting materials.

Dialdehyde xanthan gum and curcumin synergistically crosslinked bioprosthetic valve leaflets with anti-thrombotic, anti-inflammatory and anti-calcification properties.

Currently commercial glutaraldehyde (GA)-crosslinked bioprosthetic valve leaflets (BVLs) suffer from thromboembolic complications, calcification, and limited durability, which are the major stumbling block to wider clinical application of BVLs. Thus, developing new-style BVLs will be an urgent need to enhance the durability of BVLs and alleviate thromboembolic complications. In this study, a quick and effective collaborative strategy of the double crosslinking agents (oxidized polysaccharide and natural active crosslinking agent) was reported to realize enhanced mechanical, and structural stability, excellent hemocompatibility and anti-calcification properties of BVLs. Dialdehyde xanthan gum (AXG) exhibiting excellent stability to heat, acid-base, salt, and enzymatic hydrolysis was first introduced to crosslink decellularized porcine pericardium (D-PP) and then curcumin with good properties of anti-inflammatory, anti-coagulation, anti-liver fibrosis, and anti-atherosclerosis was used to synergistically crosslink and multi-functionalize D-PP to obtain AXG + Cur-PP. A comprehensive evaluation of structural characterization, hemocompatibility, endothelialization potential, mechanical properties and component stability showed that AXG + Cur-PP exhibited better anti-thrombotic properties and endothelialization potential, milder immune responses, excellent anti-calcification properties and enhanced mechanical properties compared with GA-crosslinked PP. Overall, this cooperative crosslinking strategy provides a novel solution to achieve BVLs with enhanced mechanical properties and excellent anti-coagulation, anti-inflammatory, anti-calcification, and the ability to promote endothelial cell proliferation.

Sulfonated, oxidized pectin-based double crosslinked bioprosthetic valve leaflets for synergistically enhancing hemocompatibility and cytocompatibility and reducing calcification.

Clinically frequently-used glutaraldehyde (GA)-crosslinked bioprosthetic valve leaflets (BVLs) are still curbed by acute thrombosis, malignant immunoreaction, calcification, and poor durability. In this study, an anticoagulant heparin-like biomacromolecule, sulfonated, oxidized pectin (SAP) with a dialdehyde structure was first obtained by modifying citrus pectin with sulfonation of 3-amino-1-propane sulfonic acid and then oxidating with periodate. Notably, a novel crosslinking approach was established by doubly crosslinking BVLs with SAP and the nature-derived crosslinking agent quercetin (Que), which play a synergistic role in both crosslinking and bioactivity. The double crosslinked BVLs also presented enhanced mechanical properties and enzymatic degradation resistance owing to the double crosslinking networks formed via CN bonds and hydrogen bonds, respectively, and good HUVEC-cytocompatibility. The in vitro and ex vivo assay manifested that the double-crosslinked BVLs had excellent anticoagulant and antithrombotic properties, owing to the introduction of SAP. The subcutaneous implantation also demonstrated that the obtained BVLs showed a reduced inflammatory response and great resistance to calcification, which is attributed to quercetin with multiple physiological activities and depletion of aldehyde groups by hydroxyl aldehyde reaction. With excellent stability, hemocompatibility, anti-inflammatory, anti-calcification, and pro-endothelialization properties, the obtained double-crosslinked BVLs, SAP + Que-PP, would have great potential to substitute the current clinical GA-crosslinked BVLs.

An agar-polyvinyl alcohol hydrogel loaded with tannic acid with efficient hemostatic and antibacterial capacity for wound dressing.

Rapid hemostasis, antibacterial effect and promotion of wound healing are the most important functions that wound dressings need to have. In this work, we designed and prepared a hydrogel with antibacterial effect, hemostatic ability and wound healing promotion using agar, polyvinyl alcohol (PVA) and tannic acid (TA). We performed a series of tests to characterize the structure and properties of AGAR@PVA-TA hydrogels. The results showed that the AGAR@PVA-TA hydrogels had good mechanical properties and excellent antibacterial ability as well as good hemocompatibility. The cytotoxicity results showed that the AGAR@PVA-TA hydrogels had good cytocompatibility. And the TA loaded hydrogels also presented some good performances in animal studies. In the liver hemostasis model, the AGAR@PVA-TA hydrogel showed good hemostatic ability. Also, the AGAR@PVA-TA hydrogel was able to promote wound healing in an S. aureus-infected rat wound model. More importantly, our research results demonstrated that compared to other polyphenols (such as proanthocyanidins), TA could better improve the mechanical properties, antibacterial ability and rapid hemostasis of hydrogels, which illustrated the uniqueness of TA. Therefore, the TA loaded hydrogel (AGAR@PVA-TA hydrogel) has the potential to be applied as a wound dressing.