A 3D-Printed Cuttlefish Bone Elastomeric Sponge Rapidly Controlling Noncompressible Hemorrhage.

Developing a self-expanding hemostatic sponge with high blood absorption and rapid shape recovery for noncompressible hemorrhage remains a challenge. In this study, a 3D-printed cuttlefish bone elastomeric sponge (CBES) is fabricated, which combined ordered channels and porous structures, presented tunable mechanical strength, and shape memory potentials. The incorporation of cuttlefish bone powder (CBp) plays key roles in concentrating blood components, promoting aggregation of red blood cells and platelets, and activating platelets, which makes CBES show enhanced hemostatic performance compared with commercial gelatin sponges in vivo. Moreover, CBES promotes more histiocytic infiltration and neovascularization in the early stage of degradation than gelatin sponges, which is conducive to the regeneration and repair of injured tissue. To conclude, CBp loaded 3D-printed elastomeric sponges can promote coagulation, present the potential to guide tissue healing, and broaden the hemostatic application of traditional Chinese medicine.

3D Elastomeric Stent Functionalized with Antioxidative and Perivascular Tissue Regenerative Activities Ameliorated PVT Deprivation-Induced Vein Graft Failure.

Clinically, arterial injuries are always accompanied with perivascular tissue damage, which may contribute to high failure rate of vein grafts due to intimal hyperplasia and acute thrombosis. In this study, a "perivascular tissue (PVT) deprivation" animal model is constructed to mimic clinical scenarios and identify the contribution of arterial PVT to the success of vein grafts. Proteomics analysis suggests that depriving PVT may exacerbate reactive oxygen species (ROS)-induced endothelial apoptosis by up-regulating inflammation response and oxidative stress. Locally administering metformin on vein grafts through 3D-printed external stent (PGS-PCL) shows antioxidative and anti-inflammatory properties to protect cells from ROS invasion, thereafter decreasing acute thrombosis. Moreover, metformin induce rapid regeneration of perivascular adipose tissue in recipient regions, which improves patency by inhibiting intimal hyperplasia. Proteomics, western blot, and in vitro blocking tests reveal that metformin resists endothelial apoptosis through AMPK/mTOR and NFκB signaling pathways. To conclude, PVT deprivation exacerbates inflammatory response and oxidative stress in vein grafts bridging arterial circulation. Metformin-loaded stent ameliorates "PVT damage" related vein graft failure, and enhances patency of through resisting endothelial apoptosis and regenerating arterial PVAT, offering a promising avenue to improve the success of vein grafts in clinic.

Bioconjugation of nanozyme and natural enzyme to enable a one-step cascade reaction for the detection of metabolites.

Nanozyme, with enzyme-mimicking activity and excellent stability, has attracted extensive attention. However, some inherent disadvantages, including poor dispersion, low selectivity, and insufficient peroxidase-like activity, still limit its further development. Therefore, an innovative bioconjugation of a nanozyme and natural enzyme was conducted. In the presence of graphene oxide (GO), histidine magnetic nanoparticles (H-Fe3O4) were first synthesized by a solvothermal method. The GO-supported H-Fe3O4 (GO@H-Fe3O4) exhibited superior dispersity and biocompatibility because GO was the carrier and possessed outstanding peroxidase-like activity because of the introduction of histidine. Furthermore, the mechanism of the peroxidase-like activity of GO@H-Fe3O4 was the generation of •OH. Uric acid oxidase (UAO) was selected as the model natural enzyme and covalently linked to GO@H-Fe3O4 with hydrophilic poly(ethylene glycol) as a linker. UAO could specifically catalyze the oxidation of uric acid (UA) to generate H2O2, and subsequently, the newly produced H2O2 oxidized the colorless 3,3',5,5'-tetramethylbenzidine (TMB) to blue ox-TMB under the catalysis of GO@H-Fe3O4. Based on the above cascade reaction, the GO@H-Fe3O4-linked UAO (GHFU) and GO@H-Fe3O4-linked ChOx (GHFC) were used for the detection of UA in serum samples and cholesterol (CS) in milk, respectively. The method based on GHFU exhibited a wide detection range (5-800 µM) and a low detection limit (1.5 µM) for UA, and the method based on GHFC exhibited a wide detection range (4-400 µM) and a low detection limit (1.13 µM) for CS. These results demonstrated that the proposed strategy had great potential in the field of clinical detection and food safety.

Recombinant DTß4-inspired porous 3D vascular graft enhanced antithrombogenicity and recruited circulating CD93+/CD34+ cells for endothelialization.

Matching material degradation with host remodeling, including endothelialization and muscular remodeling, is important to vascular regeneration. We fabricated 3D PGS-PCL vascular grafts, which presented tunable polymer components, porosity, mechanical strength, and degrading rate. Furthermore, highly porous structures enabled 3D patterning of conjugated heparin-binding peptide, dimeric thymosin ß4 (DTß4), which played key roles in antiplatelets, fibrinogenesis inhibition, and recruiting circulating progenitor cells, thereafter contributed to high patency rate, and unprecedentedly acquired carotid arterial regeneration in rabbit model. Through single-cell RNA sequencing analysis and cell tracing studies, a subset of endothelial progenitor cells, myeloid-derived CD93+/CD34+ cells, was identified as the main contributor to final endothelium regeneration. To conclude, DTß4-inspired porous 3DVGs present adjustable physical properties, superior anticoagulating, and re-endothelializing potentials, which leads to the regeneration of small-caliber artery, thus offering a promising tool for vessel replacement in clinical applications.

Cartilaginous Extracellular Matrix Enriched with Human Gingival Mesenchymal Stem Cells Derived "Matrix Bound Extracellular Vesicles" Enabled Functional Reconstruction of Tracheal Defect.

Stem cells derived extracellular vesicles (EVs) conceive cues essential for tissue repair. Mammalian cartilaginous extracellular matrix (cECM) may not be optimally inductive for tracheal regeneration because of the granulomatous, instead of regenerative, responses in injured adult mammalian tracheas. Given the high regenerative capacity of gingiva, it is hypothesized human gingival mesenchymal stem cells derived EVs (gEVs) can induce mammalian tracheal epithelia regeneration. Coculturing chondrocytes with GMSCs produce abundant "matrix bound gEVs (gMVs)" in forming cartilaginous ECM, which are further preserved in acellular cECM (cACM) following mild, short-period decellularization. The results show that gMVs-cACM could be well anchored on polyglycerol sebacate microporous patch thus enforce the surgical suturability and mechanical strength. In rabbit tracheal defect, the gMVs-cACM patch induces rapid regeneration of vascularized ciliated columnar epithelium, which supports long-term survival of animals. gMVs-cACM treated groups exhibit proliferation of tracheal progenitors-basal epithelial cells, as well as, activation of JAK2/STAT1 pathway in reparative cells. This study departs from conventional focuses on tissue derived ECM and introduces a new approach for tracheal tissue regeneration.

Mussel patterned with 4D biodegrading elastomer durably recruits regenerative macrophages to promote regeneration of craniofacial bone.

Crosstalk between bone marrow mesenchymal stem cells (BMSCs) and macrophages plays vital role in bone healing. By investigating the mechanism of collagen membrane-guided bone regeneration, we found compact structure and rapid membrane degradation compromised the duration of M2 macrophages influx, which restricts the recruitment of BMSCs that is essential for bone healing. To tackle this issue, a biodegrading elastomeric compound consisting of poly(glycerol sebacate) (PGS) and polycaprolactone (PCL) was fabricated into hierarchically porous membrane. The rational design of 3D microstructure enabled sufficient polydopamine (PDA) coating. Without any addition of growth factors, the 3D-patterned PDA membrane enables early and durable influx of M2 macrophages, which in turn promotes BMSCs recruitment and osteogenic differentiation. Furthermore, 4D-morphing of the membrane fully regenerates the dome shaped calvarial bone as well as arc-shape bone in peri-implant alveolar defect without filling xenogenous substitute. This study revealed the superiority of 3D printed microstructures in immunomodulatory materials. The availability of 4D-morphing for PGS/PCL construct expanded their advantages in reconstructing craniofacial bone.

Dimeric Thymosin ß4 Loaded Nanofibrous Interface Enhanced Regeneration of Muscular Artery in Aging Body through Modulating Perivascular Adipose Stem Cell-Macrophage Interaction.

Regenerating nonthrombotic and compliant artery, especially in the aging body, remains a major surgical challenge, mainly owing to the inadequate knowledge of the major cell sources contributing to arterial regeneration and insufficient bioactivity of delivered peptides in grafts. Ultrathin nanofibrous sheaths stented with biodegrading elastomer present opening channels and reduced material residue, enabling fast cell recruitment and host remodeling, while incorporating peptides offering developmental cues are challenging. In this study, a recombinant human thymosin ß4 dimer (DTß4) that contains two complete Tß4 molecules is produced. The adult perivascular adipose is found as the dominant source of vascular progenitors which, when stimulated by the DTß4-loaded nanofibrous sheath, enables 100% patency rates, near-complete structural as well as adequate functional regeneration of artery, and effectively ameliorates aging-induced defective regeneration. As compared with Tß4, DTß4 exhibits durable regenerative activity including recruiting more progenitors for endothelial cells and smooth muscle cells, when incorporated into the ultrathin polycaprolactone sheath. Moreover, the DTß4-loaded interface promotes smooth muscle cells differentiation, mainly through promoting M2 macrophage polarization and chemokines. Incorporating artificial DTß4 into ultrathin sheaths of fast degrading vascular grafts creates an effective interface for sufficient muscular remodeling thus offering a robust tool for vessel replacement.

Differential effects of ginkgol C17:1 on cisplatin-induced cytotoxicity: Protecting human normal L02 hepatocytes versus sensitizing human hepatoma HepG2 cells.

Liver cancer is a major healthcare problem and one of the leading causes of cancer-associated mortality in the world. To date, chemotherapy remains a common method for treating cancer and cisplatin is one of the most widely used chemotherapeutics. However, owing to drug resistance and side effects, it is imperative to identify a novel approach to improve the anticancer effect of cisplatin. Auxiliary chemotherapy drugs with minor toxicity to normal cells may represent a novel strategy for cancer therapy. Previous studies have indicated that ginkgol C17:1 exhibits anticancer effects in liver cancer cells in vitro and in vivo. The antitumor activity of ginkgol C17:1 has been reported in combination with cisplatin in human liver cancer cells. Owing to the route of systemic administration, liver cancer cells and normal hepatocytes were exposed to chemotherapeutics and auxiliary chemotherapy drugs. However, the effects of ginkgol C17:1 in normal hepatocytes remain unclear. In the present study, the biological effects of ginkgol C17:1 alone and as co-treatment with cisplatin were compared in human hepatoma cells and normal hepatocytes. Consistently, the results confirmed that in human hepatoma HepG2 cells, ginkgol C17:1 or cisplatin alone induced autophagy and apoptosis. The co-treatment increased cisplatin-induced apoptosis and inhibited cisplatin-induced autophagy. In comparison, the treatments in human normal L02 hepatocytes indicated that ginkgol C17:1 alone induced autophagy, whereas cisplatin alone induced apoptosis. The co-treatment inhibited cisplatin-induced apoptosis, but enhanced autophagy in L02 cells. Further investigation revealed that the AMP-activated protein kinase/serine/threonine protein kinase ULK1 and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathways were involved in the underlying regulatory mechanisms. Taken together, the results of the present study provide the first evidence that ginkgol C17:1 protects normal hepatocytes against cisplatin-induced cytotoxicity while potentiating the anticancer effect of cisplatin chemotherapy. The differential effects on normal and cancer cells suggest that ginkgol C17:1 is a promising candidate for auxiliary chemotherapy.

Evaluation of erectile function after urethral reconstruction: a prospective study.

We conducted a prospective study of erectile dysfunction (ED) after urethral reconstructive surgery, using the 5-item International Index of Erectile Function (IIEF-5), the Sexual Life Quality Questionnaire (SLQQ) and the Quality of Life Questionnaire (QoLQ). Between January 2003 and July 2007, 125 male patients with urethral strictures underwent urethroplasty, and pre- and post-surgery erectile function was assessed using these three questionnaires. A formula to predict the probability of ED after urethroplasty was derived. At 3 months post-operatively, there was a significant decrease in IIEF-5 (16.57 +/- 7.98) and SLQQ scores (28.71 +/- 14.84) compared with pre-operative scores (P < 0.05). However, the IIEF-5 scores rebounded at 6 months post-operatively (17.22 +/- 8.41). Logistical regression analysis showed that the location of the urethral stricture, the recurrence of strictures and the choice of surgical technique were predictive of the post-operative occurrence of ED. This study identified the clinical risk factors for ED after urethroplasty. Posterior urethral stricture and end-to-end anastomosis were found to have a strong relationship with erectile function. The logistical model derived in this study may be applied to clinical decision algorithms for patients with urethral strictures.