Heart transplantation (HT) has been approved as an optimal therapeutic regimen for patients with terminal-stage cardiac failure. However, cold ischaemia‒reperfusion (I/R) injury remains an ...unavoidable and outstanding challenge, which is a major factor in early graft dysfunction and an obstacle to long-term survival in HT. Cold I/R injury induces cardiac graft injury by promoting mitochondrial dysfunction and augmenting free radical production and inflammatory responses. We therefore designed a mitochondrion-targeted nanocarrier loaded with Coenzyme Q10 (CoQ10) (CoQ10@TNPs) for treatment of cold I/R injury after cardiac graft in a murine heterotopic cardiac transplantation model.
Hybrid nanoparticles composed of CaCO
/CaP/biotinylated-carboxymethylchitosan (CaCO
/CaP/BCMC) were synthesized using the coprecipitation method, and the mitochondria-targeting tetrapeptide SS31 was incorporated onto the surface of the hybrid nanoparticles through biotin-avidin interactions. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis were used for characterisation. In vitro, the hypoxia-reoxygenation model of H9c2 cells was employed to replicate in vivo cold I/R injury and treated with CoQ10@TNPs. The impact of CoQ10@TNPs on H9c2 cell injury was assessed by analysis of oxidative damage and apoptosis. In vivo, donor hearts (DHs) were perfused with preservation solution containing CoQ10@TNPs and stored in vitro at 4 °C for 12 h. The DHs were heterotopically transplanted and analysed for graft function, oxidative damage, apoptosis, and inflammatory markers 1 day post-transplantation.
CoQ10@TNPs were successfully synthesized and delivered CoQ10 to the mitochondria of the cold ischaemic myocardium. In vitro experiments demonstrated that CoQ10@TNPs was taken up by H9c2 cells at 4 °C and localized within the mitochondria, thus ameliorating oxidative stress damage and mitochondrial injury in cold I/R injury. In vivo experiments showed that CoQ10@TNPs accumulated in DH tissue at 4 °C, localized within the mitochondria during cold storage and improved cardiac graft function by attenuating mitochondrial oxidative injury and inflammation.
CoQ10@TNPs can precisely deliver CoQ10 to the mitochondria of cold I/R-injured cardiomyocytes to effectively eliminate mitochondrial reactive oxygen species (mtROS), thus reducing oxidative injury and inflammatory reactions in cold I/R-injured graft tissues and finally improving heart graft function. Thus, CoQ10@TNPs offer an effective approach for safeguarding cardiac grafts against extended periods of cold ischaemia, emphasizing the therapeutic potential in mitigating cold I/R injury during HT. These findings present an opportunity to enhance existing results following HT and broaden the range of viable grafts for transplantation.
Bisphenol A (BPA), a widely distributed pollutant, suppresses photosynthesis in leaves. In previous studies on higher plants, the plants were treated by BPA through irrigation to root. This method ...cannot distinguish whether the BPA directly suppresses photosynthesis in leaves, or indirectly influences photosynthesis through affecting the function of root. Here, only the leaves but not the roots of cucumber were infiltrated with BPA solution. The photosystem II and I (PSII, PSI) were insensitive to BPA under darkness. BPA aggravated the PSII but not the PSI photoinhibition under light. BPA also inhibited CO
assimilation, and the effect of BPA on PSII photoinhibition disappeared when the CO
assimilation was blocked. The H
O
accumulated in BPA-treated leaves under light. And the BPA-caused PSII photoinhibition was prevented under low (2%) O
. We also proved that the BPA-caused PSII photoinhibition depend on the turnover of D1 protein. In conclusion, this study proved that BPA could directly suppress photosynthesis in leaves, however, BPA does not damage PSII directly, but inhibits CO
assimilation and over-reduces the electron transport chain under light, which increases the production of reactive oxygen species (H
O
), the over-accumulated ROS inhibits the turnover of D1 protein and consequently aggravates PSII photoinhibition.
Wound healing is a complex process that requires specific interactions between multiple cells such as fibroblasts, mesenchymal, endothelial, and neural stem cells. Recent studies have shown that ...calcium silicate (CS)-based biomaterials can enhance the secretion of growth factors from fibroblasts, which further increased wound healing and skin regeneration. In addition, gelatin methacrylate (GelMa) is a compatible biomaterial that is commonly used in tissue engineering. However, it has low mechanical properties, thus restricting its fullest potential for clinical applications. In this study, we infused Si ions into GelMa hydrogel and assessed for its feasibility for skin regeneration applications by observing for its influences on human dermal fibroblasts (hDF). Initial studies showed that Si could be successfully incorporated into GelMa, and printability was not affected. The degradability of Si-GelMa was approximately 20% slower than GelMa hydrogels, thus allowing for better wound healing and regeneration. Furthermore, Si-GelMa enhanced cellular adhesion and proliferation, therefore leading to the increased secretion of collagen I other important extracellular matrix (ECM) remodeling-related proteins including Ki67, MMP9, and decorin. This study showed that the Si-GelMa hydrogels were able to enhance the activity of hDF due to the gradual release of Si ions, thus making it a potential candidate for future skin regeneration clinical applications.
The aim of this study was to investigate whether mineral trioxide aggregate (MTA) can be modified with caffeic acid (CA) to form caffeic acid/mineral trioxide aggregate (CAMTA) cement and to evaluate ...its physicochemical and biological properties as well as its capability in immune suppression and angiogenesis.
MTA was immersed in trishydroxymethyl aminomethane buffer with CA to allow coating onto MTA powders. X-ray diffractometry and tensile stress-strain tests were conducted to assess for physical characteristics of CAMTA and to evaluate for successful modification of MTA. Then, the CAMTA cement was immersed in simulated body fluid to evaluate its hydroxyapatite formation capabilities and Si release profiles. In addition, RAW 264.7 cells and human dental pulp stem cells were used to evaluate CAMTA’s immunosuppressive capabilities and cell responses, respectively. hDPSCs were also used to assess CAMTA’s angiogenic capabilities.
The X-ray diffractometry results showed that CA can be successfully coated onto MTA without disrupting or losing MTA’s original structural properties, thus allowing us to retain the initial advantages of MTA. CAMTA was shown to have higher mechanical properties compared with MTA and had rougher pitted surfaces, which were hypothesized to lead to enhanced adhesion, proliferation, and secretion of angiogenic- and odontogenic-related proteins. In addition, it was found that CAMTA was able to enhance hydroxyapatite formation and immunosuppressive capabilities compared with MTA.
CAMTA cements were found to have improved physicochemical and biological characteristics compared with their counterpart. In addition, CAMTA cements had enhanced odontogenic, angiogenic, and immunosuppressive properties compared with MTA. All of the results of this study proved that CAMTA cements could be a biomaterial for future clinical applications and tissue engineering use.
Lung cancer remains a major health problem despite the considerable research into prevention and treatment methods. Through a deeper understanding of tumors, patient‐specific ex vivo spheroid models ...with high specificity can be used to accurately investigate the cause, metastasis, and treatment strategies for lung cancer. Biofabricate lung tumors are presented, consisting of patient‐derived tumor spheroids, endothelial cells, and lung decellularized extracellular matrix, which maintain a radial oxygen gradient, as well as biophysicochemical behaviors of the native tumors for precision medicine. It is also demonstrated that the developed lung‐cancer spheroid model reproduces patient responses to chemotherapeutics and targeted therapy in a co‐clinical trial, with 85% accuracy, 86.7% sensitivity, and 80% specificity. RNA sequencing analysis validates that the gene expression in the spheroids replicates that in the patient's primary tumor. This model can be used as an ex vivo predictive model for personalized cancer therapy and to improve the quality of clinical care.
A facile route to construct a highly accurate sophisticated ex vivo lung tumor spheroid model for considering patient‐specific therapies. The LdECM provides native‐tissue‐mimetic physicochemical cues that support the organization of spheroids with a hypoxic signature. The developed patient‐derived tumor spheroid model for the prediction of the optimal chemotherapy or target therapy drug for the patient.
Bioprinting of artificial blood vessels Ng, Hooi Yee; Lee, Kai-Xing Alvin; Kuo, Che-Nan ...
International Journal of bioprinting,
01/2018, Letnik:
4, Številka:
2
Journal Article
Odprti dostop
Vascular networks have an important role to play in transporting nutrients, oxygen, metabolic wastes and maintenance of homeostasis. Bioprinting is a promising technology as it is able to fabricate ...complex, specific multi-cellular constructs with precision. In addition, current technology allows precise depositions of individual cells, growth factors and biochemical signals to enhance vascular growth. Fabrication of vascularized constructs has remained as a main challenge till date but it is deemed as an important stepping stone to bring organ engineering to a higher level. However, with the ever advancing bioprinting technology and knowledge of biomaterials, it is expected that bioprinting can be a viable solution for this problem. This article presents an overview of the biofabrication of vascular and vascularized constructs, the different techniques used in vascular engineering such as extrusion-based, droplet-based and laser-based bioprinting techniques, and the future prospects of bioprinting of artificial blood vessels.
Biofabricate Lung Tumors
In article number 2206603 by Mien‐Chie Hung, Der‐Yang Cho, Yi‐Wen Chen, and co‐workers, a facile route to construct sophisticated ex vivo lung tumors models consisting of ...patientderived tumor spheroids, vasculature barrier, and bovine lung ECMs, which maintained a radial oxygen gradient, as well as biophysical and biochemical behaviors of the native tumors is established. This model demonstrates the excellent prediction results (accuracy: 85%; sensitivity: 86.7% and specificity: 80%) for applying in patient‐specific precision therapies.
The chronic rejection responses and side effects of the systematic administration of immunosuppressants are the main obstacles to heart allograft and patient survival. The development of ...xenotransplantation also urgently requires more efficient immune regulation strategies. Herein, it is demonstrated that lymph‐node (LN)‐targeted drug delivery can realize LN‐specific immunomodulation with attenuated immune suppression on distant peripheral immune organs to effectively prolong long‐term survival after heart transplantation in a chronic murine heart transplantation model. A chemokine C‐C motif ligand 21 (CCL21) specific aptamer for LN targeting is decorated onto the surface of the hybrid nanoparticular delivery vector mainly composed of CaCO3/CaP/heparin. The targeting delivery system can dramatically enhance accumulation of the loaded immunosuppressant, fingolimod hydrochloride (FTY720), in draining lymph nodes (dLNs) for inducing powerful immune suppression. By promoting the generation of endogenous regulatory T cells (Tregs) and decreasing the proportion of effector T cells (Teffs) in dLNs after heart transplantation, the LN‐targeting strategy can effectively regulate local immune responses instead of systemic immunity, which reduces the incidence of long‐term complications. This study provides an efficient strategy to improve the survival rate after organ transplantation by precise and localized immunoregulation with minimized side effects of immunosuppression.
A targeting drug delivery system decorated by a chemokine C‐C motif ligand 21 (CCL21) specific aptamer can realize lymph‐node‐targeted immunomodulation with attenuated immune suppression on distant peripheral immune organs, resulting in effectively prolonged long‐term survival after heart transplantation. This study provides an efficient strategy to achieve precise and localized immunoregulation with minimized side effects of immunosuppression.
Numerous studies have demonstrated that calcium silicate (CS) can be doped with various trace metal elements such as strontium (Sr) or magnesium (Mg). These studies have confirmed that such ...modifications promote bone regeneration. However, the development and emergence of 3D printing have further made it possible to fabricate bone grafts with precise structural designs using multi-bioceramics so as to better suit specific clinical requirements. We fabricated scaffolds using Mg-doped CS as the outer layer with Sr-doped CS in the center. In addition, PCL was used to improve printability of the scaffolds. This enhanced Mg and Sr architecture prevented premature degradation of the scaffolds during immersion while enabling the release of ions in a sustained manner in order to achieve the desired therapeutic goals. Even the capabilities of stem cells were shown to be enhanced when cultured on these scaffolds. Furthermore, the hybrid scaffolds were found to up-regulate the expression of bone-related proteins such as factors leading to differentiation-inducing pathways, including PI3K/Akt, Wnt, and TRPM7. The in vivo performance of the proposed scaffolds was assessed using micro-CT. The histological results revealed that the hybrid scaffolds were able to further enhance bone regeneration as compared to uni-bioceramics. By combining 3D printing, multi-ceramics, and trace metal elements, a novel hybrid scaffold could be fabricated with ease and specifically suited to future bone tissue engineering applications.
Despite being the gold-standard treatment for end-stage heart disease, heart transplantation is associated with acute cardiac rejection within 1 year of transplantation. The continuous application of ...immunosuppressants may cause side effects such as hepatic and renal toxicity, infection, and malignancy. Developing new pharmaceutical strategies to alleviate acute rejection after heart transplantation effectively and safely is of critical importance. In this study, we performed a murine model of MHC-full mismatch cardiac transplantation and showed that the combination of Rhodosin (Rho) and mycophenolate mofetil (MMF) could prevent acute rejection and oxidative stress injury and prolong the survival time of murine heart transplants. The use of Rho plus MMF in allografts improved the balance of Tregs/Teff cells, which had a protective effect on allotransplantation. We also isolated bone marrow-derived dendritic cells (BMDCs) and determined that Rho inhibited DC maturation by promoting mitochondrial fusion mainly through the mitochondrial fusion-related protein MFN1. Herein, we demonstrated that Rho, an active ingredient isolated from the plant Rhodiola rosea with antioxidant and anti-inflammatory activities, could efficiently alleviate acute rejection and significantly prolong murine heart allograft survival when used with a low dose of MMF. More importantly, we found that Rho restrained DC maturation by promoting mitochondrial fusion and decreasing reactive oxygen species (ROS) levels, which then alleviated acute rejection in murine cardiac transplantation. Interestingly, as a novel immunosuppressant, Rho has almost no side effects compared with other traditional immunosuppressants. Taken together, these results suggest that Rho has good clinical auxiliary applications as an effective immunosuppressant and antioxidant, and this study provides an efficient strategy to overcome the side effects of immunosuppressive agents that are currently used in organ transplantation.
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