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Biomedical Materials · 2024 · IF 3.9

All-aqueous droplets-templated tailorable core-shell alginate microspheres for constructing vascularized intestinal mucosa in vitro models

Xin Hao,Ting Du,Feng Yang,Yilan Wang,Huatao He,Menghan Yang,Meiying Hong,Guanxiong Wang,Deqing Huang,Yaolei Wang

Recently, in vitro models of intestinal mucosa have become important tools for drug screening and studying the physiology and pathology of the intestine. These models enable the examination of cellular behavior in diseased states or in reaction to alterations in the microenvironment, potentially serving as alternatives to animal models. One of the major challenges in constructing physiologically relevant in vitro models of intestinal mucosa is the creation of three-dimensional (3D) microstructures that accurately mimic the integration of intestinal epithelium and vascularized stroma. Here, core-shell alginate (Alg) microspheres were generated to create the compartmentalized extracellular matrix (ECM) microenvironment needed to simulate the epithelial and vascularized stromal compartments of the intestinal mucosa. We demonstrated that NIH-3T3 and human umbilical vein endothelial cells (HUVECs) embedded in the core of the microspheres can proliferate and develop a vascular network, while human colorectal adenocarcinoma cells (Caco-2) can form an epithelial monolayer in the shell. Compared to Caco-2 monolayer encapsulated within the shell, the presence of the vascularized stroma enhances their proliferation and functionality. As such, our core-shell Alg microspheres provide a valuable method for generating in vitro models of vascularized intestinal mucosa with epithelial and vascularized stroma arranged in a spatially relevant manner and demonstrating near-physiological functionality.

CAS / MDL: 47165-04-8
研究领域: 生物医学工程 · 组织工程 · 细胞生物学 · 药学
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Materials Today Bio · 2024 · IF 8.7

Amorphous zinc phosphate nanoclusters loaded polycarbonate thermosensitive hydrogel: An innovative strategy for promoting wound healing

Siwen Chen,Yutong Li,Sihang Ren,Yuanyuan Yang,Zhipeng Hou,Siyu Han,Wanhong Zhang,Jing Guo,Jianshe Hu,Xing Zhang,Liqun Yang

Skin trauma is a matter of great concern for public health, emphasizing the importance of reconstructing the microenvironment at the trauma site to facilitate tissue regeneration. Therefore, the investigation of innovative wound dressings has significant research and clinical implications. In this study, we prepared a thermosensitive hydrogel based on a hydrophilic-hydrophobic-hydrophilic triblock polycarbonate polymer (PTP), and created a composite hydrogel, PTPH-AZP, by incorporating amorphous zinc phosphate (AZP) nanoclusters. We evaluated the effects of PTPH-AZP on human umbilical vein endothelial cells (HUVECs) and the ability to promote skin wound healing. According to the results, PTPH-AZP was found to promote the proliferation, migration, and tube formation of HUVECs through the sustained release of Zn 2+ at appropriate concentrations. In vivo experiments demonstrated that in the early-mid stages of wound healing, PTPH-AZP promotes increases in Platelet Endothelial Cell Adhesion Molecule-1 (CD31) and α-Smooth Muscle Actin (α-SMA) content within the wound area, facilitating accelerated re-epithelialization and enhanced collagen deposition. In later healing stages, epidermal thickness in the PTPH-AZP treated group was significantly improved, aligning with surrounding intact skin with no instances of attenuated or hypertrophic scarring observed. The findings from the in vivo study suggested that PTPH-AZP may have a positive impact on vascularization and wound healing. In conclusion, this study presents a promising strategy for skin wound healing, highlighting the potential of PTPH-AZP as an effective therapeutic approach.

研究领域: 材料科学 · 生物材料 · 组织工程 · 伤口愈合
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Biomaterials Research · 2024 · IF 8.1

Hollow Bismuth Nanoparticle-Loaded Gelatin Hydrogel Regulates M2 Polarization of Macrophages to Promote Infected Wound Healing

Dongming Lv,Zhongye Xu,Hao Yang,Yanchao Rong,Zirui Zhao,Zhicheng Hu,Rong Yin,Rui Guo,Xiaoling Cao,Bing Tang

Open wounds face severe bacterial infection, which affects the quality of healing. Photothermal antimicrobial therapy has received increasing attention as a broad-spectrum antimicrobial treatment that can avoid drug resistance. A variety of metallic materials have been used in the development of photothermal agents. However, there are few studies on bismuth as a photothermal agent and its use in tissue repair, so there is still a lack of clear understanding of its biomedical function. Here, a hollow bismuth nanosphere prepared from bismuth metal was developed for drug loading and photothermal antibacterial effect. The photothermal conversion efficiency of the hollow bismuth spheres reached 16.1%, and the bismuth-loaded gelatin-oxidized dextran (ODex)-based hydrogel achieves good antibacterial effects both in vivo and in vitro. The bismuth-loaded hydrogel can also promote the angiogenesis of human umbilical vein endothelial cells (HUVECs) and improve the proliferation of human keratinocytes cells (HaCaT) and the quality of wound healing. This discovery provides a new idea for the application of metal bismuth in the field of tissue repair and regeneration.

CAS / MDL: 107-21-1 7790-28-5
研究领域: 生物医学工程 · 材料科学 · 伤口愈合 · 传染病学 · 组织工程
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Biomed Research International · 2022 · IF 3.246

Influence of P(VDF-TrFE) Membranes with Different Surface Potentials on the Activity and Angiogenic Function of Human Umbilical Vein Endothelial Cells

Yan Xu,Mingwei Cheng,Peijun Zhu,Shuo Yang,Chunhua Lai,Shulan Xu

During bone tissue regeneration, neovascularization is critical, and the formation of a blood supply network is crucial for bone growth stimulation and remodeling. Previous studies suggest that bioelectric signals facilitate the process of angiogenesis. Owing to their biomimetic electroactivity, piezoelectric membranes have garnered substantial interest in the field of guided bone regeneration. Nevertheless, the knowledge of their influence due to varying surface potentials on the progression of angiogenesis remains ambiguous. Therefore, we proposed the preparation of an electroactive material, P(VDF-TrFE), and investigated its effects on the activity and angiogenic functions of human umbilical vein endothelial cells (HUVECs). The HUVECs were directly cultured on P(VDF-TrFE) membranes with different surface potentials. Subsequently, cell viability, proliferation, migration, tube formation, and expressions of related factors were assessed through appropriate assays. Our results revealed that the negative surface potential groups exerted differential effects on the modulation of angiogenesis in vitro. The P(VDF-TrFE) membranes with negative surface potential exhibited the greatest effect on cellular behaviors, including proliferation, migration, tube formation, and promotion of angiogenesis by releasing key factors such as VEGF-A and CD31. Overall, these results indicated that the surface potential of piezoelectric P(VDF-TrFE) membranes could exert differential effects on angiogenesis in vitro. We present a novel approach for designing bioactive materials for guided bone regeneration.

研究领域: 生物材料 · 组织工程 · 再生医学 · 细胞生物学 · 生物医学工程
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JOURNAL OF ETHNOPHARMACOLOGY · 2017 · IF 2.981

Dalbergia odorifera extract promotes angiogenesis through upregulation of VEGFRs and PI3K/MAPK signaling pathways

Zhu-Ming Fan,Da-Ying Wang,Jian-Mei Yang,Zhi-Xiu Lin,Yun-Xiao Lin,Ai-Lin Yang,Hua Fan,Min Cao,Su-yun Yuan,Zong-jun Liu,Xin Zhou,You-Hua Wang

Ethnopharmacological relevance The heart wood of Dalbergia odorifera is a Chinese herbal medicine commonly used for the treatment of various ischemic diseases in Chinese medicine practice. Aim of the study In this study, therapeutic angiogenesis effects of the Dalbergia odorifera extract (DOE) were investigated on transgenic zebrafish in vivo and human umbilical vein endothelial cells (HUVECs) in vitro . Materials and methods The pro-angiogenic effects of DOE on zebrafish were examined by subintestinal vessels (SIVs) sprouting assay and intersegmental vessels (ISVs) injury assay. And the pro-angiogenic effects of DOE on HUVECs were examined by MTT , scratch assay, protein chip and western blot . Results In the in vivo studies, we found that DOE was able to dose-dependently promote angiogenesis in zebrafish SIVs area. In addition, DOE could also restore the injury in zebrafish ISVs area and upregulate the reduced mRNA expression of VEGFRs including kdr , kdrl and flt-1 induced by VEGF receptor kinase inhibitor II (VRI). In the in vitro studies, we observed that DOE promoted the proliferation, migration of HUVECs and also restored the injury induced by VRI. Moreover, protein chip and western blot experiments showed the PI3K/MAPK cell proliferation/migration pathway were activated by DOE. Conclusions DOE has a therapeutic effects on angiogenesis, and its mechanism may be related to adjusting the VEGFRs mRNA and activation of PI3K/MAPK signaling pathway. These results suggest a strong potential for Dalbergia odorifera to be developed as an angiogenesis-promoting therapeutic.

CAS / MDL: 9041-08-1
研究领域: 药理学 · 分子生物学 · 民族药理学 · 血管生成研究
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Acta Biomaterialia · 2022 · IF 10.633

Gelatin methacryloyl-alginate core-shell microcapsules as efficient delivery platforms for prevascularized microtissues in endodontic regeneration

Xi Liang,Li Xie,Qingyuan Zhang,Ge Wang,Siyuan Zhang,Mingyan Jiang,Ruitao Zhang,Ting Yang,Xingyu Hu,Ziyang Yang,Weidong Tian

Combined injectable cell-laden microspheres and angiogenesis approaches are promising for functional vascularized endodontic regeneration. However, advanced microsphere designs and production techniques that benefit practical applications are rarely developed. Herein, gelatin methacryloyl (GelMA)-alginate core-shell microcapsules were fabricated to co-encapsulate human dental pulp stem cells (hDPSCs) and human umbilical vein endothelial cells (HUVECs) based on a coaxial electrostatic microdroplet technique. This technique enables high-throughput production, convenient collection, and minimal material waste. The average diameter of core-shell microcapsules was ∼359 µm, and that of GelMA cores was ∼278 µm. There were higher proliferation rates for hDPSCs and HUVECs co-encapsulated in the GelMA cores than for hDPSCs or HUVECs monoculture group. HUVECs assembled to form 3D capillary-like networks in co-culture microcapsules. Moreover, HUVECs promoted the osteo/odontogenic differentiation of hDPSCs in microcapsules. After 14 days of cultivation, prevascularized microtissues formed in microcapsules that contained abundant deposited extracellular matrix (ECM); no microcapsule aggregation occurred. In vivo studies confirmed that better microvessel formation and pulp-like tissue regeneration occurred in the co-culture group than in hDPSCs group. Thus, an effective platform for prevascularization microtissue preparation was proposed and showed great promise in endodontic regeneration and tissue engineering applications. Statement of significance Cell-laden microspheres combined with the proangiogenesis approach are promising in endodontic regeneration. We proposed GelMA-alginate core-shell microcapsules generated via the coaxial electrostatic microdroplet (CEM) method, which utilizes a double-lumen needle to allow for core-shell structures to form. The microcapsules were used for co-culturing hDPSCs and HUVECs to harvest large amounts of prevascularized microtissues, which further showed improved vascularization and pulp-like tissue regeneration in vivo . This CEM method and the microcapsule system have advantages of high-throughput generation, convenient collection, and avoid aggregation during long-term culturing. We proposed a high-effective platform for mass production of prevascularized microtissues, which exhibit great promise in the clinical transformation of endodontic regeneration and other applications in regenerative medicine.

CAS / MDL: 10043-52-4 68-04-2
研究领域: 生物材料 · 组织工程 · 再生医学 · 牙科科学 · 细胞生物学
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Journal of the Mechanical Behavior of Biomedical Materials · 2023 · IF 3.9

The synergetic effect of hierarchical pores and micro-nano bioactive glass on promoting osteogenesis and angiogenesis in vitro

Ting Tian,Qing Hu,Miao Shi,Cong Liu,Gang Wang,Xiaofeng Chen

Hierarchical pores are important structural components of the bone tissue and are closely related to angiogenesis, nutrient transport, and metabolism involved in the repair of a bone defect. Here, we fabricated a composite scaffold having a hierarchical structure, based on micro-nano bioactive glass (MNBG) incorporated into poly (lactic-co-glycolic acid) (PLGA), and with camphene as a pore-forming agent for bone repair. The results showed that camphene formed abundant micropores in the walls of large pores, resulting in hierarchical pore structures ranging from a few microns to a hundred microns. Moreover, there was 2–3 folds increased in compressive modulus and the scaffolds showed a stable degradation rate and a higher degree of apatite crystallization than ordinary porous scaffolds . The results of in vitro studies showed that, when compared to ordinary porous scaffolds, PLGA-MNBG scaffolds with multi-holes could better promote the proliferation of bone marrow mesenchymal stem cells (BMSCs) and the expression of angiogenic marker (CD31) of human umbilical vein endothelial cells (HUVECs).

研究领域: 生物材料 · 组织工程 · 生物医学工程 · 细胞生物学
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Advanced Science · 2024 · IF 14.3

3D Printing of a Vascularized Mini-Liver Based on the Size-Dependent Functional Enhancements of Cell Spheroids for Rescue of Liver Failure

Jiabin Zhang,Xiaodie Chen,Yurong Chai,Chenya Zhuo,Yanteng Xu,Tiantian Xue,Dan Shao,Yu Tao,Mingqiang Li

The emerging stem cell-derived hepatocyte-like cells (HLCs) are the alternative cell sources of hepatocytes for treatment of highly lethal acute liver failure (ALF). However, the hostile local environment and the immature cell differentiation may compromise their therapeutic efficacy. To this end, human adipose-derived mesenchymal stromal/stem cells (hASCs) are engineered into different-sized multicellular spheroids and co-cultured with 3D coaxially and hexagonally patterned human umbilical vein endothelial cells (HUVECs) in a liver lobule-like manner to enhance their hepatic differentiation efficiency. It is found that small-sized hASC spheroids, with a diameter of ≈50 µm, show superior pro-angiogenic effects and hepatic differentiation compared to the other counterparts. The size-dependent functional enhancements are mediated by the Wnt signaling pathway. Meanwhile, co-culture of hASCs with HUVECs, at a HUVECs/hASCs seeding density ratio of 2:1, distinctly promotes hepatic differentiation and vascularization both in vitro and in vivo, especially when endothelial cells are patterned into hollow hexagons. After subcutaneous implantation, the mini-liver, consisting of HLC spheroids and 3D-printed interconnected vasculatures, can effectively improve liver regeneration in two ALF animal models through amelioration of local oxidative stress and inflammation, reduction of liver necrosis, as well as increase of cell proliferation, thereby showing great promise for clinical translation.

CAS / MDL: 9067-32-7 9005-38-3
研究领域: 组织工程 · 再生医学 · 干细胞生物学 · 肝病 · 生物打印
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Biomaterials Science · 2021 ·Vol. 9 ·期 7 ·2631-2646 · IF 6.843

Construction of a nanofiber network within 3D printed scaffolds for vascularized bone regeneration

Mengru Geng,Qianqian Zhang,Jiani Gu,Jin Yang,Haibo Du,Yating Jia,Xiaojun Zhou,Chuanglong He

Three-dimensional (3D) printed scaffolds provide a promising prospective for application in bone tissue engineering. 3D printed scaffolds with micro- and nano-fibrous structures that facilitate cell adhesion and migration, and combined vascularization and osteoinduction bioactivity will be ideal implants for bone defect repair. Here, we fabricated a 3D printed biodegradable poly (glycerol-co-sebacic acid-co-L-lactic acid-co-polyethylene glycol) (PGSLP)-based scaffold that was internally filled with gelatin nanofibers and allowed the local release of deferoxamine (DFO), which is essential for angiogenesis and osteogenesis in bone regeneration. The nanofibrous structured gelatin/PGSLP (NGP) scaffold was fabricated using a thermally induced phase separation (TIPS) technique, and the macroporous structured gelatin/PGSLP (MGP) scaffold was prepared by directly freeze-drying. The in vitro experiments demonstrated that both DFO-loaded NGP and DFO-loaded MGP scaffolds can promote the migration and tubular formation of human umbilical vein endothelial cells (HUVECs), and enhance the mineralized nodule formation and osteogenic-related gene expression during osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). In a rat critical-sized calvarial defect model, the results suggested that the scaffolds with DFO loading significantly promote the vascular formation and accelerate bone regeneration, while the enhancement of vascularization and osteogenesis in vivo in DFO-loaded NGP scaffold was better than that in DFO-loaded MGP scaffold. Therefore, the constructed PGLSP-based scaffolds with micro- and nano-fibrous structures would be promising candidates to match the structural and functional requirements for vascularized bone regeneration.

CAS / MDL: 25952-53-8 6066-82-6
研究领域: 组织工程 · 生物医学工程 · 生物材料 · 再生医学
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MATERIALS & DESIGN · 2023 · IF 8.4

Surface bisphosphonation of polyetheretherketone to manipulate immune response for advanced osseointegration

Weifang Zhang,Lvhua Liu,Huang Zhou,Chanjuan He,Xueli Yang,Jingjing Fu,Huaiyu Wang,Ying Liu,Yanyan Zheng

Polyetheretherketone (PEEK) is deemed to be a promising alternative to biomedical metals for orthopedic and dental implantation attributed to its bone-like elastic modulus and good biocompatibility. Nevertheless, the bioinert PEEK elicits an acute and irreducible inflammatory immune response after implantation, resulting in fibrous encapsulation and ultimately inferior osseointegration. Therefore, endowing the PEEK surface with immunomodulatory function is essential for advanced osseointegration. Herein, surface bisphosphonation of PEEK is achieved by using mussel-inspired chemistry together with alendronate, which can not only mitigate the early servious inflammatory immune response by promoting macrophages polarization toward the pro-healing M2 phenotype, but also construct a favorable osteoimmune microenvironment to promote the angiogenesis of human umbilical vein endothelial cells (HUVECs) and the osteogenesis of MC3T3-E1 osteoblasts. In vivo evaluation reveals an ameliorative osseointegration of PEEK implant after surface bisphosphonation, confirming the in vitro results. Our findings elucidate that the PEEK implant after surface bisphosphonation can positively regulate early immune reaction to facilitate subsequent angiogenesis and osteogenesis processes, which is desirable for orthopedic and dental implantation.

CAS / MDL: 123-03-5
研究领域: 生物材料 · 生物医学工程 · 免疫学 · 骨科 · 牙科种植
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Advanced Healthcare Materials · 2022 ·Vol. 12 ·期 5 ·2202008 · IF 11.092

Selective Formation of Osteogenic and Vasculogenic Tissues for Cartilage Regeneration

Zeyang Liu,Haochen Nan,Yi Shiou Chiou,Zhen Zhan,Peter E. Lobie,Chengzhi Hu

Tissue-engineered periosteum substitutes (TEPSs) incorporating hierarchical architecture with osteoprogenitor and vascular niches are drawing much attention as a promising tool to support functional cells in defined zones and nourish the cortical bone. Current TEPSs usually lack technologies to closely observe cell performance, especially at the cell contact interface between distinct compartments containing defined biological configurations and functions. Here, an electrodeposition strategy is reported, which enables the selective formation of TEPSs with osteoprogenitor and vascular niches in a multiphasic scaffold in combination with different human cell types for cartilage regeneration in an in vivo osteochondral defect model. Human umbilical vein endothelial cells (HUVECs), dermal fibroblasts (HDFs), and bone marrow mesenchymal stem cells (hMSCs) are used to mirror both the vascular and osteogenic niches, respectively. It is observed that the intrinsic viscoelastic nature of the porous solid matrix is essential to successfully induce angiogenesis. Coculture of hMSCs with functional cells (HUVECs/HDFs) in TEPSs also effectively promoted periosteal regeneration, including osteogenic and angiogenic processes. The osteoarthritis cartilage histopathology assessment and histologic/histochemical grading system data indicate that the TEPSs containing hMSCs/HUVECs/HDFs exhibit superior potential for cartilage regeneration.

研究领域: 组织工程 · 再生医学 · 生物材料 · 细胞生物学 · 骨科
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Journal of Materials Chemistry B · 2019 ·Vol. 7 ·期 11 ·1882-1892 · IF 5.047

Construction of cytokine reservoirs based on sulfated chitosan hydrogels for the capturing of VEGF in situ

Chenmin Wang,Yuanman Yu,Han Chen,Shuang Zhang,Jing Wang,Changsheng Liu

Nutrients and oxygen are delivered mainly by blood vessels to nourish the cells and tissues in the body. Thus, biomaterials are processed by loading cytokines, such as vascular endothelial growth factors (VEGF), to facilitate angiogenesis in order to accelerate tissue regeneration. Nevertheless, the unpredictable biosecurity of exogenous cytokines is still a controversial issue for its clinical application. In this study, we constructed a kind of cytokine reservoir utilizing the binding affinity between heparin-like sulfate polysaccharide and endogenous growth factors. Two types of sulfated chitosan hydrogels, namely 6-O-sulfated chitosan (6-O-SCS) and 2-N,6-O-sulfated chitosan (2-N,6-O-SCS) hydrogels, were formed on the surface of the gelatin sponge matrix. The microstructure of the SCS-coated scaffolds is porous and interconnected, which is beneficial for cellular infiltration. Besides, human umbilical vein endothelial cells (HUVECs) can adhere and proliferate well on the surface of the scaffolds. Notably, sulfated chitosan-coated scaffolds exhibit an ability to capture VEGF in vitro & vivo, especially for the 2-N,6-O-SCS-coated scaffold. It is also verified by mice models that sulfated chitosan-coated scaffolds result in a concentrated VEGF microenvironment in specific domains as cytokine reservoirs and induce mass microvessels after implantation into subcutaneous tissues. As such, the sulfated chitosan-coated scaffolds served as VEGF reservoirs to accelerate angiogenesis and wound healing. This beneficial strategy may be applicable to in situ tissue regeneration by capturing more cytokines and promoting healing.

CAS / MDL: 9009-65-8
研究领域: 生物材料 · 组织工程 · 生物医学工程 · 细胞生物学
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