Co-reporter:Haoyi Niu, Dan Lin, Wei Tang, Yifan Ma, Bing Duan, Yuan Yuan, and Changsheng Liu
ACS Biomaterials Science & Engineering December 11, 2017 Volume 3(Issue 12) pp:3161-3161
Publication Date(Web):October 6, 2017
DOI:10.1021/acsbiomaterials.7b00315
The response of mesenchymal stem cell (MSCs) to elaborate microarchitectured topographies in three-dimensional environment and the underlying molecular mechanism remain poorly understood. Here, with hierarchical mesoporous bioactive glass (MBG) scaffolds as substrate model, we show the effects of specific, elaborate microtextured topographies (micrograiny, microporous and hybrid micrograiny/microporous surface) on MSCs osteogenesis and the molecular mechanism involved. With a similar size and density, the microporous surface was more favorable for the MSC osteogenesis, and the hybrid micrograiny/microporous surface exhibited a synergetic effect. All the microscaled topographies facilitated expression of integrin subunits, focal adhesion complexes, and up-regulated FAK/MAPK and ILK/β-catenin signaling pathways. Separately blocking FAK/MAPK and ILK/β-catenin cascade dramatically attenuated the heightened β-catenin signaling, and the phosphorylation of ERK1/2 and P38, respectively, indicating a typical crosstalk between FAK/MAPK and ILK/β-catenin signalings was involved. Correlating the MSCs response with the specific topographical cues, it can be inferred that the micrograiny/microporous topographies induced FAs assembly and homeostasis, and thus FAK/MAPK and ILK/β-catenin signalings played critical role in regulating MSCs osteogenic differentiation. The findings, therefore, have significant implications in better understanding of the MSCs fate in a 3D environment and provided guidance of the development of novel biomaterial for bone regeneration.Keywords: indirect mechanotransduction; micrograiny/microporous topography; MSCs osteogenic differentiation; signaling crosstalk;
Co-reporter:Yanjun Chai;Dan Lin;Yifan Ma;Changsheng Liu
Journal of Materials Chemistry B 2017 vol. 5(Issue 24) pp:4633-4647
Publication Date(Web):2017/06/22
DOI:10.1039/C7TB00505A
With the worldwide rising need of severe bone defect treatment, the development of available bone substitutes with optimal mechanical strength, sustained drug release, cell affinity and osteoinductivity remains a great challenge. In this study, an rhBMP-2 loaded polymer-coated mesoporous bioactive glass (MBG) composite scaffold was developed. The uncrosslinked poly(glycerol sebacate) (PGS) or PEGylated PGS (PEGS) coating modification had enhanced the mechanical strength of the composite scaffold, solved the brittleness problem of the MBG matrix, increased the cell affinity of the material surface, and diminished the initial burst release of rhBMP-2 from mesopores of MBG. The results indicated that the PGS coating promoted the proliferation of rat bone marrow stem cells (rBMSCs), while the PEGS coating exhibited an enhancement in the osteogenic differentiation of rBMSCs. The in vivo ectopic bone formation results provide strong evidence that the rhBMP-2-loaded MBG/PEGS composite scaffolds exhibited a rapid bone forming capacity and might yield extraordinary achievements in the field of bone tissue engineering. The design considerations can be extended to other artificial scaffolds and are expected to provide new thoughts on the development of future tissue engineering materials.
Co-reporter:Bing Duan;Haoyi Niu;Wenjing Zhang;Yifan Ma;Changsheng Liu
Journal of Materials Chemistry B 2017 vol. 5(Issue 19) pp:3586-3599
Publication Date(Web):2017/05/17
DOI:10.1039/C7TB00041C
The microporous architecture of biomaterials/scaffolds plays a critical role in cellular behaviors of marrow stromal cells in the field of tissue regeneration, but the role of microporous density in this process and its underlying molecular mechanism are poorly understood. In the present work, a series of three-dimensional (3D) trimodal macro/micro/nano-porous MBG scaffolds (TMSs) with different microporous densities were developed to investigate the influence of microporous density on the attachment, proliferation and osteogenic differentiation of rat bone marrow stromal cells (rBMSCs), and the fundamental molecular mechanism was explored. The results demonstrated that scaffolds with micropores significantly promoted initial cell adhesion, ALP activity and osteogenesis-related gene/protein expressions, especially the one with 20% microporous density (TMS 20). We found that the appropriate microporous density modulated the adsorption of fibronectin (Fn), and in turn facilitated integrin receptor binding affinity, focal adhesion complex formation and subsequent FAK/MAPK signaling pathway activation. Based on these studies, it can be confirmed that microporous density contributes to the regulation of cellular response, which can provide a new insight into the design of future bone substitutes in a 3D environment.
Co-reporter:Jiaoyang Zhu;Baolin Huang;Sai Ding;Wenjing Zhang;Xiaoyu Ma;Haoyi Niu;Changsheng Liu
RSC Advances (2011-Present) 2017 vol. 7(Issue 33) pp:20281-20292
Publication Date(Web):2017/04/05
DOI:10.1039/C7RA01908D
Localized, continuous and effective osteogenic stimulation to defected sites is still a great challenge for recombinant human bone morphogenetic protein-2 (rhBMP-2) in clinical bone regeneration. In this study, a novel delivery system was engineered to tether rhBMP-2 onto the surface of calcium phosphate cement (CPC) based on the high affinity between alendronate and CPC, as well as the strong binding of heparin and rhBMP-2. Alendronate was first grated to heparin via the EDC/NHS reaction and then the resultant alendronate–heparin (AH) was adsorbed onto the CPC surface. RhBMP-2 was further anchored onto the CPC–AH surface. The results from in vitro release and in vivo fluorescence-labeled traces all indicated that the AH-tethered rhBMP-2 exhibited a more stable and stronger adherence to the CPC surface than the CPC-adsorbed and heparin-anchored ones. Moreover, based on the results of the alkaline phosphatase (ALP) activity in skeletal myoblasts (C2C12) in vitro and osteogenic efficacy in vivo, it could be seen that rhBMP-2-induced osteogenic bioactivity was also significantly enhanced on the CPC–AH surface. These results demonstrated that the tethering of rhBMP-2 onto calcium phosphate surface via AH presented an effective method to achieve a localized and sustained exposure to targeted cells, and consequently to promote bone regeneration.
Co-reporter:Xiaoyu Ma;Yuanyuan Li;Chengwei Wang;Yi Sun;Yifan Ma;Xiuling Dong;Jiangchao Qian;Changsheng Liu
Journal of Materials Chemistry B 2017 vol. 5(Issue 46) pp:9148-9156
Publication Date(Web):2017/11/29
DOI:10.1039/C7TB02487H
Hydroxyapatites (HAps) with nano-sized structures are promising materials in various biomedical areas, but the synthesis of high quality particles is still challenged by the insufficient precision of size and morphology, as well as the presence of severe agglomeration. An inadequate knowledge of the early nucleation, growth and transformation might limit our exploration and application of HAp. Here, we report a novel oil/water microemulsion–hydrothermal hybrid strategy for the preparation of highly dispersive HAps with tailored morphologies and controlled size. Through the synergetic effect of the oleic acid and microemulsion system, a well-dispersed HAp nucleus was first generated at 2 h. By tuning the ensuing hydrothermal conditions from room temperature to 140 °C, the nucleus would grow from spherical to needle-like nanoparticles. The size of the particles could be regulated by the alteration of the hydrothermal temperature. In addition, we experimentally demonstrated the complete evolution of HAp growth and transformation at a critical temperature of 90 °C by quenching the reaction at various intervals. The obtained particles were explored as potential cellular delivery carriers and polymer fillers.
Co-reporter:Yifeng Wang, Yi Sun, Jine Wang, Yang Yang, Yulin Li, Yuan Yuan, and Changsheng Liu
ACS Applied Materials & Interfaces 2016 Volume 8(Issue 27) pp:17166-17175
Publication Date(Web):June 17, 2016
DOI:10.1021/acsami.6b05370
In this study, we demonstrate a facile strategy (DL–SF) for developing MSN-based nanosystems through drug loading (DL, using doxorubicin as a model drug) followed by surface functionalization (SF) of mesoporous silica nanoparticles (MSNs) via aqueous (3-aminopropyl)triethoxysilane (APTES) silylation. For comparison, a reverse functionalization process (i.e., SF–DL) was also studied. The pre-DL process allows for an efficient encapsulation (encapsulation efficiency of ∼75%) of an anticancer drug [doxorubicin (DOX)] inside MSNs, and post-SF allows in situ formation of an APTES outer layer to restrict DOX leakage under physiological conditions. This method makes it possible to tune the DOX release rate by increasing the APTES decoration density through variation of the APTES concentration. However, the SF–DL approach results in a rapid decrease in drug loading capacity with an increase in APTES concentration because of the formation of the APTES outer layer hampers the inner permeability of the DOX drug, resulting in a burst release similar to that of undecorated MSNs. The resulting DOX-loaded DL–SF MSNs present a slightly negatively charged surface under physiological conditions and become positively charged in and extracellular microenvironment of solid tumor due to the protonation effect under acidic conditions. These merits aid their maintenance of long-term stability in blood circulation, high cellular uptake by a kind of skin carcinoma cells, and an enhanced intracellular drug release behavior, showing their potential in the delivery of many drugs beyond anticancer chemotherapeutics.
Co-reporter:Guoying Wang, Yaying Chen, Peng Wang, Yifeng Wang, Hua Hong, Yulin Li, Jiangchao Qian, Yuan Yuan, Bo Yu, Changsheng Liu
Acta Biomaterialia 2016 Volume 29() pp:248-260
Publication Date(Web):1 January 2016
DOI:10.1016/j.actbio.2015.10.017
Abstract
Despite advances in polymeric nanoparticles (NPs) as effective delivery systems for anticancer drugs, rapid clearance from blood and poor penetration capacity in heterogeneous tumors still remain to be addressed. Here, a dual coating of poly (ethylene glycol)-poly (d,l-lactic acid) (PEG-PDLLA) and water-soluble chitosan oligosaccharide (CO) was used to develop PLGA-based NPs (PCPNPs) with colloidal stability for delivery of paclitaxel (PTX). The PCPNPs were prepared by a modified nanoprecipitation process and exhibited homogeneous size of 165.5 nm, and slight positive charge (+3.54 mV). The single PEG-PDLLA-coated PLGA NPs (PPNPs) with negative charge (−13.42 mV) were prepared as control. Human breast cancer MDA-MB-231 cell and mice MDA-MB-231 xenograft model were used for in vitro and in vivo evaluation. Compared to Taxol®, both PCPNPs and PPNPs increased the intracellular uptake and exerted stronger inhibitory effect on tumor cells in vitro, especially for PCPNPs. Particularly, due to the near neutral surface charge and shielding by the dual coating, the blank cationic NP presented low cytotoxicity. With the synergistic action of PEG-PDLLA and CO, PCPNPs not only strongly inhibited macrophage uptake and extended the blood circulation time, but also improved the selective accumulation and interstitial penetration capacity to/in tumor site. Consequently, a significantly enhanced antitumor efficacy was observed for the cationic PCPNPs. Our findings suggest that, the dual PEG-PDLLA/CO coating can effective improve the tumor accumulation and interstitial penetration of NPs and, therefore may have great potential for tumor treatment.
Statement of significance
Rapid clearance from blood and poor penetration capacity in heterogeneous tumors represent great challenge for polymeric nanoparticles (NPs) as effective delivery systems for anticancer drugs. This study provides a promising cationic nanoparticle (PCPNPs) with dual coating of chitosan oligosaccharide (CO) and PEG-PDLLA to address the above problem. The PCPNPs prepared with 165.5 nm and slight positive charge (+3.54 mV) showed an improved accumulation and interstitial penetration capacity to/in tumor site, and thus led to an enhanced antitumor efficacy. This is the first time to report the cooperative effect of PEG-PDLLA and CO on PLGA NPs in this field. This work can arouse broad interests among researchers in the fields of nanomedicine, nanotechnology, and drug delivery system.
Co-reporter:Wei Tang, Dan Lin, Yuanman Yu, Haoyi Niu, Han Guo, Yuan Yuan, Changsheng Liu
Acta Biomaterialia 2016 Volume 32() pp:309-323
Publication Date(Web):1 March 2016
DOI:10.1016/j.actbio.2015.12.006
Abstract
Critical size bone defects raise great demands for efficient bone substitutes. Mimicking the hierarchical porous architecture and specific biological cues of natural bone has been considered as an effective strategy to facilitate bone regeneration. Herein, a trimodal macro/micro/nano-porous scaffold loaded with recombinant human bone morphogenetic protein-2 (rhBMP-2) was developed. With mesoporous bioactive glass (MBG) as matrix, a trimodal MBG scaffold (TMS) with enhanced compressive strength (4.28 MPa, porosity of 80%) was prepared by a “viscosity controlling” and “homogeneous particle reinforcing” multi-template process. A 7.5 nm, 3D cubic (Im3m) mesoporous structure was tailored for a “size-matched entrapment” of rhBMP-2 to achieve sustained release and preserved bioactivity. RhBMP-2-loaded TMS (TMS/rhBMP-2) induced excellent cell attachment, ingrowth and osteogenesis in vitro. Further in vivo ectopic bone formation and orthotopic rabbit radius critical size defect results indicated that compared to the rhBMP-2-loaded bimodal macro/micro- and macro/nano-porous scaffolds, TMS/rhBMP-2 exhibited appealing bone regeneration capacity. Particularly, in critical size defect, complete bone reconstruction with rapid medullary cavity reunion and sclerotin maturity was observed on TMS/rhBMP-2. On the basis of these results, TMS/rhBMP-2 developed here represents a promising bone substitute for clinical application and the concepts proposed in this study might provide new thoughts on development of future orthopedic biomaterials.
Statement of Significance
Limited self-regenerating capacity of human body makes the reconstruction of critical size bone defect a significant challenge. Current bone substitutes often exhibit undesirable therapeutic efficacy due to poor osteoconductivity or low osteoinductivity. Herein, TMS/rhBMP-2, an advanced mesoporous bioactive glass (MBG) scaffold with osteoconductive trimodal macro/micro/nano-porosity and osteoinductive rhBMP-2 delivery was developed. The preparative and mechanical problems of hierarchical MBG scaffold were solved without affecting its excellent biocompatibilities, and rhBMP-2 immobilization in sizematched mesopores was first explored. Combining structural and biological cues, TMS/rhBMP-2 achieved a complete regeneration with rapid medullary cavity reunion and sclerotin maturity in rabbit radius critical size defects. The design conceptions proposed in this study might provide new thoughts on development of future orthopedic biomaterials.
Co-reporter:Wenjing Zhang, Yu Tian, Hongyan He, Rui Chen, Yifan Ma, Han Guo, Yuan Yuan, Changsheng Liu
Acta Biomaterialia 2016 Volume 33() pp:290-300
Publication Date(Web):15 March 2016
DOI:10.1016/j.actbio.2016.01.042
Abstract
Strontium (Sr2+) has pronounced effects on stimulating bone formation and inhibiting bone resorption in bone regeneration. In this current study, the effect and the underlying mechanism involved of Sr2+ on the biological activity of bone morphogenetic protein-2 (BMP-2) were studied in detail with pluripotent skeletal muscle myogenic progenitor C2C12 model cell line. The results indicated that Sr2+ could bind recombinant human BMP-2 (rhBMP-2) rapidly, even in the presence of Ca2+ and Mg2+, and inhibited rhBMP-2-induced osteogenic differentiation in vitro and osteogenetic efficiency in vivo. Further studies demonstrated that Sr2+ treatment undermined the binding capacity of rhBMP-2 with its receptor BMPRIA and thus attenuated Smad 1/5/8 phosphorylation without affecting their dephosphorylation in C2C12 cells. Furthermore, circular dichroism spectroscopy, fluorescence spectroscopy and X-ray photoelectron spectroscopy all revealed that the inhibitory effect of Sr2+ on the rhBMP-2 osteogenic activity was associated with the formation of Sr-rhBMP-2 complex and ensuing enhancement of β-sheet structure. Our work suggests the activity of rhBMP-2 to induce osteogenic differentiation was decreased by directly interaction with free Sr ions in solution, which should provide guide and assist for development of BMP-2-based materials for bone regeneration.
Statement of Significance
Due to easy denaturation and ensuing the reduced activity of rhBMP-2, preserving/enhancing the capacity of rhBMP-2 to induce osteogenic differentiation is of critical importance in developing the protein-based therapy. Cations as effective elements influence the conformation and thereby the bioactivity of protein. Strontium (Sr2+), stimulating bone formation and inhibiting bone resorption, has been incorporated into biomaterials/scaffold to improve the bioactivity for bone-regeneration applications. However, Sr2+-induced changes in the conformation and bioactivity of BMP-2 have never been investigated. In this study, the formation of Sr-rhBMP-2 complex inhibited the osteogenic differentiation in vitro and osteogenetic efficiency in vivo through the inhibition of BMP/Smad signaling pathway, providing guidance for development of Sr-containing BMP-2-based bone scaffold/matrice and other Sr-dopped protein therapy.
Co-reporter:Yifan Ma, Wenjing Zhang, Zihao Wang, Zi Wang, Qing Xie, Haoyi Niu, Han Guo, Yuan Yuan, Changsheng Liu
Acta Biomaterialia 2016 Volume 44() pp:110-124
Publication Date(Web):15 October 2016
DOI:10.1016/j.actbio.2016.08.023
Abstract
Calcium phosphate (CaP) scaffolds have been widely used as bone graft substitutes, but undesirable mechanical robustness and bioactivity greatly hamper its availability in clinic application. To address these issues, PEGylated poly (glycerol sebacate) (PEGS), a hydrophilic elastomer, was used to modify a model calcium phosphate cement (CPC) scaffold for bone regeneration in this study. The PEGS pre-polymer with PEG content from 0% to 40% was synthesized and was subsequently coated onto the pre-fabricated CPC scaffolds by facile infiltration and thermal-crosslink process. Compression strength and toughness of the CPC/PEGS composite scaffold (defined as CPX/Y, X referred to the PEG content in PEGS and Y referred to PEGS amount in final scaffold) were effectively tailored with increasing coating amount and PEG content, and CPX/Y exhibited an optimal compressive strength of 3.82 MPa and elongation at break of 13.20%, around 5-fold and 3-fold enhancement compared to the CPC. In vitro cell experiment with BMSCs as model indicated that coating and PEG-modified synchronously facilitated cell attachment and proliferation in a dose-dependent manner. Particularly, osteogenic differentiation of BMSCs on PEGS/CPC scaffold was strongly enhanced, especially for CP20/18. Further in vivo experiments confirmed that PEGS/CPC induced promoted osteogenesis in striking contrast to CPC and PGS/CPC. Collectively, hybrids scaffolds (around 18% coating amount and PEG content from 20% to 40%) with the combination of enhanced mechanical behavior and up-regulated cellular response were optimized and PEGS/CaP scaffolds can be deemed as a desirable option for bone tissue engineering.
Statement of Significance
Insufficient mechanical robustness and bioactivity still limit the availability of calcium phosphate (CaP) scaffolds in clinic application. Herein, calcium phosphate cement (CPC) scaffold, as a model CaP-matrix material, was modified with PEGylated PGS (PEGS) polymers by facile infiltration and thermal-crosslink process. Such biomimetic combination of PEGS and CaP-matrix porous scaffold was first explored, without affecting its porous structure. In this study, CPC scaffold was endowed with robust mechanical behavior and promoted bioactivity by simultaneously optimizing the amount of polymer-coating and the PEG content in PGS. In rat critical-sized calvarial defects repairing, osteogenic efficacy of PEGS/CPC further demonstrated the potential for application in bone tissue regeneration. The design concept proposed in this study might provide new insights into the development of future tissue engineering materials.
Co-reporter:Hua Hong, Chengwei Wang, Yuan Yuan, Xue Qu, Jie Wei, Zhaofen Lin, Huayi Zhou and Changsheng Liu
RSC Advances 2016 vol. 6(Issue 82) pp:78930-78935
Publication Date(Web):08 Aug 2016
DOI:10.1039/C6RA13999J
For emergency control of bleeding, there is a strong demand for topical hemostatic materials that can not only stop bleeding rapidly but also be carried and used conveniently. The aim of this work was to develop a novel type of porous silica material and investigate its hemostatic performance. The porous silica spherical-like granules were prepared via dry-mixing and wet-granulation with diameters of 0.40–1.10 mm. Granulation reinforced the infiltrating ability of the porous silica materials with fluid and stabilized their capillary structure. The rapid water absorption ability was enhanced 130% for the porous silica granules compared to the mesoporous silica particles. In vitro coagulation studies showed the clotting time of blood was shorten greatly from 150 seconds for mesoporous silica particles to 30 seconds for mesoporous silica granules at the early stage of hemostasis. In vivo studies using a rat injury model demonstrated the granules' ability to aid in rapid hemostasis. The usability of silica material was improved significantly by granulation through enhancing its flowability and eliminating dust. This study suggested the porous silica granules are a good candidate as a hemostatic agent in clinical and family applications.
Co-reporter:Xiaoyu Ma, Yaying Chen, Jiangchao Qian, Yuan Yuan, Changsheng Liu
Materials Chemistry and Physics 2016 Volume 183() pp:220-229
Publication Date(Web):1 November 2016
DOI:10.1016/j.matchemphys.2016.08.021
•Spherical nano-sized hydroxyapatite particles were successfully synthesized through inverse microemulsion method.•A systematical study was performed to illustrate correlation between microemulsion stability and particle morphology.•A possible mechanism for the growth of HAp was proposed.Spherical nanosized hydroxyapatite (HA) was successfully synthesized via a water-in-oil microemulsion route at room temperature in short time. The effect of water-to-oil and water-to-surfactant ratios on the stability of microemulsion system was investigated to establish a stable reaction system, with span-80, cyclohexane and Ca(NO3)2·4H2O((NH4)2HPO4) solution as surfactant, oil phase, and water phase, respectively. Size and morphology change of obtained HA under optimal microemulsion system were further studied under various reaction time and temperature, and a possible growth mechanism was proposed. A moderate reaction temperature of 25 °C and reaction time of 5 h facilitated the formation of spherical HA particles in the dimension of 70 nm with good uniformity and regularity, which served as a great candidate in biomedical applications.
Co-reporter:Sai Ding, Jing Zhang, Yu Tian, Baolin Huang, Yuan Yuan, Changsheng Liu
Colloids and Surfaces B: Biointerfaces 2016 Volume 145() pp:140-151
Publication Date(Web):1 September 2016
DOI:10.1016/j.colsurfb.2016.04.045
•Magnesium modification on CPC could enhance osteoactivity of rhBMP-2.•Mg2+ released from MCPC hardly affected the bioactivity of rhBMP-2.•Mg2+ on 5MCPC regulated rhBMP-2 conformation to facilitate receptor recognition.•5MCPC promoted rhBMP-2-induced osteogenic differentiation via Smad signaling.Efficient presentation of growth factors is one of the great challenges in tissue engineering. In living systems, bioactive factors exist in soluble as well as in matrix-bound forms, both of which play an integral role in regulating cell behaviors. Herein, effect of magnesium on osteogenic bioactivity of recombinant human bone morphogenetic protein-2 (rhBMP-2) was investigated systematically with a series of Mg modified calcium phosphate cements (xMCPCs, x means the content of magnesium phosphate cement wt%) as matrix model. The results indicated that the MCPC, especially 5MCPC, could promote the rhBMP-2-induced in vitro osteogenic differentiation via Smad signaling of C2C12 cells. Further studies demonstrated that all MCPC substrates exhibited similar rhBMP-2 release rate and preserved comparable conformation and biological activity of the released rhBMP-2. Also, the ionic extracts of MCPC made little difference to the bioactivity of rhBMP-2, either in soluble or in matrix-bound forms. However, with the quartz crystal microbalance (QCM), we observed a noticeable enhancement of rhBMP-2 mass-uptake on 5MCPC as well as a better recognition of the bound rhBMP-2 to BMPR IA and BMPR II. In vivo results demonstrated a better bone regeneration capacity of 5MCPC/rhBMP-2. From the above, our results demonstrated that it was the Mg anchored on the underlying substrates that tailored the way of rhBMP-2 bound on MCPC, and thus facilitated the recognition of BMPRs to stimulate osteogenic differentiation. The study will guide the development of Mg-doped bioactive bone implants for tissue regeneration.
Co-reporter:Xinhui Cui, Tong Liang, Changsheng Liu, Yuan Yuan, Jiangchao Qian
Materials Science and Engineering: C 2016 Volume 67() pp:453-460
Publication Date(Web):1 October 2016
DOI:10.1016/j.msec.2016.05.034
•Three types of HAPNs (L200, L300 and C200) were synthesized employing a sonochemistry-assisted microwave method.•L200 exhibited the greatest cytotoxicity to human gastric cancer (MGC80-3) cells.•L200 showed a smaller size and higher specific surface area.•The L200 nanoparticles were more efficiently uptaken by MGC80-3 cells through energy-dependent pathways.•L200 caused the most significant increase in the intracellular calcium level.Three types of hydroxyapatite nanoparticles (HAPNs) were synthesized employing a sonochemistry-assisted microwave method by changing microwave power (from 200 to 300 W) or using calcination treatment: L200 (200 W, lyophilization), L300 (300 W, lyophilization) and C200 (200 W, lyophilization & calcination). Their physiochemical properties were characterized and correlated with cytotoxicity to human gastric cancer cells (MGC80-3). The major differences among these HAPN preparations were their size and specific surface area, with the L200 showing a smaller size and higher specific surface area. Although all HAPNs inhibited cell proliferation and induced apoptosis of cancer cells, L200 exhibited the greatest toxicity. All types of HAPNs were internalized through energy-dependent pathways, but the L200 nanoparticles were more efficiently uptaken by MGC80-3 cells. Inhibitor studies with dynasore and methyl-β-cyclodextrin suggested that caveolae-mediated endocytosis and, to a much lesser extent, clathrin-mediated endocytosis, were involved in cellular uptake of the various preparations, whereas the inhibition of endocytosis was more obvious for L200. Using fluorescein isothiocyanate-labeled HAPNs and laser-scanning confocal microscopy, we found that all forms of nanoparticles were present in the cytoplasm, and some L200 HAPNs were even found within nuclei. Treatment with all HAPN preparations led to the increase in the intracellular calcium level with the highest level detected for L200.
Co-reporter:Depeng Song, Shiyuan Sun, Yu Tian, Shuai Huang, Yun Ding, Yuan Yuan and Aiguo Hu
Journal of Materials Chemistry A 2015 vol. 3(Issue 16) pp:3195-3200
Publication Date(Web):17 Feb 2015
DOI:10.1039/C4TB02018A
A pH-sensitive acyclic enediyne (1) was synthesized for efficient DNA-cleavage and tumor cell suppression. Unlike other acyclic enediynes, this novel enediyne transforms into a highly reactive enediyne (2) in an acidic environment only, which undergoes Bergman cyclization spontaneously at ambient temperature. An EPR study on the enediyne 2 confirmed the generation of free radicals through Bergman cyclization. The activated enediyne induced DNA-cleavage and exhibited cytotoxicity towards various tumor cells under the action of diradicals arising from spontaneous Bergman cyclization at physiological temperature. These findings suggest a novel strategy of anticancer drug design, where the activation of the silent compound takes place under the acidic environment inside the tumor cells.
Co-reporter:Qi Gan, Jiaoyang Zhu, Yuan Yuan, Honglai Liu, Yihua Zhu and Changsheng Liu
Journal of Materials Chemistry A 2015 vol. 3(Issue 11) pp:2281-2285
Publication Date(Web):18 Feb 2015
DOI:10.1039/C5TB00219B
A novel pH-responsive mesocellular foam-based nanocarrier was fabricated by the covalent assembly of a water-soluble N,O-carboxymethyl chitosan via the crosslinking of GPTMS. The delivery systems show excellent protein loading with programmable release in an acid environment. Moreover, the released proteins still preserve their conformational and biological activity.
Co-reporter:Depeng Song, Yu Tian, Shuai Huang, Baojun Li, Yuan Yuan and Aiguo Hu
Journal of Materials Chemistry A 2015 vol. 3(Issue 43) pp:8584-8588
Publication Date(Web):21 Sep 2015
DOI:10.1039/C5TB01867F
An acyclic enediyne with a furyl tethering group and two pH-sensitive orthoester groups at the alkynyl termini was synthesized. The enediyne compound yielded free radicals, which can be further trapped by other atoms, under acidic conditions at ambient temperature. It exhibited high cytotoxicity towards tumor cells, and affected normal cells much less, while showing very low cytotoxicity to both types of cells once the furan group was reacted with a dienophile, 4-phenyl-1,2,4-triazoline-3,5-dione. Confocal laser scanning microscopy experiments showed that the derivation of the furan group dictated the cytosis of the enediyne molecules. The cytotoxicity of the enediyne molecules disappeared when cytosis was hindered. The introduction of a furyl tethering group into enediyne represents a new design strategy of “intelligent” antitumor antibiotics that can distinguish tumor and normal cells.
Co-reporter:Qi Gan, Jiaoyang Zhu, Yuan Yuan, Honglai Liu, Jiangchao Qian, Yongsheng Li and Changsheng Liu
Journal of Materials Chemistry A 2015 vol. 3(Issue 10) pp:2056-2066
Publication Date(Web):17 Dec 2014
DOI:10.1039/C4TB01897D
Bone morphogenetic protein-2 (BMP-2) is considered one of the most effective and extensively used growth factors to induce osteoblast differentiation and accelerate bone regeneration. Dexamethasone (Dex) with suitable dosage can enhance BMP-2-induced osteoblast differentiation. To strengthen this synergistic osteoinductive effect, a pH-responsive chitosan-functionalized mesoporous silica nanoparticle (chi-MSN) ensemble was fabricated for dual-delivery of BMP-2 and Dex. The MSNs are prepared by a CTAB-templated sol–gel method, and further coated by chitosan via the crosslinking of glycidoxypropyltrimethoxysilane (GPTMS). The small Dex is encapsulated in the mesopores and the large BMP-2 is incorporated into the chitosan coating. These chi-MSNs can quickly release BMP-2 in a bioactive form and can then be efficiently endocytosed and further realize a controlled release of Dex with the decreased pH value into/in cells. With the synergistic action of BMP-2 and Dex outside and inside the cell, this dual hybrid delivery system can significantly stimulate osteoblast differentiation and bone regeneration in vitro and in vivo. Together, this dual-delivery strategy for osteogenic protein delivery may enhance clinical outcomes by retaining the bioactivity and optimizing the release mode of the drug/protein.
Co-reporter:Baolin Huang, Yuan Yuan, Sai Ding, Jianbo Li, Jie Ren, Bo Feng, Tong Li, Yuantong Gu, Changsheng Liu
Acta Biomaterialia 2015 Volume 27() pp:275-285
Publication Date(Web):November 2015
DOI:10.1016/j.actbio.2015.09.007
Abstract
Highly efficient loading of bone morphogenetic protein-2 (BMP-2) onto carriers with desirable performance is still a major challenge in the field of bone regeneration. Till now, the nanoscaled surface-induced changes of the structure and bioactivity of BMP-2 remains poorly understood. Here, the effect of nanoscaled surface on the adsorption and bioactivity of BMP-2 was investigated with a series of hydroxyapatite surfaces (HAPs): HAP crystal-coated surface (HAP), HAP crystal-coated polished surface (HAP-Pol), and sintered HAP crystal-coated surface (HAP-Sin). The adsorption dynamics of recombinant human BMP-2 (rhBMP-2) and the accessibility of the binding epitopes of adsorbed rhBMP-2 for BMP receptors (BMPRs) were examined by a quartz crystal microbalance with dissipation. Moreover, the bioactivity of adsorbed rhBMP-2 and the BMP-induced Smad signaling were investigated with C2C12 model cells. A noticeably high mass-uptake of rhBMP-2 and enhanced recognition of BMPR-IA to adsorbed rhBMP-2 were found on the HAP-Pol surface. For the rhBMP-2-adsorbed HAPs, both ALP activity and Smad signaling increased in the order of HAP-Sin < HAP < HAP-Pol. Furthermore, hybrid molecular dynamics and steered molecular dynamics simulations validated that BMP-2 tightly anchored on the HAP-Pol surface with a relative loosened conformation, but the HAP-Sin surface induced a compact conformation of BMP-2. In conclusion, the nanostructured HAPs can modulate the way of adsorption of rhBMP-2, and thus the recognition of BMPR-IA and the bioactivity of rhBMP-2. These findings can provide insightful suggestions for the future design and fabrication of rhBMP-2-based scaffolds/implants.
Statement of Significance
This study provides strong evidences that nanoscaled HAPs yield extraordinary influence on the adsorption behaviors and bioactivity of rhBMP-2. It has been found that the surface roughness and crystallinity played a crucial role in governing the way of rhBMP-2 binding to HAPs, and thus the conformation, recognition of BMPR-IA and bioactivity of adsorbed rhBMP-2. It is also for the first time to correlate numerical modeling and experimental results of the bioactivity of rhBMP-2 on nanostructured HAPs. This work can pave an avenue for the wider uses of rhBMP-2 in clinical applications and arouse broad interests among researchers in the fields of nano-biotechnology, biomaterials and bone tissue engineering.
Co-reporter:Chengwei Wang, Hua Hong, Zhaofen Lin, Yuan Yuan, Changsheng Liu, Xiaoyu Ma and Xiaoyan Cao
RSC Advances 2015 vol. 5(Issue 126) pp:104289-104298
Publication Date(Web):01 Dec 2015
DOI:10.1039/C5RA22225G
Silver ions were tethered onto amino-functionalized Ca-doped mesoporous silica (CaMSS) via the complexing action of Ag+–NH2 for enhanced antibacterial properties. Fourier-transform infrared (FTIR), transmission electron microscopy (TEM), and energy dispersive spectroscopy (EDS) indicated the successful tethering of silver ions onto CaMSS and the complexing action of amino groups enabled the silver ions to be more stable than when adsorbed without amino groups. Minimum inhibitory concentration (MIC) and growth-curve experiments were utilized to test and compare the time- and concentration-dependent antibacterial capability of silver ions tethered- and adsorbed-CaMSS with Escherichia coli (E. coli) as bacteria model. The results showed that at the same silver ion loading, surface-tethered Ag–CaMSS possessed longer and more efficient (2.5 times lower MIC) antibacterial activity during the whole test period compared to the silver ions-adsorbed CaMSS. But with the increasing amount of amino groups, the antibacterial activity was not obviously changed. Further studies demonstrated that the excellent and sustained antibacterial efficiency of silver-tethered CaMSS should be attributed to the stable amino group-based complexing action with Ag, strong interaction of positively-charged CaMSS surface to negatively-charged bacteria, and the strong inhibition effect of Ag+ and agglomerates of silver chloride localized onto the CaMSS surface. All taken together, this amino group-based tethering method is an effective strategy to load Ag ions for sustained and highly efficient antibacterial activity. This developed Ag–CaMSS is a promising surgical implantation material with excellent antibacterial activity.
Co-reporter:Hengsong Shi, Qi Gan, Xiaowei Liu, Yifan Ma, Jun Hu, Yuan Yuan and Changsheng Liu
RSC Advances 2015 vol. 5(Issue 97) pp:79703-79714
Publication Date(Web):14 Sep 2015
DOI:10.1039/C5RA13334C
Polylactic acid (PLA) has been extensively researched in biomedical engineering applications due to its superior mechanical strength and biocompatibility in vivo. But the inherent brittleness, slow degradability and inferior hydrophilicity greatly hamper its successful application. Here, a biodegradable crosslinked elastomer poly(glycerol sebacate) (PGS) was adapted to modify PLA scaffold for bone tissue engineering in this study. A highly interconnected and large porous, three-dimensional (3D) PLA-based scaffold was prepared by a NaCl particulate-leaching method and the PGS prepolymer (pre-PGS) was introduced either by pre-molding binary blend (B.B) or by surface coating (S.C) of a homogeneous PGS onto PLA-based scaffolds with and without oxygen plasma pretreatment (O.P and D.C). After curing at 130 °C, the resulting PLA/PGS scaffolds all exhibited well interconnected open-cell structures. The incorporation of PGS to PLA both by B.B and S.C could effectively improve the hydrophilicity, degradation, toughness and ductility, and the best efficacy was observed for the S.C with the oxygen plasma pretreatment. Specifically, at the ratio of PLA/PGS 9:1 and 7:3, the fracture strain of the PLA/PGS scaffolds by O.P were improved from 8% (pure PLA) to 13% and 24%, respectively. Further studies indicated that enhanced hydrophilicity and increased surface roughness were the main contributors to the above positive effect of oxygen-based plasma treatment. Additionally, these hybrid PLA/PGS scaffolds exhibited good mineralization, high cell biocompatibility, and enhanced cell adhesion and osteogenic differentiation for bone mesenchymal stem cells (BMSCs), especially for scaffolds by S.C. The present results suggest that the surface coating of PGS with oxygen-based plasma pretreatment is an effective strategy to modify the properties of PLA and the hybrid PLA/PGS scaffold represents a promising candidate in the formulation of bone tissue regeneration.
Co-reporter:Kai Yang, Jing Zhang, Xiaoyu Ma, Yifan Ma, Chao Kan, Haiyan Ma, Yulin Li, Yuan Yuan, Changsheng Liu
Materials Science and Engineering: C 2015 Volume 56() pp:37-47
Publication Date(Web):1 November 2015
DOI:10.1016/j.msec.2015.05.083
•β-TCP/PGS scaffold with robust mechanical property was developed for bone repair.•β-TCP/PGS scaffold was prepared by infiltration and in-situ crosslinking method.•The optimized β-TCP/PGS exhibited enhanced compressive strength and toughness.•PGS polymer could direct the biomineralization and balance the pH change.•β-TCP/PGS scaffolds favored for cell penetration and proliferation.Despite good biocompatibility and osteoconductivity, porous β-TCP scaffolds still lack the structural stability and mechanical robustness, which greatly limit their application in the field of bone regeneration. The hybridization of β-TCP with conventional synthetic biodegradable PLA and PCL only produced a limited toughening effect due to the plasticity of the polymers in nature. In this study, a β-TCP/poly(glycerol sebacate) scaffold (β-TCP/PGS) with well interconnected porous structure and robust mechanical property was prepared. Porous β-TCP scaffold was first prepared with polyurethane sponge as template and then impregnated into PGS pre-polymer solution with moderate viscosity, followed by in situ heat crosslinking and freezing–drying process. The results indicated that the freezing–drying under vacuum process could further facilitate crosslinking of PGS and formation of Ca2 +–COO− ionic complexing and thus synergistically improved the mechanical strength of the β-TCP/PGS with in situ heat crosslinking. Particularly, the β-TCP/PGS with 15% PGS content after heat crosslinking at 130 °C and freezing–drying at − 50 °C under vacuum exhibited an elongation at break of 375 ± 25% and a compressive strength of 1.73 MPa, 3.7-fold and 200-fold enhancement compared to the β-TCP, respectively. After the abrupt drop of compressive load, the β-TCP/PGS scaffolds exhibited a full recovery of their original shape. More importantly, the PGS polymer in the β-TCP/PGS scaffolds could direct the biomineralization of Ca/P from particulate shape into a nanofiber-interweaved structure. Furthermore, the β-TCP/PGS scaffolds allowed for cell penetration and proliferation, indicating a good cytobiocompatibility. It is believed that β-TCP/PGS scaffolds have great potential application in rigid tissue regeneration.Robust β-TCP/PGS porous scaffolds are developed by incorporation of poly(glycerol sebacate) (PGS, a flexible biodegradable polymer) into β-TCP scaffold. By impregnation of β-TCP scaffolds with low viscous PGS pre-polymer solution and further in situ crosslinking, the obtained β-TCP/PGS exhibited 3.7 time improvement in elongation at break and 200 time increase in strength as compared to pure β-TCP scaffolds, overcoming the brittleness of pure β-TCP scaffolds. Meanwhile, the β-TCP/PGS showed good pH auto-regulation ability and cytocompatibility.
Co-reporter:Dan Lin, Kai Yang, Wei Tang, Yutong Liu, Yuan Yuan, Changsheng Liu
Colloids and Surfaces B: Biointerfaces 2015 Volume 131() pp:1-11
Publication Date(Web):1 July 2015
DOI:10.1016/j.colsurfb.2015.04.031
•A PGS-coated MBG hierarchical scaffold for bone repair was designed and prepared.•The physicochemical properties of the PGS/MBG scaffold can be modulated.•Uncrosslinked PGS enhances the compressive strength and toughness of MBG scaffold.•This scaffold combines MBG's osteoinductivity and PGS's proliferation promotion.•Uncrosslinked PGS-induced scaffold comprehensive improvement is first investigated.Various requirements in the field of tissue engineering have motivated the development of three-dimensional scaffold with adjustable physicochemical properties and biological functions. A series of multiparameter-adjustable mesoporous bioactive glass (MBG) scaffolds with uncrosslinked poly(glycerol sebacate) (PGS) coating was prepared in this article. MBG scaffold was prepared by a modified F127/PU co-templating process and then PGS was coated by a simple adsorption and lyophilization process. Through controlling macropore parameters and PGS coating amount, the mechanical strength, degradation rate, controlled-release and cell behavior of the composite scaffold could be modulated in a wide range. PGS coating successfully endowed MBG scaffold with improved toughness and adjustable mechanical strength covering the bearing range of trabecular bone (2–12 MPa). Multilevel degradation rate of the scaffold and controlled-release rate of protein from mesopore could be achieved, with little impact on the protein activity owing to an “ultralow-solvent” coating and “nano-cavity entrapment” immobilization method. In vitro studies indicated that PGS coating promoted cell attachment and proliferation in a dose-dependent manner, without affecting the osteogenic induction capacity of MBG substrate. These results first provide strong evidence that uncrosslinked PGS might also yield extraordinary achievements in traditional MBG scaffold. With the multiparameter adjustability, the composite MBG/PGS scaffolds would have a hopeful prospect in bone tissue engineering. The design considerations and coating method of this study can also be extended to other ceramic-based artificial scaffolds and are expected to provide new thoughts on development of future tissue engineering materials.
Co-reporter:Wei Tang, Yuan Yuan, Dan Lin, Haoyi Niu and Changsheng Liu
Journal of Materials Chemistry A 2014 vol. 2(Issue 24) pp:3782-3790
Publication Date(Web):15 Apr 2014
DOI:10.1039/C4TB00025K
Three-dimensional mesoporous bioglass (3D MBG) scaffolds with mesoporous structures and highly interconnected macroporous networks are considered as ideal biomaterials for skeletal tissue applications. However, their inherent brittleness and poor mechanical strength greatly hamper their performance and clinical application. Here, using a modified polyurethane foam (PU) templating method with utilization of kaolin as binder, a new facile method for preparation of 3D MBG scaffolds with excellent mechanical strength, mineralization ability and desirable cellular response is proposed. The developed hybrid MBG-XK (where X refers to the final dry weight of kaolin in the scaffold) scaffolds with 85% porosity exhibited a high compressive strength from 2.6 to 6.0 MPa with increasing content of kaolin (5–20%), about 100 times higher than that of the traditional PU-template MBG scaffold. With the addition of kaolin, the MBG-10K scaffold exhibited a more stable and desirable pH environment, and an enhanced protein adsorption capacity. Furthermore, with rat bone marrow stromal cells as a model, in vitro cell culture experiments indicated that, compared with MBG, the prepared MBG-XK scaffolds possessed comparable cell proliferation, penetration capacity, enhanced cell attachment and osteogenic differentiation, especially for MBG-10K.
Co-reporter:Yingying Chen;Qin Zhu;Xinghui Cui;Weijun Tang;Heng Yang; Yuan Yuan; Aiguo Hu
Chemistry - A European Journal 2014 Volume 20( Issue 39) pp:12477-12482
Publication Date(Web):
DOI:10.1002/chem.201402530
Abstract
Novel contrast agents were developed through assembling of GdIII-containing metallosurfactant (MS) with biocompatible polyelectrolytes sodium hyaluronate (HA), heparinsodium (HS) and dextran sulfate sodium (DSS). The formed polyelectrolyte–surfactant complexes showed different structural patterns as the charge ratio increased, including spherical aggregates, rod-like aggregates and network patterns in monovalent HA system, while spherical structures emerged in multivalent HS and DSS systems. Energy dispersive spectroscopy analysis and scanning electron microscopy mapping showed the presence of GdIII in these complexes. Inductively coupled plasma atomic emission spectrometry was further used to quantify the contents of GdIII in the assemblies. T1 magnetic resonance imaging showed that these GdIII-loaded complexes exhibited relaxivity of up to 63.81 mM−1 s−1, much higher than that of Ominiscan (4.64 mM−1 s−1). The cytotoxicity test in vitro demonstrated the excellent biocompatibility of these complexes, which is essential for clinical application.
Co-reporter:Yingying Chen, Heng Yang, Weijun Tang, Xinhui Cui, Wei Wang, Xiangyu Chen, Yuan Yuan and Aiguo Hu
Journal of Materials Chemistry A 2013 vol. 1(Issue 40) pp:5443-5449
Publication Date(Web):07 Aug 2013
DOI:10.1039/C3TB20807A
A new Gd(III)-based metallosurfactant with double quaternary-ammonium-containing long alkyl chains was developed and subjected to the miniemulsion polymerization of vinyl monomers, giving nanosized colloids (50–110 nm) with narrow size distribution. The size of the colloid particles can be easily tuned by adjusting the feeding ratio of metallosurfactant to monomer. SEM and XPS analysis showed that the Gd(III) complexes were attached on the surface of the colloids. ICP-AES analysis further quantified the contents of Gd(III) in the miniemulsions. T1 magnetic resonance imaging (MRI) showed that these Gd(III)-loading colloids exhibited relaxivity of up to 22.77 mM−1 s−1, much higher than that of Ominiscan® (4.64 mM−1 s−1).
Co-reporter:Qi Gan, Xunyu Lu, Wenjie Dong, Yuan Yuan, Jiangchao Qian, Yongsheng Li, Jianlin Shi and Changsheng Liu
Journal of Materials Chemistry A 2012 vol. 22(Issue 31) pp:15960-15968
Publication Date(Web):13 Jun 2012
DOI:10.1039/C2JM32020G
Endosomal pH-driven linkage-disintegration is a promising strategy to achieve intracellular delivery and controlled drug release. In this paper, a rapid endosomal pH-sensitive MSNs ensemble (i.e., MCM-TAA-Fe3O4) with magnetic nanoparticle caps was developed by anchoring superparamagnetic Fe3O4 nanoparticles on the pore openings with an acid-labile substituted 1,3,5-triazaadamantane (TAA) group. The functionalized Fe3O4 nanoparticles served as a nanogate to regulate the release pattern and/or dosage of payload. The in vitro release experiment with model dexamethasone showed that the MCM-TAA-Fe3O4 ensembles exhibited quick release at pH 5.0–6.0 and zero release in physiological environment (pH = 7.4). Demonstrated with a MC3T3-E1 model cell line, this hybrid nanomaterial could successfully be endocytosed into cells and then release the encapsulated exogenous cargos into the cytosol. The new rapid endosomal pH-sensitive Fe3O4-capped-MSNs could serve as efficient carriers for intracellular controlled release of therapeutic agents in live cells, and may be potentially applied in clinical disease therapy, especially therapeutics and the metabolic manipulation of cells.
Co-reporter:Qi Gan;Danwei Dai;Jiangchao Qian;Sha Sha
Biomedical Microdevices 2012 Volume 14( Issue 2) pp:259-270
Publication Date(Web):2012 April
DOI:10.1007/s10544-011-9604-9
Due to the unique physicochemical properties and membrane-permeable capacity, mesoporous silica nanoparticles (MSNs) are considered as an ideal carrier for intracellular delivery. Herein, we endeavored to address the size effect of MSNs on the cellular uptake, endosomal escape and controlled release, the key steps for the intracellular delivery. The well-ordered MSNs in the range from 55-nm to 440-nm with similar pore texture were prepared by modified base-catalyzed sol–gel method. With MC3T3-E1 model cell line, the in vitro results indicated that after 12 h cultivation, MSNs within 55 ~ 440 nm could all be internalized into the cells, and further escaped out of the endosomal compartment. The efficiency of the cellular uptake and endosomal escape strongly depended on the particle size, with the best efficiencies from 100-nm MSNs. Furthermore, the MTT results indicated that these MSNs materials were all biocompatible. The controlled release experiments with hydrophobic dexamethasone and hydrophilic vitamin C as models showed that for these small-molecular drugs, the loading amount all mainly determined by the surface area of the MSNs, and the subsequent release of the drug dramatically decreased with the increasing of the particle size. By contrast, the release rate of vitamin C was much quicker than that of the dexamethasone. These findings presented here could provide new means to tailor the size of MSNs and thus to guide the design of MSNs-based intracellular delivery system. Due to the good cell biocompatibility, high cellular uptake and endosomal escape, we conjectured that the 100-nm MSNs are more favorable for the intracellular delivery of drugs in live cells.
Co-reporter:Qi Gan, Xunyu Lu, Yuan Yuan, Jiangchao Qian, Huanjun Zhou, Xun Lu, Jianlin Shi, Changsheng Liu
Biomaterials 2011 32(7) pp: 1932-1942
Publication Date(Web):
DOI:10.1016/j.biomaterials.2010.11.020
Co-reporter:Willard J. Fisher
Science 1921 Vol 53(1367) pp:236
Publication Date(Web):11 Mar 1921
DOI:10.1126/science.53.1367.236
Co-reporter:
Science 1920 Vol 52(1331) pp:8-9
Publication Date(Web):02 Jul 1920
DOI:10.1126/science.52.1331.8
Co-reporter:A. G. Böving
Science 1920 Vol 52(1340) pp:216-217
Publication Date(Web):03 Sep 1920
DOI:10.1126/science.52.1340.216
Co-reporter:
Science 1918 Vol 48(1239) pp:315
Publication Date(Web):27 Sep 1918
DOI:10.1126/science.48.1239.315
Co-reporter:Baolin Huang, Yuan Yuan, Sai Ding, Jianbo Li, Jie Ren, Bo Feng, Tong Li, Yuantong Gu, Changsheng Liu
Acta Biomaterialia (November 2015) Volume 27() pp:275-285
Publication Date(Web):1 November 2015
DOI:10.1016/j.actbio.2015.09.007
Highly efficient loading of bone morphogenetic protein-2 (BMP-2) onto carriers with desirable performance is still a major challenge in the field of bone regeneration. Till now, the nanoscaled surface-induced changes of the structure and bioactivity of BMP-2 remains poorly understood. Here, the effect of nanoscaled surface on the adsorption and bioactivity of BMP-2 was investigated with a series of hydroxyapatite surfaces (HAPs): HAP crystal-coated surface (HAP), HAP crystal-coated polished surface (HAP-Pol), and sintered HAP crystal-coated surface (HAP-Sin). The adsorption dynamics of recombinant human BMP-2 (rhBMP-2) and the accessibility of the binding epitopes of adsorbed rhBMP-2 for BMP receptors (BMPRs) were examined by a quartz crystal microbalance with dissipation. Moreover, the bioactivity of adsorbed rhBMP-2 and the BMP-induced Smad signaling were investigated with C2C12 model cells. A noticeably high mass-uptake of rhBMP-2 and enhanced recognition of BMPR-IA to adsorbed rhBMP-2 were found on the HAP-Pol surface. For the rhBMP-2-adsorbed HAPs, both ALP activity and Smad signaling increased in the order of HAP-Sin < HAP < HAP-Pol. Furthermore, hybrid molecular dynamics and steered molecular dynamics simulations validated that BMP-2 tightly anchored on the HAP-Pol surface with a relative loosened conformation, but the HAP-Sin surface induced a compact conformation of BMP-2. In conclusion, the nanostructured HAPs can modulate the way of adsorption of rhBMP-2, and thus the recognition of BMPR-IA and the bioactivity of rhBMP-2. These findings can provide insightful suggestions for the future design and fabrication of rhBMP-2-based scaffolds/implants.Statement of SignificanceThis study provides strong evidences that nanoscaled HAPs yield extraordinary influence on the adsorption behaviors and bioactivity of rhBMP-2. It has been found that the surface roughness and crystallinity played a crucial role in governing the way of rhBMP-2 binding to HAPs, and thus the conformation, recognition of BMPR-IA and bioactivity of adsorbed rhBMP-2. It is also for the first time to correlate numerical modeling and experimental results of the bioactivity of rhBMP-2 on nanostructured HAPs. This work can pave an avenue for the wider uses of rhBMP-2 in clinical applications and arouse broad interests among researchers in the fields of nano-biotechnology, biomaterials and bone tissue engineering.Nanostructured HAPs induced different adsorption states (adsorption amount and way of binding) of rhBMP-2, and thus the BMPRs-binding availability and bioactivity of adsorbed rhBMP-2. The rough surface (HAP-Pol) not only showed the highest mass-uptake of rhBMP-2, but also achieved an enhanced recruitment of BMPR-IA and up-regulated bioactivity of rhBMP-2.Download high-res image (128KB)Download full-size image
Co-reporter:Yuan Yuan, Dan Lin, Fangping Chen, Changsheng Liu
Journal of Orthopaedic Translation (April 2014) Volume 2(Issue 2) pp:49-55
Publication Date(Web):1 April 2014
DOI:10.1016/j.jot.2013.12.002
Biomedical materials have been developed for facilitating tissue regeneration and healing enhancement. Although research on biomedical materials has made great progress in material innovation and preclinical testing, the bottleneck is their translation from research and development to clinical applications; that is, the current rate of product registration and industrialization is low, which directly affects their clinical applications. In this paper, we introduce the basic features of biomedical materials towards the making of medical products and the experiences of our group in research and clinical translation of biomaterials for bone-tissue regeneration in the last few years. Based on our experience, we propose that the translational medicine platform (TMP) is an effective route to facilitate the progress of biomedical materials from bench to bedside. Moreover, from the viewpoints of scientific technology and management, the functions of TMP were also addressed. Relationships among TMP, research institution, enterprise, and government were also explored from the viewpoints of technological innovation, chemical engineering integration, fund raising, and management. This paper provides a theoretical and practical reference for clinical translation of biomedical materials.
Co-reporter:Qin Zhu, Heng Yang, Yuanyuan Li, Yu Tian, Wei Wang, Weijun Tang, Yuan Yuan and Aiguo Hu
Journal of Materials Chemistry A 2016 - vol. 4(Issue 45) pp:NaN7248-7248
Publication Date(Web):2016/10/12
DOI:10.1039/C6TB01998F
HP-DO3A-based cationic amphiphilic Gd(III) complexes bearing quaternary ammonium salts of different alkyl chain lengths were synthesized. The structures of the intermediates, the ligands and the Gd(III) complexes were characterized by 1H NMR, 13C NMR, ESI and MALDI-TOF mass spectrometry. Relaxation studies of the amphiphilic Gd(III) complexes revealed that long alkyl chains facilitated the formation of micelles in an aqueous solution and afforded high relaxivity. Electrostatic self-assembly of the GdL1 complex with polyacrylate sodium (PAAS) showed significant relaxation enhancement with the relaxivity being up to 20.03 mM−1 s−1 at 1.5 T, which was about 4 times that of the commercial MRI contrast agent, Gd-DTPA. The long hydrophobic chain was found to play an important role in the formation of the self-assembly. Zeta potential and dynamic light scattering measurements were carried out to reveal the aggregation process during the assembly. Good biocompatibility of the complexes and high cell viability were found in HepG-2 and L-02 cells by the MTT assay. The reactive oxygen species (ROS) generation study further confirmed the biocompatibility. In vivo imaging showed significant contrast enhancement in the liver and bladder regions.
Co-reporter:Depeng Song, Shiyuan Sun, Yu Tian, Shuai Huang, Yun Ding, Yuan Yuan and Aiguo Hu
Journal of Materials Chemistry A 2015 - vol. 3(Issue 16) pp:NaN3200-3200
Publication Date(Web):2015/02/17
DOI:10.1039/C4TB02018A
A pH-sensitive acyclic enediyne (1) was synthesized for efficient DNA-cleavage and tumor cell suppression. Unlike other acyclic enediynes, this novel enediyne transforms into a highly reactive enediyne (2) in an acidic environment only, which undergoes Bergman cyclization spontaneously at ambient temperature. An EPR study on the enediyne 2 confirmed the generation of free radicals through Bergman cyclization. The activated enediyne induced DNA-cleavage and exhibited cytotoxicity towards various tumor cells under the action of diradicals arising from spontaneous Bergman cyclization at physiological temperature. These findings suggest a novel strategy of anticancer drug design, where the activation of the silent compound takes place under the acidic environment inside the tumor cells.
Co-reporter:Wei Tang, Yuan Yuan, Dan Lin, Haoyi Niu and Changsheng Liu
Journal of Materials Chemistry A 2014 - vol. 2(Issue 24) pp:NaN3790-3790
Publication Date(Web):2014/04/15
DOI:10.1039/C4TB00025K
Three-dimensional mesoporous bioglass (3D MBG) scaffolds with mesoporous structures and highly interconnected macroporous networks are considered as ideal biomaterials for skeletal tissue applications. However, their inherent brittleness and poor mechanical strength greatly hamper their performance and clinical application. Here, using a modified polyurethane foam (PU) templating method with utilization of kaolin as binder, a new facile method for preparation of 3D MBG scaffolds with excellent mechanical strength, mineralization ability and desirable cellular response is proposed. The developed hybrid MBG-XK (where X refers to the final dry weight of kaolin in the scaffold) scaffolds with 85% porosity exhibited a high compressive strength from 2.6 to 6.0 MPa with increasing content of kaolin (5–20%), about 100 times higher than that of the traditional PU-template MBG scaffold. With the addition of kaolin, the MBG-10K scaffold exhibited a more stable and desirable pH environment, and an enhanced protein adsorption capacity. Furthermore, with rat bone marrow stromal cells as a model, in vitro cell culture experiments indicated that, compared with MBG, the prepared MBG-XK scaffolds possessed comparable cell proliferation, penetration capacity, enhanced cell attachment and osteogenic differentiation, especially for MBG-10K.
Co-reporter:Depeng Song, Yu Tian, Shuai Huang, Baojun Li, Yuan Yuan and Aiguo Hu
Journal of Materials Chemistry A 2015 - vol. 3(Issue 43) pp:NaN8588-8588
Publication Date(Web):2015/09/21
DOI:10.1039/C5TB01867F
An acyclic enediyne with a furyl tethering group and two pH-sensitive orthoester groups at the alkynyl termini was synthesized. The enediyne compound yielded free radicals, which can be further trapped by other atoms, under acidic conditions at ambient temperature. It exhibited high cytotoxicity towards tumor cells, and affected normal cells much less, while showing very low cytotoxicity to both types of cells once the furan group was reacted with a dienophile, 4-phenyl-1,2,4-triazoline-3,5-dione. Confocal laser scanning microscopy experiments showed that the derivation of the furan group dictated the cytosis of the enediyne molecules. The cytotoxicity of the enediyne molecules disappeared when cytosis was hindered. The introduction of a furyl tethering group into enediyne represents a new design strategy of “intelligent” antitumor antibiotics that can distinguish tumor and normal cells.
Co-reporter:Yanjun Chai, Dan Lin, Yifan Ma, Yuan Yuan and Changsheng Liu
Journal of Materials Chemistry A 2017 - vol. 5(Issue 24) pp:NaN4647-4647
Publication Date(Web):2017/05/05
DOI:10.1039/C7TB00505A
With the worldwide rising need of severe bone defect treatment, the development of available bone substitutes with optimal mechanical strength, sustained drug release, cell affinity and osteoinductivity remains a great challenge. In this study, an rhBMP-2 loaded polymer-coated mesoporous bioactive glass (MBG) composite scaffold was developed. The uncrosslinked poly(glycerol sebacate) (PGS) or PEGylated PGS (PEGS) coating modification had enhanced the mechanical strength of the composite scaffold, solved the brittleness problem of the MBG matrix, increased the cell affinity of the material surface, and diminished the initial burst release of rhBMP-2 from mesopores of MBG. The results indicated that the PGS coating promoted the proliferation of rat bone marrow stem cells (rBMSCs), while the PEGS coating exhibited an enhancement in the osteogenic differentiation of rBMSCs. The in vivo ectopic bone formation results provide strong evidence that the rhBMP-2-loaded MBG/PEGS composite scaffolds exhibited a rapid bone forming capacity and might yield extraordinary achievements in the field of bone tissue engineering. The design considerations can be extended to other artificial scaffolds and are expected to provide new thoughts on the development of future tissue engineering materials.
Co-reporter:Bing Duan, Haoyi Niu, Wenjing Zhang, Yifan Ma, Yuan Yuan and Changsheng Liu
Journal of Materials Chemistry A 2017 - vol. 5(Issue 19) pp:NaN3599-3599
Publication Date(Web):2017/04/12
DOI:10.1039/C7TB00041C
The microporous architecture of biomaterials/scaffolds plays a critical role in cellular behaviors of marrow stromal cells in the field of tissue regeneration, but the role of microporous density in this process and its underlying molecular mechanism are poorly understood. In the present work, a series of three-dimensional (3D) trimodal macro/micro/nano-porous MBG scaffolds (TMSs) with different microporous densities were developed to investigate the influence of microporous density on the attachment, proliferation and osteogenic differentiation of rat bone marrow stromal cells (rBMSCs), and the fundamental molecular mechanism was explored. The results demonstrated that scaffolds with micropores significantly promoted initial cell adhesion, ALP activity and osteogenesis-related gene/protein expressions, especially the one with 20% microporous density (TMS 20). We found that the appropriate microporous density modulated the adsorption of fibronectin (Fn), and in turn facilitated integrin receptor binding affinity, focal adhesion complex formation and subsequent FAK/MAPK signaling pathway activation. Based on these studies, it can be confirmed that microporous density contributes to the regulation of cellular response, which can provide a new insight into the design of future bone substitutes in a 3D environment.
Co-reporter:Yingying Chen, Heng Yang, Weijun Tang, Xinhui Cui, Wei Wang, Xiangyu Chen, Yuan Yuan and Aiguo Hu
Journal of Materials Chemistry A 2013 - vol. 1(Issue 40) pp:NaN5449-5449
Publication Date(Web):2013/08/07
DOI:10.1039/C3TB20807A
A new Gd(III)-based metallosurfactant with double quaternary-ammonium-containing long alkyl chains was developed and subjected to the miniemulsion polymerization of vinyl monomers, giving nanosized colloids (50–110 nm) with narrow size distribution. The size of the colloid particles can be easily tuned by adjusting the feeding ratio of metallosurfactant to monomer. SEM and XPS analysis showed that the Gd(III) complexes were attached on the surface of the colloids. ICP-AES analysis further quantified the contents of Gd(III) in the miniemulsions. T1 magnetic resonance imaging (MRI) showed that these Gd(III)-loading colloids exhibited relaxivity of up to 22.77 mM−1 s−1, much higher than that of Ominiscan® (4.64 mM−1 s−1).
Co-reporter:Qi Gan, Jiaoyang Zhu, Yuan Yuan, Honglai Liu, Yihua Zhu and Changsheng Liu
Journal of Materials Chemistry A 2015 - vol. 3(Issue 11) pp:NaN2285-2285
Publication Date(Web):2015/02/18
DOI:10.1039/C5TB00219B
A novel pH-responsive mesocellular foam-based nanocarrier was fabricated by the covalent assembly of a water-soluble N,O-carboxymethyl chitosan via the crosslinking of GPTMS. The delivery systems show excellent protein loading with programmable release in an acid environment. Moreover, the released proteins still preserve their conformational and biological activity.
Co-reporter:Qi Gan, Xunyu Lu, Wenjie Dong, Yuan Yuan, Jiangchao Qian, Yongsheng Li, Jianlin Shi and Changsheng Liu
Journal of Materials Chemistry A 2012 - vol. 22(Issue 31) pp:NaN15968-15968
Publication Date(Web):2012/06/13
DOI:10.1039/C2JM32020G
Endosomal pH-driven linkage-disintegration is a promising strategy to achieve intracellular delivery and controlled drug release. In this paper, a rapid endosomal pH-sensitive MSNs ensemble (i.e., MCM-TAA-Fe3O4) with magnetic nanoparticle caps was developed by anchoring superparamagnetic Fe3O4 nanoparticles on the pore openings with an acid-labile substituted 1,3,5-triazaadamantane (TAA) group. The functionalized Fe3O4 nanoparticles served as a nanogate to regulate the release pattern and/or dosage of payload. The in vitro release experiment with model dexamethasone showed that the MCM-TAA-Fe3O4 ensembles exhibited quick release at pH 5.0–6.0 and zero release in physiological environment (pH = 7.4). Demonstrated with a MC3T3-E1 model cell line, this hybrid nanomaterial could successfully be endocytosed into cells and then release the encapsulated exogenous cargos into the cytosol. The new rapid endosomal pH-sensitive Fe3O4-capped-MSNs could serve as efficient carriers for intracellular controlled release of therapeutic agents in live cells, and may be potentially applied in clinical disease therapy, especially therapeutics and the metabolic manipulation of cells.
Co-reporter:Qi Gan, Jiaoyang Zhu, Yuan Yuan, Honglai Liu, Jiangchao Qian, Yongsheng Li and Changsheng Liu
Journal of Materials Chemistry A 2015 - vol. 3(Issue 10) pp:NaN2066-2066
Publication Date(Web):2014/12/17
DOI:10.1039/C4TB01897D
Bone morphogenetic protein-2 (BMP-2) is considered one of the most effective and extensively used growth factors to induce osteoblast differentiation and accelerate bone regeneration. Dexamethasone (Dex) with suitable dosage can enhance BMP-2-induced osteoblast differentiation. To strengthen this synergistic osteoinductive effect, a pH-responsive chitosan-functionalized mesoporous silica nanoparticle (chi-MSN) ensemble was fabricated for dual-delivery of BMP-2 and Dex. The MSNs are prepared by a CTAB-templated sol–gel method, and further coated by chitosan via the crosslinking of glycidoxypropyltrimethoxysilane (GPTMS). The small Dex is encapsulated in the mesopores and the large BMP-2 is incorporated into the chitosan coating. These chi-MSNs can quickly release BMP-2 in a bioactive form and can then be efficiently endocytosed and further realize a controlled release of Dex with the decreased pH value into/in cells. With the synergistic action of BMP-2 and Dex outside and inside the cell, this dual hybrid delivery system can significantly stimulate osteoblast differentiation and bone regeneration in vitro and in vivo. Together, this dual-delivery strategy for osteogenic protein delivery may enhance clinical outcomes by retaining the bioactivity and optimizing the release mode of the drug/protein.
