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:Jiaoyang Zhu;Baolin Huang;Sai Ding;Wenjing Zhang;Xiaoyu Ma;Haoyi Niu;Yuan Yuan
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;Yuan Yuan
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:Haoqi Tan;Honglei Wang;Yanjun Chai;Yuanman Yu;Hua Hong;Fei Yang;Xue Qu
RSC Advances (2011-Present) 2017 vol. 7(Issue 19) pp:11439-11447
Publication Date(Web):2017/02/13
DOI:10.1039/C6RA27308D
With the development of bone tissue engineering, it is a great challenge to fabricate a bioactive surface which can provide a favourable microenvironment for cell adhesion, migration and osteo-differentiation. Coating the as-prepared substrates with bioactive components is an effective method to induce osteogenesis. In this study, we designed a multi-layered hybrid coating containing hydroxyapatite nanoparticles, heparin and chitosan. Heparin is used to mediate the electrostatic assembly of hydroxylapatite nanoparticles with chitosan, as well as the subsequent recombinant human bone morphogenetic protein-2 (rhBMP-2) loading. Several independent pieces of evidence were provided to indicate the successful fabrication of the hybrid coating. Sustained release of rhBMP-2 by this coating was also achieved. The in vitro biological studies reveal that the hybrid coating system has excellent biocompatibility and can improve the osteo-differentiation especially for rhBMP-2 present on the coating surface. The results demonstrate that the proposed rhBMP-2 loaded hybrid coating can provide a favourable osteogenic microenvironment and has the potential to improve in situ bone repair due to its superior osteoconductivity as well as osteoinductivity.
Co-reporter:Xiaoli Liu;Huan Liu;Xue Qu;Miao Lei
Journal of Materials Science: Materials in Medicine 2017 Volume 28( Issue 10) pp:146
Publication Date(Web):19 August 2017
DOI:10.1007/s10856-017-5956-x
Wound dressings play important roles in the management of wounds, and calcium cross-linked alginate (Ca2+-Alg) is a commonly used hydrogel that is adapted for wound treatment. However, conventional methods for fabricating Ca2+-Alg hydrogels can be tedious and difficult to control because of the rapid Ca2+-induced gelation of alginate. In this study, An electrodeposition method was used to rapidly and controllably fabricate Ca2+-Alg films for wound treatment. Several measures of film growth (e.g., thickness and mass) are shown to linearly correlate to the imposed charge transfer at the electrode. Similarly, this charge transfer was also observed to control important physicochemical wound healing properties such as water uptake and retention capacity. Furthermore, a wound healing animal test was performed to evaluate the performance of this electro-fabricated calcium alginate film for wound treatment. This in vivo study demonstrated that wounds dressed with an electro-fabricated Ca2+-Alg film closed faster than that of untreated wounds. Further, the new dermis tissue that formed was composed of reorganized and stratified epithelial layer, with fully developed connective tissue, hair follicle, sebaceous glands as well as aligned collagen. Therefore, our study indicates that this electrofabrication method for the rapid and controlled preparation of alginate film could provide exciting opportunities for wound treatment. More broadly, this study demonstrates the potential of electrochemistry for the fabrication of high performance polymeric materials.Here we report a rapid and controllable fabrication of free-standing alginate films by coupling anodic electrodeposition with subsequent peeling of deposited materials for wound dressing.Open image in new window
Co-reporter:Baolin Huang, Yu Tian, Wenjing Zhang, Yifan Ma, Yuan Yuan, Changsheng Liu
Colloids and Surfaces B: Biointerfaces 2017 Volume 159(Volume 159) pp:
Publication Date(Web):1 November 2017
DOI:10.1016/j.colsurfb.2017.06.041
•A low amount of fixed Sr (< 10 wt%) promoted the bioactivity of rhBMP-2 upon SCPCs.•The recognition of BMPR-IA to rhBMP-2 was notably promoted on 5SCPC/rhBMP-2.•The expression of BMPR-IA was significantly enhanced in C2C12 cells that cultured on 5SCPC/rhBMP-2.•5SCPC/rhBMP-2 could remarkably activate the Smad1/5/8 and ERK1/2 signaling pathways in C2C12 cells.Preserving and improving osteogenic activity of bone morphogenetic protein-2 (BMP-2) upon implants remains one of the key limitations in bone regeneration. With calcium phosphate cement (CPC) as model, we have developed a series of strontium (Sr)-doped CPC (SCPC) to address this issue. The effects of fixed Sr on the bioactivity of recombinant human BMP-2 (rhBMP-2) as well as the underlying mechanism were investigated. The results suggested that the rhBMP-2-induced osteogenic activity was significantly promoted upon SCPCs, especially with a low amount of fixed Sr (SrCO3 content < 10 wt%). Further studies demonstrated that the Sr-induced enhancement of bioactivity of rhBMP-2 was related to an elevated recognition of bone morphogenetic protein receptor-IA (BMPR-IA) to rhBMP-2 and an increased expression of BMPR-IA in C2C12 model cells. As a result, the activations of BMP-induced signaling pathways were different in C2C12 cells incubated upon CPC/rhBMP-2 and SCPCs/rhBMP-2. These findings explicitly decipher the mechanism of SCPCs promoting osteogenic bioactivity of rhBMP-2 and signify the promising application of the SCPCs/rhBMP-2 matrix in bone regeneration implants.Download high-res image (173KB)Download full-size image
Co-reporter:Yulin Li
Nanoscale (2009-Present) 2017 vol. 9(Issue 15) pp:4862-4874
Publication Date(Web):2017/04/13
DOI:10.1039/C7NR00835J
Bone diseases/injuries have been driving an urgent quest for bone substitutes for bone regeneration. Nanoscaled materials with bone-mimicking characteristics may create suitable microenvironments to guide effective bone regeneration. In this review, the natural hierarchical architecture of bone and its regeneration mechanisms are elucidated. Recent progress in the development of nanomaterials which can promote bone regeneration through bone-healing mimicry (e.g., compositional, nanocrystal formation, structural, and growth factor-related mimicking) is summarized. The nanoeffects of nanomaterials on the regulation of bone-related biological functions are highlighted. How to prepare nanomaterials with combinative bone-biomimicry features according to the bone healing process is prospected in order to achieve rapid bone regeneration in situ.
Co-reporter:Yulin LiYin Xiao, Changsheng Liu
Chemical Reviews 2017 Volume 117(Issue 5) pp:
Publication Date(Web):February 21, 2017
DOI:10.1021/acs.chemrev.6b00654
Although the biological functions of cell and tissue can be regulated by biochemical factors (e.g., growth factors, hormones), the biophysical effects of materials on the regulation of biological activity are receiving more attention. In this Review, we systematically summarize the recent progress on how biomaterials with controllable properties (e.g., compositional/degradable dynamics, mechanical properties, 2D topography, and 3D geometry) can regulate cell behaviors (e.g., cell adhesion, spreading, proliferation, cell alignment, and the differentiation or self-maintenance of stem cells) and tissue/organ functions. How the biophysical features of materials influence tissue/organ regeneration have been elucidated. Current challenges and a perspective on the development of novel materials that can modulate specific biological functions are discussed. The interdependent relationship between biomaterials and biology leads us to propose the concept of “materiobiology”, which is a scientific discipline that studies the biological effects of the properties of biomaterials on biological functions at cell, tissue, organ, and the whole organism levels. This Review highlights that it is more important to develop ECM-mimicking biomaterials having a self-regenerative capacity to stimulate tissue regeneration, instead of attempting to recreate the complexity of living tissues or tissue constructs ex vivo. The principles of materiobiology may benefit the development of novel biomaterials providing combinative bioactive cues to activate the migration of stem cells from endogenous reservoirs (i.e., cell niches), stimulate robust and scalable self-healing mechanisms, and unlock the body’s innate powers of regeneration.
Co-reporter:Xue Qu, Fan He, Haoqi Tan, Yuanman Yu, Akbar Axrap, Meng Wang, Kai Dai, Zheng Zhang, Fei Yang, Shenguo Wang, Joachim Kohn and Changsheng Liu
Journal of Materials Chemistry A 2016 vol. 4(Issue 28) pp:4901-4912
Publication Date(Web):15 Jun 2016
DOI:10.1039/C6TB01262K
Bone regeneration for the treatment of bone diseases represents a major clinical need. Introducing recombinant human bone morphogenetic protein-2 (rhBMP-2) into biomaterials is an extensively used approach to induce osteogenic differentiation and accelerate bone regeneration. However, serious adverse events can occur in the event of an overdose of rhBMP-2. Dexamethasone (DEX) is a synthetic hydrophobic glucocorticoid, which can enhance rhBMP-2-induced osteogenic differentiation by binding to a glucocorticoid receptor intracellularly. In this study, we have developed a multilayered composite coating made of poly(L-lactide-co-glycolide) (PLGA) nanoparticles, heparin and chitosan to deliver DEX and rhBMP-2 dually. The coating can reserve DEX and rhBMP-2 using the building blocks of the PLGA nanoparticles and heparin. Sustained release of DEX and rhBMP-2 by this coating was achieved. Moreover, a flow cytometry assay suggests that the PLGA nanoparticles could be transported across the cell membrane and presumably could improve the intracellular delivery of DEX via cell internalization. The in vitro osteogenesis studies reveal that the dual drug-loaded coating has a synergistic osteogenic differentiation effect on C2C12 myoblasts, as indicated by the upregulation of the alkaline phosphatise activity and osteo-related gene expression. In addition, μCT and histological analysis of the in vivo experiments demonstrate that the dual drug-loaded coating induced more ectopic bone formation than the individual drug-loaded coating. Therefore, this study demonstrates that our coating system can reserve these two drugs and deliver them locally to cells with the ability to induce rapid osteogenic differentiation and bone regeneration synergistically. Compared to other reported DEX/rhBMP-2 delivery systems, our coating system represents a simple, safe and effective dual drug delivery alternative. Moreover, since a layer-by-layer strategy is easily applied onto varying substrates, our coating system can be combined with many commercially available or existing biomaterials to improve their osteogenetic performance.
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: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: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: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: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:Jiankang Qin, Hongyan He, Wenjing Zhang, Fangping Chen and Changsheng Liu
RSC Advances 2016 vol. 6(Issue 57) pp:51914-51923
Publication Date(Web):20 May 2016
DOI:10.1039/C6RA09421J
Incorporation of bioactive molecules, such as bone morphogenetic proteins (rhBMP-2) is an effective way to improve the surface bioactivity and then enhance the osseointegration of the metallic implants. However, preserving/enhancing the osteogenic capacity of rhBMP-2 is still one of the greatest challenges. In this study, electrostatic spraying deposition was applied to construct a biodegradable chitosan coating loaded with rhBMP-2 on hydrophilic SLA-treated titanium disks. A series of analytical tools including scanning electron microscopy, atomic force microscopy, and contact angle measurements were used to characterize the physical/chemical properties of the coatings. The release behaviour of model proteins were compared and regulated for different surfaces. Biological evaluation in terms of cell adhesion, proliferation, and differentiation was done to study the effects of the coating materials/structure on the osteoblast response. In vitro experiments demonstrated the controlled release of proteins from the ES-P-SLA disks and showed that the released rate/concentration could be regulated by the loading amount and the spraying time. Microscopic visualization of the myblast morphology on the ES-P-SLA disks exhibited enhanced cellular adhesion at the initial incubation. MTT testing and ALP activity results confirmed the enhanced proliferation and differentiation of rhBMP-2 over a two-week period. Therefore, we believe the combination of coating properties/rhBMP-2 bioactivity with the surface topography will speed up bone-formation and improve the implant osseointegration. The key technologies developed in this study could be applied for other biomolecules, undoubtedly benefiting the healthcare sector and quality of life.
Co-reporter:Jin'e Wang, Guoying Wang, Yi Sun, Yifeng Wang, Yang Yang, Yuan Yuan, Yulin Li and Changsheng Liu
RSC Advances 2016 vol. 6(Issue 38) pp:31816-31823
Publication Date(Web):21 Mar 2016
DOI:10.1039/C5RA25628C
The development of delivery nanosystems with a high payload, desirable release controllability, and cell responsiveness is important for an efficient and safe cancer therapy. In this study, multifunctional nanohybrids are successfully constructed by self-assembling a pH sensitive poly(N-vinylpyrrolidone) (PVP) onto LAPONITE® with a nanodisk structure (25 nm in diameter and 0.92 nm in thickness) in the absence of any organic solvent. The nanohybrids can effectively encapsulate a cationic anticancer drug, doxorubicin (DOX) through its electrostatic interactions with negatively-charged LAPONITE®. The hydrophobic component (alkane polymeric chain) of PVP can bind to the surface of LAPONITE®, with its hydrophilic components (ketone and tertiary amine residues) as a protective stealth shell for stabilization of the whole system. The deprotonation/protonation switchability of PVP endows the nanohybrids with good pH- and thermo-dual sensitivity in delivery of DOX drug, as compared to that modified with the polyethylene glycol (PEG, a common hydrophilic polymer for improving the stability of nanoparticles). In vitro biological evaluation indicated that the DOX-loaded nanocarriers can be effectively taken up by KB cells (a human epithelial carcinoma cell line), and exhibit uncompromising anticancer cytotoxicity as compared to free DOX, indicating their potential therapeutic delivery application.
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:Jinyang Li;Xue Qu;Gregory F. Payne;Cheng Zhang;Yuxin Zhang;Jianbo Li;Jie Ren;Hua Hong
Advanced Functional Materials 2015 Volume 25( Issue 9) pp:1404-1417
Publication Date(Web):
DOI:10.1002/adfm.201403636
Biology provides a range of materials, mechanisms, and insights to meet the diverse requirements of nanomedicine. Here, a biologically based nanoparticle coating system that offers three characteristic features is reported. First, the coating can be self-assembled through a noncovalent biospecific interaction mechanism between a lectin protein (Concanavalin A) and the polysaccharide glycogen. This biospecific self-assembly enables the coating to be applied simply without the generation of covalent bonds. Second, glycoprotein-based biofunctionality can be incorporated into the coating through the same noncovalent biospecific interaction mechanism. Here, the glycoprotein transferrin is incorporated into the coating since this moiety is commonly used to target cancer cells through a receptor-mediated endocytosis mechanism. Third, the coating can be triggered to disassemble in response to a reduction in pH that is characteristic of endosomal uptake. In a proof-of-concept study, comparing coated and uncoated nanoparticles, model drug-loaded nanoparticles (doxorubicin-loaded mesoporous silica nanoparticles) are prepared and it is observed that the coated nanoparticle has enhanced cytotoxicity for cancer cell lines but attenuated cytotoxicity for noncancerous cell lines. These studies demonstrate that biology provides unique materials and mechanism appropriate to meet the needs for emerging applications in the medical and life sciences.
Co-reporter:Fangping Chen, Xiaoyan Cao, Xiaolong Chen, Jie Wei and Changsheng Liu
Journal of Materials Chemistry A 2015 vol. 3(Issue 19) pp:4017-4026
Publication Date(Web):09 Apr 2015
DOI:10.1039/C5TB00250H
Effective hemorrhage control is vital for reducing mortality after major trauma both in civilian life and in the military. In recent years microporous starch (MS) has been used as a hemostatic agent. However, MS has an insufficient hemostatic capacity to stop severe bleeding. To improve its hemostatic performance, in this study calcium-modified microporous starch (CaMS) was firstly developed via oxidization and self-assembly with calcium ions (Ca2+) on MS, and the hemostasis efficiency and degradation behaviour were evaluated. The results showed that the carboxyl groups and Ca2+ had been modified successfully onto MS. MS and CaMS both initiated the hemostatic response by rapid absorption and swelling due to their porous structure and high surface area. It is noteworthy that CaMS activated an intrinsic pathway of coagulation cascade and induced platelet adhesion because of the modified Ca2+ and carboxyl groups. The synergistic effects of the chemical activation mechanism and physical absorption mechanism resulted in a dramatic improvement in the hemostatic capacity of CaMS, and thus achieved an effective hemorrhage control in rabbit liver and femoral artery injuries. Additionally, the degradation of CaMS was improved greatly by the modification. In conclusion, CaMS effectively improved hemostatic performance and degradability. CaMS is a promising candidate for designing hemostatic agents in more extensive clinical applications.
Co-reporter:Fangping Chen, Zhiyan Song and Changsheng Liu
Journal of Materials Chemistry A 2015 vol. 3(Issue 47) pp:9173-9181
Publication Date(Web):27 Oct 2015
DOI:10.1039/C5TB01453K
The development of injectable calcium phosphate cements (ICPC) represents a promising approach for minimally invasive surgical techniques. However, the undesirable anti-washout property and slow setting time of ICPC greatly hinder its clinical application. Xanthan gum (XG) has strong hydrophilic, shape retention and rheological properties. In this study, a fast setting and anti-washout injectable calcium–magnesium phosphate cement (fa-ICMPC) was developed by introducing XG, as an anti-washout agent, and magnesium phosphate cement (MPC) into calcium phosphate cement (CPC). The bone-regenerative capacity and the bioresorption of the fa-ICMPC were also investigated by injecting it directly into a rabbit thigh bone defect. The result showed that XG imparted anti-washout properties to the fa-ICMPC and enhanced the injectability of the fa-ICMPC. With the protection of thick viscous films formed by XG, the setting of the fa-ICMPC was not disturbed but accelerated due to the synergistic effect of MPC. The result demonstrated that fa-ICMPC was not crumbled and could fill the defects tightly. The newly-formed bone tissue grew into fa-ICMPC along with the degradation of the materials. In short, the fa-ICMPC exhibited potent anti-washout properties, fast setting, improved injectability, good biodegradability and osteoconductivity, and has the potential to repair bone defects by minimal invasive treatment.
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: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:Cheng Zhang;Xue Qu;Jinyang Li;Hua Hong;Jianbo Li;Jie Ren;Gregory F. Payne
Advanced Healthcare Materials 2015 Volume 4( Issue 13) pp:1972-1981
Publication Date(Web):
DOI:10.1002/adhm.201500202
Biology routinely uses noncovalent interactions to perform complex functions that range from the molecular recognition of ligand–receptor binding to the reversible self-assembly/disassembly of hierarchical nanostructures (e.g., virus particles). Potentially, biological materials that offer such recognition and reversible self-assembly functionality can be applied to nanomedicine. Here, polysaccharides with the multifunctional polysaccharide-binding protein Concanavalin A (Con A) are coupled to create a functional nanoparticle coating. This coating is self-assembled in a layer-by-layer format by sequentially contacting a nanoparticle with Con A and the polysaccharide glycogen. In the final assembly step, a galactomannan targeting ligand is self-assembled into the coating. Evidence indicates that the mannose residues of the galactomannan backbone are responsible for assembly into the coating by Con A binding, while the galactose side chain residues are responsible for targeting to the liver-specific asialoglycoprotein receptor (ASGP-R). Binding to ASGP-R induces endocytic uptake, while the low endosomal pH triggers disassembly of the coating and release of the nanoparticle-entrapped drug. In vitro cell studies indicate that the coating confers liver-cell-specific function for both nanoparticle uptake and drug delivery. These studies extend the use of Con A to sugar-mediated and organ-specific targeting, and further illustrate the potential of biologically based fabrication for generating functional materials.
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: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: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:Gang Wu, Jinyang Li, Xue Qu, Yuxin Zhang, Hua Hong and Changsheng Liu
RSC Advances 2015 vol. 5(Issue 58) pp:47010-47021
Publication Date(Web):20 May 2015
DOI:10.1039/C5RA06454F
Precisely controlling the material structure is a high requirement for biological target imprinting. In situ surface imprinting immobilized templates can offer thin-film molecular imprints containing site-directed binding sites on substrates, and therefore is appropriate for biological targets. However, the correlation between the required film thickness for superior imprinting effect and the bulk structure of biological template is not clearly understood. Here we use a series of glycoprotein imprinted films as a model to give a semi-quantitative description for their correlation. Glycoproteins with distinguished molecular sizes including ribonuclease B, glucose oxidase and horseradish peroxidase were used as templates. Covalently immobilizing glycoproteins was achieved by using m-aminophenylboronic acid modified SiO2 or Fe3O4 surface. Dopamine was polymerized onto this surface for glycoprotein imprinting. Varying polymerization time provided a series of thickness tunable imprinting films in nanometer-scale. The binding isotherm study for each glycoprotein imprints with different film thickness was performed. The optimal film thickness for the highest binding capacities and imprinting factors shows a positive correlation with its template size. The each optimized glycoprotein imprints can recognize their template in a simple or complex environment. These results suggest that the thickness of imprinted film should be tailored for matching the geometric size of fixed templates, and reveal the substantial influence of template structure on imprints design.
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: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:Yuxin Zhang, Xue Qu, Jinpeng Yu, Liancai Xu, Zhiqiang Zhang, Hua Hong and Changsheng Liu
Journal of Materials Chemistry A 2014 vol. 2(Issue 10) pp:1390-1399
Publication Date(Web):06 Jan 2014
DOI:10.1039/C3TB21636E
Molecularly imprinted polymers (MIPs) with high binding performance and good selectivity are of interest not only in the field of analytical chemistry, but also in the bio-pharmaceutical industry because of their potential use as affinity sorbents for selectively preparative separation of drug molecules. The choice of a suitable functional monomer for the template molecule plays a key role in the performance of MIPs. Erythromycin (ERY; C37H67NO13; mol wt 733.9), produced by bio-fermentation, is a representative macrolide antibiotic with multiple polar groups. In the present study, 13C NMR spectroscopy for the first time was employed to evaluate the interactions between ERY and a set of functional monomers at the atomic level. Based on the 13C chemical shift changes in the ERY molecular structure when binding with different functional monomers, the optimal monomer of methacrylic acid (MAA) was selected and the rational binding sites were predicted. A sequence regarding the interaction force of these binding sites for MAA was proposed, and Density Functional Theory (DFT) theoretical calculation of Lewis basicity of the O/N atoms located at these sites confirmed its reliability. Molecularly imprinted sorbents (MIAs) for ERY were prepared by a suspension polymerization method using MAA as a functional monomer and ethylene glycol dimethacrylate (EGDMA) as a cross-linker. The effects of the monomer to template ratio and the solvent environment employed during the adsorption on the imprinting efficiency of MIAs were both discussed. The adsorption isotherm of ERY on MIAs was fitted by the Langmuir isotherm model. And the specific selectivity of these materials towards ERY was confirmed. The optimized MIAs as column packing materials can separate ERY from its crystal mother liquid with high recovery and good selectivity, exhibiting a promising capability for productive separation of ERY in a large scale. To the best of our knowledge, these results for the first time indicated that 13C NMR spectroscopy is a simple and effective method for the rational design of MIAs towards complex template molecules. The separation model built in this study represents a novel application of MIPs for future industrial production.
Co-reporter:Fangping Chen;Yuhao Mao
Journal of Materials Science: Materials in Medicine 2013 Volume 24( Issue 7) pp:1627-1637
Publication Date(Web):2013 July
DOI:10.1007/s10856-013-4920-7
Premixed injectable calcium phosphate cement (p-ICPC) pastes have advantages over aqueous injectable calcium phosphate cement (a-ICPC) because p-ICPC remain stable during storage and harden only after placement into the defect. This paper focused on the suspension stability of p-ICPC paste by using fumed silica as a stabilizing agent and propylene glycol (PEG) as a continuous phase. Multiple light scanning techniques were first applied to evaluate the suspension stability. The results indicated that fumed silica effectively enhanced the suspension stability of p-ICPC pastes. The stabilizing effect of fumed silica results from the network structure formed in PEG because of its thixotropy. The p-ICPC could be eventually hydrated to form hydroxyapatite under aqueous circumstances by the unique replacement between water and PEG. p-ICPC (1) not only possesses proper thixotropy and compressive strength but has good injectability as well. p-ICPC (1) was cytocompatible and had no adverse effect on the attachment and proliferation of MG-63 cells in vitro. These observations may have applicability to the development of other nonaqueous injectable biomaterials for non-immediate filling and long-term storage.
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;Yuan Yuan;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:Fan Yang;Jing Wang;Geng Peng;Sichao Fu
Journal of Materials Science: Materials in Medicine 2012 Volume 23( Issue 3) pp:697-710
Publication Date(Web):2012 March
DOI:10.1007/s10856-012-4555-0
A hydrogel which will undergo macroscopic transition responding to redox stimuli is prepared. Mercapto precursors are prepared from 4-armed polyethylene glycol and after deprotection of thiolate anions, they can transform into disulfide crosslinked hydrogels within 3 min by responding to oxidant H2O2. Desirable elasticity is exhibited with a wide range of storage modulus from 50 Pa to 14 kPa through rheological investigation. In addition, the hydrogels are found to be hydrolytically stable but degrade within 75 days when exposed to reductant such as glutathione (GSH). So gelation time and degradation behavior can be regulated by concentrations of precursor, oxidant, reductant, temperature, and pH value. Notably, interest arises from the long-period degradation under low GSH concentration of 0.01 mM that is similar to extracellular level, but not the fast disintegration under high concentration intracellular, providing the possibility of “smart” degradation responding to those cell-secreted biomacromolecules during the process of tissue regeneration. Furthermore, both hydrogels and their degradation products show cell viability above 90% culturing with C2C12 cells, representing nontoxic properties. Such a stimuli-responsive degradation strategy will give promising application in tissue repair and regeneration; especially enable the achievement of matching the degradation kinetics with physiological environment.
Co-reporter:Hua Hong;Jie Wei;Yuan Yuan;Fang-Ping Chen;Jing Wang;Xue Qu;Chang-Sheng Liu
Journal of Applied Polymer Science 2011 Volume 121( Issue 2) pp:855-861
Publication Date(Web):
DOI:10.1002/app.33675
Abstract
With the aim to modify the brittleness of polylactic acid (PLA), it was firstly melt blended with thermoplastic polyurethane (TPU) at six different PLA wt % of 100, 90, 80, 70, 60, and 50 compositions. The properties of PLA/TPU composite were characterized by means of electron microscopy, rheological, mechanical and thermal methods. The results showed that the brittle fracture of pure PLA was gradually transformed into ductile fracture with the addition of the TPU elastomer. The notched impact strength of the composite at 10 wt % TPU was over three times higher than that of pure PLA. The composite was found to be a partially miscible system with shifted glass transition temperatures. The molten blend was shear-thinning fluid and it could be processed by conventional thermoplastic processes such as extrusion and injection molding. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011
Co-reporter:Fangping Chen, Changsheng Liu, Jie Wei, Xiao Chen, Zhen Zhao, Yanli Gao
Materials Chemistry and Physics 2011 Volume 125(Issue 3) pp:818-824
Publication Date(Web):15 February 2011
DOI:10.1016/j.matchemphys.2010.09.050
An ICPC with high structure recoverability and paste stability was successfully developed directly incorporating PEG-6000 into the liquid phase of CPC. The rheological behavior of ICPC was investigated with rheometric scientific ARES902-30004 controlled strain rheometer. Novel approaches of flow rate, shear thinning index (SI), shear stress slowdown (Δτ) and thixotropy loop area have been applied to assess the injectability and structure recoverability of the ICPC paste. The addition of PEG-6000 to ICPC resulted in a thixotrophic structure with shortened setting time, slightly increased viscosity, larger thixotropic hysteresis loop area and lower Δτ, with the improvement largely dependent on the PEG-6000 content. With acceptable injectability and shortened setting time, ICPC (1%) showed the lowest Δτ and the highest SI, endowing the paste good structure recoverability and paste stability. The ICPC (1%) was bioactive and facilitated cell attachment and proliferation. The optimized ICPC (1%) paste with a relatively good structure stability and paste stability may serve as a good candidate for tooth root-canal fillings and percutaneous vertebroplasty in microinvasive surgery.
Co-reporter:Huanjun Zhou;Jie Wei;Xiaohui Wu
Journal of Materials Science: Materials in Medicine 2010 Volume 21( Issue 7) pp:2175-2185
Publication Date(Web):2010 July
DOI:10.1007/s10856-010-4083-8
Mesoporous silica xerogels with various amount of calcium (0, 5, 10 and 15%, named m-SXC0, m-SXC5, m-SXC10 and m-SXC15, respectively) were synthesized by template sol–gel methods, and cell responses to m-SXCs were studied using murine pre-osteoblast MC3T3-E1 in vitro. The results showed that cell morphology was not affected by m-SXCs indicating good biocompatibility. Furthermore, cell proliferation ratio on the m-SXCs increased over time, among which m-SXC10 was highest. NO production obviously rose with the increase of Ca content in m-SXCs. ALP activity and PGE2 level on m-SXC5 significantly improved compared with m-SXC0 while decreased with the increase of Ca content for m-SXC10 and m-SXC15. No obvious discrepancy on osteopontin mRNA expressions was observed among m-SXCs. The collagen I and osteocalcin mRNA expression on m-SXC5 were up-regulated, while decreased on m-SXC15 evidently. The phosphorylation level of ERK 1/2 for the m-SXC10 was highest after 7 days. In conclusion, calcium in m-SXCs plays an important role in osteoblast activity, which indicates mesoporous silica xerogel containing appropriate calcium could stimulate osteoblast proliferation, differentiation, gene expression via the activation of ERK 1/2 signaling pathway, and shows great prospects in bone regeneration field using as a drug controlled release filler.
Co-reporter:Hua Hong;Wenjing Wu
Journal of Applied Polymer Science 2009 Volume 114( Issue 2) pp:1220-1225
Publication Date(Web):
DOI:10.1002/app.30619
Abstract
Chitosan scaffolds have gained much attention in tissue engineering. However, brittleness and low biodegradability limit scaffolds application, especially in use as guided tissue regeneration membranes (GTRm) in surgical operations. The first objective of this work is to improve the brittleness of the chitosan membrane, which is not desired for use via adding polyethylene glycol (PEG) to chitosan, and the second objective is to accelerate the degradation rate by blending gelatin with the binary chitosan-PEG mixture. The addition of PEG softened the blend membrane in vision and in touch. The tensile compliant increased from 7.87 × 10−3 (MPa−1) for chitosan membrane to 3.63 × 10−1 (MPa−1) for chitosan-PEG-gelatin (CPG) membrane. Degradation results in vitro indicated that CPG membrane degraded faster and weight loss increased more significantly than chitosan membrane and the lowest tensile strength of CPG membrane could meet the requirement of the application. CPG membrane showed significant improvement in degradation and flexibility in comparison with the chitosan membrane. Cell adhesion, viability, and proliferation onto the external surface of CPG membrane with C2C12 cell had been evaluated in vitro and quantified by a methyl thiazolyl tetrazolium (MTT) reduction assay. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
Co-reporter:Yuan Yuan, Changsheng Liu, Yuan Zhang, Xiaoqian Shan
Materials Chemistry and Physics 2008 Volume 112(Issue 1) pp:275-280
Publication Date(Web):15 November 2008
DOI:10.1016/j.matchemphys.2008.05.068
In this paper, an array of highly ordered hydroxyapatite (HAP) nanotubes was synthesized by sol–gel auto-combustion method with porous anodic aluminum oxide (AAO) template for the first time. Based on thermogravimetry (DTA/TG), Fourier transform infrared (FTIR) and X-ray diffraction (XRD), the dried gel, derived from the sol solution with Ca(NO3)2·4H2O and PO(CH3O)3 as precursors and ethylene glycol as the polymeric matrix, exhibited a typical self-propagating combustion behavior at low temperature, directly resulting in hexagonal crystalline HAP materials. The resultant HAP arrays fabricated from the above sol–gel in the AAO template were uniformly distributed, highly ordered nanotubes with uniform length and diameter according to the observations of scanning electron microscopy (SEM) and transmission electron microscope (TEM). The electron diffraction (ED), XRD and X-ray photoelectron spectroscopy (XPS) survey proved the formation of HAP phase with polycrystalline structure in the AAO template. Based on these results, a potential mechanism of “an auto-combustion from dried gel to nanoparticles and a subsequent in situ reaction from nanoparticles to nanotubes” was proposed.
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:Yifeng Wang, Jine Wang, Yang Yang, Yi Sun, Yuan Yuan, Yulin Li, Changsheng Liu
Colloids and Surfaces B: Biointerfaces (1 May 2017) Volume 153() pp:
Publication Date(Web):1 May 2017
DOI:10.1016/j.colsurfb.2017.02.033
•Decorating MSN with cationic oligmer (LPEI) affords charge-reversal ability.•LPEI shell is crosslinked to form nanogate with redox-degradability.•The obtained nanohybrids display a pH/redox-sensitive anticancer drug delivery.Although layer-by-layer assembly using anionic and cationic polymer has been a popular way to develop core-shell nanoparticles, the strong electrostatic interactions may limit shell degradability, thus hampering their application as a platform for controlled therapeutic delivery. In this study, we demonstrate a simple approach to developing mesoporous nanohybrids via a process of pre-drug loading (using doxorubicin (DOX) as a model drug) into mesoporous silica nanoparticles (MSN), followed by surface functionalization with a kind of cationic oligomer (low molecular weight polyethylene imine, LPEI) and in situ crosslinking by degradable N,N′-bis(acryloyl)cystamine (BAC). The presence of LPEI shell affords the nanohybrids with charge-reversal ability, which means that the acidic tumor extracellular microenvironment can transform the negative surface charge at neutral conditions into positive-charged ones. The nanohybrids displayed a pH- and redox-dual sensitivity in DOX release under conditions that mimic intracellular reductive conditions and acidic tumor microenvironments. The nanohybrids can be effectively internalized into A549 cells (a carcinomic human alveolar basal epithelial cell line), resulting in a high DOX intracellular accumulation and an improved anticancer cytotoxicity when compared with free DOX, suggesting their high potential as a new platform for therapeutic delivery.
Co-reporter:Lingyan Cao, Yuanman Yu, Jing Wang, Jerome A Werkmeister, Keith M McLean, Changsheng Liu
Materials Science and Engineering: C (1 May 2017) Volume 74() pp:
Publication Date(Web):1 May 2017
DOI:10.1016/j.msec.2016.12.004
•Electrospun PCL fiber scaffold was superfical doped with 2-N, 6-O-sulfated chitosan.•The binding efficiency of BMP-2 was improved, as well as prolonged releasing behavior.•Enhancd osteogenic activity can be acquired ascribed to synergistic effect of 26SCS.The aim of this study was to develop a 2-N, 6-O-sulfated chitosan (26SCS) modified electrospun fibrous PCL scaffold for bone morphogenetic protein-2 (BMP-2) delivery to improve osteoinduction. The PCL scaffold was modified by an aminolysis reaction using ethylenediamine (ED) and 26SCS was immobilized via electrostatic interactions (PCL-N-S). Scaffolds were characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS) and contact angle measurements. In vitro BMP-2 adsorption and release kinetics indicated that modified PCL-N-S scaffolds showed higher levels of binding of BMP-2 (about 30–100 times), moderative burst release (about one third), and prolonged releasing time compared to the unmodified PCL scaffold. The bioactivity of released BMP-2 determined by alkaline phosphatase (ALP) activity assay was maintained and improved 8– 12 times with increasing concentration of immobilized 26SCS on the scaffolds. In vitro studies demonstrated that bone marrow mesenchymal stem cells (BMSCs) attached more readily to the PCL-N-S scaffolds with increased spreading. In conclusion, 26SCS modified PCL scaffolds can be a potent system for the sustained and bioactive delivery of BMP-2.Limited self-regenerating capacity of human body makes the reconstruction of critical size bone defect a significant challenge. Although bone morphogenetic protein-2 (BMP-2) is an important differentiation factor inducing bone regeneration, it's short half-life in vivo and potent side effect at high dosage still show lots of concerns in the clinical use. Herein, modification of electrospun PCL scaffolds was presented through immobilizing of sulfated chitosan (26SCS). The modified scaffolds effectively improve the binding capacity of BMP-2 and exhibited an enhanced bioactivity and sustained release in vitro. Thus, the use of 26SCS modified PCL scaffolds combined with BMP-2 could be a useful scaffold for tissue engineering for osteogenesis.
Co-reporter:Yuxin Zhang, Xue Qu, Jinpeng Yu, Liancai Xu, Zhiqiang Zhang, Hua Hong and Changsheng Liu
Journal of Materials Chemistry A 2014 - vol. 2(Issue 10) pp:NaN1399-1399
Publication Date(Web):2014/01/06
DOI:10.1039/C3TB21636E
Molecularly imprinted polymers (MIPs) with high binding performance and good selectivity are of interest not only in the field of analytical chemistry, but also in the bio-pharmaceutical industry because of their potential use as affinity sorbents for selectively preparative separation of drug molecules. The choice of a suitable functional monomer for the template molecule plays a key role in the performance of MIPs. Erythromycin (ERY; C37H67NO13; mol wt 733.9), produced by bio-fermentation, is a representative macrolide antibiotic with multiple polar groups. In the present study, 13C NMR spectroscopy for the first time was employed to evaluate the interactions between ERY and a set of functional monomers at the atomic level. Based on the 13C chemical shift changes in the ERY molecular structure when binding with different functional monomers, the optimal monomer of methacrylic acid (MAA) was selected and the rational binding sites were predicted. A sequence regarding the interaction force of these binding sites for MAA was proposed, and Density Functional Theory (DFT) theoretical calculation of Lewis basicity of the O/N atoms located at these sites confirmed its reliability. Molecularly imprinted sorbents (MIAs) for ERY were prepared by a suspension polymerization method using MAA as a functional monomer and ethylene glycol dimethacrylate (EGDMA) as a cross-linker. The effects of the monomer to template ratio and the solvent environment employed during the adsorption on the imprinting efficiency of MIAs were both discussed. The adsorption isotherm of ERY on MIAs was fitted by the Langmuir isotherm model. And the specific selectivity of these materials towards ERY was confirmed. The optimized MIAs as column packing materials can separate ERY from its crystal mother liquid with high recovery and good selectivity, exhibiting a promising capability for productive separation of ERY in a large scale. To the best of our knowledge, these results for the first time indicated that 13C NMR spectroscopy is a simple and effective method for the rational design of MIAs towards complex template molecules. The separation model built in this study represents a novel application of MIPs for future industrial production.
Co-reporter:Fangping Chen, Xiaoyan Cao, Xiaolong Chen, Jie Wei and Changsheng Liu
Journal of Materials Chemistry A 2015 - vol. 3(Issue 19) pp:NaN4026-4026
Publication Date(Web):2015/04/09
DOI:10.1039/C5TB00250H
Effective hemorrhage control is vital for reducing mortality after major trauma both in civilian life and in the military. In recent years microporous starch (MS) has been used as a hemostatic agent. However, MS has an insufficient hemostatic capacity to stop severe bleeding. To improve its hemostatic performance, in this study calcium-modified microporous starch (CaMS) was firstly developed via oxidization and self-assembly with calcium ions (Ca2+) on MS, and the hemostasis efficiency and degradation behaviour were evaluated. The results showed that the carboxyl groups and Ca2+ had been modified successfully onto MS. MS and CaMS both initiated the hemostatic response by rapid absorption and swelling due to their porous structure and high surface area. It is noteworthy that CaMS activated an intrinsic pathway of coagulation cascade and induced platelet adhesion because of the modified Ca2+ and carboxyl groups. The synergistic effects of the chemical activation mechanism and physical absorption mechanism resulted in a dramatic improvement in the hemostatic capacity of CaMS, and thus achieved an effective hemorrhage control in rabbit liver and femoral artery injuries. Additionally, the degradation of CaMS was improved greatly by the modification. In conclusion, CaMS effectively improved hemostatic performance and degradability. CaMS is a promising candidate for designing hemostatic agents in more extensive clinical applications.
Co-reporter:Xue Qu, Fan He, Haoqi Tan, Yuanman Yu, Akbar Axrap, Meng Wang, Kai Dai, Zheng Zhang, Fei Yang, Shenguo Wang, Joachim Kohn and Changsheng Liu
Journal of Materials Chemistry A 2016 - vol. 4(Issue 28) pp:NaN4912-4912
Publication Date(Web):2016/06/15
DOI:10.1039/C6TB01262K
Bone regeneration for the treatment of bone diseases represents a major clinical need. Introducing recombinant human bone morphogenetic protein-2 (rhBMP-2) into biomaterials is an extensively used approach to induce osteogenic differentiation and accelerate bone regeneration. However, serious adverse events can occur in the event of an overdose of rhBMP-2. Dexamethasone (DEX) is a synthetic hydrophobic glucocorticoid, which can enhance rhBMP-2-induced osteogenic differentiation by binding to a glucocorticoid receptor intracellularly. In this study, we have developed a multilayered composite coating made of poly(L-lactide-co-glycolide) (PLGA) nanoparticles, heparin and chitosan to deliver DEX and rhBMP-2 dually. The coating can reserve DEX and rhBMP-2 using the building blocks of the PLGA nanoparticles and heparin. Sustained release of DEX and rhBMP-2 by this coating was achieved. Moreover, a flow cytometry assay suggests that the PLGA nanoparticles could be transported across the cell membrane and presumably could improve the intracellular delivery of DEX via cell internalization. The in vitro osteogenesis studies reveal that the dual drug-loaded coating has a synergistic osteogenic differentiation effect on C2C12 myoblasts, as indicated by the upregulation of the alkaline phosphatise activity and osteo-related gene expression. In addition, μCT and histological analysis of the in vivo experiments demonstrate that the dual drug-loaded coating induced more ectopic bone formation than the individual drug-loaded coating. Therefore, this study demonstrates that our coating system can reserve these two drugs and deliver them locally to cells with the ability to induce rapid osteogenic differentiation and bone regeneration synergistically. Compared to other reported DEX/rhBMP-2 delivery systems, our coating system represents a simple, safe and effective dual drug delivery alternative. Moreover, since a layer-by-layer strategy is easily applied onto varying substrates, our coating system can be combined with many commercially available or existing biomaterials to improve their osteogenetic performance.
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, 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, 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.
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:Fangping Chen, Zhiyan Song and Changsheng Liu
Journal of Materials Chemistry A 2015 - vol. 3(Issue 47) pp:NaN9181-9181
Publication Date(Web):2015/10/27
DOI:10.1039/C5TB01453K
The development of injectable calcium phosphate cements (ICPC) represents a promising approach for minimally invasive surgical techniques. However, the undesirable anti-washout property and slow setting time of ICPC greatly hinder its clinical application. Xanthan gum (XG) has strong hydrophilic, shape retention and rheological properties. In this study, a fast setting and anti-washout injectable calcium–magnesium phosphate cement (fa-ICMPC) was developed by introducing XG, as an anti-washout agent, and magnesium phosphate cement (MPC) into calcium phosphate cement (CPC). The bone-regenerative capacity and the bioresorption of the fa-ICMPC were also investigated by injecting it directly into a rabbit thigh bone defect. The result showed that XG imparted anti-washout properties to the fa-ICMPC and enhanced the injectability of the fa-ICMPC. With the protection of thick viscous films formed by XG, the setting of the fa-ICMPC was not disturbed but accelerated due to the synergistic effect of MPC. The result demonstrated that fa-ICMPC was not crumbled and could fill the defects tightly. The newly-formed bone tissue grew into fa-ICMPC along with the degradation of the materials. In short, the fa-ICMPC exhibited potent anti-washout properties, fast setting, improved injectability, good biodegradability and osteoconductivity, and has the potential to repair bone defects by minimal invasive treatment.
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