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  • Development of antibacterial, ciprofloxacin‐eluting biodegradable coatings on Ti6Al7Nb implants to prevent peri‐implant infections
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2020-01-17
    Joanna Jaworska; Katarzyna Jelonek; Marzena Jaworska‐Kik; Monika Musiał‐Kulik; Andrzej Marcinkowski; Janusz Szewczenko; Wojciech Kajzer; Małgorzata Pastusiak; Janusz Kasperczyk

    Various types of biodegradable polymers containing lactide, glycolide, caprolactone, and trimethylene carbonate units have been used to obtain ciprofloxacin (CFX)‐enriched coatings developed on the Ti6Al7Nb alloy, intended for short‐term therapy. In the first step, the surface of the Ti6Al7Nb alloy was modified, mostly according to sandblasting and anodic oxidation to obtain the TiO2 layer. Anodizing can be an effective method for preparing TiO2 coatings with osteoconductive properties. The polymer containing CFX molecules was deposited on the modified alloy, and Polymer + CFX/TiO 2/Ti6Al7Nb systems were developed. CFX‐enriched coatings adhered well to the surface of the previously modified alloy. Polymer layers maintain the topography of the alloy due to the development of the surface during the sandblasting method. As polymers intended for the study possess degradation ability, they are capable of releasing the incorporated drug. Antibacterial activity of CFX‐enriched coatings was examined to verify the functionality of designed Polymer + CFX/TiO 2/Ti6Al7Nb systems, and the bactericidal effect was confirmed for all cases. The presented study is an extension of previous, initial research and creates an overview of polyester or polyestercarbonate CFX‐eluting coatings.

  • Preparation of aminoalkyl‐grafted bacterial cellulose membranes with improved antimicrobial properties for biomedical applications
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2020-01-14
    Wei He; Zhaoyu Zhang; Yudong Zheng; Shen Qiao; Yajie Xie; Yi Sun; Kun Qiao; Zhaoxuan Feng; Xiaoyang Wang; Jialong Wang

    Bacterial cellulose (BC) membranes display special properties and structures, thus attracting much attention in application in the biomedical areas, for example, as implants for bone or cartilage tissue engineering, as substitutes for skin repairing, and as supports for controlled drug delivery. However, native BC lacks the activity to inhibit bacteria growth on its surface, which limits its applications in biomedical fields. There have been reports on chemical modification of BC membranes to endow them with antimicrobial properties needed for some special biomedical applications. In the present study, aminoalkyl‐grafted BC membranes were prepared by alkoxysilane polycondensation using 3‐aminopropyltriethoxysilane (APTES). The characterization for morphology and chemical composition showed that BC membranes were successfully grafted with aminoalkylsilane groups through covalent bonding. The surface morphology and roughness of the membranes changed after chemical grafting. Furthermore, after grafting with APTES, the membranes got less hydrophilic than native BC. The aminoalkyl‐grafted BC membranes showed strong antibacterial properties against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) and moreover, they were nontoxic to normal human dermal fibroblasts (NHDF). These results indicate that aminoalkyl‐grafted BC membranes are potential to be used for biomedical applications.

  • Platelet‐Rich Fibrin Prevents Postoperative Intestinal Adhesion
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2020-01-14
    Jia Wang; Kai Le; Xu Guo; Fengcai Yan; Yifan Guo; Tao Zhang; Yu Ren; Jianlu Zhang; Bin Zhu

    Platelet rich fibrin (PRF) was prepared from the blood of BALB/C inbred mice to explore potential effects on postoperative intestinal adhesion. A murine model of intestinal adhesion characterized by abdominal wall defect/and cecum damage was established by scraping caecum serosa and cutting peritoneum and muscles in the abdominal wall. The wound was covered with PRF (group A), sodium hyaluronate (SH) (group B) or left alone (blank control; group C). All animals were monitored for 28 days. The incidence of adhesion was 35.0%, 66.7% and 73.7% in group A, B and C, respectively. The incidence of adhesion in group A was significantly lower than that in group C (p < 0.05). Histopathologically, severity of fibrosis and the number of fibroblasts or inflammatory cells in group A were lower than those in group B and C (p < 0.05); whereas the number of mesothelial cells was higher (p = 0.001). Furthermore, the severity of fibrosis and number of fibroblasts or inflammatory cells were lower in low grade than those in high grade of adhesion (p < 0.05), whereas the number of mesothelial cells was higher (p < 0.05). Collectively, PRF applied to abdominal surgery may reduce the incidence of intestinal adhesion by promoting proliferation of mesothelial cells whereas inhibiting proliferation of fibroblasts and infiltration of inflammatory cells.

  • Bioengineering strategies for bone and cartilage tissue regeneration using growth factors and stem cells
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-11-12
    Muhammad Qasim; Dong Sik Chae; Nae Yoon Lee

    Bone and cartilage tissue engineering is an integrative approach that is inspired by the phenomena associated with wound healing. In this respect, growth factors have emerged as important moieties for the control and regulation of this process. Growth factors act as mediators and control the important physiological functions of bone regeneration. Herein, we discuss the importance of growth factors in bone and cartilage tissue engineering, their loading and delivery strategies, release kinetics, and their integration with biomaterials and stem cells to heal bone fractures. We also highlighted the role of growth factors in the determination of the bone tissue microenvironment based on the reciprocal signaling with cells and biomaterial scaffolds on which future bone and cartilage tissue engineering technologies and medical devices will be based upon.

  • In vitro and in vivo biocompatibility of calcium‐phosphate scaffolds three‐dimensional printed by stereolithography for bone regeneration
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-11-21
    Laurent Le Guéhennec; Dorien Van hede; Erwan Plougonven; Grégory Nolens; Bruno Verlée; Marie‐Claire De Pauw; France Lambert

    Stereolithography (SLA) is an interesting manufacturing technology to overcome limitations of commercially available particulated biomaterials dedicated to intra‐oral bone regeneration applications. The purpose of this study was to evaluate the in vitro and in vivo biocompatibility and osteoinductive properties of two calcium‐phosphate (CaP)‐based scaffolds manufactured by SLA three‐dimensional (3D) printing. Pellets and macro‐porous scaffolds were manufactured in pure hydroxyapatite (HA) and in biphasic CaP (HA:60‐TCP:40). Physico‐chemical characterization was performed using micro X‐ray fluorescence, scanning electron microscopy (SEM), optical interferometry, and microtomography (μCT) analyses. Osteoblast‐like MG‐63 cells were used to evaluate the biocompatibility of the pellets in vitro with MTS assay and the cell morphology and growth characterized by SEM and DAPI‐actin staining showed similar early behavior. For in vivo biocompatibility, newly formed bone and biodegradability of the experimental scaffolds were evaluated in a subperiosteal cranial rat model using μCT and descriptive histology. The histological analysis has not indicated evidences of inflammation but highlighted close contacts between newly formed bone and the experimental biomaterials revealing an excellent scaffold osseointegration. This study emphasizes the relevance of SLA 3D printing of CaP‐based biomaterials for intra‐oral bone regeneration even if manufacturing accuracy has to be improved and further experiments using biomimetic scaffolds should be conducted.

  • Strategies in cell‐free tissue‐engineered vascular grafts
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-11-06
    Haoyong Yuan; Chunyang Chen; Yuhong Liu; Ting Lu; Zhongshi Wu

    Cardiovascular diseases (CVD) remain the leading cause of morbidity and mortality in the world, among which coronary artery diseases (CAD) are the most common type of CVD. Coronary artery bypass grafting (CABG) using autologous vein and artery grafts is the typical surgical intervention for CAD patients. However, for patients whose autologous grafts are not available, there are no appropriate substitutes for vascular grafts. Investigation of tissue‐engineered vascular graft (TEVG) has persisted over decades with significant advancement, utilizing different types of biomaterials. In the past two decades, a great number of studies based on cell‐seeding strategies were reported. However, limitations of cell‐based strategies made clinical application difficult. With the understanding of stem cells and tissue remodeling process, strategies without cell‐seeding emerged as potential methods to achieve in situ regeneration. A cell‐free graft may recruit host cells and guide their participation in vascular remodeling. The grafts modified by bio‐active molecules showed good results in promoting in situ regeneration and exhibited potential to make the vascular grafts off‐the‐shelf. In this review, the strategies for cell‐free TEVG manufacturing were discussed, including the materials for fabricating TEVGs, the methods of functionalization to promote in situ regeneration, the challenges researchers faced in TEVG investigation, and finally the prospects in TEVG design.

  • Evaluation of effectiveness of 45S5 bioglass doped with niobium for repairing critical‐sized bone defect in in vitro and in vivo models
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-11-07
    Lucas P. L. de Souza; João H. Lopes; Filipe V. Ferreira; Richard A. Martin; Celso A. Bertran; José A. Camilli

    Here, we investigated the biocompatibility of a bioactive sodium calcium silicate glass containing 2.6 mol% Nb2O5 (denoted BGPN2.6) and compare the results with the archetypal 45S5 bioglass. The glass bioactivity was tested using a range of in vitro and in vivo experiments to assess its suitability for bone regeneration applications. in vitro studies consisted of assessing the cytocompatibility of the BGPN2.6 glass with bone‐marrow‐derived mesenchymal stem cells (BM‐MSCs). Systemic biocompatibility was verified by means of the quantification of biochemical markers and histopathology of liver, kidneys, and muscles. The glass genotoxicity was assessed using the micronucleus test. The regeneration of a calvarial defect was assessed using both qualitative and quantitative analysis of three‐dimensional microcomputed tomography images. The BGPN2.6 glass was not cytotoxic to BM‐MSCs. It is systemically biocompatible causing no signs of damage to high metabolic and excretory organs such as the liver and kidneys. No mutagenic potential was observed in the micronucleus test. MicroCT images showed that BGPN2.6 was able to nearly fully regenerate a critical‐sized calvarial defect and was far superior to standard 45S5 Bioglass. Defects filled with BGPN2.6 glass showed over 90% coverage compare to just 66% for 45S5 Bioglass. For one animal the defect was completely filled in 8 weeks. These results clearly show that Nb‐containing bioactive glasses are a safe and effective biomaterial for bone replacement.

  • Sustained release of silibinin‐loaded chitosan nanoparticle induced apoptosis in glioma cells
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-11-11
    Maryam Alipour; Mohammad reza Bigdeli; Hadi Aligholi; Bahram Rasoulian; Mojtaba Khaksarian

    In this study, a chitosan nanoparticle formulation was synthesized for loading silibinin as a sustained‐release drug system to evaluate its effects on apoptosis in C6 glioma cells. This synthesized nanoparticle was analyzed by measurement methods including Fourier transform infrared (FTIR), field emission‐scanning electron microscopy (FE‐SEM), dynamic light scattering (DLS), X‐ray diffraction (XRD), and differential scanning calorimetry (DSC). The formation and amorphization of nanoparticle were confirmed by FTIR and XRD analysis, respectively. The mean diameter of silibinin‐loaded chitosan nanoparticles (SCNP) was 50 ± 7 and 188.6 ± 0.17 nm by using FE‐SEM and DLS, respectively. In addition, the positive zeta potential of nanoparticles was +11.5. Rhodamine‐conjugated SCNP analysis showed the internalization of silibinin to C6 glioma cells. The cytotoxicity assay indicated that the nanoformulation of silibinin was toxic to C6 glioma cells. Although SCNP significantly increased the expression of the both apoptotic genes in C6 cells, Bax and caspase3, it did not have any significant effect on the level of the antiapoptotic gene, Bcl2. In contrast, SCNP did not have any toxic effect on H9C2 cells. In conclusion, the results of the current study indicated that SCNP can be considered as a sustained‐release drug system for future cell‐based therapeutic strategies.

  • Role of implants surface modification in osseointegration: A systematic review
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-11-14
    Yu Liu; Björn Rath; Markus Tingart; Jörg Eschweiler

    Long‐term and stable fixation of implants is one of the most important points for a successful orthopedic surgery in the field of endoprosthesis. Osseointegration (OI), functional connection between bone and implants, is considered as a pivotal process of cementless implant fixation and integration, respectively. OI is affected by various factors of which the property of implants is of high significance. The modification of implants surface for better OI has raised increasing attention in modern orthopedic medicine. Here, the process of OI and the interactions between implants and ambient bone tissues were emblazed. The knowledge regarding the contemporary surface modification strategies was systematically analyzed and reviewed, including materials used for the fabrication of implants, advanced modification techniques, and key factors in the design of porous implants structure. We discussed the superiority of current surface modification programs and concluded that the problems remain to be solved. The primary intention of this systematic review is to provide comprehensive reference information and an extensive overview for better fabrication and design of orthopedic implants.

  • A comparative study on solubility improvement of tetracycline and dexamethasone by poly(propylene imine) and polyamidoamine dendrimers: An insight into cytotoxicity and cell proliferation
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-11-14
    Faezeh Najafi; Mehdi Salami‐Kalajahi; Hossein Roghani‐Mamaqani; Amir Kahaie‐Khosrowshahi

    Many of new chemical discovered in pharmaceutical industry are hydrophobic compounds. Various techniques have been used to overcome solubility problems of hydrophobic drugs in aqueous media. In the meantime, dendrimers have been considered for sustainability, nanoscale size, high carry capacity, tunable terminal functional groups in terms of drug delivery and solubility. In this work, we have synthesized poly(propylene imine) (PPI) dendrimer up to fifth generation using reduction of nitrile groups after Michael addition and also, polyamidoamine (PAMAM) dendrimer up to fourth generation using Michael addition and amidation reactions. fourth and fifth generations of PPI dendrimer and fourth and third generations of PAMAM dendrimer in different concentrations were used to evaluate the solubility of two hydrophobic drugs (tetracycline and dexamethasone). Furthermore, cytotoxicity of dendrimers and dendrimers/drugs hybrids was studied. The results showed that with increasing concentrations and also the generation of dendrimers, the solubility of these two hydrophobic drugs was increased. Cytotoxicity study through MTT assay against Osteoblast‐like cell line (MG‐63 cells) showed that dendrimers were relatively cytotoxic where adding dexamethasone caused higher cytotoxicity. However, tetracycline showed no significant effect on cytotoxicity whereas prevented cell proliferation.

  • Functional comparison of beating cardiomyocytes differentiated from umbilical cord‐derived mesenchymal/stromal stem cells and human foreskin‐derived induced pluripotent stem cells
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-11-22
    Pallavi Pushp; Bijayalaxmi Sahoo; Frederico C. Ferreira; Joaquim M. Sampaio Cabral; Ana Fernandes‐Platzgummer; Mukesh K. Gupta
  • Phosphate functionalization and enzymatic calcium mineralization synergistically enhance oligo[poly(ethylene glycol) fumarate] hydrogel osteoconductivity for bone tissue engineering
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-11-26
    Matthew N. George; Xifeng Liu; Alan Lee Miller; Haocheng Xu; Lichun Lu

    A current approach in bone tissue engineering is the implantation of polymeric scaffolds that promote osteoblast attachment and growth as well as biomineralization. One promising polymer is oligo[poly(ethylene glycol) fumarate] (OPF), a polyethylene glycol‐based material that is biocompatible, injectable, and biodegradable, but in its native form does not support robust bone cell attachment or growth. To address this issue, this study evaluated the osteoconductivity of bis[02‐(methacryloyloxy)ethyl] phosphate (BP) functionalized OPF hydrogels (OPF‐BP) using MC3T3‐E1 pre‐osteoblast cells, both before and after enzymatic mineralization with a calcium solution. The inclusion of negatively charged functional groups allowed for the tailored uptake and release of calcium, while also altering the mechanical properties and surface topography of the hydrogel surface. In cell culture, OPF‐BP hydrogels with 20 and 30% (w/w) BP optimized osteoblast attachment, proliferation, and differentiation after a 21‐day in vitro period. In addition, the OPF‐BP30 treatment, when mineralized with calcium, exhibited a 128% increase in osteocalcin expression when compared with the non‐mineralized treatment. These findings suggest that phosphate functionalization and enzymatic calcium mineralization can act synergistically to enhance the osteoconductivity of OPF hydrogels, making this processed material an attractive candidate for bone tissue engineering applications.

  • Local application of alendronate controls bone formation and β‐tricalcium phosphate resorption induced by recombinant human bone morphogenetic protein‐2
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-11-23
    Seiichiro Kitasato; Takaaki Tanaka; Masaaki Chazono; Hirokazu Komaki; Atsuhito Kakuta; Naoya Inagaki; Shoshi Akiyama; Keishi Marumo

    This study examined the ability of local alendronate (ALN) administration to control β‐tricalcium phosphate (β‐TCP) resorption as well as the induction of bone formation by recombinant human bone morphogenetic protein‐2 (rhBMP‐2). A 15‐mm critical‐sized bone defect was created in the diaphysis of rabbit ulnae. Nine female rabbits (4 to 5 months‐old) were divided into 3 groups. Group 1 (n = 6 ulnae) animals received implants consisting of β‐TCP granules and 25 μg of rhBMP‐2 in 6.5% collagen gel. Group 2 (6 ulnae) and Group 3 (6 ulnae) animals received the same implants, but with 10−6 M and 10−3 M ALN‐treated TCP granules, respectively. Two weeks postsurgery, tartrate‐resistant acid phosphatase‐positive cell counts, new bone formation, and residual β‐TCP were evaluated. This study showed that a high dose of ALN strongly reduced osteoclastic resorption of β‐TCP induced by rhBMP‐2, resulting in decreased bone formation. In contrast, a low dose of ALN slightly reduced the bone resorptive effect but increased bone formation. These results suggest that osteoclast‐mediated resorption plays an important role in bone formation and a coupling‐like phenomenon could occur in the β‐TCP‐implanted area, and that administration of a low dose of ALN may solve clinical bone resorptive problems induced by rhBMP‐2.

  • An oriented hydroxyapatite film with arrayed plate‐like particles enhance chondrogenic differentiation of ATDC5 cells
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-11-20
    Hiroaki Komuro; Wit Y. Wint; Naohiro Horiuchi; Kosuke Nozaki; Tetsuo Sasano; Michiyo Miyashin; Kimihiro Yamashita; Akiko Nagai

    Osteochondral defects of articular cartilage cannot regenerate spontaneously. For its surgical treatment, advancements in cartilage tissue engineering have particularly focused on subchondral bone lesions that tend to delay healing. Therefore, it is important to understand interactions between subchondral bone and chondrocytes. This study aimed to investigate the behavior of chondrogenic ATDC5 cells on oriented hydroxyapatite (HAp) films that mimic bone surfaces. HAp nanoparticles prepared herein were needle like and plate like. HAp films were formed through self‐organization of the nanoparticles and had 2D structures regularly arrayed with the particles. Both films prominently comprised a‐plane orientation surfaces but differed in the degree of hydrophilicity because of the patterns of particle self‐assembly. ATDC5 cells cultured on the HAp film with plate‐like particles could adhered in a shorter period but could not spread. The adhesive force of cells was weaker with the hydrophilic surface than with other surfaces, as determined using a trypsin‐based cell detachment assay. In addition, ATDC5 cells displayed enhanced proliferation and chondrogenic differentiation. Our results suggest that the oriented HAp film formed using plate‐like particles provided chondrogenic cells with a desired scaffold as that of subchondral bone to increase cell proliferation and differentiation.

  • Exosome loaded alginate hydrogel promotes tissue regeneration in full‐thickness skin wounds: An in vivo study
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-11-20
    Shilan Shafei; Mehdi Khanmohammadi; Reza Heidari; Hossein Ghanbari; Vajihe Taghdiri Nooshabadi; Saeed Farzamfar; Mostafa Akbariqomi; Nafiseh S. Sanikhani; Moloud Absalan; Gholamreza Tavoosidana
  • Bioactive glass‐containing hydrogel delivery system for osteogenic differentiation of human dental pulp stem cells
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-11-18
    Sevda P. Sevari; Faezeh Shahnazi; Chider Chen; John C. Mitchell; Sahar Ansari; Alireza Moshaverinia

    Osteoconductive hydrogels can be fabricated by incorporating necessary growth factors and bioactive particles or simply utilizing the ability of the hydrogel itself to induce bone regeneration. The osteogenic inductive potential of the bioactive glass microparticles (BG MPs) has been well‐studied. However, the role of the hydrogel embedding the BG MPs on the osteogenic differentiation of the encapsulated stem cells has not been well established. Moreover, it has been reported that the dental pulp stem cell (DPSC) has the capability of regenerating the craniofacial bone tissue when receiving the necessary osteogenic signals from the microenvironment. In the current study, we have fabricated a composite hydrogel based on alginate and Matrigel containing BG MPs and evaluated the role of the BG MPs and Matrigel on osteogenic differentiation of the encapsulated DPSCs. Our results confirmed that presence of Matrigel enhances the osteogenic differentiation of the DPSCs regardless of the decrease in elasticity of the hydrogel in presence of the BG MPs. This strategy of modifying the microenvironment can be a promising approach for craniofacial bone tissue engineering.

  • Cholesterol grafted cationic lipopolymers: Potential siRNA carriers for selective chronic myeloid leukemia therapy
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-11-26
    KC Remant; Bindu Thapa; Juliana Valencia‐Serna; Suraj S. Domun; Cailean Dimitroff; Xiaoyan Jiang; Hasan Uludağ

    Synthetic siRNA technology has emerged as a promising approach for molecular therapy of cancer but, despite its potential for post‐transcriptional gene silencing, there is an urgent need to develop efficient delivery systems particularly for difficult‐to‐transfect, anchorage‐independent cells. In this study, we designed highly hydrophobic cationic lipopolymers by grafting cholesterol (Chol) onto low‐molecular weight (0.6, 1.2, and 2.0 kDa) polyethylenimines (PEIs) to enable specific siRNA therapy to chronic myeloid leukemia (CML) cells. The siRNA binding by PEI‐Chol led to nano‐sized (100–200 nm diameter) polyplexes with enhanced ζ‐potential (+20 to +35 mV) and ability to protect the loaded siRNA completely in fresh serum. The siRNA delivery to CML (K562) cells was proportional to degree of substitution and, unexpectedly, inversely proportional to molecular size of the polymeric backbone. Chol grafting with as little as ~1.0 Chol/PEI on 0.6 and 1.2 kDa PEIs enabled silencing of the reporter Green Fluorescent Protein gene as well as the endogenous BCR‐Abl oncogene in K562 cells. The PEI‐Chol mediated delivery of siRNAs specific for BCR‐Abl and KSP genes significantly arrested the growth the cells which was significantly reflected in colony formation potency of K562 cells. BCR‐Able siRNA mediated therapeutic efficacy was also observed in significantly increased caspase activity and apoptosis of K562 cells. Thus, Chol‐grafted low‐molecular weight PEIs appear to be unique siRNA carriers to realize the molecular therapy in CML cells.

  • A step toward engineering thick tissues: Distributing microfibers within 3D printed frames
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-24
    Joseph Molde; Joseph A. M. Steele; Alexandra K. Pastino; Anisha Mahat; N. Sanjeeva Murthy; Joachim Kohn
  • The characteristic regulation of gene expression Lbp and Sod3 in peri‐implant connective tissue of rats
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-11-22
    Takafumi Kobayashi; Hodaka Sasaki; Yosuke Asami; Gentaro Mori; Masao Yoshinari; Yasutomo Yajima

    The aim of this study was to investigate the characteristic gene expression profile and localization of peri‐implant connective tissue (PICT) compared with those of periodontal connective tissue (PCT) and oral mucosal connective tissue (OMCT). Upper first molar of 5‐week‐old rats were extracted and titanium implant were placed for PICT group. PCT and OMCT were used as control. Laser microdissected connective tissue at 4 weeks used for microarray analysis. The expression and localization of selected genes were confirmed by quantitative real‐time PCR (qRT‐PCR) and immunohistochemistry. Approximately, 1000 genes of upregulated and downregulated in PICT compared with PCT and OMCT were recognized. Based on the results of microarray analysis and qRT‐PCR were demonstrated lipopolysaccharide binding protein (Lbp) as a specific upregulated gene and superoxide dismutase 3 (Sod3) as a specific downregulated gene in PICT. Immunoreaction of LBP and F4/80 as macrophage marker localized to subepithelial and implant facing connective tissue in PICT. SOD3 expression was not observed in PICT, reactive oxygen species, a target of superoxide dismutase, was strongly and locally expressed in all three tissues. Our data suggested that the upregulation of Lbp and downregulation of Sod3 are as characteristic gene expression pattern in PICT.

  • Layer‐by‐layer assembled PLGA nanoparticles carrying miR‐34a cargo inhibit the proliferation and cell cycle progression of triple‐negative breast cancer cells
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-11-26
    Chintan H. Kapadia; Stephen A. Ioele; Emily S. Day

    Triple‐negative breast cancer (TNBC) accounts for 15–25% of diagnosed breast cancers, and its lack of a clinically defined therapeutic target has caused patients to suffer from earlier relapse and higher mortality rates than patients with other breast cancer subtypes. MicroRNAs (miRNAs) are small non‐coding RNAs that regulate the expression of multiple genes through RNA interference to maintain normal tissue function. The tumor suppressor miR‐34a is downregulated in TNBC, and its loss‐of‐expression correlates with worse disease outcomes. Therefore, delivering miR‐34a mimics into TNBC cells is a promising strategy to combat disease progression. To achieve this goal, we synthesized layer‐by‐layer assembled nanoparticles (LbL NPs) comprised of spherical poly(lactic‐co‐glycolic acid) cores surrounded by alternating layers of poly‐L‐lysine (PLL) and miR‐34a. TNBC cells internalized these LbL NPs to a greater extent than polyplexes comprised of PLL and miRNA, and confocal microscopy showed that LbL NPs delivered a substantial fraction of miR‐34a cargo into the cytosol. This yielded robust suppression of the miR‐34a target genes CCND‐1, Notch‐1, Bcl‐2, Survivin, and MDR‐1, which reduced TNBC cell proliferation and induced cell cycle arrest. These data validate that miR‐34a delivery can impair TNBC cell function and support continued investigation of this platform for treatment of TNBC.

  • Dose‐dependent cytotoxicity induced by pristine graphene oxide nanosheets for potential bone tissue regeneration
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-04
    Xiliu Zhang; Changbo Wei; Yiming Li; Ye Li; Guanhui Chen; Yi He; Chen Yi; Chao Wang; Dongsheng Yu

    This study was aimed to investigate the toxic effects of pristine graphene oxide (GO) nanosheets on bone‐marrow‐derived mesenchymal stem cells (BMSCs), a type of traditional seed cells in tissue regeneration engineering. First, a GO suspension was prepared and characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, and Raman shifts. Then, rat BMSCs were isolated and characterized. Subsequently, cell proliferation, membrane integrity, cell cycle, cell apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) were measured. In addition, relevant proteins of the mitochondrial apoptotic pathway and autophagy were analyzed. Our results showed that a high concentration of GO inhibited cell viability and membrane integrity, while cell apoptosis and cell‐cycle arrest were induced by GO. Further, GO significantly increased ROS generation and MMP loss with an upregulation of Cleaved Caspase‐3, LC3‐II/I, and Beclin‐1 and a downregulation of Bcl‐2 and Caspase3. We concluded that the toxic effects of GO on BMSCs occurred in a dose‐dependent manner via the mitochondrial apoptotic pathway and autophagy.

  • Bone regeneration using β‐tricalcium phosphate (β‐TCP) block with interconnected pores made by setting reaction of β‐TCP granules
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-11-28
    Tansza S. Putri; Koichiro Hayashi; Kunio Ishikawa

    We fabricated an interconnected dual porous β‐tricalcium phosphate (β‐TCP) block via a setting reaction of β‐TCP granules. This β‐TCP block was unique because it exhibits a fully interconnected macroporous structure with micropores in the walls surrounding macropores and a roughened surface. The porosity and diametral tensile strength of the resulting product were 58.1 ± 1.7% and 1.4 ± 0.2 MPa, respectively. Rabbit distal femur bone defects were reconstructed using the porous β‐TCP block and the efficacy of the porous β‐TCP block as an artificial bone substitute was evaluated histomorphometrically. For a dense β‐TCP control, 4 weeks following implantation, only 0.2 ± 0.1% of the β‐TCP was resorbed, and the amount of newly formed bone was limited (0.1 ± 0.1%), whereas when the defect was reconstructed with porous β‐TCP, 9.2 ± 3.1% was resorbed, and the amount of new bone was 18.9 ± 5.5%. This represents an approximately 50‐fold enhancement in resorption and a 200‐fold increase in bone formation for our porous β‐TCP block. Therefore, interconnected dual porous β‐TCP made via β‐TCP granule setting has good potential as an artificial bone substitute.

  • Sintering of magnesium‐strontium doped hydroxyapatite nanocrystals: Towards the production of 3D biomimetic bone scaffolds
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-11-30
    Francesca Scalera; Barbara Palazzo; Amilcare Barca; Francesca Gervaso
  • Enhanced osteogenesis of honeycomb β‐tricalcium phosphate scaffold by construction of interconnected pore structure: An in vivo study
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-02
    Teliang Lu; Shenglei Feng; Fupo He; Jiandong Ye

    Pore structure plays an important role in the in vivo osteogenesis for bone repair materials. In this study, honeycomb β‐tricalcium phosphate (β‐TCP) scaffolds were prepared by extrusion method, and gelatin microspheres were used as porogens to modify the pore structure of the scaffolds. The honeycomb β‐TCP scaffolds were characterized by channel‐like square macropores and unidirectional interconnection. To improve the pore interconnectivity of the scaffold, the spherical pores were formed in the channel walls by burning off the gelatin microspheres. Compared with unidirectional honeycomb β‐TCP scaffold, the honeycomb β‐TCP scaffold with interconnected pore structure had significantly higher porosity and faster degradation rate, at the expense of the mechanical strength. The in vivo assessment results demonstrated excellent osteogenesis of the honeycomb scaffolds. Moreover, the honeycomb β‐TCP scaffold with interconnected pore structure markedly promoted new bone formation in comparison with the unidirectional honeycomb β‐TCP scaffold. This work provides a new approach to prepare scaffolds with interconnected pore structure, and the honeycomb β‐TCP scaffold with interconnected pore structure is expected to serve as an efficient bone repair material.

  • Development of a chitosan hydrogel containing flavonoids extracted from Passiflora edulis leaves and the evaluation of its antioxidant and wound healing properties for the treatment of skin lesions in diabetic mice
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-04
    Rita D. F. Soares; Maria G. N. Campos; Gislaine P. Ribeiro; Bruno C. C. Salles; Naiane S. Cardoso; Julia R. Ribeiro; Raphaela M. Souza; Krissia C. Leme; Caroline B. Soares; Carla M. de Oliveira; Lilian B. Elston; Clodoaldo C. P. da Fonseca; Eric B. Ferreira; Maria R. Rodrigues; Stella M. S. Duarte; Fernanda B. A. Paula

    This study aimed to develop a chitosan‐based hydrogel containing a mixture of flavonoids isolated from the leaves of Passiflora edulis Sims and to evaluate its stability, antioxidant properties, and wound healing effects on cutaneous lesions in diabetic rats. in vitro studies were carried out to evaluate the biocompatibility and flavonoid release from the chitosan hydrogel. in vivo wound healing studies were conducted on male Wistar rats, where the injured tissue was removed for histological analysis and determination of lipid peroxidation, superoxide dismutase activity, and glutathione peroxidase activity. From the histological analysis and macroscopic evaluation of the contraction of the wounds, it was observed that the formulation presented wound healing properties. In addition, treatment of the wound with the formulation stimulated the antioxidant defense system, suggesting a beneficial effect during the treatment of skin lesions in diabetic rats, especially in the first few days after wounding. According to these results, we can conclude that the chitosan hydrogel containing the flavonoid analyzed in this study has potential use as dressings in the treatment of wounds.

  • Primary osteoblasts, osteoblast precursor cells or osteoblast‐like cell lines: Which human cell types are (most) suitable for characterizing 45S5‐bioactive glass?
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-04
    Sebastian Wilkesmann; Jörg Fellenberg; Qaisar Nawaz; Bruno Reible; Arash Moghaddam; Aldo R. Boccaccini; Fabian Westhauser

    The question how bioactive glasses (BGs) influence the viability and osteogenic differentiation of human osteogenic cells has already been addressed by several studies. However, a literature review revealed great differences in the type of cells used for these experiments. Primary human osteoblasts (hOBs) represent the desired standard, but possess the limitation of patient variability and time‐consuming isolation protocols. Therefore, several alternative cell types have been used including primary mesenchymal stromal cells (BMSCs) and the “osteoblast‐like” cell lines MG‐63, Saos‐2, HOS, and U2OS. The aim of our study was the identification of the cell type most suitable for tissue engineering projects involving BGs by comparative analysis of cell viability and osteogenic differentiation in response to crystallized 45S5‐BG. We observed that hOBs, BMSCs, and MG‐63 cells were resistant to 45S5‐BG induced cytotoxicity, while the viability of Saos‐2, HOS, and U2OS cells was significantly reduced. In addition, we detected alkaline phosphatase activity, except in U2OS cells, that increased upon 45S5‐BG cocultivation, demonstrating the induction of osteogenic differentiation. Our data and the fact that the donor‐dependent variations can be avoided when using MG‐63 cells suggest that these are a promising alternative to primary cells and remain an important cell line for future BG related studies.

  • Effect of matrix stiffness and adhesion ligand density on chondrogenic differentiation of mesenchymal stem cells
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-19
    Xintang Zhan

    Adhesion ligands and mechanical properties of extracellular matrix (ECM) play significant roles in directing mesenchymal stem cells' (MSCs) behaviors, but how they affect chondrogenic differentiation of MSCs has rarely been studied. In this study, we investigated the effects of matrix stiffness and adhesion ligand density on proliferation and chondrogenic differentiation of MSCs by using UV crosslinked hydrogels comprised of methacrylated gelatin (GelMA) and poly(ethylene glycol) diacrylate (PEGDA) of different weight ratios. The PEGDA/GelMA hydrogels were fabricated by adjusting the weight ratio of PEGDA and GelMA with low or high adhesion ligand density (0.05 and 0.5% GelMA, respectively) and independent tunable stiffness (1.6, 6, and 25 kPa separately for hydrogels with 5, 10, and 15% PEGDA). MSCs presented differential behaviors to ECM by adjusting its adhesion ligand density and stiffness. Cell proliferation and chondrogenic differentiation could be enhanced with the improvement of adhesive properties and stiffness, evidenced by cell viability assay, hematoxylin–eosin staining, Safranin O staining, immunohistochemistry (Collagen types II, Col2a1), as well as the chondrogenic genes expression of Col2a1, Acan, and Sox9. This study may provide new strategies to design the scaffolds for cartilage tissue engineering.

  • Click functionalized, tissue‐specific hydrogels for osteochondral tissue engineering
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-13
    Jason L. Guo; Ang Li; Yu Seon Kim; Virginia Y. Xie; Brandon T. Smith; Emma Watson; Gang Bao; Antonios G. Mikos

    Osteochondral repair requires the induction of both articular cartilage and subchondral bone development, necessitating the presentation of multiple tissue‐specific cues for these highly distinct tissues. To provide a singular hydrogel system for the repair of either tissue type, we have developed biofunctionalized, mesenchymal stem cell‐laden hydrogels that can present in situ biochemical cues for either chondrogenesis or osteogenesis by simple click modification of a crosslinker, poly(glycolic acid)‐poly(ethylene glycol)‐poly(glycolic acid)‐di(but‐2‐yne‐1,4‐dithiol) (PdBT). After modifying PdBT with either cartilage‐specific biomolecules (N‐cadherin peptide, chondroitin sulfate) or bone‐specific biomolecules (bone marrow homing peptide 1, glycine‐histidine‐lysine peptide), the biofunctionalized, PdBT‐crosslinked hydrogels can selectively promote the desired bone‐ or cartilage‐like matrix synthesis and tissue‐specific gene expression, with effects dependent on both biomolecule selection and concentration. Our findings establish the versatility of this click functionalized hydrogel system as well as its ability to promote in vitro development of osteochondral tissue phenotypes.

  • Crayfish hemocyanin on chitin bone substitute scaffolds promotes the proliferation and osteogenic differentiation of human mesenchymal stem cells
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-08
    Benjamin Kruppke; Jana Farack; Simy Weil; Eliahu David Aflalo; Dagmar Poláková; Amir Sagi; Thomas Hanke
  • Fabrication of porous carbonate apatite granules using microfiber and its histological evaluations in rabbit calvarial bone defects
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-05
    Kazuya Akita; Naoyuki Fukuda; Kumiko Kamada; Keiko Kudoh; Naito Kurio; Kanji Tsuru; Kunio Ishikawa; Youji Miyamoto

    Carbonate apatite (CO3Ap) granules are known to show good osteoconductivity and replaced to new bone. On the other hand, it is well known that a porous structure allows bone tissue to penetrate its pores, and the optimal pore size for bone ingrowth is dependent on the composition and structure of the scaffold material. Therefore, the aim of this study was to fabricate various porous CO3Ap granules through a two‐step dissolution–precipitation reaction using CaSO4 as a precursor and 30‐, 50‐, 120‐, and 205‐μm diameter microfibers as porogen and to find the optimal pore size of CO3Ap. Porous CO3Ap granules were successfully fabricated with pore size 8.2–18.7% smaller than the size of the original fiber porogen. Two weeks after the reconstruction of rabbit calvarial bone defects using porous CO3Ap granules, the largest amount of mature bone was seen to be formed inside the pores of CO3Ap (120) [porous CO3Ap granules made using 120‐μm microfiber] followed by CO3Ap (50) and CO3Ap (30). At 4 and 8 weeks, no statistically significant difference was observed based on the pore size, even though largest amount of mature bone was formed in case of CO3Ap (120). It is concluded, therefore, that the optimal pore size of the CO3Ap is that of CO3Ap (120), which is 85 μm.

  • Bioresponsive microspheres for on‐demand delivery of anti‐inflammatory cytokines for articular cartilage repair
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-12
    Eunjae Park; Melanie L. Hart; Bernd Rolauffs; Jan P. Stegemann; Ramkumar T. Annamalai

    Despite innovations in surgical interventions, treatment of cartilage injury in osteoarthritic joints remains a challenge due to concomitant inflammation. Obstructing a single dominant inflammatory cytokine has shown remarkable clinical benefits in rheumatoid arthritis, and similar strategies are being suggested to target inflammatory pathways in osteoarthritis (OA). Here, we describe the utility of gelatin microspheres that are responsive to proteolytic enzymes typically expressed in arthritic flares, resulting in on‐demand and spatiotemporally controlled release of anti‐inflammatory cytokines for cartilage preservation and repair. These microspheres were designed with a net negative charge to sequester cationic anti‐inflammatory cytokines, and the magnitude of the negative charge potential increased with an increase in crosslinking density. Collagenase‐mediated degradation of the microspheres was dependent on the concentration of the enzyme. Release of anti‐inflammatory cytokines from the loaded microspheres directly correlated with the degradation of the gelatin matrix. Exposure of the IL‐4 and IL‐13 loaded microspheres reduced the inflammation of chondrocytes up to 80%. Hence, the delivery of these microspheres in an OA joint can attenuate the stimulation of chondrocytes and the resulting secretion of catabolic factors such as proteinases and nitric oxide. The microsphere format also allows for minimally invasive delivery and is less susceptible to mechanically induced drug release. Consequently, bioresponsive microspheres can be an effective tool for cartilage preservation and arthritis treatment.

  • The impact of intercellular communication for the generation of complex multicellular prevascularized tissue equivalents
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-13
    Martin Heller; Heide‐Katharina Bauer; Roxana Schwab; Sebastian Blatt; Katharina Peters; Sandra Nezi‐Cahn; Ronald E. Unger; Annette Hasenburg; Walburgis Brenner

    In reconstructive surgery the use of prevascularized soft tissue equivalents is a promising approach for wound coverage of defects after tumor resection or trauma. However, in previous studies to generate soft tissue equivalents on collagen membranes, microcapillaries were restricted to superficial areas. In this study, to understand which factors were involved in the formation of these microcapillaries, the levels of the angiogenic factors vascular endothelial growth factor (VEGF), Interleukin‐8 (IL‐8), and basic fibroblast growth factor (bFGF) in the supernatants of the tissue equivalents were examined at various time points and conditions. Additionally, the influence of these factors on viability, proliferation, migration, and tube formation in monocultures compared to cocultures of fibroblast and endothelial cells was examined. The results showed that VEGF production was decreased in cocultures compared to fibroblast monocultures and the lowest VEGF levels were observed in endothelial cell monocultures. Additionally, the highest levels of IL‐8 were observed in cocultures compared to monocultures. Similar results were observed for bFGF with lowest levels seen within the first 24 hr and highest levels in cocultures. VEGF and IL‐8 were shown to promote endothelial cell viability, proliferation and migration and angiogenic parameters such as tube density, total tube length, and number of tube branches. Addition of VEGF and IL‐8 to cocultures resulted in accelerated and denser formation of capillary‐like structures. The results indicate that VEGF, IL‐8, and bFGF strongly influence cellular behavior of endothelial cells and this information should be useful in promoting the formation of microcapillary‐like structures in complex tissue equivalents.

  • Tissue‐engineered islet‐like cell clusters generated from adipose tissue‐derived stem cells on three‐dimensional electrospun scaffolds can reverse diabetes in an experimental rat model and the role of porosity of scaffolds on cluster differentiation
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-17
    Rakhi Anitha; Dhanesh Vaikkath; Sachin J. Shenoy; Prabha D. Nair

    In the current study, three‐dimensional (3D) nanofibrous scaffolds with pore sizes in the range of 24–250 μm and 24–190 μm were fabricated via a two‐step electrospinning method to overcome the limitation of obtaining three‐dimensionality with large pore sizes for islet culture using conventional electrospinning. The scaffolds supported the growth and differentiation of adipose‐derived mesenchymal stem cells to islet‐like clusters (ILCs). The pore size of the scaffolds was found to influence the cluster size, viability and insulin release of the differentiated islets. Hence, islet clusters of the desired size could be developed for transplantation to overcome the loss of bigger islets due to hypoxia which adversely impacts the outcome of transplantation. The tissue‐engineered constructs with ILC diameter of 50 μm reduced glycemic value within 3–4 weeks after implantation in the omental pouch of diabetic rats. Detection of insulin in the serum of implanted rats demonstrates that the tissue‐engineered construct is efficient to control hyperglycemia. Our findings prove that the 3D architecture and pore size of scaffolds regulates the morphology and size of islets during differentiation which is critical in the survival and function of ILCs in vitro and in vivo.

  • A multifunctional long‐term release system for treatment of hypothyroidism
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-11
    Ceren Kutlu Kaya; Selin Gümrükçü; Abdulkadir Sezai Saraç; Fatma Neşe Kök

    Hypothyroidism is an autoimmune disease associated with underactive thyroid gland. In this study, a dual effect polymeric system was designed to release Cepharanthine (CEP) to block T cell activation and Selenium (Se) to decrease the anti‐thyroid peroxidase (TPOAb) concentration in order to treat hypothyroidism. For this purpose, poly(ethylene‐vinyl acetate) (PEVA) and polyethylene glycol (PEG) nanoparticles (NPs) including CEP were synthesized by emulsion solvent evaporation method and they were loaded to polyurethane (PU)/PEG‐PUSe‐PEG block copolymer blends which were fabricated by particulate leaching technique as porous sponges. Fourier‐Transform Infrared (FTIR), Raman, and Nuclear Magnetic Resonance (NMR) analysis showed successful synthesis of PEG‐PUSe‐PEG block copolymer. A long‐term zero‐order release profile was obtained for CEP. Se release rate from matrices showed an oxidative stress‐mediated release which can be used to adjust Se amount. According to MTS results conducted by NIH 3T3 fibroblasts, both NPs and matrices have no adverse effect on cell viability. Fluorescence microscopy and SEM images confirm the MTS results. The dual release system has potential to be effectively used in long‐term treatment of hypothyroidism by addressing both auto‐immune response and hormone regulation.

  • Systematic in vitro biocompatibility studies of multimodal cellulose nanocrystal and lignin nanoparticles
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-13
    Surachet Imlimthan; Alexandra Correia; Patrícia Figueiredo; Kalle Lintinen; Vimalkumar Balasubramanian; Anu J. Airaksinen; Mauri A. Kostiainen; Hélder A. Santos; Mirkka Sarparanta

    Natural biopolymer nanoparticles (NPs), including nanocrystalline cellulose (CNC) and lignin, have shown potential as scaffolds for targeted drug delivery systems due to their wide availability, cost‐efficient preparation, and anticipated biocompatibility. As both CNC and lignin can potentially cause complications in cell viability assays because of their ability to scatter the emitted light and absorb the assay reagents, we investigated the response of bioluminescent (CellTiter‐Glo®), colorimetric (MTT® and AlamarBlue®), and fluorometric (LIVE/DEAD®) assays for the determination of the biocompatibility of the multimodal CNC and lignin constructs in murine RAW 264.7 macrophages and 4T1 breast adenocarcinoma cell lines. Here, we have developed multimodal CNC and lignin NPs harboring the radiometal chelator 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid and the fluorescent dye cyanine 5 for the investigation of nanomaterial biodistribution in vivo with nuclear and optical imaging, which were then used as the model CNC and lignin nanosystems in the cell viability assay comparison. CellTiter‐Glo® based on the detection of ATP‐dependent luminescence in viable cells revealed to be the best assay for both nanoconstructs for its robust linear response to increasing NP concentration and lack of interference from either of the NP types. Both multimodal CNC and lignin NPs displayed low cytotoxicity and favorable interactions with the cell lines, suggesting that they are good candidates for nanosystem development for targeted drug delivery in breast cancer and for theranostic applications. Our results provide useful guidance for cell viability assay compatibility for CNC and lignin NPs and facilitate the future translation of the materials for in vivo applications.

  • A BMSCs‐laden quercetin/duck's feet collagen/hydroxyapatite sponge for enhanced bone regeneration
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-16
    Jeong Eun Song; Jingwen Tian; Yeon Ji Kook; Muthukumar Thangavelu; Joo Hee Choi; Gilson Khang

    Treating critical‐sized bone defects is an important issue in the field of tissue engineering and bone regeneration. From the various biomaterials for bone regeneration, collagen is an important and widely used biomaterial in biomedical applications, hence, it has numerous attractive properties including biocompatibility, hyper elastic behavior, prominent mechanical properties, support cell adhesion, proliferation, and biodegradability. In the present study, collagen was extracted from duck's feet (DC) as a new collagen source and combined with quercetin (Qtn), a type of flavonoids found in apple and onions and has been reported to affect the bone metabolism, for increasing osteogenic differentiation. Further, improving osteoconductive properties of the scaffold hydroxyapatite (HAp) a biodegradable material was used. We prepared 0, 25, 50, and 100 μM Qtn/DC/HAp sponges using Qtn, DC, and HAp. Their physiochemical characteristics were evaluated using scanning electron microscopy, compressive strength, porosity, and Fourier transform infrared spectroscopy. To assess the effect of Qtn on osteogenic differentiation, we cultured bone marrow mesenchymal stem cells on the sponges and evaluated by alkaline phosphatase, 3‐4‐2, 5‐diphenyl tetrazolium bromide assay, and real‐time polymerase chain reaction. Additionally, they were studied implanting in rat, analyzed through Micro‐CT and histological staining. From our in vitro and in vivo results, we found that Qtn has an effect on bone regeneration. Among the different experimental groups, 25 μM Qtn/DC/HAp sponge was found to be highly increased in cell proliferation and osteogenic differentiation compared with other groups. Therefore, 25 μM Qtn/DC/HAp sponge can be used as an alternative biomaterial for bone regeneration in critical situations.

  • Developing a self‐organized tubulogenesis model of human renal proximal tubular epithelial cells in vitro
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-16
    Xiuli Wang; Chengchen Guo; Ying Chen; Lorenzo Tozzi; Sophia Szymkowiak; Chunmei Li; David L. Kaplan

    Three‐dimensional tissue culture models which recapitulate the phenotype and function of human renal tissue have attracted significant interest as valuable tools for studying kidney development, disease pathophysiology, and nephrotoxicity. Here, a layer‐by‐layered three‐dimensional (3D) co‐culture technique was employed to bioengineer an improved human proximal tubule tissue model through incorporating human renal proximal tubule epithelial cells (RPTECs) with two types of interstitial cells on the layered extracellular matrix‐like culture matrix. The resulting cultures were characterized by their growth profile, metabolic and proliferative activity, morphological characteristics as well as their functional gene expression. Our results found that the cultures were able to enable the self‐organization of RPTECs and promote the tubule‐like structure formation in vitro. A well‐defined lumen structure and polarized expression of some key protein markers including actin, P‐gp, Na+‐K+‐ATPase, and SGLT2 were also observed in the 3D co‐cultures. Moreover, compared to the 3D monocultures, the tubule‐like structures formed within the 3D co‐cultures displayed more significant polarity and enhanced functional gene expression. This suggested the important role played by the renal stromal cells in supporting the tubulogenesis and differentiation of RPTECs. Thus, the 3D co‐culture model reported here would benefit bioengineering approaches toward more physiologically relevant proximal tubule tissue in vitro, providing more robust tool not only for better understanding kidney development and pathophysiology but also for drug screening for nephrotoxicity.

  • 3D‐engineered GelMA conduit filled with ECM promotes regeneration of peripheral nerve
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-16
    Hui Gong; Haosheng Fei; Qifan Xu; Maling Gou; Harry H. Chen

    Autologous transplantation remains the golden standard for peripheral nerve repair. However, many drawbacks, such as the risk of reoperation or nerve injury remain associated with this method. To date, commercially available artificial nerve conduits comprise hollow tubes. By providing physical guiding and biological cues, tissue engineered conduits are promising for bridging peripheral nerve defects. The present study focuses on the preparation of artificial composite nerve conduits by 3D bio‐printing. 3D‐printed molds with a tubular cavity were filled with an Engelbreth‐Holm‐Swarm (EHS) Hydrogel mimicking the extracellular matrix (ECM) basement membrane. Chemically cross‐linked gelatin methacryloyl (GelMA) was used to form the conduit backbone, while EHS Hydrogels improved nerve fiber growth while shortening repair time. Statistical significant difference had been found between the blank conduit and the composite conduit group on compound muscle action potential after 4 months. On the other hand, results between the composite conduit group and the autograft group were of no statistical differences. All results above showed that the composite conduit filled with EHS Hydrogel can promote the repair of peripheral nerve and may become a promising way to treat peripheral nerve defects.

  • The mechanism of PDA/PEI/5‐Fu coated esophageal stent material on inhibiting cancer associated pathological cells
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-13
    Kun Zhang; Yuxin Bai; Ru Xu; Jingan Li; Fangxia Guan

    Metal stent implantation is usually applied to alleviate nonoperative palliative esophageal obstruction for esophageal cancer in the later period. However, in‐stent restenosis after stent implantation limits the esophageal stents' performance due to lack of effective suppression of pathological cells from cancer microenvironment. In previous work, we modified the esophageal stent material 317L stainless steel (317LSS) surface with a poly‐dopamine/poly‐ethylenimine/5‐fluorouracil layer (PDA/PEI/5‐Fu), which had strong anti‐tumor and anti‐restenosis functions. Nevertheless, the mechanism of PDA/PEI/5‐Fu layer against tumor and inflammation remains unclear. In this work, we revealed the mechanism of PDA/PEI/5‐Fu suppressing the esophageal cancer related pathological cells (esophageal tumor cells, epithelial cells, and fibroblast) and inflammatory cells (macrophages) via series of experiments. Our data suggested that the PEI inhibited viability and E‐cadherin expression of the pathological cells, and blocked the NF‐κB signal pathway (reducing levels of p‐NF‐κB proteins). The loaded 5‐Fu inhibited the inflammatory factors (TNF‐α and IL‐1β) release and promoted the anti‐inflammation/anti‐tumor factors (IL‐10 and IL‐4) release from macrophages, and also suppressed pathological cells migration; both the PEI and 5‐Fu contributed to the upregulation of Bax and Caspase‐3 (pro‐tumor‐apoptosis factor), as well as the downregulation of Bcl‐2 (anti‐tumor‐apoptosis factor) in esophageal tumor cells. All the results showed that PDA/PEI/5‐Fu coating had potential multipath anti‐cancer and anti‐inflammatory effects in the surface modification of esophageal stents.

  • Current advances in biodegradable synthetic polymer based cardiac patches
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2020-01-12
    Sara McMahan; Alan Taylor; Katherine M. Copeland; Zui Pan; Jun Liao; Yi Hong

    The number of people affected by heart disease such as coronary artery disease and myocardial infarction increases at an alarming rate each year. Currently, the methods to treat these diseases are restricted to lifestyle change, pharmaceuticals, and eventually heart transplant if the condition is severe enough. While these treatment options are the standard for caring for patients who suffer from heart disease, limited regenerative ability of the heart restricts the effectiveness of treatment and may lead to other heart‐related health problems in the future. Because of the increasing need for more effective therapeutic technologies for treating diseased heart tissue, cardiac patches are now a large focus for researchers. The cardiac patches are designed to be integrated into the patients' natural tissue to introduce mechanical support and healing to the damaged areas. As a promising alternative, synthetic biodegradable polymer based biomaterials can be easily manipulated to customize material properties, as well as possess certain desired characteristics for cardiac patch use. This comprehensive review summarizes recent works on synthetic biodegradable cardiac patches implanted into infarcted animal models. In addition, this review describes the basic requirements that should be met for cardiac patch development, and discusses the inspirations to designing new biomaterials and technologies for cardiac patches.

  • Maximizing the strength of calcium sulfate for structural bone grafts
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2020-01-12
    Sacha Cavelier; Michael Tanzer; Francois Barthelat

    Calcium sulfate (CS) combines remarkable properties of biodegradability, biocompatibility, and osteoconductivity but its low strength limits the range of its applications in orthopaedic surgery. In this study we have addressed this limitation by optimizing the fabrication process for pure CS, and by using mechanical testing procedures which are relevant for load carrying, or structural bone grafts (flexural tests in hydrated condition). By optimizing the processing parameters (pressure during setting, CS powder to water ratio, saturated solution) we produced CS samples with the highest flexural strength ever reported in hydrated conditions. Once these optimal conditions are used, the addition of “reinforcing” inclusions in the material decreased its strength because these inclusions actually act as defects instead of reinforcements. In addition, the CS can be formed in precise shapes while maintaining optimal processing conditions and provided a strength similar to that of bone with the same dimensions. Dense and porous materials can be combined to duplicate the trabecular and cortical architecture of long bones, with only a small loss of overall strength.

  • Enhanced hemocompatibility and antibacterial activity on titania nanotubes with tanfloc/heparin polyelectrolyte multilayers
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2020-01-11
    Roberta M. Sabino; Kirsten Kauk; Liszt Y. C. Madruga; Matt J. Kipper; Alessandro F. Martins; Ketul C. Popat

    Biomaterial‐associated thrombus formation and bacterial infection remain major challenges for blood‐contacting devices. For decades, titanium‐based implants have been largely used for different medical applications. However, titanium can neither suppress blood coagulation, nor prevent bacterial infections. To address these challenges, tanfloc/heparin polyelectrolyte multilayers on titania nanotubes array surfaces (NT) were developed. The surfaces were characterized by scanning electron microscopy (SEM), X‐ray photoelectron spectroscopy (XPS), and water contact angle measurements. To evaluate the hemocompatibility of the surfaces, fibrinogen adsorption, Factor XII activation, and platelet adhesion and activation were analyzed. The antibacterial activity was investigated against Gram‐negative P. aeruginosa and Gram‐positive S. aureus. Bacterial adhesion and morphology, as well as biofilm formation, were analyzed using fluorescence microscopy and SEM. The anti‐thrombogenic properties of the surfaces were demonstrated by significant decreases in fibrinogen adsorption, Factor XII activation, and platelet adhesion and activation. Modifying NT with tanfloc/heparin also reduces the adhesion and proliferation of P. aeruginosa and S. aureus bacteria after 24 hr of incubation, with no biofilm formation. The modified NT surfaces with tanfloc/heparin polyelectrolyte multilayers are a promising biomaterial for use on implant surfaces because of their enhanced blood biocompatibility and antibacterial properties.

  • An anti‐oxidative cell culture dish inhibits intracellular ROS accumulation and modulates pluripotency‐associated gene expression in mesenchymal stem cells
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2020-01-13
    Yutaka Ikeda; Naoki Inuzuka; Mitsuaki Goto; Toshihiro Akaike; Yukio Nagasaki

    Maintenance of the pluripotent state of mesenchymal stem cells (MSCs) during in vitro expansion is an important factor for the successful proliferation of MSCs possessing high differentiation capacity. However, the differentiation potential of MSCs can easily be lost during in vitro expansion, particularly at late passages. ROS are signaling molecules that help to maintain MSC function; however, excessive ROS generation can induce senescence and impair both the differentiation capacity and proliferation of MSCs. In this study, we have designed an amphiphilic block copolymer (redox copolymer), which possesses ROS scavenging capacity in the hydrophobic site. When this redox copolymer was coated on cell culture dishes coupled with human E‐cadherin chimeric antibody (hE‐cad‐Fc), it had an antioxidative effect on cultured MSCs. We also confirmed that the redox polymer construct poly(ethylene glycol) tethered chain on the surface prevented non‐specific cell binding, whereas the co‐immobilized surface allowed high adhesion of E‐cadherin‐positive MSCs. Interestingly, the intracellular ROS level was significantly decreased by the prepared cell culture dish, despite ROS being scavenged only on the surface of the dish, on the cell exterior. Consequently, the cultured MSCs retained high expression levels of pluripotency‐associated genes, including SOX2.

  • The Implication of the Notch Signaling Pathway in Biphasic Calcium Phosphate Ceramic‐induced Ectopic Bone Formation: A Preliminary Experiment
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2020-01-11
    Xiaoshuang Guo; Haiyue Jiang; Xianlei Zong; Le Du; Jingyi Zhao; Dong Zhang; Guodong Song; Xiaolei Jin

    Calcium phosphate (BCP) ceramic is a promising material in bone regeneration because it was proved biocompatible, osteoconductive, osteoinductive and effective. Although it manifests favorable characteristics in critical‐sized bone defects repair, the mechanism of its osteoinduction is still unclear. In the present study, we studied the mechanism of ectopic bone formation, with interest in the Notch signaling pathway. BCP ceramics with or without Notch signaling inhibitor RO4929097 were cocultured with bone marrow‐derived stem cells in vitro. The expression of osteogenesis (OPN/Col/Runx2) and Notch signaling pathway‐related genes (Hes1/Jagged/Notch1) were increased in the BCP group compared with the control group without BCP but significantly decreased after adding RO4929097. Furthermore, a higher level of alkaline phosphatase activity was observed in the BCP group compared with RO4929097 and control group separately. For further confirmation, the intramuscularly ectopic implantation models of Beagle dogs were used. Quantitative real‐time polymerase chain reaction showed a similar trend with the in vitro experiment. Histological and histomorphometric analysis indicated that bone formation was delayed by RO4929097. These findings illustrated that the Notch signaling pathway plays a pivotal role in bone formation induced by BCP; Notch signaling pathway may positively influence ectopic bone formation by promoting BMSCs to differentiate towards osteoblasts.

  • Regenerative Engineered Vascularized Bone Mediated by Calcium Peroxide
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2020-01-11
    Leila Daneshmandi; Cato T. Laurencin

    One of the main challenges hindering the clinical translation of bone tissue engineering scaffolds is the lack of establishment of functional vasculature. Insufficient vascularization and poor oxygen supply limit cell survival within the constructs resulting in poor osseointegration with the host tissue and eventually leading to inadequate bone regeneration. Inspired by cues from developmental biology, we regenerative engineered a composite matrix by incorporating calcium peroxide (CaO2) into PLGA microsphere‐based matrices and sought to assess whether the delivery of the byproducts of CaO2 decomposition, namely O2, Ca2+, and H2O2 could enhance the regeneration of vascularized bone tissue. The composite microspheres were successfully fabricated via the oil‐in‐water emulsion method. The presence and encapsulation of CaO2 was confirmed using SEM, EDS, TGA, and XRD. The microspheres were further heat sintered into 3D porous scaffolds and characterized for their degradation and release of byproducts. The in vitro cytocompatibility of the matrices and their ability to support osteogenic differentiation was confirmed using human adipose‐derived stem cells. Lastly, an in vivo study was performed in a mouse critical‐sized calvarial defect model to evaluate the capacity of these matrices in supporting vascularized bone regeneration. Results demonstrated that the presence of CaO2 increased cellularization and biological activity throughout the matrices. There was greater migration of host cells to the interior of the matrices and greater survival and persistence of donor cells after 8 weeks, which in synergy with the composite matrices led to enhanced vascularized bone regeneration.

  • Incorporating Silica‐coated Graphene in Bioceramic Nanocomposites to Simultaneously Enhance Mechanical and Biological Performance
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2020-01-11
    Zhong Li; Wenyu Zhu; Shuguang Bi; Ruitao Li; Huanlong Hu; Hang Lin; Rocky S. Tuan; Khiam Aik Khor

    The applications of a variety of bioactive ceramics such as hydroxyapatite (HA) in orthopedics are limited by their insufficient mechanical properties, especially poor fracture toughness. Thus, further extending the clinical applications of these materials warrants the enhancement of their mechanical properties. Although the reinforcement of ceramics by 2D nanomaterials has been well recognized, integrated structural, mechanical and functional considerations have been neglected in the design and synthesis of such composite materials. Herein, we report the first use of silica‐coated reduced graphene oxide (S‐rGO) hybrid nanosheets to create bioceramic‐based composites with simultaneously enhanced mechanical and biological properties. In the representative HA‐based bioceramic systems prepared by spark plasma sintering, S‐rGO incorporation was found to be more effective for increasing the Young's modulus, hardness and fracture toughness than the incorporation of uncoated reduced GO (rGO). Furthermore, when assessed with osteoblast‐like MG‐63 cells, such novel materials led to faster cell proliferation and higher cell viability and alkaline phosphatase (ALP) activity than are generally observed with pure HA; additionally, cells demonstrate stronger affinity to S‐rGO/HA than to rGO/HA composites. The S‐rGO/bioceramic composites are therefore promising for applications in orthopedic tissue engineering, and this research provides valuable insights into the fabrication of silica‐coated hybrid nanosheet‐reinforced ceramics.

  • Self‐assembled biomimetic Nano‐Matrix for stem cell anchorage
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2020-01-10
    Libo Zhou; Anne Yau; Hongchuan Yu; Liisa Kuhn; Wei Guo; Yupeng Chen

    Mesenchymal stem cells (MSCs) have been widely applied in biomedicine due to their ability to differentiate into many different cell types and their ability to synthesize a broad spectrum of growth factors and cytokines that directly and indirectly influence other cells in their vicinity. To guide MSC infiltration to a bone fracture site, we developed a novel self‐assembled Nano‐Matrix which can be used as an injectable scaffold to repair bone fractures. The Nano‐Matrix is formed by Janus base nanotubes (JBNTs) and fibronectin (FN). JBNTs are nucleobase‐derived nanotubes mimicking collagen fibers, and FN is one of the cell adhesive glycoproteins which is responsible for cell–extracellular matrix interactions and guides stem cell migration and differentiation to desired cells types. Here, we demonstrated the successful fabrication and characterization of the JBNT/FN Nano‐Matrix as well as its excellent bioactivity that encouraged human MSC migration and adhesion. This work lays a solid foundation for using the Nano‐Matrix as an injectable approach to improve MSC retention and function during bone fracture healing.

  • Fabrication of multifunctional cellulose/TiO2/Ag composite nanofibers scaffold with antibacterial and bioactivity properties for future tissue engineering applications
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2020-01-10
    Roqia Ashraf; Hasham S. Sofi; Towseef Akram; Hilal Ahmad Rather; Abdalla Abdal‐hay; Nadeem Shabir; Rajesh Vasita; Salman H. Alrokayan; Haseeb A. Khan; Faheem A. Sheikh

    In the present work, a novel strategy was explored to fabricate nanofiber scaffolds consisting of cellulose assimilated with titanium dioxide (TiO2) and silver (Ag) nanoparticles (NPs). The concentration of the TiO2 NPs in the composite was adjusted to 1.0, 1.5, and 2.0 wt % with respect to polymer concentration used for the electrospinning of colloidal solutions. The fabricated composite scaffolds were dispensed to alkaline deacetylation using 0.05 M NaOH to remove the acetyl groups in order to generate pure cellulose nanofibers containing TiO2 NPs. Moreover, to augment our nanofiber scaffolds with antibacterial activity, the in situ deposition approach of using Ag NPs was utilized with varied molar concentrations of 0.14, 0.42, and 0.71 M. The physicochemical properties of the nanofibers were identified by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) and contact angle meter studies. This demonstrated the presence of both TiO2 and Ag NPs and complete deacetylation of nanofibers. The antibacterial efficiency of the nanofibers was scrutinized against Escherichia coli and Staphylococcus aureus, revealing proper in situ deposition of Ag NPs and confirming the nanofibers are antibacterial in nature. The biocompatibility of the scaffolds was accustomed using chicken embryo fibroblasts, which confirmed their potential role to be used as wound‐healing materials. Furthermore, the fabricated scaffolds were subjected to analysis in simulated body fluid at 37°C to induce mineralization for future osseous tissue integration. These results indicate that fabricated composite nanofiber scaffolds with multifunctional characteristics will have a highest potential as a future candidate for promoting new tissues artificially.

  • RGD‐functionalized supported lipid bilayers modulate pre‐osteoblast adherence and promote osteogenic differentiation
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2020-01-08
    Johanna F. M. Verstappen; Jianfeng Jin; Gülistan Koçer; Mohammad Haroon; Pascal Jonkheijm; Astrid D. Bakker; Jenneke Klein‐Nulend; Richard T. Jaspers

    Biomaterial integration into bone requires optimal surface conditions to promote osteoprogenitor behavior, which is affected by integrin‐binding via arginine‐glycine‐aspartate (RGD). RGD‐functionalized supported lipid bilayers (SLBs) might be interesting as biomaterial coating in bone regeneration, because they allow integration of proteins, for example, growth factors, cytokines, and/or antibacterial agents. Since it is unknown whether and how they affect osteoprogenitor adhesion and differentiation, the aim was to investigate adhesion, focal adhesion formation, morphology, proliferation, and osteogenic potential of pre‐osteoblasts cultured on RGD‐functionalized SLBs compared to unfunctionalized SLBs and poly‐l‐lysine (PLL). After 17 hr, pre‐osteoblast density on SLBs without or with RGD was similar, but lower than on PLL. Cell surface area, elongation, and number and size of phospho‐paxillin clusters were also similar. Cells on SLBs without or with RGD were smaller, more elongated, and had less and smaller phospho‐paxillin clusters than on PLL. OPN expression was increased on SLBs with RGD compared to PLL. Moreover, after 1 week, COL1a1 expression was increased on SLBs without or with RGD. In conclusion, pre‐osteoblast adhesion and enhanced differentiation were realized for the first time on RGD‐functionalized SLBs, pointing to a new horizon in the management of bone regeneration using biomaterials. Together with SLBs nonfouling nature and the possibility of adjusting SLB fluidity and peptide content make SLBs highly promising as substrate to develop innovative biomimetic coatings for biomaterials in bone regeneration.

  • Production and evaluation of decellularized extracellular matrix hydrogel for cartilage regeneration derived from knee cartilage
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2020-01-08
    Sima Bordbar; Nasrin Lotfi Bakhshaiesh; Mehdi Khanmohammadi; Forough Azam Sayahpour; Mauro Alini; Mohamadreza Baghaban Eslaminejad

    Cartilage tissue engineering is the interdisciplinary science that will help to improve cartilage afflictions, such as arthrosis, arthritis, or following joints traumatic injuries. In the present work, we developed an injectable hydrogel which derived from decellularized extracellular matrix of sheep cartilage. Successful decellularization was evaluated by measuring the DNA, glycosaminoglycans (GAG), collagen contents, and histological analyses. There was a minor difference in GAG and collagen contents among natural cartilage and decellularized tissue as well as ultimate hydrogel. Rheological analysis showed that the temperature and gelation time of prepared hydrogel were 37°C and between 5 and 7 min, respectively. Mechanical properties evaluation indicated a storage modulus of 20 kPa. The results show that prepared hydrogel possessed cell‐friendly microenvironment as confirmed via calcein staining and MTT assay. Also, cells were able to proliferate which observed by H&E and alcian blue staining. Cell attachment and proliferation at the surface of the decellularized hydrogel was apparent by Scanning Electron Microscope (SEM) images and microphotographs. Furthermore, the cells embedded within the hydrogel were able to differentiate into chondrocyte with limited evidence of hypertrophy and osteogenesis in utilized cells which proved by SOX9, CoL2, ACAN, and also CoL1 and CoL10 gene expression levels. In summary, the results suggest that developed novel injectable hydrogel from decellularized cartilage could be utilized as a promising substrate for cartilage tissue engineering applications.

  • Nanodiamond in composite: Biomedical application
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2020-01-02
    Aisha Rehman; Shadi Houshyar; Xin Wang

    The biocompatibility of materials is the determining factor for them to be applied in biomedical areas. Nanodiamond (ND) has gained increasing interest in this area due to its biocompatibility, ease of surface functionalization and excellent mechanical performance. ND has been widely used to reinforce biopolymers, and the resultant biocomposites have found applications in bone tissue engineering, chemotherapeutic drug delivery, and wound healing. Fluorescent ND, when combined with biopolymers, is serving for bioimaging and sensing applications. Herein, we contribute a description of ND, recent trends in its adoption for biopolymers, functionalization methods, amalgamation techniques of ND with biopolymers, potential applications of these composites in the biomedical field and future perspectives.

  • Recent progress in biomedical applications of RGD‐based ligand: From precise cancer theranostics to biomaterial engineering: A systematic review
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-30
    Mohsen Alipour; Marzieh Baneshi; Saman Hosseinkhani; Reza Mahmoudi; Ali Jabari Arabzadeh; Mohammad Akrami; Jalil Mehrzad; Hassan Bardania

    Arginine‐glycine‐aspartic acid (RGD) peptide family is known as the most prominent ligand for extracellular domain of integrin receptors. Specific expression of these receptors in various tissue of human body and tight association of their expression profile with various pathophysiological conditions made these receptors a suitable targeting candidate for several disease diagnosis and treatment as well as regeneration of various organs. For these reasons, various forms of RGD‐based integrins ligands have been greatly used in biomedical studies. Here, we summarized the last decade application progress of RGD for cancer theranostics, control of inflammation, thrombosis inhibition and critically discussed the effect of RGD peptides structure and sequence on the efficacy of gene/drug delivery systems in preclinical studies. Furthermore, we will show recent advances in application of RGD functionalized biomaterials for various tissue regenerations including cornea repair, artificial neovascularization and bone tissue regeneration. Finally, we analyzed clinically translatability of RGD peptides, considering examples of integrin ligands in clinical trials. In conclusion, prospects on using RGD peptide for precise drug delivery and biomaterial engineering are well discussed.

  • Meso‐macroporous crack‐free nanohydroxyapatite coatings templated by C12E10 diblock copolymer on Ti6Al4V implant materials toward human osteoblast‐like cells
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-30
    Marjan Sharafipour; Hamid Oveisi; Azadeh Meshkini

    Meso‐macroporous nanohydroxyapatite coatings (MHACs) were synthesized on Ti6Al4V implant materials calcined at different temperatures using a nonionic diblock copolymer template (C12E10) by sol–gel and dip‐coating methods. To improve the bonding strength between the substrate and coating, a TiO2 intermediate layer was applied on the surface of the substrates. The physicochemical and structural properties of MHAC samples were fully studied by X‐ray diffraction, X‐ray photoelectron spectroscopy, Fourier‐transform infrared spectroscopy, scanning probe microscopy, field‐emission scanning electron microscopy (FESEM), Brunauer–Emmett–Teller method, and contact angle measurements. Based on the data obtained, the hydroxyapatite phase with a flower‐like morphology was formed on the Ti6Al4V substrates in all of the samples. According to confocal optical microscopy and FESEM images, there was no macrocrack and microcrack on the MHACs, whereas they were accompanied by macroporosities and mesoporosities on top of the coatings. By increasing the calcination temperature from 500°C to 650°C, the crystallite sizes increased, while the surface roughness value and hydrophilicity decreased. A reduction in specific surface area and an increase in the pore diameters occurred as the calcination temperature increased. In addition, the assessment of protein adsorption behavior over the samples revealed that the adsorption amounts significantly increased as the substrates were coated with HAP; however, the affinity of surface for protein adsorption was strictly dependent on the surface topography and hydrophilicity. in vitro cellular assay disclosed a great cytocompatibility in terms of adhesion and proliferation in MHAC samples as compared with that in TiO2‐coated and bare substrates. Regarding the physicochemical properties and biological studies, MHAC calcined at 650°C was deemed optimal for bone tissue engineering.

  • Effects of copper‐impregnated collagen implants on local pro‐ and anti‐inflammatory and regenerative tissue reactions following implantation in rats
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-27
    Andreas Hoene; Silke Lucke; Uwe Walschus; Christine Hackbarth; Cornelia Prinz; Friedrich‐Karl Evert; Hans‐Georg Neumann; Michael Schlosser

    Combining collagen, an established regenerative biomaterial, and copper (Cu) with its known antibacterial and angiogenic effects could improve wound healing. However, Cu is also cytotoxic. Thus, this study aimed at examining the tissue reactions after simultaneous intramuscular implantation of collagen discs either without Cu (controls) or impregnated in 2, 20, or 200 mmol/L Cu acetate in 24 rats. After 7, 14, and 56 days, implants with peri‐implant tissue were retrieved from 8 rats/day for immunohistochemical detection of CD68+ monocytes/macrophages and CD163+ macrophages, MHC‐II+ cells, T lymphocytes and nestin as tissue regeneration marker. CD68+ monocytes/macrophages around implants increased with Cu amount but decreased over time except for the highest Cu amount, while CD163+ macrophages increased over time around and within implants. MHC‐II+ cells were similar to CD68+ monocytes/macrophages. T lymphocyte numbers around implants were higher for Cu‐impregnated samples vs. controls on day 7 and highest on day 14, but declined afterwards. Nestin expression around and within implants was largely unaffected by Cu. In conclusion, pro‐inflammatory reactions around implants were dose‐dependently influenced by Cu but mostly decreased over time, while Cu did not negatively affect anti‐inflammatory and regenerative reactions. These results suggest that Cu‐impregnated collagen could be beneficial in wound treatment.

  • Graphene oxide‐based nanomaterial interaction with human breast cancer cells
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-27
    Beatriz F.M. Ribeiro; Marcelo M. Souza; Daniela S. Fernandes; Devaney R. do Carmo; Glaucia M. Machado‐Santelli

    Graphene and graphene‐based nanomaterials have great potential for various biomedical applications due to their unique physicochemical properties. However, how graphene‐based nanomaterials interact with biological systems has not been thoroughly studied. This study shows that 24, 48, and 72 hr exposure of 2.4 μg/cm2 of graphene oxide (GOX) and GOX modified with DAB‐AM‐16 and PAMAM dendrimers (GOXD and GOXP, respectively) did not exhibit toxicity to MCF‐7 cells. However, higher graphene concentrations, such as 24 and 48 μg/cm2, induced low cytotoxic effects. The GOX, GOXD, and GOXP particles have a strong affinity with the cellular membrane. Cells that internalized the nanomaterials presented morphological alterations and modifications in the organization of microfilaments and microtubules compared with control cells. Then, cells were treated with 24 μg/cm2 of GOX, GOXD or GOXP for 24 hr and recovered for an additional period of 24 hr in normal medium. Nanoparticles remained in the cytoplasm of some cells, apparently with no effect on cellular morphology, being consistent with the data found in the cell proliferation experiment, which showed that the cells remained alive up to 72 hr.

  • Strontium‐substituted biphasic calcium phosphate microspheres promoted degradation performance and enhanced bone regeneration
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-26
    Ying Chen; Zhongning Liu; Ting Jiang; Xinyu Zou; Lei Lei; Wenjuan Yan; Jingwen Yang; Bo Li

    Biphasic calcium phosphate (BCP) ceramics are the subject of much attention for use as bone replacement material. However, it remains a challenge to promote the degradation and osteoinductivity performances of BCP ceramics. In this work, novel BCP ceramic microspheres with good degradation and excellent osteoinductivity were prepared through high‐content strontium (Sr) doping. The in vitro results indicated that the Sr10‐BCP, Sr40‐BCP, and Sr80‐BCP microspheres all had their HA crystals partially transformed to the beta tricalcium phosphate phase following high‐temperature sintering because of Ca‐deficient HA formed by the partial substitution of Ca ions by Sr ions. In addition, the degradation rate was increased with the doping of increasing amounts of Sr. All prepared microspheres enhanced human bone marrow‐derived mesenchymal stem cells attachment and proliferation. Specifically, among these modified microspheres, the Sr40‐BCP microspheres showed the highest osteogenic potential. Furthermore, Sr40‐BCP and HA microspheres were implanted in a calvarial defect model of rat to evaluate the in vivo bone augmentation ability. The results indicated that Sr40‐BCP microspheres degraded more completely and significantly promoted new bone regeneration compared with HA microspheres. In conclusion, Sr40‐BCP microspheres have excellent potential for degradation and bone regeneration and are promising osteogenic materials.

  • Osteoclasts degrade fibrinogen scaffolds and induce mesenchymal stem/stromal osteogenic differentiation
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-24
    Ana R. Almeida; Mafalda Bessa‐Gonçalves; Daniel M. Vasconcelos; Mário A. Barbosa; Susana G. Santos

    Fibrinogen (Fg) is a pro‐inflammatory protein with pro‐healing properties. Previous work showed that fibrinogen 3D scaffolds (Fg‐3D) promote bone regeneration, but the cellular players were not identified. Osteoclasts are bone resorbing cells that promote bone remodeling in close crosstalk with osteoblasts. Herein, the capacity of osteoclasts differentiated on Fg‐3D to degrade the scaffolds and promote osteoblast differentiation was evaluated in vitro. Fg‐3D scaffolds were prepared by freeze‐drying and osteoclasts were differentiated from primary human peripheral blood monocytes. Results obtained showed osteoclasts expressing the enzymes cathepsin K and tartrate resistant acid phosphatase colonizing Fg‐3D scaffolds. Osteoclasts were able to significantly degrade Fg‐3D, reducing the scaffold's area, and increasing D‐dimer concentration, a Fg degradation product, in their culture media. Osteoclast conditioned media from the first week of differentiation promoted significantly stronger human primary mesenchymal stem/stromal cell (MSC) osteogenic differentiation, evaluated by alkaline phosphatase activity. Moreover, week 1 osteoclast conditioned media promoted earlier MSC osteogenic differentiation, than chemical osteogenesis inductors. TGF‐β1 was found increased in osteoclast conditioned media from week 1, when compared to week 3 of differentiation. Taken together, our results suggest that osteoclasts are able to differentiate and degrade Fg‐3D, producing factors like TGF‐β1 that promote MSC osteogenic differentiation.

  • Electrospinning of tyrosine‐based oligopeptides: Self‐assembly or forced assembly?
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2019-12-19
    Yasaman Hamedani; Prathyushakrishna Macha; Elvira L. Evangelista; Vamshikrishna R. Sammeta; Vijaya Chalivendra; Sivappa Rasapalli; Milana C. Vasudev

    Short oligomeric peptides typically do not exhibit the entanglements required for the formation of nanofibers via electrospinning. In this study, the synthesis of nanofibers composed of tyrosine‐based dipeptides via electrospinning, has been demonstrated. The morphology, mechanical stiffness, biocompatibility, and stability under physiological conditions of such biodegradable nanofibers were characterized. The electrospun peptide nanofibers have diameters less than 100 nm and high mechanical stiffness. Raman and infrared signatures of the peptide nanofibers indicate that the electrostatic forces and solvents used in the electrospinning process lead to secondary structures different from self‐assembled nanostructures composed of similar peptides. Crosslinking of the dipeptide nanofibers using 1,6‐diisohexanecyanate (HMDI) improved the physiological stability, and initial biocompatibility testing with human and rat neural cell lines indicate no cytotoxicity. Such electrospun peptides open up a realm of biomaterials design with specific biochemical compositions for potential biomedical applications such as tissue repair, drug delivery, and coatings for implants.

  • Preparation of chitosan/silk fibroin/hydroxyapatite porous scaffold and its characteristics in comparison to bi‐component scaffolds
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2013-05-14
    Xiao‐Ni Qi, Zhao‐Li Mou, Jing Zhang, Zhi‐Qi Zhang

    Composite porous scaffolds have attracted extensive attention in the biomedical material field. The aim of this research was to prepare a novel tri‐component composite porous scaffold and to evaluate its relevant properties. The porous scaffold was composed of chitosan (CS), silk fibroin (SF), and nanohydroxyapatite particles (nHA), which we named CS/SF/nHA scaffold and prepared via salt fractionation method combined with lyophilization. The porous structure was achieved using a porogen (salt), and the pore size was controlled by the size of porogen. To evaluate the characteristics of the tri‐component scaffold, three bi‐component scaffolds, CS/SF, CS/nHA, and SF/nHA, were simultaneously prepared for comparison. The scaffolds were subjected to morphological, micro‐structural, and biodegradation analyses. Results demonstrated that all of the scaffolds had pore sizes of 100–300 μm and a porosity of 90.5–96.1%. The biodegradation characteristics of all scaffolds meet the requirements of good biomedical materials. The investigation of the mechanical properties showed that the tri‐component scaffold has better properties than the bi‐component scaffolds. The in vitro biocompatibility with osteoblast‐like MG‐63 cells showed that all the scaffolds are suitable for cell attachment and proliferation; however, the CS/SF/nHA composite porous scaffold is much more effective than the others. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.

  • Chitosan/collagen scaffold containing bone morphogenetic protein‐7 DNA supports dental pulp stem cell differentiation in vitro and in vivo
    J. Biomed. Mater. Res. Part A (IF 3.221) Pub Date : 2012-02-18
    Xuechao Yang, Guangli Han, Xin Pang, Mingwen Fan

    In this study, porous chitosan/collagen scaffolds were prepared through a freeze‐drying process, and loaded with the plasmid vector encoding human bone morphogenetic protein‐7 (BMP‐7) gene. To investigate the feasibility and efficacy of this gene‐activated scaffold on dental tissue engineering, human dental pulp stem cells (DPSCs) were seeded in this scaffold for in vitro and in vivo study. In vitro results indicated that cells can be transfected successfully by loaded plasmid and secrete BMP‐7 until day 24. Evaluation of DNA content, ALP activity, calcium content, SEM, and real‐time PCR revealed that cells on gene‐activated scaffold showed better proliferation properties and odontoblastic differentiation behaviors than cells on pure scaffolds. Then, these cell–scaffold complexes were implanted subcutaneously and retrieved after 4 weeks for histology evaluation. In vivo results that gene‐activated scaffold group could still trace the existence of tranfected cells at week 4 and showed the upregulated expression of DSPP compared to pure scaffold groups. On the basis of our results, chitosan/collagen‐loaded BMP‐7 DNA appears to be an effective substrate candidate for gene delivery and indeed enhanced DPSCs differentiation toward an odontoblast‐like phenotype in vitro and in vivo. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A:, 2012.

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上海纽约大学William Glover