3D cell printing of in vitro stabilized skin model and in vivo pre-vascularized skin patch using tissue-specific extracellular matrix bioink: A step towards advanced skin tissue engineering Biomaterials (IF 8.402) Pub Date : 2018-03-23 Byoung Soo Kim, Yang Woo Kwon, Jeong-Sik Kong, Gyu Tae Park, Ge Gao, Wonil Han, Moon-Bum Kim, Hyungseok Lee, Jae Ho Kim, Dong-Woo Cho
3D cell-printing technique has been under spotlight as an appealing biofabrication platform due to its ability to precisely pattern living cells in pre-defined spatial locations. In skin tissue engineering, a major remaining challenge is to seek for a suitable source of bioink capable of supporting and stimulating printed cells for tissue development. However, current bioinks for skin printing rely on homogeneous biomaterials, which has several shortcomings such as insufficient mechanical properties and recapitulation of microenvironment. In this study, we investigated the capability of skin-derived extracellular matrix (S-dECM) bioink for 3D cell printing-based skin tissue engineering. S-dECM was for the first time formulated as a printable material and retained the major ECM compositions of skin as well as favorable growth factors and cytokines. This bioink was used to print a full thickness 3D human skin model. The matured 3D cell-printed skin tissue using S-dECM bioink was stabilized with minimal shrinkage, whereas the collagen-based skin tissue was significantly contracted during in vitro tissue culture. This physical stabilization and the tissue-specific microenvironment from our bioink improved epidermal organization, dermal ECM secretion, and barrier function. We further used this bioink to print 3D pre-vascularized skin patch able to promote in vivo wound healing. In vivo results revealed that endothelial progenitor cells (EPCs)-laden 3D-printed skin patch together with adipose-derived stem cells (ASCs) accelerates wound closure, re-epithelization, and neovascularization as well as blood flow. We envision that the results of this paper can provide an insightful step towards the next generation source for bioink manufacturing.
Design of drug delivery systems for physical energy-induced chemical surgery Biomaterials (IF 8.402) Pub Date : 2018-03-22 Takahiro Nomoto, Nobuhiro Nishiyama
Physical energy-induced chemical surgery, a technique that induces antitumor effects by delivering a drug that exerts a therapeutic effect in response to physical energy and irradiating the diseased part with the corresponding physical energy, is a useful method to treat cancers with minimal systemic side effects. Among chemical surgery, photodynamic therapy (PDT) and neutron capture therapy (NCT) require a system that selectively delivers drugs to the diseased site. Although PDT and NCT have a similar concept, drug delivery systems (DDSs) for their purpose need different functions to solve the unique problems derived from the characteristics of respective physical energy. In this review, we will describe recent chemistry-based solutions including ours to overcome these challenges.
Rapid and selective sampling of IgG from skin in less than one minute using a high surface area wearable immunoassay patch Biomaterials (IF 8.402) Pub Date : 2018-03-22 Jacob Coffey, Simon Corrie, Mark Kendall
Microprojection array (MPA) patches are an attractive approach to selectively capture circulating proteins from the skin with minimal invasiveness for diagnostics at the point-of-care or in the home. A key challenge to develop this technology is to extract sufficient quantities of specific proteins from within the skin to enable high diagnostic sensitivity within a convenient amount of time. To achieve this, we investigated the effect of MPA geometry (i.e. projection density, length and array size) on protein capture. We hypothesised that the penetrated surface area of MPAs is a major determinant of protein capture however it was not known if simultaneously increasing projection density, length and array size is possible without adversely affecting penetration and/or tolerability. We show that increasing the projection density (5,000 - 30,000 proj.cm-2) and array size (4 – 36 mm2) significantly increases biomarker capture whilst maintaining of a similar level tolerability, which supports previous literature for projection length (40 – 190 µm). Ultimately, we designed a high surface area MPA (30,000 proj.cm-2, 36 mm2, 140 µm) with a 4.5-fold increase in penetrated surface area compared to our standard MPA design (20,408 proj.cm-2, 16 mm2, 100 µm). The high surface area MPA captured antigen-specific IgG from mice in 30 s with 100% diagnostic sensitivity compared with 10 - 30 min for previous MPA immunoassay patches, which is over an order of magnitude reduction in wear time. This demonstrates for the first time that MPAs may be used for ultra-rapid (< 1 min) protein capture from skin in a time competitive with standard clinical procedures like the needle and lancet, which has broad implications for minimally invasive and point-of-care diagnostics.
Dynamics of dual-fluorescent polymersomes with durable integrity in living cancer cells and zebrafish embryos Biomaterials (IF 8.402) Pub Date : 2018-03-22 Sven H.C. Askes, Nelli Bossert, Jeroen Bussmann, Victorio Saez Talens, Michael S. Meijer, Roxanne E. Kieltyka, Alexander Kros, Sylvestre Bonnet, Doris Heinrich
The long-term fate of biomedical nanoparticles after endocytosis is often only sparsely addressed in vitro and in vivo, while this is a crucial parameter to conclude on their utility. In this study, dual-fluorescent polyisobutylene-polyethylene glycol (PiB-PEG) polymersomes were studied for several days in vitro and in vivo. In order to optically track the vesicles' integrity, one fluorescent probe was located in the membrane and the other in the aqueous interior compartment. These non-toxic nanovesicles were quickly endocytosed in living A549 lung carcinoma cells but unusually slowly transported to perinuclear lysosomal compartments, where they remained intact and luminescent for at least 90 h without being exocytosed. Fluorescence-assisted flow cytometry indicated that after endocytosis, the nanovesicles were eventually degraded within 7–11 days. In zebrafish embryos, the polymersomes caused no lethality and were quickly taken up by the endothelial cells, where they remained fully intact for as long as 96 h post-injection. This work represents a novel case-study of the remarkable potential of PiB-PEG polymersomes as an in vivo bio-imaging and slow drug delivery platform.
Engineering Nanoparticle Strategies for Effective Cancer Immunotherapy Biomaterials (IF 8.402) Pub Date : 2018-03-21 Hong Yeol Yoon, Subramanian Tamil Selvan, Yoosoo Yang, Min Ju Kim, Dong Kee Yi, Ick Chan Kwon, Kwangmeyung Kim
Cancer immunotherapy has been emerging in recent years, due to the inherent nature of the immune system. Although recent successes of immunotherapeutics in clinical application have attracted development of a novel immunotherapeutics, the off-target side effect and low immunogenicity of them remain challenges for the effective cancer immunotherapy. Theranostic nanoparticle system may one of key technology to address these issues by offering targeted delivery of various types of immunotherapeutics, resulting in significant improvements in the tumor immunotherapy. However, appropriate design or engineering of nanoparticles will be needed to improve delivery efficiency of antigen, adjuvant and therapeutics, resulting in eliciting antitumor immunity. Here, we review the current state of the art of cancer immunotherapeutic strategies, mainly based on nanoparticles (NPs). This includes NP-based antigen/adjuvant delivery vehicles to draining lymph nodes, and tumor antigen-specific T-lymphocytes for cancer immunotherapy. Several NP-based examples are shown for immune checkpoint modulation and immunogenic cell death. These overall studies demonstrate the great potential of NPs in cancer immunotherapy. Finally, engineering NP strategies will provide great opportunities to improve therapeutic effects as well as optimization of treatment processes, allowing to meet the individual needs in the cancer immunotherapy.
Anti-inflammatory polymersomes of redox-responsive polyprodrug amphiphiles with inflammation-triggered indomethacin release characteristics Biomaterials (IF 8.402) Pub Date : 2018-03-21 Jiajia Tan, Zhengyu Deng, Guhuan Liu, Jinming Hu, Shiyong Liu
Hyaluronic acid coated albumin nanoparticles for targeted peptide delivery in the treatment of retinal ischaemia Biomaterials (IF 8.402) Pub Date : 2018-03-20 Di Huang, Ying-Shan Chen, Colin R. Green, Ilva D. Rupenthal
Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial Biomaterials (IF 8.402) Pub Date : 2018-03-19 Enrique Gómez-Barrena, Philippe Rosset, Florian Gebhard, Philippe Hernigou, Nicola Baldini, Helène Rouard, Luc Sensebé, Rosa M. Gonzalo-Daganzo, Rosaria Giordano, Norma Padilla-Eguiluz, Eduardo García-Rey, José Cordero-Ampuero, Juan Carlos Rubio-Suárez, Julien Stanovici, Christian Ehrnthaller, Markus Huber-Lang, Charles Henri Flouzat-Lachaniette, Nathalie Chevallier, Davide MariaDonati, Gabriela Ciapetti, Sandrine Fleury, Manuel-Nicolás Fernandez, José-Rafael Cabrera, Cristina Avendaño-Solá, Tiziana Montemurro, Carmen Panaitescu, Elena Veronesi, Markus Thomas Rojewski, Ramin Lofti, Massimo Dominici, Hubert Schrezenmeier, Pierre Layrolle
Background ORTHO-1 is a European, multicentric, first in human clinical trial to prove safety and feasibility after surgical implantation of commercially available biphasic calcium phosphate bioceramic granules associated during surgery with autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSC) under good manufacturing practices, in patients with long bone pseudarthrosis. Methods: Twenty-eight patients with femur, tibia or humerus diaphyseal or metaphyso-diaphyseal non-unions were recruited and surgically treated in France, Germany, Italy and Spain with 100 or 200 million BM-hMSC/mL associated with 5–10 cc of bioceramic granules. Patients were followed up during one year. The investigational advanced therapy medicinal product (ATMP) was expanded under the same protocol in all four countries, and approved by each National Competent Authority. Findings: With safety as primary end-point, no severe adverse event was reported as related to the BM-hMSC. With feasibility as secondary end-point, the participating production centres manufactured the BM-hMSC as planned. The ATMP combined to the bioceramic was surgically delivered to the non-unions, and 26/28 treated patients were found radiologically healed at one year (3 out of 4 cortices with bone bridging). Interpretation: Safety and feasibility were clinically proven for surgical implantation of expanded autologous BM-hMSC with bioceramic. Funding: EU-FP7-HEALTH-2009, REBORNE Project (GA: 241876).
Molecular bottlebrush as a unimolecular vehicle with tunable shape for photothermal cancer therapy Biomaterials (IF 8.402) Pub Date : 2018-03-19 Huaan Li, Hong Liu, Tianqi Nie, Yi Chen, Zhiyong Wang, Huahua Huang, Lixin Liu, Yongming Chen
Folate receptor-directed orthogonal click-functionalization of siRNA lipopolyplexes for tumor cell killing in vivo Biomaterials (IF 8.402) Pub Date : 2018-03-19 Philipp Michael Klein, Sarah Kern, Dian-Jang Lee, Johannes Schmaus, Miriam Höhn, Jan Gorges, Uli Kazmaier, Ernst Wagner
Fucoidan/VEGF-based surface modification of decellularized pulmonary heart valve improves the antithrombotic and Re-endothelialization potential of bioprostheses Biomaterials (IF 8.402) Pub Date : 2018-03-16 N. Marinval, M. Morenc, M.N. Labour, A. Samotus, A. Mzyk, V. Ollivier, M. Maire, K. Jesse, K. Bassand, A. Niemiec-Cyganek, O. Haddad, M.P. Jacob, F. Chaubet, N. Charnaux, P. Wilczek, H. Hlawaty
Decellularized porcine heart valves offer promising potential as biocompatible prostheses. However, this procedure alter matrix fibres and glycans, leading to lower biomechanical resistance and increased their thrombotic potential. Therefore, their durability is limited due to calcification and weak regeneration in vivo. Surface modifications are highly requested to improve the scaffolds re-endothelialization required to restore functional and haemocompatible heart valve. Fucoidan, a natural sulphated polysaccharide, carries antithrombotic and anti-inflammatory properties and is known to enhance endothelial adhesion and proliferation when associated with vascular endothelial growth factor (VEGF). Based on these features, we constructed fucoidan/VEGF polyelectrolyte multilayer film (PEM) coated valve scaffold in an attempt to develop functional heart valve bioprosthesis. We investigated the haemocompatibility of the PEM coated valve scaffolds, the adhesion and growth potential of endothelial cells (HUVECs) in flow, as well as long term culture with stem cells. Fucoidan/VEGF PEM coated scaffolds demonstrated antithrombotic and non-calcifying properties. The PEM application increased HUVECs adhesion in flow (6 h) and HUVECs viability over time (72 h). HUVECs were well spread and aligned in flow direction. Interestingly, stem cells infiltration was improved by the PEM coating at 21 days. Thus, the fucoidan/VEGF PEM is a promising surface modification to obtain valve bioprostheses for clinical applications with increased antithrombotic and re-endothelialization potential.
The spatial molecular pattern of integrin recognition sites and their immobilization to colloidal nanobeads determine α2β1 integrin-dependent platelet activation Biomaterials (IF 8.402) Pub Date : 2018-03-16 Augusto Martins Lima, Seraphine V. Wegner, Ana C. Martins Cavaco, Maria Inacia Estevão-Costa, Raquel Sanz-Soler, Stephan Niland, Georgii Nosov, Jürgen Klingauf, Joachim P. Spatz, Johannes A. Eble
Collagen, a strong platelet activator, is recognized by integrin α2β1 and GPVI. It induces aggregation, if added to suspended platelets, or platelet adhesion if immobilized to a surface. The recombinant non-prolylhydroxylated mini-collagen FC3 triple helix containing one α2β1 integrin binding site is a tool to specifically study how α2β1 integrin activates platelet. Whereas soluble FC3 monomers antagonistically block collagen-induced platelet activation, immobilization of several FC3 molecules to an interface or to colloidal nanobeads determines the agonistic action of FC3. Nanopatterning of FC3 reveals that intermolecular distances below 64 nm between α2β1 integrin binding sites trigger signaling through dot-like clusters of α2β1 integrin, which are visible in high resolution microscopy with dSTORM. Upon signaling, these integrin clusters increase in numbers per platelet, but retain their individual size. Immobilization of several FC3 to 100 nm-sized nanobeads identifies α2β1 integrin-triggered signaling in platelets to occur at a twentyfold slower rate than collagen, which activates platelet in a fast integrative signaling via different platelet receptors. As compared to collagen stimulation, FC3-nanobead-triggered signaling cause a significant stronger activation of the protein kinase BTK, a weak and dispensable activation of PDK1, as well as a distinct phosphorylation pattern of PDB/Akt.
Functionalized poly(pyrrole-3-carboxylic acid) nanoneedles for dual-imaging guided PDT/PTT combination therapy Biomaterials (IF 8.402) Pub Date : 2018-03-16 Xin Liu, Huiling Su, Wei Shi, Yang Liu, Yanan Sun, Dongtao Ge
Herein, poly(pyrrole-3-carboxylic acid) (PPyCOOH) nanoneedles with abundant carboxyl groups were synthesized by aqueous dispersion polymerization method using pyrrole-3-carboxylic acid as conductive polymer monomer. The PPyCOOH nanoneedles not only owned good photothermal performance, but also more importantly showed enhanced tumor cell uptake efficiency (1.64 fold) compared with size and zeta-potential matched nanospheres. After loading photosensitizer aluminum phthalocyanine tetrasulfonate (AlPCS4) and modifying with poly(allylamine hydrochloride) (PAH) and poly(acrylic acid) (PAA) onto the PPyCOOH nanoneedles, novel nanoneedle complexes (AlPCS4@PPyCONH-PAH-PAA) integrating photodynamic therapy (PDT) and photothermal therapy (PTT) were successfully fabricated. The as-prepared nanoneedle complexes improved uptake efficiency of AlPCS4 both in vitro and in vivo. Moreover, the nanoneedle complexes have infrared thermal and fluorescent properties. By combined PDT/PTT under the guiding of dual modal imaging, the tumors in mice were completely eliminated and no recurrence was observed in 30 days after treatment, indicating that PPyCOOH nanoneedles have great potential as a novel drug carrier for constructing multifunctional nanoplatform used for cancer treatment.
Potent anti-viral vaccine adjuvant based on pH-degradable nanogels with covalently linked small molecule imidazoquinoline TLR7/8 agonist Biomaterials (IF 8.402) Pub Date : 2018-03-16 Lutz Nuhn, Lien Van Hoecke, Kim Deswarte, Bert Schepens, Yupeng Li, Bart N. Lambrecht, Stefaan De Koker, Sunil A. David, Xavier Saelens, Bruno G. De Geest
Improving the immunogenicity of subunit vaccines, in particular skewing of the immune response towards Th1 type immunity, is crucial for the development of effective vaccines against intracellular infections and for the development of anti-cancer vaccines. Small molecule TLR7/8 agonist hold high potential for this purpose, but suffer from an undesirable pharmacokinetic profile, resulting in systemic inflammatory responses. An effective solution to this problem is covalent ligation to a larger carrier. Here, a degradable nanogel carrier containing a covalently linked imidazoquinoline (IMDQ) TLR7/8 agonist is explored as adjuvant for vaccination against the respiratory syncytial virus (RSV). In vitro and in vivo experiments in mice provide a solid rational base for preferring nanogels over soluble polymers as IMDQ carrier in terms of cellular uptake and lymph node accumulation.
The influence of hypoxia and IFN-γ on the proteome and metabolome of therapeutic mesenchymal stem cells Biomaterials (IF 8.402) Pub Date : 2018-03-15 Holly M. Wobma, Manuel A. Tamargo, Shahar Goeta, Lewis M. Brown, Raimon Duran-Struuck, Gordana Vunjak-Novakovic
Over the past 15 years, mesenchymal stem cells (MSCs) have been assessed for their capacity to suppress inflammation and promote tissue repair. Regardless of whether the cells are primed (exposed to instructive cues) before administration, their phenotype will respond to environmental signals present in the pathophysiological setting being treated. Since hypoxia and inflammation coexist in the settings of acute injury and chronic diseases, we sought to explore how the proteome and metabolome of MSCs changes when cells were exposed to 48 h of 1% oxygen, interferon gamma (IFN-γ), or both cues together. We specifically focused on changes in cell metabolism, immune modulation, extracellular matrix secretion and modification, and survival capacity. IFN-γ promoted expression of anti-pathogenic proteins and induced MSCs to limit inflammation and fibrosis while promoting their own survival. Hypoxia instead led to cell adaption to low oxygen, including upregulation of proteins involved in anaerobic metabolism, autophagy, angiogenesis, and cell migration. While dual priming resulted in additive effects, we also found many instances of synergy. These data lend insight to how MSCs may behave after administration to a patient and suggest how priming cells beforehand could improve their therapeutic capacity.
Wnt signaling and bone regeneration: Can't have one without the other Biomaterials (IF 8.402) Pub Date : 2018-03-15 Philipp Leucht, Nury Yim
Advances in the understanding of the complexities of the Wnt signaling pathway during development and tissue homeostasis have made the Wnt pathway one of the prime candidates for translational applications during tissue regeneration. Wnts are key components of the stem cell niche and are short range signaling molecules responsible for cellular decisions such as proliferation and differentiation. Systemic treatment using biologics targeting the Wnt signaling pathway have shown promising early results and will likely enter the clinical arena in the near future. This comprehensive review summarizes the intricacies how Wnts function in the context of the bone regeneration.
Non-eluting, surface-bound enzymes disrupt surface attachment of bacteria by continuous biofilm polysaccharide degradation Biomaterials (IF 8.402) Pub Date : 2018-03-14 Dalal Asker, Tarek S. Awad, Perrin Baker, P. Lynne Howell, Benjamin D. Hatton
Bacterial colonization and biofilm formation on surfaces are typically mediated by the deposition of exopolysaccharides and conditioning protein layers. Pseudomonas aeruginosa is a nosocomial opportunistic pathogen that utilizes strain-specific exopolysaccharides such as Psl, Pel or alginate for both initial surface attachment and biofilm formation. To generate surfaces that resist P. aeruginosa colonization, we covalently bound a Psl-specific glycoside hydrolase (PslGh) to several, chemically-distinct surfaces using amine functionalization (APTMS) and glutaraldehyde (GDA) linking. In situ quartz crystal microbalance (QCM) experiments and confocal microscopy demonstrated a complete lack of Psl adsorption on the PslGh-bound surfaces. Covalently-bound PslGh was also found to significantly reduce P. aeruginosa surface attachment and biofilm formation over extended growth periods (8 days). The PslGh surfaces showed a ∼99.9% (∼3-log) reduction in surface associated bacteria compared to control (untreated) surfaces, or those treated with inactive enzyme. This work demonstrates a non-eluting ‘bioactive’ surface that specifically targets a mechanism of cell adhesion, and that surface-bound glycoside hydrolase can significantly reduce surface colonization of bacteria through local, continuous enzymatic degradation of exopolysaccharide (Psl). These results have significant implications for the surface design of medical devices to keep bacteria in a planktonic state, and therefore susceptible to antibiotics and antimicrobials.
Targeting epigenetic pathway with gold nanoparticles for acute myeloid leukemia therapy Biomaterials (IF 8.402) Pub Date : 2018-03-14 Rong Deng, Na Shen, Yang Yang, Hongliang Yu, Shuping Xu, Ying-Wei Yang, Shujun Liu, Kamel Meguellati, Fei Yan
Leukemia remains a fatal disease for most patients and novel therapeutic strategies are urgently needed. Aberrant DNA methylation is an epigenetic modification that is importance in the initiation and progression of leukemia. Here, we demonstrated NCL/miR-221/NFκB/DNMT1 axis as a new molecular pathway promoting aggressive acute myeloid leukemia (AML) leukemogenesis and successfully designed and prepared a nuclear localization signal (NLS) peptide-targeted gold nanoparticles with co-loaded anti-221 and AS1411 (NPsN-AS1411/a221), which can specifically target NCL/miR-221/NFκB/DNMT1 signaling pathway in AML. NPsN-AS1411/a221 synergistically abrogate endogenous miR-221 promoting cancerous growth by inhibiting the expression of p27Kip1 suppressor gene, as well as effectively deregulate the DNMT1 expression through NFκB signaling which led to a reduction of global DNA methylation and the restoration of tumor suppressor p15INK4B via its promoter DNA hypomethylation. Functionally, NPsN-AS1411/a221 remarkably blockage leukemia proliferation and clonogenic potential in NCL/miR-221/NFκB/DNMT1 positive AML cell lines. More importantly, NPsN-AS1411/a221 cooperatively extend the overall survival, lower the white blood cells, reverse splenomegaly, inhibit blasts in bone marrow and metastatic to lung in a preclinical AML animal model. Altogether, our studies provide a proof of concept for multiple-functional drug delivery system that based on the specific gene network involved in tumor growth, and highlight the clinical potential of NCL/miR-221/NFκB/DNMT1-targeted AML nanotherapy.
Lanthanide-doped nanoparticles conjugated with an anti-CD33 antibody and a p53-activating peptide for acute myeloid leukemia therapy Biomaterials (IF 8.402) Pub Date : 2018-03-14 Fan Niu, Jin Yan, Bohan Ma, Shichao Li, Yongping Shao, Pengcheng He, Wanggang Zhang, Wangxiao He, Peter X. Ma, Wuyuan Lu
Roughly one third of all human cancers are attributable to the functional inhibition of the tumor suppressor protein p53 by its two negative regulators MDM2 and MDMX, making dual-specificity peptide antagonists of MDM2 and MDMX highly attractive drug candidates for anticancer therapy. Two pharmacological barriers, however, remain a major obstacle to the development of peptide therapeutics: susceptibility to proteolytic degradation in vivo and inability to traverse the cell membrane. Here we report the design of a fluorescent lanthanide oxyfluoride nanoparticle (LONp)-based multifunctional peptide drug delivery system for potential treatment of acute myeloid leukemia (AML) that commonly harbors wild type p53, high levels of MDM2 and/or MDMX, and an overexpressed cell surface receptor, CD33. We conjugated to LONp via metal-thiolate bonds a dodecameric peptide antagonist of both MDM2 and MDMX, termed PMI, and a CD33-targeted, humanized monoclonal antibody to allow for AML-specific intracellular delivery of a stabilized PMI. The resultant nanoparticle antiCD33-LONp-PMI, while nontoxic to normal cells, induced apoptosis of AML cell lines and primary leukemic cells isolated from AML patients by antagonizing MDM2 and/or MDMX to activate the p53 pathway. Fluorescent antiCD33-LONp-PMI also enabled real-time visualization of a series of apoptotic events in AML cells, proving a useful tool for possible disease tracking and treatment response monitoring. Our studies shed light on the development of antiCD33-LONp-PMI as a novel class of antitumor agents, which, if further validated, may help targeted molecular therapy of AML.
Substrate stiffness modulates the multipotency of human neural crest derived ectomesenchymal stem cells via CD44 mediated PDGFR signaling Biomaterials (IF 8.402) Pub Date : 2018-03-14 Akshaya Srinivasan, Shu-Yung Chang, Shipin Zhang, Wei Seong Toh, Yi-Chin Toh
Mesenchymal stem cells (MSCs) have been isolated from various mesodermal and ectodermal tissues. While the phenotypic and functional heterogeneity of MSCs stemming from their developmental origins has been acknowledged, the genetic and environmental factors underpinning these differences are not well-understood. Here, we investigated whether substrate stiffness mediated mechanical cues can directly modulate the development of ectodermal MSCs (eMSCs) from a precursor human neural crest stem cell (NCSC) population. We showed that NCSC-derived eMSCs were transcriptionally and functionally distinct from mesodermal bone marrow MSCs. eMSCs derived on lower substrate stiffness specifically increased their expression of the MSC marker, CD44 in a Rho-ROCK signaling dependent manner, which resulted in a concomitant increase in the eMSCs' adipogenic and chondrogenic differentiation potential. This mechanically-induced effect can only be maintained for short-term upon switching back to a stiff substrate but can be sustained for longer-term when the eMSCs were exclusively maintained on soft substrates. We also discovered that CD44 expression modulated eMSC self-renewal and multipotency via the downregulation of downstream platelet-derived growth factor receptor beta (PDGFRβ) signaling. This is the first instance demonstrating that substrate stiffness not only influences the differentiation trajectories of MSCs but also their derivation from upstream progenitors, such as NCSCs.
Inducing hair follicle neogenesis with secreted proteins enriched in embryonic skin Biomaterials (IF 8.402) Pub Date : 2018-03-13 Sabrina Mai-Yi Fan, Chia-Feng Tsai, Chien-Mei Yen, Miao-Hsia Lin, Wei-Hung Wang, Chih-Chieh Chan, Chih-Lung Chen, Kyle K.L. Phua, Szu-Hua Pan, Maksim V. Plikus, Sung-Liang Yu, Yu-Ju Chen, Sung-Jan Lin
Organ development is a sophisticated process of self-organization. However, despite growing understanding of the developmental mechanisms, little is known about how to reactivate them postnatally for regeneration. We found that treatment of adult non-hair fibroblasts with cell-free extract from embryonic skin conferred upon them the competency to regenerate hair follicles. Proteomics analysis identified three secreted proteins enriched in the embryonic skin, apolipoprotein-A1, galectin-1 and lumican that together were essential and sufficient to induce new hair follicles. These 3 proteins show a stage-specific co-enrichment in the perifolliculogenetic embryonic dermis. Mechanistically, exposure to embryonic skin extract or to the combination of the 3 proteins altered the gene expression to an inductive hair follicle dermal papilla fibroblast-like profile and activated Igf and Wnt signaling, which are crucial for the regeneration process. Therefore, a cocktail of organ-specific extracellular proteins from the embryonic environment can render adult cells competent to re-engage in developmental interactions for organ neogenesis. Identification of factors that recreate the extracellular context of respective developing tissues can become an important strategy to promote regeneration in adult organs.
Osteogenesis potential of different titania nanotubes in oxidative stress microenvironment Biomaterials (IF 8.402) Pub Date : 2018-03-13 Yonglin Yu, Xinkun Shen, Zhong Luo, Yan Hu, Menghuan Li, Pingping Ma, Qichun Ran, Liangliang Dai, Ye He, Kaiyong Cai
Oxidative stress is commonly existed in bone degenerative disease (osteoarthritis, osteoporosis etc.) and some antioxidants had great potential to enhance osteogenesis. In this study, we aim to investigate the anti-oxidative properties of various TiO2 nanotubes (TNTs) so to screen the desirable size for improved osteogenesis and reveal the underlying molecular mechanism in vitro. Comparing cellular behaviors under normal and oxidative stress conditions, an interesting conclusion was obtained. In normal microenvironment, small TNTs were beneficial for adhesion and proliferation of osteoblasts, but large TNTs greatly increased osteogenic differentiation. However, after H2O2 (300 μM) treatment (mimicking oxidative stress), only large TNTs samples demonstrated superior cellular behaviors of increased osteoblasts' adhesion, survival and differentiation when comparing with those of native titanium (control). Molecular results revealed that oxidative stress resistance of large nanotubes was closely related to the high expression of integrin α5β1 (ITG α5β1), which further up-regulated the production of anti-apoptotic proteins (p-FAK, p-Akt, p-FoxO3a and Bcl2) and down-regulated the expression of pro-apoptotic protein (Bax). Moreover, we found that Wnt signals (Wnt3a, Wnt5a, Lrp5, Lrp6 and β-catenin) played an important role in promoting osteogenic differentiation of osteoblasts under oxidative condition.
Polyphenol uses in Biomaterials Engineering Biomaterials (IF 8.402) Pub Date : 2018-03-13 Amin Shavandi, Alaa El-Din Ahmed Bekhit, Pouya Saeedi, Zohreh Izadifar, Adnan A. Bekhit, Ali Khademhosseini
Polyphenols are micronutrients obtained from diet that have been suggested to play an important role in health. The health benefits of polyphenols and their protective effects in food systems as antioxidant compounds are well known and have been extensively investigated. However, their functional roles as a “processing cofactor” in tissue engineering applications are less widely known. This review focuses on the functionality of polyphenols and their application in biomaterials. Polyphenols have been used to stabilize collagen and to improve its resistance to degradation in biological systems. Therefore, they have been proposed to improve the performance of biomedical devices used in cardiovascular systems by improving the mechanical properties of grafted heart valves, enhancing microcirculation through the relaxation of the arterial walls and improving the capillary blood flow and pressure resistance. Polyphenols have been found to stimulate bone formation, mineralization, as well as the proliferation, differentiation, and the survival of osteoblasts. These effects are brought about by the stimulatory effect of polyphenols on osteoblast cells and their protective effect against oxidative stress and inflammatory cytokines. In addition, polyphenols inhibit the differentiation of the osteoclast cells. Collectively, these actions lead to promote bone formation and to reduce bone resorption, respectively. Moreover, polyphenols can increase the cross-linking of dentine and hence its mechanical stability. Overall, polyphenols provide interesting properties that will stimulate further research in the bioengineering field.
Transcutaneous implantation of valproic acid-encapsulated dissolving microneedles induces hair regrowth Biomaterials (IF 8.402) Pub Date : 2018-03-13 Shayan Fakhraei Lahiji, Seol Hwa Seo, Suyong Kim, Manita Dangol, Jiyong Shim, Cheng Guo Li, Yonghao Ma, Chisong Lee, Geonwoo Kang, Huisuk Yang, Kang-Yell Choi, Hyungil Jung
The interest in alternative material systems and delivery methods for treatment of androgenetic alopecia has been increasing in the recent decades. Topical application of valproic acid (VPA), an FDA-approved anticonvulsant drug, has been shown to effectively stimulate hair follicle (HF) regrowth by upregulating Wnt/β-catenin, a key pathway involved in initiation of HF development. Moreover, a majority of studies have suggested that cutaneous wound re-epithelialization is capable of inducing HF through Wnt/β-catenin pathway. Here, we report fabrication and evaluation of a novel VPA-encapsulating dissolving microneedle (DMN-VPA) that creates minimally invasive dermal micro-wounds upon application, significantly improving the VPA delivery efficiency. DMN-VPA not only delivers encapsulated VPA with higher accuracy than topical application, it also stimulates wound re-epithelialization signals involved in HF regrowth. Through a series of in vivo studies, we show that micro-wounding-mediated implantation of DMN-VPA upregulates expression of Wnt/β-catenin pathway, alkaline phosphatase, proliferating cell nuclear antigen, loricrin and HF stem cell markers, including keratin 15, and CD34 more effectively than topical application.
Novel angiogenesis therapeutics by redox injectable hydrogel - Regulation of local nitric oxide generation for effective cardiovascular therapy Biomaterials (IF 8.402) Pub Date : 2018-03-13 Long B. Vong, Thang Q. Bui, Tsutomu Tomita, Hiroki Sakamoto, Yuji Hiramatsu, Yukio Nagasaki
Nitric oxide (NO) possesses various functions in cardiovascular diseases; however, due to an extremely short half-life and low bioavailability, its therapeutic application is limited. In inflamed tissues, overproduced reactive oxygen species (ROS) rapidly react with the endogenous NO, reducing its bioavailability. Here, we developed a controllable NO-releasing injectable hydrogel (NO-RIG) formed by the electrostatic crosslinking between the polyion complex flower-type micelles composing of functional polymers to scavenge overproduced ROS and regulate the local NO expression level simultaneously. After the intracardiac injection to mice, NO-RIG converted to gel via physiological temperature-responsive character, distributed homogeneously, and retained in the myocardial tissue for more than 10 d. Treatment with NO-RIG remarkably decreased the infarction size and improved the heart function after myocardial infarction when compared to control injectable hydrogels, such as a simple NO-releasing or ROS-scavenging injectable gels. We found that NO-RIG treatment significantly enhanced the angiogenesis and new blood vessels formation in mice through the regulation of the NO sustained release and redox equilibrium. NO-RIG presents high potential in preventing and treating cardiovascular diseases.
The transgenic chicken derived anti-CD20 monoclonal antibodies exhibits greater anti-cancer therapeutic potential with enhanced Fc effector functions Biomaterials (IF 8.402) Pub Date : 2018-03-13 Young Min Kim, Jin Se Park, Sang Kyung Kim, Kyung Min Jung, Young Sun Hwang, Mookyoung Han, Hong Jo Lee, Hee Won Seo, Jeong-Yong Suh, Beom Ku Han, Jae Yong Han
Modern genetic techniques, enable the use of animal bioreactor systems for the production and functional enhancement of anti-cancer antibodies. Chicken is the most efficient animal bioreactor for the production of anti-cancer antibodies because of its relatively short generation time, plentiful reproductive capacity, and daily deposition in the egg white. Although several studies have focused on the production of anti-cancer antibodies in egg white, in-depth studies of the biological activity and physiological characteristics of transgenic chicken-derived anti-cancer antibodies have not been fully carried out. Here, we report the production of an anti-cancer monoclonal antibody against the CD20 protein from egg whites of transgenic hens, and validated the bio-functional activity of the protein in B-lymphoma and B-lymphoblast cells. Quantitative analysis showed that deposition of the chickenised CD20 monoclonal antibody (cCD20 mAb) from transgenic chickens increased in successive generations and with increasing transgene copy number. Ultra-performance liquid chromatography (UPLC) tandem mass spectrometry (LC/MS/MS) analysis showed that the cCD20 mAb exhibited 14 N-glycan patterns with high-mannose, afucosylation and terminal galactosylation. The cCD20 mAb did not exhibit significantly improved Fab-binding affinity, but showed markedly enhanced Fc-related functions, including complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) compared to commercial rituximab, a chimeric mAb against CD20. Our results suggest that the transgenic chicken bioreactor is an efficient system for producing anti-cancer therapeutic antibodies with enhanced Fc effector functions.
Nucleosome-inspired nanocarrier obtains encapsulation efficiency enhancement and side effects reduction in chemotherapy by using fullerenol assembled with doxorubicin Biomaterials (IF 8.402) Pub Date : 2018-03-12 Jinglong Tang, Ruirui Zhang, Mengyu Guo, Leihou Shao, Ying Liu, Yuliang Zhao, Suojiang Zhang, Yan Wu, Chunying Chen
Infections associated with mesh repairs of abdominal wall hernias: Are antimicrobial biomaterials the longed-for solution? Biomaterials (IF 8.402) Pub Date : 2018-03-12 O. Guillaume, R. Pérez-Tanoira, R. Fortelny, H. Redl, F. Moriarty, R.G. Richards, D. Eglin, A. Petter Puchner
The incidence of mesh-related infection after abdominal wall hernia repair is low, generally between 1 to 4 %; however, worldwide, this corresponds to tens of thousands of difficult cases to treat annually. Adopting best practices in prevention is one of the keys to reduce the incidence of mesh-related infection. Once the infection is established, however, only a limited number of options are available that provides an efficient and successful treatment outcome. Over the past few years, there has been a tremendous amount of research dedicated to the functionalization of prosthetic meshes with antimicrobial properties, with some receiving regulatory approval and are currently available for clinical use. In this context, it is important to review the clinical importance of mesh infection, its risk factors, prophylaxis and pathogenicity. In addition, we give an overview of the main functionalization approaches that have been applied on meshes to confer anti-bacterial protection, the respective benefits and limitations, and finally some relevant future directions.
Aluminum hydroxide colloid vaccine encapsulated in yeast shells with enhanced humoral and cellular immune responses Biomaterials (IF 8.402) Pub Date : 2018-03-12 Hui Liu, Zhenghu Jia, Chengmao Yang, Mei Song, Zhe Jing, Yapu Zhao, Zhenzhou Wu, Liqing Zhao, Dongsheng Wei, Zhinan Yin, Zhangyong Hong
Understanding interactions between biomaterials and biological systems using proteomics Biomaterials (IF 8.402) Pub Date : 2018-03-12 Ziryan Othman, Berta Cillero Pastor, Sabine van Rijt, Pamela Habibovic
The role that biomaterials play in the clinical treatment of damaged organs and tissues is changing. While biomaterials used in permanent medical devices were required to passively take over the function of a damaged tissue long term, current biomaterials are expected to trigger and harness the self-regenerative potential of the body in situ and then to degrade, the foundation of regenerative medicine. To meet these different requirements, it is imperative to fully understand the interactions biomaterials have with biological systems, in space and in time. This knowledge will lead to a better understanding of the regenerative capabilities of biomaterials aiding their design with improved functionalities (e.g. biocompatibility, bioactivity). Proteins play a pivotal role in the interaction between biomaterials and cells or tissues. Protein adsorption on the material surface is the very first event of this interaction, which is determinant for the subsequent processes of cell growth, differentiation, and extracellular matrix formation. Against this background, the aim of the current review is to provide insight in the current knowledge of the role of proteins in cell–biomaterial and tissue–biomaterial interactions. In particular, the focus is on proteomics studies, mainly using mass spectrometry, and the knowledge they have generated on protein adsorption of biomaterials, protein production by cells cultured on materials, safety and efficacy of new materials based on nanoparticles and the analysis of extracellular matrices and extracellular matrix–derived products. In the outlook, the potential and limitations of this approach are discussed and mass spectrometry imaging is presented as a powerful technique that complements existing mass spectrometry techniques by providing spatial molecular information about the material-biological system interactions.
Regeneration of diaphragm with bio-3D cellular patch Biomaterials (IF 8.402) Pub Date : 2018-03-09 Xiu-Ying Zhang, Yusuke Yanagi, Zijing Sheng, Kouji Nagata, Koichi Nakayama, Tomoaki Taguchi
Neonates with congenital diaphragmatic hernia often require surgical defect closure with a patch. Alternatives to native diaphragmatic tissue are critically needed for this paediatric surgery. The clinical efficacy of mesh patches is limited by complications associated with residual foreign material and by hernia recurrence. In this study, we used a novel bio-3D printer method to generate large scaffold-free tissue patches composed of human cells. The resulting large tissue constructs had high elasticity and strength. Cellular patches were transplanted into rats with surgically created diaphragmatic defects. Rats survived for over 710 days after implantation of tissue constructs. CT confirmed complete tissue integration of the grafts during rat growth. Histology revealed regeneration of muscle structure, neovascularization, and neuronal networks within the reconstructed diaphragms. Our results demonstrate that created cellular patches are a highly safe and effective therapeutic strategy for repairing diaphragmatic defects, and thus pave the way for a clinical trial.
Influence of dynamic flow conditions on adsorbed plasma protein corona and surface-induced thrombus generation on antifouling brushes Biomaterials (IF 8.402) Pub Date : 2018-03-08 Kai Yu, Paula Andruschak, Han Hung Yeh, Dana Grecov, Jayachandran N. Kizhakkedathu
The information regarding the nature of protein corona (and its changes) and cell binding on biomaterial surface under dynamic conditions is critical to dissect the mechanism of surface-induced thrombosis. In this manuscript, we investigated the nature of protein corona and blood cell binding in heparinized recalcified human plasma, platelet rich plasma and whole blood on three highly hydrophilic antifouling polymer brushes, (poly(N, N-dimethylacrylamide) (PDMA), poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) and poly[N-(2-hydroxypropyl) methacrylamide] (PHPMA)) using an in vitro blood loop model at comparable arterial and venous flow, and static conditions. A fluid dynamics model was used initially to better understand the resulting flow patterns in a vertical channel containing the substrates to arrive at the placement of the substrates within the blood loop. The protein binding on the brush modified substrates was determined using ellipsometry, fluorescence microscopy and the nature of the protein corona was investigated using mass spectrometry based proteomics. The flow elevated fouling on brush coated surface from blood. The extent of plasma protein adsorption and platelet adhesion onto PDMA brush was lower than other surfaces in both static and flow conditions. The profiles of adsorbed protein corona showed strong dependence on static or flow condition, and the chemistry of the polymer brushes. Specially, the PDMA brushes under flow conditions was more enriched with coagulation proteins, complement proteins, vitronectin and fibronectin but was less enriched with serum albumin. Apolipoprotein B-100 and complement proteins were the most abundant proteins seen on PMPC and PHPMA surfaces under both flow and static conditions, respectively. Unlike PDMA brush, the flow conditions did not affect the composition of protein corona on PMPC and PHPMA brushes. The nature of the protein corona formed in flow conditions influenced the platelet and red blood cell binding. The dependence of shear stress on platelet adhesion from platelet rich plasma and whole blood highlights the contribution of red blood cells in enhancing platelet adhesion on the surface under high shear condition.
Combinatorial library of chalcogen-containing lipidoids for intracellular delivery of genome-editing proteins Biomaterials (IF 8.402) Pub Date : 2018-03-08 Yamin Li, Tao Yang, Yingjie Yu, Nicola Shi, Liu Yang, Zachary Glass, Justin Bolinger, Isaac James Finkel, Wenhan Li, Qiaobing Xu
“Stepwise extraction” strategy-based injectable bioresponsive composite implant for cancer theranostics Biomaterials (IF 8.402) Pub Date : 2018-03-07 Bowen Yang, Han Lin, Chen Dai, Yu Chen, Jianlin Shi
Production-scale fibronectin nanofibers promote wound closure and tissue repair in a dermal mouse model Biomaterials (IF 8.402) Pub Date : 2018-03-05 Christophe O. Chantre, Patrick H. Campbell, Holly M. Golecki, Adrian T. Buganza, Andrew K. Capulli, Leila F. Deravi, Stephanie Dauth, Sean P. Sheehy, Jeffrey A. Paten, Karl Gledhill, Yanne S. Doucet, Hasan E. Abaci, Seungkuk Ahn, Benjamin D. Pope, Jeffrey W. Ruberti, Simon P. Hoerstrup, Angela M. Christiano, Kevin Kit Parker
Wounds in the fetus can heal without scarring. Consequently, biomaterials that attempt to recapitulate the biophysical and biochemical properties of fetal skin have emerged as promising pro-regenerative strategies. The extracellular matrix (ECM) protein fibronectin (Fn) in particular is believed to play a crucial role in directing this regenerative phenotype. Accordingly, Fn has been implicated in numerous wound healing studies, yet remains untested in its fibrillar conformation as found in fetal skin. Here, we show that high extensional (∼1.2 × 105 s−1) and shear (∼3 × 105 s−1) strain rates in rotary jet spinning (RJS) can drive high throughput Fn fibrillogenesis (∼10 mL/min), thus producing nanofiber scaffolds that are used to effectively enhance wound healing. When tested on a full-thickness wound mouse model, Fn nanofiber dressings not only accelerated wound closure, but also significantly improved tissue restoration, recovering dermal and epidermal structures as well as skin appendages and adipose tissue. Together, these results suggest that bioprotein nanofiber fabrication via RJS could set a new paradigm for enhancing wound healing and may thus find use in a variety of regenerative medicine applications.
Programmable Hydrogels Biomaterials (IF 8.402) Pub Date : 2018-03-05 Yong Wang
Programmable hydrogels are defined as hydrogels that are able to change their properties and functions periodically, reversibly and/or sequentially on demand. They are different from those responsive hydrogels whose changes are passive or cannot be stopped or reversed once started and vice versa. The purpose of this review is to summarize major progress in developing programmable hydrogels from the viewpoints of principles, functions and biomedical applications. The principles are first introduced in three categories including biological, chemical and physical stimulation. With the stimulation, programmable hydrogels can undergo functional changes in dimension, mechanical support, cell attachment and molecular sequestration, which are introduced in the middle of this review. The last section is focused on the introduction and discussion of four biomedical applications including mechanistic studies in mechanobiology, tissue engineering, cell separation and protein delivery.
The effects of monocytes on tumor cell extravasation in a 3D vascularized microfluidic model Biomaterials (IF 8.402) Pub Date : 2018-03-05 A. Boussommier-Calleja, Y. Atiyas, K. Haase, M. Headley, C. Lewis, R.D. Kamm
Metastasis is the leading cause of cancer-related deaths. Recent developments in cancer immunotherapy have shown exciting therapeutic promise for metastatic patients. While most therapies target T cells, other immune cells, such as monocytes, hold great promise for therapeutic intervention. In our study, we provide primary evidence of direct engagement between human monocytes and tumor cells in a 3D vascularized microfluidic model. We first characterize the novel application of our model to investigate and visualize at high resolution the evolution of monocytes as they migrate from the intravascular to the extravascular micro-environment. We also demonstrate their differentiation into macrophages in our all-human model. Our model replicates physiological differences between different monocyte subsets. In particular, we report that inflammatory, but not patrolling, monocytes rely on actomyosin based motility. Finally, we exploit this platform to study the effect of monocytes, at different stages of their life cycle, on cancer cell extravasation. Our data demonstrates that monocytes can directly reduce cancer cell extravasation in a non-contact dependent manner. In contrast, we see little effect of monocytes on cancer cell extravasation once monocytes transmigrate through the vasculature and are macrophage-like. Taken together, our study brings novel insight into the role of monocytes in cancer cell extravasation, which is an important step in the metastatic cascade. These findings establish our microfluidic platform as a powerful tool to investigate the characteristics and function of monocytes and monocyte-derived macrophages in normal and diseased states. We propose that monocyte-cancer cell interactions could be targeted to potentiate the anti-metastatic effect we observe in vitro, possibly expanding the milieu of immunotherapies available to tame metastasis.
Injectable and detachable heparin-based hydrogel micropatches for hepatic differentiation of hADSCs and their liver targeted delivery Biomaterials (IF 8.402) Pub Date : 2018-03-03 YoungMin Hwang, MeeiChyn Goh, Mihye Kim, Giyoong Tae
A micropatterned heparin-based hydrogel system that can provide sustained release of multiple growth factors upon one time loading was prepared via photopolymerization and lithography and it was employed as a culture matrix for differentiating hADSCs into hepatic lineage. Mature differentiation of hADSCs into hepatic lineage in terms of gene expression and immunofluorostaining of hepatic markers, and functional characteristics such as glycogen storage ability and production of albumin and urea was observed on the soft hydrogel (∼400 Pa) when the gel elasticity was modulated. This optimal heparin-based hydrogel was used to prepare micropatches containing hepatic-differentiated cells by 1) micropatterning of the gel on a polyelectrolyte multilayer (PEM), 2) seeding of hADSCs and inducing hepatic differentiation, and 3) electrochemical retrieval of cell-attached micropatches. Upon i.v. injection, the retrieved cell micropatches showed a prolonged retention in the liver and promoted function compared to single cell injection in a rat model. In conclusion, this injectable and detachable miropatterned heparin-based hydrogel system could serve as a total platform for the stem cell differentiation under well-controlled microenvironment in vitro and for targeted delivery of the differentiated cells in vivo.
Systemic study of solvent-assisted active loading of gambogic acid into liposomes and its formulation optimization for improved delivery Biomaterials (IF 8.402) Pub Date : 2018-03-03 Wei-Lun Tang, Wei-Hsin Tang, Andras Szeitz, Jayesh Kulkarni, Pieter Cullis, Shyh-Dar Li
Cargo-free particles of ammonio methacrylate copolymers: From pharmaceutical inactive ingredients to effective anticancer immunotherapeutics Biomaterials (IF 8.402) Pub Date : 2018-03-02 Maryam Alsadat Shetab Boushehri, Valentin Stein, Alf Lamprecht
Inhibition of LYPD1 is critical for endothelial network formation in bioengineered tissue with human cardiac fibroblasts Biomaterials (IF 8.402) Pub Date : 2018-03-02 Shinako Masuda, Katsuhisa Matsuura, Tatsuya Shimizu
Fibroblasts not only play key roles under physiological and pathological conditions in various tissues and organs including the heart but also are indispensable for fabricating bioengineered cardiac tissues and their functions through cell–cell interactions. Because tissue functions and cells surarounding fibroblasts in vivo are different among tissues, the properties of fibroblasts might be different according to their tissue origin. Understanding the molecular mechanisms of fibroblasts may lead to fabrication of bioengineered tissues close to biological tissues. In this study, we found a unique less angiogenic property of human cardiac fibroblasts in vitro compared with human dermal fibroblasts and identified the responsible gene. Cardiac fibroblasts inhibited vascular network formation in co-cultures with various types of vascular endothelial cells. Using microarray analysis and short interfering RNA (siRNA) screening experiments, we identified Ly6/Plaur domain-containing 1 (LYPD1) as responsible for the lack of endothelial cell network formation mediated by cardiac fibroblasts. Inhibition of the LYPD1 gene by siRNA attenuated the anti-angiogenic properties of cardiac fibroblasts, whereas the functional defect was rescued by addition of recombinant LYPD1. These findings suggest that cardiac fibroblasts possess anti-angiogenic properties mediated by LYPD1 and that inhibition of LYPD1 might contribute to the fabrication of vascularized functional bioengineered tissues.
Competition of charge-mediated and specific binding by peptide-tagged cationic Liposome–DNA nanoparticles in vitro and in vivo Biomaterials (IF 8.402) Pub Date : 2018-03-02 Emily Wonder, Lorena Simón-Gracia, Pablo Scodeller, Ramsey N. Majzoub, Venkata Ramana Kotamraju, Kai K. Ewert, Tambet Teesalu, Cyrus R. Safinya
Engineering spheroids potentiating cell-cell and cell-ECM interactions by self-assembly of stem cell microlayer Biomaterials (IF 8.402) Pub Date : 2018-03-01 Yu Bin Lee, Eun Mi Kim, Hayeon Byun, Hyung-kwan Chang, Kwanghee Jeong, Zachary M. Aman, Yu Suk Choi, Jungyul Park, Heungsoo Shin
Numerous methods have been reported for the fabrication of 3D multi-cellular spheroids and their use in stem cell culture. Current methods typically rely on the self-assembly of trypsinized, suspended stem cells, however, show limitations with respect to cell viability, throughput, and accurate recapitulation of the natural microenvironment. In this study, we developed a new system for engineering cell spheroids by self-assembly of micro-scale monolayer of stem cells. We prepared synthetic hydrogels with the surface of chemically formed micropatterns (squares/circles with width/diameter of 200 μm) on which mesenchymal stem cells isolated from human nasal turbinate tissue (hTMSCs) were selectively attached and formed a monolayer. The hydrogel is capable of thermally controlled expansion. As the temperature was decreased from 37 to 4 °C, the cell layer detached rapidly (<10 min) and assembled to form spheroids with consistent size (∼100 μm) and high viability (>90%). Spheroidization was significantly delayed and occurred with reduced efficiency on circle patterns compared to square patterns. Multi-physics mapping supported that delamination of the micro-scale monolayer may be affected by stress concentrated at the corners of the square pattern. In contrast, stress was distributed symmetrically along the boundary of the circle pattern. In addition, treatment of the micro-scale monolayer with a ROCK inhibitor significantly retarded spheroidization, highlighting the importance of contraction mediated by actin stress fibers for the stable generation of spheroidal stem cell structures. Spheroids prepared from the assembly of monolayers showed higher expression, both on the mRNA and protein levels, of ECM proteins (fibronectin and laminin) and stemness markers (Oct4, Sox2, and Nanog) compared to spheroids prepared from low-attachment plates, in which trypsinized single cells are assembled. The hTMSC spheroids also presented enhanced expression levels of markers related to tri-lineage (osteogenic, chondrogenic and adipogenic) differentiation. The changes in microcellular environments and functionalities were double-confirmed by using adipose derived mesenchymal stem cells (ADSCs). This spheroid engineering technique may have versatile applications in regenerative medicine for functionally improved 3D culture and therapeutic cell delivery.
Characterization and application of size-sorted zonal chondrocytes for articular cartilage regeneration Biomaterials (IF 8.402) Pub Date : 2018-03-01 Lu Yin, Yingnan Wu, Zheng Yang, Vinitha Denslin, Xiafei Ren, Ching Ann Tee, Zhangxing Lai, Chwee Teck Lim, Jongyoon Han, Eng Hin Lee
Current clinical approaches for articular cartilage repair have not been able to restore the tissue with zonal architecture, and its biomechanical and functional properties. Mimicking the zonal organization of articular cartilage in neo-tissue by implanting zonal chondrocyte subpopulations in multilayer construct could enhance the functionality of the graft, engineering of stratified tissue has not yet been realized due to lack of efficient and specific zonal chondrocyte isolation protocol. We show that by using a spiral microchannel device, the superficial, middle and deep zone chondrocytes can be separated based on cell size, and enriched from full thickness porcine cartilage in a high-throughput, label-free manner. The size-sorted cells show zone-specific characteristics in RT-PCR analysis of zonal cartilage markers. Both freshly sorted and two-passage expanded zonal chondrocytes formed cartilage tissue in 3D hydrogel, bearing respective zonal characteristics, indicated by RT-PCR, histology, extracellular matrix proteins, and mechanical compression test. In the proof-of-concept in vivo study using a rodent cartilage defect model, the size-sorted zonal chondrocytes when delivered in bi-layered hydrogel construct, facilitated better cartilage repair with mechanically enhanced cartilage tissue, in comparison to conventional chondrocytes implantation. This study provides an effective approach to obtain large numbers of zonal chondrocytes, and demonstrates the translational potential of stratified zonal chondrocyte implantation for clinical repair of critical size cartilage defects.
Supramolecular polymeric chemotherapy based on cucurbituril-PEG copolymer Biomaterials (IF 8.402) Pub Date : 2018-02-28 Hao Chen, Yueyue Chen, Han Wu, Jiang-Fei Xu, Zhiwei Sun, Xi Zhang
We develop a strategy of supramolecular polymeric chemotherapy based on a new kind of water-soluble polymer that bears cucurbituril (CB) in the main-chain. To this end, we synthesized a bis-alkynyl functionalized CB and polymerized it with α,ω-diazide-PEG through click reaction to form the desired CB based main-chain polymer (poly-CB). Anticancer drug, oxaliplatin, could be encapsulated into the cavity of poly-CB to form a supramolecular polymeric complex, which displayed low cytotoxicity to normal cells. In addition, the cytotoxicity of the oxaliplatin was recovered when the complex met cancer cells that could overexpress spermine, e.g. colorectal cancer cell, through competitive replacement of oxaliplatin from CB cavity by spermine. Interestingly, the cytotoxicity of the supramolecular polymeric complex to cancer cells is higher than oxaliplatin itself. The enhanced cytotoxicity should result from a combined effect by combining the release of oxaliplatin from the supramolecular polymeric complex and decrease of spermine in the micro-environment of the cancer cells, as spermine is needed for cell growth and proliferation. One more advantage of the supramolecular polymeric complex is its long circulation performance in vivo compared with the supramolecular complex between oxaliplatin and CB. Therefore, this line of research may open new horizons for supramolecular polymeric chemotherapy.
Biomaterial scaffolds for non-invasive focal hyperthermia as a potential tool to ablate metastatic cancer cells Biomaterials (IF 8.402) Pub Date : 2018-02-28 Francisco Pelaez, Navid Manuchehrabadi, Priyatanu Roy, Harishankar Natesan, Yiru Wang, Emilian Racila, Heather Fong, Kevin Zeng, Abby M. Silbaugh, John C. Bischof, Samira M. Azarin
Stem cell derived phenotypic human neuromuscular junction model for dose response evaluation of therapeutics Biomaterials (IF 8.402) Pub Date : 2018-02-27 Navaneetha Santhanam, Lee Kumanchik, Xiufang Guo, Frank Sommerhage, Yunqing Cai, Max Jackson, Candace Martin, George Saad, Christopher W. McAleer, Ying Wang, Andrea Lavado, Christopher J. Long, James J. Hickman
There are currently no functional neuromuscular junction (hNMJ) systems composed of human cells that could be used for drug evaluations or toxicity testing in vitro. These systems are needed to evaluate NMJs for diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy or other neurodegenerative diseases or injury states. There are certainly no model systems, animal or human, that allows for isolated treatment of motoneurons or muscle capable of generating dose response curves to evaluate pharmacological activity of these highly specialized functional units. A system was developed in which human myotubes and motoneurons derived from stem cells were cultured in a serum-free medium in a BioMEMS construct. The system is composed of two chambers linked by microtunnels to enable axonal outgrowth to the muscle chamber that allows separate stimulation of each component and physiological NMJ function and MN stimulated tetanus. The muscle's contractions, induced by motoneuron activation or direct electrical stimulation, were monitored by image subtraction video recording for both frequency and amplitude. Bungarotoxin, BOTOX® and curare dose response curves were generated to demonstrate pharmacological relevance of the phenotypic screening device. This quantifiable functional hNMJ system establishes a platform for generating patient-specific NMJ models by including patient-derived iPSCs.
Harnessing biochemical and structural cues for tenogenic differentiation of adipose derived stem cells (ADSCs) and development of an in vitro tissue interface mimicking tendon-bone insertion graft Biomaterials (IF 8.402) Pub Date : 2018-02-27 Sajeesh Kumar Madhurakkat Perikamana, Jinkyu Lee, Taufiq Ahmad, Eun Mi Kim, Hayeon Byun, Sangmin Lee, Heungsoo Shin
Tendon-bone interface tissue is extremely challenging to engineer because it exhibits complex gradients of structure, composition, biologics, and cellular phenotypes. As a step toward engineering these transitional zones, we initially analyzed how different (topographical or biological) cues affect tenogenic differentiation of adipose-derived stem cells (ADSCs). We immobilized platelet-derived growth factor - BB (PDGF-BB) using polydopamine (PD) chemistry on random and aligned nanofibers and investigated ADSC proliferation and tenogenic differentiation. Immobilized PDGF greatly enhanced the proliferation and tenogenic differentiation of ADSCs; however, nanofiber alignment had no effect. Interestingly, the PDGF immobilized aligned nanofiber group showed a synergistic effect with maximum expression of tenogenic markers for 14 days. We also generated a nanofiber surface with spatially controlled presentation of immobilized PDGF on an aligned architecture, mimicking native tendon tissue. A gradient of immobilized PDGF was able to control the phenotypic differentiation of ADSCs into tenocytes in a spatially controlled manner, as confirmed by analysis of the expression of tenogenic markers and immunofluorescence staining. We further explored the gradient formation strategy by generation of a symmetrical gradient on the nanofiber surface for the generation of a structure mimicking bone-patellar-tendon-bone with provision for gradient immobilization of PDGF and controlled mineralization. Our study reveals that, together with biochemical cues, favorable topographical cues are important for tenogenic differentiation of ADSCs, and gradient presentation of PDGF can be used as a tool for engineering stem cell–based bone-tendon interface tissues.
Perfluorooctyl bromide & indocyanine green co-loaded nanoliposomes for enhanced multimodal imaging-guided phototherapy Biomaterials (IF 8.402) Pub Date : 2018-02-24 Danli Sheng, Tianzhi Liu, Liming Deng, Liang Zhang, Xuelin Li, Jie Xu, Lan Hao, Pan Li, Haitao Ran, Hangrong Chen, Zhigang Wang
Hypoxia-inducible Factor-1α directs renal regeneration induced by decellularized scaffolds Biomaterials (IF 8.402) Pub Date : 2018-02-24 Yaling Yu, Haomin Cui, Chuan Chen, Gen Wen, Jia Xu, Binbin Zheng, Jianse Zhang, Chunyang Wang, Yimin Chai, Jin Mei
Although mammalian kidney regeneration has been reported to occur throughout life, mature kidneys in mammals are not thought to regenerate sufficiently, particularly glomeruli. In our previous work, we found that renal regeneration could be enhanced by decellularized renal scaffolds after partial nephrectomy. In this study, we verified that the enhanced renal regeneration mediated by decellularized scaffolds could be attributed to regenerated glomeruli, which were counted both indirectly and directly under a microscope. Using the isobaric tag for relative and absolute quantitation, we performed proteomics analysis and found that hypoxia-inducible factor (HIF)-1α may be a key factor involved in induced renal regeneration. Dimethyloxyallyl glycine (DMOG), a propyl hydroxylase inhibitor, was applied to stabilize constitutive expression of HIF-1α protein, and small interfering RNA was used to inhibit gene expression. Administration of DMOG to decellularized scaffold-grafted rats improved the induced renal regeneration, whereas siHif1α transfection decreased the regeneration capacity. These findings revealed the critical role of HIF-1α in renal regeneration and provided important insights into our understanding of kidney development and the treatment of various kidney diseases.
A ratiometric fluorescence probe for lysosomal polarity Biomaterials (IF 8.402) Pub Date : 2018-02-23 Miao Li, Jiangli Fan, Haidong Li, Jianjun Du, Saran Long, Xiaojun Peng
Lysosomal polarity affects the interaction activities between enzymes and substrates at the cellular level. Abnormal lysosomal polarity closely linked with disorders and diseases is worthy of attention. The first fluorescence probe, which can image polarity ratiometrically and detect lysosomal polarity quantitatively, is reported herein. The probe termed NOH can emit dual-peaks both in solvents (λem = 474, 552 nm) and in micro-environment. NOH exhibits the Boltzmann function response of the fluorescence intensity ratio to the polarity in a wide range and localizes at lysosomes specifically (Rr = 0.97). In the method of ratiometric fluorescence imaging with NOH, the variation of lysosomal polarity (Δf) can be directly discerned by the color changes. In virtue of ratiometric fluorescence imaging and the Boltzmann function relationship between the fluorescence intensity ratio and the polarity, lysosomal polarity in MCF-7 cells was calculated to be 0.224 and the polarity in the condition of lysosomal storage disorders (or cell death) could also be obtained. This probe will be a promising tool for studying lysosome-related physiological or pathological processes.
Bacteria-like mesoporous silica-coated gold nanorods for positron emission tomography and photoacoustic imaging-guided chemo-photothermal combined therapy Biomaterials (IF 8.402) Pub Date : 2018-02-23 Cheng Xu, Feng Chen, Hector F. Valdovinos, Dawei Jiang, Shreya Goel, Bo Yu, Haiyan Sun, Todd E. Barnhart, James J. Moon, Weibo Cai
Erythrocyte membrane bioinspired near-infrared persistent luminescence nanocarriers for in vivo long-circulating bioimaging and drug delivery Biomaterials (IF 8.402) Pub Date : 2018-02-23 Jing-Min Liu, Dong-Dong Zhang, Guo-Zhen Fang, Shuo Wang
Combination of biological entities with functional nanostructure would produce the excellent systemic drug-delivery vehicles that possess the ability to cross the biological barriers. Herein, from a biomimetic point of view, erythrocyte membrane bioinspired optical nanocarrier is fabricated by integrating Red Blood Cell (RBC) membrane vesicle with near-infrared persistent luminescence nanophosphors (PLNPs). The triple-doped zinc gallogermanate nanostructures with super-long near-infrared persistent luminescence (ZGGO) are used as optical emission center, mesoporous silica coated on the PLNPs (ZGGO@mSiO2) is employed for drug delivery, and the RBC membrane vesicle is introduced for biomimetic functionalization to ensure the developed nanocarriers bypass macrophage uptake and systemic clearance. Owing to the coating of natural erythrocyte membrane along with membrane lipids and associated membrane proteins, the proposed bioinspired nanocarriers have exhibited cell-mimicking property. Retaining the applicability of PLNPs core that favored in vitro excitation, the developed RBC-ZGGO@mSiO2 biomimetic nanocarriers have demonstrated intense fluorescence, super-long persistent luminescence, monodispersed nanosize, red light renewability, and excellent biocompatibility. In vivo mice bioimaging and biodistribution study demonstrate the erythrocyte membrane bioinspired nanoprobe loaded with doxorubicin as ideal nanocarriers for long-circulating bioimaging, in situ real-time monitoring and drug delivery. We believe the PLNPs-based biomimetic nanocarriers offer a promising nano-platform for diagnostics and therapeutics application.
Necroptotic cancer cells-mimicry nanovaccine boosts anti-tumor immunity with tailored immune-stimulatory modality Biomaterials (IF 8.402) Pub Date : 2018-02-23 Ting Kang, Yukun Huang, Qianqian Zhu, Hao Chen, Yuanyuan Pei, Jingxian Feng, Minjun Xu, Gan Jiang, Qingxiang Song, Tianze Jiang, Hongzhuan Chen, Xiaoling Gao, Jun Chen
A synthetic stroma-free germinal center niche for efficient generation of humoral immunity ex vivo Biomaterials (IF 8.402) Pub Date : 2018-02-21 Kyung-Ho Roh, Hannah K. Wilson, Pallab Pradhan, Kevin Bai, Caitlin D. Bohannon, Gordon Dale, Jardin Leleux, Joshy Jacob, Krishnendu Roy
B cells play a major role in the adaptive immune response by producing antigen-specific antibodies against pathogens and imparting immunological memory. Following infection or vaccination, antibody-secreting B cells and memory B cells are generated in specialized regions of lymph nodes and spleens, called germinal centers. Here, we report a fully synthetic ex-vivo system that recapitulates the generation of antigen-specific germinal-center (GC) like B cells using material-surface driven polyvalent signaling. This synthetic germinal center (sGC) reaction was effectively induced using biomaterial-based artificial “follicular T helper cells (TFH)” that provided both natural CD40−CD40L ligation as well as crosslinking of CD40; and by mimicking artificial “follicular dendritic cells (FDC)” to provide efficient, polyvalent antigen presentation. The artificial sGC reaction resulted in efficient B cell expansion, immunoglobulin (Ig) class switching, and expression of germinal center phenotypes. Antigen presentation during sGC reaction selectively enhanced the antigen-specific B cell population and induced somatic hyper-mutations for potential affinity maturation. The resulting B cell population consisted primarily of GC-like B cells (centrocytes) as well as some plasma-like B cells expressing CD138. With concurrent cell sorting, we successfully created highly enriched populations of antigen-specific B cells. Adoptive transfer of these GC-like B cells into non-irradiated isogeneic or non-lethally irradiated congenic recipient mice showed successful engraftment and survival of the donor cells for the 4 week test period. We show that this material-surface driven sGC reaction can be successfully applied to not only splenic B cells but also B cells isolated from more therapeutically relevant sources such as peripheral blood mononuclear cells (PBMCs), thus making our current work an exciting prospect in the new era of personalized medicine and custom-immunotherapy.
Biodegradable near-infrared-photoresponsive shape memory implants based on black phosphorus nanofillers Biomaterials (IF 8.402) Pub Date : 2018-02-20 Hanhan Xie, Jundong Shao, Yufei Ma, Jiahong Wang, Hao Huang, Na Yang, Huaiyu Wang, Changshun Ruan, Yanfeng Luo, Qu-Quan Wang, Paul K. Chu, Xue-Feng Yu
In this paper, we propose a new shape memory polymer (SMP) composite with excellent near-infrared (NIR)-photoresponsive shape memory performance and biodegradability. The composite is fabricated by using piperazine-based polyurethane (PU) as thermo-responsive SMP incorporated with black-phosphorus (BP) sheets as NIR photothermal nanofillers. Under 808 nm light irradiation, the incorporated BP sheets with concentration of only 0.08 wt% enable rapid temperature increase over the glass temperature of PU and trigger the shape change of the composite with shape recovery rate of ∼100%. The in vitro and in vivo toxicity examinations demonstrate the good biocompatibility of the PU/BP composite, and it degrades naturally into non-toxic carbon dioxide and water from PU and non-toxic phosphate from BP. By implanting PU/BP columns into back subcutis and vagina of mice, they exhibit excellent shape memory activity to change their shape quickly under moderate 808 nm light irradiaiton. Such SMP composite enable the development of intelligent implantable devices, which can be easily controlled by the remote NIR light and degrade gradually after performing the designed functions in the body.
Blood brain barrier (BBB)-disruption in intracortical silicon microelectrode implants Biomaterials (IF 8.402) Pub Date : 2018-02-20 Cassie Bennett, Malaroviyam Samikkannu, Farrah Mohammed, W. Dalton Dietrich, Suhrud M. Rajguru, Abhishek Prasad
Chronically implanted microelectrodes in the neural tissue elicit inflammatory responses that are time varying and have been shown to depend on multiple factors. Among these factors, blood brain barrier (BBB)-disruption has been hypothesized as one of the dominant factors resulting in electrode failure. A series of events that includes BBB and cell-membrane disruption occurs during electrode implantation that triggers multiple biochemical cascades responsible for microglial and astroglial activation, hemorrhage, edema, and release of pro-inflammatory neurotoxic cytokines that causes neuronal degeneration and dysfunction. Typically, microwire arrays and silicon probes are inserted slowly into the neural tissue whereas the silicon Utah MEAs (UMEA) are inserted at a high speed using a pneumatic inserter. In this work, we report the sequelae of electrode-implant induced cortical injury at various acute time points in UMEAs implanted in the brain tissue by quantifying the expression profile for key genes mediating the inflammatory response and tight junction (TJ) and adherens junction (AJ) proteins that form the BBB and are critical to the functioning of the BBB. Our results indicated upregulation of most pro-inflammatory genes relative to naïve controls for all time points. Expression levels for the genes that form the TJ and AJ were downregulated suggestive of BBB-dysfunction. Moreover, there was no significant difference between stab and implant groups suggesting the effects of UMEA insertion-related trauma in the brain tissue. Our results provide an insight into the physiological events related to neuroinflammation and BBB-disruption occurring at acute time-points following insertion of UMEAs.
In vivo spatiotemporal dynamics of NG2 glia activity caused by neural electrode implantation Biomaterials (IF 8.402) Pub Date : 2018-02-20 Steven M. Wellman, Takashi D.Y. Koza
Neural interface technology provides direct sampling and analysis of electrical and chemical events in the brain in order to better understand neuronal function and treat neurodegenerative disease. However, intracortical electrodes experience inflammatory reactions that reduce long-term stability and functionality and are understood to be facilitated by activated microglia and astrocytes. Emerging studies have identified another cell type that participates in the formation of a high-impedance glial scar following brain injury; the oligodendrocyte precursor cell (OPC). These cells maintain functional synapses with neurons and are a crucial source of neurotrophic support. Following injury, OPCs migrate toward areas of tissue injury over the course of days, similar to activated microglia. The delayed time course implicates these OPCs as key components in the formation of the outer layers of the glial scar around the implant. In vivo two-photon laser scanning microscopy (TPLSM) was employed to observe fluorescently-labeled OPC and microglia reactivity up to 72 h following probe insertion. OPCs initiated extension of cellular processes (2.5 ± 0.4 μm h−1) and cell body migration (1.6 ± 0.3 μm h−1) toward the probe beginning 12 h after insertion. By 72 h, OPCs became activated at a radius of about 190.3 μm away from the probe surface. This study characterized the early spatiotemporal dynamics of OPCs involved in the inflammatory response induced by microelectrode insertion. OPCs are key mediators of tissue health and are understood to have multiple fate potentials. Detailed spatiotemporal characterization of glial behavior under pathological conditions may allow identification of alternative intervention targets for mitigating the formation of a glial scar and subsequent neurodegeneration that debilitates chronic neural interfaces.
Engineering functional and histological regeneration of vascularized skeletal muscle Biomaterials (IF 8.402) Pub Date : 2018-02-20 Jordana Gilbert-Honick, Shama R. Iyer, Sarah M. Somers, Richard M. Lovering, Kathryn Wagner, Hai-Quan Mao, Warren Grayson
Tissue engineering strategies to treat patients with volumetric muscle loss (VML) aim to recover the structure and contractile function of lost muscle tissue. Here, we assessed the capacity of novel electrospun fibrin hydrogel scaffolds seeded with murine myoblasts to regenerate the structure and function of damaged muscle within VML defects to the mouse tibialis anterior muscle. The electrospun fibrin scaffolds provide pro-myogenic alignment and stiffness cues, myomimetic hierarchical structure, suturability, and scale-up capabilities. Myoblast-seeded scaffolds enabled remarkable muscle regeneration with high myofiber and vascular densities after 2 and 4 weeks, mimicking that of native skeletal muscle, while acellular scaffolds lacked muscle regeneration. Both myoblast-seeded and acellular scaffolds fully recovered muscle contractile function to uninjured values after 2 and 4 weeks. Electrospun scaffolds pre-vascularized with co-cultured human endothelial cells and human adipose-derived stem cells implanted into VML defects for 2 weeks anastomosed with host vasculature and were perfused with host red blood cells. These data demonstrate the significant potential of electrospun fibrin scaffolds seeded with myoblasts to fully regenerate the structure and function of volumetric muscle defects and these scaffolds offer a promising treatment option for patients with VML.
A bilayer swellable drug-eluting ureteric stent: Localized drug delivery to treat urothelial diseases Biomaterials (IF 8.402) Pub Date : 2018-02-20 Wei Shan Lim, Kenneth Chen, Tsung Wen Chong, Gordon Minru Xiong, William R. Birch, Jisheng Pan, Bae Hoon Lee, Pei Shan Er, Abhijit Vijay Salvekar, Subbu S. Venkatraman, Yingying Huang
A bilayer swellable drug-eluting ureteric stent (BSDEUS) is engineered and implemented, as a sustained drug delivery platform technology that enhances localized drug delivery to the highly impermeable urothelium, for the treatment of urothelial diseases such as strictures and carcinomas. On deployment, the device swells to co-apt with the ureteric wall and ensure drug availability to these tissues. BSDEUS consists of a stent spray-coated with a polymeric drug containing polylactic acid-co-caprolactone (PLC) layer which is overlaid by a swellable polyethylene glycol diacrylate (PEGDA) based hydrogel. In-vitro quantification of released drug demonstrated a tunable time-profile, indicating sustained delivery over 1-month. The PEGDA hydrogel overlayer enhanced drug release and transport into explanted porcine ureteric tissues ex-vivo, under a simulated dynamic fluid flow. A preliminary pilot in-vivo feasibility study, in a porcine model, demonstrated that the swollen hydrogel co-apts with the urothelium and thus enables localized drug delivery to the target tissue section. Kidney functions remained unaffected and device did not result in either hydronephrosis or systemic toxicity. This successful engineering of a bilayer coated stent prototype, demonstrates its feasibility, thus offering a unique solution for drug-based urological therapy.
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