pinecone/core-2020-05-10-deduplication huggingface dataset:
Eyes on 3D-Current 3D biomimetic disease concept models and potential applications in age-related macular degeneration

Three dimensional cellular models that mimic disease are being increasingly investigated and have opened an exciting new research area into understanding pathomechanisms. The advantage of 3D in vitro disease models is that they allow systematic and in-depth studies of physiological and pathophysiological processes with less costs and ethical concerns that have arisen with animal models. The purpose of the 3D approach is to allow crosstalk between cells and microenvironment, and with cues from the microenvironment, cells can assemble their niche similar to in vivo conditions. The use of 3D models for mimicking disease processes such as cancer, osteoarthritis etc., is only emerging and allows multidisciplinary teams consisting of tissue engineers, biologist biomaterial scientists and clinicians to work closely together. While in vitro systems require rigorous testing before they can be considered as replicates of the in vivo model, major steps have been made, suggesting that they will become powerful tools for studying physiological and pathophysiological processes. This paper aims to summarize some of the existing 3D models and proposes a novel 3D model of the eye structures that are involved in the most common cause of blindness in the Western World, namely age-related macular degeneration (AMD)
Arsonium-Containing Lipophosphoramides, Poly-Functional Nano-Carriers for Simultaneous Antibacterial Action and Eukaryotic Cell Transfection.

International audienceGene therapy of diseases like cystic fibrosis (CF) would consist of delivering a gene medicine towards the lungs via the respiratory tract into the target epithelial cells. Accordingly, poly-functional nano-carriers are required in order to overcome the various successive barriers of such a complex environment, such as airway colonization with bacterial strains. In this work, the antibacterial effectiveness of a series of cationic lipids is investigated before evaluating its compatibility with gene transfer into human bronchial epithelial cells. Among the various compounds considered, some bearing a trimethyl-arsonium headgroup demonstrate very potent biocide effects towards clinically relevant bacterial strains. In contrast to cationic lipids exhibiting no or insufficient antibacterial potency, arsonium-containing lipophosphoramides can simultaneously inhibit bacteria while delivering DNA into eukaryotic cells, as efficiently and safely as in absence of bacteria. Moreover, such vectors can demonstrate antibacterial activity in vitro while retaining high gene transfection efficiency to the nasal epithelium as well as to the lungs in mice in vivo. Arsonium-containing amphiphiles are the first synthetic compounds shown to achieve efficient gene delivery in the presence of bacteria, a property particularly suitable for gene therapy strategies under infected conditions such as within the airways of CF patients
Implantable Silk Composite Microneedles for Programmable Vaccine Release Kinetics and Enhanced Immunogenicity in Transcutaneous Immunization

Microneedle vaccines mimic several aspects of cutaneous pathogen invasion by targeting antigen to skin-resident dendritic cells and triggering local inflammatory responses in the skin, which are correlated with enhanced immune responses. Here, we tested whether control over vaccine delivery kinetics can enhance immunity through further mimicry of kinetic profiles present during natural acute infections. An approach for the fabrication of silk/poly(acrylic acid) (PAA) composite microneedles composed of a silk tip supported on a PAA base is reported. On brief application of microneedle patches to skin, the PAA bases rapidly dissolved to deliver a protein subunit vaccine bolus, while also implanting persistent silk hydrogel depots into the skin for a low-level sustained cutaneous vaccine release over 1–2 weeks. Use of this platform to deliver a model whole-protein vaccine with optimized release kinetics resulted in >10-fold increases in antigen-specific T-cell and humoral immune responses relative to traditional parenteral needle-based immunization.Ragon Institute of MGH, MIT and HarvardNational Institutes of Health (U.S.) (AI095109)United States. Dept. of Defense (Contract W911NF-13-D-0001)United States. Dept. of Defense (Contract W911NF-07-D0004
Rapid Prototyping of Concave Microwells for the Formation of 3D Multicellular Cancer Aggregates for Drug Screening

Microwell technology has revolutionized many aspects of in vitro cellular studies from 2D traditional cultures to 3D in vivo-like functional assays. However, existing lithography-based approaches are often costly and time-consuming. This study presents a rapid, low-cost prototyping method of CO[subscript 2] laser ablation of a conventional untreated culture dish to create concave microwells used for generating multicellular aggregates, which can be readily available for general laboratories. Polymethylmethacrylate (PMMA), polydimethylsiloxane (PDMS), and polystyrene (PS) microwells are investigated, and each produces distinctive microwell features. Among these three materials, PS cell culture dishes produce the optimal surface smoothness and roundness. A549 lung cancer cells are grown to form cancer aggregates of controllable size from ≈40 to ≈80 μm in PS microwells. Functional assays of spheroids are performed to study migration on 2D substrates and in 3D hydrogel conditions as a step towards recapitulating the dissemination of cancer cells. Preclinical anti-cancer drug screening is investigated and reveals considerable differences between 2D and 3D conditions, indicating the importance of assay type as well as the utility of the present approach.Singapore-MIT Alliance for Research and TechnologyMechanobiology Institute, Singapor
Nanostructured hollow tubes based on chitosan and alginate multilayers

The design and production of structures with nanometer-sized polymer ﬁ lms  based on layer-by-layer (LbL) are of particular interest for tissue engineering  since they allow the precise control of physical and biochemical cues of implantable devices. In this work, a method is developed for the preparation of nanostructured hollow multilayers tubes combining LbL and template leaching. The aim is to produce hollow tubes based on polyelectrolyte multilayer ﬁ lms with tuned physical-chemical properties and study their effects on cell behavior. The ﬁnal tubular structures are characterized by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), microscopy, swelling, and mechanical tests, including dynamic mechanical analysis (DMA) in physiological simulated conditions. It is found that more robust ﬁlms could be produced upon chemical cross-linking with genipin. In particular, the mechanical properties conﬁ rms the viscoelastic properties and a storage and young modulus about two times higher. The water uptake decreases from about 390% to 110% after the cross-linking. The biological performance is assessed in terms of cell adhesion, viability, and proliferation. The results obtained with the cross-linked tubes demonstrate that these are more suitable structures for cell adhesion and spreading. The results suggest the potential of these structures to boost the development of innovative tubular structures for tissue engineering approaches.The authors acknowledge the financial support by the Portuguese Foundation for Science and Technology (FCT) through the doctoral and post-doctoral grants with the reference numbers SFRH/BD/81372/2011 (J.M.S.), SFRH/BD/61390/2009 (C.A.C.), SFRH/BD/73119/2010 (I.N.), and SFRH/BPD/489948/2008 (P.S.), respectively, co-financed by the Operational Human Potential Program (POPH) developed under the scope of the National Strategic Reference Framework (QREN) from the European Social Fund (FSE). The authors would also like to acknowledge the project novel smart and biomimetic materials for innovative regenerative medicine approaches (Ref.: RL1 - ABMR - NORTE-01-0124-FEDER-000016) co-financed by North Portugal Regional Operational Programme (ON.2 - O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF)
Osteotropic Therapy via Targeted Layer-by-Layer Nanoparticles

Current treatment options for debilitating bone diseases such as osteosarcoma, osteoporosis, and bone metastatic cancer are suboptimal and have low efficacy. New treatment options for these pathologies require targeted therapy that maximizes exposure to the diseased tissue and minimizes off-target side effects. This work investigates an approach for generating functional and targeted drug carriers specifically for treating primary osteosarcoma, a disease in which recurrence is common and the cure rate has remained around 20%. This approach utilizes the modularity of Layer-by-Layer (LbL) assembly to generate tissue-specific drug carriers for systemic administration. This is accomplished via surface modification of drug-loaded nanoparticles with an aqueous polyelectrolyte, poly(acrylic acid) (PAA), side-chain functionalized with alendronate, a potent clinically used bisphosphonate. Nanoparticles coated with PAA-alendronate are observed to bind and internalize rapidly in human osteosarcoma 143B cells. Encapsulation of doxorubicin, a front-line chemotherapeutic, in an LbL-targeted liposome demonstrates potent toxicity in vitro. Active targeting of 143B xenografts in NCR nude mice with the LbL-targeted doxorubicin liposomes promotes enhanced, prolonged tumor accumulation and significantly improved efficacy. This report represents a tunable approach towards the synthesis of drug carriers, in which LbL enables surface modification of nanoparticles for tissue-specific targeting and treatment.National Institutes of Health (U.S.) (P30 CA14051 (NCI))National Institutes of Health (U.S.) (5 U54 CA151884–02 (CCNE))National Institutes of Health (U.S.) (R01 AG029601 (NIA))National Institutes of Health (U.S.) (R01 EB010246 (NIBIB))David H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute Swanson Biotechnology Center)National Science Foundation (U.S.) (Graduate Research Fellowship)National Health and Medical Research Council (Australia)Massachusetts Institute of Technology (David H. Koch (1962) Chair Professorship in Engineering
Bioactive supramolecular peptide nanofibers for regenerative medicine

Cataloged from PDF version of article.Recent advances in understanding of cell-matrix interactions and the role of the extracellular matrix (ECM) in regulation of cellular behavior have created new perspectives for regenerative medicine. Supramolecular peptide nanofiber systems have been used as synthetic scaffolds in regenerative medicine applications due to their tailorable properties and ability to mimic ECM proteins. Through designed bioactive epitopes, peptide nanofiber systems provide biomolecular recognition sites that can trigger specific interactions with cell surface receptors. The present Review covers structural and biochemical properties of the self-assembled peptide nanofibers for tissue regeneration, and highlights studies that investigate the ability of ECM mimetic peptides to alter cellular behavior including cell adhesion, proliferation, and/or differentiation. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Molecularly engineered self-assembling membranes for cell-mediated degradation.

The use of peptide engineering to develop self-assembling membranes that are responsive to cellular enzyme activities is reported. The membranes are obtained by combining hyaluronan (HA) and a rationally designed peptide amphiphile (PA) containing a proteolytic domain (GPQGIWGQ octapeptide) sensitive to matrix metalloproteinase-1 (MMP-1). Insertion of an octapeptide in a typical PA structure does not disturb its self-assembly into fibrillar nanostructures neither the ability to form membranes with HA. In vitro enzymatic degradation with hyaluronidase and MMP-1 shows that membranes containing the MMP-1 substrate exhibit enhanced enzymatic degradation, compared with control membranes (absence of MMP-1 cleavable peptide or containing a MMP-1 insensitive sequence), being completely degraded after 7 days. Cell viability and proliferation is minimally affected by the enzymatically cleavable functionality of the membrane, but the presence of MMP-1 cleavable sequence does stimulate the secretion of MMP-1 by fibroblasts and interfere with matrix deposition, particularly the deposition of collagen. By showing cell-responsiveness to biochemical signals presented on self-assembling membranes, this study highlights the ability of modulating certain cellular activities through matrix engineering. This concept can be further explored to understand the cellular remodeling process and as a strategy to develop artificial matrices with more biomimetic degradation for tissue engineering applications
Additively manufactured device for dynamic culture of large arrays of 3D tissue engineered constructs

The ability to test large arrays of cell and biomaterial combinations in 3D environments is still rather limited in the context of tissue engineering and regenerative medicine. This limitation can be generally addressed by employing highly automated and reproducible methodologies. This study reports on the development of a highly versatile and upscalable method based on additive manufacturing for the fabrication of arrays of scaffolds, which are enclosed into individualized perfusion chambers. Devices containing eight scaffolds and their corresponding bioreactor chambers are simultaneously fabricated utilizing a dual extrusion additive manufacturing system. To demonstrate the versatility of the concept, the scaffolds, while enclosed into the device, are subsequently surface-coated with a biomimetic calcium phosphate layer by perfusion with simulated body fluid solution. 96 scaffolds are simultaneously seeded and cultured with human osteoblasts under highly controlled bidirectional perfusion dynamic conditions over 4 weeks. Both coated and noncoated resulting scaffolds show homogeneous cell distribution and high cell viability throughout the 4 weeks culture period and CaP-coated scaffolds result in a significantly increased cell number. The methodology developed in this work exemplifies the applicability of additive manufacturing as a tool for further automation of studies in the field of tissue engineering and regenerative medicine.P.F.C. and D.W.H. contributed equally to this work. This work was supported by the Australian Research Council. P.F.C. acknowledges the Portuguese Foundation for Science and Technology for his PhD grant (SFRH/BD/62452/2009)
Recombinant Technology in the Development of Materials and Systems for Soft-Tissue Repair

Producción CientíficaThe field of biomedicine is constantly investing significant research efforts in order to gain a more in-depth understanding of the mechanisms that govern the function of body compartments and to develop creative solutions for the repair and regeneration of damaged tissues. The main overall goal is to develop relatively simple systems that are able to mimic naturally occurring constructs and can therefore be used in regenerative medicine. Recombinant technology, which is widely used to obtain new tailored synthetic genes that express polymeric protein-based structures, now offers a broad range of advantages for that purpose by permitting the tuning of biological and mechanical properties depending on the intended application while simultaneously ensuring adequate biocompatibility and biodegradability of the scaffold formed by the polymers. This Progress Report is focused on recombinant protein-based materials that resemble naturally occurring proteins of interest for use in soft tissue repair. An overview of recombinant biomaterials derived from elastin, silk, collagen and resilin is given, along with a description of their characteristics and suggested applications. Current endeavors in this field are continuously providing more-improved materials in comparison with conventional ones. As such, a great effort is being made to put these materials through clinical trials in order to favor their future use.Ministerio de Industria, Economía y Competitividad (proyectos PRI-PIBAR-2011–1403, MAT2012–38043, MAT2013–42473-R y MAT2013–41723-R)Junta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA152A12, VA155A12 y VA313U14)CIBER-BBN, y la Junta de Castilla y León y el Instituto de Salud Carlos III mediante el "Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León
Cell Invasion in Collagen Scaffold Architectures Characterized by Percolation Theory

The relationship between biological scaffold interconnectivity and cell migration is an important but poorly understood factor in tissue regeneration. Here a scale-independent technique for characterization of collagen scaffold interconnectivity is presented, using a combination of X-ray microcomputed tomography and percolation theory. Confocal microscopy of connective tissue cells reveals this technique as highly relevant for determining the extent of cell invasion.The authors acknowledge financial support from EPSRC, Geistlich Pharma AG and ERC Advanced Grant 320598 3D-E.This is the final version of the article. It first appeared from Wiley at http://dx.doi.org/10.1002/adhm.201500197
Combination Growth Factor Therapy via Electrostatically Assembled Wound Dressings Improves Diabetic Ulcer Healing In Vivo

Chronic skin ulcerations are a common complication of diabetes mellitus, affecting up to one in four diabetic individuals. Despite the prevalence of these wounds, current pharmacologic options for treating them remain limited. Growth factor-based therapies have displayed a mixed ability to drive successful healing, which may be due to nonoptimal delivery strategies. Here, a method for coating commercially available nylon dressings using the layer-by-layer process is described to enable both sustained release and independent control over the release kinetics of vascular endothelial growth factor 165 and platelet-derived growth factor BB. It is shown that the use of strategically spaced diffusion barriers formed spontaneously by disulfide bonds enables independent control over the release rates of incorporated growth factors, and that in vivo these dressings improve several aspects of wound healing in db/db mice
Bioinspired Nanoparticulate Medical Glues for Minimally Invasive Tissue Repair

Delivery of tissue glues through small-bore needles or trocars is critical for sealing holes, affixing medical devices, or attaching tissues together during minimally invasive surgeries. Inspired by the granule-packaged glue delivery system of sandcastle worms, a nanoparticulate formulation of a viscous hydrophobic light-activated adhesive based on poly(glycerol sebacate)-acrylate is developed. Negatively charged alginate is used to stabilize the nanoparticulate surface to significantly reduce its viscosity and to maximize injectability through small-bore needles. The nanoparticulate glues can be concentrated to ≈30 w/v% dispersions in water that remain localized following injection. With the trigger of a positively charged polymer (e.g., protamine), the nanoparticulate glues can quickly assemble into a viscous glue that exhibits rheological, mechanical, and adhesive properties resembling the native poly(glycerol sebacate)-acrylate based glues. This platform should be useful to enable the delivery of viscous glues to augment or replace sutures and staples during minimally invasive procedures.United States. National Institutes of Health (GM086433)United States. National Institutes of Health (DE013023
Controlling shear stress in 3D bioprinting is a key factor to balance printing resolution and stem cell integrity

A microvalve‐based bioprinting system for the manufacturing of high‐resolution, multimaterial 3D‐structures is reported. Applying a straightforward fluid‐dynamics model, the shear stress at the nozzle site can precisely be controlled. Using this system, a broad study on how cell viability and proliferation potential are affected by different levels of shear stress is conducted. Complex, multimaterial 3D structures are printed with high resolution. This work pioneers the investigation of shear stress‐induced cell damage in 3D bioprinting and might help to comprehend and improve the outcome of cell‐printing studies in the future
Poly(Limonene Thioether) Scaffold for Tissue Engineering

A photocurable thiol-ene network polymer, poly(limonene thioether) (PLT32o), is synthesized, characterized, fabricated into tissue engineering scaffolds, and demonstrated in vitro and in vivo. Micromolded PLT32o grids exhibit compliant, elastomeric mechanical behavior similar to grids made of poly(glycerol sebacate) (PGS), an established biomaterial. Multilayered PL32o scaffolds with regular, geometrically defined pore architectures support heart cell seeding and culture in a manner similar to multilayered PGS scaffolds. Subcutaneous implantation of multilayered PLT32o scaffolds with cultured heart cells provides long-term 3D structural support and retains the exogenous cells, whereas PGS scaffolds lose both their structural integrity and the exogenous cells over 31 d in vivo. PLT32o membrane implants retain their dry mass, whereas PGS implants lose 70 percent of their dry mass by day 31. Macrophages are initially recruited to PLT32o and PGS membrane implants but are no longer present by day 31. Facile synthesis and processing in combination with the capability to support heart cells in vitro and in vivo suggest that PLT32o can offer advantages for tissue engineering applications where prolonged in vivo maintenance of 3D structural integrity and elastomeric mechanical behavior are required.United States. National Institutes of Health (R01-HL107503
Harnessing the versatility of bacterial collagen to improve the chondrogenic potential of porous collagen scaffolds

Collagen I foams are used in the clinic as scaffolds to promote articular cartilage repair as they provide a bioactive environment for cells with chondrogenic potential. However, collagen I as a base material does not allow for precise control over bioactivity. Alternatively, recombinant bacterial collagens can be used as  blank slate  collagen molecules to offer a versatile platform for incorporation of selected bioactive sequences and fabrication into 3D scaffolds. Here, we show the potential of Streptococcal collagen-like 2 (Scl2) protein foams modified with peptides designed to specifically and noncovalently bind hyaluronic acid and chondroitin sulfate to improve chondrogenesis of human mesenchymal stem cells (hMSCs) compared to collagen I foams. Specific compositions of functionalized Scl2 foams lead to improved chondrogenesis compared to both nonfunctionalized Scl2 and collagen I foams, as indicated by gene expression, extracellular matrix accumulation, and compression moduli. hMSCs cultured in functionalized Scl2 foams exhibit decreased collagens I and X gene and protein expression, suggesting an advantage over collagen I foams in promoting a chondrocytic phenotype. These highly modular foams can be further modified to improve specific aspects chondrogenesis. As such, these scaffolds also have the potential to be tailored for other regenerative medicine applications