24,521 research outputs found
Nanosized Drug Delivery Systems: Colloids and Gels for Site Specific Targeting
Get PDFRecent advances in nanomedicine and biomaterials have provided new promising tools for in vitro models and targeted drug administration in vivo, aiming to increase efficacy while limiting side effects. Nanosized drug delivery systems are designed to modify the biodistribution of therapeutic agents, in order to enhance their accumulation in the pathological site. Bioactive molecules can be either conjugated to or entrapped into colloidal nanocarriers. Biocompatible nanoparticles (NPs), polymer nanotherapeutics, lipid-based nanomaterials may enhance the stability and the targeted delivery of low molecular weight drugs, as well as nucleic acids and therapeutic proteins. Once administered in vivo, these colloids will face sequential biological barriers, which represent a major challenge for site specific drug delivery. A fine control of key physicochemical characteristics of the nanocarriers, including size, drug loading, and functionality, may lead to a successful barrier penetration and an effective release at the targeted site
Cartilage on chip: Hyper-Physiological Compression in a microscale platform triggers osteoarthritic traits in a cartilage model EUROoC 2019 TU Graz
No full textOsteoarthritis (OA), the musculoskeletal disease with the highest prevalence, is characterized by pathological responses to factors such as mechanical overload. Repeated failures in translating promising disease-modifying OA drugs into clinical success highlight the requirement for more effective disease models. Organs-on-chip are micro-fabricated devices that aim at recapitulating organ functions. Here, we developed an OA-like cartilage model through a microbioreactor providing 3D micro-constructs with confined compression representative of either physiological (10%) or hyperphysiological (30%) strains. The PDMS device comprises two compartments separated by a flexible membrane. The upper compartment consists in a central channel, hosting a 3D cell-laden hydrogel, divided by two series of overhanging posts from culture medium channels. Posts were designed to limit lateral expansion. The bottom compartment is a pneumatic chamber. (Fig.1a) A poro-elastic description of the cell-laden hydrogel was adopted (Fig.1b) Human articular chondrocytes were cultured in a 3D enzymatically cross-linkable and MMP-degradable poly-(ethylene-glycol)-based hydrogel. After 14 days of static culture a cartilage on chip model was achieved (Aggrecan and Col2a1 deposition, Fig.1c increased GAG/DNA ratio). Furthermore, genes highly expressed in human articular cartilage (e.g. PRG4), and of cartilage interzone (GDF5, ATX) were upregulated. (Fig. 1d) Hyper-physiological cyclical compression, applied for 7 days, induced reduction of cartilage ECM constituents, (COL2A1, ACAN) onset of an inflammatory microenvironment (IL6 and IL8 upregulation, enhanced MMP13 production) and hypertrophy related genes (COL10A1, IHH) upregulation. Results testify the possibility of inducing OA-like traits within the model. The proposed device can thus be considered as a proof of concept for in-chip OA modelling
Cartilage-on-chip model: triggering osteoarthritis traits through mechanical compression
No full textOsteoarthritis (OA) is the most common musculoskeletal disease worldwide and yet an effective therapy is still absent. Associated with cartilage degeneration, OA is recognized as a complex whole joint disease [1], making in vitro modelling particularly cumbersome. Available in vitro models are, however, largely 2D based and not representative of the joint environment. As a result, failure meets attempts at translating promising pre-clinical OA disease modifying drugs (DMOADs) into clinical success. This shortcoming calls for more efficient pre-clinical tools, able to reliably predict DMOA drugs’ efficacy in vivo. In this study we developed a microscale platform providing 3D microconstructs with mechanical compression. The device was used in generating an OA cartilage-on-chip model, and DMOADs screening capability assessed
Cartilage on chip: Hyper-Physiological Compression in a microscale platform triggers osteoarthritic traits in a cartilage model
No full textOsteoarthritis (OA) is the musculoskeletal disease with the highest prevalence, however, no effective treatment is currently available. OA is recognized as a whole joint disorder, characterized by pathological responses to environmental factors, being mechanical overload and oxidative stress the most relevant. (1) Repeated failures in translating promising disease-modifying OA drugs into clinical success highlight the requirement for more effective disease modeling tools. Organs-on-chip are micro-fabricated devices that, integrating cellular 3D architecture and specific chemo-mechanical in vivo-like milieu, allow recapitulation of organ functions with unprecedented precision. In this study, we developed healthy and OA-like cartilage models through a microbioreactor providing 3D micro-constructs with confined compression representative of either physiological (10%) or hyperphysiological (30%) strains
A microfluidic platform to assess the response of cartilage progenitor cells within 3D hydrogels to mechanical loading
No full textAdult human nasal chondrocytes (NCs) have been shown to exhibit a large degree of plasticity and regenerative properties typical of mesenchymal progenitor/stem cells. In a recent first-in-human clinical trial it was proven that the use of NCs for treating traumatic articular cartilage defects is safe and feasible. With the final goal to assess whether NCs can be used for the repair of degenerative joint diseases (osteoarthritis, OA), often associated with abnormal loading, proper mechanical conditioning must be considered.
In this study, we present a novel microbioreactor able to mimic the state of compression that chondrocytes experience in human joints, either under physiological (10%) or hyperphysiological (30%) conditions. Based on a previously reported platform for the generation of 3D cardiac constructs, the PDMS device comprises two integrated compartments separated by a flexible membrane. The upper compartment consists in a central channel hosting a 3D cell-laden hydrogel, divided by two series of overhanging posts from two lateral channels for medium perfusion. The bottom one consists in a pneumatic chamber actuated by a custom-made programmable control unit. The posts were specifically designed to limit the lateral expansion of the cell-laden hydrogel, thus ensuring its confined compression while allowing a physiological fluid motion. A computational model was implemented to evaluate the strain field distribution. An enzymatically cross-linkable and degradable poly(ethylene glycol)-based hydrogel was used to encase cells. The microbioreactor was then exploited for predicting the response of human NCs to normal vs abnormal loading.
Pilot tests revealed high cartilage matrix deposition (Aggrecan, Collagen II) after two weeks of static culture. The 10% compression caused a slight increase of the cartilaginous properties of the tissue. The 30% compression led, instead, to a significant decrease in the COL2A1/COL1A1 ratio (index of hyaline cartilage) and to an increase in MMP13 production.
The presented platform thus allows the recapitulation in a chip of physiological/pathological compression levels experienced by cells in the joint microenvironment. Further studies are ongoing to couple inflammatory and mechanical signals to more closely model an OA environment. We propose the system as a medium-throughput tool for screening therapeutic agents in combination with NC or cartilage progenitor cells towards treatment of OA conditions
Jack Alive / Martin Dead : The Location of the "Author" in Jack London\u27s Martin Eden
No full textThis essay is an attempt to read Martin Eden, Jack Londonʼs autobiographical novel, in terms of the inextricable relationship between the author and the protagonist. Critics have often taken the unbalanced plot and the lack of ironic distance between narrator and character in Martin Eden as the technical weakness of London, but this paper argues that the achievement of this novel owes a great deal to the attachment of London to Martin. The unbalanced structure is a necessary product of the severe struggle of the author to kill his romantic alter ego. // Martin, who aspires to win Ruth Morse, tries to cross class boundaries by making a career of a writer. Even after realizing the emptiness of Ruth, who turns out to be nothing but a typical figure of the bourgeoisie, he somehow persists in loving her. The notion underlying here is that, for Martin, love, career and art are fundamentally inseparable. He objects to the aestheteʼs view of Brissenden on account of his separation of art from career. Martinʼs identity and life consist only in the triunity of love/career/art; the alternative is the repudiation of life. Thus, the unnatural delay of his disappointment in love can be regarded as Londonʼs strategy to set the suicide of Martin as the necessary consequence of the story. // By finishing the story and killing Martin, London finally detaches himself from Martin, reconstructs his self, and, unlike Martin, survives as a professional writer. In this sense, Martin Eden is a story about “writerʼs self-reconstruction.
Hyperphysiological compression of articular cartilage induces an osteoarthritic phenotype in a cartilage-on-a-chip model
No full textOwing to population aging, the social impact of osteoarthritis (OA)-the most common musculoskeletal disease-is expected to increase dramatically. Yet, therapy is still limited to palliative treatments or surgical intervention, and disease-modifying OA (DMOA) drugs are scarce, mainly because of the absence of relevant preclinical OA models. Therefore, in vitro models that can reliably predict the efficacy of DMOA drugs are needed. Here, we show, using a newly developed microphysiological cartilage-on-a-chip model that enables the application of strain-controlled compression to three-dimensional articular cartilage microtissue, that a 30% confined compression recapitulates the mechanical factors involved in OA pathogenesis and is sufficient to induce OA traits. Such hyperphysiological compression triggers a shift in cartilage homeostasis towards catabolism and inflammation, hypertrophy, and the acquisition of a gene expression profile akin to those seen in clinical osteoarthritic tissue. The cartilage on-a-chip model may enable the screening of DMOA candidates
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Letter from Martin Chizzick
No full textCongratulations to Duane Pearsall for receiving the Enterpreneur of the Year award; note on the letter was written by Pearsall and it mentions that Martin, the author of the letter, died in a airplane accident
Robert Martin Tiffin's Mystery Man Newspaper Articles
No full textAdvertiser-Tribune newspaper clippings featuring a story about Robert Martin (written by Nancy Kleinhenz), a local author from Tiffin (Ohio) who wrote under the pseudonym of Lee Roberts, and two of his short stories. Martin wrote mystery novels in his spare time, creating more than 22 mystery novels. For more information about Robert Martin and a list of books go to http://www.mysteryfile.com/RMartin/JBennett.html
Towards the joint on a chip: A microfluidic osteochondral model
No full textOsteoarthritis (OA) is the most prevalent musculoskeletal disease, but no pharmacological treatment is yet available. This lack in anti-OA drugs finds among its causes the inadequacy of present OA in vitro models. OA is a multi-factorial disease leading to pathological changes not only in the cartilage but also in the subchondral bone and in the calcified hypertrophic interzone interfacing these two tissues. Classic in vitro systems do not capture this complexity. Here, building on our recently developed microfluidic techniques [1,2], we established a 3D microsystem (Fig. 1a) capable of hosting two directly interfaced microtissues and suitable for induction of OA traits through chemical or mechanical stimulation. Specifically, we aimed at generating a cartilaginous layer in contact with a layer mimicking the hypertrophic interzone
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