Recent Advances in Additive Manufacturing and 3D Bioprinting for Organs-On-A-Chip and Microphysiological Systems.

The re-creation of physiological cellular microenvironments that truly resemble complex in vivo architectures is the key aspect in the development of advanced in vitro organotypic tissue constructs. Among others, organ-on-a-chip technology has been increasingly used in recent years to create improved models for organs and tissues in human health and disease, because of its ability to provide spatio-temporal control over soluble cues, biophysical signals and biomechanical forces necessary to maintain proper organotypic functions. While media supply and waste removal are controlled by microfluidic channel by a network the formation of tissue-like architectures in designated micro-structured hydrogel compartments is commonly achieved by cellular self-assembly and intrinsic biological reorganization mechanisms. The recent combination of organ-on-a-chip technology with three-dimensional (3D) bioprinting and additive manufacturing techniques allows for an unprecedented control over tissue structures with the ability to also generate anisotropic constructs as often seen in in vivo tissue architectures. This review highlights progress made in bioprinting applications for organ-on-a-chip technology, and discusses synergies and limitations between organ-on-a-chip technology and 3D bioprinting in the creation of next generation biomimetic in vitro tissue models.

A Decade of Organs-on-a-Chip Emulating Human Physiology at the Microscale: A Critical Status Report on Progress in Toxicology and Pharmacology.

Organ-on-a-chip technology has the potential to accelerate pharmaceutical drug development, improve the clinical translation of basic research, and provide personalized intervention strategies. In the last decade, big pharma has engaged in many academic research cooperations to develop organ-on-a-chip systems for future drug discoveries. Although most organ-on-a-chip systems present proof-of-concept studies, miniaturized organ systems still need to demonstrate translational relevance and predictive power in clinical and pharmaceutical settings. This review explores whether microfluidic technology succeeded in paving the way for developing physiologically relevant human in vitro models for pharmacology and toxicology in biomedical research within the last decade. Individual organ-on-a-chip systems are discussed, focusing on relevant applications and highlighting their ability to tackle current challenges in pharmacological research.

Monitoring tissue-level remodelling during inflammatory arthritis using a three-dimensional synovium-on-a-chip with non-invasive light scattering biosensing.

Rheumatoid arthritis is a chronic, systemic joint disease in which an autoimmune response translates into an inflammatory attack resulting in joint damage, disability and decreased quality of life. Despite recent introduction of therapeutic agents such as anti-TNFα, even the best current therapies fail to achieve disease remission in most arthritis patients. Therefore, research into the mechanisms governing the destructive inflammatory process in rheumatoid arthritis is of great importance and may reveal novel strategies for the therapeutic interventions. To gain deeper insight into its pathogensis, we have developed for the first time a three-dimensional synovium-on-a-chip system in order to monitor the onset and progression of inflammatory synovial tissue responses. In our study, patient-derived primary synovial organoids are cultivated on a single chip platform containing embedded organic-photodetector arrays for over a week in the absence and presence of tumor-necrosis-factor. Using a label-free and non-invasive optical light-scatter biosensing strategy inflammation-induced 3D tissue-level architectural changes were already detected after two days. We demonstrate that the integration of complex human synovial organ cultures in a lab-on-a-chip provides reproducible and reliable information on how systemic stress factors affect synovial tissue architectures.

Optimized plasma-assisted bi-layer photoresist fabrication protocol for high resolution microfabrication of thin-film metal electrodes on porous polymer membranes.

Structured metal thin-film electrodes are heavily used in electrochemical assays to detect a range of analytes including toxins, biomarkers, biological contaminants and cell cultures using amperometric, voltammetric and impedance-based (bio)sensing strategies as well as separation techniques such as dielectrophoresis. Over the last decade, thin-film electrodes have been fabricated onto various durable and flexible substrates including glass, silicon and polymers. However, the combination of thin-film technology with porous polymeric substrates frequently used for biochips often results in limited resolution and poor adhesion of the metal thin-film, thus severely restricting reproducible fabrication and reliable application in e.g. organ-on-a-chip systems. To overcome common problems associated with micro-structured electrode manufacturing on porous substrates, we have optimized a bi-layer lift-off method for the fabrication of thin-film electrodes on commercial porous polyester membranes using a combination of LOR3A with AZ5214E photoresists. To demonstrate practical application of our porous electrode membranes for trans-epithelial electrical resistance measurements a tetrapolar biosensing set-up was used to eliminate the artificial resistance of the porous polymer membrane from the electrochemical recordings. Furthermore, barrier resistance of Bewo trophoblast epithelial cells was compared to a standard Transwell assay readout using a EVOM2 volt-ohm meter. •Bi-layer photo resist lift-off yields resolution down to 2.5 µm.•Argon Plasma-assisted lift-off results in improved adhesion of gold thin films and eliminates the need for chromium adhesion layers.•Membrane electrodes can be used for elimination of the porous membrane resistance during tetra-polar epithelial resistance measurements.

Heart Valve Surgery Performed by Trainee Surgeons: Meta-Analysis of Clinical Outcomes.

BACKGROUND: Cardiac surgical units must balance trainee education with the duty to provide optimal patient care. This is particularly challenging with valvular surgery, given the lower volume and increased complexity of these procedures. The present meta-analysis was conducted to assess the impact of trainee operator status on clinical outcomes following valvular surgery. METHODS: Medline, Embase and CENTRAL databases were systematically searched for studies reporting clinical outcomes according to the training status of the primary operator (consultant or trainee). Data were extracted and meta-analysed according to pre-defined endpoints. RESULTS: Eleven observational studies met the inclusion criteria, reporting on five patient cohorts undergoing mitral valve surgery (n=3975), six undergoing aortic valve replacement (AVR) (n=6236) and three undergoing combined AVR and coronary artery bypass grafting (CABG) (n=3495). Perioperative mortality was not significantly different between trainee and consultant cases for mitral valve surgery (odds ratio [OR] 0.92; 95% confidence interval [CI], 0.62-1.37), AVR (OR 0.67; 95% CI, 0.37-1.24), or combined AVR and CABG (OR 1.07; 95% CI, 0.40-2.85). The incidences of perioperative stroke, myocardial infarction, arrhythmias, acute renal failure, reoperation or wound infection were not significantly different between trainee and consultant cases. There was a paucity of mid-term survival data. CONCLUSIONS: Valvular surgery cases performed primarily by trainees were not associated with adverse perioperative outcomes. These findings suggest the rigorous design of cardiac surgical trainee programs can sufficiently mitigate trainee deficiencies. However, studies with longer follow-up duration and echocardiographic data are required to assess long-term durability and safety.

Equivalent outcomes after coronary artery bypass graft surgery performed by consultant versus trainee surgeons: A systematic review and meta-analysis.

OBJECTIVE: In recent years, concerns have been raised about the learning opportunities available to cardiac surgical trainees. This meta-analysis was conducted to assess the impact of trainee operator status on clinical outcomes after coronary artery bypass graft (CABG) surgery. METHODS: Medline, EMBASE, and the Cochrane Library were systematically searched for studies that reported CABG outcomes according to the training status of the primary operator (consultant vs trainee). Data were independently extracted by 2 investigators; a meta-analysis was conducted according to predefined clinical endpoints. RESULTS: Sixteen observational studies (n = 52,966) met criteria for inclusion, with 8 studies (n = 36,479) reporting propensity-adjusted analyses. Trainee cases were associated with increased aortic crossclamp duration (mean difference: 4.80; 95% confidence interval [CI], 0.76-8.83) and cardiopulmonary bypass duration (mean difference: 4.24; 95% CI, 0.00-8.47). Perioperative mortality was similar for CABG performed primarily by trainees versus consultants (odds ratio 0.98; 95% CI, 0.81-1.18). No significant difference was found in the incidence of perioperative stroke, myocardial infarction, acute renal failure, reoperation for bleeding, or wound infection. Trainee operator status was not associated with increased midterm mortality (hazard ratio 1.00; 95% CI, 0.90-1.11). In subgroup analysis that included 5 studies and 8025 patients, off-pump CABG trainee cases were not associated with increased perioperative mortality or morbidity. CONCLUSIONS: With appropriate supervision, conventional CABG can be performed by trainee surgeons without an adverse impact on perioperative outcomes or midterm survival. Data regarding off-pump CABG are limited, and further research is warranted to ascertain the impact of trainee operator status on long-term outcomes after off-pump CABG.

The engineering of an interventional MRI with a movable 1.5 Tesla magnet.

The engineering of a novel intra-operative MRI system is described. A movable, 1.5 Tesla MRI magnet was placed in a neurosurgical operating room without affecting established neurosurgical procedure. The system allows fast, high-quality MR intra-operative imaging of the brain and spine without the necessity of patient transportation. A neuro-navigational device capable of displaying and updating spatially referenced MR images in the operating room was integrated with the MRI system. Over 100 procedures have been carried out with this system without limiting surgical access and without compromising traditional neurosurgical, nursing or anesthetic techniques. J. Magn. Reson. Imaging 2001;13:78-86.

Analysis of ovariectomy and estrogen effects on body composition in rats by X-ray and magnetic resonance imaging techniques.

Resistance of bone to fracture--bone strength--has been shown to depend on both the amount of bone and its architectural spatial organization. In vivo magnetic resonance (MR) techniques have the capability of imaging bone tissue, including the trabecular microarchitecture and the marrow composition. We have applied in vivo and ex vivo MR methods to the tibia in an ovariectomized rat model of osteoporosis. Specifically, in vivo high-resolution three-dimensional MR imaging and localized MRS were facilitated by specialized coils and high field magnets, resulting in enhanced sensitivity of detection. As a result, in vivo and ex vivo differences in marrow composition were found between sham-ovariectomized, ovariectomized, and ovariectomized animals treated with 17-beta-estradiol. Estrogen effects were detected in vivo 7 days after surgery (3 days into treatment) as a decrease in the tibial fat signal level. The in vivo effects of ovariectomy were observed 56 days after surgery as an increase in MR image fat signal level and spectral fat/water ratio in the proximal tibia. Ex vivo measurements of tibial marrow water signal discriminated clearly between the sham and ovariectomized groups and showed increased individual variations in the treatment group. Imaging further showed that the highest fat content is observed in the epiphysis. Computed tomography confirmed ovariectomy-induced loss of bone in the proximal tibial metaphysis compared with the sham group. This loss of cancellous bone with ovariectomy is consistent with the MR observations of increases in both fat and water in the metaphysis. These data showed that MR techniques complement X-ray techniques in the bone, water, and fat compositional analysis of the appendicular skeleton in response to ovariectomy and pharmacological treatment.