Premature neonates suffer from respiratory morbidity as their lungs are immature, and current supportive treatment such as mechanical ventilation or extracorporeal membrane oxygenation causes iatrogenic injuries. A non‐invasive and biomimetic concept known as the “artificial placenta” (AP) would be beneficial to overcome complications associated with the current respiratory support of preterm infants. Here, a pumpless oxygenator connected to the systemic circulation supports the lung function to relieve respiratory distress. In this paper, the first successful operation of a microfluidic, artificial placenta type neonatal lung assist device (LAD) on a newborn piglet model, which is the closest representation of preterm human infants, is demonstrated. This LAD has high oxygenation capability in both pure oxygen and room air as the sweep gas. The respiratory distress that the newborn piglet is put under during experimentation, repeatedly and over a significant duration of time, is able to be relieved. These findings indicate that this LAD has a potential application as a biomimetic artificial placenta to support the respiratory needs of preterm neonates.
Global meat consumption has been growing on a per capita basis over the past 20 years resulting in ever-increasing devotion of resources in the form of arable land and potable water to animal husbandry which is unsustainable and inefficient. One approach to meet this insatiable demand is to use biofabrication methods used in tissue engineering in order to make skeletal muscle tissue-like constructs known as cultivated meat to be used as a food source. Here, we demonstrate the use of a scaffold-free biofabrication method that forms cell sheets composed of murine adipocytes and skeletal muscle cells and assembles these sheets in parallel to create a 3D meat-like construct without the use of any exogenous materials. This layer-by-layer self-assembly and stacking process is fast (4 days of culture to form sheets and few hours for assembly) and scalable (stable sheets with diameters >3 cm are formed). Tissues formed with only muscle cells were equivalent to lean meat with comparable protein and fat contents (lean beef had 1.5 and 0.9 times protein and fat, respectively, as our constructs) and incorporating adipocyte cells in different ratios to myoblasts and/or treatment with different media cocktails resulted in a 5% (low fat meat) to 35% (high fat meat) increase in the fat content. Not only such constructs can be used as cultivated meat, they can also be used as skeletal muscle models.
Bioprinting is rapidly developing into a powerful tool in tissue engineering, for both organ printing and the development of in vitro models that can be used in drug discovery, toxicology and in vitro bioreactors. Nevertheless, the ability to create complex 3D culture systems with different types of cells and extracellular matrices integrated with perfusable channels has been a challenge. Here we develop an approach that combines the xurography of a scaffold material (cellulose) with extrusion printing of bioinks onto it, followed by assembly in a layer-by-layer fashion to create complex 3D culture systems that could be used as in vitro models of biological processes. This new method, termed ExCeL, can recapitulate the complexities of natural tissues with a proper 3D distribution of cells, extracellular matrices, and different molecules, while providing the whole structure with mechanical stability, and direct and easy access to the cells, even the ones that are positioned deep in the bulk of the structure, without the need to fix or section the samples. Briefly, the bioprinting of predefined patterns with a feature size of ∼1 mm has been made possible by treating paper with the hydrogel’s crosslinker and printing cell-embedded hydrogel that will solidify immediately upon contact with the paper. These impregnated layers can be used as single layers or in a layer-by-layer approach by stacking them (here up to four layers) for applications such as cell migration and proliferation in 3D structures composed of collagen or alginate. Cells are generally sensitive to the amount of FBS in their culture media and we have shown how FBS amount will effect cell migration. By cutting the paper in certain patterns, printing hydrogel on the remaining parts of it, and stacking the paper in layers, features like embedded channels are formed that will provide cells will better mass transfer in thick structures. This technique provides biologists with a unique tool to perform sophisticated in vitro assays.
The molecular mechanisms of the development and progression of diabetes and obesity involve complex interactions between adipocytes and skeletal muscle cells. Although 2D in‐vitro models are the gold standard for the mechanistic study of such behaviors, they do not recreate the complexity and dynamics of the interactions between the cell types involved. Alternatively, animal models are used but are expensive, difficult to visualize or analyze, are not completely representative of human physiology or genetic background, and have associated ethical considerations. 3D co‐culture systems can be complementary to these approaches. Here, using a newly developed 3D biofabrication method, adipocytes and myoblasts are positioned precisely either in direct physical contact or in close proximity such that the paracrine effects could be systematically studied. Suitable protocols for growth and differentiation of both cells in the co‐culture system is also developed. Cells show more restrained lipid and protein production in 3D systems compared to 2D ones and adipocytes show more lipolysis in indirect contact with myoblasts as response to drug treatment. These findings emphasize importance of physical contact between cells that have been overlooked in co‐culture systems using transwell inserts and can be used in studies for the development of anti‐obesity drugs.
Osteocytes are key contributors to bone remodeling. During the remodeling process, trapped osteoblasts undergo a phenotypic change to become osteocytes. The specific mechanisms by which osteocytes work are still debatable and models that exist to study them are sparse. This work presents an in vitro, bioprinted model based on the previously developed technique, ExCeL, in which a cell‐embedded hydrogel is printed and immediately crosslinked using paper as a crosslinker‐storing substrate. This process mimics the phenotypical change of osteoblast to osteocyte by altering the mechanical properties of the hydrogel. By printing Saos‐2, osteosarcoma cells, embedded in the alginate hydrogel with differing mechanical properties, their morphology, protein, and gene expression can be changed from osteoblast‐like to osteocyte‐like. The stiffer gel is 30 times stiffer and results in significantly smaller cells with reduced alkaline phosphatase activity and expression of osteoblast‐marker genes such as MMP9 and TIMP2. There is no change in viability between cells despite encapsulation in gels with different mechanical properties. The results show that the phenomenon of osteoblasts becoming encapsulated during the bone remodeling process can be replicated using the ExCeL bioprinting technique. This model has potential for studying how osteocytes can interact with external mechanical stimuli or drugs.
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