Biology subjects

Ashammakhi, N.

Publications and source records attributed to Ashammakhi, N..

5 recordsLinked to original sources

bioRxiv2024

The role of mitochondrial complex I in the proinflammatory response to polylactide implants

During the foreign body response, immune cells are metabolically rewired after exposure to breakdown products of various biomaterials, including polylactide (PLA) and polyethylene. Particles of polyethylene interact with Toll-like receptor 4 on macrophages, resulting in increased oxygen consumption that forms reactive oxygen species at complex I of the mitochondrial electron transport chain (mETC). However, PLA degradation products bind to monocarboxylate transporters for downstream signaling with elevated oxygen consumption rates, whose functional implication is unclear and remains inferred from cellular responses to polyethylene biomaterials. By chemically probing the function of the mETC, we show that proinflammatory macrophages activated by exposure to amorphous PLA (aPLA) breakdown products rely on mitochondrial respiration for ATP production, independent of oxygen consumption rates. In contrast, macrophages activated by semi-crystalline PLA (cPLA) breakdown products exhibit a metabolic phenotype wherein ATP levels are unaffected by changing oxygen consumption rates. In subcutaneous implants, the incorporation of metformin in aPLA or cPLA to chemically inhibit complex I did not effectively modulate the proinflammatory response to biomaterials, suggesting that PLA degradation products elicit a distinct metabolic program, thus providing an alternative perspective on the role of mitochondrial respiration in the inflammatory response to biomaterials.

bioengineering↗

bioRxiv2023

Regulating the proinflammatory response to implanted composite biomaterials comprising polylactide and hydroxyapatite by targeting immunometabolism

Composite biomaterials comprising polylactide (PLA) and hydroxyapatite (HA) are applied in bone, cartilage and dental regenerative medicine, where HA confers osteoconductive properties. However, after surgical implantation, adverse immune responses to these composites can occur, which have been attributed to size and morphology of HA particles. Approaches to effectively modulate these adverse immune responses have not been described. PLA degradation products have been shown to alter immune cell metabolism, which drives the inflammatory response. Therefore, we aimed to modulate the inflammatory response to composite biomaterials by regulating glycolytic flux with small molecule inhibitors incorporated into composites comprised of amorphous PLA (aPLA) and HA (aPLA+HA). Inhibition at specific steps in glycolysis reduced proinflammatory (CD86+CD206-) and increased pro-regenerative (CD206+) immune cell populations around implanted aPLA+HA resulting in a pro-regenerative microenvironment. Notably, neutrophil and dendritic cell (DC) numbers along with proinflammatory monocyte and macrophage populations were decreased, and Arginase 1 expression among DCs was increased. Targeting immunometabolism to control the inflammatory response to biomaterial composites, and creating a pro-regenerative microenvironment, is a significant advance in tissue engineering where immunomodulation enhances osseointegration, and angiogenesis, which will lead to improved bone regeneration.

bioengineering↗

bioRxiv2022

First Biodegradable Bioactive Glass-based Humidity Sensor

Monitoring changes in edema-associated intracranial pressure that complicates trauma or surgery would lead to improved outcomes. Implantable pressure sensors have been explored, but, these sensors require post-surgical removal leading to risks of injury to brain tissue. Biodegradable implantable sensors would eliminate the risks while providing sensing when needed. Here, we demonstrate a bioactive glass (BaG)-based hydration sensor. A fluorine (CaF2) containing BaG (BaG-F) was produced using a melting manufacturing technique. The structure and electrical properties of the resulting constructs were evaluated to understand the electrical behaviors of this BaG-based sensor. The synthetic process of producing the BaG-F-based sensor was validated by assessing the electrical properties. We demonstrated that this BaG-F chemical composition is highly sensitive to hydration, and that electrical activity (resistive-capacitive) is induced by hydration and reversed by dehydration. These properties make BaG-F suitable for use as a humidity sensor to monitor brain edema and consequently provide an alert for increasing intracranial pressure.

bioengineering↗

bioRxiv2021

A New Bioink For Improved 3D Bioprinting Of Bone-Like Constructs

Bone tissue loss can occur due to disease, trauma or following surgery, in each case treatment involving the use of bone grafts or biomaterials is usually required. Recent development of three-dimensional (3D) bioprinting (3DBP) has enabled the printing of customized bone substitutes. Bioinks used for bone 3DBP employ various particulate phases such as ceramic and bioactive glass particles embedded in the bioink creating a composite. When composite bioinks are used for 3DBP based on extrusion, particles are heterogeneously distributed causing damage to cells due to stresses created during flow in the matrix of the composite. Therefore, the objective of this study was to develop cell-friendly osteopromotive bioink mitigating the risk of cell damage due to the flow of particles. Towards this end, we have linked organic and inorganic components, gelatin methacryloyl (GelMA) and Ag-doped bioactive glass (Ag-BaG), to produce a hybrid material, GelMA-Ag-BaG (GAB). The distribution of the elements present in the Ag-BaG in the resulting hybrid GAB structure was examined. Rheological properties of the resulting hydrogel and its printability, as well as the degree of swelling and degradation over time, were also evaluated. GAB was compared to GelMA alone and GelMA-Ag-BaG nanocomposites. Results showed the superiority of the hybrid GAB bioink in terms of homogenous distribution of the elements in the structure, rheological properties, printability, and degradation profiles. Accordingly, this new bioink represents a major advance for bone 3DBP.

bioengineering↗

bioRxiv2018

An Array of Gut-on-a-Chips for Drug Development

Drug development is a time and cost-consuming long process. Conventionally, this involves the use of two-dimensional (2D) cell culture and animal testing. However, these methods often fail to mimic normal human physiology and drug metabolism, and sometimes complications may occur later because they do not appear in preclinical studies. With recent development of organ-on-a-chip devices, these biomimetic systems try to recapitulate human physiology more than other methods, and promise to largely replace animal studies and reduce costs and complications. Because gut is an important route for drug administration and absorption, gut-on-a-chip platform was developed. To develop a high throughput system, a recent work reported on using a multiplication array of several chip devices, demonstrating the efficiency in studying drug effect on gut barrier function as compared to conventional methods. Huge data was generated, and thus new multidisciplinary approach is needed where data collection, communication and analysis platforms need to be developed. This will enable validation of organ-on-a-chip approach and lay basis for its establishment as efficient and cost-effective tool in drug development. Because of the importance of the work, this commentary highlights important aspects of the topic and try to stimulate new the development of innovations in the field.\n\nDisclosureNo conflict of interest.

cell biology↗