| 1. |
- Almendros, Isaac, et al.
(författare)
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Early Career Members at the ERS Lung Science Conference: cell-matrix interactions in lung disease and regeneration: Early career forum
- 2018
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Ingår i: Breathe. - : European Respiratory Society (ERS). - 1810-6838 .- 2073-4735. ; 14:2, s. 78-83
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Tidskriftsartikel (refereegranskat)abstract
- The 16th ERS Lung Science Conference (LSC) took place on March 8–11, 2018, in Estoril, Portugal, with around 200 delegates from all over the world. This year’s topic was “Cell-matrix interactions in lung disease and regeneration” and involved excellent presentations by leading experts in the field covering everything from exploratory studies on how the matrix functions, matrix remodelling and biomarkers in disease, to more technical knowledge described in the field of lung bioengineering. As in previous years, the Saturday afternoon was reserved for a programme dedicated to early career delegates, which this year focussed on “Maximising your publication output”. In this article, we summarise the Early Career Member highlights of this year’s LSC.
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| 2. |
- Augusto Silva, Iran, et al.
(författare)
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A Semi-quantitative Scoring System for Green Histopathological Evaluation of Large Animal Models of Acute Lung Injury
- 2022
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Ingår i: Bio-protocol. - 2331-8325. ; 12:16
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Tidskriftsartikel (refereegranskat)abstract
- Acute respiratory distress syndrome (ARDS) is a life-threatening, high mortality pulmonary condition characterized by acute lung injury (ALI) resulting in diffuse alveolar damage. Despite progress regarding the understanding of ARDS pathophysiology, there are presently no effective pharmacotherapies. Due to the complexity and multiorgan involvement typically associated with ARDS, animal models remain the most commonly used research tool for investigating potential new therapies. Experimental models of ALI/ARDS use different methods of injury to acutely induce lung damage in both small and large animals. These models have historically played an important role in the development of new clinical interventions, such as fluid therapy and the use of supportive mechanical ventilation (MV). However, failures in recent clinical trials have highlighted the potential inadequacy of small animal models due to major anatomical and physiological differences, as well as technical challenges associated with the use of clinical co-interventions [e.g., MV and extracorporeal membrane oxygenation (ECMO)]. Thus, there is a need for larger animal models of ALI/ARDS, to allow the incorporation of clinically relevant measurements and co-interventions, hopefully leading to improved rates of clinical translation. However, one of the main challenges in using large animal models of preclinical research is that fewer species-specific experimental tools and metrics are available for evaluating the extent of lung injury, as compared to rodent models. One of the most relevant indicators of ALI in all animal models is evidence of histological tissue damage, and while histological scoring systems exist for small animal models, these cannot frequently be readily applied to large animal models. Histological injury in these models differs due to the type and severity of the injury being modeled. Additionally, the incorporation of other clinical support devices such as MV and ECMO in large animal models can lead to further lung damage and appearance of features absent in the small animal models. Therefore, semi-quantitative histological scoring systems designed to evaluate tissue-level injury in large animal models of ALI/ARDS are needed. Here we describe a semi-quantitative scoring system to evaluate histological injury using a previously established porcine model of ALI via intratracheal and intravascular lipopolysaccharide (LPS) administration. Additionally, and owing to the higher number of samples generated from large animal models, we worked to implement a more sustainable and greener histopathological workflow throughout the entire process.
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| 3. |
- Bölükbas, Deniz A., et al.
(författare)
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Current and Future Engineering Strategies for ECMO Therapy
- 2023
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Ingår i: Advances in Experimental Medicine and Biology. - 2214-8019 .- 0065-2598. ; 1413, s. 313-326
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Bokkapitel (refereegranskat)abstract
- Extracorporeal membrane oxygenation (ECMO) is a last resort therapy for patients with respiratory failure where the gas exchange capacity of the lung is compromised. Venous blood is pumped through an oxygenation unit outside of the body where oxygen diffusion into the blood takes place in parallel to carbon dioxide removal. ECMO is an expensive therapy which requires special expertise to perform. Since its inception, ECMO technologies have been evolving to improve its success and minimize the complications associated with it. These approaches aim for a more compatible circuit design capable of maximum gas exchange with minimal need for anticoagulants. This chapter summarizes the basic principles of ECMO therapy with the latest advancements and experimental strategies aiming for more efficient future designs.
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| 4. |
- Bölükbas, Deniz A., et al.
(författare)
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The Preparation of Decellularized Mouse Lung Matrix Scaffolds for Analysis of Lung Regenerative Cell Potential
- 2019
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Ingår i: Methods in molecular biology (Clifton, N.J.). - New York, NY : Springer New York. - 1940-6029. ; 1940, s. 275-295
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Tidskriftsartikel (refereegranskat)abstract
- Lung transplantation is the only option for patients with end-stage lung disease, but there is a shortage of available lung donors. Furthermore, efficiency of lung transplantation has been limited due to primary graft dysfunction. Recent mouse models mimicking lung disease in humans have allowed for deepening our understanding of disease pathomechanisms. Moreover, new techniques such as decellularization and recellularization have opened up new possibilities to contribute to our understanding of the regenerative mechanisms involved in the lung. Stripping the lung of its native cells allows for unprecedented analyses of extracellular matrix and sets a physiologic platform to study the regenerative potential of seeded cells. A comprehensive understanding of the molecular pathways involved for lung development and regeneration in mouse models can be translated to regeneration strategies in higher organisms, including humans. Here we describe and discuss several techniques used for murine lung de- and recellularization, methods for evaluation of efficacy including histology, protein/RNA isolation at the whole lung, as well as lung slices level.
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| 5. |
- Bölükbas, Deniz, et al.
(författare)
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Organ-Restricted Vascular Delivery of Nanoparticles for Lung Cancer Therapy
- 2020
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Ingår i: Advanced Therapeutics. - : Wiley. - 2366-3987. ; 3:7
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Tidskriftsartikel (refereegranskat)abstract
- Nanoparticle-based targeted drug delivery holds promise for treatment of cancers. However, most approaches fail to be translated into clinical success due to ineffective tumor targeting in vivo. Here, the delivery potential of mesoporous silica nanoparticles (MSN) functionalized with targeting ligands for epidermal growth factor receptor and C─C chemokine receptor type 2 is explored in lung tumors. The addition of active targeting ligands on MSNs enhances their uptake in vitro but fails to promote specific delivery to tumors in vivo, when administered systemically via the blood or locally to the lung into immunocompetent murine lung cancer models. Ineffective tumor targeting is due to efficient clearance of the MSNs by the phagocytic cells of the liver, spleen, and lung. These limitations, however, are successfully overcome using a novel organ-restricted vascular delivery (ORVD) approach. ORVD in isolated and perfused mouse lungs of Kras-mutant mice enables effective nanoparticle extravasation from the tumor vasculature into the core of solid lung tumors. In this study, ORVD promotes tumor cell-specific uptake of nanoparticles at cellular resolution independent of their functionalization with targeting ligands. Organ-restricted vascular delivery thus opens new avenues for optimized nanoparticles for lung cancer therapy and may have broad applications for other vascularized tumor types.
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| 6. |
- Bölükbas, Deniz, et al.
(författare)
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Preclinical evidence for the role of stem/stromal cells in COPD
- 2019. - 1
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Ingår i: Stem Cell-Based Therapy for Lung Disease. - Cham : Springer International Publishing. - 9783030294021 - 9783030294038 ; , s. 73-96
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Bokkapitel (refereegranskat)abstract
- Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide and there are currently limited treatment options for these patients. The disease is characterized by a reduction in airflow due to chronic bronchitis, as well as airspace enlargement in the distal lung, resulting in a loss of surface area available for gas exchange. At end-stage disease, oxygen therapy and lung transplantation remain the only potential options. The disease is heterogeneous and both inflammatory cells as well as structural cells are thought to play a role in disease onset and progression. Pharmaceutical approaches are ineffective at reversing disease pathology and currently aim only to provide symptomatic relief. A recent area of investigation focuses on exogenous cell therapy, including stem cell administration, and its potential for directing lung regeneration. Cell therapies from a variety of sources, as well as cell-derived products such as extracellular vesicles, have recently shown efficacy in animal models of COPD, but early clinical trials have not yet shown efficacy. In this chapter, we discuss the different animal models of COPD as well as the studies which have been conducted to date with cell therapies. We conclude the chapter with a discussion regarding the limitations of current animal models and discuss potential areas for future study.
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| 7. |
- Bölükbas, Deniz, et al.
(författare)
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X-Ray Dark-Field Imaging of Lung Cancer in Mice
- 2019. - 1
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Ingår i: Lung Imaging and CADx. - Boca Raton : Taylor & Francis, 2018. : CRC Press. - 9780429055959
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Bokkapitel (refereegranskat)abstract
- Lung cancer accounts for 1.6 million deaths per year worldwide. The majority of patients are diagnosed at advanced stages of the disease and often present with metastasis. Thus, the 5-year survival rate of lung cancer remains around 15%. Early diagnosis of lung cancer allows for better control of the disease with 5-year survival rates up to around 70%. Chest radiography is the most common technique for visualizing lungs. However, small lesions in the lung are often missed by conventional X-ray radiography. New technological advances, such as grating-based imaging, allow for better contrast in soft tissue. Grating-based imaging depends on the interactions between the specimen and the X-rays while they pass through, resulting in interference and refraction of the beam. Contrast acquisition from these interactions are categorized as interferometric methods. X-ray dark-field imaging relies on quantification of small-angle scattering of the X-rays during this traverse and has shown success in obtaining enhanced contrast from soft tissues such as the lung. In in vivo models, dark-field imaging has been shown to be superior to conventional radiography for visualization of pulmonary diseases including lung cancer. In this chapter, we summarize applications of this technology for imaging of lung cancer in small animals and discuss its future perspectives and potential challenges in translation.
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| 8. |
- De Santis, Martina M, et al.
(författare)
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Extracellular-Matrix-Reinforced Bioinks for 3D Bioprinting Human Tissue
- 2021
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Ingår i: Advanced Materials. - : Wiley. - 1521-4095 .- 0935-9648. ; 33:3
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Tidskriftsartikel (refereegranskat)abstract
- Recent advances in 3D bioprinting allow for generating intricate structures with dimensions relevant for human tissue, but suitable bioinks for producing translationally relevant tissue with complex geometries remain unidentified. Here, a tissue-specific hybrid bioink is described, composed of a natural polymer, alginate, reinforced with extracellular matrix derived from decellularized tissue (rECM). rECM has rheological and gelation properties beneficial for 3D bioprinting while retaining biologically inductive properties supporting tissue maturation ex vivo and in vivo. These bioinks are shear thinning, resist cell sedimentation, improve viability of multiple cell types, and enhance mechanical stability in hydrogels derived from them. 3D printed constructs generated from rECM bioinks suppress the foreign body response, are pro-angiogenic and support recipient-derived de novo blood vessel formation across the entire graft thickness in a murine model of transplant immunosuppression. Their proof-of-principle for generating human tissue is demonstrated by 3D bioprinting human airways composed of regionally specified primary human airway epithelial progenitor and smooth muscle cells. Airway lumens remained patent with viable cells for one month in vitro with evidence of differentiation into mature epithelial cell types found in native human airways. rECM bioinks are a promising new approach for generating functional human tissue using 3D bioprinting.
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| 9. |
- De Santis, Martina M, et al.
(författare)
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How to build a lung : latest advances and emerging themes in lung bioengineering
- 2018
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 52, s. 1-19
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Forskningsöversikt (refereegranskat)abstract
- Chronic respiratory diseases remain a major cause of morbidity and mortality worldwide. The only option at end-stage disease is lung transplantation, but there are not enough donor lungs to meet clinical demand. Alternative options to increase tissue availability for lung transplantation are urgently required to close the gap on this unmet clinical need. A growing number of tissue engineering approaches are exploring the potential to generate lung tissue ex vivo for transplantation. Both biologically derived and manufactured scaffolds seeded with cells and grown ex vivo have been explored in pre-clinical studies, with the eventual goal of generating functional pulmonary tissue for transplantation. Recently, there have been significant efforts to scale-up cell culture methods to generate adequate cell numbers for human-scale bioengineering approaches. Concomitantly, there have been exciting efforts in designing bioreactors that allow for appropriate cell seeding and development of functional lung tissue over time. This review aims to present the current state-of-the-art progress for each of these areas and to discuss promising new ideas within the field of lung bioengineering.
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| 10. |
- Edström, Dag, et al.
(författare)
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Integrin α10β1-selected mesenchymal stem cells reduced hypercoagulopathy in a porcine model of acute respiratory distress syndrome
- 2023
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Ingår i: Respiratory Research. - 1465-9921. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Mesenchymal stem cells (MSCs) have been studied for their potential benefits in treating acute respiratory distress syndrome (ARDS) and have reported mild effects when trialed within human clinical trials. MSCs have been investigated in preclinical models with efficacy when administered at the time of lung injury. Human integrin α10β1-selected adipose tissue-derived MSCs (integrin α10β1-MSCs) have shown immunomodulatory and regenerative effects in various disease models. We hypothesized that integrin α10β1 selected-MSCs can be used to treat a sepsis-induced ARDS in a porcine model when administering cells after established injury rather than simultaneously. This was hypothesized to reflect a clinical picture of treatment with MSCs in human ARDS. 12 pigs were randomized to the treated or placebo-controlled group prior to the induction of mild to moderate ARDS via lipopolysaccharide administration. The treated group received 5 × 10 6 cells/kg integrin α10β1-selected MSCs and both groups were followed for 12 h. ARDS was confirmed with blood gases and retrospectively with histological changes. After intervention, the treated group showed decreased need for inotropic support, fewer signs of histopathological lung injury including less alveolar wall thickening and reduction of the hypercoagulative disease state. The MSC treatment was not associated with adverse events over the monitoring period. This provides new opportunities to investigate integrin α10β1-selected MSCs as a treatment for a disease which does not yet have any definitive therapeutic options.
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