| 1. |
- Almendros, Isaac, et al.
(author)
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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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In: Breathe. - : European Respiratory Society (ERS). - 1810-6838 .- 2073-4735. ; 14:2, s. 78-83
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Journal article (peer-reviewed)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.
(author)
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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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In: Bio-protocol. - 2331-8325. ; 12:16
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Journal article (peer-reviewed)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.
(author)
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Current and Future Engineering Strategies for ECMO Therapy
- 2023
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In: Advances in Experimental Medicine and Biology. - 0065-2598 .- 2214-8019. ; 1413, s. 313-326
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Book chapter (peer-reviewed)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.
(author)
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The Preparation of Decellularized Mouse Lung Matrix Scaffolds for Analysis of Lung Regenerative Cell Potential
- 2019
-
In: Methods in molecular biology (Clifton, N.J.). - New York, NY : Springer New York. - 1940-6029. ; 1940, s. 275-295
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Journal article (peer-reviewed)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.
(author)
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Organ-Restricted Vascular Delivery of Nanoparticles for Lung Cancer Therapy
- 2020
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In: Advanced Therapeutics. - : Wiley. - 2366-3987. ; 3:7
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Journal article (peer-reviewed)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.
(author)
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Preclinical evidence for the role of stem/stromal cells in COPD
- 2019. - 1
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In: Stem Cell-Based Therapy for Lung Disease. - Cham : Springer International Publishing. - 9783030294021 - 9783030294038 ; , s. 73-96
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Book chapter (peer-reviewed)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.
(author)
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X-Ray Dark-Field Imaging of Lung Cancer in Mice
- 2019. - 1
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In: Lung Imaging and CADx. - Boca Raton : Taylor & Francis, 2018. : CRC Press. - 9780429055959
-
Book chapter (peer-reviewed)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.
(author)
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Extracellular-Matrix-Reinforced Bioinks for 3D Bioprinting Human Tissue
- 2021
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In: Advanced Materials. - : Wiley. - 1521-4095 .- 0935-9648. ; 33:3
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Journal article (peer-reviewed)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.
(author)
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How to build a lung : latest advances and emerging themes in lung bioengineering
- 2018
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In: European Respiratory Journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 52, s. 1-19
-
Research review (peer-reviewed)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.
(author)
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Integrin α10β1-selected mesenchymal stem cells reduced hypercoagulopathy in a porcine model of acute respiratory distress syndrome
- 2023
-
In: Respiratory Research. - 1465-9921. ; 24:1
-
Journal article (peer-reviewed)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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| 11. |
- Hägerbrand, Karin, et al.
(author)
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Bispecific antibodies targeting CD40 and tumor-associated antigens promote cross-priming of T cells resulting in an antitumor response superior to monospecific antibodies
- 2022
-
In: Journal for ImmunoTherapy of Cancer. - : BMJ. - 2051-1426. ; 10:11
-
Journal article (peer-reviewed)abstract
- Background Indications with poor T-cell infiltration or deficiencies in T-cell priming and associated unresponsiveness to established immunotherapies represent an unmet medical need in oncology. CD40-targeting therapies designed to enhance antigen presentation, generate new tumor-specific T cells, and activate tumor-infiltrating myeloid cells to remodel the tumor microenvironment, represent a promising opportunity to meet this need. In this study, we present the first in vivo data supporting a role for tumor-associated antigen (TAA)-mediated uptake and cross-presentation of tumor antigens to enhance tumor-specific T-cell priming using CD40×TAA bispecific antibodies, a concept we named Neo-X-Prime. Methods Bispecific antibodies targeting CD40 and either of two cell-surface expressed TAA, carcinoembryonic antigen-related cell adhesion molecule 5 (CEA) or epithelial cell adhesion molecule (EpCAM), were developed in a tetravalent format. TAA-conditional CD40 agonism, activation of tumor-infiltrating immune cells, antitumor efficacy and the role of delivery of tumor-derived material such as extracellular vesicles, tumor debris and exosomes by the CD40×TAA bispecific antibodies were demonstrated in vitro using primary human and murine cells and in vivo using human CD40 transgenic mice with different tumor models. Results The results showed that the CD40×TAA bispecific antibodies induced TAA-conditional CD40 activation both in vitro and in vivo. Further, it was demonstrated in vitro that they induced clustering of tumor debris and CD40-expressing cells in a dose-dependent manner and superior T-cell priming when added to dendritic cells (DC), ovalbumin (OVA)-specific T cells and OVA-containing tumor debris or exosomes. The antitumor activity of the Neo-X-Prime bispecific antibodies was demonstrated to be significantly superior to the monospecific CD40 antibody, and the resulting T-cell dependent antitumor immunity was directed to tumor antigens other than the TAA used for targeting (EpCAM). Conclusions The data presented herein support the hypothesis that CD40×TAA bispecific antibodies can engage tumor-derived vesicles containing tumor neoantigens to myeloid cells such as DCs resulting in an improved DC-mediated cross-priming of tumor-specific CD8 + T cells. Thus, this principle may offer therapeutics strategies to enhance tumor-specific T-cell immunity and associated clinical benefit in indications characterized by poor T-cell infiltration or deficiencies in T-cell priming.
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| 12. |
- Lovén, Karin, et al.
(author)
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Toxicological effects of zinc oxide nanoparticle exposure : an in vitro comparison between dry aerosol air-liquid interface and submerged exposure systems
- 2021
-
In: Nanotoxicology. - : Taylor and Francis Ltd.. - 1743-5390 .- 1743-5404. ; 15:4, s. 494-510
-
Journal article (peer-reviewed)abstract
- Engineered nanomaterials (ENMs) are increasingly produced and used today, but health risks due to their occupational airborne exposure are incompletely understood. Traditionally, nanoparticle (NP) toxicity is tested by introducing NPs to cells through suspension in the growth media, but this does not mimic respiratory exposures. Different methods to introduce aerosolized NPs to cells cultured at the air-liquid-interface (ALI) have been developed, but require specialized equipment and are associated with higher cost and time. Therefore, it is important to determine whether aerosolized setups induce different cellular responses to NPs than traditional ones, which could provide new insights into toxicological responses of NP exposure. This study evaluates the response of human alveolar epithelial cells (A549) to zinc oxide (ZnO) NPs after dry aerosol exposure in the Nano Aerosol Chamber for In Vitro Toxicity (NACIVT) system as compared to conventional, suspension-based exposure: cells at ALI or submerged. Similar to other studies using nebulization of ZnO NPs, we found that dry aerosol exposure of ZnO NPs via the NACIVT system induced different cellular responses as compared to conventional methods. ZnO NPs delivered at 1.0 µg/cm2 in the NACIVT system, mimicking occupational exposure, induced significant increases in metabolic activity and release of the cytokines IL-8 and MCP-1, but no differences were observed using traditional exposures. While factors associated with the method of exposure, such as differing NP aggregation, may contribute toward the different cellular responses observed, our results further encourage the use of more physiologically realistic exposure systems for evaluating airborne ENM toxicity. © 2021 The Author(s).
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| 13. |
- Petrou, Cassandra L., et al.
(author)
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Clickable decellularized extracellular matrix as a new tool for building hybrid-hydrogels to model chronic fibrotic diseases in vitro
- 2020
-
In: Journal of Materials Chemistry B. - 2050-7518. ; 8:31, s. 6814-6826
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Journal article (peer-reviewed)abstract
- Fibrotic disorders account for over one third of mortalities worldwide. Despite great efforts to study the cellular and molecular processes underlying fibrosis, there are currently few effective therapies. Dual-stage polymerization reactions are an innovative tool for recreating heterogeneous increases in extracellular matrix (ECM) modulus, a hallmark of fibrotic diseases in vivo. Here, we present a clickable decellularized ECM (dECM) crosslinker incorporated into a dynamically responsive poly(ethylene glycol)-α-methacrylate (PEGαMA) hybrid-hydrogel to recreate ECM remodeling in vitro. An off-stoichiometry thiol-ene Michael addition between PEGαMA (8-arm, 10 kg mol-1) and the clickable dECM resulted in hydrogels with an elastic modulus of E = 3.6 ± 0.24 kPa, approximating healthy lung tissue (1-5 kPa). Next, residual αMA groups were reacted via a photo-initiated homopolymerization to increase modulus values to fibrotic levels (E = 13.4 ± 0.82 kPa) in situ. Hydrogels with increased elastic moduli, mimicking fibrotic ECM, induced a significant increase in the expression of myofibroblast transgenes. The proportion of primary fibroblasts from dual-reporter mouse lungs expressing collagen 1a1 and alpha-smooth muscle actin increased by approximately 60% when cultured on stiff and dynamically stiffened hybrid-hydrogels compared to soft. Likewise, fibroblasts expressed significantly increased levels of the collagen 1a1 transgene on stiff regions of spatially patterned hybrid-hydrogels compared to the soft areas. Collectively, these results indicate that hybrid-hydrogels are a new tool that can be implemented to spatiotemporally induce a phenotypic transition in primary murine fibroblasts in vitro.
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| 14. |
- Petrou, Cassandra L., et al.
(author)
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Clickable, hybrid hydrogels as tissue culture platforms for modeling chronic pulmonary diseases in vitro
- 2019
-
In: Society for Biomaterials Annual Meeting and Exposition 2019 : The Pinnacle of Biomaterials Innovation and Excellence - Transactions of the 42nd Annual Meeting - The Pinnacle of Biomaterials Innovation and Excellence - Transactions of the 42nd Annual Meeting. - 9781510883901 ; 40
-
Conference paper (peer-reviewed)abstract
- Statement of Purpose: Many chronic pulmonary diseases, including idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD), are complex and poorly understood. While great progress has been made to elucidate the cellular and molecular pathways underlying these diseases, treatment options remain limited. The dynamic alterations in mechanical properties and composition of the ECM that occur during pathologic tissue remodeling have been extensively studied as a major driver of cellular activation and disease progression. However, current in vitro models of pulmonary tissues rely almost exclusively on naturally derived materials, such as Matrigel, collagen or decellularized ECM (dECM), which provide biological activity but cannot be easily tuned to emulate the time-dependent changes in mechanical properties that occur during disease progression. We aim to develop a new class of clickable, dynamically tunable hybrid hydrogels that will allow for the manipulation of microenvironmental mechanical properties through a two-stage polymerization process while also maintaining the complex biological composition of the lung ECM to provide a new tool for studying cell behavior in vitro. Using PH as a model, this hydrogel system will contain dECM from healthy and pathologic lung tissue in order to study the influence of both composition and dynamic mechanical properties on the initiation and progression of PH. Here, we determined the primary amine content in Rat-Tail Collagen Type I (Col I) and three decellularized porcine lung samples. We converted free amines to thiol groups using Traut’s reagent. These thiol groups will ultimately be used to crosslink polyethylene glycol alpha methacrylate (PEGαMA) off-stoichiometry in a Michael addition reaction to form the hybrid hydrogel that can later be stiffened through a secondary, light-initiated homopolymerization of MA moieties to emulate disease progression in vitro (Fig 1A).
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| 15. |
- Ryan, Amy L, et al.
(author)
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Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases 2017 : An Official American Thoracic Society Workshop Report
- 2019. - 4
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Reports (other academic/artistic)abstract
- The University of Vermont Larner College of Medicine, in collaboration with the National Heart, Lung, and Blood Institute (NHLBI), the Alpha-1 Foundation, the American Thoracic Society, the Cystic Fibrosis Foundation, the European Respiratory Society, the International Society for Cell & Gene Therapy, and the Pulmonary Fibrosis Foundation, convened a workshop titled "Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases" from July 24 through 27, 2017, at the University of Vermont, Burlington, Vermont. The conference objectives were to review and discuss current understanding of the following topics: 1) stem and progenitor cell biology and the role that they play in endogenous repair or as cell therapies after lung injury, 2) the emerging role of extracellular vesicles as potential therapies, 3) ex vivo bioengineering of lung and airway tissue, and 4) progress in induced pluripotent stem cell protocols for deriving lung cell types and applications in disease modeling. All of these topics are research areas in which significant and exciting progress has been made over the past few years. In addition, issues surrounding the ethics and regulation of cell therapies worldwide were discussed, with a special emphasis on combating the growing problem of unproven cell interventions being administered to patients with lung diseases. Finally, future research directions were discussed, and opportunities for both basic and translational research were identified.
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| 16. |
- Stenlo, Martin, et al.
(author)
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Increased particle flow rate from airways precedes clinical signs of ARDS in a porcine model of LPS-induced acute lung injury
- 2020
-
In: American Journal of Physiology: Lung Cellular and Molecular Physiology. - : American Physiological Society. - 1522-1504 .- 1040-0605. ; 318:3, s. 510-517
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Journal article (peer-reviewed)abstract
- Acute respiratory distress syndrome (ARDS) is a common cause of death in the intensive care unit, with mortality rates of ~30-40%. To reduce invasive diagnostics such as bronchoalveolar lavage and time-consuming in-hospital transports for imaging diagnostics, we hypothesized that particle flow rate (PFR) pattern from the airways could be an early detection method and contribute to improving diagnostics and optimizing personalized therapies. Porcine models were ventilated mechanically. Lipopolysaccharide (LPS) was administered endotracheally and in the pulmonary artery to induce ARDS. PFR was measured using a customized particles in exhaled air (PExA 2.0) device. In contrast to control animals undergoing mechanical ventilation and receiving saline administration, animals who received LPS developed ARDS according to clinical guidelines and histologic assessment. Plasma levels of TNF-α and IL-6 increased significantly compared with baseline after 120 and 180 min, respectively. On the other hand, the PFR significantly increased and peaked 60 min after LPS administration, i.e., ~30 min before any ARDS stage was observed with other well-established outcome measurements such as hypoxemia, increased inspiratory pressure, and lower tidal volumes or plasma cytokine levels. The present results imply that PFR could be used to detect early biomarkers or as a clinical indicator for the onset of ARDS.
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| 17. |
- Stenlo, Martin, et al.
(author)
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Monitoring lung injury with particle flow rate in LPS- and COVID-19-induced ARDS
- 2021
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In: Physiological Reports. - : Wiley. - 2051-817X. ; 9:13
-
Journal article (peer-reviewed)abstract
- In severe acute respiratory distress syndrome (ARDS), extracorporeal membrane oxygenation (ECMO) is a life-prolonging treatment, especially among COVID-19 patients. Evaluation of lung injury progression is challenging with current techniques. Diagnostic imaging or invasive diagnostics are risky given the difficulties of intra-hospital transportation, contraindication of biopsies, and the potential for the spread of infections, such as in COVID-19 patients. We have recently shown that particle flow rate (PFR) from exhaled breath could be a noninvasive, early detection method for ARDS during mechanical ventilation. We hypothesized that PFR could also measure the progress of lung injury during ECMO treatment. Lipopolysaccharide (LPS) was thus used to induce ARDS in pigs under mechanical ventilation. Eight were connected to ECMO, whereas seven animals were not. In addition, six animals received sham treatment with saline. Four human patients with ECMO and ARDS were also monitored. In the pigs, as lung injury ensued, the PFR dramatically increased and a particular spike followed the establishment of ECMO in the LPS-treated animals. PFR remained elevated in all animals with no signs of lung recovery. In the human patients, in the two that recovered, PFR decreased. In the two whose lung function deteriorated while on ECMO, there was increased PFR with no sign of recovery in lung function. The present results indicate that real-time monitoring of PFR may be a new, complementary approach in the clinic for measurement of the extent of lung injury and recovery over time in ECMO patients with ARDS.
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| 18. |
- Tas, Sinem, et al.
(author)
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3D printing of decellularised porcine lung ECM
- 2019
-
In: Society for Biomaterials Annual Meeting and Exposition 2019 : The Pinnacle of Biomaterials Innovation and Excellence - Transactions of the 42nd Annual Meeting - The Pinnacle of Biomaterials Innovation and Excellence - Transactions of the 42nd Annual Meeting. - 9781510883901 ; 40, s. 962-962
-
Conference paper (peer-reviewed)abstract
- Statement of Purpose: Chronic lung diseases are one of the major health problems that cause death and disability. Approximately 65 million people suffer from chronic lung diseases, and the number of patients is predicted to increase worldwide 1 . Lung transplantation is the only available treatment option for patients at end-stage disease. However, there is a chronic shortage of donor organs, resulting in a large unmet clinical need. To tackle this issue, the concept of transplantable bioengineered lungs has been proposed as a solution which might help to meet current transplantation needs 2 One of the ways to potentially build complex lung structure is 3D bioprinting, but bioinks which are compatible with 3D printers, support cell growth, and can maintain appropriate mechanical stability are unknown. In this regard, decellularized extracellular matrix (dECM) based materials are considered as a potential novel source of material for bioinks because they have been shown in other contexts to provide a suitable microenvironment for regeneration. However, there has been no investigation of their use in 3D printing of complex shapes. In this study, we evaluated the rheological properties of porcine lungderived dECM solutions and hydrogels to assess their suitability for 3D printing and to determine parameters which can be used to produce stable structures.
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| 19. |
- Tas, Sinem, et al.
(author)
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Chain End-Functionalized Polymer Brushes with Switchable Fluorescence Response
- 2019
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In: Macromolecular Chemistry and Physics. - : Wiley. - 1022-1352. ; 220:5
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Journal article (peer-reviewed)abstract
- Herein is described the switchable fluorescence response of poly(methyl methacrylate) (PMMA) brushes. Chain end fluorescein labeled PMMA brushes are prepared by combining surface-initiated atom transfer radical polymerization (SI-ATRP) with a copper-catalyzed alkyne-azide cycloaddition (CuAAC) click reaction. Successful attachment of fluorescein is confirmed by measuring fluorescence of the as-prepared films. Utilizing co-solvency of PMMA in isopropanol-water mixtures, responsive behavior of the end-functionalized brushes is demonstrated by measuring the changes in fluorescence intensity between the swollen and collapsed states.
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