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![Classification of CFTR mutations. A schematic showing six categories of CFTR mutations [4].](publication/352753188/figure/fig1/AS:1038761446084609@1624671436846/Classification-of-CFTR-mutations-A-schematic-showing-six-categories-of-CFTR-mutations.png)
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Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene: the gene product responsible for transporting chloride and bicarbonate ions through the apical membrane of most epithelial cells. Major clinical features of CF include respiratory failure, pancreatic exocrine insuff...
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... the first description of CF in 1938 [1], over 2000 mutations in the CFTR gene that produce a broad range of patient phenotypes have been discovered [2,3]. Presently, mutations are categorized into six classes based on their primary biological defect (Figure 1) [4]. Class I (synthesis) mutations result in a total or partial loss of CFTR protein expression caused by the introduction of a premature termination codon [3]. ...
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... In the modern context, such situations arise where the biological characteristics that define cause and needed treatment are very rare, or even unique, so that n (the number of research participants with a condition) does not allow statistically based inferences or aggregations of populations altogether. This may be because the genetic variant in itself is very rare or unique (i.e., rare disease) (Ogden et al. 2021;Synofzik et al. 2022). It may also be the case if the combination of or interplay between all the causally relevant factors and/or the combination of treatments that are thought needed to tackle them produce very rare or unique cases (Klauschen et al. 2014). ...
Modern personalized medicine or precision medicine (PM) promises to take medical epistemology and evidence-based medicine a step further by accounting for variation among individuals. It promises tailoring of treatments to the unique biological characteristics of each person’s specific health problem through analysis of data from genomic and other molecular “omics” technologies, a widening array of monitoring technologies, as well as organoids and related technologies. In an important sense, it promises both personalization and scientific reliability, turning what has previously often been thought of as the art of medicine into a science. But how can treatments directed at the uniqueness of individuals be known and shown to work in an evidence-based world dependent on population- based knowledge? A main method for documenting that treatments work in PM is stratification, which is a population-based strategy that compares the patient to smaller, more similar, subgroups. But PM also sometimes promises to move beyond stratification: To treat the individual as a truly unique case without relying on population-based clinical studies. This chapter asks if and how this might be done. It is divided in two main parts: The first considers strategies that go into such personalization before a treatment is first given through an historically informed survey of different forms of PM. The second considers strategies that may allow personalization beyond stratification after the treatment is first given. The chapter ends by arguing that the art of medicine resurfaces amid promises of scientific, high-tech PM.
... Organ-on-a-chip technology [17] aims to model human organs using microfluidic channels, separated by membranes with different levels of permeability to allow communication between cell types. CF-like conditions can be reproduced with the addition of an extracellular matrix and controlled oxygen conditions [18]. Miniaturized sensors on these chips allow real-time monitoring and rapid adjustments to pH, substrate levels, etc. [19]. ...
A workshop was held by the PIPE-CF strategic research centre to consider preclinical testing of antimicrobials for cystic fibrosis (CF). The workshop brought together groups of people from the CF community to discuss current challenges and identify priorities when developing CF therapeutics. This paper summarizes the key points from the workshop from the different sessions, including talks given by presenters on the day and round table discussions. Currently, it is felt that there is a large disconnect throughout the community, with communication between patients, clinicians and researchers being the main issue. This leads to little consideration being given to factors such as treatment regimes, routes of administration and side effects when developing new therapies, that could alter the day-to-day lifestyles of people living with CF. Translation of numerical data that are obtained in the laboratory to successful outcomes of clinical trials is also a key challenge facing researchers today. Laboratory assays in preclinical testing involve basing results on bacterial clearance and decrease in viable cells, when these are not factors that are considered when determining the success of a treatment in the clinic. However, there are several models currently in development that seek to tackle some of these issues, such as the organ-on-a-chip technology and adaptation of a hollow-fibre model, as well as the development of media that aim to mimic the niche environments of a CF respiratory tract. It is hoped that by summarizing these opinions and discussing current research, the communication gap between groups can begin to close.
... Additionally, examining the correlation between microbiome changes and inflammatory alterations using later-generation CFTR modulators such as elexacaftor/tezacaftor/ivacaftor in various age groups will likely provide both greater insight into underlying pathobiological interactions and, potentially, further opportunities for therapeutic intervention. Moreover, organs-ona-chip, modern microengineered systems that mimic the physiological, functional, and physiochemical characteristics of human tissue, provide a platform to study inflammation, drug efficacy, pathogenesis, and disease model development in CF [129]. The uptake of this technology is in the early stages as the chip model undergoes further refinement in cell adhesion and mixing, as well as moves toward a 3D cell culture. ...
The interplay between airway inflammation and infection is now recognized as a major factor in the pathobiology in cystic fibrosis (CF). A proinflammatory environment is seen throughout the CF airway resulting in classic marked and enduring neutrophilic infiltrations, irreversibly damaging the lung. Although this is seen to occur early, independent of infection, respiratory microbes arising at different timepoints in life and the world environment perpetuate this hyperinflammatory state. Several selective pressures have allowed for the CF gene to persist until today despite an early mortality. Comprehensive care systems, which have been a cornerstone of therapy for the past few decades, are now revolutionized by CF transmembrane conductance regulator (CTFR) modulators. The effects of these small-molecule agents cannot be overstated and can be seen as early as in utero. For an understanding of the future, this review looks into CF studies spanning the historical and present period.
... CF was discovered in 1938 [5] and over 2,000 mutations have now been identified [6,7]. CFTR mutations have been classified into six categories based upon the molecular defect of the CFTR protein: Class I (defect in protein synthesis), Class II (defect in protein trafficking), Class III (defect in channel gating function), Class IV (defect in channel conductance), Class V (defect in mRNA stability) and Class VI (defect in protein stability) [6,8]. Deletion of the phenylala-nine codon at position 508 (ΔF508) is well studied overall and causes a trafficking disorder that leads to the most common and severe dysfunction in the CFTR protein. ...
We report a rare case of a patient with cystic fibrosis suffering from debilitating abdominal pain due to chronic pancreatitis. This 13-year-old patient was evaluated for surgical intervention to relieve pain from chronic pancreatitis and to improve quality of life. The patient carried two mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene; the most common ΔF508 variant and a second variant, p.Glu1044Gly, which has not been previously described. The patient's condition did not improve despite medical management and multiple endoscopic interventions, and therefore total pancreatectomy with islet autotransplantation and a near-total duodenectomy was offered for definitive management. Patient-derived duodenal crypts were isolated and cultured from the resected duodenum, and duodenal organoids were generated to test CFTR function. Our studies demonstrate that this novel mutation (ΔF508/p.Glu1044Gly) caused severely impaired CFTR function in vitro. The Food and Drug Administration (FDA)-approved drug ivacaftor, a CFTR potentiator, was identified to robustly improve CFTR function in the context of this novel mutation. Herein, we describe a personalized medicine approach consisting of performing drug testing on individual patient derived organoids that has potential to guide management of patients with novel CFTR genetic mutations. Identified effective medical therapeutics using this approach may avoid irreversible surgical treatments such as total pancreatectomy with islet autotransplantation in the future.
... The design of lung tissue focuses on creating a device that would replicate a mechanically active alveolar-capillary interface with a functional basement membrane (BM) [4][5][6]. Among the diseases designed on-chip are pneumonia [7,8], chronic obstructive pulmonary disease (COPD) [9], asthma [10,11], tuberculosis (TB) [12], lung cancer [13][14][15][16][17][18][19], and cystic fibrosis [20,21]. To simulate a diseased state, 'healthy' tissues are treated with chemicals and/or particles that induce pathological changes. ...
Microfluidic organs-on-chips or microphysiological systems (MPS) are promising tools that can potentially replace animal testing in drug development. MPS are platforms with microchannels seeded with certain organ cells used to emulate in vivo environments in laboratory conditions. Among them, platforms seeded with lung cells called lung-on-chip devices can evaluate the influence of toxic particles, gases, and chemicals on lung tissue in vitro. Lung-on-chip devices allow the mimicry of healthy lung conditions and a wide range of dis-eases (asthma, cancer, autoimmune, infections). This review focuses on the use of electrospun nanofiber membranes as a functional basement membrane which plays a central role in the development of lung-on-a-chip platforms. Here, we briefly introduce microfluidic devices, MPS, and lung-on-chip devices. Existing basement membrane models such as thin-film and gel-based membranes, and their challenges/disadvantages are discussed. Next, the concepts of electrospinning and nanofiber membranes are introduced. Finally, the nanofiber membranes used in lung-on-chip devices are reviewed. Implementation of different polymer mate-rials used to synthesize the nanofiber membranes and different methods for incorporation of the membrane inside the device are discussed. Electrospun nanofiber membranes provide good mechanical properties, allow transmigration of the immune cells, and withstand the physiological strain without affecting the cell viability.
... Dysfunction of CFTR leads to impaired hydration of epithelial surfaces and to the formation of a thick, dehydrated secretion in the excretory glands. The main lesions are seen in the lungs and pancreas; changes are also observed in many other organs and systems, including the intestines, liver and gonads [4]. Multiple lesions of organs and systems in patients with CF may lead to changes affecting drugs pharmacokinetics. ...
(1) Background: Ciprofloxacin (CPF) is widely used for the treatment of cystic fibrosis, including pediatric patients, but its pharmacokinetics is poorly studied in this population. Optimal CPF dosing in pediatric patients may be affected by gene polymorphism of the enzymes involved in its biotransformation. (2) Materials and Methods: a two-center prospective non-randomized study of CPF pharmacokinetics with sequential enrollment of patients (n-33, mean age 9.03 years, male-33.36%), over a period from 2016 to 2021. All patients received tablets of the original CPF drug Cyprobay® at a dose of 16.5 mg/kg to 28.80 mg/kg. Blood sampling schedule: 0 (before taking the drug), 1.5 h; 3.0 h; 4.5 h; 6.0 h; 7.5 h after the first dosing. CPF serum concentrations were analyzed by high performance liquid chromatography mass spectrometry. The genotype of biotransformation enzymes was studied using total DNA isolated from whole blood leukocytes by the standard method. (4) Results: a possible relationship between the CA genotype of the CYP2C9 gene (c.1075A > C), the GG genotype of the CYP2D6*4 gene (1846G > A), the AG genotype of the GSTP1 gene (c.313A > G), the GCLC* genotype 7/7 and the CPF concentration in plasma (increased value of the area under the concentration–time curve) was established. Conclusions: Gene polymorphism of biotransformation enzymes may affect ciprofloxacin pharmacokinetics in children.
... This led to researchers searching for new ways to allow testing on human cells (Wikswo et al., 2013;Marx, 2016;Zheng et al., 2016;Kodzius et al., 2017;Jusoh et al., 2019). The concept of OoC is revolutionary, having a "minime" (personalized chip) on which different drugs can be tested on a system similar to that of the patient, making it possible to detect the correct drug without harming the patient, in same time permitting the selecting of optimal treatment that would be useful for the selected OoC design (Zhang and Radisic, 2017;Ogden et al., 2021). OoC uses at its base the control of microfluids, which are generally restricted geometrically to a small quantity of fluid in the range of nanoliters. ...
Organ-on-a-chip (OoC), also known as micro physiological systems or “tissue chips” have attracted substantial interest in recent years due to their numerous applications, especially in precision medicine, drug development and screening. Organ-on-a-chip devices can replicate key aspects of human physiology, providing insights into the studied organ function and disease pathophysiology. Moreover, these can accurately be used in drug discovery for personalized medicine. These devices present useful substitutes to traditional preclinical cell culture methods and can reduce the use of in vivo animal studies. In the last few years OoC design technology has seen dramatic advances, leading to a wide range of biomedical applications. These advances have also revealed not only new challenges but also new opportunities. There is a need for multidisciplinary knowledge from the biomedical and engineering fields to understand and realize OoCs. The present review provides a snapshot of this fast-evolving technology, discusses current applications and highlights advantages and disadvantages for biomedical approaches.
The advancement of microfluidics (MFs) for use in a variety of fields has pushed forward technology in many areas, including rapid diagnostics, point-of-care devices, therapeutic manufacturing, and non-animal trial methods for the testing of therapeutics and cosmetics. The importance of MFs was especially highlighted by the role they played in the COVID-19 pandemic, both in the manufacturing of COVID vaccines and in rapid antigen tests that were used widely in clinical and non-clinical settings. In this chapter, the most recent of these advancements in these fields will be discussed. Additionally, ways in which the field of MFs could change in order to push forward further progress will be discussed along with what potential advancements in adjacent fields would be useful for the continued improvement and expansion of MFs.
Human organoids-on-chips (OrgOCs) are the synergism of human organoids (HOs) technology and microfluidic organs-on-chips (OOCs). OOCs can mimic extrinsic characteristics of organs, such as environmental clues of living tissue, while HOs are more amenable to biological analysis and genetic manipulation. By spatial cooperation, OrgOCs served as 3D organotypic living models allowing them to recapitulate critical tissue-specific properties and forecast human responses and outcomes. It represents a giant leap forward from the regular 2D cell monolayers and animal models in the improved human ecological niche modeling. In recent years, OrgOCs have offered potential promises for clinical studies and advanced the preclinical-to-clinical translation in medical and industrial fields. In this review, we highlight the cutting-edge achievements in OrgOCs, introduce the key features of OrgOCs architectures, and share the revolutionary applications in basic biology, disease modeling, preclinical assay and precision medicine. Furthermore, we discuss how to combine a wide range of disciplines with OrgOCs and accelerate translational applications, as well as the challenges and opportunities of OrgOCs in biomedical research and applications.
The treatment of cancers is a significant challenge in the healthcare context today. Spreading circulating tumor cells (CTCs) throughout the body will eventually lead to cancer metastasis and produce new tumors near the healthy tissues. Therefore, separating these invading cells and extracting cues from them is extremely important for determining the rate of cancer progression inside the body and for the development of individualized treatments, especially at the beginning of the metastasis process. The continuous and fast separation of CTCs has recently been achieved using numerous separation techniques, some of which involve multiple high-level operational protocols. Although a simple blood test can detect the presence of CTCs in the blood circulation system, the detection is still restricted due to the scarcity and heterogeneity of CTCs. The development of more reliable and effective techniques is thus highly desired. The technology of microfluidic devices is promising among many other bio-chemical and bio-physical technologies. This paper reviews recent developments in the two types of microfluidic devices, which are based on the size and/or density of cells, for separating cancer cells. The goal of this review is to identify knowledge or technology gaps and to suggest future works.
