Biomicrofluidic Systems for Hematologic Cancer Research and Clinical Applications.

A persistent challenge in developing personalized treatments for hematologic cancers is the lack of patient specific, physiologically relevant disease models to test investigational drugs in clinical trials and to select therapies in a clinical setting. Biomicrofluidic systems and organ-on-a-chip technologies have the potential to change how researchers approach the fundamental study of hematologic cancers and select clinical treatment for individual patient. Here, we review microfluidics cell-based technology with application toward studying hematologic tumor microenvironments (TMEs) for the purpose of drug discovery and clinical treatment selection. We provide an overview of state-of-the-art microfluidic systems designed to address questions related to hematologic TMEs and drug development. Given the need to develop personalized treatment platforms involving this technology, we review pharmaceutical drugs and different modes of immunotherapy for hematologic cancers, followed by key considerations for developing a physiologically relevant microfluidic companion diagnostic tool for mimicking different hematologic TMEs for testing with different drugs in clinical trials. Opportunities lie ahead for engineers to revolutionize conventional drug discovery strategies of hematologic cancers, including integrating cell-based microfluidics technology with machine learning and automation techniques, which may stimulate pharma and regulatory bodies to promote research and applications of microfluidics technology for drug development.

Elaboration of a finite element model of pancreatic islet dielectric response to gap junction expression and insulin release.

Dielectric spectroscopy could potentially be a powerful tool to monitor isolated human pancreatic islets for applications in diabetes therapy and research. Isolated intact human islets provide the most relevant means to understand the cellular and molecular mechanisms associated with diabetes. The advantages of dielectric spectroscopy for continuous islet monitoring are that it is a non-invasive, inexpensive and real-time technique. We have previously assessed the dielectric response of human islet samples during stimulation and differentiation. Because of the complex geometry of islets, analytical solutions are not sufficiently representative to provide a pertinent model of islet dielectric response. Here, we present a finite element dielectric model of a single intact islet that takes into account the tight packing of islet cells and intercellular junctions. The simulation yielded dielectric spectra characteristic of cell aggregates, similar to those produced with islets. In addition, the simulation showed that both exocytosis, such as what occurs during insulin secretion, and differential gap junction expression have significant effects on islet dielectric response. Since the progression of diabetes has some connections with dysfunctional islet gap junctions and insulin secretion, the ability to monitor these islet features with dielectric spectroscopy would benefit diabetes research.

Microfluidic perfusion systems for secretion fingerprint analysis of pancreatic islets: applications, challenges and opportunities.

A secretome signature is a heterogeneous profile of secretions present in a single cell type. From the secretome signature a smaller panel of proteins, namely a secretion fingerprint, can be chosen to feasibly monitor specific cellular activity. Based on a thorough appraisal of the literature, this review explores the possibility of defining and using a secretion fingerprint to gauge the functionality of pancreatic islets of Langerhans. It covers the state of the art regarding microfluidic perfusion systems used in pancreatic islet research. Candidate analytical tools to be integrated within microfluidic perfusion systems for dynamic secretory fingerprint monitoring were identified. These analytical tools include patch clamp, amperometry/voltametry, impedance spectroscopy, field effect transistors and surface plasmon resonance. Coupled with these tools, microfluidic devices can ultimately find applications in determining islet quality for transplantation, islet regeneration and drug screening of therapeutic agents for the treatment of diabetes.

Dielectric spectroscopy as a viable biosensing tool for cell and tissue characterization and analysis.

The use of dielectric spectroscopy to carry out real time observations of cells and to extract a wealth of information about their physiological properties has expanded in recent years. This popularity is due to the simple, easy to use, non-invasive and real time nature of dielectric spectroscopy. The ease of integrating dielectric spectroscopy with microfluidic devices has allowed the technology to further expand into biomedical research. Dielectric spectra are obtained by applying an electrical signal to cells, which is swept over a frequency range. This review covers the different methods of interpreting dielectric spectra and progress made in applications of impedance spectroscopy for cell observations. First, methods of obtaining specific electrical properties of cells (cell membrane capacitance and cytoplasm conductivity) are discussed. These electrical properties are obtained by fitting the dielectric spectra to different models and equations. Integrating models to reduce the effects of the electrical double layer are subsequently covered. Impedance platforms are then discussed including electrical cell substrate impedance sensing (ECIS). Categories of ECIS systems are divided into microelectrode arrays, interdigitated electrodes and those that allow differential ECIS measurements. Platforms that allow single cell and sub-single cell measurements are then discussed. Finally, applications of impedance spectroscopy in a range of cell observations are elaborated. These applications include observing cell differentiation, mitosis and the cell cycle and cytotoxicity/cell death. Future applications such as drug screening and in point of care applications are then covered.