Biomimetic scaffolds generally aim at structurally and compositionally imitating native tissue, thus providing a supportive microenvironment to the transplanted or recruited cells in the tissue. Native decellularized porcine extracellular matrix (ECM) is becoming the ultimate bioactive material for the regeneration of different organs. Particularly for cardiac regeneration, ECM is studied as a patch and injectable scaffolds, which improve cardiac function, yet lack reproducibility and are difficult to control or fine‐tune for the desired properties, like most natural materials. Seeking to harness the natural advantages of ECM in a reproducible, scalable, and controllable scaffold, for the first time, a matrix that is produced from whole decellularized porcine cardiac ECM using electrospinning technology, is developed. This unique electrospun cardiac ECM mat preserves the composition of ECM, self‐assembles into the same microstructure of cardiac ECM ,and ,above all, preserves key cardiac mechanical properties. It supports cell growth and function, and demonstrates biocompatibility in vitro and in vivo. Importantly, this work reveals the great potential of electrospun ECM‐based platforms for a wide span of biomedical applications, thus offering the possibility to produce complex natural materials as tailor‐made, well‐defined structures.
High hopes are held for cardiac regenerative therapy, driving a vast research effort towards the development of various cardiac scaffolds using diverse technologies and materials. Nevertheless, the role of factors such as fabrication process and structure in determining scaffold’s characteristics is yet to be discovered. In the present study, the effects of 3D structure and processing method on cardiac scaffolds are addressed using three distinct scaffolds made through different production technologies from the same biomaterial: decellularized porcine cardiac extracellular matrix (pcECM). pcECM patch, injectable pcECM hydrogel, and electrospun pcECM scaffolds were all proven as viable prospective therapies for MI, thus generally preserving pcECM beneficial properties. Yet, as we demonstrate, minor differences in scaffolds composition and micro-morphology as well as substantial differences in their mechanical properties, which arise from their production process, highly affect the interactions of the scaffold with both proliferating cells and functional cells. Hence, the rates of cell attachment, survival, and proliferation significantly vary between the different scaffolds. Moreover, major differences in cell morphology and alignment as well as in matrix remodeling are obtained. Overall, the effects revealed herein can guide a more rational scaffold design for the improved cellular or acellular treatment of different cardiac disease scenarios.
Porcine extracellular matrix (pECM)-derived hydrogels were introduced, in recent years, aiming to benefit the pECM’s microstructure and bioactivity, while controlling the biomaterial’s physical and mechanical properties. The use of pECM from different tissues, however, offers tissue-specific features that can better serve different applications. In this study, pECM hydrogels derived from cardiac, artery, pancreas, and adipose tissues were compared in terms of composition, structure, and mechanical properties. While major similarities were demonstrated between all the pECM hydrogels, their distinctive attributes were also identified, and their substantial effects on cell-ECM interactions were revealed. Furthermore, through comprehensive protein and gene expression analyses, we show, for the first time, that each pECM hydrogel supports the spontaneous differentiation of induced pluripotent stem cells towards the resident cells of its origin tissue. These findings imply that the origin of ECM should be carefully considered when designing a biomedical platform, to achieve a maximal bioactive impact.
The field of angiogenesis research provides deep understanding regarding this important process, which plays fundamental roles in tissue development and different abnormalities. In vitro models offer the advantages of low‐cost high‐throughput research of angiogenesis while sparing animal lives, and enabling the use of human cells. Nevertheless, prevailing in vitro models lack stability and are limited to a few days' assays. This study, therefore, examines the hypothesis that closely mimicking the vascular microenvironment can more reliably support longer angiogenesis processes in vitro. To this end, porcine arterial extracellular matrix (paECM)— a key component of blood vessels—was isolated and processed into a thermally induced hydrogel and characterized in terms of composition, structure, and mechanical properties, thus confirming the preservation of important characteristics of arterial extracellular matrix. This unique hydrogel was further tailored into a three‐dimensional model of angiogenesis using endothelial cells and supporting cells, in a configuration that allows high‐throughput quantitative analysis of cell viability and proliferation, cell migration, and apoptosis, thus revealing the advantages of paECM over frequently used biomaterials. Markedly, when applied with well‐known effectors of angiogenesis, the model measures reflected the expected response, hence validating its efficacy and establishing its potential as a promising tool for the research of angiogenesis.
Whole cell bioreporters, such as bacterial cells, can be used for environmental and clinical sensing of specific analytes. However, the current methods implemented to observe such bioreporters in the form of chemotactic responses heavily rely on microscope analysis, fluorescent labels, and hard-to-scale microfluidic devices. Herein, we demonstrate that chemotaxis can be detected within minutes using intrinsic optical measurements of silicon femtoliter well arrays (FMAs). This is done via phase-shift reflectometric interference spectroscopic measurements (PRISM) of the wells, which act as silicon diffraction gratings, enabling label-free, real-time quantification of the number of trapped bacteria cells in the optical readout. By generating unsteady chemical gradients over the wells, we first demonstrate that chemotaxis toward attractants and away from repellents can be easily differentiated based on the signal response of PRISM. The lowest concentration of chemorepellent to elicit an observed bacterial response was 50 mM, whereas the lowest concentration of chemoattractant to elicit a response was 10 mM. Second, we employed PRISM, in combination with a computational approach, to rapidly scan for and identify a novel synthetic histamine chemoreceptor strain. Consequently, we show that by using a combined computational design approach, together with a quantitative, real-time, and label-free detection method, it is possible to manufacture and characterize novel synthetic chemoreceptors in Escherichia coli (E. coli).
Demonstration of de novo chemotaxis in E. coli using a real-time,
Cancer cell therapy using cytotoxic T lymphocytes (CTL) or mesenchymal stem cells (MSC) possesses hurdles due to the cells, susceptibility to host induced changes. Here, versatile inanimate broadly applicable nanovesicles, termed immunotherapeutic-nano-ghosts (iNGs), are armed with inherent surface-associated targeting and therapeutic capabilities in which the promise and benefits of MSC therapy and T cell immunotherapy are combined into one powerful off-the-shelf approach for treating malignant diseases. To mimic the cytotoxic or immunosuppressive functions of T cells, iNG are produced from MSC that were genetically engineered (GE) or metabolically manipulated to express additional membrane-bound proteins, endowing the NGs derived therefrom with additional surface-associated functions such as tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). iNGs from GE-MSCs (GE-iNGs) show superior TRAIL retention and induce apoptosis in different cancer cell lines in vitro. In vivo studies on a human melanoma model demonstrate that a systemic, three-day frequency, administration of GE-iNGs result in tumor inhibition comparable to a six orders of magnitude higher concentration of soluble TRAIL. The iNGs are therefore a promising nanovesicle platform that can affect tumors in a non-immunogenic manner while avoiding the need for a highly effective therapeutic concentration.
Human-induced pluripotent stem cells (hiPSCs) hold great promise in the fields of regenerative therapy and personalized in vitro tissue models as they provide an almost endless autologous source of virtually any cell type. Their potential benefits can be highly enhanced through polymeric cell microencapsulation, which offers the cells structural support and immune protection from the host tissue. However, in contrast to biologically-inert polymers, decellularized extracellular matrix (dECM)-based microencapsulation also provides the cells a physiologically mimetic bioactive microenvironment while providing reproducibility and scalability. Here we describe the entrapment of hiPSCs in a porcine pancreatic ECM (pECM)-based microencapsulation platform and address its key aspects. To promote high levels of cell survival and
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