Publications by authors named "Carlo D"

509 Publications

Development and validation of a cellular host response test as an early diagnostic for sepsis.

PLoS One 2021 15;16(4):e0246980. Epub 2021 Apr 15.

Louisiana State University Health Sciences Center, Baton Rouge, Louisiana, United States of America.

Sepsis must be diagnosed quickly to avoid morbidity and mortality. However, the clinical manifestations of sepsis are highly variable and emergency department (ED) clinicians often must make rapid, impactful decisions before laboratory results are known. We previously developed a technique that allows the measurement of the biophysical properties of white blood cells as they are stretched through a microfluidic channel. In this study we describe and validate the resultant output as a model and score-the IntelliSep Index (ISI)-that aids in the diagnosis of sepsis in patients with suspected or confirmed infection from a single blood draw performed at the time of ED presentation. By applying this technique to a high acuity cohort with a 23.5% sepsis incidence (n = 307), we defined specific metrics-the aspect ratio and visco-elastic inertial response-that are more sensitive than cell size or cell count in predicting disease severity. The final model was trained and cross-validated on the high acuity cohort, and the performance and generalizability of the model was evaluated on a separate low acuity cohort with a 6.4% sepsis incidence (n = 94) and healthy donors (n = 72). For easier clinical interpretation, the ISI is divided into three interpretation bands of Green, Yellow, and Red that correspond to increasing disease severity. The ISI agreed with the diagnosis established by retrospective physician adjudication, and accurately identified subjects with severe illness as measured by SOFA, APACHE-II, hospital-free days, and intensive care unit admission. Measured using routinely collected blood samples, with a short run-time and no requirement for patient or laboratory information, the ISI is well suited to aid ED clinicians in rapidly diagnosing sepsis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246980PLOS
April 2021

Single-Domain Multiferroic Array-Addressable Terfenol-D (SMArT) Micromagnets for Programmable Single-Cell Capture and Release.

Adv Mater 2021 Apr 8:e2006651. Epub 2021 Apr 8.

Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA.

Programming magnetic fields with microscale control can enable automation at the scale of single cells ≈10 µm. Most magnetic materials provide a consistent magnetic field over time but the direction or field strength at the microscale is not easily modulated. However, magnetostrictive materials, when coupled with ferroelectric material (i.e., strain-mediated multiferroics), can undergo magnetization reorientation due to voltage-induced strain, promising refined control of magnetization at the micrometer-scale. This work demonstrates the largest single-domain microstructures (20 µm) of Terfenol-D (Tb Dy Fe ), a material that has the highest magnetostrictive strain of any known soft magnetoelastic material. These Terfenol-D microstructures enable controlled localization of magnetic beads with sub-micrometer precision. Magnetically labeled cells are captured by the field gradients generated from the single-domain microstructures without an external magnetic field. The magnetic state on these microstructures is switched through voltage-induced strain, as a result of the strain-mediated converse magnetoelectric effect, to release individual cells using a multiferroic approach. These electronically addressable micromagnets pave the way for parallelized multiferroics-based single-cell sorting under digital control for biotechnology applications.
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http://dx.doi.org/10.1002/adma.202006651DOI Listing
April 2021

Microbiological Surveillance of Endoscopes in a Southern Italian Transplantation Hospital: A Retrospective Study from 2016 to 2019.

Int J Environ Res Public Health 2021 Mar 16;18(6). Epub 2021 Mar 16.

Istituto di Ricovero e Cura a Carattere Scientifico-Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IRCCS-ISMETT), 90127 Palermo, Italy.

Endoscopes are medical instruments that are used routinely in health structures. Due to their invasive nature and contact with many patients, they may cause hospital-acquired infections if not disinfected correctly. To ensure a high-level disinfection procedure or reprocessing, since the methods currently adopted in our institute are adequate, we evaluated retrospectively the presence of microorganisms in our endoscopes after reprocessing. Microbiological surveillance was performed from January 2016 to December 2019 in the instruments in use in our endoscopic room after reprocessing. In total, 35 endoscopes (3 duodenoscopes, 3 echoendoscopes, 12 bronchoscopes, 5 colonoscopes, and 12 gastroscopes) were evaluated for the presence of microorganisms, including multidrug-resistant pathogens and indicator microorganisms (IMOs). Our procedures were in agreement with an internal protocol based on Italian, international, and the Center for Disease Control and Prevention (CDC) recommendations. Of a total of 811 samples, 799 (98.5%) complied with the regulatory guidelines, while 9 (1.1%) were positive for IMOs, and 3 (0.4%) displayed more than 10 colony-forming units (CFU) of environmental and commensal pathogens. Our results show that the internal reprocessing protocol is very efficient, leading to a very low number of observed contaminations, and it could be easily implemented by other health facilities that face a huge number of hospital-acquired infections due to incorrectly disinfected endoscopes.
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http://dx.doi.org/10.3390/ijerph18063057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002344PMC
March 2021

Injectable, macroporous scaffolds for delivery of therapeutic genes to the injured spinal cord.

APL Bioeng 2021 Mar 9;5(1):016104. Epub 2021 Mar 9.

Department of Bioengineering, University of California, Los Angeles, California 90095, USA.

Biomaterials are being developed as therapeutics for spinal cord injury (SCI) that can stabilize and bridge acute lesions and mediate the delivery of transgenes, providing a localized and sustained reservoir of regenerative factors. For clinical use, direct injection of biomaterial scaffolds is preferred to enable conformation to unique lesions and minimize tissue damage. While an interconnected network of cell-sized macropores is necessary for rapid host cell infiltration into-and thus integration of host tissue with-implanted scaffolds, injectable biomaterials have generally suffered from a lack of control over the macrostructure. As genetic vectors have short lifetimes , rapid host cell infiltration into scaffolds is a prerequisite for efficient biomaterial-mediated delivery of transgenes. We present scaffolds that can be injected and assembled from hyaluronic acid (HA)-based, spherical microparticles to form scaffolds with a network of macropores (∼10 m). The results demonstrate that addition of regularly sized macropores to traditional hydrogel scaffolds, which have nanopores (∼10 nm), significantly increases the expression of locally delivered transgene to the spinal cord after a thoracic injury. Maximal cell and axon infiltration into scaffolds was observed in scaffolds with more regularly sized macropores. The delivery of lentiviral vectors encoding the brain-derived neurotrophic factor (BDNF), but not neurotrophin-3, from these scaffolds further increased total numbers and myelination of infiltrating axons. Modest improvements to the hindlimb function were observed with BDNF delivery. The results demonstrate the utility of macroporous and injectable HA scaffolds as a platform for localized gene therapies after SCI.
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http://dx.doi.org/10.1063/5.0035291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946441PMC
March 2021

Injectable Drug-Releasing Microporous Annealed Particle Scaffolds for Treating Myocardial Infarction.

Adv Funct Mater 2020 Oct 6;30(43). Epub 2020 Sep 6.

Department of Bioengineering, University of California, Los Angeles, CA 90095, USA.

Intramyocardial injection of hydrogels offers great potential for treating myocardial infarction (MI) in a minimally invasive manner. However, traditional bulk hydrogels generally lack microporous structures to support rapid tissue ingrowth and biochemical signals to prevent fibrotic remodeling toward heart failure. To address such challenges, a novel drug-releasing microporous annealed particle (drugMAP) system is developed by encapsulating hydrophobic drug-loaded nanoparticles into microgel building blocks via microfluidic manufacturing. By modulating nanoparticle hydrophilicity and pregel solution viscosity, drugMAP building blocks are generated with consistent and homogeneous encapsulation of nanoparticles. In addition, the complementary effects of forskolin (F) and Repsox (R) on the functional modulations of cardiomyocytes, fibroblasts, and endothelial cells in vitro are demonstrated. After that, both hydrophobic drugs (F and R) are loaded into drugMAP to generate FR/drugMAP for MI therapy in a rat model. The intramyocardial injection of MAP gel improves left ventricular functions, which are further enhanced by FR/drugMAP treatment with increased angiogenesis and reduced fibrosis and inflammatory response. This drugMAP platform represents a new generation of microgel particles for MI therapy and will have broad applications in regenerative medicine and disease therapy.
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http://dx.doi.org/10.1002/adfm.202004307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942842PMC
October 2020

MeltingPlot, a user-friendly online tool for epidemiological investigation using High Resolution Melting data.

BMC Bioinformatics 2021 Feb 18;22(1):76. Epub 2021 Feb 18.

Department of Biomedical and Clinical Sciences "L. Sacco", Pediatric Clinical Research Center "Romeo and Enrica Invernizzi", Università Di Milano, 20157, Milan, Italy.

Background: The rapid identification of pathogen clones is pivotal for effective epidemiological control strategies in hospital settings. High Resolution Melting (HRM) is a molecular biology technique suitable for fast and inexpensive pathogen typing protocols. Unfortunately, the mathematical/informatics skills required to analyse HRM data for pathogen typing likely limit the application of this promising technique in hospital settings.

Results: MeltingPlot is the first tool specifically designed for epidemiological investigations using HRM data, easing the application of HRM typing to large real-time surveillance and rapid outbreak reconstructions. MeltingPlot implements a graph-based algorithm designed to discriminate pathogen clones on the basis of HRM data, producing portable typing results. The tool also merges typing information with isolates and patients metadata to create graphical and tabular outputs useful in epidemiological investigations and it runs in a few seconds even with hundreds of isolates.

Availability: https://skynet.unimi.it/index.php/tools/meltingplot/ .

Conclusions: The analysis and result interpretation of HRM typing protocols can be not trivial and this likely limited its application in hospital settings. MeltingPlot is a web tool designed to help the user to reconstruct epidemiological events by combining HRM-based clustering methods and the isolate/patient metadata. The tool can be used for the implementation of HRM based real time large scale surveillance programs in hospital settings.
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http://dx.doi.org/10.1186/s12859-021-04020-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891011PMC
February 2021

Magnetic microparticle concentration and collection using a mechatronic magnetic ratcheting system.

PLoS One 2021 18;16(2):e0246124. Epub 2021 Feb 18.

California NanoSystems Institute, Los Angeles, California, United States of America.

Magnetic ratcheting cytometry is a promising approach to separate magnetically-labeled cells and magnetic particles based on the quantity of magnetic material. We have previously reported on the ability of this technique to separate magnetically-labeled cells. Here, with a new chip design, containing high aspect ratio permalloy micropillar arrays, we demonstrate the ability of this technique to rapidly concentrate and collect superparamagnetic iron oxide particles. The platform consists of a mechatronic wheel used to generate and control a cycling external magnetic field that impinges on a "ratcheting chip." The ratcheting chip is created by electroplating a 2D array of high aspect ratio permalloy micropillars onto a glass slide, which is embedded in a thin polymer layer to create a planar surface above the micropillars. By varying magnetic field frequency and direction through wheel rotation rate and angle, we direct particle movement on chip. We explore the operating conditions for this system, identifying the effects of varying ratcheting frequency, along with time, on the dynamics and resulting concentration of these magnetic particles. We also demonstrate the ability of the system to rapidly direct the movement of superparamagnetic iron oxide particles of varying sizes. Using this technique, 2.8 μm, 500 nm, and 100 nm diameter superparamagnetic iron oxide particles, suspended within an aqueous fluid, were concentrated. We further define the ability of the system to concentrate 2.8 μm superparamagnetic iron oxide particles, present in a liquid suspension, into a small chip surface area footprint, achieving a 100-fold surface area concentration, and achieving a concentration factor greater than 200%. The achieved concentration factor of greater than 200% could be greatly increased by reducing the amount of liquid extracted at the chip outlet, which would increase the ability of achieving highly sensitive downstream analytical techniques. Magnetic ratcheting-based enrichment may be useful in isolating and concentrating subsets of magnetically-labeled cells for diagnostic automation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246124PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891735PMC
February 2021

Microsurgical anatomy of the amygdaloid body and its connections.

Brain Struct Funct 2021 Apr 2;226(3):861-874. Epub 2021 Feb 2.

Department of Translational Research On New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.

The amygdaloid body is a limbic nuclear complex characterized by connections with the thalamus, the brainstem and the neocortex. The recent advances in functional neurosurgery regarding the treatment of refractory epilepsy and several neuropsychiatric disorders renewed the interest in the study of its functional Neuroanatomy. In this scenario, we felt that a morphological study focused on the amygdaloid body and its connections could improve the understanding of the possible  implications in functional neurosurgery. With this purpose we performed a morfological study using nine formalin-fixed human hemispheres dissected under microscopic magnification by using the fiber dissection technique originally described by Klingler. In our results the  amygdaloid body presents two divergent projection systems named dorsal and ventral amygdalofugal pathways connecting the nuclear complex with the septum and the hypothalamus. Furthermore, the amygdaloid body is connected with the hippocampus through the amygdalo-hippocampal bundle, with the anterolateral temporal cortex through the amygdalo-temporalis fascicle, the anterior commissure and the temporo-pulvinar bundle of Arnold, with the insular cortex through the lateral olfactory stria, with the ambiens gyrus, the para-hippocampal gyrus and the basal forebrain through the cingulum, and with the frontal cortex through the uncinate fascicle. Finally, the amygdaloid body is connected with the brainstem through the medial forebrain bundle. Our description of the topographic anatomy of the amygdaloid body and its connections, hopefully represents a useful tool for clinicians and scientists, both in the scope of application and speculation.
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http://dx.doi.org/10.1007/s00429-020-02214-3DOI Listing
April 2021

Dolutegravir-Based Regimen for Maintenance of Viral Suppression in People Living with HIV: 48-Week Results in Real-Life Setting.

AIDS Res Hum Retroviruses 2021 Mar 1. Epub 2021 Mar 1.

Department of Molecular Medicine, University of Rome Sapienza, Rome, Italy.

To evaluate the efficacy, safety, and tolerability of switching to a dolutegravir (DTG)-based regimen in a cohort of virological suppressed HIV-infected patients who have previously been treated with different antiretroviral combination. The dynamics of total HIV-DNA and levels of high-sensitivity c-reactive protein, interleukin-6, soluble-CD14, and D-Dimer were also analyzed. Ninety-six individuals who switched to a DTG-containing regimen were followed up for 48 weeks. HIV RNA, CD4 T cell count, weight, and levels of laboratory parameters were recorded at baseline, after 24 and 48 weeks of treatment for all study participants. In a subgroup of patients, HIV DNA and inflammation/coagulation marker levels were also analyzed until week 24. Ninety-three out of 96 patients maintained virological suppression, including patients who switched to dual-therapy from triple-drug combination. Eighteen out of 96 patients had residual viremia at baseline, of which 13 reached the maximal viral suppression at W48. Serum creatinine levels showed a significant increase at weeks 24 and 48. A progressive reduction of total cholesterol was observed from week 24 and up to week 48. No variation in body mass index was detected. HIV DNA, inflammation, and coagulation marker levels did not significantly change during follow-up. Switching to a DTG-based regimen may be a key option for achieving and maintaining maximal virological suppression, even in patients showing residual viremia at baseline. Furthermore, the improvement in blood lipid profile and the overall tolerability observed in this study strongly support the use of these regimens in the aging HIV population.
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http://dx.doi.org/10.1089/AID.2020.0196DOI Listing
March 2021

Automated synthesis of [F]Ga-rhPSMA-7/ -7.3: results, quality control and experience from more than 200 routine productions.

EJNMMI Radiopharm Chem 2021 Jan 23;6(1). Epub 2021 Jan 23.

Chair of Pharmaceutical Radiochemistry, Technical University of Munich, Walther-Meißner-Str. 3, 85748, Garching, Germany.

Introduction: The radiohybrid (rh) prostate-specific membrane antigen (PSMA)-targeted ligand [F]Ga-rhPSMA-7 has previously been clinically assessed and demonstrated promising results for PET-imaging of prostate cancer. The ligand is present as a mixture of four stereoisomers ([F]Ga-rhPSMA-7.1, - 7.2, - 7.3 and - 7.4) and after a preclinical isomer selection process, [F]Ga-rhPSMA-7.3 has entered formal clinical trials. Here we report on the establishment of a fully automated production process for large-scale production of [F]Ga-rhPSMA-7/ -7.3 under GMP conditions (EudraLex).

Methods: [F]Fluoride in highly enriched [O]HO was retained on a strong anion exchange cartridge, rinsed with anhydrous acetonitrile and subsequently eluted with a solution of [K ⊂ 2.2.2]OH in anhydrous acetonitrile into a reactor containing Ga-rhPSMA ligand and oxalic acid in DMSO. F-for-F isotopic exchange at the Silicon-Fluoride Acceptor (SiFA) was performed at room temperature, followed by dilution with buffer and cartridge-based purification. Optimum process parameters were determined on the laboratory scale and thereafter implemented into an automated synthesis. Data for radiochemical yield (RCY), purity and quality control were analyzed for 243 clinical productions (160 for [F]Ga-rhPSMA-7; 83 for [F]Ga-rhPSMA-7.3).

Results: The automated production of [F]Ga-rhPSMA-7 and the single isomer [F]Ga-rhPSMA-7.3 is completed in approx. 16 min with an average RCY of 49.2 ± 8.6% and an excellent reliability of 98.8%. Based on the different starting activities (range: 31-130 GBq, 89 ± 14 GBq) an average molar activity of 291 ± 62 GBq/μmol (range: 50-450 GBq/μmol) was reached for labeling of 150 nmol (231 μg) precursor. Radiochemical purity, as measured by radio-high performance liquid chromatography and radio-thin layer chromatography, was 99.9 ± 0.2% and 97.8 ± 1.0%, respectively.

Conclusion: This investigation demonstrates that F-for-F isotopic exchange is well suited for the fast, efficient and reliable automated routine production of F-labeled PSMA-targeted ligands. Due to its simplicity, speed and robustness the development of further SiFA-based radiopharmaceuticals is highly promising and can be of far-reaching importance for future theranostic concepts.
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http://dx.doi.org/10.1186/s41181-021-00120-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826325PMC
January 2021

Selective and Improved Photoannealing of Microporous Annealed Particle (MAP) Scaffolds.

ACS Biomater Sci Eng 2021 02 6;7(2):422-427. Epub 2021 Jan 6.

Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22904, United States.

Microporous annealed particle (MAP) scaffolds consist of a slurry of hydrogel microspheres that undergo annealing to form a solid scaffold. MAP scaffolds have contained functional groups with dual abilities to participate in Michael-type addition (gelation) and radical polymerization (photoannealing). Functional groups with efficient Michael-type additions react with thiols and amines under physiological conditions, limiting usage for therapeutic delivery. We present a heterofunctional maleimide/methacrylamide 4-arm PEG macromer (MethMal) engineered for selective photopolymerization compatible with multiple polymer backbones. Rheology using two classes of photoinitiators demonstrates advantageous photopolymerization capabilities. Functional assays show benefits for therapeutic delivery and 3D printing without impacting cell viability.
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http://dx.doi.org/10.1021/acsbiomaterials.0c01580DOI Listing
February 2021

Differential induction of type I and III interferon genes in the upper respiratory tract of patients with coronavirus disease 2019 (COVID-19).

Virus Res 2021 04 5;295:198283. Epub 2021 Jan 5.

Laboratory of Virology, Department of Molecular Medicine, Sapienza University, Affiliated to Istituto Pasteur Italia, Rome 00185, Italy; Microbiology and Virology Unit, Hospital "Policlinico Umberto I", Sapienza University, Rome 00185, Italy.

The natural course of type I and III interferon (IFN) response in the respiratory tract of COVID-19 patients needs to be better defined. We showed that type I/III IFNs, IFN-regulatory factor 7 (IRF7), and IFN stimulated genes (ISGs), are highly expressed in the oropharyngeal cells of SARS-CoV-2 positive patients compared to healthy controls. Notably, the subgroup of critically-ill patients that required invasive mechanical ventilation had a general decrease in expression of IFN/ISG genes. Heterogeneous patterns of IFN-I/III response in the respiratory tract of COVID-19 patients may be associated to COVID-19 severity.
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http://dx.doi.org/10.1016/j.virusres.2020.198283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834390PMC
April 2021

Engineering Design of Concentric Amphiphilic Microparticles for Spontaneous Formation of Picoliter to Nanoliter Droplet Volumes.

Anal Chem 2021 02 7;93(4):2317-2326. Epub 2021 Jan 7.

Department of Bioengineering, University of California, Los Angeles, Los Angeles, California 90095, United States.

Simple mixing of aqueous and oil solutions with amphiphilic particles leads to the spontaneous formation of uniform reaction volumes (dropicles) that can enable numerous applications in the analysis of biological entities (e.g., cells and molecules). Approaches to manufacture such amphiphilic particles are just starting to be investigated. Here, we investigate the tunable manufacturing of concentric amphiphilic particles, with outer hydrophobic and inner hydrophilic layers, fabricated by flowing reactive precursor streams through a 3D printed device with coaxial microfluidic channels, and curing the structured flow by UV exposure through a photomask. The dimensions of the engineered amphiphilic particles, including height, inner and outer diameters, and thicknesses of the hydrophobic and hydrophilic layers, are precisely controlled by modulating the UV exposure time, the precursor flow rate ratios, and the size of the channel in the exposure region. The particle design is systematically engineered to hold a wide range of droplet volumes, that is, from a few hundred picoliters to several nanoliters. We show that the particle size can be significantly reduced from previous reports to not only hold subnanoliter drops but the shape can also be tuned to increase the seeding density and orientation of dropicles within a well plate for imaging and analysis.
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http://dx.doi.org/10.1021/acs.analchem.0c04184DOI Listing
February 2021

Scanning two-photon continuous flow lithography for the fabrication of multi-functional microparticles.

Opt Express 2020 Dec;28(26):40088-40098

In this work, we demonstrate the high-throughput fabrication of 3D microparticles using a scanning two-photon continuous flow lithography (STP-CFL) technique in which microparticles are shaped by scanning the laser beam at the interface of laminar co-flows. The results demonstrate the ability of STP-CFL to manufacture high-resolution complex geometries of cell carriers that possess distinct regions with different functionalities. A new approach is presented for printing out-of-plane features on the microparticles. The approach eliminates the use of axial scanning stages, which are not favorable since they induce fluctuations in the flowing polymer media and their scanning speed is slower than the speed of galvanometer mirror scanners.
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http://dx.doi.org/10.1364/OE.410090DOI Listing
December 2020

Single Cell Mechanotype and Associated Molecular Changes in Urothelial Cell Transformation and Progression.

Front Cell Dev Biol 2020 19;8:601376. Epub 2020 Nov 19.

Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

Cancer cell mechanotype changes are newly recognized cancer phenotypic events, whereas metastatic cancer cells show decreased cell stiffness and increased deformability relative to normal cells. To further examine how cell mechanotype changes in early stages of cancer transformation and progression, an multi-step human urothelial cell carcinogenic model was used to measure cellular Young's modulus, deformability, and transit time using single-cell atomic force microscopy, microfluidic-based deformability cytometry, and quantitative deformability cytometry, respectively. Measurable cell mechanotype changes of stiffness, deformability, and cell transit time occur early in the transformation process. As cells progress from normal, to preinvasive, to invasive cells, Young's modulus of stiffness decreases and deformability increases gradually. These changes were confirmed in three-dimensional cultured microtumor masses and urine exfoliated cells directly from patients. Using gene screening and proteomics approaches, we found that the main molecular pathway implicated in cell mechanotype changes appears to be epithelial to mesenchymal transition.
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http://dx.doi.org/10.3389/fcell.2020.601376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711308PMC
November 2020

Repeatability and reproducibility of the wzi high resolution melting-based clustering analysis for Klebsiella pneumoniae typing.

AMB Express 2020 Dec 14;10(1):217. Epub 2020 Dec 14.

Department of Biomedical and Clinical Sciences "L. Sacco", Università di Milano, Pediatric Clinical Research Center "Romeo and Enrica Invernizzi", Milan, Italy.

High resolution melting (HRM) is a fast closed-tube method for nucleotide variant scanning applicable for bacterial species identification or molecular typing. Recently a novel HRM-based method for Klebsiella pneumoniae typing has been proposed: it consists of an HRM protocol designed on the capsular wzi gene and an HRM-based algorithm of strains clustering. In this study, we evaluated the repeatability and reproducibility of this method by performing the HRM typing of a set of K. pneumoniae strains, on three different instruments and by two different operators. The results showed that operators do not affect melting temperatures while different instruments can. Despite this, we found that strain clustering analysis, performed using MeltingPlot separately on the data from the three instruments, remains almost perfectly consistent. The HRM method under study resulted highly repeatable and thus reliable for large studies, even when several operators are involved. Furthermore, the HRM clusters obtained from the three different instruments were highly conserved, suggesting that this method could be applied in multicenter studies, even if different instruments are used.
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http://dx.doi.org/10.1186/s13568-020-01164-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736600PMC
December 2020

Preclinical comparison of four [F, Ga]rhPSMA-7 isomers: influence of the stereoconfiguration on pharmacokinetics.

EJNMMI Res 2020 Dec 7;10(1):149. Epub 2020 Dec 7.

Chair of Pharmaceutical Radiochemistry, Technical University of Munich, Walther-Meißner-Str. 3, 85748, Garching, Germany.

Introduction: Radiohybrid (rh) ligands, a novel class of prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals, can be labeled either with [F]fluorine via isotopic exchange or with radiometals (such as [Ga]Gallium, [Lu]Lutetium, [Ac]Actinium). Among these, [F, Ga]rhPSMA-7 has recently entered clinical assessment.

Aim: Since [F, Ga]rhPSMA-7 is composed of four stereoisomers ([F, Ga]rhPSMA-7.1, -7.2, -7.3 and -7.4), we initiated a preclinical selection process to identify the isomer with the most favorable pharmacokinetics for further clinical investigation.

Methods: A synthetic protocol for enantiopure [F, Ga]rhPSMA-7 isomers has been developed. The comparative evaluation of the four isomers comprised human serum albumin binding, lipophilicity, IC, internalization and classical biodistribution studies and competition experiments in LNCaP tumor-bearing CB-17 SCID mice. In addition, a radio high-performance liquid chromatography-based method was developed allowing quantitative, intraindividual comparison of [F, Ga]rhPSMA-7.1 to -7.4 in LNCaP tumor-bearing mice.

Results: Cell studies revealed high PSMA affinity and internalization for [F, Ga]rhPSMA-7.2, -7.3 and -7.4, whereas [F, Ga]rhPSMA-7.1 showed approximately twofold lower values. Although the biodistribution profile obtained was typical of PSMA inhibitors, it did not allow for selection of a lead candidate for clinical studies. Thus, an intraindividual comparison of all four isomers in LNCaP tumor-bearing mice was carried out by injection of a diastereomeric mixture, followed by analysis of the differential uptake and excretion pattern of each isomer. Based on its high tumor accumulation and low uptake in blood, liver and kidneys, [F, Ga]rhPSMA-7.3 was identified as the preferred isomer and transferred into clinical studies.

Conclusion: [F, Ga]rhPSMA-7.3 has been selected as a lead compound for clinical development of a [F]rhPSMA-based candidate. The intraindividual differential uptake and excretion analysis in vivo allowed for an accurate comparison and assessment of radiopharmaceuticals.
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http://dx.doi.org/10.1186/s13550-020-00740-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721954PMC
December 2020

IBDs and the pediatric age: Their peculiarities and the involvement of the microbiota.

Dig Liver Dis 2021 Jan 11;53(1):17-25. Epub 2020 Nov 11.

"L. Sacco" Department of Biomedical and Clinical Sciences and Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Università di Milano, Italy.

Inflammatory Bowel Diseases (IBDs) are gastrointestinal disorders characterized by chronic, relapsing inflammation, with growing incidence worldwide over the last decades and distinctive features in the pediatric age. An increasing body of evidence indicates that gut microbiota plays a major role in inflammatory disorders, including IBDs. In this review we will discuss the most recent evidences on dysbiotic changes associated with gut inflammation, as well as environmental and genetic factors contributing to IBD pathogenesis, with a focus on the peculiarities of the pediatric age.
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http://dx.doi.org/10.1016/j.dld.2020.10.033DOI Listing
January 2021

Acute Cervical Longitudinally Extensive Transverse Myelitis in a Child With Lipopolysaccharide-Responsive-Beige-Like-Anchor-Protein (LRBA) Deficiency: A New Complication of a Rare Disease.

Front Pediatr 2020 16;8:580963. Epub 2020 Oct 16.

Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

Lipopolysaccharide responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency disorder (PID) that can cause a common variable immunodeficiency (CVID)-like disease. The typical features of the disease are autoimmunity, chronic diarrhea, and hypogammaglobulinemia. Neurological complications are also reported in patients affected by LRBA deficiency. We describe a 7-year old female with an acute cervical longitudinally extensive transverse myelitis (LETM) as a feature of LRBA deficiency. This is the first case of LETM associated with LRBA deficiency described in literature.
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http://dx.doi.org/10.3389/fped.2020.580963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596261PMC
October 2020

Activating an adaptive immune response from a hydrogel scaffold imparts regenerative wound healing.

Nat Mater 2021 Apr 9;20(4):560-569. Epub 2020 Nov 9.

Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

Microporous annealed particle (MAP) scaffolds are flowable, in situ crosslinked, microporous scaffolds composed of microgel building blocks and were previously shown to accelerate wound healing. To promote more extensive tissue ingrowth before scaffold degradation, we aimed to slow MAP degradation by switching the chirality of the crosslinking peptides from L- to D-amino acids. Unexpectedly, despite showing the predicted slower enzymatic degradation in vitro, D-peptide crosslinked MAP hydrogel (D-MAP) hastened material degradation in vivo and imparted significant tissue regeneration to healed cutaneous wounds, including increased tensile strength and hair neogenesis. MAP scaffolds recruit IL-33 type 2 myeloid cells, which is amplified in the presence of D-peptides. Remarkably, D-MAP elicited significant antigen-specific immunity against the D-chiral peptides, and an intact adaptive immune system was required for the hydrogel-induced skin regeneration. These findings demonstrate that the generation of an adaptive immune response from a biomaterial is sufficient to induce cutaneous regenerative healing despite faster scaffold degradation.
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http://dx.doi.org/10.1038/s41563-020-00844-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005402PMC
April 2021

Vitamin D levels in liver transplantation recipients and early postoperative outcomes: Prospective observational DLiverX study.

Clin Nutr 2021 Apr 24;40(4):2355-2363. Epub 2020 Oct 24.

Department of Anesthesia and Intensive Care, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Palermo, Italy.

Background & Aims: In critically ill patients with liver disease, vitamin D deficiency is associated with higher disease severity, increased frequency of infections, and worse outcomes. This study sought to describe the trend of vitamin D in orthotopic liver transplantation (OLT) recipients and its association with outcomes.

Methods: Prospective observational study of 67 consecutive OLT recipients enrolled between September, 2016 and August, 2017 at IRCCS-ISMETT, Palermo (Italy). Trend of vitamin D levels and potential factors influencing it levels were evaluated through a generalized linear mixed regression model.

Results: Sixty-four (95.5%) recipients were vitamin D deficient (<20 ng/ml), with a median value of 8.8 ng/ml [6.2-12.9], and forty-seven of these (70.1%) showed severe deficiency (<12 ng/ml) at baseline, 7.9 ng/ml [5.4-8.9]. The baseline vitamin D showed an inverse correlation with liver disease severity: Child-Pugh, MELD score, bilirubin, INR, and organ failure (p < 0.01) at baseline. Vitamin D increased on postoperative day (POD) 28 compared with POD1: +4.5 ng/ml, C.I. 95% 3.6-5.3 ng/ml, p < 0.01. Lower baseline vitamin D, donor age, transfusion of fresh frozen plasma (negative impact, all p < 0.05), and intra-operative bypass (positive impact at POD 28, p < 0.01) were associated with variation of vitamin D levels after transplantation. Incomplete graft recovery was associated with lower vitamin D on POD28: 8.2 ± 4.4 versus 13.8 ± 9.4 ng/ml, p < 0.01; the odds ratio (OR) was 0.84; CI 95% 0.73-0.97, p = 0.014. The OR for infections within POD 28 was inversely associated with baseline vitamin D: 0.87; CI 95% 0.79-0.98, p = 0.02, and with vitamin D level at baseline <12 ng/ml: OR 6.44; CI 95% 1.66-24.94; p < 0.01.

Conclusions: Preoperative Vitamin D is correlated with disease severity, and was highly associated with invasive infection in the first 28 PODs. After OLT, the value on POD 28 had a strong association with graft function.
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http://dx.doi.org/10.1016/j.clnu.2020.10.027DOI Listing
April 2021

Monodisperse drops templated by 3D-structured microparticles.

Sci Adv 2020 Nov 4;6(45). Epub 2020 Nov 4.

Department of Bioengineering, University of California, Los Angeles, CA 90095, USA.

The ability to create uniform subnanoliter compartments using microfluidic control has enabled new approaches for analysis of single cells and molecules. However, specialized instruments or expertise has been required, slowing the adoption of these cutting-edge applications. Here, we show that three dimensional-structured microparticles with sculpted surface chemistries template uniformly sized aqueous drops when simply mixed with two immiscible fluid phases. In contrast to traditional emulsions, particle-templated drops of a controlled volume occupy a minimum in the interfacial energy of the system, such that a stable monodisperse state results with simple and reproducible formation conditions. We describe techniques to manufacture microscale drop-carrier particles and show that emulsions created with these particles prevent molecular exchange, concentrating reactions within the drops, laying a foundation for sensitive compartmentalized molecular and cell-based assays with minimal instrumentation.
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http://dx.doi.org/10.1126/sciadv.abb9023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673687PMC
November 2020

Endoscopic Forehead Approach for Minimally Invasive Frontal Osteoma Excision.

J Craniofac Surg 2020 Nov/Dec;31(8):e767-e769

Department of Maxillofacial Surgery, Sapienza University of Rome, Rome, Italy.

Benign osseous tumors of the frontal bone can be treated with endoscopic surgery, minimizing postoperative complications associated with the coronal approach and guaranteeing more functional and aesthetic results. The authors describe a case of a patient who had endoscopic removal of osteoma of the forehead using two 1 cm incisions behind the hairline. No complications such as hematoma and edema were detected. Endoscopic technique offered both good illumination and excellent magnification; it permitted safe anatomic dissection, minimum bleeding, avoiding visible scars. The outcome achieved with endoscopic technique could be the first-line surgical treatment of benign bone tumors of the frontal area, offering more advantages and better results than the conventional surgical approaches.
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http://dx.doi.org/10.1097/SCS.0000000000006715DOI Listing
March 2021

Detection of SARS-COV N2 Gene: Very low amounts of viral RNA or false positive?

J Clin Virol 2020 12 14;133:104660. Epub 2020 Oct 14.

Department of Molecular Medicine, Sapienza University, Rome, Italy; Sapienza University Hospital "Policlinico Umberto I", Rome, Italy. Electronic address:

Background: The detection of a low amount of viral RNA is crucial to identify a SARS-CoV-2 positive individual harboring a low level of virus, especially during the convalescent period. However, the detection of one gene at high Cycle threshold (Ct) has to be interpreted with caution. In this study we address this specific issue and report our real-life experience.

Study Design: A total of 1639 nasopharyngeal swabs (NPS) were analyzed with Xpert® Xpress SARS-CoV-2. Positive samples showing high Ct values (Ct>35) were concentrated by centrifugation and re-tested with Cepheid or other methods (RealStar SARS-CoV2 RT-PCR, Altona Diagnostics; GeneFinder COVID-19 Plus RealAmp Kit, Elitech).

Results: 1599 (97.5%) negative samples, 36 (2.3%) positive samples and 4 (0.2%) presumptive positive samples were detected. In 17 out of 36 positive patients, very low viral RNA copies were suspected since positivity was detected at high Ct. We confirmed positivity for patients who showed both E and N genes detected and for patients with only N detected but with Ct <39. On the contrary, samples with only gene N detected with Ct values >39 were found negative. NPS taken 24 hours after the first collection confirmed the negativity of the 12 samples. Clinical data sustained these results since only 2 of these 12 patients showed COVID-19-like symptoms.

Conclusions: These data support our consideration that detection of the N2 gene at high Ct needs to be interpreted with caution, suggesting that collaboration between virologists and clinicians is important for better understanding of results.
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http://dx.doi.org/10.1016/j.jcv.2020.104660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553900PMC
December 2020

A review of biosensor technologies for blood biomarkers toward monitoring cardiovascular diseases at the point-of-care.

Biosens Bioelectron 2021 Jan 18;171:112621. Epub 2020 Sep 18.

Department of Bioengineering, University of California, Los Angeles, 420 Westwood Plaza, Los Angeles, CA, 90095, USA. Electronic address:

Cardiovascular diseases (CVDs) cause significant mortality globally. Notably, CVDs disproportionately negatively impact underserved populations, such as those that are economically disadvantaged and often located in remote regions. Devices to measure cardiac biomarkers have traditionally been focused on large instruments in a central laboratory but the development of affordable, portable devices that measure multiple cardiac biomarkers at the point-of-care (POC) are needed to improve clinical outcomes for patients, especially in underserved populations. Considering the enormity of the global CVD problem, complexity of CVDs, and the large candidate pool of biomarkers, it is of great interest to evaluate and compare biomarker performance and identify potential multiplexed panels that can be used in combination with affordable and robust biosensors at the POC toward improved patient care. This review focuses on describing the known and emerging CVD biosensing technologies for analysis of cardiac biomarkers from blood. Initially, the global burden of CVDs and the standard of care for the primary CVD categories, namely heart failure (HF) and acute coronary syndrome (ACS) including myocardial infarction (MI) are discussed. The latest United States, Canadian and European society guidelines recommended standalone, emerging, and add-on cardiac biomarkers, as well as their combinations are then described for the prognosis, diagnosis, and risk stratification of CVDs. Finally, both commercial in vitro biosensing devices and recent state-of-art techniques for detection of cardiac biomarkers are reviewed that leverage single and multiplexed panels of cardiac biomarkers with a view toward affordable, compact devices with excellent performance for POC diagnosis and monitoring.
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http://dx.doi.org/10.1016/j.bios.2020.112621DOI Listing
January 2021

Detection of EGFR Mutations in cfDNA and CTCs, and Comparison to Tumor Tissue in Non-Small-Cell-Lung-Cancer (NSCLC) Patients.

Front Oncol 2020 8;10:572895. Epub 2020 Oct 8.

Vortex Biosciences, Inc., Pleasanton, CA, United States.

Lung cancer is the leading cause of cancer-related mortality worldwide. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapies, based on the evaluation of mutations, have shown dramatic clinical benefits. mutation assays are mainly performed on tumor biopsies, which carry risks, are not always successful and give results relevant to the timepoint of the assay. To detect secondary mutations, which cause resistance to 1st and 2nd generation TKIs and lead to the administration of a 3rd generation drug, effective and non-invasive monitoring of mutation status is needed. Liquid biopsy analytes, such as circulating tumor cells (CTCs) and circulating tumor DNA (cfDNA), allow such monitoring over the course of the therapy. The aim of this study was to develop and optimize a workflow for the evaluation of cfDNA and CTCs in NSCLC patients all from one blood sample. Using Vortex technology and EntroGen ctEGFR assay, mutations were identified at 0.5 ng of DNA (∼83 cells), with a sensitivity ranging from 0.1 to 2.0% for a total DNA varying from 25 ng (∼4 CTCs among 4000 white blood cells, WBCs) to 1 ng (∼4 CTCs among 200 WBCs). The processing of plasma-depleted-blood provided comparable capture recovery as whole blood, confirming the possibility of a multimodality liquid biopsy analysis (cfDNA and CTC DNA) from a single tube of blood. Different anticoagulants were evaluated and compared in terms of respective performance. Blood samples from 24 NSCLC patients and 6 age-matched healthy donors were analyzed with this combined workflow to minimize blood volume needed and sample-to-sample bias, and the mutation profile detected from CTCs and cfDNA was compared to matched tumor tissues. Despite the limited size of the patient cohort, results from this non-invasive mutation analysis are encouraging and this combined workflow represents a valuable means for informing therapy selection and for monitoring treatment of patients with NSCLC.
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http://dx.doi.org/10.3389/fonc.2020.572895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578230PMC
October 2020

Sperm cryopreservation during the SARS-CoV-2 pandemic.

J Endocrinol Invest 2021 May 10;44(5):1091-1096. Epub 2020 Oct 10.

Laboratory of Seminology - Sperm Bank "Loredana Gandini", Department of Experimental Medicine, "Sapienza" University of Rome, Viale del Policlinico 155, 00161, Rome, Italy.

Purpose: Sperm cryopreservation is fundamental in the management of patients undergoing gonadotoxic treatments. Concerns have risen in relation to SARS-CoV-2 and its potential for testicular involvement, since SARS-CoV-2-positive cryopreserved samples may have unknown effects on fertilization and embryo safety. This study therefore aimed to analyze the safety of sperm cryopreservation for cancer patients after the onset of the pandemic in Italy, through assessment of the risk of SARS-CoV-2 exposure and viral RNA testing of semen samples.

Methods: We recruited 10 cancer patients (mean age 30.5 ± 9.6 years) referred to our Sperm Bank during the Italian lockdown (from March 11th to May 4th 2020) who had not undergone a nasopharyngeal swab for SARS-CoV-2 testing. Patients were administered a questionnaire on their exposure to COVID-19, and semen samples were taken. Before cryopreservation, SARS-CoV-2 RNA was extracted from a 150 µl aliquot of seminal fluid in toto using QIAamp viral RNA kit (Qiagen) and amplified by a real time RT PCR system (RealStar SARS-CoV2 RT PCR, Altona Diagnostics) targeting the E and S genes.

Results: The questionnaire and medical interview revealed that all patients were asymptomatic and had had no previous contact with COVID-19 infected patients. All semen samples were negative for SARS-CoV-2 RNA.

Conclusion: This preliminary assessment suggests that a thorough evaluation (especially in the setting of a multidisciplinary team) and molecular confirmation of the absence of SARS-CoV-2 in seminal fluid from asymptomatic cancer patients may assist in ensuring the safety of sperm cryopreservation.
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http://dx.doi.org/10.1007/s40618-020-01438-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547554PMC
May 2021

A ferrobotic system for automated microfluidic logistics.

Sci Robot 2020 02;5(39)

Interconnected & Integrated Bioelectronics Lab (IBL), Department of Electrical and Computer Engineering, University of California, Los Angeles, CA, USA.

Automated technologies that can perform massively parallelized and sequential fluidic operations at small length scales can resolve major bottlenecks encountered in various fields, including medical diagnostics, -omics, drug development, and chemical/material synthesis. Inspired by the transformational impact of automated guided vehicle systems on manufacturing, warehousing, and distribution industries, we devised a ferrobotic system that uses a network of individually addressable robots, each performing designated micro-/nanofluid manipulation-based tasks in cooperation with other robots toward a shared objective. The underlying robotic mechanism facilitating fluidic operations was realized by addressable electromagnetic actuation of miniature mobile magnets that exert localized magnetic body forces on aqueous droplets filled with biocompatible magnetic nanoparticles. The contactless and high-strength nature of the actuation mechanism inherently renders it rapid (~10 centimeters/second), repeatable (>10,000 cycles), and robust (>24 hours). The robustness and individual addressability of ferrobots provide a foundation for the deployment of a network of ferrobots to carry out cross-collaborative logistics efficiently. These traits, together with the reconfigurability of the system, were exploited to devise and integrate passive/active advanced functional components (e.g., droplet dispensing, generation, filtering, and merging), enabling versatile system-level functionalities. By applying this ferrobotic system within the framework of a microfluidic architecture, the ferrobots were tasked to work cross-collaboratively toward the quantification of active matrix metallopeptidases (a biomarker for cancer malignancy and inflammation) in human plasma, where various functionalities converged to achieve a fully automated assay.
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http://dx.doi.org/10.1126/scirobotics.aba4411DOI Listing
February 2020

In situ forming microporous gelatin methacryloyl hydrogel scaffolds from thermostable microgels for tissue engineering.

Bioeng Transl Med 2020 Sep 2;5(3):e10180. Epub 2020 Sep 2.

Department of Bioengineering University of California, Los Angeles Los Angeles California USA.

Converting biopolymers to extracellular matrix (ECM)-mimetic hydrogel-based scaffolds has provided invaluable opportunities to design in vitro models of tissues/diseases and develop regenerative therapies for damaged tissues. Among biopolymers, gelatin and its crosslinkable derivatives, such as gelatin methacryloyl (GelMA), have gained significant importance for biomedical applications due to their ECM-mimetic properties. Recently, we have developed the first class of in situ forming GelMA microporous hydrogels based on the chemical annealing of physically crosslinked GelMA microscale beads (microgels), which addressed several key shortcomings of bulk (nanoporous) GelMA scaffolds, including lack of interconnected micron-sized pores to support on-demand three-dimensional-cell seeding and cell-cell interactions. Here, we address one of the limitations of in situ forming microporous GelMA hydrogels, that is, the thermal instability (melting) of their physically crosslinked building blocks at physiological temperature, resulting in compromised microporosity. To overcome this challenge, we developed a two-step fabrication strategy in which thermostable GelMA microbeads were produced via semi-photocrosslinking, followed by photo-annealing to form stable microporous scaffolds. We show that the semi-photocrosslinking step (exposure time up to 90 s at an intensity of ~100 mW/cm and a wavelength of ~365 nm) increases the thermostability of GelMA microgels while decreasing their scaffold forming (annealing) capability. Hinging on the tradeoff between microgel and scaffold stabilities, we identify the optimal crosslinking condition (exposure time ~60 s) that enables the formation of stable annealed microgel scaffolds. This work is a step forward in engineering in situ forming microporous hydrogels made up from thermostable GelMA microgels for in vitro and in vivo applications at physiological temperature well above the gelatin melting point.
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http://dx.doi.org/10.1002/btm2.10180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510466PMC
September 2020