Publications by authors named "John Johnson"

640 Publications

Arthroscopic Versus Open Anterior Shoulder Stabilization: A Prospective Randomized Clinical Trial With 15-Year Follow-up With an Assessment of the Glenoid Being "On-Track" and "Off-Track" as a Predictor of Failure.

Am J Sports Med 2021 Jun 8:3635465211018212. Epub 2021 Jun 8.

Department of Orthopaedic Surgery, Tripler Army Medical Center, Honolulu, Hawaii, USA.

Background: Recent studies have demonstrated equivalent short-term results when comparing arthroscopic versus open anterior shoulder stabilization. However, none have evaluated the long-term clinical outcomes of patients after arthroscopic or open anterior shoulder stabilization, with inclusion of an assessment of preoperative glenoid tracking.

Purpose: To compare long-term clinical outcomes of patients with recurrent anterior shoulder instability randomized to open and arthroscopic stabilization groups. Additionally, preoperative magnetic resonance imaging (MRI) studies were used to assess whether the shoulders were "on-track" or "off-track" to ascertain a prediction of increased failure risk.

Study Design: Randomized controlled trial; Level of evidence, 1.

Methods: A consecutive series of 64 patients with recurrent anterior shoulder instability were randomized to receive either arthroscopic or open stabilization by a single surgeon. Follow-up assessments were performed at minimum 15-year follow-up using established postoperative evaluations. Clinical failure was defined as any recurrent dislocation postoperatively or subjective instability. Preoperative MRI scans were obtained to calculate the glenoid track and designate shoulders as on-track or off-track. These results were then correlated with the patients' clinical results at their latest follow-up.

Results: Of 64 patients, 60 (28 arthroscopic and 32 open) were contacted or examined for follow-up (range, 15-17 years). The mean age at the time of surgery was 25 years (range, 19-42 years), while the mean age at the time of this assessment was 40 years (range, 34-57 years). The rates of arthroscopic and open long-term failure were 14.3% (4/28) and 12.5% (4/32), respectively. There were no differences in subjective shoulder outcome scores between the treatment groups. Of the 56 shoulders, with available MRI studies, 8 (14.3%) were determined to be off-track. Of these 8 shoulders, there were 2 surgical failures (25.0%; 1 treated arthroscopically, 1 treated open). In the on-track group, 6 of 48 had failed surgery (12.5%; 3 open, 3 arthroscopic [ = .280]).

Conclusion: Long-term clinical outcomes were comparable at 15 years postoperatively between the arthroscopic and open stabilization groups. The presence of an off-track lesion may be associated with a higher rate of recurrent instability in both cohorts at long-term follow-up; however, this study was underpowered to verify this situation.
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http://dx.doi.org/10.1177/03635465211018212DOI Listing
June 2021

Plant-expressed virus-like particles reveal the intricate maturation process of a eukaryotic virus.

Commun Biol 2021 May 24;4(1):619. Epub 2021 May 24.

Department of Biological Chemistry, John Innes Centre, Colney, UK.

Many virus capsids undergo exquisitely choreographed maturation processes in their host cells to produce infectious virions, and these remain poorly understood. As a tool for studying virus maturation, we transiently expressed the capsid protein of the insect virus Nudaurelia capensis omega virus (NωV) in Nicotiana benthamiana and were able to purify both immature procapsids and mature capsids from infiltrated leaves by varying the expression time. Cryo-EM analysis of the plant-produced procapsids and mature capsids to 6.6 Å and 2.7 Å resolution, respectively, reveals that in addition to large scale rigid body motions, internal regions of the subunits are extensively remodelled during maturation, creating the active site required for autocatalytic cleavage and infectivity. The mature particles are biologically active in terms of their ability to lyse membranes and have a structure that is essentially identical to authentic virus. The ability to faithfully recapitulate and visualize a complex maturation process in plants, including the autocatalytic cleavage of the capsid protein, has revealed a ~30 Å translation-rotation of the subunits during maturation as well as conformational rearrangements in the N and C-terminal helical regions of each subunit.
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http://dx.doi.org/10.1038/s42003-021-02134-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144610PMC
May 2021

Freeze-Casting with 3D-Printed Templates Creates Anisotropic Microchannels and Patterned Macrochannels within Biomimetic Nanofiber Aerogels for Rapid Cellular Infiltration.

Adv Healthc Mater 2021 May 24:e2100238. Epub 2021 May 24.

Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA.

A new approach is described for fabricating 3D poly(ε-caprolactone) (PCL)/gelatin (1:1) nanofiber aerogels with patterned macrochannels and anisotropic microchannels by freeze-casting with 3D-printed sacrificial templates. Single layer or multiple layers of macrochannels are formed through an inverse replica of 3D-printed templates. Aligned microchannels formed by partially anisotropic freezing act as interconnected pores between templated macrochannels. The resulting macro-/microchannels within nanofiber aerogels significantly increase preosteoblast infiltration in vitro. The conjugation of vascular endothelial growth factor (VEGF)-mimicking QK peptide to PCL/gelatin/gelatin methacryloyl (1:0.5:0.5) nanofiber aerogels with patterned macrochannels promotes the formation of a microvascular network of seeded human microvascular endothelial cells. Moreover, nanofiber aerogels with patterned macrochannels and anisotropic microchannels show significantly enhanced cellular infiltration rates and host tissue integration compared to aerogels without macrochannels following subcutaneous implantation in rats. Taken together, this novel class of nanofiber aerogels holds great potential in biomedical applications including tissue repair and regeneration, wound healing, and 3D tissue/disease modeling.
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http://dx.doi.org/10.1002/adhm.202100238DOI Listing
May 2021

Rationally designed DNA therapeutics can modulate human tyrosine hydroxylase expression by controlling specific G-quadruplex formation in its promoter.

Mol Ther 2021 May 13. Epub 2021 May 13.

Department of Chemistry and Biochemistry, Kent State University, Kent, OH 44242, USA. Electronic address:

Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in catecholamine (CA) biosynthesis pathway making TH a molecular target for controlling CA production, specifically dopamine. Dysregulation of dopamine is correlated with neurological diseases such as Parkinson's disease (PD) and post-traumatic stress disorder (PTSD) among others. Previously, we showed that a 49-nucleotide guanine (G)-rich sequence within the human TH promoter adopts two different sets of G-quadruplex (GQ) structures (5'GQ and 3'GQ) where the 5'GQ uses G-stretches I, II, IV and VI in TH49 which enhances TH transcription, while the 3'GQ utilizes G-stretches II, IV, VI and VII which represses transcription. Herein, we demonstrated targeted switching of these GQs to their active state using rationally designed DNA GQ Clips (5'GQ and 3'GQ Clips) to modulate endogenous TH gene expression and dopamine production. As a translational approach, we synthesized a targeted nanoparticle delivery system to effectively deliver the 5'GQ Clip in vivo. We believe this strategy could potentially be an improved approach for controlling dopamine production in a multitude of neurological disorders including PD.
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http://dx.doi.org/10.1016/j.ymthe.2021.05.013DOI Listing
May 2021

A Closer Look at the Adequacy of Proposed Frameworks for a "Virtue Theory for Moral Enhancement".

Authors:
John A Johnson

AJOB Neurosci 2021 Apr-Sep;12(2-3):103-105

Pennsylvania State University, DuBois.

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http://dx.doi.org/10.1080/21507740.2021.1904027DOI Listing
May 2021

Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis.

N Engl J Med 2021 05;384(18):1705-1718

From the Medical University of South Carolina, Charleston (S.E.D.); the UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco (P.N., P.P.J.P., R.M.S.); the Vietnam National Tuberculosis Program-University of California, San Francisco Research Collaboration Unit (P.N., P.P.J.P., H.T.T.P., N.V.N., T.H.P., R.M.S.) and the National Lung Hospital (N.V.N., T.H.P.) - both in Hanoi; the Centers for Disease Control and Prevention, Atlanta (E.V.K., K.B., S.V.G., A.E.P., N.A.S., E.S., A.V.); the University of Texas Health Science Center at San Antonio and the South Texas Veterans Health Care System, San Antonio (M.E., M.W.); the University of Zimbabwe College of Health Sciences, Harare (J.H., W.S.); Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland (J.L.J.); the Uganda-Case Western Reserve University Research Collaboration, Kampala (J.L.J., G.M.); TASK (M.L.), the University of Cape Town Lung Institute (K.N.), and the South African Tuberculosis Vaccine Initiative (J.S.), Cape Town, the Perinatal HIV Research Unit, University of the Witwatersrand (N.A.M., Z.W.), and the Wits Health Consortium (I.S.), Johannesburg - all in South Africa; Johns Hopkins University School of Medicine, Baltimore (K.E.D., N.A.M., R.E.C.), and the U.S. Public Health Service Commissioned Corps, Rockville (A.E.P.) - both in Maryland; the Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (GHESKIO), Port-au-Prince (S.N., S.P.); and the University of Nebraska Medical Center, Omaha (S.S.).

Background: Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis.

Methods: In an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points. In one 4-month regimen, rifampin was replaced with rifapentine; in the other, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was survival free of tuberculosis at 12 months.

Results: Among 2516 participants who had undergone randomization, 2343 had a culture positive for that was not resistant to isoniazid, rifampin, or fluoroquinolones (microbiologically eligible population; 768 in the control group, 791 in the rifapentine-moxifloxacin group, and 784 in the rifapentine group), of whom 194 were coinfected with human immunodeficiency virus and 1703 had cavitation on chest radiography. A total of 2234 participants could be assessed for the primary outcome (assessable population; 726 in the control group, 756 in the rifapentine-moxifloxacin group, and 752 in the rifapentine group). Rifapentine with moxifloxacin was noninferior to the control in the microbiologically eligible population (15.5% vs. 14.6% had an unfavorable outcome; difference, 1.0 percentage point; 95% confidence interval [CI], -2.6 to 4.5) and in the assessable population (11.6% vs. 9.6%; difference, 2.0 percentage points; 95% CI, -1.1 to 5.1). Noninferiority was shown in the secondary and sensitivity analyses. Rifapentine without moxifloxacin was not shown to be noninferior to the control in either population (17.7% vs. 14.6% with an unfavorable outcome in the microbiologically eligible population; difference, 3.0 percentage points [95% CI, -0.6 to 6.6]; and 14.2% vs. 9.6% in the assessable population; difference, 4.4 percentage points [95% CI, 1.2 to 7.7]). Adverse events of grade 3 or higher occurred during the on-treatment period in 19.3% of participants in the control group, 18.8% in the rifapentine-moxifloxacin group, and 14.3% in the rifapentine group.

Conclusions: The efficacy of a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in the treatment of tuberculosis. (Funded by the Centers for Disease Control and Prevention and others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.).
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http://dx.doi.org/10.1056/NEJMoa2033400DOI Listing
May 2021

Rigorizing COVID-19 Blind-Spotting for Competent Political Leadership and Public Health Cognizance.

J Glob Infect Dis 2021 Jan-Mar;13(1):62-63. Epub 2021 Feb 26.

Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.

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http://dx.doi.org/10.4103/jgid.jgid_447_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054783PMC
February 2021

Immune cells in bronchoalveolar lavage fluid of Ugandan adults who resist versus those who develop latent Mycobacterium tuberculosis infection.

PLoS One 2021 9;16(4):e0249477. Epub 2021 Apr 9.

Tuberculosis Research Unit and Division of Infectious Diseases, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, Ohio, United States of America.

Background: The search for immune correlates of protection against Mycobacterium tuberculosis (MTB) infection in humans is limited by the focus on peripheral blood measures. Bronchoalveolar lavage (BAL) can safely be done and provides insight into cellular function in the lung where infection is first established. In this study, blood and lung samples were assayed to determine if heavily MTB exposed persons who resist development of latent MTB infection (RSTR) vs those who develop latent MTB infection (LTBI), differ in the make-up of resident BAL innate and adaptive immune cells.

Methods: Bronchoscopy was performed on 21 healthy long-term Ugandan RSTR and 25 LTBI participants. Immune cell distributions in BAL and peripheral blood were compared by differential cell counting and flow cytometry.

Results: The bronchoscopy procedure was well tolerated with few adverse reactions. Differential macrophage and lymphocyte frequencies in BAL differed between RSTR and LTBI. When corrected for age, this difference lost statistical significance. BAL CD4+ and CD8+ T cells were almost entirely composed of effector memory T cells in contrast to PBMC, and did not differ between RSTR and LTBI. BAL NKT, γδ T cells and NK cells also did not differ between RTSR and LTBI participants. There was a marginally significant increase (p = 0.034) in CD8 T effector memory cells re-expressing CD45RA (TEMRA) in PBMC of LTBI vs RSTR participants.

Conclusion: This observational case-control study comparing unstimulated BAL from RSTR vs LTBI, did not find evidence of large differences in the distribution of baseline BAL immune cells. PBMC TEMRA cell percentage was higher in LTBI relative to RSTR suggesting a role in the maintenance of latent MTB infection. Functional immune studies are required to determine if and how RSTR and LTBI BAL immune cells differ in response to MTB.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249477PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034721PMC
April 2021

Myocardial TGFβ2 Is Required for Atrioventricular Cushion Remodeling and Myocardial Development.

J Cardiovasc Dev Dis 2021 Mar 2;8(3). Epub 2021 Mar 2.

Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA.

Among the three transforming growth factor beta (TGFβ) ligands, TGFβ2 is essential for heart development and is produced by multiple cell types, including myocardium. Heterozygous mutations in in patients of connective tissue disorders result in congenital heart defects and adult valve malformations, including mitral valve prolapse (MVP) with or without regurgitation. germline knockout fetuses exhibit multiple cardiac defects but the role of myocardial-TGFβ2 in heart development is yet to be elucidated. Here, myocardial conditional knockout (CKO) embryos were generated by crossing mice with ; Cre mice. embryos were normal, viable. Cell fate mapping was done using dual-fluorescent mice. Cre-mediated deletion was assessed by genomic PCR. RNAscope in situ hybridization was used to detect the loss of myocardial expression. Histological, morphometric, immunohistochemical, and in situ hybridization analyses of CKOs and littermate controls at different stages of heart development (E12.5-E18.5) were used to determine the role of myocardium-derived TGFβ2 in atrioventricular (AV) cushion remodeling and myocardial development. CKOs exhibit a thin ventricular myocardium, AV cushion remodeling defects and developed incomplete AV septation defects. The loss of myocardial resulted in impaired cushion maturation and dysregulated cell death. Phosphorylated SMAD2, a surrogate for TGFβ signaling, was "paradoxically" increased in both AV cushion mesenchyme and ventricular myocardium in the CKOs. Our results indicate that TGFβ2 produced by cardiomyocytes acting as cells autonomously on myocardium and via paracrine signaling on AV cushions are required for heart development.
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http://dx.doi.org/10.3390/jcdd8030026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999251PMC
March 2021

Icosahedral virus structures and the protein data bank.

J Biol Chem 2021 Mar 17:100554. Epub 2021 Mar 17.

Department of Integrative Structural and Computational Biology, The Scripps Research Institute , La Jolla, CA 92037.

The structural study of icosahedral viruses has a long and impactful history in both crystallographic methodology and molecular biology. The evolution of the Protein Data Bank has paralleled and supported these studies providing readily accessible formats dealing with novel features associated with viral particle symmetries and subunit interactions. This overview describes the growth in size and complexity of icosahedral viruses from the first early studies of small RNA plant viruses and human picorna viruses up to the larger and more complex bacterial phage, insect and human disease viruses such as Zika, hepatitis B, Adeno and Polyoma virus. The analysis of icosahedral viral capsid protein domain folds has shown striking similarities, with the beta jelly roll motif observed across multiple evolutionarily divergent species. The icosahedral symmetry of viruses drove the development of non-crystallographic symmetry averaging as a powerful phasing method, and the constraints of maintaining this symmetry resulted in the concept of quasi-equivalence in viral structures. Symmetry also played an important early role in demonstrating the power of cryo-electron microscopy as an alternative to crystallography in generating atomic resolution structures of these viruses. The Protein Data Bank has been a critical resource for assembling and disseminating these structures to a wide community, and the virus particle explorer (VIPER) was developed to enable users to easily generate and view complete viral capsid structures from their asymmetric building blocks. Finally, we share a personal perspective on the early use of computer graphics to communicate the intricacies, interactions and beauty of these virus structures.
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http://dx.doi.org/10.1016/j.jbc.2021.100554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081926PMC
March 2021

Considerations for robotic-assisted laparoscopic surgery in children.

J Minim Access Surg 2021 Apr-Jun;17(2):276-277

Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.

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http://dx.doi.org/10.4103/jmas.JMAS_327_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083759PMC
March 2021

Dynamics and stability in the maturation of a eukaryotic virus: a paradigm for chemically programmed large-scale macromolecular reorganization.

Arch Virol 2021 Jun 8;166(6):1547-1563. Epub 2021 Mar 8.

John Innes Centre, The John Innes Centre, Norwich Research Park, Norwich, NR4 7UH, UK.

Virus maturation is found in all animal viruses and dsDNA bacteriophages that have been studied. It is a programmed process, cued by cellular environmental factors, that transitions a noninfectious, initial assembly product (provirus) to an infectious particle (virion). Nudaurelia capensis omega virus (NωV) is an ssRNA insect virus with T=4 quasi-symmetry. Over the last 20 years, NωV virus-like particles (VLPs) have been an attractive model for the detailed study of maturation. The novel feature of the system is the progressive transition from procapsid to capsid controlled by pH. Homogeneous populations of maturation intermediates can be readily produced at arbitrary intervals by adjusting the pH between 7.6 and 5.0. These intermediates were investigated using biochemical and biophysical methods to create a stop-frame transition series of this complex process. The studies reviewed here characterized the large-scale subunit reorganization during maturation (the particle changes size from 48 nm to 41 nm) as well as the mechanism of a maturation cleavage, a time-resolved study of cleavage site formation, and specific roles of quasi-equivalent subunits in the release of membrane lytic peptides required for cellular entry.
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http://dx.doi.org/10.1007/s00705-021-05007-zDOI Listing
June 2021

Need for a systems integration methodology for effective implementation of simulation-based training.

Ann Thorac Med 2021 Jan-Mar;16(1):126. Epub 2021 Jan 14.

Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.

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http://dx.doi.org/10.4103/atm.ATM_518_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908896PMC
January 2021

Functional Dissection of the Dominant Role of CD55 in Protecting Vesicular Stomatitis Virus against Complement-Mediated Neutralization.

Viruses 2021 02 26;13(3). Epub 2021 Feb 26.

Pathogen Biology, Virology, Rajiv Gandhi Center for Biotechnology, Thiruvananthapuram, Kerala 695014, India.

The human complement system is an important part of the innate immune system. Its effector pathways largely mediate virus neutralization. Vesicular stomatitis virus (VSV) activates the classical pathway of the complement, leading to virus neutralization by lysis. Two host-derived membrane-associated regulators of complement activation (RCA), CD55 and CD46, which are incorporated into the VSV envelope during egress, confer protection by delaying/resisting complement-mediated neutralization. We showed previously that CD55 is more effective than CD46 in the inhibition of neutralization. In this study, we identified that, at the protein level, VSV infection resulted in the down-regulation of CD46 but not CD55. The mRNA of both the RCAs was significantly down-regulated by VSV, but it was delayed in the case of CD55. The immunoblot analysis of the levels of RCAs in the progeny virion harvested at three specific time intervals, points to an equal ratio of its distribution relative to viral proteins. Besides reconfirming the dominant role of CD55 over CD46 in shielding VSV from complement, our results also highlight the importance of the subtle modulation in the expression pattern of RCAs in a system naturally expressing them.
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http://dx.doi.org/10.3390/v13030373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996768PMC
February 2021

Advances in the application of Doppler ultrasonography in the newborn.

Med Ultrason 2021 Feb;23(1):124-125

Department of Biomedical Engineering, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada.

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http://dx.doi.org/10.11152/mu-3018DOI Listing
February 2021

Ultra-absorptive Nanofiber Swabs for Improved Collection and Test Sensitivity of SARS-CoV-2 and other Biological Specimens.

Nano Lett 2021 02 27;21(3):1508-1516. Epub 2021 Jan 27.

Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, Nebraska 68130, United States.

Following the COVID-19 outbreak, swabs for biological specimen collection were thrust to the forefront of healthcare materials. Swab sample collection and recovery are vital for reducing false negative diagnostic tests, early detection of pathogens, and harvesting DNA from limited biological samples. In this study, we report a new class of nanofiber swabs tipped with hierarchical 3D nanofiber objects produced by expanding electrospun membranes with a solids-of-revolution-inspired gas foaming technique. Nanofiber swabs significantly improve absorption and release of proteins, cells, bacteria, DNA, and viruses from solutions and surfaces. Implementation of nanofiber swabs in SARS-CoV-2 detection reduces the false negative rates at two viral concentrations and identifies SARS-CoV-2 at a 10× lower viral concentration compared to flocked and cotton swabs. The nanofiber swabs show great promise in improving test sensitivity, potentially leading to timely and accurate diagnosis of many diseases.
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http://dx.doi.org/10.1021/acs.nanolett.0c04956DOI Listing
February 2021

Dual Delivery of Alendronate and E7-BMP-2 Peptide via Calcium Chelation to Mineralized Nanofiber Fragments for Alveolar Bone Regeneration.

ACS Biomater Sci Eng 2020 04 20;6(4):2368-2375. Epub 2020 Mar 20.

Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.

The fixation and stability of dental implants is governed by the quality of the underlying alveolar bone. The current study investigates if the dual delivery of calcium chelating bone therapeutics from mineralized nanofiber fragments can help regenerate alveolar bone . Alendronate (ALN) or/and bone morphogenetic protein-2-mimicking peptide conjugated to a heptaglutamate moiety (E7-BMP-2) were incorporated onto mineralized nanofiber fragments of polylactide--glycolide-collagen-gelatin (PCG in 2:1:1 weight ratios) via calcium coupling/chelation. Two mg of the single-loaded (ALN) and coloaded (ALN + E7-BMP-2) mineralized nanofiber PCG grafts was filled into critical-sized (2 mm diameter × 2 mm depth) alveolar bone defects in rat maxillae and let heal for 4 weeks. X-ray microcomputed tomography analysis of the retrieved maxillae revealed significantly elevated new bone formation parameters for the ALN and ALN + E7-BMP-2 groups compared with the unfilled defect controls. However, no significant differences between the single and coloaded nanofiber grafts were noted. Furthermore, the histopathological analysis of the tissue sections divulged islands of new bone tissue in the ALN and ALN + E7-BMP-2 groups, whereas the control defect was covered with gingival tissue. Together, the presented strategy using mineralized nanofiber fragments in the sustained delivery of dual calcium chelating therapeutics could have potential applications in enhancing bone regeneration.
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http://dx.doi.org/10.1021/acsbiomaterials.0c00145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818347PMC
April 2020

Periosteum Mimetic Coating on Structural Bone Allografts Electrospray Deposition Enhances Repair and Reconstruction of Segmental Defects.

ACS Biomater Sci Eng 2020 11 22;6(11):6241-6252. Epub 2020 Oct 22.

Center for Musculoskeletal Research, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642, United States.

Structural bone allograft transplantation remains one of the common strategies for repair and reconstruction of large bone defects. Due to the loss of periosteum that covers the outer surface of the cortical bone, the healing and incorporation of allografts is extremely slow and limited. To enhance the biological performance of allografts, herein, we report a novel and simple approach for engineering a periosteum mimetic coating on the surface of structural bone allografts polymer-mediated electrospray deposition. This approach enables the coating on allografts with precisely controlled composition and thickness. In addition, the periosteum mimetic coating can be tailored to achieve desired drug release profiles by making use of an appropriate biodegradable polymer or polymer blend. The efficacy study in a murine segmental femoral bone defect model demonstrates that the allograft coating composed of poly(lactic--glycolic acid) and bone morphogenetic protein-2 mimicking peptide significantly improves allograft healing as evidenced by decreased fibrotic tissue formation, increased periosteal bone formation, and enhanced osseointegration. Taken together, this study provides a platform technology for engineering a periosteum mimetic coating which can greatly promote bone allograft healing. This technology could eventually result in an off-the-shelf and multifunctional structural bone allograft for highly effective repair and reconstruction of large segmental bone defects. The technology can also be used to ameliorate the performance of other medical implants by modifying their surfaces.
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http://dx.doi.org/10.1021/acsbiomaterials.0c00421DOI Listing
November 2020

Decreased plasma rifapentine concentrations associated with AADAC single nucleotide polymorphism in adults with tuberculosis.

J Antimicrob Chemother 2021 Feb;76(3):582-586

University of California San Francisco, San Francisco, CA, USA.

Background: Rifapentine exposure is associated with bactericidal activity against Mycobacterium tuberculosis, but high interindividual variation in plasma concentrations is encountered.

Objectives: To investigate a genomic association with interindividual variation of rifapentine exposure, SNPs of six human genes involving rifamycin metabolism (AADAC, CES2), drug transport (SLCO1B1, SLCO1B3) and gene regulation (HNF4A, PXR) were evaluated.

Methods: We characterized these genes in 173 adult participants in treatment trials of the Tuberculosis Trials Consortium. Participants were stratified by self-identified race (black or non-black), and rifapentine AUC from 0 to 24 h (AUC0-24) was adjusted by analysis of covariance for SNPs, rifapentine dose, sex, food and HIV coinfection. This study was registered at ClinicalTrials.gov under identifier NCT01043575.

Results: The effect on rifapentine least squares mean AUC0-24 in black participants overall decreased by -10.2% for AADAC rs1803155 G versus A allele (Wald test: P = 0.03; false discovery rate, 0.10). Black participants with one G allele in AADAC rs1803155 were three times as likely to have below target bactericidal rifapentine exposure than black participants with the A allele (OR, 2.97; 95% CI: 1.16, 7.58). With two G alleles, the OR was greater. In non-black participants, AADAC rs1803155 SNP was not associated with rifapentine exposure. In both black and non-black participants, other evaluated genes were not associated with rifapentine exposure (P > 0.05; false discovery rate > 0.10).

Conclusions: Rifapentine exposure in black participants varied with AADAC rs1803155 genotype and the G allele was more likely to be associated with below bactericidal target rifapentine exposure. Further pharmacogenomic study is needed to characterize the association of the AADAC rs1803155 with inadequate rifapentine exposure in different patient groups.
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http://dx.doi.org/10.1093/jac/dkaa490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879139PMC
February 2021

VIPERdb v3.0: a structure-based data analytics platform for viral capsids.

Nucleic Acids Res 2021 01;49(D1):D809-D816

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.

VIrus Particle ExploreR data base (VIPERdb) (http://viperdb.scripps.edu) is a curated repository of virus capsid structures and a database of structure-derived data along with various virus specific information. VIPERdb has been continuously improved for over 20 years and contains a number of virus structure analysis tools. The release of VIPERdb v3.0 contains new structure-based data analytics tools like Multiple Structure-based and Sequence Alignment (MSSA) to identify hot-spot residues within a selected group of structures and an anomaly detection application to analyze and curate the structure-derived data within individual virus families. At the time of this writing, there are 931 virus structures from 62 different virus families in the database. Significantly, the new release also contains a standalone database called 'Virus World database' (VWdb) that comprises all the characterized viruses (∼181 000) known to date, gathered from ICTVdb and NCBI, and their capsid protein sequences, organized according to their virus taxonomy with links to known structures in VIPERdb and PDB. Moreover, the new release of VIPERdb includes a service-oriented data engine to handle all the data access requests and provides an interface for futuristic data analytics using machine leaning applications.
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http://dx.doi.org/10.1093/nar/gkaa1096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779063PMC
January 2021

Level of education and preferred language of informed consent for clinical research in a multi-lingual community.

Afr Health Sci 2020 Jun;20(2):955-959

Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda.

Background: Low education levels and language barriers present challenges in obtaining informed consent for clinical research.

Objective: To describe and correlate the association between the level of education and the participant's preferred language of consent.

Design: Descriptive-analytical cross-sectional study.

Participants: Adults being consented for participation in tuberculosis(TB) research studies in an East African community with varying levels of education.

Procedures: We analyzed data on demographic and educational characteristics collected from adults being consented for participation in TB studies .Only participants who could understand and speak Luganda (the main local language) or English (the official language of Uganda) were included in this analysis.

Results: A total of 523 participants were consented between April 2015 and December 2017 and included in this analysis; 250 below Senior four (< 11yrs of education), 114 senior four (at 11yrs of education),73 senior five-senior six (12-13yrs of education) and 86 beyond senior six (> 13yrs of education). We noted that the preference for English rises with the rising levels of education and peaked at beyond senior six (83%Vs17%,OR=49,95%CI:22.8-106.3,p<0.001).Participants below senior four preferred Luganda Vs senior four and above(OR=16.9,95%CI:9.9-28.8,p<0.001).

Conclusion: Rising education levels of participants were associated with preference for English language usage during initial consent for clinical research studies.
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http://dx.doi.org/10.4314/ahs.v20i2.51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609127PMC
June 2020

In the Crosshairs: RNA Viruses OR Complement?

Front Immunol 2020 29;11:573583. Epub 2020 Sep 29.

Viral Disease Biology, Department of Pathogen Biology, Rajiv Gandhi Center for Biotechnology, Thiruvananthapuram, India.

Complement, a part of the innate arm of the immune system, is integral to the frontline defense of the host against innumerable pathogens, which includes RNA viruses. Among the major groups of viruses, RNA viruses contribute significantly to the global mortality and morbidity index associated with viral infection. Despite multiple routes of entry adopted by these viruses, facing complement is inevitable. The initial interaction with complement and the nature of this interaction play an important role in determining host resistance versus susceptibility to the viral infection. Many RNA viruses are potent activators of complement, often resulting in virus neutralization. Yet, another facet of virus-induced activation is the exacerbation in pathogenesis contributing to the overall morbidity. The severity in disease and death associated with RNA virus infections shows a tip in the scale favoring viruses. Growing evidence suggest that like their DNA counterparts, RNA viruses have co-evolved to master ingenious strategies to remarkably restrict complement. Modulation of host genes involved in antiviral responses contributed prominently to the adoption of unique strategies to keep complement at bay, which included either down regulation of activation components (C3, C4) or up regulation of complement regulatory proteins. All this hints at a possible "hijacking" of the cross-talk mechanism of the host immune system. Enveloped RNA viruses have a selective advantage of not only modulating the host responses but also recruiting membrane-associated regulators of complement activation (RCAs). This review aims to highlight the significant progress in the understanding of RNA virus-complement interactions.
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http://dx.doi.org/10.3389/fimmu.2020.573583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550403PMC
September 2020

Stimulator of interferon genes (STING) is an essential proviral host factor for human rhinovirus species A and C.

Proc Natl Acad Sci U S A 2020 11 15;117(44):27598-27607. Epub 2020 Oct 15.

Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;

Human rhinoviruses (RVs) are positive-strand RNA viruses that cause respiratory tract disease in children and adults. Here we show that the innate immune signaling protein STING is required for efficient replication of members of two distinct RV species, RV-A and RV-C. The host factor activity of STING was identified in a genome-wide RNA interference (RNAi) screen and confirmed in primary human small airway epithelial cells. Replication of RV-A serotypes was strictly dependent on STING, whereas RV-B serotypes were notably less dependent. Subgenomic RV-A and RV-C RNA replicons failed to amplify in the absence of STING, revealing it to be required for a step in RNA replication. STING was expressed on phosphatidylinositol 4-phosphate (PI4P)-enriched membranes and was enriched in RV-A16 compared with RV-B14 replication organelles isolated in isopycnic gradients. The host factor activity of STING was species-specific, as murine STING (mSTING) did not rescue RV-A16 replication in STING-deficient cells. This species specificity mapped primarily to the cytoplasmic, ligand-binding domain of STING. Mouse-adaptive mutations in the RV-A16 2C protein allowed for robust replication in cells expressing mSTING, suggesting a role for 2C in recruiting STING to RV-A replication organelles. Palmitoylation of STING was not required for RV-A16 replication, nor was the C-terminal tail of STING that mediates IRF3 signaling. Despite co-opting STING to promote its replication, interferon signaling in response to STING agonists remained intact in RV-A16 infected cells. These data demonstrate a surprising requirement for a key host mediator of innate immunity to DNA viruses in the life cycle of a small pathogenic RNA virus.
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http://dx.doi.org/10.1073/pnas.2014940117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959528PMC
November 2020

Role of the complement in Leptospira virulence and infection.

Biomed J 2020 10 27;43(5):462-463. Epub 2020 Aug 27.

Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; Faculty of Engineering, University of Alberta, Edmonton, Alberta, Canada.

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http://dx.doi.org/10.1016/j.bj.2020.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680810PMC
October 2020

Pandemic practice: Horror fans and morbidly curious individuals are more psychologically resilient during the COVID-19 pandemic.

Pers Individ Dif 2021 Jan 15;168:110397. Epub 2020 Sep 15.

Department of English, School of Communication and Culture, Aarhus University, Denmark.

One explanation for why people engage in frightening fictional experiences is that these experiences can act as simulations of actual experiences from which individuals can gather information and model possible worlds. Conducted during the COVID-19 pandemic, this study (n = 310) tested whether past and current engagement with thematically relevant media fictions, including horror and pandemic films, was associated with greater preparedness for and psychological resilience toward the pandemic. Since morbid curiosity has previously been associated with horror media use during the COVID-19 pandemic, we also tested whether trait morbid curiosity was associated with pandemic preparedness and psychological resilience during the COVID-19 pandemic. We found that fans of horror films exhibited greater resilience during the pandemic and that fans of "prepper" genres (alien-invasion, apocalyptic, and zombie films) exhibited both greater resilience and preparedness. We also found that trait morbid curiosity was associated with positive resilience and interest in pandemic films during the pandemic. Taken together, these results are consistent with the hypothesis that exposure to frightening fictions allow audiences to practice effective coping strategies that can be beneficial in real-world situations.
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http://dx.doi.org/10.1016/j.paid.2020.110397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492010PMC
January 2021

Converting 2D Nanofiber Membranes to 3D Hierarchical Assemblies with Structural and Compositional Gradients Regulates Cell Behavior.

Adv Mater 2020 Oct 18;32(43):e2003754. Epub 2020 Sep 18.

Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, 68198, USA.

New methods are described for converting 2D electrospun nanofiber membranes to 3D hierarchical assemblies with structural and compositional gradients. Pore-size gradients are generated by tuning the expansion of 2D membranes in different layers with incorporation of various amounts of a surfactant during the gas-foaming process. The gradient in fiber organizations is formed by expanding 2D nanofiber membranes composed of multiple regions collected by varying rotating speeds of mandrel. A compositional gradient on 3D assemblies consisting of radially aligned nanofibers is prepared by dripping, diffusion, and crosslinking. Bone mesenchymal stem cells (BMSCs) on the 3D nanofiber assemblies with smaller pore size show significantly higher expression of hypoxia-related markers and enhanced chondrogenic differentiation compared to BMSCs cultured on the assemblies with larger pore size. The basic fibroblast growth factor gradient can accelerate fibroblast migration from the surrounding area to the center in an in vitro wound healing model. Taken together, 3D nanofiber assemblies with gradients in pore sizes, fiber organizations, and contents of signaling molecules can be used to engineer tissue constructs for tissue repair and build biomimetic disease models for studying disease biology and screening drugs, in particular, for interface tissue engineering and modeling.
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http://dx.doi.org/10.1002/adma.202003754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606784PMC
October 2020

Dissolvable Microneedles Coupled with Nanofiber Dressings Eradicate Biofilms Effectively Delivering a Database-Designed Antimicrobial Peptide.

ACS Nano 2020 09 27;14(9):11775-11786. Epub 2020 Aug 27.

Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, Nebraska 68130, United States.

Biofilms in chronic wounds, including diabetic foot ulcers, pressure ulcers, and venous leg ulcers, pose a major challenge to wound management. Herein, we report a Janus-type antimicrobial dressing for eradication of biofilms in chronic wounds. The dressing consists of electrospun nanofiber membranes coupled with dissolvable microneedle arrays to enable effective delivery of a database-designed antimicrobial peptide to both inside and outside biofilms. This antimicrobial dressing exhibited high efficacy against a broad spectrum of resistant pathogens . Importantly, such a dressing was able to eradicate methicillin-resistant (MRSA) biofilms in both an human skin wound infection model and a type II diabetic mouse wound infection model after daily treatment without applying surgical debridement. Most importantly, the dressing can also completely remove the and MRSA, dual-species biofilm in an human skin infection model. In addition, our computational simulations also suggested that microneedles were more effective in the delivery of peptides to the biofilms than free drugs. Our results indicate that the Janus-type antimicrobial dressings may provide an effective treatment and management of chronic wound polymicrobial infections.
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http://dx.doi.org/10.1021/acsnano.0c04527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673654PMC
September 2020

Genome-wide analysis of brassinosteroid responsive small RNAs in Arabidopsis thaliana.

Genes Genomics 2020 08 9;42(8):957-969. Epub 2020 Jul 9.

Department of Biological Sciences, College of Biological Sciences and Biotechnology, Chungnam National University, Daejeon, 34134, Korea.

Background: Brassinosteroids (BRs) are a class of phytohormones with important roles in regulating physiological and developmental processes. Small RNAs, including small interfering RNAs and microRNAs (miRNAs), are non-protein coding RNAs that regulate gene expression at the transcriptional and post-transcriptional levels. However, the roles of small RNAs in BR response have not been studied well.

Objective: In this study, we aimed to identify BR-responsive small RNA clusters and miRNAs in Arabidopsis. In addition, the effect of BR-responsive small RNAs on their transcripts and target genes were examined.

Methods: Small RNA libraries were constructed from control and epibrassinolide-treated seedlings expressing wild-type BRI1-Flag protein under its native promoter in the bri1-5 mutant. After sequencing the small RNA libraries, differentially expressed small RNA clusters were identified by examining the expression levels of small RNAs in 100-nt bins of the Arabidopsis genome. To identify the BR-responsive miRNAs, the expression levels of all the annotated mature miRNAs, registered in miRBase, were analyzed. Previously published RNA-seq data were utilized to monitor the BR-responsive expression patterns of differentially expressed small RNA clusters and miRNA target genes.

Results: In results, 38 BR-responsive small RNA clusters, including 30 down-regulated and eight up-regulated clusters, were identified. These differentially expressed small RNA clusters were from miRNA loci, transposons, protein-coding genes, pseudogenes and others. Of these, a transgene, BRI1, accumulates small RNAs, which are not found in the wild type. Small RNAs in this transgene are up-regulated by BRs while BRI1 mRNA is down-regulated by BRs. By analyzing the expression patterns of mature miRNAs, we have identified BR-repressed miR398a-5p and BR-induced miR156g. Although miR398a-5p is down-regulated by BRs, its predicted targets were not responsive to BRs. However, SPL3, a target of BR-inducible miR156g, is down-regulated by BRs.

Conclusion: BR-responsive small RNAs and miRNAs identified in this study will provide an insight into the role of small RNAs in BR responses in plants. Especially, we suggest that miR156g/SPL3 module might play a role in BR-mediated growth and development in Arabidopsis.
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http://dx.doi.org/10.1007/s13258-020-00964-2DOI Listing
August 2020

Fluorescence Imaging of the Ureter in Minimally Invasive Pelvic Surgery.

J Minim Invasive Gynecol 2021 02 29;28(2):332-341.e14. Epub 2020 Jun 29.

Division of Gynecologic Oncology, University of Alabama, Birmingham, Alabama (Drs. Kim, Johnson, Leath III, Huh, and Ms. Elliott); Department of Obstetrics and Gynecology, University of Tennessee Medical Center Knoxville, Graduate School of Medicine, Knoxville, Tennessee (Dr. Boone); Clinical Research and Development, LI-COR, Inc., Lincoln, Nebraska (Ms. Kovar).

Study Objective: Determine near-optimal dose, safety, and efficacy of nerindocianine in pelvic ureter detection with near-infrared fluorescence imaging in women undergoing minimally invasive pelvic surgery with 3 Food and Drug Administration-cleared imaging systems.

Design: Open label, phase 1/2a study.

Setting: University of Alabama at Birmingham.

Patients: Forty-one female subjects undergoing minimally invasive gynecologic surgery.

Interventions: Subjects received a single dose of nerindocianine sodium, starting at 0.06-mg/kg body weight and increased/decreased until the near-optimal dose was determined (part A). Examine the degree of concordance between endoscopic and robotic devices (part B).

Measurements And Main Results: In part A, composite scores were collected every 10 minutes for 30 minutes and then every 15 minutes through 90 minutes using a scale measuring the anatomy/laterality of ureter visualization. In part B (paired imaging system efficacy), 2 cohorts of 8 subjects each received the near-optimal dose. Composite scores for visualization of the ureter were collected at 10 and 30 minutes postinfusion with the Firefly Imaging System and either the PINPOINT or 1588 AIM endoscope. Composite scores were compared to examine the degree of concordance between devices. Part A comprised 25 total subjects enrolled in dosing groups 1, 2, and 3 (0.06-, 0.12-, and 0.045-mg/kg, respectively). Median time to first ureter visualization was 10 minutes (all groups). The nerindocianine 0.06-mg/kg and 0.12-mg/kg groups had longer length of time of visualization than the 0.045-mg/kg group, resulting in the selection of 0.06 mg/kg as the near-optimal dose. Part B enrolled 16 total subjects in 2 groups dosed at 0.06 mg/kg. Efficacy analysis showed no statistically significant difference in composite scores with Firefly versus PINPOINT or 1588 AIM.

Conclusion: Nerindocianine was well tolerated with visualization of the ureter demonstrated in 88.9% of the subjects through 90 minutes postdosing. No meaningful visualization differences were observed among the Food and Drug Administration-cleared surgical imaging systems used.
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http://dx.doi.org/10.1016/j.jmig.2020.06.022DOI Listing
February 2021

Fast transformation of 2D nanofiber membranes into pre-molded 3D scaffolds with biomimetic and oriented porous structure for biomedical applications.

Appl Phys Rev 2020 Jun;7(2):021406

Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.

The ability to transform two-dimensional (2D) structures into three-dimensional (3D) structures leads to a variety of applications in fields such as soft electronics, soft robotics, and other biomedical-related fields. Previous reports have focused on using electrospun nanofibers due to their ability to mimic the extracellular matrix. These studies often lead to poor results due to the dense structures and small poor sizes of 2D nanofiber membranes. Using a unique method of combining innovative gas-foaming and molding technologies, we report the rapid transformation of 2D nanofiber membranes into predesigned 3D scaffolds with biomimetic and oriented porous structure. By adding a surfactant (pluronic F-127) to poly(ε-caprolactone) (PCL) nanofibers, the rate of expansion is dramatically enhanced due to the increase in hydrophilicity and subsequent gas bubble stability. Using this novel method together with molding, 3D objects with cylindrical, hollow cylindrical, cuboid, spherical, and irregular shapes are created. Interestingly, these 3D shapes exhibit anisotropy and consistent pore sizes throughout entire object. Through further treatment with gelatin, the scaffolds become superelastic and shape-recoverable. Additionally, gelatin-coated, cube-shaped scaffolds were further functionalized with polypyrrole coatings and exhibited dynamic electrical conductivity during cyclic compression. Cuboid-shaped scaffolds have been demonstrated to be effective for compressible hemorrhage in a porcine liver injury model. In addition, human neural progenitor cells can be uniformly distributed and differentiated into neurons throughout the cylinder-shaped nanofiber scaffolds, forming ordered 3D neural tissue constructs. Taken together, the approach presented in this study is very promising in the production of pre-molded 3D nanofiber scaffolds for many biomedical applications.
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http://dx.doi.org/10.1063/1.5144808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233601PMC
June 2020