Hyaluronidase-1-mediated glycocalyx impairment underlies endothelial abnormalities in polypoidal choroidal vasculopathy.

BACKGROUND: Polypoidal choroidal vasculopathy (PCV), a subtype of age-related macular degeneration (AMD), is a global leading cause of vision loss in older populations. Distinct from typical AMD, PCV is characterized by polyp-like dilatation of blood vessels and turbulent blood flow in the choroid of the eye. Gold standard anti-vascular endothelial growth factor (anti-VEGF) therapy often fails to regress polypoidal lesions in patients. Current animal models have also been hampered by their inability to recapitulate such vascular lesions. These underscore the need to identify VEGF-independent pathways in PCV pathogenesis. RESULTS: We cultivated blood outgrowth endothelial cells (BOECs) from PCV patients and normal controls to serve as our experimental disease models. When BOECs were exposed to heterogeneous flow, single-cell transcriptomic analysis revealed that PCV BOECs preferentially adopted migratory-angiogenic cell state, while normal BOECs undertook proinflammatory cell state. PCV BOECs also had a repressed protective response to flow stress by demonstrating lower mitochondrial functions. We uncovered that elevated hyaluronidase-1 in PCV BOECs led to increased degradation of hyaluronan, a major component of glycocalyx that interfaces between flow stress and vascular endothelium. Notably, knockdown of hyaluronidase-1 in PCV BOEC improved mechanosensitivity, as demonstrated by a significant 1.5-fold upregulation of Krüppel-like factor 2 (KLF2) expression, a flow-responsive transcription factor. Activation of KLF2 might in turn modulate PCV BOEC migration. Barrier permeability due to glycocalyx impairment in PCV BOECs was also reversed by hyaluronidase-1 knockdown. Correspondingly, hyaluronidase-1 was detected in PCV patient vitreous humor and plasma samples. CONCLUSIONS: Hyaluronidase-1 inhibition could be a potential therapeutic modality in preserving glycocalyx integrity and endothelial stability in ocular diseases with vascular origin.

Single-Cell Transcriptome of Wet AMD Patient-Derived Endothelial Cells in Angiogenic Sprouting.

Age-related macular degeneration (AMD) is a global leading cause of visual impairment in older populations. 'Wet' AMD, the most common subtype of this disease, occurs when pathological angiogenesis infiltrates the subretinal space (choroidal neovascularization), causing hemorrhage and retinal damage. Gold standard anti-vascular endothelial growth factor (VEGF) treatment is an effective therapy, but the long-term prevention of visual decline has not been as successful. This warrants the need to elucidate potential VEGF-independent pathways. We generated blood out-growth endothelial cells (BOECs) from wet AMD and normal control subjects, then induced angiogenic sprouting of BOECs using a fibrin gel bead assay. To deconvolute endothelial heterogeneity, we performed single-cell transcriptomic analysis on the sprouting BOECs, revealing a spectrum of cell states. Our wet AMD BOECs share common pathways with choroidal neovascularization such as extracellular matrix remodeling that promoted proangiogenic phenotype, and our 'activated' BOEC subpopulation demonstrated proinflammatory hallmarks, resembling the tip-like cells in vivo. We uncovered new molecular insights that pathological angiogenesis in wet AMD BOECs could also be driven by interleukin signaling and amino acid metabolism. A web-based visualization of the sprouting BOEC single-cell transcriptome has been created to facilitate further discovery research.

Mechano-Activated Cell Therapy for Accelerated Diabetic Wound Healing.

Chronic diabetic wounds are a significant global healthcare challenge. Current strategies, such as biomaterials, cell therapies, and medical devices, however, only target a few pathological features and have limited efficacy. A powerful platform technology combining magneto-responsive hydrogel, cells, and wireless magneto-induced dynamic mechanical stimulation (MDMS) is developed to accelerate diabetic wound healing. The hydrogel encapsulates U.S. Food and Drug Administration (FDA)-approved fibroblasts and keratinocytes to achieve ∼3-fold better wound closure in a diabetic mouse model. MDMS acts as a nongenetic mechano-rheostat to activate fibroblasts, resulting in ∼240% better proliferation, ∼220% more collagen deposition, and improved keratinocyte paracrine profiles via the Ras/MEK/ERK pathway to boost angiogenesis. The magneto-responsive property also enables on-demand insulin release for spatiotemporal glucose regulation through increasing network deformation and interstitial flow. By mining scRNAseq data, a mechanosensitive fibroblast subpopulation is identified that can be mechanically tuned for enhanced proliferation and collagen production, maximizing therapeutic impact. The "all-in-one" system addresses major pathological factors associated with diabetic wounds in a single platform, with potential applications for other challenging wound types.

Digital health professions education on chronic wound management: A systematic review.

BACKGROUND: Continuing education is crucial for healthcare professionals to keep up with research but attending classroom lectures is a major barrier. Chronic wound management is increasingly relevant for continuous professional training. Digital education offers learning tailored to individual needs and could be an effective alternative to healthcare professionals' training. However, the effectiveness of digital education for chronic wound management training has not been explored. OBJECTIVES: To assess the effectiveness of digital education in improving healthcare professionals' knowledge, attitudes, practical skills and behaviour change on chronic wound management, and their satisfaction with the intervention. DESIGN: This systematic review follows Cochrane methodology and is one of a series of reviews on the use of digital education for health professions education. Protocol registration: PROSPERO CRD42018109971 DATA SOURCES: Searches were conducted in MEDLINE, Embase, Web of Science, ERIC, PsycINFO, CINAHL, CENTRAL, and ProQuest Dissertation and Theses Database. REVIEW METHODS: We included randomised control trials, cluster randomised control trials and quasi-randomised control trials comparing digital or blended education with traditional learning, no intervention or other forms of digital or blended education for pre- or post-registration healthcare professionals in chronic wound management. A narrative summary of findings is presented. RESULTS: Seven studies (1,404 participants) were included. All studies investigated interventions for nursing students or professionals working in hospitals or community settings, and all but one study focused on pressure ulcers. Five studies (935 participants) assessed post-intervention knowledge, and indicated that digital education was more effective than no intervention, while blended learning was superior to exclusive digital education. Three studies (543 participants) assessed post-intervention skills and reported mixed results. One study (140 participants) compared post-intervention behaviour change and satisfaction with blended and online digital education, and reported no difference in behaviour between the groups, and higher satisfaction with blended education. For knowledge retention up to six months, digital education was more effective than no intervention, while blended learning was superior to digital education. The risk of bias in included studies was mostly high or unclear. CONCLUSIONS: Digital education on chronic wound management appears to be less effective than blended education and more effective than no intervention in improving knowledge among nurses and nursing students. Data for other outcomes is scarce and inconclusive. Future studies should assess participants' skills, attitudes, satisfaction and behaviour change; cost-effectiveness and potential untoward effects of digital education, compare digital education to other learning modalities and include other healthcare professionals in diverse clinical settings.

Choroidal Neovascularization: Mechanisms of Endothelial Dysfunction.

Many conditions affecting the heart, brain, and even the eyes have their origins in blood vessel pathology, underscoring the role of vascular regulation. In age-related macular degeneration (AMD), there is excessive growth of abnormal blood vessels in the eye (choroidal neovascularization), eventually leading to vision loss due to detachment of retinal pigmented epithelium. As the advanced stage of this disease involves loss of retinal pigmented epithelium, much less attention has been given to early vascular events such as endothelial dysfunction. Although current gold standard therapy using inhibitors of vascular endothelial growth factor (VEGF) have achieved initial successes, some drawbacks include the lack of long-term restoration of visual acuity, as well as a subset of the patients being refractory to existing treatment, alluding us and others to hypothesize upon VEGF-independent mechanisms. Against this backdrop, we present here a nonexhaustive review on the vascular underpinnings of AMD, implications with genetic and systemic factors, experimental models for studying choroidal neovascularization, and interestingly, on both endothelial-centric pathways and noncell autonomous mechanisms. We hope to shed light on future research directions in improving vascular function in ocular disorders.

Digital Education for the Management of Chronic Wounds in Health Care Professionals: Protocol for a Systematic Review by the Digital Health Education Collaboration.

BACKGROUND: Digital education is "the act of teaching and learning by means of digital technologies." Digital education comprises a wide range of interventions that can be broadly divided into offline digital education, online digital education, digital game-based learning, massive open online courses (MOOCs), psychomotor skills trainers, virtual reality environments, virtual patient simulations, and m-learning. Chronic wounds pose an immense economic and psychosocial burden to patients and the health care system, as caring for them require highly specialized personnel. Current training strategies face significant barriers, such as lack of time due to work commitments, distance from provider centers, and costs. Therefore, there is an increased need to synthesize evidence on the effectiveness of digital education interventions on chronic wounds management in health care professionals. OBJECTIVE: Our main objective is to assess the effectiveness of digital education as a stand-alone approach or as part of a blended-learning approach in improving pre- and postregistration health care professionals' knowledge, attitudes, practical skills, and behavior in the management of chronic wounds, as well as their satisfaction with the intervention. Secondary objectives are to evaluate patient-related outcomes, cost-effectiveness of the interventions, and any unfavorable or undesirable outcomes that may arise. METHODS: This systematic review will follow the methodology as described in the Cochrane Handbook for Systematic Reviews of Interventions. As our systematic review is one of a series of reviews on digital education for health professionals' education, we will use a previously developed search strategy. This search includes the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library), MEDLINE (Ovid), Embase (Ovid), Web of Science, the Educational Resource Information Centre (ERIC) (Ovid), PsycINFO (Ovid), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCO), the ProQuest Dissertation and Theses database, and trial registries. Databases will be searched for studies published from January 1990 to August 2018. Two independent reviewers will screen the library for included studies. We will describe the screening process using a flowchart as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We will extract the data using a previously developed, structured data extraction form. Included studies will be quality-assessed using the Risk of Bias tool from Cochrane. We will narratively summarize the data and, if possible, we will conduct a meta-analysis. We will use Cochrane's RevMan 5.3 software for data analysis. RESULTS: We have completed the screening of titles and abstracts for this systematic review and are currently selecting papers against our inclusion and exclusion criteria through full-text revision. We are expecting to complete our review by the end of April 2019. CONCLUSIONS: This systematic review will provide an in-depth analysis of digital education strategies to train health care providers in the management of chronic wounds. We consider this topic particularly relevant given the current challenges facing health care systems worldwide, including shortages of skilled personnel and a steep increase in the population of older adults as a result of a prolonged life expectancy. TRIAL REGISTRATION: PROSPERO CRD42018109971; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=109971. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/12488.