Growth factor (GF) patterning in stem cell spheroids, such as embryoid bodies (EBs), has been sought to guide their differentiation and organization into functional 3D tissue models and organoids. Current approaches relying on exposure of EBs to gradients of GFs suffer from poor molecular transport in the spheroid microenvironment and from high cost of production and low stability of recombinant GFs. We have developed an alternative method for establishing GF gradients in EBs utilizing stem cell surface engineering with membrane-targeting heparan sulfate-glycomimetic co-receptors for GFs. We have capitalized on the ability of amphiphilic lipid-functionalized glycopolymers with affinity for FGF2 to assemble into nanoscale vesicles with tunable dimensions and extracellular matrix penetrance. Upon size-dependent diffusion into EBs, the vesicles fused with the plasma membranes of stem cells, giving rise to concentric gradients of cells with enhanced FGF2-binding. The extracellular matrix-assisted cell surface remodeling process described is the first example of spatially-targeted glycocalyx engineering in multicellular systems to control GF localization. The glycopolymer structure, vesicle dimensions, and remodeling conditions determine the level of FGF2 adhesion and gradient slope. The increased chemical and thermal stability of the synthetic glycomimetics and the tunability of their GF-binding profile, which is defined by their glycosylation and may be extended to other recombinant or endogenous morphogens beyond FGF2, further increase the versatility of this method.

BACKGROUND: There is a lack of physician ethnic and gender diversity amongst surgical specialties. This study analyzes the literature that promotes diversity amongst surgical trainees. Specifically, this study sought to answer (i) how the number of publications regarding diversity in orthopaedic surgery compares to other surgical specialties, (ii) how the number of publications amongst all surgical subspecialties trends over time and (iii) which specific topics regarding diversity are discussed in the surgical literature. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used to query articles from PubMed, Web of Science, Embase and the Cumulative Index to Nursing and Allied Health Literature. Broad inclusion criteria for both ethnic and gender diversity of any surgical specialty were utilized. RESULTS: Our query resulted 1429 publications, of which 408 duplicates were removed, and 701 were excluded on title and abstract screening, leaving 320 to be included. The highest number of related publications was in orthopaedic surgery (n = 73) followed by general surgery (n = 56). Out of 320 total articles, 260 (81.3 %) were published after 2015, and 56 of 73 (76.7 %) orthopaedic-specific articles were published after 2015. CONCLUSION: Orthopaedic surgery published the most about ethnic and gender diversity, however, still remains one of the least diverse surgical specialties. With the recent increase in publications on diversity in surgical training, close attention should be paid to ethnic and gender diversity amongst surgical trainees over the coming years. Should diversity remain stagnant, diversification efforts may need to be restructured to achieve a diverse surgeon workforce. KEY MESSAGE: Orthopaedic surgery is the surgical subspecialty that publishes the most about trainee ethnic and gender diversity followed by general surgery. With most of this literature being published over the last eight years, it is imperative to pay close attention to the ethnic and gender landscape of the surgeon workforce over the coming years.

We show that SARS-CoV-2 spike protein interacts with both cellular heparan sulfate and angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD). Docking studies suggest a heparin/heparan sulfate-binding site adjacent to the ACE2-binding site. Both ACE2 and heparin can bind independently to spike protein in vitro, and a ternary complex can be generated using heparin as a scaffold. Electron micrographs of spike protein suggests that heparin enhances the open conformation of the RBD that binds ACE2. On cells, spike protein binding depends on both heparan sulfate and ACE2. Unfractionated heparin, non-anticoagulant heparin, heparin lyases, and lung heparan sulfate potently block spike protein binding and/or infection by pseudotyped virus and authentic SARS-CoV-2 virus. We suggest a model in which viral attachment and infection involves heparan sulfate-dependent enhancement of binding to ACE2. Manipulation of heparan sulfate or inhibition of viral adhesion by exogenous heparin presents new therapeutic opportunities.