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Introduction: Damage-associated molecular patterns (DAMPs) are molecules released in response to tissue or cellular damage to facilitate tissue regeneration. This inflammatory response can occur in sterile environments and is promoted by the release of damaged extracellular components such as the extracellular matrix (ECM). DAMPs have been implicated in various stages of wound healing but have yet to be explicitly utilized for regenerative medicine by leveraging selective modulation of the inflammatory response. With this in mind, we leverage inflammation to drive tissue regeneration by utilizing DAMPs collected from the native ECM, extracellular matrix motifs (mECM). Methods: Here, mECMs were derived from UV-damaged rat tail collagen I. Fibroblast response to various concentrations and presentation of mECMs was investigated by evaluating changes in viability, proliferation, cell phenotype, and cytokine secretion. Results: mECMs had reduced intensity in collagen I associated bands, indicating successful fragmentation to lower molecular weights. Soluble (mobile) mECMs induced changes in fibroblast phenotype as indicated by a decrease in proliferation, a decrease in nuclei area, and an increase in the percentage of elongated cells. In addition, mobile mECMs contributed to significant increases in cytokine secretion compared to insoluble (bound) mECMs. Across all experiments, bound mECMs exhibited effects on fibroblasts compared to the collagen control. Conclusion: Fibroblasts in vitro recognize mECMs, with significant differences observed based on the presentation of these proteins. These data indicate that cryptic regions that are recognized by fibroblasts may be exposed in the mobile version of the mECMs, which lead to a myofibroblast-like phenotype in fibroblasts. This work highlights the potential of DAMPs to serve as immunomodulatory therapeutics for tissue regeneration. 

Abstract BackgroundLaryngeal injury associated with traumatic or prolonged intubation may lead to voice, swallow, and airway complications. The interplay between inflammation and microbial population shifts induced by intubation may relate to clinical outcomes. The objective of this study was to investigate laryngeal mechanics, tissue inflammatory response, and local microbiome changes with laryngotracheal injury and localized delivery of therapeutics via drug-eluting endotracheal tube. MethodsA simulated traumatic intubation injury was created in Yorkshire crossbreed swine under direct laryngoscopy. Endotracheal tubes electrospun with roxadustat or valacyclovir- loaded polycaprolactone (PCL) fibers were placed in the injured airway for 3, 7, or 14 days (n = 3 per group/time and ETT type). Vocal fold stiffness was then evaluated with normal indentation and laryngeal tissue sections were histologically examined. Immunohistochemistry and inflammatory marker profiling were conducted to evaluate the inflammatory response associated with injury and ETT placement. Additionally, ETT biofilm formation was visualized using scanning electron microscopy and micro-computed tomography, while changes in the airway microbiome were profiled through 16S rRNA sequencing. ResultsLaryngeal tissue with roxadustat ETT placement had increasing localized stiffness outcomes over time and histological assessment indicated minimal epithelial ulceration and fibrosis, while inflammation remained severe across all timepoints. In contrast, vocal fold tissue with valacyclovir ETT placement showed no significant changes in stiffness over time; histological analysis presented a reduction in epithelial ulceration and inflammation scores along with increased fibrosis observed at 14 days. Immunohistochemistry revealed a decline in M1 and M2 macrophage markers over time for both ETT types. Among the cytokines, IL-8 levels differed significantly between the roxadustat and valacyclovir ETT groups, while no other cytokines showed statistically significant differences. Additionally, increased biofilm formation was observed in the coated ETTs with notable alterations in microbiota distinctive to each ETT type and across time. ConclusionThe injured and intubated airway resulted in increased laryngeal stiffness. Local inflammation and the type of therapeutic administered impacted the bacterial composition within the upper respiratory microbiome, which in turn mediated local tissue healing and recovery. 

Scientific literature represents the informal economy in two opposite ways, either as a sector characterised by low wages and productivity, and as a provider of livelihood for billions of people around the world. Macroeconomic theories and studies provide contrasting explanations of this complex phenomenon. Using institutional theory, we develop a microeconomic approach from an individual perspective to understand the social dynamics that can explain the choice of informal entrepreneurship. Drawing from a rich tradition of cognitive models and institutional theories, this study provides evidence of the differential effect of institutional asymmetry on nascent entrepreneurs through attitudes and subjective norms. Social pressure exerts a critical role in differentiating the entrepreneurial process between formal and informal nascent entrepreneurs. The theoretical and practical implications are discussed. 

Abstract Corticosteroid-eluting endotracheal tubes (ETTs) were developed and employed in a swine laryngotracheal injury model to maintain airway patency and provide localized drug delivery to inhibit fibrotic scarring. Polycaprolactone (PCL) fibers with or without dexamethasone were electrospun onto the ETT surface PCL-only coated ETTs and placed in native airways of 18 Yorkshire swine. Regular and dexamethasone-PCL coated ETTs were placed in airways of another 18 swine injured by inner laryngeal mucosal abrasion. All groups were evaluated after 3, 7 and 14 days (n = 3/treatment/time). Larynges were bisected and localized stiffness determined by normal indentation, then sequentially matched with histological assessment. In the native airway, tissue stiffness with PCL-only ETT placement increased significantly from 3 to 7 days (p = 0.0016) and 3 to 14 days (p < 0.0001) while dexamethasone-PCL ETT placement resulted in stiffness decreasing from 7 to 14 days (p = 0.031). In the injured airway, localized stiffness at 14 days was significantly greater after regular ETT placement (23.1 ± 0.725 N/m) versus dexamethasone-PCL ETTs (17.10 ± 0.930 N/m,p < 0.0001). Dexamethasone-loaded ETTs were found to reduce laryngotracheal tissue stiffening after simulated intubation injury compared to regular ETTs, supported by a trend of reduced collagen in the basement membrane in injured swine over time. Findings suggest localized corticosteroid delivery allows for tissue stiffness control and potential use as an approach for prevention and treatment of scarring caused by intubation injury. 

Abstract Beta-tricalcium phosphate (β-TCP)-based bioinks were developed to support direct-ink 3D printing-based manufacturing of macroporous scaffolds. Binding of the gelatin:β-TCP ink compositions was optimized by adding carboxymethylcellulose (CMC) to maximize the β-TCP content while maintaining printability. Post-sintering, the gelatin:β-TCP:CMC inks resulted in uniform grain size, uniform shrinkage of the printed structure, and included microporosity within the ceramic. The mechanical properties of the inks improved with increasing β-TCP content. The gelatin:β-TCP:CMC ink (25:75 gelatin:β-TCP and 3% CMC) optimized for mechanical strength was used to 3D print several architectures of macroporous scaffolds by varying the print nozzle tip diameter and pore spacing during the 3D printing process (compressive strength of 13.1 ± 2.51 MPa and elastic modulus of 696 ± 108 MPa was achieved). The sintered, macroporous β-TCP scaffolds demonstrated both high porosity and pore size but retained mechanical strength and stiffness compared to macroporous, calcium phosphate ceramic scaffolds manufactured using alternative methods. The high interconnected porosity (45–60%) and fluid conductance (between 1.04 ×10 −9 and 2.27 × 10 −9  m 4 s/kg) of the β-TCP scaffolds tested, and the ability to finely tune the architecture using 3D printing, resulted in the development of novel bioink formulations and made available a versatile manufacturing process with broad applicability in producing substrates suitable for biomedical applications. 

Electrical stimulus-responsive drug delivery from conducting polymers such as polypyrrole (PPy) has been limited by lack of versatile polymerization techniques and limitations in drug-loading strategies. In the present study, we report an in-situ chemical polymerization technique for incorporation of biotin, as the doping agent, to establish electrosensitive drug release from PPy-coated substrates. Aligned electrospun polyvinylidene fluoride (PVDF) fibers were used as a substrate for the PPy-coating and basic fibroblast growth factor and nerve growth factor were the model growth factors demonstrated for potential applications in musculoskeletal tissue regeneration. It was observed that 18-h of continuous polymerization produced an optimal coating of PPy on the surface of the PVDF electrospun fibers with significantly increased hydrophilicity and no substantial changes observed in fiber orientation or individual fiber thickness. This PPy-PVDF system was used as the platform for loading the aforementioned growth factors, using streptavidin as the drug-complex carrier. The release profile of incorporated biotinylated growth factors exhibited electrosensitive release behavior while the PPy-PVDF complex proved stable for a period of 14 days and suitable as a stimulus responsive drug delivery depot. Critically, the growth factors retained bioactivity after release. In conclusion, the present study established a systematic methodology to prepare PPy coated systems with electrosensitive drug release capabilities which can potentially be used to encourage targeted tissue regeneration and other biomedical applications.