Multifunctional GelMA platforms with nanomaterials for advanced tissue therapeutics.

Multifunctional GelMA platforms with nanomaterials for advanced tissue therapeutics

Tissue engineering scaffolds with complex geometries can provide an architecture that directs tissue formation. Drug delivery from these scaffolds to promote regeneration is often challenging due to the complex fabrication processes. Surface-mediated DNA delivery from multiple channel bridges was applied to deliver lipoplexes in vivo to the injured spinal cord. The surface properties of the polymer, DNA deposition with or without drying, and the presence of ECM components were investigated. In vitro studies revealed that fibronectin produced greater expression levels and immobilization efficiencies compared with collagen, laminin, and no coating. In addition, lipoplex incubation on ECM-coated PLG increased expression relative to either of the drying methods. Additionally, the incubation method had more homogeneously distributed lipoplexes and a higher number of transfected cells relative to the dried conditions. Translation to three-dimensional bridges led to high levels of transgene expression in vitro. In vivo, lipoplexes immobilized to the bridge produced transgene expression levels in a rat spinal cord hemisection model that were 2-fold greater than naked plasmid. Additionally, expression with lipoplexes persisted for at least three weeks. Surface-mediated delivery can be applied to scaffolds with complex geometries to promote transgene expression in vivo.

Local gene delivery from Ecm coated Poly (lactide co glycolide) multiple channel bridges after spinal cord injury

Detailed understanding of the pathogenesis and development of effective therapies for pulmonary fibrosis (PF) have been hampered by lack of in vitro human models that recapitulate disease pathophysiology. In this study, we generated alveolar organoids (AOs) derived from human pluripotent stem cells (hPSCs) for use as an PF model and for drug efficacy evaluation. Stepwise direct differentiation of hPSCs into alveolar epithelial cells by mimicking developmental cues in a temporally controlled manner was used to generate multicellular AOs. Derived AOs contained the expected spectrum of differentiated cells, including alveolar progenitors, type 1 and 2 alveolar epithelial cells and mesenchymal cells. Treatment with transforming growth factor (TGF-β1) induced fibrotic changes in AOs, offering a PF model for therapeutic evaluation of a structurally truncated form (NP-011) of milk fat globule-EGF factor 8 (MFG-E8) protein. The significant fibrogenic responses and collagen accumulation that were induced by treatment with TGF-β1 in these AOs were effectively ameliorated by treatment with NP-011 via suppression of extracellular signal-regulated kinase (ERK) signaling. Furthermore, administration of NP-011 reversed bleomycin-induced lung fibrosis in mice also via ERK signaling suppression and collagen reduction. This anti-fibrotic effect mirrored that following Pirfenidone and Nintedanib administration. Furthermore, NP-011 interacted with macrophages, which accelerated the collagen uptake for eliminating accumulated collagen in fibrotic lung tissues. This study provides a robust in vitro human organoid system for modeling PF and assessing anti-fibrotic mechanisms of potential drugs and suggests that modified MGF-E8 protein has therapeutic potential for treating PF.

/pdf/human-pluripotent-stem-cell-derived-alveolar-organoids-for-4sxs35yxhd.pdf

Human pluripotent stem-cell-derived alveolar organoids for modeling pulmonary fibrosis and drug testing.

Congenital diaphragmatic hernia

Three-dimensional lung organoids (LOs) derived from pluripotent stem cells have the potential to enhance our understanding of disease mechanisms and to enable novel therapeutic approaches in neonates with pulmonary disorders. We established a reproducible ex vivo model of lung development using transgene-free human induced pluripotent stem cells generated from fetuses and infants with Bochdalek congenital diaphragmatic hernia (CDH), a polygenic disorder associated with fetal lung compression and pulmonary hypoplasia at birth. Molecular and cellular comparisons of CDH LOs revealed impaired generation of NKX2.1+ progenitors, type II alveolar epithelial cells, and PDGFRα+ myofibroblasts. We then subjected these LOs to disease relevant mechanical cues through ex vivo compression and observed significant changes in genes associated with pulmonary progenitors, alveolar epithelial cells, and mesenchymal fibroblasts. Collectively, these data suggest both primary cell-intrinsic and secondary mechanical causes of CDH lung hypoplasia and support the use of this stem cell-based approach for disease modeling in CDH.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/sctm.20-0199

Human induced pluripotent stem cell-derived lung organoids in an ex vivo model of the congenital diaphragmatic hernia fetal lung.

Studying how the fetal spinal cord regenerates in an ex vivo model of spina bifida repair may provide insights into the development of new tissue engineering treatment strategies to better optimize...

https://journals.sagepub.com/doi/pdf/10.1177/2041731420943833

Hydrogel and neural progenitor cell delivery supports organotypic fetal spinal cord development in an ex vivo model of prenatal spina bifida repair.

Blunt impact-induced traumatic abdominal wall hernia (TAWH) is an uncommon pediatric surgical problem classically associated with handlebar injury but increasingly seen with seatbelt use in motor vehicle collisions (MVC). Herein we describe the largest case series of pediatric TAWH to date and review the literature to establish the unique syndromic characteristics of MVC-associated TAWH. In this single-institution series, we discuss four pediatric patients, all with seatbelt-associated TAWH after high-speed MVC characterized by full-thickness disruption of the lateral abdominal wall. We then performed a review of the literature to identify additional pediatric MVC-associated TAWH and define the characteristics of patients who sustained this unique injury. In addition to the four patients in our case series, five additional pediatric patients presenting with TAWH after restrained MVC were identified in the literature. Of these nine patients, eight (89%) presented with an obvious seatbelt sign (bruising/laceration to the abdominal wall). Six (67%) had associated injuries typical of the seatbelt syndrome, including four spinal flexion injuries (44%) and five bowel injuries requiring repair or resection (56%). Overall, 56% of seatbelt-associated TAWH occurred in children with a BMI percentile > 95%. In this case series and literature review, we note a high rate of seatbelt syndrome injuries in pediatric patients presenting with TAWH after restrained MVC. Suspicion for TAWH should be high in children presenting with a seatbelt sign and should trigger a low threshold for pursuing additional axial imaging. Level IV; case series.

Pediatric traumatic abdominal wall hernia as a component of the seatbelt syndrome: a case series and review of the literature.

This chapter discusses the major pearls and tricks in the diagnosis and management of congenital lung lesions, which include congenital pulmonary airway malformations, bronchogenic cysts, bronchopulmonary sequestrations, and congenital lobar emphysema. Collectively, congenital lung malformations can be uniquely challenging for pediatric surgeons in part because they are rarely encountered in most clinical practices and often require multi-disciplinary expertise, including maternal-fetal medicine specialists, neonatologists, and pediatric radiologists. Moreover, lung lesions can have highly variable clinical presentations and unclear natural histories. The current standard of care for the most common clinical scenarios is discussed, and specific areas of controversy are highlighted.

Shaun M. Kunisaki

Papers

Human induced pluripotent stem cell-derived lung organoids in an ex vivo model of the congenital diaphragmatic hernia fetal lung.

Hydrogel and neural progenitor cell delivery supports organotypic fetal spinal cord development in an ex vivo model of prenatal spina bifida repair.

Pediatric traumatic abdominal wall hernia as a component of the seatbelt syndrome: a case series and review of the literature.

Congenital Lung Malformations

Increased survival following fetoscopic endoluminal tracheal occlusion for diaphragmatic hernia.