Binary fabrication of decellularized lung extracellular matrix hybridgels for in vitro chronic obstructive pulmonary disease modeling.

Limited treatments and a lack of appropriate animal models have spurred the study of scaffolds to mimic lung disease in vitro. Decellularized human lung and its application in extracellular matrix (ECM) hydrogels has advanced the development of these lung ECM models. Controlling the biochemical and mechanical properties of decellularized ECM hydrogels continues to be of interest due to inherent discrepancies of hydrogels when compared to their source tissue. To optimize the physiologic relevance of ECM hydrogel lung models without sacrificing the native composition we engineered a binary fabrication system to produce a Hybridgel composed of an ECM hydrogel reinforced with an ECM cryogel. Further, we compared the effect of ECM-altering disease on the properties of the gels using elastin poor Chronic Obstructive Pulmonary Disease (COPD) vs non-diseased (ND) human lung source tissue. Nanoindentation confirmed the significant loss of elasticity in hydrogels compared to that of ND human lung and further demonstrated the recovery of elastic moduli in ECM cryogels and Hybridgels. These findings were supported by similar observations in diseased tissue and gels. Successful cell encapsulation, distribution, cytotoxicity, and infiltration were observed and characterized via confocal microscopy. Cells were uniformly distributed throughout the Hybridgel and capable of survival for 7 days. Cell-laden ECM hybridgels were found to have elasticity similar to that of ND human lung. Compositional investigation into diseased and ND gels indicated the conservation of disease-specific elastin to collagen ratios. In brief, we have engineered a composited ECM hybridgel for the 3D study of cell-matrix interactions of varying lung disease states that optimizes the application of decellularized lung ECM materials to more closely mimic the human lung while conserving the compositional bioactivity of the native ECM. STATEMENT OF SIGNIFICANCE: The lack of an appropriate disease model for the study of chronic lung diseases continues to severely inhibit the advancement of treatments and preventions of these otherwise fatal illnesses due to the inability to recapture the biocomplexity of pathologic cell-ECM interactions. Engineering biomaterials that utilize decellularized lungs offers an opportunity to deconstruct, understand, and rebuild models that highlight and investigate how disease specific characteristics of the extracellular environment are involved in driving disease progression. We have advanced this space by designing a binary fabrication system for a ECM Hybridgel that retains properties from its source material required to observe native matrix interactions. This design simulates a 3D lung environment that is both mechanically elastic and compositionally relevant when derived from non-diseased tissue and pathologically diminished both mechanically and compositionally when derived from COPD tissue. Here we describe the ECM hybridgel as a model for the study of cell-ECM interactions involved in COPD.

Control and management of multidrug resistant Acinetobacter baumannii: A review of the evidence and proposal of novel approaches.

Hospital-acquired infections are on the rise and are a substantial cause of clinical and financial burden for healthcare systems. While infection control plays a major role in curtailing the spread of outbreak organisms, it is not always successful. One organism of particular concern is Acinetobacter baumannii, due to both its persistence in the hospital setting and its ability to acquire antibiotic resistance. A. baumannii has emerged as a nosocomial pathogen that exhibits high levels of resistance to antibiotics, and remains resilient against traditional cleaning measures with resistance to Colistin increasingly reported. Given the magnitude and costs associated with hospital acquired infections, and the increase in multidrug-resistant organisms, it is worth re-evaluating our current approaches and looking for alternatives or adjuncts to traditional antibiotics therapies. The aims of this review are to look at how this organism is spread within the hospital setting, discuss current treatment modalities, and propose alternative methods of outbreak management.

Synthesis and structure-activity relationships of 3-hydrazono-1H-2-indolinones with antituberculosis activity.

A series of 3-[S-(4-substituted phenacyl)-4-substituted-isothiosemicarbazono]-1H-2-indolinones+ ++ 2a-h and 3-[(3,4-disubstituted-4-thiazolin-2-ylidene)hydrazono]-1H-2- indolinones 3a-f were synthesized. These new hydrazonoindolinone derivatives and 3-(4-substituted-thiosemicarbazono)-1H/1-acetyl-2-indolinones++ + 1a-g 3-[(2-substituted-4-thiazolidinon-2-ylidene)hydrazono]-1H-2- indolinones 4a-o, 3-[(2-substituted-4-carboxy/carbetoxy-5-methyl-4-thiazolin-2 -ylidene) hydrazono]-1H-2-indolinones 5a-e and 3-substituted-hydrazono-1H-2-indolinones 6a-o which had been previously reported were evaluated for antituberculosis activity against Mycobacterium tuberculosis H37Rv. These compounds exhibited varying degrees of inhibition in the in vitro primary screening that was conducted at 12 micrograms/ml against M. tuberculosis H37Rv in BACTEC 12B medium using the BACTEC 460 radiometric system. 2a, 2c, 2f-h, 3c and 3f demonstrating activity in the primary screen were re-tested at lower concentrations against M. tuberculosis H37Rv to determine the actual minimum inhibitory concentration (MIC) in CABTEC 460. The structure-activity relationships of the derivatives were investigated.