Safety and Tolerability of Continuous Inhaled Iloprost Therapy for Severe Pulmonary Hypertension in Neonates and Infants.

This is a single-center retrospective study to assess the safety and tolerability of continuous inhaled iloprost use as rescue therapy for refractory pulmonary hypertension (PH) in critically ill neonates and infants. A retrospective chart review was performed on 58 infants and data were collected at baseline, 1, 6, 12, 24, 48 and 72 h of iloprost initiation. Primary outcomes were change in heart rate (HR), fraction of inspired oxygen (FiO2), mean airway pressures (MAP), blood pressure (BP) and oxygenation index (OI). Secondary outcomes were need for extracorporeal membrane oxygenation (ECMO) and death. 51 patients treated for >6 h were analyzed in 2 age groups, neonate (≤28 days: n = 32) and infant (29-365 days: n = 19). FiO2 (p < 0.001) and OI (p = 0.01) decreased, while there were no significant changes in MAP, BP and HR. Of the fifteen patients placed on ECMO, seven were bridged off ECMO on iloprost and eight died. Twenty-four out of fifty-one patients (47%) recovered without requiring ECMO, while twelve (23%) died. Iloprost as add-on therapy for refractory PH in critically ill infants in the NICU has an acceptable tolerability and safety profile. Large prospective multicenter studies using iloprost in the neonatal ICU are necessary to validate these results.

Neonate with congenital pulmonary airway malformation concurrent with enteric duplication cyst: a case report of a rare anomaly.

A congenital pulmonary airway malformation (CPAM) occurring concurrently with an enteric duplication cyst is a rare anomaly. Definitive management for both abnormalities is usually surgical resection. We present the uncommon case of a neonate with a CPAM and ileal duplication cyst, including pre-natal and post-natal workup. The patient was brought to the operating room for laparoscopic duplication cyst excision at 3 months of age. The patient returned to the operating room for a thoracoscopic right lower lobectomy at five months of age. This case presents a rare congenital anomaly with the concurrent presentation of a CPAM and enteric duplication cyst, with both being successfully excised minimally invasively.

Effect of wheat gluten on improved thermal cross-linking and osteogenesis of hydroxyapatite-gelatin composite scaffolds.

Promising strategies to stabilize gelatin or collagen include glutaraldehyde-based chemical cross-linking or dehydrothermal treatment at different temperatures (120-180 °C). However, these procedures require 24-48 h for complete cross-linking to occur. The present study aims to evaluate the role of wheat gluten on enhancing thermal cross-linking of silica-nanohydroxyapatite (nanoHA)-gelatin composite scaffolds within a shorter period (2 h). Changes in properties were evaluated by varying the ratio of gelatin and gluten in silica-nanoHA matrix (60 wt% ceramic: 40 wt% polymer). The results showed that the scaffolds cross-linked at 170 °C were stable in phosphate-buffered saline for 21 days. It was crystalline and porous in nature. However, the scaffolds with high weight percentage of wheat gluten were brittle, while those with low gluten degraded fast in vitro. The mesenchymal stem cells could adhere, proliferate and differentiate into osteogenic lineage on wheat gluten-containing scaffolds for 21 days (mainly medium concentration). The scaffold also supported new bone formation in critical-sized rat calvarial defect, showing its osteoconductive and osteointegrative nature. In short, this study showed the potential of wheat gluten on improving thermal cross-linking within a shorter period and its suitability to use as a biomimetic bone graft for bone tissue engineering.

Decellularization and oxidation process of bamboo stem enhance biodegradation and osteogenic differentiation.

Many features that are appropriate for an ideal tissue engineered biomaterial are found in plant tissues. Hierarchically organized Bambusa vulgaris exhibits structural similarities to native bone, but the degradation of cellulose that is the main component of the plant cell wall is a challenge. In this study, Bamboo stem was subjected to decellularization followed by a chemical oxidation process (treated with sodium periodate) to enhance biocompatibility and biodegradation. The crystallinity of oxidised plant scaffolds was reduced, resulting in lower mechanical strength. In contrast, hydrophilicity was enhanced in those scaffolds. In vitro studies demonstrated better mesenchymal stem cell adhesion, viability, and osteogenic differentiation on oxidized scaffolds. Those scaffolds also induced angiogenesis, biocompatibility, and biodegradation when implanted subcutaneously in vivo. Hence, the present study demonstrated the usefulness of "oxidized decellularized plant" as bone scaffold for non-load-bearing applications.

Biodegradable nanocomposite fibrous scaffold mediated local delivery of vancomycin for the treatment of MRSA infected experimental osteomyelitis.

There is an increased demand for an ideal biodegradable biomaterial that eradicates infection, while concurrently promoting tissue regeneration in osteomyelitic bone, which eliminates the need for revision surgery. In this study, our objective was to evaluate the efficacy of a nanocomposite fibrous scaffold (silica coated nanohydroxyapatite-gelatin reinforced with poly-l-lactic acid yarns) containing vancomycin for treating methicillin-resistant Staphylococcus aureus (MRSA) induced osteomyelitis in rat models. The antibiotic was either incorporated during scaffold synthesis (SE-V) or loaded directly after the development of the scaffold (SA-V) at 5 wt% and 15 wt%. There was a sustained release of vancomycin from both the groups of scaffolds for 30 days and the released drug demonstrated antibacterial activity against MRSA. Furthermore, implantation of the composite scaffold into osteomyelitic rat femur resulted in significant bacterial reduction, mainly with 15 wt% drug and its efficacy was comparable to that of commercial graft Stimulan. Both drug entrapped and absorbed composite scaffolds promoted bone regeneration in 3 months, with no distinguishable difference between them. However, Stimulan resorbed fast and there were bone voids at the defect site after 3 months. Hence, the nanocomposite fibrous scaffold containing vancomycin can be proposed as a bi-functional graft that can reduce bacterial infection, while subsequently engineer new bone in osteomyelitis.

Poly(L-lactic acid) nanofibers containing Cissus quadrangularis induced osteogenic differentiation in vitro.

Cissus quadrangularis (CQ) is known as "bone setter" in Ayurvedic Medicine because of its ability to promote fracture healing. Polymers incorporated with CQ at lower concentration have shown to enhance osteogenic differentiation of mesenchymal stem cells (MSCs) in vitro. However, for the healing of clinically relevant critical sized bone defects, large amount of CQ would be required. Based on this perception, a herbal fibrous sheet containing high weight percentage of CQ [20,40 and 60wt/wt% in poly (L-lactic acid) (PLLA)] was fabricated through electrospinning. The solution concentration, flow rate, voltage and tip-target distance was optimized to obtain nanofibers. The hydrophobicity of PLLA fibers was reduced through CQ incorporation. There was considerable increase in the adhesion, proliferation and osteogenic differentiation of MSCs on herbal fibers than normal fibers, mainly on P-Q20 and P-CQ40. MSCs were differentiated into osteoblasts without providing any osteogenic supplements in the medium, indicating its osteoinductive capability. The herbal sheet also could promote mineralization when immersed in simulated body fluid for 14days. These studies specify that PLLA nanofibers loaded with 20 and 40wt% of CQ could serve as a potential candidate for bone tissue engineering applications.

Antibacterial and cytocompatible nanotextured Ti surface incorporating silver via single step hydrothermal processing.

Nanosurface modification of Titanium (Ti) implants and prosthesis is proved to enhance osseointegration at the tissue-implant interface. However, many of these products lack adequate antibacterial capability, which leads to implant loosening. As a curative strategy, in this study, nanotextured Ti substrates embedded with silver nanoparticles were developed through a single step hydrothermal processing in an alkaline medium containing silver nitrate at different concentrations (15, 30 and 75µM). Scanning electron micrographs revealed a non-periodically oriented nanoleafy structure on Ti (TNL) decorated with Ag nanoparticles (nanoAg), which was verified by XPS, XRD and EDS analysis. This TNLAg substrate proved to be mechanically stable upon nanoindentation and nanoscratch tests. Silver ions at detectable levels were released for a period of ~28days only from substrates incorporating higher nanoAg content. The samples demonstrated antibacterial activity towards both Escherichia coli and Staphylococcus aureus, with a more favorable response to the former. Simultaneously, Ti substrates incorporating nanoAg at all concentrations supported the viability, proliferation and osteogenic differentiation of mesenchymal stem cells. Overall, nanoAg incorporation into surface modified Ti via a simple one-step thermochemical method is a favorable strategy for producing implants with dual characteristics of antibacterial activity and cell compatibility.

Graphene oxide nanoflakes incorporated gelatin-hydroxyapatite scaffolds enhance osteogenic differentiation of human mesenchymal stem cells.

In this study, graphene oxide (GO) nanoflakes (0.5 and 1 wt%) were incorporated into a gelatin-hydroxyapatite (GHA) matrix through a freeze drying technique and its effect to enhance mechanical strength and osteogenic differentiation was studied. The GHA matrix with GO demonstrated less brittleness in comparison to GHA scaffolds. There was no significant difference in mechanical strength between GOGHA0.5 and GOGHA1.0 scaffolds. When the scaffolds were immersed in phosphate buffered saline (to mimic physiologic condition) for 60 days, around 50-60% of GO was released in sustained and linear manner and the concentration was within the toxicity limit as reported earlier. Further, GOGHA0.5 scaffolds were continued for cell culture experiments, wherein the scaffold induced osteogenic differentiation of human adipose derived mesenchymal stem cells without providing supplements like dexamethasone, L-ascorbic acid and ß glycerophosphate in the medium. The level of osteogenic differentiation of stem cells was comparable to those cultured on GHA scaffolds with osteogenic supplements. Thus biocompatible, biodegradable and porous GO reinforced gelatin-HA 3D scaffolds may serve as a suitable candidate in promoting bone regeneration in orthopaedics.

Evaluation of antibacterial activity and cytocompatibility of ciprofloxacin loaded gelatin-hydroxyapatite scaffolds as a local drug delivery system for osteomyelitis treatment.

Surgical debridement of the dead bone and subsequent systemic antibiotic therapy is often ineffective in eliminating Staphylococcus aureus infections in osteomyelitic patients. The recurrence of S. aureus infection is mainly due to the intracellular growth of bacterial colonies within osteoblast cells that protect the organism from extracellular host defences and/or antibiotic therapy. In this study, porous gelatin-hydroxyapatite (HAP) scaffolds with various amounts of ciprofloxacin (1, 2, 5, and 10 wt%) were fabricated by freeze-drying technique and the release of the antibiotic was characterized, as was the efficacy of the released antibiotic against methicillin-sensitive and methicillin-resistant S. aureus. Furthermore, the impact of the released antibiotic on the viability and osteogenic differentiation of human adipose-derived mesenchymal stem cells (ADMSCs) cultured on the scaffolds were assessed. Finally, the efficacy of the released ciprofloxacin to enter the cells and abate intracellularly located S. aureus was evaluated. All the groups of CGHA scaffolds displayed sustained release of ciprofloxacin against S. aureus for 60 days above the minimum inhibitory concentration for the target species with zero-order kinetics and Korsmeyer-Peppas models. While comparing, the released antibiotic from CGHA5 scaffolds was found to be effective at reducing S. aureus through the study period, without detrimental effects on human ADMSC viability or osteogenic potential. When stem cells internalized with S. aureus were cultured onto the drug-loaded scaffolds, a significant reduction in the colony count of internalized bacteria was observed, resulting in the osteogenic differentiation capability of those cells. Our results clearly demonstrate that the ciprofloxacin incorporated gelatin-HAP scaffolds, which were cytocompatible and could target both intracellular and extracellular S. aureus, defining its potential to be used as local drug delivery system.

Antibiotic releasing biodegradable scaffolds for osteomyelitis.

Osteomyelitis is characterized by progressive inflammatory bone degeneration. In the management of chronic osteomyelitis, it is necessary to remove the infected bone tissue followed by implantation of an antibiotic releasing biomaterial that can release antibiotic locally for long periods of time. The main carrier used in clinics for this application is polymethylmethacrylate (PMMA) (Eg. Septopal beads). However, major drawback is the need of an additional surgery to remove the beads after therapy, as PMMA is not biodegradable. This necessitates the requirement of biodegradable carrier systems that can release antibiotics and simultaneously support debrided bone formation. This review summarizes biodegradable carrier systems that have been reported for the localised treatment and prophylaxis of osteomyelitis.

ZnO nanoparticle incorporated nanostructured metallic titanium for increased mesenchymal stem cell response and antibacterial activity.

Recent trends in titanium implants are towards the development of nanoscale topographies that mimic the nanoscale properties of bone tissue. Although the nanosurface promotes the integration of osteoblast cells, infection related problems can also occur, leading to implant failure. Therefore it is imperative to reduce bacterial adhesion on an implant surface, either with or without the use of drugs/antibacterial agents. Herein, we have investigated two different aspects of Ti surfaces in inhibiting bacterial adhesion and concurrently promoting mammalian cell adhesion. These include (i) the type of nanoscale topography (Titania nanotube (TNT) and Titania nanoleaf (TNL)) and (ii) the presence of an antibacterial agent like zinc oxide nanoparticles (ZnOnp) on Ti nanosurfaces. To address this, periodically arranged TNT (80-120 nm) and non-periodically arranged TNL surfaces were generated by the anodization and hydrothermal techniques respectively, and incorporated with ZnOnp of different concentrations (375 µM, 750 µM, 1.125 mM and 1.5 mM). Interestingly, TNL surfaces decreased the adherence of staphylococcus aureus while increasing the adhesion and viability of human osteosarcoma MG63 cell line and human mesenchymal stem cells, even in the absence of ZnOnp. In contrast, TNT surfaces exhibited an increased bacterial and mammalian cell adhesion. The influence of ZnOnp on these surfaces in altering the bacterial and cell adhesion was found to be concentration dependent, with an optimal range of 375-750 µM. Above 750 µM, although bacterial adhesion was reduced, cellular viability was considerably affected. Thus our study helps us to infer that nanoscale topography by itself or its combination with an optimal concentration of antibacterial ZnOnp would provide a differential cell behavior and thereby a desirable biological response, facilitating the long term success of an implant.