Basic Salt Additives Modulate the Acidic Microenvironment Around In Situ Forming Implants.

There is a growing number of protein drugs, yet their limited oral bioavailability requires that patients receive frequent, high dose injections. In situ forming implants (ISFIs) for controlled release of biotherapeutics have the potential to greatly reduce the injection frequency and improve patient compliance. However, protein release from ISFIs is a challenge due to their proclivity for instability. Specifically, factors such as the acidic microclimate within ISFIs can lead to protein aggregation and denaturation. Basic salts have been shown in PLGA microparticle and microcylinder formulations to significantly reduce protein instability by neutralizing this acidic environment. The overall objective of the study was to demonstrate that basic salts can be used with an ISFI system to neutralize the implant acidification. To this end, the basic salts MgCO3 and Mg(OH)2 were added to a protein-releasing ISFI and the effect on drug release, pH, implant swelling, implant diffusivity, and implant erosion were evaluated. Either salt added at 3 wt% neutralized the acidic environment surrounding the implants, keeping the pH at 6.64 ± 0.03 (MgCO3) and 6.46 ± 0.11 (Mg(OH)2) after 28 day compared to 3.72 ± 0.05 with no salts added. The salts initially increased solution uptake into the implants but delayed implant degradation and erosion. The 3 wt% Mg(OH)2 formulation also showed slightly improved drug release with a lower burst and increased slope. We showed that salt additives can be an effective way to modulate the pH in the ISFI environment, which can improve protein stability and ultimately improve the capacity of ISFIs for delivering pH-sensitive biomolecules. Such a platform represents a low-cost method of improving overall patient compliance and reducing the overall healthcare burden.

Sustained degradation of hyaluronic acid using an in situ forming implant.

In pancreatic cancer, excessive hyaluronic acid (HA) in the tumor microenvironment creates a viscous stroma, which reduces systemic drug transport into the tumor and correlates with poor patient prognosis. HA can be degraded through both enzymatic and nonenzymatic methods to improve mass transport properties. Here, we use an in situ forming implant to provide sustained degradation of HA directly at a local, targeted site. We formulated and characterized an implant capable of sustained release of hyaluronidase (HAase) using 15 kDa poly(lactic-co-glycolic) acid and bovine testicular HAase. The implant releases bioactive HAase to degrade the HA through enzymatic hydrolysis at early timepoints. In the first 24 h, 17.9% of the HAase is released, which can reduce the viscosity of a 10 mg/mL HA solution by 94.1% and deplete the HA content within primary human pancreatic tumor samples and ex vivo murine tumors. At later timepoints, as lower quantities of HAase are released (51.4% released in total over 21 d), the degradation of HA is supplemented by the acidic by-products that accumulate as a result of implant degradation. Acidic conditions degrade HA through nonenzymatic methods. This formulation has potential as an intratumoral injection to allow sustained degradation of HA at the pancreatic tumor site.

Noninvasive characterization of in situ forming implant diffusivity using diffusion-weighted MRI.

In situ forming implants (ISFIs) form a solid drug-eluting depot, releasing drug for an extended period of time after a minimally-invasive injection. Clinical use of ISFIs has been limited because many factors affect drug release kinetics. The aim of this study was to use diffusion-weighted MRI (DWI) to noninvasively quantify spatial-temporal changes in implant diffusivity in situ. ISFIs were formed using poly(lactic-co-glycolic) acid, with a molecular weight of either 15 kDa or 52 kDa, and fluorescein as the mock drug. Drug release, polymer erosion, polymer degradation, and implant diffusivity were analyzed in vitro over 21 days. DWI was also performed in vivo over 5 days. Spatial diffusivity maps of the implant were generated using DWI data. Results showed constant diffusivity at the implant shell ((1.17 ±â€¯0.13) × 10-3 mm2/s) and increasing diffusivity within the interior over time (from (0.268 ±â€¯0.081) × 10-3 mm2/s during day 1 to (1.88 ±â€¯0.04) × 10-3 mm2/s at 14 d), which correlated with increasing porosity of the implant microstructure. Implants formed in vivo followed the same diffusivity trend as those in vitro. This study validates the use of DWI to provide novel functional information about implant behavior through its ability to noninvasively characterize transport properties within the implant both in vitro and in vivo.

The built environment and active transportation safety in children and youth: a study protocol.

BACKGROUND: Active transportation, such as walking and biking, is a healthy way for children to explore their environment and develop independence. However, children can be injured while walking and biking. Many cities make changes to the built environment (e.g., traffic calming features, separated bike lanes) to keep people safe. There is some research on how effective these changes are in preventing adult pedestrians and bicyclists from getting hurt, but very little research has been done to show how safe various environments are for children and youth. Our research program will study how features of the built environment affect whether children travel (e.g., to school) using active modes, and whether certain features increase or decrease their likelihood of injury. METHODS: First, we will use a cross-sectional study design to estimate associations between objectively measured built environment and objectively measured active transportation to school among child elementary students. We will examine the associations between objectively measured built environment and child and youth pedestrian-motor vehicle collisions (MVCs) and bicyclist-MVCs. We will also use these data to determine the space-time distribution of pedestrian-MVCs and bicyclist-MVCs. Second, we will use a case-crossover design to compare the built environment characteristics of the site where child and youth bicyclists sustain emergency department reported injuries and two randomly selected sites (control sites) along the bicyclist's route before the injury occurred. Third, to identify implementation strategies for built environment change at the municipal level to encourage active transportation we will conduct: 1) an environmental scan, 2) key informant interviews, 3) focus groups, and 4) a national survey to identify facilitators and barriers for implementing built environment change in municipalities. Finally, we will develop a built environment implementation toolkit to promote active transportation and prevent child pedestrian and bicyclist injuries. DISCUSSION: This program of research will identify the built environment associated with active transportation safety and form an evidence base from which municipalities can draw information to support change. Our team's national scope will be invaluable in providing information regarding the variability in built environment characteristics and is vital to producing evidence-based recommendations that will increase safe active transportation.

From tube to breast: the bridging role of semi-demand breastfeeding.

Determination of the optimal timing of breastfeeding initiation for preterm infants is still a challenge for health professionals. Often unjustified delays and restrictions of breastfeeding occur due to non-evidence-based current opinions about preterm infants' feeding capacity. Semi-demand feeding has been proposed for preterm infants during the transition from scheduled to full demand feeding, to promote the establishment of self-regulated oral feeding. Although semi-demand feeding has been shown to be safe and effective in reducing time to reaching oral feeding, the implementation of this feeding pattern for preterm infants in the neonatal intensive care unit (NICU) is still limited. We developed a protocol for the application of semi-demand feeding in preterm infants based on the existing knowledge of preterm infant neurodevelopment and NICU organization and staff experience. The protocol's aim is to attain successful transition from tube feeding to breastfeeding. In this article, we describe the protocol used in the neonatal unit of the Maternal and Child Health Institute of Trieste, a third level care center in northeastern Italy.

Intermittent kangaroo mother care: a NICU protocol.

The practice of kangaroo mother care (KMC) is steadily increasing in high-tech settings due to its proven benefits for both infants and parents. In spite of that, clear guidelines about how to implement this method of care are lacking, and as a consequence, some restrictions are applied in many neonatal intensive care units (NICUs), preventing its practice. Based on recommendations from the Expert Group of the International Network on Kangaroo Mother Care, we developed a hospital protocol in the neonatal unit of the Institute for Maternal and Child Health in Trieste, Italy, a level 3 unit, aimed to facilitate and promote KMC implementation in high-tech settings. Our guideline is therefore proposed, based both on current scientific literature and on practical considerations and experience. Future adjustments and improvements would be considered based on increasing clinical KMC use and further knowledge.