Long-term Delivery Research Articles

Poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate) Copolymers for the Formulation of In Situ Forming Depot Long-Acting Injectables.

This article describes the utilization of (methoxy)poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate) ((m)PEG–PTMC) diblock and triblock copolymers for the formulation of in situ forming depot long-acting injectables by solvent exchange. The results shown in this manuscript demonstrate that it is possible to achieve long-term drug deliveries from suspension formulations prepared with these copolymers, with release durations up to several months in vitro. The utilization of copolymers with different PEG and PTMC molecular weights affords to modulate the release profile and duration. A pharmacokinetic study in rats with meloxicam confirmed the feasibility of achieving at least 28 days of sustained delivery by using this technology while showing good local tolerability in the subcutaneous environment. The characterization of the depots at the end of the in vivo study suggests that the rapid phase exchange upon administration and the surface erosion of the resulting depots are driving the delivery kinetics from suspension formulations. Due to the widely accepted utilization of meloxicam as an analgesic drug for animal care, the results shown in this article are of special interest for the development of veterinary products aiming at a very long-term sustained delivery of this therapeutic molecule.

Application of solid lipid nanoparticles as a long-term drug delivery platform for intramuscular and subcutaneous administration: In vitro and in vivo evaluation

The purpose of this work was to evaluate solid lipid nanoparticles (SLNs) as a long acting injectable drug delivery platform for intramuscular and subcutaneous administration. SLNs were developed with a low (unsaturated) and high (supersaturated) drug concentration at equivalent lipid doses. The impact of the drug loading as well as the administration route for the SLNs using two model compounds with different physicochemical properties were explored for their in vitro and in vivo performance. Results revealed that drug concentration had an influence on the particle size and entrapment efficiency of the SLNs and, therefore, indirectly an influence on the Cmax/dose and AUC/dose after administration to rats. Furthermore, the in vitro drug release was compound specific, and linked to the affinity of the drug compounds towards the lipid matrix and release medium. The pharmacokinetic parameters resulted in an increased tmax, t1/2 and mean residence time (MRT) for all formulations after intramuscular and subcutaneous dosing, when compared to intravenous administration. Whereas, the subcutaneous injections performed better for those parameters than the intramuscular injections, because of the higher blood perfusion in the muscles compared with the subcutaneous tissues. In conclusion, SLNs extend drug release, need to be optimized for each drug, and are appropriate carriers for the delivery of drugs that require a short-term sustained release in a timely manner.

Inner ear drug delivery through a cochlear implant: Pharmacokinetics in a Macaque experimental model

ObjectivesThe method of drug delivery directly into the cochlea with an implantable pump connected to a CI electrode array ensures long-term delivery and effective dose control, and also provides the possibility to use different drugs. The objective is to develop a model of inner ear pharmacokinetics of an implanted cochlea, with the delivery of FITC-Dextran, in the non-human primate model. DesignA preclinical cochlear electrode array (CI Electrode Array HL14DD, manufactured by Cochlear Ltd.) attached to an implantable peristaltic pump filled with FITC-Dextran was implanted unilaterally in a total of 15 Macaca fascicularis (Mf). Three groups were created (5 Mf in each group), according to three different drug delivery times: 2 hours, 24 hours and 7 days. Perilymph (10 samples, 1μL each) was sampled from the apex of the cochlea and measured immediately after extraction with a spectrofluorometer. After scarifying the specimens, x-Rays and histological analysis were performed. ResultsSurgery, sampling and histological analysis were performed successfully in all specimens. FITC-Dextran quantification showed different patterns, depending on the delivery group. In the 2 hours injection experiment, an increase in FITC-Dextran concentrations over the sample collection time was seen, reaching maximum concentration peaks (420-964µM) between samples 5 and 7, decreasing in successive samples, without returning to baseline. The 24-hours and 7-days injection experiments showed even behaviour throughout the 10 samples obtained, reaching a plateau with mean concentrations ranging from 2144 to 2564 µM and from 1409 to 2502µM, respectively. Statistically significant differences between the 2 hours and 24 hours groups (p = 0.001) and between the 2 hours and 7 days groups (p = 0.037) were observed, while between the 24 hours and 7 days groups no statistical differences were found. ConclusionsThis experimental study shows that a model of drug delivery and pharmacokinetics using an active pump connected to an electrode array is feasible in Mf. An infusion time ranging from 2 to 24 hours is required to reach a maximum concentration peak at the apex. It establishes then an even concentration profile from base to apex that is maintained throughout the infusion time in Mf. Flow mechanisms during injection and during sampling that may explain such findings may involve cochlear aqueduct flow as well as the possible existence of substance exchange from scala tympani to extracellular spaces, such as the modiolar space or the endolymphatic sinus, acting as a substance reservoir to maintain a relatively flat concentration profile from base to apex during sampling.Leveraging the learnings achieved by experimentation in rodent models, we can move to experiment in non-human primate with the aim of achieving a useful model that provides transferrable data to human pharmacokinetics. Thus, it may broaden clinical and therapeutic approaches to inner ear diseases.

How business legacy influences organising body legitimacy in the delivery of mega events: The drift to myth at Rio 2016

The extent to which mega events, such as the Olympics and World Expos, catalyse meaningful legacies is a contentious issue. However, the organisers of such events go to great lengths to develop business legacy plans in order to gain legitimacy with their wider stakeholders. This process constitutes a critical cornerstone for the overall success of the event, but business legacy plans tend to fade away after the delivery phase. Drawing upon the legitimacy literature, our study investigates this gap between planning and long-term delivery through a case study of the 2016 Rio Olympic Games. Interviews with forty-three directors of Rio 2016 were conducted between February-April 2016, in addition to the collection of field notes and secondary data. We find that Rio 2016 applied a decoupling strategy before and during the event to gain short-term legitimacy via legacy planning. However, a legitimacy drift was identified, whereby legacy delivery was side-lined and positive outcomes were minimal. We argue that the drive for legitimacy tends to be short-lived, and as legitimacy drifts, legacy becomes mythical. This has important implications for literature on legitimacy and legacy, organising bodies and for all businesses involved in event management.

Resin-based dental materials containing 3-aminopropyltriethoxysilane modified halloysite-clay nanotubes for extended drug delivery

ObjectiveTo synthesize and characterize a novel resin-based dental material containing 3-aminopropyltriethoxysilane (APTES) surface-modified halloysite-clay nanotubes (HNTs) for long-term delivery of guest molecules. MethodsThe optimal concentrations of HNT (10, 15, 20 wt.%) and silane (0, 2, 4 vol.%sil) to be incorporated into the resin-based materials were determined (15 wt.%HNT, 4 vol.%sil) after assessment of the mechanical properties (DC%, degree of conversion; FS, flexural strength; FM, flexural modulus; and UTS, ultimate tensile strength). The HNTsil-powder was loaded with chlorhexidine (CHX) to evaluate the effect of the silanization on drug release. Resin-discs were prepared for the following groups: RES (resin), HNT (resin+15 wt.%HNT), HNTsil (resin+15 wt.%HNT silanized), HNT-CHX (resin+15 wt.%HNT loaded with chlorhexidine), HNTsil-CHX (resin+15 wt.%HNTsil-CHX), and 0.2 vol.%CHX (resin+0.2 vol.%CHX solution). Specimens were stored in water for 1, 3, 5, 10, and 15 days at 37 °C. Aliquots from each time point and the final 15-day specimens were evaluated for the zone of inhibition (ZOI) against Streptococcus mutans. CHX release was analyzed using spectrophotometry at absorbance of 300 nm. Data were statistically analyzed (α = 0.05). ResultsAll materials presented similar DC%. Reduced FS but increased FM was detected for 20 wt.%HNT–4%APTES. Groups with 15 wt.% and 20 wt.%HNT with/without APTES presented higher values of UTS. Agar diffusion data indicates that the HNTsil-CHX had a greater ZOI than all other groups over 15 days. HNTsil-CHX had the highest absorbance for day 1 but presented similar values to other groups every time point after. SignificanceSilanization of nanotubes followed by encapsulation of chlorhexidine is a promising technique for long-term delivery of guest molecules.

Chimeric Antigen Receptor beyond CAR-T Cells.

Simple SummaryChimeric antigen receptors (CAR) are engineered molecules expressed on the cell surface that can recognise specific proteins and deliver an activation signal to the cells. Human T lymphocytes equipped with CAR, also called CAR-T cells, can target and kill tumour cells. This technology has been successfully used in treating some of the blood cancers in the last decade. Although the majority of research interest in CAR technology has been focused on CAR-T cells to date, the CAR design has also been used in other types of immune cells to fight against cancers. In this review, we discuss recent advances in CAR design beyond that used in conventional CAR-T cells and their novel indications to develop more potent CAR-based therapy for cancers.Chimeric antigen receptors (CAR) are genetically engineered receptors that can recognise specific antigens and subsequently activate downstream signalling. Human T cells engineered to express a CAR, also known as CAR-T cells, can target a specific tumour antigen on the cell surface to mediate a cytotoxic response against the tumour. CAR-T cell therapy has achieved remarkable success in treating hematologic malignancies, but not in solid tumours. Currently, extensive research is being carried out to make CAR-T cells a therapy for solid tumours. To date, most of the research interest in the field has focused on cytotoxic T lymphocytes as the carrier of CAR products. However, in addition to T cells, the CAR design can be introduced in other immune cells, such as natural killer (NK)/NKT cells, γδ T cells, mucosal-associated invariant T (MAIT) cells, dendritic cells (DC), macrophages, regulatory T cells (Treg), B cells, etc. Some of the CAR-engineered immune cells, such as CAR- γδ T and CAR-NK/NK-T cells, are directly involved in the anti-tumour response, demonstrated in preclinical studies and/or clinical trials. CAR-Tregs showed promising therapeutic potential in treating autoimmune diseases. In particular, B cells engineered with chimeric receptors can be used as a platform for long-term delivery of therapeutic proteins, such as recombinant antibodies or protein replacement, in an antigen-specific manner. CAR technology is one of the most powerful engineering platforms in immunotherapy, especially for the treatment of cancers. In this review, we will discuss the recent application of the CAR design in non-CAR-T cells and future opportunities in immunotherapy.

Electrospun Nanofibers for Dual and Local Delivery of Neuroprotective Drugs

Drug delivery for neuroprotection/neuroregeneration after traumatic peripheral nerve injuries still remains a challenge. For this purpose, we formulated composite nanofiber formulation for the dual local delivery of alpha lipoic acid (ALA) and atorvastatin (ATR) to enhance regeneration process after peripheral nerve injury. The initial stage involved encapsulation of ATR into nanosprayed chitosan (CH) nanoparticles after which the CH nanoparticles were embedded into poly(lactic-co-glycolic acid) (PLGA) nanofibers containing freely dispersed ALA within the fiber structure. Morphology investigations revealed that smooth and randomly aligned nanofibers with mean diameter of 340±69 nm were formed. Encapsulation efficiency for ALA and ATR were calculated as 92.76±3.53 % and 89.27±5.053 %, respectively. Differential Scanning Calorimetry and FT-IR analysis confirmed successful encapsulation of ALA and ATR into the composite nanofibers; however, XRD results indicated surface localization of ALA within the structure. Porosity and pore volume of the nanofibers increased in accordance with increase in density of the electrospunned solution. Similarly, mechanical strength of the nanofibers was found to increase significantly following the incorporation of ALA and ATR with respect to the unloaded nanofibers (p<0.05). Dual release of ALA and ATR in different fashions was confirmed by in-vitro release test of the nanofibers. For ALA, an immediate release percentage of 83.90 % within the first hour was observed. On the other hand, ATR exhibited a three-stage release profile which begins with a relatively lower initial release (22.07 %) in comparison to ALA followed by an increasing release (82.439%) up to 150 h. According to cell viability results, blank and loaded formulations were found to have no cytotoxic effect on both L-929 and B35 cell lines after incubation for up to 48 h. Based on this, composite PLGA nanofibers could be classified as suitable candidates for long-term and local delivery of neuroprotective drugs in peripheral nerve injury.

Private assets for public benefit: the challenge of long-term management of domestic rainwater tanks

Abstract This study explored the relationship private landowners have with their domestic rainwater tank and how that relationship influences the reliability of privately operated rainwater tanks for long-term performance and delivery of service. It found that tank owners generally placed a high value on their tank, desired to have them fully operational and made a reasonable effort to keep them functioning. However, the frequency and extent of maintenance action and effort was variable, and in the context of a private residence, rainwater tanks were typically afforded a low relative priority for repair when compared with other residential assets. This low relative priority could be a primary driver for the reported delay between when a fault occurs with the tank and when it is repaired. This ‘repair lag’ means that a portion of domestic rainwater tanks are likely to be non-operational at any one time. When planning a decentralised system for the management of stormwater, redundancies should be included to cover these gaps in service delivery. It is also recommended that programmes that support private landowners to maintain their rainwater tanks are implemented to minimise repair lag.

Prospective predictors of sustainment of multiple EBPs in a system-driven implementation context: Examining sustained delivery based on administrative claims.

System-driven scale-up of multiple evidence-based practices (EBPs) is an increasingly common method used in public mental health to improve care. However, there are little data on the long-term sustained delivery of EBPs within these efforts, and previous studies have relied on retrospective self-report within cross-sectional studies. This study identified prospective predictors of sustained EBP delivery at the EBP-, therapist-, and organizational-levels using survey and administrative claims data within a large-scale system-driven implementation effort. 777 therapists and 162 program leaders delivering at least one of six EBPs of interest completed surveys assessing perceptions of EBPs and organizational context. These surveys were linked to administrative data to examine prospective predictors of therapists' EBP delivery over 33 months. Five of the six EBPs implemented showed sustained delivery in the system, with volume varying by EBP. Although total EBP claim volume per therapist decreased over time, the volume ratio (ratio of EBP-specific claims to total EBP and non-EBP claims) stayed relatively stable. Multilevel models revealed that EBPs that required consultation, had unstructured content, higher therapist self-efficacy with the EBP, and more positive program leader perceptions of the EBP were associated with greater sustained volume and volume ratio of the EBP. Therapists who were trained in fewer EBPs, who were unlicensed, and who worked in agencies rated by program leaders as lower on organizational staff autonomy and stress showed greater sustained EBP volume and volume ratio. Finally, more direct service hours per week provided by therapist predicted greater sustained EBP volume, but lower volume ratio. The results point to the importance of EBP, therapist, and organizational factors that may be targeted in implementation strategies to promote the sustainment of EBPs.

Two-Photon Excitable Membrane Targeting Polyphenolic Carbon Dots for Long-Term Imaging and pH-Responsive Chemotherapeutic Drug Delivery for Synergistic Tumor Therapy

Two-Photon Excitable Membrane Targeting Polyphenolic Carbon Dots for Long-Term Imaging and pH-Responsive Chemotherapeutic Drug Delivery for Synergistic Tumor Therapy

Stromal cell-derived factor loaded co-electrospun hydrophilic/hydrophobic bicomponent membranes for wound protection and healing.

Chronic wounds are one of the key concerns for people with diabetes, frequently leading to infections and non-healing ulcers, and finally resulting in the amputation of limbs/organs. Stromal cell-derived factor 1 (SDF1) is a major chemokine that plays a significant role in tissue repair, vascularization, and wound healing. However, the long-term sustained delivery of SDF1 in a chronic wound environment is a great challenge. In order to facilitate the sustained release of SDF1 in diabetic wounds, it could be incorporated into wound-healing patches. Herein, we report the fabrication of a hydrophilic/hydrophobic bicomponent fiber-based membrane, where SDF1 was encapsulated inside hydrophilic fibers, and its applicability in wound healing. A co-electrospinning technique was employed for the fabrication of polymeric membranes where PVA and PCL form the hydrophilic and hydrophobic components, respectively. Morphological analysis of the developed membranes was conducted via scanning electron microscopy (SEM). The mechanical strength of the membranes was investigated via uniaxial tensile testing. The water uptake capacity of the membranes was also determined to understand the hydrophilicity and exudate uptake capacity of the membranes. To understand the proliferation, viability, and migration of skin-specific cells in the presence of SDF1-loaded membranes, in vitro cell culture experiments were carried out using fibroblasts, keratinocytes, and endothelial cells. The results showed the excellent porous morphology of the developed membranes with distinguishable differences in fiber diameters for the PVA and PCL fibers. The developed membranes possessed enough mechanical strength for use as wound-healing membranes. The co-electrospun membranes showed good exudate uptake capacity. The controlled and extended delivery of SDF1 from the developed membranes was observed over a prolonged period. The SDF1-loaded membranes showed enhanced cell proliferation, cell viability, and cell migration. These biocompatible and biodegradable SDF1-loaded bicomponent membranes with excellent exudate uptake capacity, and cell proliferation and cell migration properties can be exploited as a novel wound-dressing membrane aimed at chronic diabetic wounds.

Transcriptomic profile of ataxia telangiectasia cells treated for 30 days with a low dose of dexamethasone

Dexamethasone administered by autologous red blood cells (RBCs) is used in clinical trials and as compassionate therapy to alleviate ataxia telangiectasia (AT) symptoms, providing long-term delivery of low doses of the drug. In the present paper, we report a dexamethasone-induced variation in gene expression that differed between healthy and AT primary fibroblasts simulating patient conditions. Gene expression levels were analysed by a microarray platform. The obtained gene-set data were used for biological pathway analysis by Reactome functional network clustering. Over 3000 probes were differentially modulated by dexamethasone in wild-type (WT) and AT fibroblasts. Consequently, the biological pathways induced by dexamethasone treatment also differed between the two samples. Some of the pathways were the same as those normally altered in AT compared to WT cells. Our results were consistent with earlier studies on HDAC4 and DDIT4 dynamics. The 30-day low dose dexamethasone treatment induced differential gene expression in AT and WT cells, leading to the partial recovery of genes that are usually dysregulated in AT. This is probably due to glucocorticoid receptor diversity in AT, which is likely genetically imprinted in AT, thus accounting for the differential response of AT cells to dexamethasone treatment.

Engineering microenvironment of biodegradable polyester systems for drug stability and release control.

Polymeric systems made of poly(lactic acid) or poly(lactic-co-glycolic acid)are widely used for long-term delivery of small and large molecules. The advantages of poly(lactic acid)/poly(lactic-co-glycolic acid) systems include biodegradability, safety and a long history of use in US FDA-approved products. However, asdrugs delivered by the polymeric systems and their applications become more diverse, the significance of microenvironment change of degrading systems on long-term drug stability and release kinetics has gained renewed attention. In this review, we discuss various issues experienced with acidifying microenvironment of biodegradable polymer systems and approaches to overcome the detrimental effects of polymer degradation on drug stability and release control.

Teachers’ perspective on implementation of menstrual hygiene management and puberty education in a pilot study in Bangladeshi schools

ABSTRACT Objective To assess the perspectives of Bangladeshi teachers on the feasibility of delivery and potential for long-term sustainability of puberty and menstruation education in urban and rural schools. Method We developed a multi-module puberty and menstrual hygiene management education curriculum that teachers piloted for six months in four urban and rural government and private schools in Bangladesh. We conducted monthly assessments during piloting, discussion for manual revision and four group discussions with 20 participating teachers to understand perceived benefits, barriers, and sustainability of puberty and menstruation education among school children. Results Teachers acknowledged the importance of school-based puberty and menstruation education to improve students’ perception and preparedness. They found that the training and instructors’ manual they received were useful tools for effectively communicating with students. Teachers noted school and community pressure to de-emphasize educational content not included on nationally standardized examinations, and insufficient time and pre-service training for teaching sensitive topics served as barriers to implementing the pilot curriculum. Conclusion Pressure from school authorities and community may hinder the successful long-term delivery of school-based puberty and menstruation education programs that are external to the national curriculum. Our findings indicate that feasibly and sustainably improving education on these topics in Bangladeshi classrooms should be achieved through 1) revision of the current national curriculum to incorporate more comprehensive puberty and menstruation information including its physiology, management, and social context, 2) adequate training and support for teachers to deliver the content, and 3) incorporation of puberty and menstruation content into students’ national examinations which may better ensure teachers are given the tools and opportunity to prioritize teaching this content.

A New Long-Term Composite Drug Delivery System Based on Thermo-Responsive Hydrogel and Nanoclay.

Several problems and limitations faced in the treatment of many diseases can be overcome by using controlled drug delivery systems (DDS), where the active compound is transported to the target site, minimizing undesirable side effects. In situ-forming hydrogels that can be injected as viscous liquids and jellify under physiological conditions and biocompatible clay nanoparticles have been used in DDS development. In this work, polymer–clay composites based on Pluronics (F127 and F68) and nanoclays were developed, aiming at a biocompatible and injectable system for long-term controlled delivery of methylene blue (MB) as a model drug. MB release from the systems produced was carried out at 37 °C in a pH 7.4 medium. The Pluronic formulation selected (F127/F68 18/2 wt.%) displayed a sol/gel transition at approx. 30 °C, needing a 2.5 N force to be injected at 25 °C. The addition of 2 wt.% of Na116 clay decreased the sol/gel transition to 28 °C and significantly enhanced its viscoelastic modulus. The most suitable DDS for long-term application was the Na116-MB hybrid from which, after 15 days, only 3% of the encapsulated MB was released. The system developed in this work proved to be injectable, with a long-term drug delivery profile up to 45 days.

Designing a drone delivery network with automated battery swapping machines

Drones are projected to alter last-mile delivery, but their short travel range is a concern. This study proposes a drone delivery network design using automated battery swapping machines (ABSMs) to extend ranges. The design minimizes the long-term delivery costs, including ABSM investment, drone ownership, and cost of the delivery time, and locates ABSMs to serve a set of customers. We build a mixed-integer nonlinear program that captures the nonlinear waiting time of drones at ABSMs. To solve the problem, we create an exact solution algorithm that finds the globally optimal solution using a derivative-supported cutting-plane method. To validate the applicability of our program, we conduct a case study on the Chicago Metropolitan area using cost data from leading ABSM manufacturer and geographical data from the planning and operations language for agent-based regional integrated simulation (more commonly known as POLARIS). A sensitivity analysis identifies that ABSM service times and costs are the key parameters impacting the long-term adoption of drone delivery.

Calibrating a long-term meteoric &amp;lt;sup&amp;gt;10&amp;lt;/sup&amp;gt;Be delivery rate into eroding western US glacial deposits by comparing meteoric and in situ produced &amp;lt;sup&amp;gt;10&amp;lt;/sup&amp;gt;Be depth profiles

Abstract. Meteoric 10Be (10Bemet) concentrations in soil profiles have great potential as a geochronometer and a tracer of Earth surface processes, particularly in fine-grained soils lacking quartz that would preclude the use of in situ produced 10Be (10Bein situ). One prerequisite for using this technique for accurately calculating rates and dates is constraining the delivery, or flux, of 10Bemet to a site. However, few studies to date have quantified long-term (i.e., millennial) delivery rates, and none have determined a delivery rate for an eroding soil. In this study, we compared existing concentrations of 10Bein situ with new measurements of 10Bemet in eroding soils sampled from the same depth profiles to calibrate a long-term 10Bemet delivery rate. We did so on the Pinedale (∼ 21–25 kyr) and Bull Lake (∼ 140 kyr) glacial moraines at Fremont Lake, Wyoming (USA), where age, grain sizes, weathering indices, and soil properties are known, as are erosion and denudation rates calculated from 10Bein situ. After ensuring sufficient beryllium retention in each profile, solving for the delivery rate of 10Bemet, and normalizing for paleomagnetic and solar intensity variations over the Holocene, we calculate 10Bemet fluxes of 1.46 (±0.20) × 106 atoms cm−2 yr−1 and 1.30 (±0.48) × 106 atoms cm−2 yr−1 to the Pinedale and Bull Lake moraines, respectively, and compare these values to two widely used 10Bemet delivery rate estimation methods that substantially differ for this site. Accurately estimating the 10Bemet flux using these methods requires a consideration of spatial scale and temporally varying parameters (i.e., paleomagnetic field intensity, solar modulation) to ensure the most realistic estimates of 10Bemet-derived erosion rates in future studies.

A multi-functionalized calcitriol sustainable delivery system for promoting osteoporotic bone regeneration both in vitro and in vivo

Among metabolic and systemic bone diseases, osteoporosis is known as one of the most progressive disease characterized by bone microstructural deterioration and bone mass reduction. Calcitriol (Cal) is widely accepted as a fat-soluble small molecule drug with reported anti-osteoporotic activity. However, delivery systems capable of local sustained release of small molecule drugs remain a significant challenge. Herein, based on poly(D, L-lactide)-poly(ethylene glycol)-poly(D, L-lactide) (PDLLA-PEG-PDLLA) hydrogels, we developed a thermosensitive and multifunctional sustainable delivery system by doubly integrating with polydopamine modified nano-hydroxyapatite (HA-D) and calcitriol-loaded amino-terminated poly(ethylene glycol)-block-poly(epsilon-caprolactone) (PCL-PEG-NH2) micelles to realize the long-term delivery of small molecule drugs. The sustained release of Cal from the system was associate with triple controlled release effects including the protective screen of the hydrogels over micelles, the reservoir effect of the HA nanoparticles for Cal, and the encapsulation of Cal in micelles. In vitro, results from the present study demonstrated that sustainable delivery system effectively activated osteogenesis, proliferation and migration in these bone mesenchymal stromal cells of ovariectomized rats (OVX-rBMSCs). In vivo, the composite Cal-loaded system was verified to promote bone regeneration in the critical-size femoral epicondyle bone defect model. Meanwhile, little cytotoxicity and appropriate degradation rate of the composite Cal delivery system were revealed. Thus, incorporating Cal into a multifunctional delivery system to perform a long-acting drug delivery in an injectable hydrogel form is a promising therapeutic to improve anti-osteoporotic ability and promote bone regeneration of osteoporosis.

Development and Field Validation of Lidocaine-Loaded Castration Bands for Bovine Pain Mitigation.

Simple SummaryCastration is among the most common management procedures performed in the dairy and beef cattle industries. Despite the widely accepted benefits of castration, all castration methods produce pain and distress. While slower than other approaches, castration by banding is simple, inexpensive, and produces fewer complications. We have therefore focused the present study on developing herd-level pain mitigation during banded castration. Because lidocaine is effective at reducing pain and can be delivered topically, we have formulated lidocaine-loaded castration bands (LLBs) to deliver local pain relief to calves and bulls during banded castration. Laboratory results indicated a rapid release of lidocaine for the first 30 min, followed by a slow release for at least 48 h. Field studies indicated that, for both lidocaine delivery into tissues and pain mitigation, LLBs performed at least as well as standard lidocaine injections in the short term and outperformed lidocaine injections in the long term. LLBs delivered therapeutic quantities of lidocaine into scrotal tissues over a period of at least seven days in cattle. This approach would provide long-term pain mitigation to the animals and, by avoiding surgery or the administration of injections, would also decrease the time and handling costs for the producer.Castration is among the most common management procedures performed in the dairy and beef cattle industries and is mainly performed by surgery or elastic banding. Despite the various benefits of castration, all methods produce pain and distress. Castration by banding is simple, inexpensive, produces fewer complications, and can be performed in a high-throughput manner. Because lidocaine, a local anesthetic, can be delivered to trauma sites topically, we have formulated lidocaine-loaded castration bands (LLBs) to deliver local pain relief to calves during banded castration. The initial lidocaine content of three band types developed was between 80 and 200 mg per band. The transfer kinetics of lidocaine into tissue was determined in vitro, indicating a rapid release for the first 30 min, followed by a slow release lasting at least 48 h. Furthermore, the lidocaine delivery and pain mitigation effects of these LLBs were compared to standard lidocaine injections in vivo. Field studies indicated that LLBs performed at least as well as lidocaine injections for short-term lidocaine delivery into tissues and pain mitigation. Moreover, LLBs significantly outperformed lidocaine injections for long-term delivery and pain mitigation. The concentrations of lidocaine in the LLB-treated tissue samples were generally in the range of 0.5–3.5 mg of lidocaine per gram of tissue and were overall highest after 6 h. Lidocaine-loaded elastration bands deliver therapeutic quantities of lidocaine into scrotal tissues over a period of at least seven days in cattle. This approach would provide long-term pain mitigation to the animals and, by avoiding surgery or the administration of injections, would also decrease the time and handling costs for the producer.

The Impact of Human Immunodeficiency Virus and Menopause on Bone Mineral Density: A Longitudinal Study of Urban-Dwelling South African Women.

An estimated 25% of South African women live with human immunodeficiency virus (HIV). Antiretroviral therapy roll-out has improved life expectancy, so many more women now reach menopause. We aimed to quantify changes in bone mineral density (BMD) during the menopausal transition in urban-dwelling South African women with and without HIV and determine whether HIV infection modified the effect of menopause on BMD changes. A 5-year population-based longitudinal study recruited women aged 40-60 years residing in Soweto and collected demographic and clinical data, including HIV status, anthropometry, and BMD, at baseline and at 5-year follow-up. All women were staged as pre-, peri-, or postmenopausal at both time points. Multivariable linear regression assessed relationships and interactions between HIV infection, menopause, and change in BMD. At baseline, 450 women had mean age 49.5 (SD 5.7) years, 65 (14.4%) had HIV, and 140 (31.1%), 119 (26.4%), and 191 (42.4%) were pre-, peri-, and postmenopausal, respectively; 34/205 (13.6%) women ≥50 years had a total hip (TH) or lumbar spine (LS) T-score ≤ -2.5. At follow-up 38 (8.4%), 84 (18.7%), and 328 (72.9%) were pre-, peri-, and postmenopausal. Those with HIV at baseline lost more total body (TB) BMD (mean difference -0.013 [95% confidence interval -0.026, -0.001] g/cm2 , p=0.040) and gained more weight 1.96 [0.32, 3.60] kg; p=0.019 than HIV-uninfected women. After adjusting for age, baseline weight, weight change, and follow-up time, the transition from pre- to postmenopause was associated with greater TB BMD losses in women with HIV (-0.092 [-0.042, -0.142] g/cm2 ; p=0.001) than without HIV (-0.038 [-0.016, -0.060] g/cm2 , p=0.001; interaction p=0.034). Similarly, in women who were postmenopausal at both time points, those with HIV lost more TB BMD (-0.070 [-0.031, -0.108], p=0.001) than women without HIV (-0.036 [-0.015, -0.057], p=0.001, interaction p=0.049). Findings were consistent but weaker at the LS and TH. Menopause-related bone loss is greater in women with HIV, suggesting women with HIV may be at greater risk of osteoporotic fractures. HIV services should consider routine bone health assessment in midlife women as part of long-term HIV care delivery. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).