Bioplastics for a circular economy.

Bioplastics - typically plastics manufactured from bio-based polymers - stand to contribute to more sustainable commercial plastic life cycles as part of a circular economy, in which virgin polymers are made from renewable or recycled raw materials. Carbon-neutral energy is used for production and products are reused or recycled at their end of life (EOL). In this Review, we assess the advantages and challenges of bioplastics in transitioning towards a circular economy. Compared with fossil-based plastics, bio-based plastics can have a lower carbon footprint and exhibit advantageous materials properties; moreover, they can be compatible with existing recycling streams and some offer biodegradation as an EOL scenario if performed in controlled or predictable environments. However, these benefits can have trade-offs, including negative agricultural impacts, competition with food production, unclear EOL management and higher costs. Emerging chemical and biological methods can enable the 'upcycling' of increasing volumes of heterogeneous plastic and bioplastic waste into higher-quality materials. To guide converters and consumers in their purchasing choices, existing (bio)plastic identification standards and life cycle assessment guidelines need revision and homogenization. Furthermore, clear regulation and financial incentives remain essential to scale from niche polymers to large-scale bioplastic market applications with truly sustainable impact.

Additive manufacturing in drug delivery: Innovative drug product design and opportunities for industrial application.

Additive manufacturing (AM) or 3D printing is enabling new directions in product design. The adoption of AM in various industrial sectors has led to major transformations. Similarly, AM presents new opportunities in the field of drug delivery, opening new avenues for improved patient care. In this review, we discuss AM as an innovative tool for drug product design. We provide a brief overview of the different AM processes and their respective impact on the design of drug delivery systems. We highlight several enabling features of AM, including unconventional release, customization, and miniaturization, and discuss several applications of AM for the fabrication of drug products. This includes products that have been approved or are in development. As the field matures, there are also several new challenges to broad implementation in the pharmaceutical landscape. We discuss several of these from the regulatory and industrial perspectives and provide an outlook for how these issues may be addressed. The introduction of AM into the field of drug delivery is an enabling technology and many new drug products can be created through productive collaboration of engineers, materials scientists, pharmaceutical scientists, and industrial partners.

Inverse Pneumatic Artificial Muscles for Application in Low-Cost Ventilators.

The procurement and maintenance cost of high-end ventilators preclude their stockpiles sufficient for the mass emergency situations. Therefore, there is a significant demand for mechanical ventilators in such situations. Herein, a low-cost, portable, yet high-performance design for a volume-controlled mechanical ventilator is proposed. Pneumatic artificial muscles, such as air cylinders, are used in the inverse mode of operation to achieve mechanical ventilation. With the current design, the two fundamental modes of operation (controlled mode and assisted mode) are demonstrated. Unlike most intensive care unit ventilators, the proposed device does not need a high-pressure air pipeline to operate. The device is capable of mechanical ventilation for respiration rate ranging from 10 to 30 b min-1 with a tidal volume (VT) range of 150-1000 mL and the I:E ratio of 1:1-1:5. A total cost of less than $400 USD is achieved to make one device. The cost to produce the device in larger volumes can be estimated to be less than $250 USD.

Development of a long-acting direct-acting antiviral system for hepatitis C virus treatment in swine.

Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis worldwide and kills more Americans than 59 other infections, including HIV and tuberculosis, combined. While direct-acting antiviral (DAA) treatments are effective, limited uptake of therapy, particularly in high-risk groups, remains a substantial barrier to eliminating HCV. We developed a long-acting DAA system (LA-DAAS) capable of prolonged dosing and explored its cost-effectiveness. We designed a retrievable coil-shaped LA-DAAS compatible with nasogastric tube administration and the capacity to encapsulate and release gram levels of drugs while resident in the stomach. We formulated DAAs in drug-polymer pills and studied the release kinetics for 1 mo in vitro and in vivo in a swine model. The LA-DAAS was equipped with ethanol and temperature sensors linked via Bluetooth to a phone application to provide patient engagement. We then performed a cost-effectiveness analysis comparing LA-DAAS to DAA alone in various patient groups, including people who inject drugs. Tunable release kinetics of DAAs was enabled for 1 mo with drug-polymer pills in vitro, and the LA-DAAS safely and successfully provided at least month-long release of sofosbuvir in vivo. Temperature and alcohol sensors could interface with external sources for at least 1 mo. The LA-DAAS was cost-effective compared to DAA therapy alone in all groups considered (base case incremental cost-effectiveness ratio $39,800). We believe that the LA-DAA system can provide a cost-effective and patient-centric method for HCV treatment, including in high-risk populations who are currently undertreated.

A gastric resident drug delivery system for prolonged gram-level dosing of tuberculosis treatment.

Multigram drug depot systems for extended drug release could transform our capacity to effectively treat patients across a myriad of diseases. For example, tuberculosis (TB) requires multimonth courses of daily multigram doses for treatment. To address the challenge of prolonged dosing for regimens requiring multigram drug dosing, we developed a gastric resident system delivered through the nasogastric route that was capable of safely encapsulating and releasing grams of antibiotics over a period of weeks. Initial preclinical safety and drug release were demonstrated in a swine model with a panel of TB antibiotics. We anticipate multiple applications in the field of infectious diseases, as well as for other indications where multigram depots could impart meaningful benefits to patients, helping maximize adherence to their medication.

Parallel In Vivo Assessment of Drug Phenotypes at Various Time Points during Systemic BRAF Inhibition Reveals Tumor Adaptation and Altered Treatment Vulnerabilities.

PURPOSE: Treatment of BRAF-mutated melanoma tumors with BRAF inhibitor-based therapy produces high response rates, but of limited duration in the vast majority of patients. Published investigations of resistance mechanisms suggest numerous examples of tumor adaptation and signal transduction bypass mechanisms, but without insight into biomarkers that would predict which mechanism will predominate. Monitoring phenotypic response of multiple adaptive mechanisms simultaneously within the same tumor as it adapts during treatment has been elusive. EXPERIMENTAL DESIGN: This study reports on a method to provide a more complete understanding of adaptive tumor responses. We simultaneously measured in vivo antitumor activity of 12 classes of inhibitors, which are suspected of enabling adaptive escape mechanisms, at various time points during systemic BRAF inhibition. We used implantable microdevices to release multiple compounds into distinct regions of a tumor to measure the efficacy of each compound independently and repeated these measurements as tumors progressed on systemic BRAF treatment. RESULTS: We observed varying phenotypic responses to specific inhibitors before, during, and after prolonged systemic treatment with BRAF inhibitors. Our results specifically identify PI3K, PDGFR, EGFR, and HDAC inhibitors as becoming significantly more efficacious during systemic BRAF inhibition. The sensitivity to other targeted inhibitors remained mostly unchanged, whereas local incremental sensitivity to PLX4720 declined sharply. CONCLUSIONS: These findings suggest redundancy of several resistance mechanisms and may help identify optimal constituents of more effective combination therapy in BRAF-mutant melanoma. They also represent a new paradigm for dynamic measurement of adaptive signaling mechanisms within the same tumor during therapy. Clin Cancer Res; 22(24); 6031-8. ©2016 AACR.

Simple battery armor to protect against gastrointestinal injury from accidental ingestion.

Inadvertent battery ingestion in children and the associated morbidity and mortality results in thousands of emergency room visits every year. Given the risk for serious electrochemical burns within hours of ingestion, the current standard of care for the treatment of batteries in the esophagus is emergent endoscopic removal. Safety standards now regulate locked battery compartments in toys, which have resulted in a modest reduction in inadvertent battery ingestion; specifically, 3,461 ingestions were reported in 2009, and 3,366 in 2013. Aside from legislation, minimal technological development has taken place at the level of the battery to limit injury. We have constructed a waterproof, pressure-sensitive coating, harnessing a commercially available quantum tunneling composite. Quantum tunneling composite coated (QTCC) batteries are nonconductive in the low-pressure gastrointestinal environment yet conduct within the higher pressure of standard battery housings. Importantly, this coating technology enables most battery-operated equipment to be powered without modification. If these new batteries are swallowed, they limit the external electrolytic currents responsible for tissue injury. We demonstrate in a large-animal model a significant decrease in tissue injury with QTCC batteries compared with uncoated control batteries. In summary, here we describe a facile approach to increasing the safety of batteries by minimizing the risk for electrochemical burn if the batteries are inadvertently ingested, without the need for modification of most battery-powered devices.

Molecular pathogenesis of post-transplant acute kidney injury: assessment of whole-genome mRNA and miRNA profiles.

Acute kidney injury (AKI) affects roughly 25% of all recipients of deceased donor organs. The prevention of post-transplant AKI is still an unmet clinical need. We prospectively collected zero-hour, indication as well as protocol kidney biopsies from 166 allografts between 2011 and 2013. In this cohort eight cases with AKI and ten matched allografts without pathology serving as control group were identified with a follow-up biopsy within the first twelve days after engraftment. For this set the zero-hour and follow-up biopsies were subjected to genome wide microRNA and mRNA profiling and analysis, followed by validation in independent expression profiles of 42 AKI and 21 protocol biopsies for strictly controlling the false discovery rate. Follow-up biopsies of AKI allografts compared to time-matched protocol biopsies, further baseline adjustment for zero-hour biopsy expression level and validation in independent datasets, revealed a molecular AKI signature holding 20 mRNAs and two miRNAs (miR-182-5p and miR-21-3p). Next to several established biomarkers such as lipocalin-2 also novel candidates of interest were identified in the signature. In further experimental evaluation the elevated transcript expression level of the secretory leukocyte peptidase inhibitor (SLPI) in AKI allografts was confirmed in plasma and urine on the protein level (p<0.001 and p = 0.003, respectively). miR-182-5p was identified as a molecular regulator of post-transplant AKI, strongly correlated with global gene expression changes during AKI. In summary, we identified an AKI-specific molecular signature providing the ground for novel biomarkers and target candidates such as SLPI and miR-182-5p in addressing AKI.

[50-year history of kidney transplantation in Hungary]. / A veseátültetés elso 50 éve Magyarországon.

The first Hungarian kidney transplantation was performed by András Németh in Szeged in 1962, approximately 50 years ago. A preliminary agreement with Eurotransplant was signed in 2011, and special patient groups gained benefit from this cooperation in 2012, wnich lead to a full membership to Eurotransplant. This event inspired the authors to review the history of Hungarian kidney transplantation of the past 50 years, from the first operation to recent via the specific cornerstones of the transplant program. The donor of the first Hungarian kidney transplantation was the brother of the recipient. The operation itself was technically successful, but the lack of immunosuppression caused graft rejection, and the patient died after 79 days. His brother, the donor, is still healthy, after 50 years, and he encourages everybody to donate organs. Organized kidney transplant program started more than 10 years later, such as 1973, in Budapest. The program was supported by the Ministry of Health. New centers joined the program later, Szeged in 1979, Debrecen in 1991 and Pécs in 1993. These four transplant centers work currently in Hungary, and 6611 kidney transplantation has been performed up to the end of year 2012.

Laparoscopic donor nephrectomy techniques.

PURPOSE OF REVIEW: To highlight the latest improvements and modifications aimed at better outcomes in laparoscopic live-donor nephrectomies. RECENT FINDINGS: Because the most important consideration is the safety of the donor, there are strict instructions on the usage of vascular instruments. Decreasing the cost of the procedure is also important. Deviceless techniques were introduced. Multiple renal arteries, venous variations and right kidney removal are no longer absolute contraindications; preoperative planning is mandatory. Increasing positive experiences have been reported with novel procedures such as laparoendoscopic single site and transvaginal live-donor nephrectomy. SUMMARY: Minimally invasive laparoscopic nephrectomy became a prevalent procedure in the field of live kidney donation. The surgical technique must be developed and refined continually in order to secure the integrity and safety of the donor. Recent surgical innovations - represented by laparoendoscopic single site and transvaginal live-donor nephrectomy - successfully result in excellent patient and graft outcomes and better cosmesis.

Progress in the tissue engineering and stem cell industry "are we there yet?".

This report presents a detailed update to our 2008 publication on the tissue engineering (TE) and stem cell industry. Data are reported through mid 2011 showing an almost three-fold growth in commercial sales over the past 4 years. In addition, the number of companies selling products or offering services has increased over two-fold to 106, and they are generating a remarkable $3.5 billion in sales. Overall, the TE and stem cell sector is spending $3.6 billion and employing almost 14,000 employees. These data suggest the TE and stem cell industry has stabilized and is on a path pointing toward continued success.

Reshaping the future of nanopharmaceuticals: ad iudicium.

We present views on the future development of biologics-based nanopharmaceuticals from a "high risk-high gain" perspective and within the context of personalized therapies. Integrated scientific, commercial, and societal aspects are addressed, and provocative combined realistic biotech, computational, and nanotech approaches for tailor-made engineering of nanopharmaceuticals are discussed.

Assessment of canine vocal fold function after injection of a new biomaterial designed to treat phonatory mucosal scarring.

OBJECTIVES: Most cases of irresolvable hoarseness are due to deficiencies in the pliability and volume of the superficial lamina propria of the phonatory mucosa. By using a US Food and Drug Administration-approved polymer, polyethylene glycol (PEG), we created a novel hydrogel (PEG30) and investigated its effects on multiple vocal fold structural and functional parameters. METHODS: We injected PEG30 unilaterally into 16 normal canine vocal folds with survival times of 1 to 4 months. High-speed videos of vocal fold vibration, induced by intratracheal airflow, and phonation threshold pressures were recorded at 4 time points per subject. Three-dimensional reconstruction analysis of 11.7 T magnetic resonance images and histologic analysis identified 3 cases wherein PEG30 injections were the most superficial, so as to maximally impact vibratory function. These cases were subjected to in-depth analyses. RESULTS: High-speed video analysis of the 3 selected cases showed minimal to no reduction in the maximum vibratory amplitudes of vocal folds injected with PEG30 compared to the non-injected, contralateral vocal fold. All PEG30-injected vocal folds displayed mucosal wave activity with low average phonation threshold pressures. No significant inflammation was observed on microlaryngoscopic examination. Magnetic resonance imaging and histologic analyses revealed time-dependent resorption of the PEG30 hydrogel by phagocytosis with minimal tissue reaction or fibrosis. CONCLUSIONS: The PEG30 hydrogel is a promising biocompatible candidate biomaterial to restore form and function to deficient phonatory mucosa, while not mechanically impeding residual endogenous superficial lamina propria.

Contaminated heparin associated with adverse clinical events and activation of the contact system.

BACKGROUND: There is an urgent need to determine whether oversulfated chondroitin sulfate (OSCS), a compound contaminating heparin supplies worldwide, is the cause of the severe anaphylactoid reactions that have occurred after intravenous heparin administration in the United States and Germany. METHODS: Heparin procured from the Food and Drug Administration, consisting of suspect lots of heparin associated with the clinical events as well as control lots of heparin, were screened in a blinded fashion both for the presence of OSCS and for any biologic activity that could potentially link the contaminant to the observed clinical adverse events. In vitro assays for the activation of the contact system and the complement cascade were performed. In addition, the ability of OSCS to recapitulate key clinical manifestations in vivo was tested in swine. RESULTS: The OSCS found in contaminated lots of unfractionated heparin, as well as a synthetically generated OSCS reference standard, directly activated the kinin-kallikrein pathway in human plasma, which can lead to the generation of bradykinin, a potent vasoactive mediator. In addition, OSCS induced generation of C3a and C5a, potent anaphylatoxins derived from complement proteins. Activation of these two pathways was unexpectedly linked and dependent on fluid-phase activation of factor XII. Screening of plasma samples from various species indicated that swine and humans are sensitive to the effects of OSCS in a similar manner. OSCS-containing heparin and synthetically derived OSCS induced hypotension associated with kallikrein activation when administered by intravenous infusion in swine. CONCLUSIONS: Our results provide a scientific rationale for a potential biologic link between the presence of OSCS in suspect lots of heparin and the observed clinical adverse events. An assay to assess the amidolytic activity of kallikrein can supplement analytic tests to protect the heparin supply chain by screening for OSCS and other highly sulfated polysaccharide contaminants of heparin that can activate the contact system.

Microfluidics for drug discovery and development: from target selection to product lifecycle management.

Microfluidic technologies' ability to miniaturize assays and increase experimental throughput have generated significant interest in the drug discovery and development domain. These characteristics make microfluidic systems a potentially valuable tool for many drug discovery and development applications. Here, we review the recent advances of microfluidic devices for drug discovery and development and highlight their applications in different stages of the process, including target selection, lead identification, preclinical tests, clinical trials, chemical synthesis, formulations studies and product management.