Luminal Delivery of Pectin-Modified Oxygen Microbubbles Mitigates Rodent Experimental Intestinal Ischemia.

INTRODUCTION: Ischemic gut injury is common in the intensive care unit, impairs gut barrier function, and contributes to multiorgan dysfunction. One novel intervention to mitigate ischemic gut injury is the direct luminal delivery of oxygen microbubbles (OMB). Formulations of OMB can be modified to control the rate of oxygen delivery. This project examined whether luminal delivery of pectin-modified OMB (OMBp5) can reduce ischemic gut injury in a rodent model. METHODS: The OMBp5 formulation was adapted to improve delivery of oxygen along the length of small intestine. Adult Sprague-Dawley rats (n = 24) were randomly allocated to three groups: sham-surgery (SS), intestinal ischemia (II), and intestinal ischemia plus luminal delivery of OMBp5 (II + O). Ischemia-reperfusion injury was induced by superior mesenteric artery occlusion for 45 min followed by reperfusion for 30 min. Outcome data included macroscopic score of mucosal injury, the histological score of gut injury, and plasma biomarkers of intestinal injury. RESULTS: Macroscopic, microscopic data, and intestinal injury biomarker results demonstrated minimal intestinal damage in the SS group and constant damage in the II group. II + O group had a significantly improved macroscopic score throughout the gut mucosa (P = 0.04) than the II. The mean histological score of gut injury for the II + O group was significantly improved on the II group (P ≤ 0.01) in the proximal intestine only, within 30 cm of delivery. No differences were observed in plasma biomarkers of intestinal injury following OMBp5 treatment. CONCLUSIONS: This proof-of-concept study has demonstrated that luminal OMBp5 decreases ischemic injury to the proximal small intestine. There is a need to improve oxygen delivery over the full length of the intestine. These findings support further studies with clinically relevant end points, such as systemic inflammation and vital organ dysfunction.

Roadmap on multifunctional materials for drug delivery.

This Roadmap on drug delivery aims to cover some of the most recent advances in the field of materials for drug delivery systems (DDSs) and emphasizes the role that multifunctional materials play in advancing the performance of modern DDSs in the context of the most current challenges presented. The Roadmap is comprised of multiple sections, each of which introduces the status of the field, the current and future challenges faced, and a perspective of the required advances necessary for biomaterial science to tackle these challenges. It is our hope that this collective vision will contribute to the initiation of conversation and collaboration across all areas of multifunctional materials for DDSs. We stress that this article is not meant to be a fully comprehensive review but rather an up-to-date snapshot of different areas of research, with a minimal number of references that focus upon the very latest research developments.

Electrically responsive release of proteins from conducting polymer hydrogels.

Electrically modulated delivery of proteins provides an avenue to target local tissues specifically and tune the dose to the application. This approach prolongs and enhances activity at the target site whilst reducing off-target effects associated with systemic drug delivery. The work presented here explores an electrically active composite material comprising of a biocompatible hydrogel, gelatin methacryloyl (GelMA) and a conducting polymer, poly(3,4-ethylenedioxythiophene), generating a conducting polymer hydrogel. In this paper, the key characteristics of electroactivity, mechanical properties, and morphology are characterized using electrochemistry techniques, atomic force, and scanning electron microscopy. Cytocompatibility is established through exposure of human cells to the materials. By applying different electrical-stimuli, the short-term release profiles of a model protein can be controlled over 4 h, demonstrating tunable delivery patterns. This is followed by extended-release studies over 21 days which reveal a bimodal delivery mechanism influenced by both GelMA degradation and electrical stimulation events. This data demonstrates an electroactive and cytocompatible material suitable for the delivery of protein payloads over 3 weeks. This material is well suited for use as a treatment delivery platform in tissue engineering applications where targeted and spatio-temporal controlled delivery of therapeutic proteins is required. STATEMENT OF SIGNIFICANCE: Growth factor use in tissue engineering typically requires sustained and tunable delivery to generate optimal outcomes. While conducting polymer hydrogels (CPH) have been explored for the electrically responsive release of small bioactives, we report on a CPH capable of releasing a protein payload in response to electrical stimulus. The composite material combines the benefits of soft hydrogels acting as a drug reservoir and redox-active properties from the conducting polymer enabling electrical responsiveness. The CPH is able to sustain protein delivery over 3 weeks, with electrical stimulus used to modulate release. The described material is well suited as a treatment delivery platform to deliver large quantities of proteins in applications where spatio-temporal delivery patterns are paramount.

Patternable Gelatin Methacrylate/PEDOT/Polystyrene Sulfonate Microelectrode Coatings for Neuronal Recording.

This manuscript addresses the need for new soft biomaterials that can be fabricated on the surface of microelectrodes to reduce the mechanical mismatch between biological tissues and electrodes and improve the performance at the neural interface. By electrochemical polymerization of poly(3,4-dioxythiophene) (PEDOT)/polystyrene sulfonate (PSS) through a gelatin methacrylate (GelMA) hydrogel, we demonstrate the synthesis of a conducting polymer hydrogel (CPH) to meet the performance criteria of bioelectrodes. The hybrid material can be photolithographically patterned and covalently attached to gold microelectrodes, forming an interpenetrating network, as confirmed by infrared spectroscopy. The GelMA/PEDOT/PSS coatings were found to be reversibly electroactive by cyclic voltammetry and had low impedance compared to bare gold and GelMA-coated microelectrodes. The CPH coatings showed impedance at levels similar to conventional PEDOT/PSS coatings at a frequency of 1000 Hz. CPH exhibited electrochemical stability over 1000 CV cycles, and its performance was maintained over 14 days. Biocompatibility of the CPH coatings was confirmed by primary hippocampal neuronal cultures via a neuronal viability assay. The CPH-coated microelectrode arrays (MEAs) successfully recorded neuronal activity from primary hippocampal neuronal cells. The CPH GelMA/PEDOT/PSS is a highly promising coating material to enhance microelectrode performance at the neural interface.

A Subdural Bioelectronic Implant to Record Electrical Activity from the Spinal Cord in Freely Moving Rats.

Bioelectronic devices have found use at the interface with neural tissue to investigate and treat nervous system disorders. Here, the development and characterization of a very thin flexible bioelectronic implant inserted along the thoracic spinal cord in rats directly in contact with and conformable to the dorsal surface of the spinal cord are presented. There is no negative impact on hind-limb functionality nor any change in the volume or shape of the spinal cord. The bioelectronic implant is maintained in rats for a period of 12 weeks. The first subdural recordings of spinal cord activity in freely moving animals are presented; rats are plugged in via a recording cable and allowed to freely behave and move around on a raised platform. Recordings contained multiple distinct voltage waveforms spatially localize to individual electrodes. This device has great potential to monitor electrical signaling in the spinal cord after an injury and in the future, this implant will facilitate the identification of biomarkers in spinal cord injury and recovery, while enabling the delivery of localized electroceutical and chemical treatments.

Externally triggered release of growth factors - A tissue regeneration approach.

Tissue regeneration aims to achieve functional restoration following injury by creating an environment to enable the body to self-repair. Strategies for regeneration rely on the introduction of biomaterial scaffolding, cells and bioactive molecules into the body, at or near the injury site. Of these bioactive molecules, growth factors (GFs) play a pivotal role in directing regenerative pathways for many cell populations. However, the therapeutic use of GFs has been limited by the complexity of biological injury and repair, and the properties of the GFs themselves, including their short half-life, poor tissue penetration, and off-target side effects. Externally triggered delivery systems have the potential to facilitate the delivery of GFs into the target tissues with considerations of the timing, sequence, amount, and location of GF presentation. This review briefly discusses the challenges facing the therapeutic use of GFs, then, we discuss approaches to externally trigger GF release from delivery systems categorised by stimulation type; ultrasound, temperature, light, magnetic fields and electric fields. Overall, while the use of GFs for tissue regeneration is still in its infancy, externally controlled GF delivery technologies have the potential to achieve robust and effective solutions to present GFs to injured tissues. Future technological developments must occur in conjunction with a comprehensive understanding of the biology at the injury site to ensure translation of promising technologies into real world benefit.