Monitoring homeostasis with ultrasound.

An implant could allow at-home monitoring of deep-tissue changes after surgery.

RNAi therapies: Expanding applications for extrahepatic diseases and overcoming delivery challenges.

The era of RNA medicine has become a reality with the success of messenger RNA (mRNA) vaccines against COVID-19 and the approval of several RNA interference (RNAi) agents in recent years. Particularly, therapeutics based on RNAi offer the promise of targeting intractable and previously undruggable disease genes. Recent advances have focused in developing delivery systems to enhance the poor cellular uptake and insufficient pharmacokinetic properties of RNAi therapeutics and thereby improve its efficacy and safety. However, such approach has been mainly achieved via lipid nanoparticles (LNPs) or chemical conjugation with N-Acetylgalactosamine (GalNAc), thus current RNAi therapy has been limited to liver diseases, most likely to encounter liver-targeting limitations. Hence, there is a huge unmet medical need for intense evolution of RNAi therapeutics delivery systems to target extrahepatic tissues and ultimately extend their indications for treating various intractable diseases. In this review, challenges of delivering RNAi therapeutics to tumors and major organs are discussed, as well as their transition to clinical trials. This review also highlights innovative and promising preclinical RNAi-based delivery platforms for the treatment of extrahepatic diseases.

Trend in seroprevalence of HTLV-1/2 in Taiwanese blood donors-A 10-year follow-up.

OBJECTIVES: This study evaluated the Human T-lymphotropic virus (HTLV) screening policy impact on the HTLV seroprevalence from 2009 to 2018 as well as the differences between administrative districts in terms of prevalence distribution in Taiwan. BACKGROUND: Since February 1996, the Taiwan Blood Services Foundation (TBSF) had conducted HTLV screening of blood donors. The HTLV seroprevalence was 0.032% in 1999. MATERIALS AND METHODS: This cross-sectional study included donors' data collected from blood donation centres across Taiwan from 2009 to 2018. Enzyme immunoassay and Western blot assay were used for screening and confirmation of HTLV infections. In this study, the researchers calculated the trends in the HTLV rates of first-time and repeat donors across time as well as the HTLV prevalence distribution across the 22 administrative districts of Taiwan. RESULTS: Amongst 17 977 429 employed blood donations, 739 HTLV-seropositive donations (4.11 per 100 000 donations) were identified. The HTLV-positive donors were aged between 17 and 64 years, with a median age of 49 years. The overall seropositivity rates of first-time and repeat donors were 34.36/100 000 and 1.27/100 000. HTLV seroprevalence in first-time blood donors significantly decreased by 57% (crude odds ratio [95% confidence interval] (crude OR [95% CI]) = 0.43 [0.28-0.64]) within 10 years. A slight decline was also identified in repeat donors (crude OR [95% CI] = 0.73 [0.4-1.32]). Donors from different districts showed significantly varied prevalence. Most districts with high prevalence are situated in eastern Taiwan, for both donation types. Older blood donors were more likely to be infected with HTLV than younger ones in first time and repeat donors. Middle age donors (50-65 years) had an 18.47-39.65 greater risk than those aged <20 years. Significant higher risk of female was observed in both donation types. Amongst different age groups, first-time female donors increase 1.31-1.88 times infection risk and female in repeat donor group had 1.55-3.43 times greater risk. CONCLUSION: Over years of implementation of the HTLV blood donor screening policy by the TBSF, the HTLV seroprevalence of first-time donors has decreased consistently. Moreover, the HTLV seroprevalence of repeat donors has dropped considerably. This implies that the screening policy provides continued benefit. Females and older blood donors were more likely infected with HTLV than males and younger blood donors. The influence of age on infection was greater amongst first-time donors than amongst repeat donors. Therefore, appropriate measures should be taken to ensure public safety.

Fast-Curing Injectable Microporous Hydrogel for In Situ Cell Encapsulation.

Injectable hydrogels have previously demonstrated potential as a temporary scaffold for tissue regeneration or as a delivery vehicle for cells, growth factors, or drugs. However, most injectable hydrogel systems lack a microporous structure, preventing host cell migration into the hydrogel interior and limiting spreading and proliferation of encapsulated cells. Herein, an injectable microporous hydrogel assembled from gelatin/gelatin methacryloyl (GelMA) composite microgels is described. Microgels are produced by a water-in-oil emulsion using a gelatin/GelMA aqueous mixture. These microgels show improved thermal stability compared to GelMA-only microgels and benefit from combined photopolymerization using UV irradiation (365 nm) in the presence of a photoinitiator (PI) and enzymatic reaction by microbial transglutaminase (mTG), which together enable fast curing and tissue adhesion of the hydrogel. The dual-crosslinking approach also allows for the reduction of PI concentration and minimizes cytotoxicity during photopolymerization. When applied for in situ cell encapsulation, encapsulated human dermal fibroblasts and human mesenchymal stem cells (hMSCs) are able to rapidly spread and proliferate in the pore space of the hydrogel. This hydrogel has the potential to enhance hMSC anti-inflammatory behavior through the demonstrated secretion of prostaglandin E2 (PGE2) and interleukin-6 (IL-6) by encapsulated cells. Altogether, this injectable formulation has the potential to be used as a cell delivery vehicle for various applications in regenerative medicine.

Daily transient coating of the intestine leads to weight loss and improved glucose tolerance.

INTRODUCTION: Roux-en-Y gastric bypass surgery (RYGB) has been shown to be the gold standard treatment for obesity associated type-2-diabetes (T2D), however many T2D patients do not qualify or are reluctant to proceed with surgery due to its potential risks and permanent changes to GI anatomy. We have previously described a novel oral formulation, LuCI, that provides a transient coating of the proximal bowel and mimics the effects of RYGB. Herein, we aim to investigate the outcome of chronic LuCI administration on weight and glucose homeostasis. METHODS: Sprague-Dawley rats on a high fat diet achieving diet-induced obesity (DIO) received 5 weeks of daily LuCI or normal saline as control (n = 8/group). Daily weights and glucose tolerance were monitored throughout the experiment. At 5 weeks, systemic blood was sampled through a surgically placed jugular vein catheter, before and during an intestinal glucose bolus, to investigate changes in key hormones involved in glucose metabolism. To elucidate the effects of LuCI on nutrient absorption, fecal output and food intake were measured simultaneously with the analysis of homogenized stool samples performed using bomb calorimetry. RESULTS: At 5 weeks, LuCI animals weighted 8.3% less and had lower fasting glucose levels than Controls (77.6 ±â€¯3.8 mg/dl vs. 99.1 ±â€¯2.7 mg/dl, P < 0.001). LuCI-treated animals had lower baseline insulin and HOMA-IR. Post-prandially, LuCI group had increased GLP-1 and GIP secretion following a glucose challenge. Serum lipid analysis revealed lowered LDL levels highlighting the potential to not only improve glucose control but also modify cardiovascular risk. We then investigated whether LuCI's effect on proximal bowel exclusion may play a role in energy balance. Bomb calorimetry analysis suggested that LuCI reduced calorie absorption with no difference in caloric consumption. CONCLUSION: We demonstrated that LuCI recapitulates the physical and hormonal changes seen after RYGB and can ameliorate weight gain and improve insulin sensitivity in a DIO rat model. Since LuCI's effect is transient and without systemic absorption, LuCI has the potential to be a novel therapy for overweight or obese T2D patients.

Spin-Selective Hole-Exciton Coupling in a V-Doped WSe2 Ferromagnetic Semiconductor at Room Temperature.

While valley polarization with strong Zeeman splitting is the most prominent characteristic of two-dimensional (2D) transition metal dichalcogenide (TMD) semiconductors under magnetic fields, enhancement of the Zeeman splitting has been demonstrated by incorporating magnetic dopants into the host materials. Unlike Fe, Mn, and Co, V is a distinctive dopant for ferromagnetic semiconducting properties at room temperature with large Zeeman shifting of band edges. Nevertheless, little known is the excitons interacting with spin-polarized carriers in V-doped TMDs. Here, we report anomalous circularly polarized photoluminescence (CPL) in a V-doped WSe2 monolayer at room temperature. Excitons couple to V-induced spin-polarized holes to generate spin-selective positive trions, leading to differences in the populations of neutral excitons and trions between left and right CPL. Using transient absorption spectroscopy, we elucidate the origin of excitons and trions that are inherently distinct for defect-mediated and impurity-mediated trions. Ferromagnetic characteristics are further confirmed by the significant Zeeman splitting of nanodiamonds deposited on the V-doped WSe2 monolayer.

A therapeutic convection-enhanced macroencapsulation device for enhancing ß cell viability and insulin secretion.

Islet transplantation for type 1 diabetes treatment has been limited by the need for lifelong immunosuppression regimens. This challenge has prompted the development of macroencapsulation devices (MEDs) to immunoprotect the transplanted islets. While promising, conventional MEDs are faced with insufficient transport of oxygen, glucose, and insulin because of the reliance on passive diffusion. Hence, these devices are constrained to two-dimensional, wafer-like geometries with limited loading capacity to maintain cells within a distance of passive diffusion. We hypothesized that convective nutrient transport could extend the loading capacity while also promoting cell viability, rapid glucose equilibration, and the physiological levels of insulin secretion. Here, we showed that convective transport improves nutrient delivery throughout the device and affords a three-dimensional capsule geometry that encapsulates 9.7-fold-more cells than conventional MEDs. Transplantation of a convection-enhanced MED (ceMED) containing insulin-secreting ß cells into immunocompetent, hyperglycemic rats demonstrated a rapid, vascular-independent, and glucose-stimulated insulin response, resulting in early amelioration of hyperglycemia, improved glucose tolerance, and reduced fibrosis. Finally, to address potential translational barriers, we outlined future steps necessary to optimize the ceMED design for long-term efficacy and clinical utility.

Chirality-Dependent Anti-Inflammatory Effect of Glutathione after Spinal Cord Injury in an Animal Model.

Neuroinflammation forms a glial scar following a spinal cord injury (SCI). The injured axon cannot regenerate across the scar, suggesting permanent paraplegia. Molecular chirality can show an entirely different bio-function by means of chiral-specific interaction. In this study, we report that d-chiral glutathione (D-GSH) suppresses the inflammatory response after SCI and leads to axon regeneration of the injured spinal cord to a greater extent than l-chiral glutathione (L-GSH). After SCI, axon regrowth in D-GSH-treated rats was significantly increased compared with that in L-GSH-treated rats (*** p < 0.001). Secondary damage and motor function were significantly improved in D-GSH-treated rats compared with those outcomes in L-GSH-treated rats (** p < 0.01). Moreover, D-GSH significantly decreased pro-inflammatory cytokines and glial fibrillary acidic protein (GFAP) via inhibition of the mitogen-activated protein kinase (MAPK) signaling pathway compared with L-GSH (*** p < 0.001). In primary cultured macrophages, we found that D-GSH undergoes more intracellular interaction with activated macrophages than L-GSH (*** p < 0.001). These findings reveal a potential new regenerative function of chiral GSH in SCI and suggest that chiral GSH has therapeutic potential as a treatment of other diseases.

Light-controlled growth factors release on tetrapodal ZnO-incorporated 3D-printed hydrogels for developing smart wound scaffold.

Advanced wound scaffolds that integrate active substances to treat chronic wounds have gained significant recent attention. While wound scaffolds and advanced functionalities have previously been incorporated into one medical device, the wirelessly triggered release of active substances has remained the focus of many research endeavors. To combine multiple functions including light-triggered activation, anti-septic, angiogenic, and moisturizing properties, we have developed a 3D printed hydrogel patch encapsulating vascular endothelial growth factor (VEGF) decorated with photoactive and antibacterial tetrapodal zinc oxide (t-ZnO) microparticles. To achieve the smart release of VEGF, t-ZnO was modified by chemical treatment and activated through UV/visible light exposure. This process would also make the surface rough and improve protein adhesion. The elastic modulus and degradation behavior of the composite hydrogels, which must match the wound healing process, were adjusted by changing t-ZnO concentrations. The t-ZnO-laden composite hydrogels can be printed with any desired micropattern to potentially create a modular elution of various growth factors. The VEGF decorated t-ZnO-laden hydrogel patches showed low cytotoxicity and improved angiogenic properties while maintaining antibacterial functions in vitro. In vivo tests showed promising results for the printed wound patches, with less immunogenicity and enhanced wound healing.

Parenting Stress and Child Behavior Problems in Young Children with Autism Spectrum Disorder: Transactional Relations Across Time.

This longitudinal study examined the transactional relations between parenting stress and both internalizing and externalizing behavioral problems in young children with autism spectrum disorder (ASD) over 1.5 years using a cross-lagged panel analysis. Participants included 75 young children with ASD (Time 1; mean age = 25.68 months) and their parents. Parenting stress that was related to parent's perceptions on child characteristics was found to predict externalizing behavioral problems in young children with ASD across two time points. However, behavioral problems in young children with ASD did not predict parenting stress. These findings provide implications for early intervention and family services for young children with ASD and their families.

A 3D culture platform enables development of zinc-binding prodrugs for targeted proliferation of ß cells.

Advances in treating ß cell loss include islet replacement therapies or increasing cell proliferation rate in type 1 and type 2 diabetes, respectively. We propose developing multiple proliferation-inducing prodrugs that target high concentration of zinc ions in ß cells. Unfortunately, typical two-dimensional (2D) cell cultures do not mimic in vivo conditions, displaying a markedly lowered zinc content, while 3D culture systems are laborious and expensive. Therefore, we developed the Disque Platform (DP)-a high-fidelity culture system where stem cell-derived ß cells are reaggregated into thin, 3D discs within 2D 96-well plates. We validated the DP against standard 2D and 3D cultures and interrogated our zinc-activated prodrugs, which release their cargo upon zinc chelation-so preferentially in ß cells. Through developing a reliable screening platform that bridges the advantages of 2D and 3D culture systems, we identified an effective hit that exhibits 2.4-fold increase in ß cell proliferation compared to harmine.

Genetically Programmable Self-Regenerating Bacterial Hydrogels.

A notable challenge for the design of engineered living materials (ELMs) is programming a cellular system to assimilate resources from its surroundings and convert them into macroscopic materials with specific functions. Here, an ELM that uses Escherichia coli as its cellular chassis and engineered curli nanofibers as its extracellular matrix component is demonstrated. Cell-laden hydrogels are created by concentrating curli-producing cultures. The rheological properties of the living hydrogels are modulated by genetically encoded factors and processing steps. The hydrogels have the ability to grow and self-renew when placed under conditions that facilitate cell growth. Genetic programming enables the gels to be customized to interact with different tissues of the gastrointestinal tract selectively. This work lays a foundation for the application of ELMs with therapeutic functions and extended residence times in the gut.

Purification of lysozyme from chicken egg white using nanofiber membrane immobilized with Reactive Orange 4 dye.

Nanofiber membrane chromatography integrates liquid membrane chromatography and nanofiber filtration into a single-step purification process. Nanofiber membrane can be functionalised with affinity ligands for promoting binding specificity of membrane. Dye molecules are a good affinity ligand for nanofiber membrane due to their low cost and high binding affinity. In this study, a dye-affinity nanofiber membrane (P-Chitosan-Dye membrane) was prepared by using polyacrylonitrile nanofiber membrane modified with chitosan molecules and immobilized with dye molecules. Reactive Orange 4, commercially known as Procion Orange MX2R, was found to be the best dye ligand for membrane chromatography. The binding capacity of P-Chitosan-Dye membrane for lysozyme was investigated under different operating conditions in batch mode. Furthermore, desorption of lysozyme using the P-Chitosan-Dye membrane was evaluated systematically. The recovery percentage of lysozyme was found to be ~100%. The optimal conditions obtained from batch-mode study were adopted to develop a purification process to separate lysozyme from chicken egg white. The process was operated continuously using the membrane chromatography and the characteristic of the breakthrough curve was evaluated. At a lower flow rate (i.e., 0.1 mL/min), the total recovery of lysozyme and purification factor of lysozyme were 98.59% and 56.89 folds, respectively.

Magnetic imaging of a single ferromagnetic nanowire using diamond atomic sensors.

Recent advances in nanorobotic manipulation of ferromagnetic nanowires bring new avenues for applications in the biomedical area, such as targeted drug delivery, diagnostics or localized surgery. However, probing a single nanowire and monitoring its dynamics remains a challenge since it demands high precision sensing, high-resolution imaging, and stable operations in fluidic environments. Here, we report on a novel method of imaging and sensing magnetic fields from a single ferromagnetic nanowire with an atomic-scale sensor in diamond, i.e. diamond nitrogen-vacancy (NV) defect center. The distribution of static magnetic fields around a single Co nanowire is mapped out by spatially distributed NV centers and the obtained image is further compared with numerical simulation for quantitative analysis. DC field measurements such as continuous-wave ODMR and Ramsey sequence are used in the paper and sub Gauss level of field sensing is demonstrated. By imaging magnetic fields at a single nanowire level, this work represents an important step toward tracking and probing of ferromagnetic nanowires in biomedical applications.

Therapeutic luminal coating of the intestine.

The gastrointestinal tract is the site of most drug delivery and therapeutic interventions for the management and treatment of numerous diseases. However, selective access to its mucosa, especially in the small bowel, is challenging. Here we develop an orally administered gut-coating formulation that provides a transient coating of the bowel. Through a materials screening campaign, we identified a sucrose octasulfate aluminium complex and further engineered the pH-dependent material into a complex coacervate formulation linked via pH-independent electrostatic interaction, which allowed an effective transient physical coating on the gastrointestinal mucosa, independent of gastric acid exposure. We tested the therapeutic values of this technology in two settings. Oral administration of this gut-coating formulation modulated the nutrient contact with bowel mucosa, which lowered the glucose responses in rodent models indicating a potential therapeutic utility in diabetes. Furthermore, the formulation protected biological agents from gastric acid exposure and degradation, which enabled oral delivery to the small bowel mucosa.

A Growth-Accommodating Implant for Paediatric Applications.

Medical implants of fixed size cannot accommodate normal tissue growth in children, and often require eventual replacement or in some cases removal, leading to repeated interventions, increased complication rates and worse outcomes. Implants that can correct anatomic deformities and accommodate tissue growth remain an unmet need. Here, we report the design and use of a growth-accommodating device for paediatric applications that consists of a biodegradable core and a tubular braided sleeve, with inversely related sleeve length and diameter. The biodegradable core constrains the diameter of the sleeve, and gradual core degradation following implantation enables sleeve and overall device elongation in order to accommodate tissue growth. By using mathematical modeling and ex vivo experiments using harvested swine hearts, we demonstrate the predictability and tunability of the behavior of the device for disease- and patient-specific needs. We also used the rat tibia and the piglet heart valve as two models of tissue growth to demonstrate that polymer degradation enables device expansion and growth accommodation in vivo.

A light-reflecting balloon catheter for atraumatic tissue defect repair.

A congenital or iatrogenic tissue defect often requires closure by open surgery or metallic components that can erode tissue. Biodegradable, hydrophobic light-activated adhesives represent an attractive alternative to sutures, but lack a specifically designed minimally invasive delivery tool, which limits their clinical translation. We developed a multifunctional, catheter-based technology with no implantable rigid components that functions by unfolding an adhesive-loaded elastic patch and deploying a double-balloon design to stabilize and apply pressure to the patch against the tissue defect site. The device uses a fiber-optic system and reflective metallic coating to uniformly disperse ultraviolet light for adhesive activation. Using this device, we demonstrate closure on the distal side of a defect in porcine abdominal wall, stomach, and heart tissue ex vivo. The catheter was further evaluated as a potential tool for tissue closure in vivo in rat heart and abdomen and as a perventricular tool for closure of a challenging cardiac septal defect in a large animal (porcine) model. Patches attached to the heart and abdominal wall with the device showed similar inflammatory response as sutures, with 100% small animal survival, indicating safety. In the large animal model, a ventricular septal defect in a beating heart was reduced to <1.6 mm. This new therapeutic platform has utility in a range of clinical scenarios that warrant minimally invasive and atraumatic repair of hard-to-reach defects.

Bioinspired Nanoparticulate Medical Glues for Minimally Invasive Tissue Repair.

Delivery of tissue glues through small-bore needles or trocars is critical for sealing holes, affixing medical devices, or attaching tissues together during minimally invasive surgeries. Inspired by the granule-packaged glue delivery system of sandcastle worms, a nanoparticulate formulation of a viscous hydrophobic light-activated adhesive based on poly(glycerol sebacate)-acrylate is developed. Negatively charged alginate is used to stabilize the nanoparticulate surface to significantly reduce its viscosity and to maximize injectability through small-bore needles. The nanoparticulate glues can be concentrated to ≈30 w/v% dispersions in water that remain localized following injection. With the trigger of a positively charged polymer (e.g., protamine), the nanoparticulate glues can quickly assemble into a viscous glue that exhibits rheological, mechanical, and adhesive properties resembling the native poly(glycerol sebacate)-acrylate based glues. This platform should be useful to enable the delivery of viscous glues to augment or replace sutures and staples during minimally invasive procedures.

A blood-resistant surgical glue for minimally invasive repair of vessels and heart defects.

Currently, there are no clinically approved surgical glues that are nontoxic, bind strongly to tissue, and work well within wet and highly dynamic environments within the body. This is especially relevant to minimally invasive surgery that is increasingly performed to reduce postoperative complications, recovery times, and patient discomfort. We describe the engineering of a bioinspired elastic and biocompatible hydrophobic light-activated adhesive (HLAA) that achieves a strong level of adhesion to wet tissue and is not compromised by preexposure to blood. The HLAA provided an on-demand hemostatic seal, within seconds of light application, when applied to high-pressure large blood vessels and cardiac wall defects in pigs. HLAA-coated patches attached to the interventricular septum in a beating porcine heart and resisted supraphysiologic pressures by remaining attached for 24 hours, which is relevant to intracardiac interventions in humans. The HLAA could be used for many cardiovascular and surgical applications, with immediate application in repair of vascular defects and surgical hemostasis.

Chitosan-g-hematin: enzyme-mimicking polymeric catalyst for adhesive hydrogels.

Phenol derivative-containing adhesive hydrogels has been widely recognized as having potential for biomedical applications, but their conventional production methods, utilizing a moderate/strong base, alkaline buffers, the addition of oxidizing agents or the use of enzymes, require alternative approaches to improve their biocompatibility. In this study, we report a polymeric, enzyme-mimetic biocatalyst, hematin-grafted chitosan (chitosan-g-hem), which results in effective gelation without the use of alkaline buffers or enzymes. Furthermore, gelation occurs under mild physiological conditions. Chitosan-g-hem biocatalyst (0.01%, w/v) has excellent catalytic properties, forming chitosan-catechol hydrogels rapidly (within 5 min). In vivo adhesive force measurement demonstrated that the hydrogel formed by the chitosan-g-hem activity showed an increase in adhesion force (33.6 ± 5.9 kPa) compared with the same hydrogel formed by pH-induced catechol oxidation (20.6 ± 5.5 kPa) in mouse subcutaneous tissue. Using the chitosan-g-hem biocatalyst, other catechol-functionalized polymers (hyaluronic acid-catechol and poly(vinyl alcohol)-catechol) also formed hydrogels, indicating that chitosan-g-hem can be used as a general polymeric catalyst for preparing catechol-containing hydrogels.