Reversal of pancreatic desmoplasia by a tumour stroma-targeted nitric oxide nanogel overcomes TRAIL resistance in pancreatic tumours.

OBJECTIVE: Stromal barriers, such as the abundant desmoplastic stroma that is characteristic of pancreatic ductal adenocarcinoma (PDAC), can block the delivery and decrease the tumour-penetrating ability of therapeutics such as tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), which can selectively induce cancer cell apoptosis. This study aimed to develop a TRAIL-based nanotherapy that not only eliminated the extracellular matrix barrier to increase TRAIL delivery into tumours but also blocked antiapoptotic mechanisms to overcome TRAIL resistance in PDAC. DESIGN: Nitric oxide (NO) plays a role in preventing tissue desmoplasia and could thus be delivered to disrupt the stromal barrier and improve TRAIL delivery in PDAC. We applied an in vitro-in vivo combinatorial phage display technique to identify novel peptide ligands to target the desmoplastic stroma in both murine and human orthotopic PDAC. We then constructed a stroma-targeted nanogel modified with phage display-identified tumour stroma-targeting peptides to co-deliver NO and TRAIL to PDAC and examined the anticancer effect in three-dimensional spheroid cultures in vitro and in orthotopic PDAC models in vivo. RESULTS: The delivery of NO to the PDAC tumour stroma resulted in reprogramming of activated pancreatic stellate cells, alleviation of tumour desmoplasia and downregulation of antiapoptotic BCL-2 protein expression, thereby facilitating tumour penetration by TRAIL and substantially enhancing the antitumour efficacy of TRAIL therapy. CONCLUSION: The co-delivery of TRAIL and NO by a stroma-targeted nanogel that remodels the fibrotic tumour microenvironment and suppresses tumour growth has the potential to be translated into a safe and promising treatment for PDAC.

Development of hybrid scaffolds with biodegradable polymer composites and bioactive hydrogels for bone tissue engineering.

The development of treatments for critical-sized bone defects has been considered an important topic in the biomedical field because of the high demand for transplantable bone grafts. Following the concept of tissue engineering, implantation of biocompatible porous scaffolds carrying cells and regulating factors is the most efficient strategy to stimulate clinical bone regeneration. With the advancement in the development of 3D-printing techniques, scaffolds with highly controllable architectures can be fabricated to further improve healing efficacies. However, challenges such as the limited biocompatibility of resin materials and poor cell-carrying capacities still exist in the application of current scaffolds. In this study, a novel biodegradable polymer, poly (ethylene glycol)-co-poly (glycerol sebacate) acrylate (PEGSA), was synthesized and blended with hydroxyapatite (HAP) nanoparticles to produce osteoinductive and photocurable resins for 3D printing. The composites were optimized and applied in the fabrication of gyroid scaffolds with biomimetic characteristics and high permeability, followed by the combination of bioactive hydrogels containing Wharton's jelly-derived mesenchymal stem cells (WJMSC) to increase the efficiency of cell delivery. The promotion of osteogenesis from 3D-printed scaffolds was confirmed in-vivo while the hybrid scaffolds were proven to be great platforms for WJMSC culture and differentiation in-vitro. These results indicate that the proposed hybrid systems, combining osteoinductive 3D-printed scaffolds and cell-laden hydrogels, have great potential for bone tissue engineering and are expected to be applied in the treatment of bone defects based on active tissue regeneration.

Controllable-Swelling Microneedle-Assisted Ultrasensitive Paper Sensing Platforms for Personal Health Monitoring.

Microneedle (MN) patches, which allow the extraction of skin interstitial fluid (ISF) without a pain sensation, are powerful tools for minimally invasive biofluid sampling. Herein, an MN-assisted paper-based sensing platform that enables rapid and painless biofluid analysis with ultrasensitive molecular recognition capacity is developed. First, a controllable-swelling MN patch is constructed through the engineering of a poly(ethylene glycol) diacrylate/methacrylated hyaluronic acid hydrogel; it combines rapid, sufficient extraction of ISF with excellent structural integrity. Notably, the analyte molecules in the needles can be recovered into a moist cellulose paper through spontaneous diffusion. More importantly, the paper can be functionalized with enzymatic colorimetric reagents or a plasmonic array, enabling a desired detection capacity-for example, the use of paper-based surface-enhanced Raman spectroscopy sensors leads to label-free, trace detection (sub-ppb level) of a diverse set of molecules (cefazolin, nicotine, paraquat, methylene blue). Finally, nicotine is selected as a model drug to evaluate the painless monitoring of three human volunteers. The changes in the nicotine levels can be tracked, with the levels varying significantly in response to the metabolism of drug in different volunteers. This as-designed minimally invasive sensing system should open up new opportunities for precision medicine, especially for personal healthcare monitoring.

The selection of photoinitiators for photopolymerization of biodegradable polymers and its application in digital light processing additive manufacturing.

Digital light processing additive manufacturing (DLP-AM) technology has received a lot of attention in the field of biomedical engineering due to its high precision and customizability. However, some photoinitiators, as one of the key components in DLP-AM, may present toxicity and limit the application of DLP-AM toward biomedical applications. In order to gain further insights into the correlation between biocompatibility and photoinitiators in photoresins, a study on the selection of photoinitiators used in DLP-AM is conducted. The light absorbance range and cytocompatibility of four photoinitiators, vitamin B2 combined with triethanolamine (B2/TEOA), diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (TPO), 2-dimethoxy-2-phenylacetophenone (DMPA), and 2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone (I2959), are characterized. Each photoinitiator is then combined with poly(glycerol sebacate) acrylate (PGSA) and poly(ε-caprolactone) diacrylate (PCLDA), to evaluate their miscibility and film formation ability through photopolymerization. The mechanical properties, in vitro and in vivo biocompatibility studies on bulk films are investigated. It is found that B2/TEOA and TPO exhibit a wider light absorbance range than I2959 and DMPA. PGSA films with B2/TEOA (PGSA-B2/TEOA) is capable of sustaining cell proliferation up to 10 days and showing low immune responses after 14 days post implantation, proving its biocompatibility. Although B2/TEOA requires longer photopolymerization time, the mechanical strength of PGSA-B2/TEOA is comparable to PGSA films with TPO and DMPA, and this combination is 3D-printable through DLP-AM at the rate of 100 s per layer. In summary, B2/TEOA is a promising photoinitiator for 3D printing.

Dual-functional antibiofilm polymer composite for biodegradable medical devices.

Urinary tract infections (UTI) represent one of the most common problem within the urological disorders, and it is mainly caused by biofilm formation which leads to bacterial infection. Anti-adhesion and antibacterial agents are two primary mechanisms to prevent biofilm formation; however, current strategies are insufficiently effective. In this study, we developed an effective antibiofilm biodegradable polymer with high biocompatibility. Here we embedded silver nanoparticles (AgNPs) in poly(glycerol sebacate) acrylate (PGSA) followed by superhydrophilic modification on the polymer surfaces. The modified surfaces were characterized using SEM, AFM and contact angle measurements. This anti-adhesive surface prevented the adhesion of E. coli and limited the biofilm coverage percentage to less than 3% in 24 h. In the in vitro degradation, the long-term antibiofilm performance was evaluated in Nowatzki-Stoodley artificial urine (NSAU). The surface modified AgNPs embedded PGSA (sPGSA-AgNPs) was able to effectively inhibit the formation of biofilm by reducing the biofilm coverage to less than 0.01%, and it also showed low cytotoxicity with human bladder carcinoma cell. With the effective antibiofilm, biocompatibility and biodegradability, it is possible to be applied in urological devices to ameliorate the situation of UTIs.

Design of photocurable, biodegradable scaffolds for liver lobule regeneration via digital light process-additive manufacturing.

The regeneration of damaged or lost tissue is considered to be a critical step toward realizing full organ regeneration in modern medicine. Although surgical techniques continue to advance, treatment for missing tissues in irregular wounds remains particularly difficult. With increasing interest in the application of additive manufacturing in tissue engineering, the fabrication of customized scaffolds for the regeneration of missing tissue via three-dimensional (3D) printing has become especially promising. Amongst the work on the regeneration of many important organs, liver regeneration is particularly interesting because liver diseases are increasingly prevalent in many countries around the world, resulting in a greater need for liver transplantation. The generation of hexagonal scaffolds for the regeneration of liver lobules is highly demanding, but their 3D structure has been proved difficult to reproduce by traditional fabrication methods. In this work, various hexagonal scaffolds are developed for liver lobule regeneration via 3D printing using novel biodegradable polymeric materials, including poly(glycerol sebacate) acrylate and poly(ethylene glycol) diacrylate. Through fine-tuning of printing parameters, a series of hexagonal scaffolds were designed and printed to mimic liver lobule units. The scaffolds were printed with various structures together with varying surface areas and 3D structures to enhance cell seeding density and diffusivity of the culture medium. Analysis of cell metabolic activities showed that the high-diffusion staircase (HDS) scaffold could support potential differences in cell proliferation rate. Furthermore, the HDS scaffolds composed of different copolymers were cultured with cells for up to 16 days to investigate the relationship between physical properties and hepatocyte proliferation. The results indicate that the combination of the high flexibility 3D printing with biodegradable, photocurable copolymers shows great promise for the regeneration of 3D liver lobules.

Development of biomimetic micro-patterned device incorporated with neurotrophic gradient and supportive Schwann cells for the applications in neural tissue engineering.

In these years, the artificial nerve guidance conduit (NGC) has been developed as an alternative way to repair peripheral nerve injury. Unlike autologous nerve graft, the artificial NGC without proper stimulating factors and guidance cues still cannot obtain satisfactory prognosis for clinical patients. In this study, a biodegradable polymer-based implantable device has been developed and characterized. By incorporating three stimulating factors: (1) micro-patterned surface that can directionally guide the axon as physical cue; (2) neurotrophic gradient membrane that can continually attract axon outgrowth from the proximal to distal stump as chemical cue; (3) Schwann cells (SCs) that can support the growth of neurite and form myelin sheath around axon as biological cue, we expect that this construct can be used as a promising NGC for peripheral nerve regeneration. The results showed that the micro-patterned surface with specific dimension of channels and chambers can be precisely fabricated by laser ablation. Attachment and directional extension of differentiated neural stem cells (NSCs) were observed in micro-channels. The gradient distribution of nerve growth factor 7S on gelatin membrane was successfully achieved. Significant improvement in neurite length and increase in neuronal gene expressions were also noticed in higher concentration region. When co-culturing with SCs, NSCs can differentiate toward neuronal cells with strong expression of mature neuronal markers: ßIII tubulin and microtubule-associated protein-2 (Map 2). Meanwhile, myelin basic protein was also observed, suggesting that SCs can provide biological support to neuronal cells in vitro. In the future, this advanced artificial NGC may be used as implantable prosthesis for the treatment of peripheral nerve injury with better functional recovery.

Fully biodegradable airway stents using amino alcohol-based poly(ester amide) elastomers.

Airway stents are often used to maintain patency of the tracheal and bronchial passages in patients suffering from central airway obstruction caused by malignant tumors, scarring, and injury. Like most conventional medical implants, they are designed to perform their functions for a limited period of time, after which surgical removal is often required. Two primary types of airway stents are in general use, metal mesh devices and elastomeric tubes; both are constructed using permanent materials, and must be removed when no longer needed, leading to potential complications. This paper describes the development of process technologies for bioresorbable prototype elastomeric airway stents that would dissolve completely after a predetermined period of time or by an enzymatic triggering mechanism. These airway stents are constructed from biodegradable elastomers with high mechanical strength, flexibility and optical transparency. This work combines microfabrication technology with bioresorbable polymers, with the ultimate goal of a fully biodegradable airway stent ultimately capable of improving patient safety and treatment outcomes.

Biodegradable microfluidic scaffolds for tissue engineering from amino alcohol-based poly(ester amide) elastomers.

Biodegradable polymers with high mechanical strength, flexibility and optical transparency, optimal degradation properties and biocompatibility are critical to the success of tissue engineered devices and drug delivery systems. Most biodegradable polymers suffer from a short half life due to rapid degradation upon implantation, exceedingly high stiffness, and limited ability to functionalize the surface with chemical moieties. This work describes the fabrication of microfluidic networks from poly(ester amide), poly(1,3-diamino-2-hydroxypropane-co-polyol sebacate) (APS), a recently developed biodegradable elastomeric poly(ester amide). Microfluidic scaffolds constructed from APS exhibit a much lower Young's Modulus and a significantly longer degradation half-life than those of previously reported systems. The device is fabricated using a modified replica-molding technique, which is rapid, inexpensive, reproducible, and scalable, making the approach ideal for both rapid prototyping and manufacturing of tissue engineering scaffolds.

Silicone migration from silicone-injected breasts: magnetic resonance images.

Injection of liquid silicone into the breast was performed illicitly in the 1950s to 1960s and was subsequently prohibited. Many complications arise from silicone injection, and liquid silicone migration is a complication that has not been widely reported. The authors present magnetic resonance images of a patient with liquid silicone migration from the breast to the upper chest and lower neck. Breast ultrasonographic and mammographic findings are also presented for correlation.