Nitinol thin films functionalized with CAR-T cells for the treatment of solid tumours.

Micropatterned nickel titanium (commonly known as nitinol) thin films with complex designs, high structural resolution and excellent biocompatibility can be cheaply fabricated using magnetron sputtering. Here, we show that these benefits can be leveraged to fabricate micromesh implants that are loaded with tumour-specific human chimeric antigen receptor (CAR)-T cells for the treatment of solid tumours. In a mouse model of non-resectable ovarian cancer, the cell-loaded nitinol thin films spatially conformed to the implantation site, fostered the rapid expansion of T cells, delivered a high density of T cells directly to the tumour and significantly improved animal survival. We also show that self-expandable stents that were coated with T-cell-loaded films and implanted into subcutaneous tumours in mice improved the duration of stent patency by delaying tumour ingrowth. By providing direct access to tumours, CAR-T-cell-loaded micropatterned nitinol thin films can improve the effects of cell-based therapies.

An in vivo pilot study of a microporous thin film nitinol-covered stent to assess the effect of porosity and pore geometry on device interaction with the vessel wall.

Sputter-deposited thin film nitinol constructs with various micropatterns were fabricated to evaluate their effect on the vessel wall in vivo when used as a covering for commercially available stents. Thin film nitinol constructs were used to cover stents and deployed in non-diseased swine arteries. Swine were sacrificed after approximately four weeks and the thin film nitinol-covered stents were removed for histopathologic evaluation. Histopathology revealed differences in neointimal thickness that correlated with the thin film nitinol micropattern. Devices covered with thin film nitinol with a lateral × vertical length = 20 × 40 µm diamond pattern had minimal neointimal growth with well-organized cell architecture and little evidence of ongoing inflammation. Devices covered with thin film nitinol with smaller fenestrations exhibited a relatively thick neointimal layer with inflammation and larger fenestrations showed migration of inflammatory and smooth muscle cells through the micro fenestrations. This "proof-of-concept" study suggests that there may be an ideal thin film nitinol porosity and pore geometry to encourage endothelialization and incorporation of the device into the vessel wall. Future work will be needed to determine the optimal pore size and geometry to minimize neointimal proliferation and in-stent stenosis.

In Vitro Study of a Superhydrophilic Thin Film Nitinol Endograft that is Electrostatically Endothelialized in the Catheter Prior to the Endovascular Procedure.

Electrostatic endothelial cell seeding has evolved as an exceptional technique to improve the efficiency of cell seeding in terms of frequency of attached cells and the amount of cell adhesion for the treatment of vascular diseases. In the recent times, both untreated and superhydrophilic thin film nitinol (TFN) have exhibited strong prospects as substrates for creation of small-diameter endovascular grafts due to their hallmark properties of superelasticity, ultra low-profile character, and grown hemocompatible oxide layer with the presence of a uniform endothelial layer on the surface. The purpose of the current study is to understand the effects of endothelial cell seeding parameters (i.e., applied voltage, incubation time, substrate chemistry, and cell suspension solution) to investigate the cell seeding phenomenon and to improve the cell adhesion and growth on the TFN surface under electrostatic transplantation. Both parallel plate and cylindrical capacitor models were used along with the Taguchi Design of Experiment (DOE) methods to design in vitro test parameters. A novel in vitro system for a cylindrical capacitor model was created using a micro flow pump, micro incubation system, and silicone tubings. The augmented endothelialization on thin film nitinol was developed to determine the effect of cell seeding and deployed in a 6 Fr intravascular catheter setup. Cell viability along with morphology and proliferation of adhered cells were evaluated using fluorescent and scanning electron microscopy. Our results demonstrated that the maximum number of cells attached on STFN in the catheter was observed in 5 V with the 2 h exposure of in the cell culture medium (CCM) solution. The condition showed 5 V voltage with 0.68 × 10-6 µC electrostatic charge and 5.11 V·mm-1 electric field. Our findings have first demonstrated that the electrostatic endothelialization on the superhydrophilic thin film nitinol endograft within the catheter prior to the endovascular procedure could enhance the biocompatibility for low-profile endovascular applications.

Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy.

OBJECTIVE: To explore the safety and efficacy of external trigeminal nerve stimulation (eTNS) in patients with drug-resistant epilepsy (DRE) using a double-blind randomized controlled trial design, and to test the suitability of treatment and control parameters in preparation for a phase III multicenter clinical trial. METHODS: This is a double-blind randomized active-control trial in DRE. Fifty subjects with 2 or more partial onset seizures per month (complex partial or tonic-clonic) entered a 6-week baseline period, and then were evaluated at 6, 12, and 18 weeks during the acute treatment period. Subjects were randomized to treatment (eTNS 120 Hz) or control (eTNS 2 Hz) parameters. RESULTS: At entry, subjects were highly drug-resistant, averaging 8.7 seizures per month (treatment group) and 4.8 seizures per month (active controls). On average, subjects failed 3.35 antiepileptic drugs prior to enrollment, with an average duration of epilepsy of 21.5 years (treatment group) and 23.7 years (active control group), respectively. eTNS was well-tolerated. Side effects included anxiety (4%), headache (4%), and skin irritation (14%). The responder rate, defined as >50% reduction in seizure frequency, was 30.2% for the treatment group vs 21.1% for the active control group for the 18-week treatment period (not significant, p = 0.31, generalized estimating equation [GEE] model). The treatment group experienced a significant within-group improvement in responder rate over the 18-week treatment period (from 17.8% at 6 weeks to 40.5% at 18 weeks, p = 0.01, GEE). Subjects in the treatment group were more likely to respond than patients randomized to control (odds ratio 1.73, confidence interval 0.59-0.51). eTNS was associated with reductions in seizure frequency as measured by the response ratio (p = 0.04, analysis of variance [ANOVA]), and improvements in mood on the Beck Depression Inventory (p = 0.02, ANOVA). CONCLUSIONS: This study provides preliminary evidence that eTNS is safe and may be effective in subjects with DRE. Side effects were primarily limited to anxiety, headache, and skin irritation. These results will serve as a basis to inform and power a larger multicenter phase III clinical trial. CLASSIFICATION OF EVIDENCE: This phase II study provides Class II evidence that trigeminal nerve stimulation may be safe and effective in reducing seizures in people with DRE.

In vivo terahertz imaging of rat skin burns.

A reflective, pulsed terahertz (THz) imaging system was used to acquire high-resolution (d(10-90)/λ~1.925) images of deep, partial thickness burns in a live rat. The rat's abdomen was burned with a brass brand heated to ~220°C and pressed against the skin with contact pressure for ~10 sec. The burn injury was imaged beneath a Mylar window every 15 to 30 min for up to 7 h. Initial images display an increase in local water concentration of the burned skin as evidenced by a marked increase in THz reflectivity, and this likely correlates to the post-injury inflammatory response. After ~1 h the area of increased reflectivity consolidated to the region of skin that had direct contact with the brand. Additionally, a low reflecting ring of tissue could be observed surrounding the highly reflective burned tissue. We hypothesize that these regions of increased and decreased reflectivity correlate to the zones of coagulation and stasis that are the classic foundation of burn wound histopathology. While further investigations are necessary to confirm this hypothesis, if true, it likely represents the first in vivo THz images of these pathologic zones and may represent a significant step forward in clinical application of THz technology.

Terahertz imaging of biological tissues.

A reflective THz imaging system sensitive to small variations in water concentrations has been developed. Biological tissues such as skin, eyes and teeth were imaged to ascertain the systems response to tissue hydration. Difference in water concentrations translated to contrast in the THz images. Contrast was also seen in THz images of skin cancer and burns suggesting the potential diagnostic capability of THz imaging system in clinical settings. All specimens analyzed were freshly excised ex-vivo tissues. These encouraging preliminary results have motivated us to explore the in vivo potential of our imaging system.

THz Medical Imaging: in vivo Hydration Sensing.

The application of THz to medical imaging is experiencing a surge in both interest and federal funding. A brief overview of the field is provided along with promising and emerging applications and ongoing research. THz imaging phenomenology is discussed and tradeoffs are identified. A THz medical imaging system, operating at ~525 GHz center frequency with ~125 GHz of response normalized bandwidth is introduced and details regarding principles of operation are provided. Two promising medical applications of THz imaging are presented: skin burns and cornea. For burns, images of second degree, partial thickness burns were obtained in rat models in vivo over an 8 hour period. These images clearly show the formation and progression of edema in and around the burn wound area. For cornea, experimental data measuring the hydration of ex vivo porcine cornea under drying is presented demonstrating utility in ophthalmologic applications.

Bacterial biofilm disruption using laser generated shockwaves.

A system was built to test the efficacy of bacterial biofilm disruption using laser generated shockwaves. The system is based on a Q-switched, ND:YAG pulsed laser operating at a rep rate of 10 Hz with 1500 mJ pulses centered at 1064 nm. The laser pulses were used to create shockwave pulses in Al coated polycarbonate substrates and a resulting peak stress of greater than 50 MPa was measured. These stress pulses were coupled to bacteria grown to confluence on agar plates and cell death as a result of shockwave stress was assessed. The results show a 55% reduction in the number living bacteria between shocked and control samples. This type of biofilm disruption method could prove useful in the treatment of infected wounds where standard treatment methods such as debridement and topical antibiotics have proven to be ineffectual or harmful.

(Using) complementary and alternative medicine: the perceptions of palliative patients with cancer.

Use of complementary and alternative medicine (CAM) is increasingly common within Western societies, including Australia. This parallels calls for or claims of integration of CAM into mainstream medical practice, with oncology and palliative care specifically nominated as appropriate arenas for integration. However, there is an absence of studies examining patient perceptions of both CAM and CAM users. In this study, 28 adult patients with cancer close to death were interviewed regarding treatment decisions at the end of life, including decisions about CAM. Thematic analysis of transcribed interviews found consistent differences in talk around CAM between 12 users and 16 nonusers of CAM, primarily related to the perceived value of these treatments. Drawing upon a mind-body discourse that holds individuals responsible for their health, users valued CAM for the perceived benefit to physical or psychological well-being and compatibility with a holistic approach to health care, deemed to complement or augment conventional medicine. However, some were self-critical of their failure to continue with CAM, despite practical and financial difficulties experienced. Nonusers devalued CAM as unable to cure their disease (but did not similarly devalue conventional medicine), and negatively construed CAM users as desperate, or as challenging medical wisdom. Despite increased legitimation and medicalization of CAM, patients assess CAM differently to allopathic medicine, with different (positive and negative) assessments attributable to users. The misperception by many (nonusers) that CAM are intended to cure and available negative moral and social judgments centred around CAM use may deter patient uptake of CAM in areas where they have proven efficacy in symptom control.