Naturally occurring internal bleeding, such as in stomach ulcers, and complications following interventions, such as polyp resection post-colonoscopy, may result in delayed (5-7 days) post-operative adverse events-such as bleeding, intestinal wall perforation, and leakage. Current solutions for controlling intra- and post-procedural complications are limited in effectiveness. Hemostatic powders only provide a temporary solution due to their short-term adhesion to GI mucosal tissues (less than 48 h). In this study, a sprayable adhesive hydrogel for facile application and sustained adhesion to GI lesions is developed using clinically available endoscopes. Upon spraying, the biomaterial (based on polyethyleneimine-modified Pluronic micelles precursor and oxidized dextran) instantly gels upon contact with the tissue, forming an adhesive shield. In vitro and in vivo studies in guinea pigs, rabbits, and pig models confirm the safety and efficacy of this biomaterial in colonic and acidic stomach lesions. The authors' findings highlight that this family of hydrogels ensures prolonged tissue protection (3-7 days), facilitates wound healing, and minimizes the risk of delayed complications. Overall, this technology offers a readily adoptable approach for gastrointestinal wound management.

Safe and accurate in situ delivery of biocompatible materials is a fundamental requirement for many biomedical applications. These include sustained and local drug release, implantation of acellular biocompatible scaffolds, and transplantation of cells and engineered tissues for functional restoration of damaged tissues and organs. The common practice today includes highly invasive operations with major risks of surgical complications including adjacent tissue damage, infections, and long healing periods. In this work, a novel non-invasive delivery method is presented for scaffold, cells, and drug delivery deep into the body to target inner tissues. This technology is based on acousto-sensitive materials which are polymerized by ultrasound induction through an external transducer in a rapid and local fashion without additional photoinitiators or precursors. The applicability of this technology is demonstrated for viable and functional cell delivery, for drug delivery with sustained release profiles, and for 3D printing. Moreover, the mechanical properties of the delivered scaffold can be tuned to the desired target tissue as well as controlling the drug release profile. This promising technology may shift the paradigm for local and non-invasive material delivery approach in many clinical applications as well as a new printing method - "acousto-printing" for 3D printing and in situ bioprinting. A promising ultrasound-based method has been developed to induce non-invasive safe and localized polymerization deep in the patient body for multiple biomedical applications. These include in situ cellular bioprinting, sustained and local drug release, implantation of acellular biocompatible scaffolds, and the delivery of living cells for functional restoration of damaged tissues and organs. image

Glioblastoma (GBM) is a universally lethal form of brain cancer. The success of novel treatments is hindered by the blood–brain barrier (BBB), which prevents most drugs from penetrating GBM tumors. Sorafenib (SFB), a proapoptotic multikinase inhibitor, has been investigated for the treatment of GBM; however, survival benefit among patients has not improved. Recently, an indocyanine‐stabilized nanoparticulate form of SFB (SFB NPs) with improved tumor accumulation was developed in comparison to SFB alone. Herein, the benefit of SFB NPs and focused ultrasound (FUS)‐mediated BBB disruption is assessed to enable noninvasive, safe, and reversible BBB permeation for enhanced SFB NPs brain accumulation. Treatment of SFB NPs and FUS yields lower IC50 values (2.7 and 29 μm in 2D and 3D U87 cell models vs 7.5 and 37.1 μm for SFB NPs alone). SFB NPs and FUS with microbubbles improve SFB NPs uptake by U87 cells compared to SFB NPs alone (46% increase; p = 0.0123). In vivo, FUS enhances SFB NPs brain accumulation by 2.5‐fold compared to the contralateral hemisphere, and 3.6‐fold compared to unsonicated brains. In conclusion, SFB NPs are a promising agent for GBM treatment and its therapeutic capacity can be potentially enhanced when combined with FUS‐mediated BBB disruption.

Real-time monitoring of immune state and response to therapy can provide a means to stratify patients and increase the number of responders who will benefit from approved and emerging immunotherapies. The accessibility of immune cells in the skin provides an opportunity for local immune modulation as well as for noninvasive sampling of disease biomarkers in the skin interstitial fluid (ISF). Here, a monitoring strategy for melanoma immunotherapy is investigated by longitudinal sampling of biomarkers in the skin ISF using Hyaluronic acid (HA)-based microneedles (MNs). Focused ultrasound ablation and delivery of nanoparticulate stimulator of interferon genes agonist are used as model immunotherapies. It is shown that this combination therapy induces potent inflammatory responses in a melanoma mouse model, promoting tumor elimination and immune memory formation. Indeed, quantifying soluble, protein-based biomarkers following therapy using conventional immunoassay reveals a pronounced proinflammatory program in the tumor. However, conventional assays fail to detect the low concentration of biomarkers in plasma and in MN-sampled ISF. It is shown that ultrasensitive single molecule arrays (Simoa) effectively detected proinflammatory biomarkers that are upregulated in response to the therapy in MN-sampled ISF, in plasma, and in tumors, supporting the feasibility of monitoring melanoma immunotherapy using MNs.

Thermal monitoring during focused ultrasound (FUS) transcranial procedures is mandatory and commonly performed by MRI. Transcranial ultrasonic thermal monitoring is an attractive alternative. Furthermore, using the therapeutic FUS transducer itself for this task is highly desirable. Nonetheless, such application is challenged by massive skull-induced signal attenuation and aberrations. This study examined the feasibility of implementing the Golay-coded excitations (CoE) for temperature monitoring in bovine brain samples in the range of 35 °C-43 °C (hyperthermia). Feasibility was assessed using computer simulations, water-based phantoms, and ex vivo bovine brain white-matter samples. The samples were gradually heated to about 45 °C and sonicated during cool down with a 1-MHz therapeutic FUS implementing Golay CoE. Initially, a calibration curve correlating the normalized time-of-flight (TOF) changes and the temperature was generated. Next, a bovine bone was positioned between the FUS and the brain samples, and the scanning process was repeated for different fresh samples. The calibration curve was then used as a mean for estimating the temperature, which was compared to thermocouple measurements. The simulations demonstrated a substantial improvement in signal-to-noise ratio (SNR) and suggested that the implementation of 4-bit sequences is advantageous. The experimental measurements with bone demonstrated good temperature estimation with an average absolute error for the water phantoms and brains of 1.46 °C ± 1.22 °C and 1.23 °C ± 0.99 °C, respectively. In conclusion, a novel noninvasive method utilizing the Golay CoE for ultrasonic thermal monitoring using a therapeutic FUS transducer is introduced. This method can lead to the development of an acoustic tool for brain thermal monitoring.

Multifunctional nanocarriers have attracted considerable interest in improving cancer treatment outcomes. Poly(lactide-co-glycolide) (PLGA) nanospheres encapsulating copper oxide nanoparticles (CuO-NPs) are characterized by antitumor activity and exhibit dual-modal contrast-enhancing capabilities. An in vitro evaluation demonstrates that this delivery system allows controlled and sustained release of CuO-NPs. To achieve localized release on demand, an external stimulation by laser irradiation is suggested. Furthermore, to enable simultaneous complementary photothermal therapy, polydopamine (PDA) coating for augmented laser absorption is proposed. To this aim, two formulations of CuO-NPs loaded nanospheres are prepared from PLGA polymers RG-504 H (H-PLGA) and RG-502 H (L-PLGA) as scaffolds for surface modification through in situ polymerization of dopamine and then PEGylation. The obtained CuO-NPs-based multifunctional nanocarriers are characterized, and photothermal effects are examined as a function of wavelength and time. The results show that 808 nm laser irradiation of the coated nanospheres yields maximal temperature elevation (T = 41°C) and stimulates copper release at a much faster rate compared to non-irradiated formulations. Laser-triggered CuO-NP release is mainly depended on the PLGA core, resulting in faster release with L-PLGA, which also yielded potent anti-tumor efficacy in head and neck cancer cell line (Cal-33). In conclusion, the suggested multifunctional nanoplatform offers the integrated benefits of diagnostic imaging and laser-induced drug release combined with thermal therapy.

Objectives Brain treatments using focused ultrasound (FUS) offer a new range of noninvasive transcranial therapies. The acoustic energy deposition during these procedures may induce a temperature elevation in the tissue; therefore, noninvasive thermal monitoring is essential. Magnetic resonance imaging is the current adopted monitoring modality, but its high operational costs and limited availability may hinder the accessibility to FUS treatments. Aiming at the development of a thermometric ultrasound (US) method for the brain, the specific objective of this investigation was to study the acoustic thermal response of the speed of sound (SOS) and attenuation coefficient (AC) of different brain tissues: namely white matter (WM) and cortical matter. Methods Sixteen ex vivo bovine brain samples were investigated. These included 7 WM and 9 cortical matter samples. The samples were gradually heated to about 45°C and then repeatedly scanned while cooling using a computerized US system in the through‐transmission mode. The temperature was simultaneously registered with thermocouples. From the scans, the normalized SOS and AC for both tissues were calculated. Results The results demonstrated a characteristic cooldown temporal behavior for the normalized AC and SOS curves, which were related to the temperature. The SOS curves enabled clear differentiation between the tissue types but depicted more scattered trajectories for the WM tissue. As for the AC curves, the WM depicted a linear behavior in relation to the temperature. However, both tissue types had rather similar temperature patterns. Conclusions These findings may contribute to the development of a US temperature‐monitoring method during FUS procedures.