Sound speed and attenuation of human pancreas and pancreatic tumors and their influence on focused ultrasound thermal and mechanical therapies

Background There is increasing interest in using ultrasound for thermal ablation, histotripsy, and thermal or cavitational enhancement of drug delivery for the treatment of pancreatic cancer. Ultrasonic and thermal modelling conducted as part of the treatment planning process requires acoustic property values for all constituent tissues, but the literature contains no data for the human pancreas. Purpose This study presents the first acoustic property measurements of human pancreatic samples and provides examples of how these properties impact a broad range of ultrasound therapies. Methods Data were collected on human pancreatic tissue samples at physiological temperature from 23 consented patients in cooperation with a hospital pathology laboratory. Propagation of ultrasound over the 2.1–4.5 MHz frequency range through samples of various thicknesses and pathologies was measured using a set of custom-built ultrasonic calipers, with the data processed to estimate sound speed and attenuation. The results were used in acoustic and thermal simulations to illustrate the impacts on extracorporeal ultrasound therapies for mild hyperthermia, thermal ablation, and histotripsy implemented with a CE-marked clinical system operating at 0.96 MHz. Results The mean sound speed and attenuation coefficient values for human samples were well below the range of values in the literature for non-human pancreata, while the human attenuation power law exponents were substantially higher. The simulated impacts on ultrasound mediated therapies for the pancreas indicated that when using the human data instead of the literature average, there was a 30% reduction in median temperature elevation in the treatment volume for mild hyperthermia and 43% smaller volume within a 60°C contour for thermal ablation, all driven by attenuation. By comparison, impacts on boiling and intrinsic threshold histotripsy were minor, with peak pressures changing by less than 15% (positive) and 1% (negative) as a consequence of the counteracting effects of attenuation and sound speed. Conclusion This study provides the most complete set of speed of sound and attenuation data available for the human pancreas, and it reiterates the importance of acoustic material properties in the planning and conduct of ultrasound-mediated procedures, particularly thermal therapies

Sum-of-harmonics method for improved narrowband and broadband signal quantification during passive monitoring of ultrasound therapies

Passive Acoustic Mapping (PAM) enables real-time monitoring of ultrasound therapies by beamforming acoustic emissions emanating from the ultrasound focus. Reconstruction of the narrowband or broadband acoustic emissions component enables mapping of different physical phenomena, with narrowband emissions arising from non-linear propagation and scattering, non-inertial cavitation or tissue boiling, and broadband (generally, of significantly lower amplitude) indicating inertial cavitation. Currently, accurate classification of the received signals based on pre- defined frequency-domain comb filters cannot be guaranteed because varying levels of leakage occur as a function of signal amplitude and the choice of windowing function. This work presents a time-domain parametric model aimed at enabling accurate estimation of the amplitude of time-varying narrowband components in the presence of broadband signals. Conversely, the method makes it possible to recover a weak broadband signal in the presence of a dominant harmonic or other narrowband component. Compared to conventional comb filtering, the proposed sum-of- harmonics method enables PAM of cavitation sources that better reflect their physical location and extent

Clinical trial protocol for TARDOX: a phase I study to investigate the feasibility of targeted release of lyso-thermosensitive liposomal doxorubicin (ThermoDox®) using focused ultrasound in patients with liver tumours.

Background TARDOX is a Phase I single center study of ultrasound triggered targeted drug delivery in adult oncology patients with incurable liver tumours. This proof of concept study is designed to demonstrate the safety and feasibility of targeted drug release and enhanced delivery of doxorubicin from thermally sensitive liposomes (ThermoDox®) triggered by mild hyperthermia induced by focused ultrasound in liver tumours. A key feature of the study is the direct quantification of the doxorubicin concentration before and after ultrasound exposure from tumour biopsies, using high performance liquid chromatography (HPLC). Methods/Design The study is conducted in two parts: Part 1 includes minimally-invasive thermometry via a thermistor or thermocouple implanted through the biopsy co-axial needle core, to confirm ultrasound-mediated hyperthermia, whilst Part 2 is carried out without invasive thermometry, to more closely mimic the ultimately intended clinical implementation of the technique. Whilst under a general anaesthetic, adult patients with incurable confirmed hepatic primary or secondary (metastatic) tumours receive a single cycle of ThermoDox®, immediately followed by ultrasound-mediated hyperthermia in a single target liver tumour. For each patient in Part 1, the HPLC-derived total doxorubicin concentration in the ultrasound-treated tumour is directly compared to the concentration before ultrasound exposure in that same tumour. For each patient in Part 2, as the tumour biopsy taken before ultrasound exposure is not available, the mean of those Part 1 tumour concentrations is used as the comparator. Success of the study requires at least a two-fold increase in the total intratumoural doxorubicin concentration, or final concentrations over 10 μg/g, in at least 50% of all patients receiving the drug, where tissue samples are evaluable by HPLC. Secondary outcome measures evaluate safety and feasibility of the intervention. Radiological response in the target tumour and control liver tumours are analysed as a tertiary outcome measure, in addition to plasma pharmacokinetics, fluorescence microscopy and immunohistochemistry of the biopsy samples. Discussion If this early phase study can demonstrate that ultrasound-mediated hyperthermia can effectively enhance the delivery and penetration of chemotherapy agents intratumorally, it could enable application of the technique to enhance therapeutic outcomes across a broad range of drug classes to treat solid tumours

Cavitation-mediated transcutaneous delivery of protein and nucleotide-based antigen for rapid high-level immune responses

Alternatives are needed to remove the pain, injury, cross-infection, and hazardous waste associated with needle and syringe (N+S)-based vaccination. Reported here is the use of novel ultrasound-responsive protein cavitation nuclei (pCaN), formed using the model antigen bovine serum albumin (BSA), to achieve effective transcutaneous delivery. Upon exposure to ultrasound (US), these pCaN instigate cavitation events which propel themselves and co-located DNA vectors into the skin. US parameters as well as pCaN and DNA concentration are refined to achieve optimal expression of encoded luciferase transgene. Twenty-four hours post-treatment, luciferase expression in the skin, by IVIS imaging, was 1.67 × 106 ±941943, photons per sec for N+S intradermal injection and 1.49 × 106 ±261832 for cavitation-mediated delivery (p>0.05). Hence, there is no significant difference in luciferase level achieved, but improved homogeneity and reproducibility of expression are evident in mice treated using US-mediated cavitation. Despite this equivalence in luciferase levels, a >5× higher level (p<0.02) of anti-luciferase antibodies is achieved when cavitation is used versus N+S injection. Antibody levels against BSA, resulting from the use of BSA pCaN, are equivalent for the two groups. PCaN can be formed from a range of antigenic proteins and DNA can encode a range of antigenic proteins, so this approach has wide-ranging implications for needle-free vaccination

Effect of normothermic machine perfusion on outcomes after steatotic liver transplantation: a first assessment

departmental bulletin pape

Assessing metabolism and function of normothermically perfused ex vivo livers by multinuclear MR imaging and spectroscopy

Synopsis Liver transplantation is the only cure for end-stage liver disease. Unfortunately, 20% of patients die waiting for a donor. New techniques for preserving transplant livers, such as normothermic machine perfusion (NMP), provide an opportunity to utilise ‘marginal’ (currently discarded) donated livers if their viability can be assessed accurately. We present initial results from a CE-marked NMP system that we adapted for use in an MRI scanner. We demonstrate the power of NMP-MRI to assess structure and metabolism in a freshly donated pig liver, dynamically over a 10-hour period. Our protocol includes H imaging, P spectroscopy, and hyperpolarised C spectroscopy.This work was funded by a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society (Grant No. 098436/Z/12/Z) and by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC)

Ultrasound‐Triggered Gelation for Restoring Biomechanical Properties of Degenerated Functional Spinal Units

Lower back pain is closely associated with intervertebral disc (IVD) degeneration and is a leading cause of global disability. Existing treatment options are unable to provide suitable long‐term outcomes, and emerging strategies employing injectable biomaterials are hindered by factors including limited native tissue integration and depth‐ or time‐constrained gelation mechanisms. To overcome these issues, the present research evaluates a new concept employing ultrasound to remotely trigger in situ implant formation. The concept centers around an implant precursor biomaterial consisting of an anionic polysaccharide solution containing thermally sensitive liposomes loaded with ionic crosslinkers. Ultrasound‐mediated heating to 4–5 °C above normal body temperature triggers liposomal release of the crosslinking species, thereby initiating hydrogel formation. Optimization studies define the implant precursor material (1.5% wt/v sodium alginate seeded with calcium‐loaded liposomes (10–15 mm calcium chloride) and 6% wt/v glass microspheres) and the ultrasound parameters (0.95 MHz, 1.6 MPa amplitude, 87% duty cycle). Proof‐of‐concept experiments in degenerated ex vivo bovine IVDs indicate partial restoration of biomechanical function, with the implanted biomaterial well‐integrated into the disc tissue and without material herniation. These results offer promise for treating intervertebral disc degeneration, with continued refinement of biomaterials and protocols being essential for achieving robust in‐disc efficacy