Transformative Anatomically accurate Microvascular flow Phantoms for Ultrasound therapy research (TAMP-US)

Lead Research Organisation: University of Strathclyde
Department Name: Biomedical Engineering

Abstract

Using real tissue data we will develop, commission and demonstrate Transformative Anatomically accurate Microvascular flow Phantoms for Ultrasound therapy research (TAMP-US). Using commercially available tools, so that researchers in other labs will be able to replicate our methods for their own needs, we will recreate microvessel networks in hydrogel materials that have similar acoustic and mechanical properties to tissue. These materials are also optically transparent so that we will be able to image our systems using a microscope, and biologically compatible such that we will be able to incorporate cell culture into our systems. Our aim is to create a fully controllable lab-based system suitable for systematic investigation of ultrasound therapy without the need for animal testing.
Targeted delivery of drugs is attractive across medicine. It improves patient experience by reducing damage to healthy cells and side effects. It can also lead to higher local drug uptake and better patient outcomes. It is particularly suited to the delivery of chemotherapy in the treatment of cancer. Despite this there are not many practical methods for targeting drug delivery that can be used safely and repeatedly. Ultrasound mediated targeted drug delivery (UmTDD) uses ultrasound to image tissues and identify the region to be treated, and then to excite tiny bubbles of gas that have been delivered to the patient along with the drug they are receiving. These microbubbles are used routinely to increase the brightness of ultrasound images and are naturally eliminated from the body within 30 minutes, but can also act to stimulate tissues and cells to increase their uptake of drugs. UmTDD has shown huge promise but an incomplete understanding of how the microbubbles force greater drug uptake has limited its development as a clinical treatment. One issue is that there are currently no lab-based systems that allow thorough and controlled investigation of UmTDD.
Using recent advances in 3D printing that have allowed biologically compatible dyes to be used as photoblockers to create complex 3D channels in soft materials and using microCT to gather real microvessel images we use real tissue data to develop an acoustically compatible and fully controlled system to investigate ultrasound driven MB - microvessel interactions. The platform will allow identification of the factors that define how effective UmTDD will be in a certain circumstance to be identified for the first time. Our systems will incorporate cells to allow the effects to be investigated in the lab and these systems will be available for other researchers to replicate in their own research.

Technical Summary

Targeted delivery of drugs is attractive across medicine. It reduces systemic toxicity and side effects, leads to higher local drug uptake and better patient outcomes. It is particularly relevant to chemotherapy in cancer. With few viable targeting approaches available, ultrasound mediated targeted drug delivery (UmTDD), where ultrasound radially oscillates microbubbles (MB) to generate bioeffects in cells and tissues capable of driving localised delivery of drugs, has shown significant promise.
The physical effects of UmTDD include shock wave formation, MB jetting, sonoporation, microstreaming, and localised strains dependent on the extent of MB expansion. Cellular responses include stimuli for mechano-receptors, up-regulation of membrane trafficking (e.g. endocytosis), puncture of the plasma membrane and disruption of cellular tight junctions, but the conditions required for each are not yet fully understood.
We propose novel lab-based microvascular flow phantoms to equip researchers with the tools and methodology to undertake systematic investigation of UmTDD for the first time. We will accurately replicate real micro-vessel architectures in tissue-mimicking materials to produce Transformative Anatomically accurate Microvascular flow Phantoms for Ultrasound therapy research (TAMP-US). TAMP-US will allow detailed investigation of the multiple and complex variables involved in UmTDD. Our ultimate aim is to demonstrate functionalisation of these systems with cells, such that any cell line of interest may be investigated. This ambitious project has the potential to bridge the problematic gulf between in vitro investigation and in vivo or clinical realisation in the context of ultrasound therapy research. Delivery of our aims will significantly advance the field, while complete realisation will deliver a truly transformative tool capable of supporting ground-breaking research in the drive to develop UmTDD for clinical application.

Planned Impact

This proposal concerns the development of a novel, anatomically accurate, acoustically and biologically compatible experimental platform to investigate ultrasound mediated targeted drug delivery (UmTDD). Our outcomes will allow lab-based investigation of UmTDD and reveal new knowledge to support clinical translation. Our impacts are both wide reaching and significant and will have a wide sphere of influence, it is anticipated that impact will be directed on a global scale in direct response to the BBSRC aim to push back the frontiers of biology to deliver a healthy, prosperous and sustainable future. The impact of this project is focussed across four main themes: society, knowledge, people and the economy.
Realisation of UmTDD as a clinically viable therapy will revolutionise cancer treatment. Non-invasive and safe targeting of drugs or genes can reduce systemic toxicity and side effects, lead to higher local drug uptake and ultimately deliver better patient outcomes. The provision of effective research tools will underpin research that has the potential to directly impact patients, their families and their carers (society).
We expect strong academic interest in our work, thus our impacts will directly benefit the active community of researchers working on UmTDD, those working on other therapeutic applications of ultrasound and in ultrasound imaging, particularly those using ultrasound contrast agent microbubbles. Benefit will extend to academics who require low cost, easily accessible and well characterised experimental systems to rapidly demonstrate and pilot UmTDD or other TDD protocols and research. The ability to conduct research more easily using our systems will reduce the need for animals in research. Reliable lab-based systems can provide critical data, potentially with greater sensitivity to subtle variables otherwise unrecoverable in vivo, ahead of pre-clinical translation (knowledge).
The clinical impact of our work will include clinical researchers investigating new drug and gene therapies and clinicians seeking novel treatments to improve patient outcomes. This in turn will lead to benefits to clinical accreditation bodies and those involved in making funding decisions in the NHS for example. UmTDD aims to improve treatment efficacy and patient outcomes, reducing treatment costs and delivery efficiency savings to healthcare providers (knowledge, economy, society).
Of course we anticipate that our work will have significant economic benefits and we anticipate that the outcomes of this work will support new funding applications that can capitalise on this. New technologies, in the form of experimental platforms and outcomes that promote clinical translation of UmTDD, will attract technology companies with an interest in commercialising our outcomes, clinical ultrasound imaging system developers, producers of ultrasound contrast-agent microbubbles and laboratory equipment suppliers. We will disseminate through our Clinical seminar, journal and Conference publications and engage with commercial interest at the trade shows encompassed in the latter. Wherever this is successful, our outcomes have the capability to contribute directly to the UK economy through the generation of new intellectual property (knowledge, economy, society).
Finally our research will directly benefit the research team providing opportunities for new skills and expertise development. The PDRA will be inducted to a vibrant research community with multiple opportunities for learning and technology and skills transfer. There will be mutual benefit for our research team as we seek to share our outcomes to our networks, for example Centre de Recerca Matemàtica, Barcelona for technology transfer. Through our dissemination and public engagement activities we will directly impact the general public, spreading knowledge of ultrasound and its underlying physics and its wider and yet unrealised potential as a tool in therapy (people, knowledge).

Publications

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Domingo-Roca R (2022) Non-destructive Analysis of the Mechanical Properties of 3D-Printed Materials. in Journal of nondestructive evaluation

 
Description We have demonstrated that the backscattered ultrasound signal arising from microbubbles in suspension (where we intend that our experiments will mimic what would occur when administered in vivo) can be influenced by flow rate, vessel diameter and acoustic excitation pressure. The last variable, acoustic pressure, was already widely documented within the research community, while vessel diameter was also accepted as an influencing factor but to our knowledge the nature of this factor had not been thoroughly described. We believe this is new information that could have diagnostic value.
Exploitation Route data arising is forming the basis of a new funding proposal in preparation.
Sectors Healthcare

 
Title Optimised protocols for 3D printing of UV curable hydrogels to achieve high resolution microchannels 
Description UV cured polymers can be subject to over cure as the object is built up layer by layer with a curing step to lay down each. As a result of over curing features can be altered and in particular it can become impossible to achieve the high resolution, small length scale features as required in this work to replicate microvessels. Through thorough systematic characterisation we have build in accommodation of over cure such that influence over feature dimensions is limited but crucially also predictable. 
Type Of Material Improvements to research infrastructure 
Year Produced 2021 
Provided To Others? No  
Impact We will shortly submit our findings for review as part of a peer reviewed publication 
 
Title Data for: "3D-Printing of non-cytotoxic high-resolution microchannels in bisphenol-A ethoxylate dimethacrylate tissue-mimicking materials" 
Description Set of data used to write the Journal paper '3D-Printing of non-cytotoxic high-resolution microchannels in bisphenol-A ethoxylate dimethacrylate tissue-mimicking materials', to be submitted to the Journal 3D Printing and Additive Manufacturing. 
Type Of Material Database/Collection of data 
Year Produced 2022 
Provided To Others? Yes  
Impact not known 
URL https://pureportal.strath.ac.uk/en/datasets/data-for-3d-printing-of-non-cytotoxic-high-resolution-mi...
 
Title Data for: "Non-destructive analysis of the mechanical properties of 3D-printed materials" 
Description This dataset contains data obtained from 3D laser Doppler vibrometry, put together in Excel sheets to do the relevant maths. The data is provided for three different materials. The data obtained is plotted using OriginPro, which is also provided in this data set (strain-stress plots). OriginPro is required to open one of the provided files and the rest can be accesses using Excel. 
Type Of Material Database/Collection of data 
Year Produced 2022 
Provided To Others? Yes  
Impact not known 
URL https://pureportal.strath.ac.uk/en/datasets/data-for-non-destructive-analysis-of-the-mechanical-prop...
 
Title Data for: "Ultrasonic activation of microbubbles in 3D-printed microchannels: experimental demonstration of wall influence in microbubble acoustic backscattering in physiologically-relevant environments" 
Description Dataset for the journal paper entitled 'Ultrasonic activation of microbubbles in 3D-printed microchannels: experimental demonstration of wall influence in microbubble acoustic backscattering in physiologically-relevant environments', to be submitted in the journal IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency. 
Type Of Material Database/Collection of data 
Year Produced 2022 
Provided To Others? Yes  
Impact not known 
URL https://pureportal.strath.ac.uk/en/datasets/data-for-ultrasonic-activation-of-microbubbles-in-3d-pri...
 
Description 3D-Printed platform enables study of physiologically-relevant conditions in microbubble-wall interactions 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Research presentation given as part of Scottish Ultrasound annual scientific meeting sponsored by COMULIS
Year(s) Of Engagement Activity 2021
URL https://www.comulis.eu/schedule/2021/8/27/scottish-ultrasound-annual-symposium-and-training-school
 
Description 3D-printed high-resolution microchannels for contrast enhanced ultrasound research 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Research presentation given at IEEE International Ultrasonics Symposium
Year(s) Of Engagement Activity 2021
URL https://2021.ieee-ius.org/
 
Description 3D-printed high-resolution phantom microvasculature enables measurement of microbubble acoustic backscattering 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Research presentation given as part of international conference on ultrasound, presented within medical imaging session
Year(s) Of Engagement Activity 2021
URL https://2021.ieee-laus.org/
 
Description 3D-printed tissue-mimicking and cell compatible hybrid hydrogels for ultrasound and microbubble-mediated drug delivery research 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Research presentation given as part of SINAPSE annual scientific conference
Year(s) Of Engagement Activity 2021
URL http://www.sinapse.ac.uk/
 
Description Measurement of microbubble backscattering signals in 3D-printed, physiologically-relevant platforms 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact Research presentation given at the annual SINAPSE (Scottish Imaging Network: A platform for Scientific Excellence) Scientific Conference
Year(s) Of Engagement Activity 2021
URL http://www.sinapse.ac.uk/
 
Description Physiologically-relevant 3D-printed microchannels to study microbubble ultrasound backscatter 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact research presentation given at the International Symposium on Therapeutic Ultrasound
Year(s) Of Engagement Activity 2021
URL https://istu2021.org/