A versatile platform for the non-invasive evaluation of biomaterials, cell containing structures and tissues

The Need: The Market

Advances in the field of tissue engineering and regenerative medicine promise to provide new approaches to treating disease and to repair damaged tissue.[1] In its essence, this approach consists of the combination of bio-compatible materials such as hydrogels, together with cells. Such combinations can also be termed as cellular constructs. These constructs are being used for the development of functional artificial tissues or as an alternative approach to pharmaceutical testing. With the advent of 3D bioprinting, these constructs can be created in an organised fashion to form more complex and representative models to native tissues or can have the prospect of being implantable into human beings. [1, 2]

The global tissue engineering market accounted for USD 9.9 Billion in 2019 and is expected to increase from 2020 to 2027 at CAGR rate of 14.7 %. [3] These numbers embrace all the areas of tissue engineering, including bone, [4] cartilage, [5] and skin regeneration,[6] to name some examples. Tissue engineering technology is therefore of great potential impact, and is highly pursued by many industries and universities around the globe.

The use of 3D tissue mimicking models of macroscopic dimensions, that is of millimetre dimensions or larger, requires the development of non-destructive approaches for their characterisation.[7] Cellular constructs are of high value and fragile and should be undisturbed during development, and yet, they require close monitoring over extended periods of time. The monitoring and characterization of these constructs is essential.

Evaluation techniques with imaging capabilities are preferred as they provide an additional level of information, allowing the spatial visualization of the biological features within the tissue. Imaging techniques that are currently being used as routine tests are found in optic-based techniques, as they provide information at a high detail. [8, 9] In addition, their technological development is mature and of widespread use. However, optic-based techniques have some drawbacks, including:

  1. Limited volumetric imaging capabilities due to the high resolution involved. Since these constructs of interest have macroscopic dimensions, it becomes challenging to image large sample volumes within practical terms. In some cases, the use of contrast agents is needed in order to differentiate the tissue of interest from the background. Contrast agents may not affect the tissue development, but they are not present in native tissues and introduce complexity and uncertainties;

  2. Due to the light scattering properties of cells, light penetration and resolution dissipates as a function of depth. Hence, optic-based techniques are often limited in these type of constructs to about 1 millimetre in thickness.[9] To overcome such limitations, destructive, time-consuming, and highly skilled approaches such as histology are required.

The use of high frequency (>20 MHz) ultrasound offers a solution to the sample thickness limitations found in optic-based techniques. [8] This approach does not require the use of markers, and image acquisition time is reduced as it does not require the use histology processes. The application of spectral analysis of the acquired radiofrequency signals enables Quantitative Ultrasound Imaging (QUI). This approach allows the detection of small features such as cells, or the detection of changes of the hydrogel matrix due to cell activity. The difference between QUI and conventional grayscale is that the QUI approach applies a series of signal corrections, allowing a refined data interpretation. Despite the many useful attributes of ultrasound to evaluate soft tissues, such as cellular constructs, there is only a limited collection of reports of QUI applied to tissue engineering. [8, 10-13] One of the reasons QUI has not been widely used in tissue engineering is due to the lack of suitable commercial products.

Our Position: What We Can Offer

We have developed UltraImage, a benchtop quantitative ultrasonic imaging device, designed to overcome the limitations found in optic-based imaging technologies. The UltraImage prototype allows for the full size imaging of biomaterials and cell containing structures, non-destructively, and without the need of using additives. The application and accuracy of UltraImage for the investigation of diverse cellular constructs has recently been validated at our facilities. [14-16] A summary of the UltraImage application examples are shown below, of remarkable versatility for the imaging and quantification of the key structural, acoustical and biological properties of cellular constructs.

We offer the possibility to engage in an exciting opportunity to further develop ultrasound characterization for non-destructive characterisation of cellular constructs. We are also interested in commercialising our UltraImage product and exclusive software to other commercial and academic research centres.

UltraImage Applications

1 m

Summary of UltraImage application examples performed until date

Our Team

The team comprises of researchers with skills and expertise in biomaterials, cell biology, electronics and engineering. The project is led by Dr Andres Ruland.

Our Network and Facilities

The project team is underpinned by the Australian Research Council Centre of Excellence for Electromaterials Science (ACES), which includes some 200 researchers across seven Australian institutions in partnership with other universities across the globe. The team has access to the Australian National Fabrication Facility Materials Node – a national capability also headquartered at the University of Wollongong.

The Opportunity to Engage

We seek to engage with investors to take our technology through to commercial exploitation.

We seek to engage with researchers and clinicians interested in collaborative projects.



[1] S.V. Murphy, A. Atala, 3D bioprinting of tissues and organs, Nat Biotechnol 32(8) (2014) 773-85.

[2] C.D. O’Connell, S. Konate, C. Onofrillo, R. Kapsa, C. Baker, S. Duchi, T. Eekel, Z. Yue, S. Beirne, G. Barnsley, C. Di Bella, P.F. Choong, G.G. Wallace, Free-form co-axial bioprinting of a gelatin methacryloyl bio-ink by direct in situ photo-crosslinking during extrusion, Bioprinting 19 (2020).

[3] G.V. Research, Global tissue engineering market, Last accesed 02/2021. https://www.grandviewresearch.com/industry-analysis/tissue-engineering-and-regeneration-industry.

[4] H. Petite, V. Viateau, W. Bensaid, A. Meunier, C. de Pollak, M. Bourguignon, K. Oudina, L. Sedel, G. Guillemin, Tissue-engineered bone regeneration, Nat Biotechnol 18(9) (2000) 959-63.

[5] A.R. Martin, J.M. Patel, H.M. Zlotnick, J.L. Carey, R.L. Mauck, Emerging therapies for cartilage regeneration in currently excluded 'red knee' populations, NPJ Regen Med 4 (2019) 12.

[6] K. Vig, A. Chaudhari, S. Tripathi, S. Dixit, R. Sahu, S. Pillai, V.A. Dennis, S.R. Singh, Advances in Skin Regeneration Using Tissue Engineering, Int J Mol Sci 18(4) (2017).

[7] A.A. Appel, M.A. Anastasio, J.C. Larson, E.M. Brey, Imaging challenges in biomaterials and tissue engineering, Biomaterials 34(28) (2013) 6615-30.

[8] S.Y. Nam, L.M. Ricles, L.J. Suggs, S.Y. Emelianov, Imaging strategies for tissue engineering applications, Tissue Eng Part B Rev 21(1) (2015) 88-102.

[9] I. Georgakoudi, W.L. Rice, M. Hronik-Tupaj, D.L. Kaplan, Optical spectroscopy and imaging for the noninvasive evaluation of engineered tissues, Tissue Eng Part B Rev 14(4) (2008) 321-40.

[10] D. Dalecki, D.C. Hocking, Ultrasound technologies for biomaterials fabrication and imaging, Ann Biomed Eng 43(3) (2015) 747-61.

[11] C.X. Deng, X. Hong, J.P. Stegemann, Ultrasound Imaging Techniques for Spatiotemporal Characterization of Composition, Microstructure, and Mechanical Properties in Tissue Engineering, Tissue Eng Part B Rev 22(4) (2016) 311-21.

[12] M.L. Oelze, J. Mamou, Review of Quantitative Ultrasound: Envelope Statistics and Backscatter Coefficient Imaging and Contributions to Diagnostic Ultrasound, IEEE Trans Ultrason Ferroelectr Freq Control 63(2) (2016) 336-51.

[13] K. Kim, W.R. Wagner, Non-invasive and Non-destructive Characterization of Tissue Engineered Constructs Using Ultrasound Imaging Technologies: A Review, Ann Biomed Eng 44(3) (2016) 621-35.

[14] A. Ruland, X. Chen, A. Khansari, C.D. Fay, S. Gambhir, Z. Yue, G.G. Wallace, A contactless approach for monitoring the mechanical properties of swollen hydrogels, Soft Matter 14(35) (2018) 7228-7236.

[15] A. Ruland, K.J. Gilmore, L.Y. Daikuara, C.D. Fay, Z. Yue, G.G. Wallace, Quantitative ultrasound imaging of cell-laden hydrogels and printed constructs, Acta Biomater 91 (2019) 173-185.

[16] A. Ruland, J.M. Hill, G.G. Wallace, Reference Phantom Method for Ultrasonic Imaging of Thin Dynamic Constructs, Ultrasound Med Biol 47(8) (2021) 2388-2403.