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Using Sound for Tissue Engineering

Ultrasound-based technologies are a versatile tool that offers unique advantages to disease diagnosis and therapy, as well as to the fabrication process of biomaterials. These technologies allow for site-specific heating, thereby enabling controlled thermal and mechanical avenues to engineered constructs. This kind of technique can also enhance cell-mediated ECM remodeling behavior, thus modifying, indirectly, the structure of engineered scaffolds. Combining this methodology with other approaches that were previously used in tissue engineering can provide highly effective therapeutic materials for regenerative medicine [1,2]. Mesenchymal stromal cells (MSCs), a popular platform for cell-based therapy in regenerative medicine, have been applied along with ultrasound-based methodologies. The association of the benefits of both therapies, including MSC propensity to act as a repository of regenerative molecules and immunomodulatory effects, represents an effective approach to promote tissue repair [3].

There are several modalities of ultrasound applications to cell-based therapies, such as low-intensity pulsed ultrasound, pulsed focused ultrasound, and extracorporeal shockwave therapy. The pulsed focused ultrasound (pFUS) uses short-duration, high-intensity pulses to nondestructively target tissues of interest. This technique is relatively safe, causing minimal histological alterations and promoting MSC homing to the sonicated area [3].

Figure 1: Currently known mechanisms by which pulsed focused ultrasound (pFUS) enhances mesenchymal stromal cell homing in vivo [3].

A similar approach comprises the use of extracorporeal shock waves (ESW). This technology has been used in clinical practice since the ’80s and is emerging as a leading choice of treatment for several orthopedic diseases. It consists of a transient short-term acoustic pulse with high peak pressure [4,5].

A recent study associated the extracorporeal shock waves with human adipose-derived stem cells (hASCs) to achieve tendon healing. When damaged, the tendon can never completely restore its biological and biomechanical properties, so the ESW along with the hASCs provide a good alternative for tendon tissue engineering. The results of the study showed that the technique improved the differentiation of hASCs towards tenoblast-like cells [4,5]

Another way to use ultrasound-based therapies is with low-intensity pulsed ultrasound (LIPUS). A recent study by Kuang et al. (2019) investigated the effects of LIPUS on the osteogenic differentiation of dental follicle cells (DFCs) in vitro and the regenerative effects of this combination in vivo. The authors concluded that low-intensity pulsed ultrasound may promote the osteogenic differentiation of rat DFCs by increasing the mRNA expression of osteogenesis-related genes and forming mineralized nodules in vitro, enhancing the regenerative effect when implanted into the subcutaneous dorsal of a nude mouse. Further analysis must be developed to clarify the underlying mechanisms of LIPUS and to filter the most qualified parameters to make the best use in tissue engineering [6,7].

Figure 2: Histological examination of the harvested complexes at eight weeks. (A): empty scaffold; (B): DFCs + scaffold; (C): DFCs + scaffold + LIPUS. C, cell; F, newly formed fibrous tissue; BV, newly formed blood vessels [9].


1- Norris, E.G.; Dalecki, D.; Hocking, D.C. (2020). Using Acoustic Fields to Fabricate ECM-Based Biomaterials for Regenerative Medicine Applications. Recent Progress in Materials 2(3).

2- Dalecki, D.; Hocking, D.C. (2015). Ultrasound technologies for biomaterials fabrication and imaging. Annals of Biomedical Engineering 43, 747-761.

3- Liu, D.D.; Ullah, M.; Concepcion, W.; Dahl J.J.; Thakor, A.S. (2020). The role of ultrasound in enhancing mesenchymal stromal cell-based therapies. Stem Cells Translational Medicine 9, 850-866.

4- Rinella, L.; Marano, F.; Paletto, L.; et al. (2018). Extracorporeal shock waves trigger tenogenic differentiation of human adipose-derived stem cells. Connect Tissue Research 59(6).

5- Uysal, A.C.; Mizuno, H. (2010). Tendon regeneration and repair with adipose-derived stem cells. Current Stem Cell Research and Therapy 5(2),161-167.

6-Tanaka, E.; Kuroda, S.; Horiuchi, S.; Tabata, A.; El-Bialy, T. (2015). Low-intensity pulsed ultrasound in dentofacial tissue engineering. Annals of Biomedical Engineering 43(4), 871-886.

7- Kuang, Y. et al. (2019). Low-intensity pulsed ultrasound promotes tissue regeneration in rat dental follicle cells in a porous ceramic scaffold. Brazilian Oral Research 33, 0045.

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