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Project

Application of novel 3D polymer scaffolds for skeletal muscle tissue engineering

About 40% of the human body mass consists of skeletal muscle (Liu et al. 2018). Upon injury, the skeletal muscle tissue can regenerate physiologically till some extend. However, when there is a volumetric muscle loss (VML), the remaining muscle tissue is unable to fully regenerate itself. This VML causes scar tissue and substantial negative impact on patients’ morbidity and life quality (Liu et al. 2018, Grasman et al. 2015). The current standard of care for VML is surgical transfer of autologous muscle tissue (e.g. latissimus dorsi muscle, gracilis muscle) in combination with physical exercise. However, this procedure fails in 10% of the cases due to infection or necrosis of the transferred tissue. Moreover, the extraction of autologous tissue as such causes a certain decrease in patients’ morbidity and is not possible in every patient (Liu et al. 2018). Therefore, it is needed to develop off-the-shelf biomimetic scaffolds for skeletal muscle regeneration (Grasman et al. 2015).

This joint-PhD project aims to create novel 3D-printed polymer scaffolds which are applicable for skeletal muscle tissue engineering. The skeletal muscle will thus be mimicked In vitro as closely as possible resulting in a bio-artificial muscle (BAM). The extracellular matrix (ECM) of the tissue will be mimicked using polymers that are biocompatible and biodegradable. These polymers also need to be strong enough to support the skeletal muscle cells and soft enough to allow the cells to grow through the matrix. According to previous research, hydrogels can be synthesized with perfect mechanical, biological and chemical characteristics to be applicable in the context of skeletal muscle engineering (Van Vlierberghe et al. 2011, Billiet et al. 2012). In addition, scaffolds can be made with the hydrogels using 3D-printing of the polymers (Billiet et al. 2012). This adds to the possible complexity of the BAM needed for future challenges in the field of skeletal muscle engineering.

During this project, the polymers will be synthesized and characterized to meet the theoretical required characteristics. Then, the polymers will be 3D-printed (direct or indirect) to accomplish the desired scaffold. After positive materialistic and structural evaluation, the hydrogels will be tested in vitro for cell compatibility with life/dead-staining and for functional BAM-formation with histology, thickness measurements, immunocytochemistry, fluorescence staining and confocal light microscopy. An in vitro positively evaluated material, can be tested in vivo by implantation of the BAM in immunodeficient (NOD/SCID) mice (Thorrez et al. 2008).

In the field of skeletal muscle engineering, the following future challenges need to be investigated.

Detailed imaging of the physiological human tissue

Pre-vascularization and pre-innervation of the BAM

Structurally organized BAMs with initial strength

In vitro creation of bone-tendon-muscle connections

This PhD project fits in the Interreg project 3D4Med which aims to develop biodegradable shape-memory matrices which mimic the structure and activity of the biological tissue. The complex tissue-structures will be created by use of polymer 3D-printing while the activity of the tissue will be mimicked using shape-memory polymers. These shape-memory polymers can change upon a stimulus such as temperature, pH and heath (Raquez et al. 2011). Since, 3D-printing allows the formation of polymer matrices with patient specific geometry, the combination of shape-memory polymers and 3D-printing opens a broad perspective to develop organ constructs that can be implanted with a minimal surgical procedure. These of the shelf organ constructs can overcome the problem of organ donor shortage and immune rejection upon transplantation.

 

References

Liu, J., Saul, D., Böker, K. O., Ernst, J., Lehman, W., & Schilling, A. F. (2018). Current Methods for Skeletal Muscle Tissue Repair and Regeneration. BioMed Research International, 2018, 1–11. https://doi.org/10.1155/2018/1984879

Grasman, J. M., Zayas, M. J., Page, R. L., & Pins, G. D. (2015). Biomimetic scaffolds for regeneration of volumetric muscle loss in skeletal muscle injuries. Acta Biomaterialia, 25, 2–15. https://doi.org/10.1016/j.actbio.2015.07.038

Van Vlierberghe, S., Dubruel, P., & Schacht, E. (2011). Biopolymer-based hydrogels as scaffolds for tissue engineering applications: A review. Biomacromolecules, 12(5), 1387–1408. https://doi.org/10.1021/bm200083n

Billiet, T., Vandenhaute, M., Schelfhout, J., Van Vlierberghe, S., & Dubruel, P. (2012). A review of trends and limitations in hydrogel-rapid prototyping for tissue engineering. Biomaterials, 33(26), 6020–6041. https://doi.org/10.1016/j.biomaterials.2012.04.050

Thorrez, L., Shansky, J., Wang, L., Fast, L., VandenDriessche, T., Chuah, M., … Vandenburgh, H. (2008). Growth, differentiation, transplantation and survival of human skeletal myofibers on biodegradable scaffolds. Biomaterials, 29(1), 75–84. https://doi.org/10.1016/j.biomaterials.2007.09.014

Raquez, J. M., Vanderstappen, S., Meyer, F., Verge, P., Alexandre, M., Thomassin, J. M., … Dubois, P. (2011). Design of cross-linked semicrystalline poly(ε-caprolactone)-based networks with one-way and two-way shape-memory properties through Diels-Alder reactions. Chemistry - A European Journal, 17(36), 10135–10143. https://doi.org/10.1002/chem.201100496

Date:1 Sep 2019 →  31 Aug 2021
Keywords:Skeletal muscle, Regeneration
Disciplines:Regenerative medicine not elsewhere classified
Project type:PhD project