Magnetic nanoparticle-mediated activation of the Activin IIA receptor for tenogenic differentiation

Righelli, Lucrezia (2023). Magnetic nanoparticle-mediated activation of the Activin IIA receptor for tenogenic differentiation. University of Birmingham. Ph.D.

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Abstract

Tendon injuries are among the most frequent orthopaedic conditions affecting a large part of the population worldwide and represent a huge burden for the healthcare system. In fact, tendon tears and lacerations can lead to chronic or degenerative tendinopathies as a common complication caused by tendon limited intrinsic healing properties. Despite the high frequency of tendon injuries and their major socioeconomic impact, an effective and widely-accepted treatment is missing. Current strategies include non-surgical and surgical treatments which are often not fully successful due to recurrent injury of the same tendon. Hence, there is an immediate need to find an alternative treatment strategy which could offer an effective and durable resolution of tendon injuries.

Tissue engineering offers a potential alternative approach to treat tendon injuries, wherein the use of stem cells has been shown to improve the healing response and minimise scar formation. In this Thesis, stem cells were studied in conjunction with remotely-controlled magnetic nanoparticles (MNPs) to target and stimulate the mechano-receptor Activin RIIA towards the initiation of the tenogenic differentiation pathway. Several relevant cell types were investigated along with different antibodies targeting different regions of the receptor, in order to better stimulate the mechano-responsive domain. The remote mechanical activation of the Smad2/3 signalling cascade and the expression of some tenogenic proteins was verified in human tenocytes, human bone marrow stem cells (hBMSCs) and human adipose stem cells (hASCs); raising the possibility to remotely control cell behaviour towards the tenogenic commitment. Furthermore, two 3D scaffolds were developed and characterised as potential cell delivery methods for in vivo applications or in vitro tendon 3D modelling. The first 3D scaffold consisted of an oriented fibres collagen gel which allowed for the parallel alignment of hASCs in vitro. The second developed scaffold was an injectable fibrin gel which was shown to be cytocompatible and stable in vitro for 21 days. Finally, the tenogenic regenerative potential of remotely-activated MNPs-labelled human adipose stem cells was studied in vivo, as an essential step prior to translation into clinic. This study revealed that remotely-activated MNPs-labelled hASCs might have a positive impact in the deposition of an organised ECM during tendon healing.

The obtained results suggest that the application of a mechanical stimulus can enhance stem cell tenogenic potential and can be considered as a valid integrated approach for tissue engineering strategies in tendon injuries treatment.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):