12 September 2017
After several years of intensive research Marc Simonet (Senior Application Scientist) defended his PhD thesis successfully. This research forms part of the Project P1.01 iValve of the research program of the BioMedical Materials institute. We, as IME Technologies, are proud to have Marc Simonet in our team and are grateful that we could contribute to his promotion.
Tissue engineering enables the production of living tissue replacements. The scaffold represents the basis for such a replacement, providing the appropriate environment for cells to produce their tissue. In order to fully unlock the potential of tissue engineering, it is crucial that the scaffold mimics the native extracellular matrix (ECM) of the target tissue as closely as possible. This current paradigm in regenerative medicine is one of the reasons why electrospinning gained so much attention to produce scaffolds for tissue engineering. Electrospinning enables numerous types of materials to be spun into different kinds of fibrous scaffolds, which structurally resemble the native extracellular matrix. Many key biomimetic factors, such as the mechanical properties, the biocompatibility, and the biodegradation profile are related to the choice of the electrospinning material, but can also be adjusted by the electrospinning process itself. To instruct cells and guide tissue formation, bioresponsive or bioactive molecules can be included into electrospun scaffolds. In this thesis, tools are presented to improve the reproducibility, functionality and applicability of electrospun scaffolds for in-vivo and in-situ applications. All with the overall goal to underline and improve the suitability of electrospinning as a method to develop products for regenerative medicine/purposes.
Lack of reproducibility is one of the main challenges holding back the development of electrospun medical products. Using a, over the course of this PhD developed, climate controlled electrospinning chamber vastly increases the reproducibility of the electrospinning process regarding process stability, fiber morphology and orientation. Moreover, it allows to use ambient parameters, such as relative humidity, to adjust scaffold features like the fiber morphology.
Proper cell infiltration into the scaffold is crucial to produce a homogeneous tissue. A drawback of conventional electrospun scaffolds is the limited cell infiltration since the fibrous layers are densely packed on top of each other. This stops cell infiltration particularly when using fibers with a diameter smaller than a few micrometers. The first part of the thesis focuses on increasing and controlling the void space in electrospun scaffolds by developing a process called low-temperature electrospinning (LTE). Cooling the electrospinning target to -35°C and below, allows the simultaneous deposition of polymer fibers and ice crystals from condensing humidity. These ice crystals are intimately embedded between the polymer fibers and serve as a pore template, increasing the voids and thereby facilitating cell ingrowth also for submicrometer fibrous scaffolds. In line with the increase in void space, the tangent modulus of the scaffolds shifts towards the range of native soft tissues like blood vessels. While both the physiological mechanical properties and high porosity are promising for tissue engineering applications, control of the spatial fiber distance (SFD), often also referred to as pore size, is crucial for cell attachment, proliferation and migration. Based on a range of LTE spun scaffolds made of poly(lactic acid) and poly(ɛ-caprolactone) (PCL), it was found that the fiber stiffness offered considerable control on the resulting scaffold void spaces. In addition to adjustable void space, other advantages of this process are its straightforward design, the fact that it does not require the use of additional chemicals and it offers the possibility to create three-dimensional structures with any material and, as long as the relative humidity is kept above 30%, its robust process design.
The second part of the thesis focuses on the application and functionality of electrospun scaffolds for in-situ heart valve tissue engineering. For this tissue engineering approach, scaffolds with an appropriate biomechanical and spatial structure are required to assure immediate functionality and durability, and to enable cellular infiltration. A PCL-bisurea-based polymer represents a promising material to capture these features. It is fatigue resistant for more than 3 million cycles at 10% elongation. The corresponding electrospun valves, formed from an electrospun tube, showed a good hemodynamic performance in a pulse duplicator at “pulmonary plus” (50/25 mmHg) conditions for 20 hours. Furthermore, these valves showed immediate functionality in a sheep model as well as cellular infiltration with subsequent collagen production up to 5 weeks. However, due to too fast degradation of the scaffold, the valves failed after 4 to 5 weeks. Despite the required improvement of the degradation characteristics of the polymeric valve, this shows that in-situ tissue engineering of heart valves by electrospun polymeric scaffolds is a promising approach towards a living heart valve prosthesis
In conclusion, we could establish that stable environmental conditions vastly improve the reproducibility of the electrospinning technique while new tools were demonstrated to mimic the ECM more closely and improve the scaffold functionality. Furthermore, this thesis shows that electrospun scaffolds have promising potential even for use in highly demanding in-situ tissue engineering applications.
A catalogue record is available from the Eindhoven University of Technology Library
Design by: Ferdinand van Nispen, Citroenvlinder DTP&Vormgeving
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More information: http://repository.tue.nl/139e05c4-f4e6-460d-a609-cb80b606a314