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The Balance between Transport and Mechanical Issues in 3D Regenerative Tissues, Using the Perfusion Bioreactor

Final Report Summary - TRANSMEX (The balance between transport and mechanical issues in 3d regenerative tissues, using the perfusion bioreactor)

Overview of results:
While trying to understand the physical demands inavertedly placed on developing tissues by direct perfusion, this project investigated the advantages and limitations of media perfusion for neo-tissue development. As result, it demonstrated the awareness of an operational range within which perfusion is useful, and the mechanical and experimental parameters, which defines this range. As well as bringing these parameters into the light, the contributions of factors, stemming either from a system's design or the experimental model, to these experimental parameters were demonstrated. To this end, it was stressed that a need exists to identify iteratively, the operational capacity of a perfusion system and the cell-scaffold model. Having done so, these may be incorporated into a culture strategy to maximise nutrient supply to the developing tissue, while imposing minimal pressure on either the cells or the scaffold in which they are seeded.

The experimental findings of this project may therefore be summarised as follows:
- The enhanced nutrient delivery by medium perfusion benefits developing tissue cultures.
- Although a high perfusion rate equates to a high rate of nutrient delivery, it does not indefinitely translate to a higher rate of development of the developing cultures.
- Pressure-build up inside the perfusion bioreactor during direct perfusion is unavoidable, and damage to the tissue is inevitable if the perfusion is prolonged.
- The magnitude of pressure required to cause disruption to the cells is negligible, compared to that in hydrostatic experiments, or in a physically-uncompromised cell-seeded scaffold.
- While the magnitude of pressure required to physically compromise the tissue is a function of the scaffolds mechanical properties, the time taken for the system to build up such pressure depends on both the bioreactors characteristics and the flow rate.

Scientific implication:
This project proposes that pressure will build up inside a perfusion bioreactor irrespective of the flow rate, and may eventually compromise the culture. Moreover, the pressure required to do so is considerably lower with fluid flow, than in a hydrostatic environment. Since this pressure and the time required to achieve it will differ system-to-system, a good strategy for tissue engineering is to adapt ones system to enable constant, online monitoring of the differential pressure inside a perfusion culture system, investigate the failure pressure for the chosen cell-scaffold model, and profile the time required to reach this pressure when using a range of flow rates. Once this is done, the online-monitoring of pressure during perfusion culture means that high and low flow rates may be used interchangeably to maximise cellular nutrition, while ensuring that the pressure remains within the safe boundary.

Impact:
Direct perfusion bioreactors were introduced to tissue engineering research to improve the delivery of essential nutrients to cells cultured in 3D scaffolds. Despite their success in moving both small- and large-sized molecules to all regions of tissue-engineered structures they are known to cause physical harm to the cultured tissue, often rendering them unusable. Since this occurs readily at high perfusion rates, the pressure generated by fluid flow has been highlighted as a major factor. Thought to increase with flow rate, much effort, particularly with theoretical models have aimed to determine optimal perfusion rates for tissue-engineered cultures, to minimise the adverse mechanical effects.

Although principally targeted towards scientists in the fields of tissue engineering and regenerative medicine; once published, the exploitation of these findings by researchers and clinicians in their respective strategies for tissue regeneration will join the ongoing multidisciplinary efforts in disburdening national and international healthcare systems of costly illnesses such as musculoskeletal diseases.