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Active tissue scaffolds substrates to deliver responsive mechanostimulation for target compositions and functionalities of tissue constructs for regenerative medicine (Industry Project)

   EPSRC Centre for Doctoral Training in Advanced Biomedical Materials

  , Dr N Green,  Friday, February 10, 2023  Funded PhD Project (Students Worldwide)

About the Project

The ABM CDT is a partnership between The Universities of Manchester and Sheffield. ALL APPLICATIONS should however, be submitted via the Manchester application system only.

In this project we will develop a novel technology for tissue engineering and regenerative medicine: a tissue active and responsive interface for in vitro 2D planar stimulation of tissue. This tissue-robotic interface resides at the base of the cell-seeded scaffold and embeds novel mechanical stimulatory and sensory elements. Consequently it applies peristaltic-like physiologically-realistic stimulation patterns to the tissue construct.

Intestinal tissue constructs in vitro have typically been applied tension and shear stress using cyclic deformation and fluidic flow, respectively, in order to recreate the microenvironment of the epithelium. The stimulation of the intestinal smooth muscle has received limited attention. In this project, due to the capabilities of our system we can apply for the first time both strain and compressive cues to mimic peristaltic motility of the intestinal muscle (for both longitudinal and radial layers, respectively).

The state of the tissue is identified by embedded sensors, which is an essential and innovative element of the tissue scaffold-robot interface, enabling fine tuning of the mechanostimulation.

Due to the scaffolds’ novel capabilities of distributed, localised and responsive mechanostimulation, the scaffold can be an enhanced research tool for researchers in various areas of regenerative medicine working on muscle tissue engineering and regeneration.

Project Description

There is a critical need of effective regenerative therapies for various clinical conditions where our biological regenerative capabilities fall short in restoring diseased organs. Examples include gastrointestinal diseases, such as long-gap esophageal atresia and short bowel in which up to two thirds of the organ is missing. Additionally, due to high unmet demand of organ transplantation, advanced tissue engineering techniques are also needed.

Tissue regeneration is a complex, long-term, dynamic, physiologically and metabolically demanding process [10]. Effective therapies will be those which respond to these dynamic processes with the appropriate combination of therapeutic remedies. It has been shown that mechanical stimulation has significant influence upon cells’ fate, e.g., proliferation, differentiation, and apoptosis [11]. This effect has been leveraged in the pervasive use of bioreactors. However the mechanical stimulation provided by off-the-shelf and state-of-the-art bioreactors have typically preprogrammed stimulation waveforms and little sensitivity or adjustment to the evolving tissue construct. Additionally once the tissue construct is implanted inside the body it is deprived of much of the prior stimulation leaving it with limited guidance and control.

Our group has pioneered robotic and smart materials technologies that apply mechanical stimulation in a responsive way depending on the tissue’s evolving mechanical properties. This technology has been demonstrated in vivo with swine where we showed that we can grow 77% de novo tissue in 9 days [2]. We also demonstrated the technology in vitro with fibroblast-seeded PGSM scaffolds, showing we could advance the features of current bioreactors [1].

The aim of this proposed research is to realise physical-biological devices in the form of active scaffold interfaces which allow responsive tissue regeneration in a complex and dynamic biological environment [13,14]. The scaffold is sensorised and provides responsive spatiotemporal control of mechanical stimulation to tissue constructs in vitro.

Main questions to be answered:

The underlying questions that we will seek to answer through this project are the following:

  1. Can we realise a tissue construct with a cellular arrangement and peristaltic-like response similar to the intestinal muscle by applying both strain and compressive cues enabled by the technology developed during this project? Strain will be applied by our in-lab robotic bioreactor [1], while compression will be conveyed by the robotic scaffold interface, using realistic physiological motility parameters [12].
  2. What are the most promising mechanostimulation regimens which could create a biomechanically-functionalised (muscle) structure of the gastrointestinal tract (bowel or/and esophagus)? The real-time optimisation of the tissue growth via mechanostimulation patterns produced by the proposed technology will be carried out taking into account physiologically-realistic spatiotemporal parameters and dynamic state of the tissue (e.g., its stiffness) at a given moment in the evolution of the tissue (construct).
  3. How are the diverse applied mechanostimulation patterns contributing to the cellular composition, e.g., cell proliferation, ECM production, of the tissue construct? We will seek to understand how to precisely control the cellular responses and use this knowledge as a guideline for future in vivo mechanostimulation toward accelerating tissue growth and minimising the fibrotic response to implantable devices. We will culture myoblasts initially and smooth muscle cells in the advanced phases of this project, on PGSM scaffolds [1]. For the active scaffold interface we will explore moldable biocompatible materials, e.g., MED-4805 and MDX4-4210, and hydrogels [3].

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