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REBTX Report Summary

Project ID: 626934
Funded under: FP7-PEOPLE
Country: Netherlands

Final Report Summary - REBTX (Integrative strategy for the development of urinary bladder analogs)

What if we could mimic body parts outside the body? What if we could design biocompatible implants that would promote tissue regeneration? How can we reduce implant rejection and failure?
The interdisciplinary field of tissue engineering (TE) could provide the answers to these questions. TE makes use of the fundamental understanding of the human body, tissue damage and disease, and regeneration process to translate it towards the design of customizable solutions that meet specific clinical demands. One strategy of TE is to replace lost tissues or organs with polymeric templates (or scaffolds) that contain specialized populations of living cells, with the goal of to restore their normal function. Once implanted, the construct guides the growth and development of newly formed tissue, while the polymer scaffold degrades away to be replaced by healthy functioning tissue. Despite that TE principles can be applied to virtually any organ system in the body, much emphasis has been awarded to bone, cartilage, skin, cardiac and neurological disorders, while others, for instance, the urogenital tract (kidney, ureter, bladder, urethra, prostate, pelvic floor, reproductive organs), have been neglected. Currently, urological disorders encompass a heavy economic and social burden, and the lack of personalized treatment options encourage the application of TE in the design of more refined, efficient and cost-effective solutions. Thus, the Marie Curie project on “Integrative strategy for the development of urinary bladder analogs (ReBTx)” aimed at providing an important leverage in the development of such solutions (Fig 1), by deconstructing the intricate organization of the native tissue to its biological, structural and organizational elements and assembling these parts into bladder-like templates.
The urogenital tract comprises of anatomical structures that fulfil different roles. For instance, kidneys cleanse the blood and produce urine, the ureters (long tubular structures) transport the urine from the kidney to the bladder (a reservoir for urine that when full contracts and voids its content) and is eliminated by voluntary muscle movements of the urethra, another tubular structure. There are a number of conditions of the urinary tract that can lead to loss of function (cancer, infections, trauma). Many of these require the removal the damaged/disease tissue and the replacement with implants together with reconstructive procedures. However, current techniques may lead to a number of complications. Therefore, there is a serious clinical demand for alternative solutions that would enable a better integration of the implants within the host tissue, without the loss of control, while avoiding rejection and complications due to impaired regeneration. Below, we will describe our approach and achievements to tackle some of the concerns mentioned above.
1. Development of tissue-like templates for guided tissue remodeling
Cells in the body grow within an organized 3D extracellular matrix (ECM), surrounded by other cells, and are constantly exposed to mechanical loads. The interactions between cell-cell and cell-ECM can determine whether a given cell undergoes proliferation, differentiation, apoptosis or invasion, and therefore predict the quality of the regenerative processes. Using the TE tool box, we have designed templates (or scaffolds) made of collagen (the building material of the body) to provide the support and the mechanical strength for cells to grow and build their own matrix. For the regeneration of the bladder wall, we developed scaffolds that have a linear orientation which mimic the orientation of the muscle fibers within the bladder. We showed that the cells infiltrated much deeper in the template when compared to the ones with a random orientation and were able align along this pattern. The cells acquired mature muscle signature, a proof that scaffolds architecture influences the outcome of the cells.
2. Exploring the potential (role) of (stem) cells for the regeneration of the bladder muscle
Not only the specific tissue architecture, but also the well-orchestrated cell-cell and cell-matrix interactions, should be at the center of regeneration strategies. It is expected that the combination of tissue-like scaffolds with stem and/or primary cells and supportive factors would result in a more specific, customized bioactivation of the microenvironment with improved regeneration capacities and biomechanical compliance. Thus, to improve scaffolds functionality and integration into the surrounding tissue, cell-seeded scaffolds are suggested. However, the use of primary cells is often limited by their low availability, short life span, invasive retrieval procedures and high donor-site morbidity, thus jeopardizing their clinical applicability. Moreover, when considering an from-the-patient-to-the-patient (autologous) approach, the patient’s own cells are already compromised (e.g., muscle cells in bladder cancers or stress urinary incontinence), requiring the use of alternative cells sources, such as stem cells. In our approach, we made use of stem cells isolated from the adipose tissue, which has emerged as one of the most promising stem cell populations identified thus far. They are clinically attractive as they are easy to harvest and culture, and can be applied in an autologous strategy. We have successfully isolated them and seeded them in our matrices. Cells were able to infiltrate and populate the scaffolds entirely. Initially, we considered triggering the cells to become muscle cells, however, that meant the use of conditions that do not find a correspondent in the physiological environment. Thus, we preferred to explore more the stem cells potential to remotely activate and orchestrate the regeneration process through the components they secrete into the environment. We have shown that stem cells seeded on scaffolds promote endothelial cells (major component of the blood vessels) migration and organization, and maturation of smooth muscle cells (major cellular component of the bladder).
3. Addressing the physiological aspects of the urinary tract: replicating tissue mechanics and acquisition of vascularization
Many of the current strategies for tissue reconstruction rely on the mere substitution of the damaged tissue with biologically inert materials, while the functional aspects of the tissues are ignored. Let’s consider bladder which is a dynamic organ that is constantly exposed to stretching (filling with urine) and contracting (voiding). Thus, we have used a specially designed bioreactor where scaffolds loaded with cells were mounted and subjected to mechanical stimulations that replicate this dynamic regime. We have showed that cells cultured in scaffolds under dynamic loading align along the direction of the stretch (similar to the muscle bundles within the bladder wall) and that they acquire a mature muscle characteristics. On the contrary, cells cultured on scaffolds under static conditions (no stretch) do not organize and do not undergo a transformation into muscle.
Even more, vascularization is also a crucial part in regeneration as it provides the nutrient and oxygen to the cells within the constructs. If host blood vessels do not penetrate the implant, the cells die and the regeneration is compromised. We have address this component by using the an innovative biomaterial that can promote blood vessels ingrowth and their organization into a network. We were able to show that cells (stem cells, endothelial cells, muscle cells) can grow and organize in this matrix. Given the novelty and versatility of this material, several patent application have been filled.

Final remarks
The Marie Curie grant on “Integrative strategy for the development of urinary bladder analogs (ReBTx)” was our first attempt to tackle the regeneration of the bladder wall by means of tissue engineering. Besides the scientific challenges, this project offered many training/learning and networking opportunities, both for the fellow as well as for the host institution. We believe that this grant is the catalyst for future exploration of this research line towards tuning scaffolds architectures and the regenerative potential of stem cells in urological applications, an highly underestimated area of research.

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