Project Portugal 2030

Summary

The proposed research project addresses a significant challenge of modern society: the need for effective strategies to address the complex lesion pathophysiology and the massive tissue loss of SCI which cannot be repaired by natural endogenous processes. Although existing treatments prevent the spinal cord lesion exacerbation and enhance plasticity of spared circuits, the extensive axonal regrowth and network connectivity remains elusive. The SUPRANEURO project aims to address acute and chronic spinal cord lesions in a personalized fashion by designing a library of UPy-functionalized biopolymers and peptide conjugates to create bioactive hydrogen-bonded multilayers. The nanoassemblies of UPy-conjugates will function as LbL nanoshells for human neural progenitor cells (hNPCs) encapsulation aiming to stimulate neuronal differentiation and survival by promoting enhanced cell-cell communication by complementary interaction between UPy-conjugated outermost layers. The further integration of hNPCs aggregates into an injectable system that promote their differentiation in situ and provide a mechanical and biochemical (source of growth factors) support to the encapsulated cells, is particularly important to address strong inflammation in the instable acute spinal cord injuries. On the other hand, chronic injuries will benefit from the implantation of a dynamic multilayered patterned patch mimicking native tissue properties, able to release key neurotrophic factors, and guide neurite extension across lesion cavity, particularly important in chronic lesions. Both objectives are ambitious once they propose a novel approach by leveraging advancements in supramolecular chemistry, biology, tissue engineering and material science to create innovative bioinstructive supramolecular polymeric biomaterials that not only exhibit properties reminiscent of macromolecules, but also dynamic, bioactive and adaptive behavior owing to the UPy enabling supramolecular interactions being used as patches, or incorporated into human protein-based hydrogels, if assembled over cellular surface, and used as injectable systems. Our multidisciplinary approach aims to combine LbL assembly with advanced properties of UPy-functionalized supramolecular polymers to replicate the bioactive and dynamic functionality of native neural tissue, offering a significant advancement beyond existing methodologies for stem cell transplantation and in situ differentiation aiming for neuronal tissue regeneration. The LbL assembly of UPy-conjugates over any type of surface, including cellular surfaces, to stimulate cellular differentiation is a novel concept that goes well-beyond the current state-of-the-art, introducing a new level of complexity to fabricate dynamic and functional neuronal tissues for cell transplantation therapies. This strategy can improve the efficacy of cell therapy, by providing suitable synthetic microenvironment to support neuronal differentiation and increased cell survival in situ by combining the cost-effective and versatile bottom up LbL technology with innovative and inherently responsive supramolecular materials. We envisage that this project could lead to a paradigm shift in neural tissue regeneration by improving stem cell transplantation and integration in living tissues, holding great potential for being translated towards functional outcomes and enhanced quality of life of patients facing spinal cord injuries.