Longobardo, Gennaro (2024) Platforms based on micro- and nano-shaped natural materials for lung regenerative medicine and biomedical applications. [Tesi di dottorato]

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Abstract

By 2030, according to the World Health Organization (WHO), pulmonary diseases are expected to cause one in five deaths globally. Many of these conditions arise from immune dysfunctions and defects in lung tissue repair, particularly in the alveolar region, leading to abnormal extracellular matrix (ECM) remodeling and progressive respiratory function loss. Type II alveolar cells, essential for lung function, are particularly vulnerable to external damage,yet current therapies are only palliative. Natural compounds, due to their biomimicry, biocompatibility, and biodegradability, are used as substrates for lung engineering and bioengineered platforms. Polymers like hyaluronic acid, collagen, and alginate, in addition to compounds like folic acid and urea, have been optimized in terms of composition and molecular weight throughout this doctorate work. The use of mixtures and chemical modifications, including conjugation with other molecules, has been explored to enhance these materials’ properties. Therefore, the goal of this PhD thesis is to develop micro- and nano-structured platforms based on polymers and natural compounds, both for regenerative purposes in pulmonary diseases and infections and for constructing three-dimensional lung models. Specifically: The first part of the thesis focuses on developing a microstructured platform made of natural polymers and mesenchymal stem cells (MSCs) in a biomimetic biphasic suspension. This platform aims to promote lung tissue regeneration and potentially reverse tissue damage by optimizing MSC release, enhancing retention at damaged lung sites, and encouraging targeted adhesion. Notably, collagen microspheres were created without using chemical crosslinkers for the sustained release of MSCs and their differentiation into ATII cells, suspended in an injectable, low-molecular-weight, ECM-like hyaluronic acid solution. Next, the challenge of lung infections, linked to accelerated functional decline from acute and chronic damage, was addressed. As a solution, folic acid was used to produce carbon dots (CDs), a class of nanoparticles with specific surface chemistry, biocompatibility toward human lung fibroblasts, and antimicrobial activity that counters the increasing issue of drug resistance. These CDs exhibited synthesis-dependent structural properties, which were then correlated with their biological activities. Within this context arose the need to optimize and validate a novel 3D biomimetic lung construct using microfabrication techniques to create a more efficient and realistic model. This model aims to replicate the complexity of the distal airways, focusing on interactions among different cell types, such as fibroblasts and pulmonary epithelial cells. This led to the development of an innovative construct that can be conveniently scaled, functioning as a promising biomimetic study platform for modeling both healthy and fibrotic lung tissue following inflammatory insult. The results collectively demonstrate the remarkable versatility of these natural materials, as they can be tailored to specific applications, from regenerative lung tissue medicine to the fabrication of constructs for pulmonary engineering.

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