Results

Crohn’s Disease and Ulcerative Colitis, the main types of Inflammatory Bowel Disease (IBD), are life-threatening gastrointestinal disorders with no definitive cure. The establishment of biorelevant in vitro models that closely recapitulate the IBD microenvironment is of utmost importance to validate newly developed IBD therapies. To address the existing flaws in the current representation of the IBD microenvironment, we propose a novel three-dimensional (3D) in vitro model comprising a multi-layered gastrointestinal tissue with functional immune responses under inflammatory conditions. The multi-layered architecture consists of a lamina propria-like hydrogel with human intestinal fibroblasts (HIF), supporting an epithelial layer composed of Caco-2 and HT29-MTX cells, along with an endothelial layer surrogating the absorptive capillary network. A collagen-alginate composite matrix was optimized for the lamina propria-like hydrogel, preserving HIF metabolic activity and morphology over time. To achieve immune competence, pre-differentiated THP-1-derived macrophages were incorporated into the epithelial barrier. Inflammation was induced through the optimization of an inflammatory cocktail consisting of E. coli O111:B4 lipopolysaccharide combined with a specialized cytokine array (tumor necrosis factor-α, interferon-γ, and interleukin-1β). This inflammation-inducing stimulus led to a significant upregulation of pro-inflammatory cytokines commonly associated with IBD onset, including CCL20, IL-6, CXCL9 and CXCL10. Altogether, this 3D in vitro model has the potential to accelerate the drug development pipeline by providing reliable permeability and efficacy outputs for emerging therapies, reducing unnecessary animal experiments. Moreover, it offers a valuable in vitro platform for studying IBD pathophysiology and cell interplay dynamics.

An emerging concern globally, particularly in developed countries, is the rising prevalence of Inflammatory Bowel Disease (IBD), such as Crohn’s disease. Oral delivery technologies that can release the active therapeutic cargo specifically at selected sites of inflammation offer great promise to maximise treatment outcomes and minimise off-target effects. Therapeutic strategies for IBD have expanded in recent years, with an increasing focus on biologic and nucleic acid-based therapies. Reliable site-specific delivery in the gastrointestinal (GI) tract is particularly crucial for these therapeutics to ensure sufficient concentrations in the targeted cells. Ingestible smart capsules hold great potential for precise drug delivery. Despite previous unsuccessful endeavours to commercialise drug delivery smart capsules, the current rise in demand and recent advancements in component development, manufacturing, and miniaturisation have reignited interest in ingestible devices. Consequently, this review analyses the advancements in various mechanical and electrical components associated with ingestible smart drug delivery capsules. These components include modules for device localisation, actuation and retention within the GI tract, signal transmission, drug release, power supply, and payload storage. Challenges and constraints associated with previous capsule design functionality are presented, followed by a critical outlook on future design considerations to ensure efficient and reliable site-specific delivery for the local treatment of GI disorders.

Inflammatory bowel disease (IBD) encompasses a set of chronic inflammatory conditions, namely Crohn’s disease and ulcerative colitis. Despite all advances in the management of IBD, a definitive cure is not available, largely due to a lack of a holistic understanding of its etiology and pathophysiology. Several in vitro, in vivo, and ex vivo models have been developed over the past few decades in order to abbreviate remaining gaps. The establishment of reliable and predictable in vitro intestinal inflammation models may indeed provide valuable tools to expedite and validate the development of therapies for IBD. Three-dimensional (3D) models provide a more accurate representation of the different layers of the intestine, contributing to a stronger impact on drug screening and research on intestinal inflammation, and bridging the gap between in vitro and in vivo research. This work provides a critical overview on the state-of-the-art on existing 3D models of intestinal inflammation and discusses the remaining challenges, providing insights on possible pathways towards achieving IBD mimetic models. We also address some of the main challenges faced by implementing cell culture models in IBD research while bearing in mind clinical translational aspects.