Engineering the Gut–Liver–Joint–Skin Axis Against Inflammation-Driven Fibrosis: Biomaterials, Organoid Models, and Immunoengineered Platforms

The gut, liver, joint, and skin represent four of the most clinically consequential sites of inflammation-driven fibrosis. Inflammatory bowel disease (IBD)–associated intestinal fibrosis, metabolic dysfunction–associated steatohepatitis (MASH/NASH) and chronic hepatic fibrosis, osteoarthritis or rheumatoid synovitis with progressive joint destruction, and cutaneous fibrotic disorders — including non-regenerative wound healing, hypertrophic scarring, keloids, and systemic sclerosis–related dermal fibrosis — together affect hundreds of millions of patients worldwide. Although these conditions appear anatomically distinct, they share a common pathological logic: barrier disruption, persistent innate immune activation, dysregulated macrophage–fibroblast crosstalk, microbial or mechanical stress, and progressive extracellular-matrix (ECM) deposition that ultimately compromises organ function.Increasing evidence supports a tightly interconnected gut–liver–joint–skin axis. Dysbiotic microbial metabolites translocating through a compromised intestinal barrier fuel hepatic inflammation, while circulating gut- and liver-derived immune signals modulate synovial inflammation, joint fibrogenesis, and cutaneous immune programming. The gut–skin and liver–skin axes — documented in IBD-associated dermatoses, MASH-related cutaneous manifestations, and microbiome-driven dermal inflammation — place the skin as a natural fourth barrier organ within this multi-organ continuum. Cutaneous wound healing itself can be framed as the earliest, most accessible window onto the inflammation-to-fibrosis transition: the same axis of macrophage–fibroblast crosstalk, ECM remodeling, and innate immune programming that governs gut, hepatic, and synovial fibrosis also dictates whether a healing wound resolves into regenerated tissue or into fibrotic scarring. Innate immune cells — particularly macrophages — orchestrate this cross-organ communication, and their polarization state is shaped by both microbial signals and the mechanical and chemical properties of the surrounding ECM. Despite this shared biology, anti-fibrotic interventions are typically developed in isolation, organ by organ, with limited integration across the axis.Current anti-fibrotic interventions face fundamental limitations. Systemic small-molecule drugs lack organ specificity and a robust therapeutic window. Biologics rarely reach the mucosa, the hepatic stellate-cell niche, the avascular synovial cartilage, or the deep dermal fibrotic compartment at meaningful concentrations. Conventional in vitro models — 2D cell cultures and short-term animal studies — fail to recapitulate the multicellular, immune-rich, matrix-stiffening microenvironment in which gut, hepatic, joint, and dermal fibrosis actually unfold. As a consequence, candidates that perform well in classical screens routinely fail in clinical translation.Bioengineering and biotechnology offer new strategies that cut across these limitations. Dynamic, stimuli-responsive, and ECM-mimetic biomaterials can be engineered with organ-specific physicochemical and immunological signatures. Immunoengineered scaffolds, dressings, and coatings can re-educate macrophage polarization, fibroblast, myofibroblast, or synoviocyte activation, and innate immune signaling at the inflammation interface — and, in the skin, can steer wound healing toward regenerative, scarless outcomes rather than fibrotic scarring. Intestinal, hepatic, synovial, and dermal organoids — together with immune-co-cultured constructs and emerging skin-on-chip platforms — are providing physiologically faithful systems in which the inflammation-to-fibrosis transition can be dissected and biomaterial interventions evaluated. Connecting these material and model innovations to the shared biology of the gut–liver–joint–skin axis is, we believe, where the next translational breakthroughs in anti-fibrotic medicine will originate.GoalThis Research Topic consolidates and accelerates bioengineering and biotechnology approaches targeting the gut–liver–joint–skin inflammation-to-fibrosis axis. By bringing together work on engineered biomaterials, organoid-based models, immunomodulatory delivery systems, and mechanistic studies of cross-organ immune crosstalk, the collection seeks to:• Advance organ-specific anti-fibrotic biomaterials that exploit the unique physicochemical, immunological, and microbial features of the gut, liver, joint, and skin microenvironments.• Promote physiologically faithful in vitro and ex vivo models — intestinal, hepatic, synovial, and dermal organoids, immune-co-cultured systems, and emerging skin-on-chip platforms — used to interrogate biomaterial behavior and screen anti-fibrotic interventions at the inflammation–fibrosis interface.• Highlight immunoengineering strategies that re-educate macrophage–fibroblast, macrophage–synoviocyte, and macrophage–dermal fibroblast crosstalk, modulate innate immunity, and restore epithelial, synovial, or dermal barrier integrity.• Showcase biomaterial-driven strategies for steering cutaneous wound healing toward regenerative, scarless outcomes by modulating the inflammation-to-fibrosis transition rather than only accelerating wound closure.• Encourage mechanistic studies that connect microbiome-derived signals, epithelial, synovial, or keratinocyte cell death (necroptosis, pyroptosis, ferroptosis), innate immune activation, and downstream fibrogenic reprogramming across organ boundaries.• Accelerate translational pipelines by emphasizing preclinical validation, scalability, and the unique delivery and regulatory considerations of mucosal, hepatic, intra-articular, and dermal / intra-lesional biomaterial platforms.By focusing on a single, biologically coherent multi-organ axis — rather than fibrosis as a generic phenomenon or wound healing as an isolated closure problem — the collection bridges materials science, immunology, organoid biology, clinical gastroenterology, hepatology, rheumatology / orthopaedics, and dermatology / plastic surgery.Scope and Information for AuthorsWe welcome Original Research, Review, Mini Review, Perspective, Methods, and Technology and Code articles addressing the engineering and biological understanding of the gut–liver–joint–skin axis in inflammation-driven fibrosis. In line with the Biomaterials section, the engineered biomaterial or engineered model must be the central object of study — its design, interfacial chemistry, mechanical and immunomodulatory properties, and structure–property–function behavior — whether evaluated in vitro, ex vivo, or in vivo.Submissions focused on cutaneous fibrosis are scoped to wound-healing strategies that explicitly modulate the inflammation-to-fibrosis transition, including scarless / regenerative wound healing, hypertrophic scar prevention and treatment, keloid management, systemic sclerosis–related dermal fibrosis, and post-surgical or post-burn fibrotic remodeling. Submissions whose primary endpoint is wound-closure rate or general chronic-wound management without a fibrotic-outcome readout fall outside the present collection.Topics of interest include, but are not limited to:• Dynamic-covalent, stimuli-responsive, and ECM-mimetic hydrogels and scaffolds — with established expertise in synovial / intra-articular delivery for joint fibrosis and osteoarthritis, and in dermal / intra-lesional delivery for regenerative wound healing, hypertrophic scar, and keloid management — and welcoming submissions that extend these design principles to intestinal mucosal repair and minimally invasive hepatic intervention.• Physiologically faithful in vitro and ex vivo models — including intestinal, hepatic, synovial, and dermal organoids, immune-co-cultured systems, and emerging skin-on-chip platforms — used to interrogate biomaterial behavior, dissect the inflammation-to-fibrosis transition, and screen anti-fibrotic biomaterial interventions across the axis.• Immunoengineered biomaterials that direct macrophage polarization (pro-inflammatory to resolution-phase), modulate innate immune signaling (TLR, STING, NLRP3), and re-educate fibroblast, myofibroblast, synoviocyte, or dermal-fibroblast activation at mucosal, hepatic, synovial, and dermal interfaces — including biomaterial-based delivery of biologics, exosomes, and extracellular vesicles where the material or scaffold remains the central object of study.• Conductive, piezoelectric, ECM-modified, and bioactive nanofibrous dressings or scaffolds engineered to steer skin wound healing toward regenerative, anti-fibrotic outcomes — preventing hypertrophic scarring and keloid formation through macrophage re-education, myofibroblast deactivation, collagen-architecture modulation, and ECM remodeling.• Microbiome-driven mechanisms of barrier disruption and cross-organ fibrogenic signaling, and biomaterial strategies that interface with the intestinal or cutaneous microbiota — including microbiota-modulating scaffolds, postbiotic-presenting surfaces, and barrier-restoring coatings — to interrupt downstream hepatic, articular, or dermal fibrogenesis.• Epithelial, synovial, and dermal barrier restoration technologies, including bioactive coatings, regenerative scaffolds, and cell-instructive matrices that promote mucosal, synovial, or dermal healing and reduce systemic translocation of fibrogenic signals.• Mechanistic studies of the inflammation-to-fibrosis transition — including epithelial, hepatocyte, synoviocyte, or keratinocyte cell death pathways (necroptosis, pyroptosis, ferroptosis), innate immune programming, and macrophage–stellate-cell, macrophage–fibroblast, macrophage–synoviocyte, or macrophage–dermal-fibroblast crosstalk — across gut, liver, joint, and skin, particularly when coupled to biomaterial or model-based investigation.• Preclinical and translational studies of biomaterial-based anti-fibrotic platforms in physiologically relevant models of IBD-associated intestinal fibrosis, MASH/NASH, cholestatic liver disease, osteoarthritis, rheumatoid synovitis, scarless / regenerative wound healing, hypertrophic scar, keloid, systemic sclerosis, and post-surgical adhesion or stricture.Article TypesThis Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:• Brief Research Report• Case Report• Data Report• Editorial• FAIR² Data• FAIR² Data Direct Submission• General Commentary• Hypothesis and Theory• Methods• Mini Review• Opinion• Original Research• Perspective• Review• Systematic Review• Technology and CodeArticles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders. Topic editors: Yujie Hua, Claudia Günther Source: https://www.frontiersin.org/research-topics/82195/engineering-the-gut-liver-joint-skin-axis-against-inflammation-driven-fibrosis-biomaterials-organoid-models-and-immunoengineered-platforms