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Mitigating inflammation associated with the foreign body response (FBR) remains a significant challenge in enhancing the performance of implantable medical devices. Current anti-inflammatory approaches aim to suppress implant fibrosis, the major outcome of the FBR, but also inadvertently inhibit beneficial immune signalling necessary for tissue healing and vascularization. In a previous study, we demonstrated the feasibility of 'selective' immunosuppression targeting the NLRP3 inflammasome using the small molecule inhibitor MCC950, leading to reduced implant fibrosis without compromising healing and leading to enhanced vascularization. However, the clinical potential of MCC950 is severely limited due to its failure to pass Phase I clinical safety trials. This has triggered substantial efforts to develop safer analogues of NLRP3 inhibitors. Dapansutrile (OLT1177) is emerging as a leading candidate amongst current NLRP3 inhibitors, demonstrating both safety and effectiveness in a growing number of clinical indications and Phase 2 trials. While the anti-inflammatory effects of OLT1177 have been shown, validation of these effects in the context of implanted materials and the FBR have not yet been demonstrated. In this study, we show OLT1177 possesses beneficial effects on key cell types which drive FBR outcomes, including macrophages, fibroblasts, and smooth muscle cells. Evaluation of OLT1177 in a 28 day subcutaneous implantation model showed OLT1177 reduced fibrotic capsule formation while promoting implant vascularization. Mechanistic studies revealed that this occurred through activation of early pro-angiogenic markers while suppressing late-stage anti-angiogenic markers. These findings establish OLT1177 as a promising therapeutic approach for mitigating implant fibrosis while supporting vascularisation, suggesting a highly promising selective immunosuppressive strategy for the FBR warranting further research to explore its optimal integration into medical materials and devices. [ABSTRACT FROM AUTHOR]

Atherosclerosis is the primary cause of cardiovascular disease, resulting in mortality, elevated healthcare costs, diminished productivity, and reduced quality of life for individuals and their communities. This is exacerbated by the limited understanding of its underlying causes and limitations in current therapeutic interventions, highlighting the need for sophisticated models of atherosclerosis. This review critically evaluates the computational and biological models of atherosclerosis, focusing on the study of hemodynamics in atherosclerotic coronary arteries. Computational models account for the geometrical complexities and hemodynamics of the blood vessels and stenoses, but they fail to capture the complex biological processes involved in atherosclerosis. Different in vitro and in vivo biological models can capture aspects of the biological complexity of healthy and stenosed vessels, but rarely mimic the human anatomy and physiological hemodynamics, and require significantly more time, cost, and resources. Therefore, emerging strategies are examined that integrate computational and biological models, and the potential of advances in imaging, biofabrication, and machine learning is explored in developing more effective models of atherosclerosis. [ABSTRACT FROM AUTHOR]

Skin injuries pose significant health challenges, with conditions like burns and diabetic, venous, and pressure ulcers presenting complex wound management scenarios. Effective wound care strategies for these injuries encompass a range of interventions, from simple wound dressings to bioactive materials and surgical procedures involving skin substitutes and skin grafting. This review explores the potential of natural polymers, including silk, collagen, gelatin, elastin, cellulose, chitosan, alginate, and hyaluronic acid, in wound management. Natural polymers offer several advantages, including abundance, biodegradability, and compatibility with traditional and modern material fabrication techniques, and have demonstrated safety and efficacy in clinical applications, modulating various facets of the wound healing process. Highlighting preclinical and clinical studies, along with commercial products, this review showcases the versatility and utility of natural polymers in wound management and provides insights into emerging developments, such as 3D bioprinting and stimuli‐responsive materials, which hold promise for personalized wound treatments. Additionally, we discuss the importance of the material format and morphology in engineering the next generation of wound dressings and skin substitutes, offering a pathway to optimize natural polymers for enhanced wound healing outcomes. [ABSTRACT FROM AUTHOR]

Atherosclerotic plaques are commonly observed at low shear regions, in particular, the left main coronary artery (LMCA) bifurcation. Low shear regions at bifurcations promote endothelial dysfunction, a key factor initiating atherogenesis, however, mechanisms underlying this process are poorly understood. Dynamic in vitro models are critical to investigate endothelial dysfunction, but current static and vessels‐on‐chip systems typically lack physiologically complex geometries and local shear changes. Here, a bifurcating coronary artery‐on‐a‐chip is developed, mimicking the human LMCA, displaying reduced shear near the bifurcation, verified using computational fluid dynamics simulations. Over 7 days of dynamic culture, human coronary artery endothelial cells aligned with the flow and expressed more Endothelial nitric oxide synthase (eNOS) and intercellular cell adheison molecule‐1 (ICAM‐1) at high shear regions (12.7 dyn cm−2) adjacent to, but not at the bifurcation (0–3 dyn cm−2). After tumor necrosis factor‐alpha (TNFα) stimulation to induce endothelial dysfunction, spatially mapping cellular changes and shear gradients revealed cell alignment is disrupted over a larger area surrounding the bifurcation at a higher shear, and ICAM‐1 expression is increased closer to the bifurcation at a lower shear. This coronary artery‐on‐a‐chip establishes a system to spatially map endothelial cell behavior in response to differential shear and vessel geometry, enabling future studies into plaque initiation events, treatment targets, and drug screening. [ABSTRACT FROM AUTHOR]

The use of tissue adhesives dates to 1940s when surgical glues were introduced for wound closure applications. However, current clinically used tissue adhesives (fibrin and cyanoacrylate glues) have limited adhesion strength and biocompatibility issues which restrict their performance in targeted applications. Due to this unmet clinical challenge, there is a need to develop next‐generation tissue adhesives to expand the current limited available options. Another factor that is often overlooked in the field is the consequence of when these tissue adhesives fail while in use in specific applications. In this review, the complications arising from tissue adhesives that have insufficient adhesion strength are covered, where unintentional loosening and detachment can lead to serious complications depending on both the applications and scenarios in which the adhesives are used. Next, the current methodologies employed to design tissue‐adhesive hydrogels targeting specific applications are also collated. Finally, the different strategies to engineer on‐demand removal property of these tissue‐adhesive hydrogels are consolidated, including some perspectives on current challenges and outlooks in this field. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) has garnered considerable attention due to its morbidity and mortality. Although the precise mechanisms underlying HCC tumorigenesis remain to be elucidated, evidence suggests that host immunity plays a pivotal role in its development. IL-36 and IL-37 are important immunoregulatory cytokines classified as pro-inflammatory and anti-inflammatory respectively. In the context of HCC, the downregulation of intrahepatic IL-36 is inversely correlated with cirrhosis, but positively correlated with 5-year survival rates, suggesting that IL-36 offers protection during HCC development. However, IL-36 may lose its hepatoprotective effects as the disease progresses to HCC in the context of dysregulated immunity in cirrhotic patients. Substantially increased circulating IL-36 in HCC patients is likely a systemic response to HCC stimulation, but is insufficient to suppress progression towards HCC. Intrahepatic IL-37 is suppressed in HCC patients, consistent with the inverse correlation between intrahepatic IL-37 and the level of AFP in HCC patients, suggesting IL-37 exerts hepatoprotection. There is no significant difference in IL-37 among differentiations of HCC or with respect to clinical BCLC stages or cirrhosis status in HCC patients. However, IL-37 protection is demonstrated in an IL-37 transfected HCC animal model, showing significantly reduced tumour size. IL-36/37 may inhibit HCC by enhancing M1 tumour-associated macrophages while not affecting M2 macrophages. The interplay between IL-36 (pro-inflammatory) and IL-37 (anti-inflammatory) is emerging as a crucial factor in host protection against the development of HCC. Further research is needed to investigate the complex mechanisms involved and the therapeutic potential of targeting these cytokines in HCC management. [ABSTRACT FROM AUTHOR]

Covalent biofunctionalization of implant surfaces using anti microbial agents is a promising approach to reducing bone infection and implant failure. Radical‐rich, ion‐assisted plasma polymerized (IPP) coatings enable surface covalent biofunctionalization in a simple manner; but until now, they are limited to only 2D surfaces. Here a new technology is demonstrated to create homogenous IPP coatings on 3D materials using a rotating, conductive cage that is negatively biased while immersed in RF plasma. Evidence is provided that under controlled energetic ion bombardment, this technology enables the formation of highly robust and homogenous radical‐rich coatings on 3D objects for subsequent covalent attachment of antimicrobial agents. To functionally apply this technology, the broad‐spectrum antimicrobial CSA‐90 is attached to the surfaces, where it retained potent antibacterial activity against Staphylococcus aureus. CSA‐90 covalent functionalization of stainless‐steel pins used in a murine model of orthopedic infection revealed the highly promising potential of this coating system to reduce S. aureus infection‐related bone loss. This study takes the previous research on plasma‐based covalent functionalization of 2D surfaces a step further, with important implications for ushering in a new dimension in the biofunctionalization of 3D structures for applications in bone implants and beyond. [ABSTRACT FROM AUTHOR]

The periosteum is a thin layer of connective tissue covering bone. It is an essential component for bone development and fracture healing. There has been considerable research exploring the application of the periosteum in bone regeneration since the 19th century. An increasing number of studies are focusing on periosteal progenitor cells found within the periosteum and the use of hydrogels as scaffold materials for periosteum engineering and guided bone development. Here, we provide an overview of the research investigating the use of the periosteum for bone repair, with consideration given to the anatomy and function of the periosteum, the importance of the cambium layer, the culture of periosteal progenitor cells, periosteum-induced ossification, periosteal perfusion, periosteum engineering, scaffold vascularization, and hydrogel-based synthetic periostea. [ABSTRACT FROM AUTHOR]

Models of arterial injury in rodents have been invaluable to our current understanding of vessel restenosis and play a continuing role in the development of endovascular interventions for cardiovascular disease. Mechanical distention of the vessel wall and denudation of the vessel endothelium are the two major modes of vessel injury observed in most clinical pathologies and are critical to the reproducible modelling of progressive neointimal hyperplasia. The current models which have dominated this research area are the mouse wire carotid or femoral injury and the rat carotid balloon injury. While these elicit simultaneous distension of the vessel wall and denudation of the luminal endothelium, each model carries limitations that need to be addressed using a complementary injury model. Wire injuries in mice are highly technical and procedurally challenging due to small vessel diameters, while rat balloon injuries require permanent blood vessel ligation and disruption of native blood flow. Complementary models of vascular injury with reproducibility, convenience, and increased physiological relevance to the pathophysiology of endovascular injury would allow for improved studies of neointimal hyperplasia in both basic and translational research. In this study, we developed a new surgical model that elicits vessel distention and endothelial denudation injury using sequential steps using microforceps and a standard needle catheter inserted via arteriotomy into a rat common carotid artery, without requiring permanent ligation of branching arteries. After 2 weeks post-injury this model elicits highly reproducible neointimal hyperplasia and rates of re-endothelialisation similar to current wire and balloon injury models. Furthermore, evaluation of the smooth muscle cell phenotype profile, inflammatory response and extracellular matrix within the developing neointima, showed that our model replicated the vessel remodelling outcomes critical to restenosis and those becoming increasingly focused upon in the development of new anti-restenosis therapies. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are increasingly recognised as key regulators of the development and progression of many diseases due to their ability to modulate gene expression post-translationally. While this makes them an attractive therapeutic target, clinical application of miRNA therapy remains at an early stage and in part is limited by the lack of effective delivery modalities. Here, we determined the feasibility of delivering miRNA using a new class of plasma-polymerised nanoparticles (PPNs), which we have recently isolated and characterised. We showed that PPN-miRNAs have no significant effect on endothelial cell viability in vitro in either normal media or in the presence of high-glucose conditions. Delivery of a miRNA inhibitor targeting miR-503 suppressed glucose-induced miR-503 upregulation and restored the downstream mRNA expression of CCNE1 and CDC25a in endothelial cells. Subsequently, PPN delivery of miR-503 inhibitors enhanced endothelial angiogenesis, including tubulogenesis and migration, in culture conditions that mimic diabetic ischemia. An intramuscular injection of a PPN-miR-503 inhibitor promoted blood-perfusion recovery in the hindlimb of diabetic mice following surgically induced ischemia, linked with an increase in new blood vessel formation. Together, this study demonstrates the effective use of PPN to deliver therapeutic miRNAs in the context of diabetes. [ABSTRACT FROM AUTHOR]

Minimally invasive interventions using drug‐eluting stents or balloons are a first‐line treatment for certain occlusive cardiovascular diseases, but the major long‐term cause of failure is neointimal hyperplasia (NIH). The drugs eluted from these devices are non‐specific anti‐proliferative drugs, such as paclitaxel (PTX) or sirolimus (SMS), which do not address the underlying inflammation. MCC950 is a selective inhibitor of the NLRP3‐inflammasome, which drives sterile inflammation commonly observed in NIH. Additionally, in contrast to broad‐spectrum anti‐inflammatory drugs, MCC950 does not compromise global immune function due this selective activity. In this study, MCC950 is found to not impact the viability, integrity, or function of human coronary endothelial cells, in contrast to the non‐specific anti‐proliferative effects of PTX and SMS. Using an in vitro model of NLRP3‐mediated inflammation in murine macrophages, MCC950 reduced IL‐1β expression, which is a key driver of NIH. In an in vivo mouse model of NIH in vascular grafts, MCC950 significantly enhanced re‐endothelialization and reduced NIH compared to PTX or SMS. These findings show the effectiveness of a targeted anti‐inflammatory drug‐elution strategy with significant implications for cardiovascular device intervention. [ABSTRACT FROM AUTHOR]

Periosteum is a highly vascularized membrane lining the surface of bones. It plays essential roles in bone repair following injury and reconstruction following invasive surgeries. To broaden the use of periosteum, including for augmenting in vitro bone engineering and/or in vivo bone repair, we have developed an ex vivo perfusion bioreactor system to maintain the cellular viability and metabolism of surgically resected periosteal flaps. Each specimen was placed in a 3D printed bioreactor connected to a peristaltic pump designed for the optimal flow rates of tissue perfusate. Nutrients and oxygen were perfused via the periosteal arteries to mimic physiological conditions. Biochemical assays and histological staining indicate component cell viability after perfusion for almost 4 weeks. Our work provides the proof-of-concept of ex vivo periosteum perfusion for long-term tissue preservation, paving the way for innovative bone engineering approaches that use autotransplanted periosteum to enhance in vivo bone repair. [ABSTRACT FROM AUTHOR]

The inability of adult cells to produce well-organized, robust elastic fibers has long been a barrier to the successful engineering of certain tissues. In this review, we focus primarily on elastin with respect to tissue-engineered vascular substitutes. To understand elastin regulation during normal development, we describe the role of various elastic fiber accessory proteins. Biochemical pathways regulating expression of the elastin gene are addressed, with particular focus on tissue-engineering research using adult-derived cells.