Selective Immunosuppression Targeting the NLRP3 Inflammasome Mitigates the Foreign Body Response to Implanted Biomaterials While Preserving Angiogenesis.

Medical devices are a mainstay of the healthcare industry, providing clinicians with innovative tools to diagnose, monitor, and treat a range of medical conditions. For implantable devices, it is widely regarded that chronic inflammation during the foreign body response (FBR) is detrimental to device performance, but also required for tissue regeneration and host integration. Current strategies to mitigate the FBR rely on broad acting anti-inflammatory drugs, most commonly, dexamethasone (DEX), which can inhibit angiogenesis and compromise long-term device function. This study challenges prevailing assumptions by suggesting that FBR inflammation is multifaceted, and selectively targeting its individual pathways can stop implant fibrosis while preserving beneficial repair pathways linked to improved device performance. MCC950, an anti-inflammatory drug that selectively inhibits the NLRP3 inflammasome, targets pathological inflammation without compromising global immune function. The effects of MCC950 and DEX on the FBR are compared using implanted polycaprolactone (PCL) scaffolds. The results demonstrate that both DEX and MCC950 halt immune cell recruitment and cytokine release, leading to reduced FBR. However, MCC950 achieves this while supporting capillary growth and enhancing tissue angiogenesis. These findings support selective immunosuppression approaches as a potential future direction for treating the FBR and enhancing the longevity and safety of implantable devices.

Highly reproducible rat arterial injury model of neointimal hyperplasia.

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.

Selective NLRP3 Inflammasome Inhibitor MCC950 Suppresses Inflammation and Facilitates Healing in Vascular Materials.

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-1ß 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.

Evaluation of the Immune Response to Chitosan-graft-poly(caprolactone) Biopolymer Scaffolds.

Biomimetic scaffolds recreating key elements of the architecture and biological activity of the extracellular matrix have enormous potential for soft tissue engineering applications. Combining appropriate mechanical properties with select biological cues presents a challenge for bioengineering, as natural materials are most bioactive but can lack mechanical integrity, while synthetic polymers have strength but are often biologically inert. Blends of synthetic and natural materials, aiming to combine the benefits of each, have shown promise but inherently require a compromise, diluting down favorable properties in each polymer to accommodate the other. Here, we electrospun a material comprising chitosan, a natural polysaccharide, and polycaprolactone (PCL), one of the most widely studied synthetic polymers used in materials engineering. In contrast to a classical blend, here PCL was chemically grafted onto the chitosan backbone to create chitosan-graft-polycaprolactone (CS-g-PCL) and then combined further with unmodified PCL to generate scaffolds with discreet chitosan functionalization. These small amounts of chitosan led to significant changes in scaffold architecture and surface chemistry, reducing the fiber diameter, pore size, and hydrophobicity. Interestingly, all CS-g-PCL-containing blends were stronger than control PCL, though with reduced elongation. In in vitro assessments, increasing the CS-g-PCL content led to significant improvements in in vitro blood compatibility compared to PCL alone while increasing fibroblast attachment and proliferation. In a mouse subcutaneous implantation model, a higher CS-g-PCL content improved the immune response to the implants. Macrophages in tissues surrounding CS-g-PCL scaffolds decreased proportionately to the chitosan content by up to 65%, with a corresponding decrease in pro-inflammatory cytokines. These results suggest that CS-g-PCL is a promising hybrid material comprising natural and synthetic polymers with tailorable mechanical and biological properties, justifying further development and in vivo evaluation.

Impact of a mobile integrated healthcare and community paramedicine program on improving medication adherence in patients with heart failure and chronic obstructive pulmonary disease after hospital discharge: A pilot study.

Background: The mobile integrated health-community paramedicine (MIH-CP) program affiliated with the University of Maryland Medical Center focuses on improving patient transitions from hospital to home by addressing both medical and social determinants of health. Until recently, only self-contained health systems could integrate inpatient and outpatient medication data. Without some means to track patients in transition, there is a significant risk of medication-related problems and errors. Objective: To evaluate the impact of the MIH-CP program on medication adherence among patients with congestive heart failure (CHF) and/or chronic obstructive pulmonary disease (COPD). Methods: This is a pilot observational study designed to compare adherence to drug regimens prescribed at hospital discharge (measured by the proportion of days covered [PDC]) between patients enrolled in the MIH-CP program and a propensity-matched control group. Propensity scores were calculated using 11 demographic, diagnostic, third-party payer, and patient care-associated variables. Discharge medication details were obtained from electronic medical records. PDC for each of the medications were calculated from pharmacy claims data. Results: Eighty-three patients were included in the study; forty-three patients were placed in the intervention group and 40 were propensity-matched controls. After adjusting for age, sex, and third-party payer, findings indicated that medication adherence was higher among patients enrolled in the MIH-CP program compared with control during the first 30 days post-discharge, specifically among patients diagnosed with CHF (8% difference in PDC, 95% confidence interval [CI], -0.12-0.28%) and COPD (14% difference, 95% CI, -0.15-0.43%), although neither result achieved statistical significance. The differences in medication adherence between patients who were enrolled and those who were not enrolled in the MIH-CP program diminished after 30 days post-discharge. Conclusion: This pilot study demonstrated a trend toward improved medication adherence among patients enrolled in the MIH-CP program. Future research involving a larger patient cohort will be required to confirm these preliminary findings.

Bioengineering artificial blood vessels from natural materials.

Bioengineering an effective, small diameter (<6 mm) artificial vascular graft for use in bypass surgery when autologous grafts are unavailable remains a persistent challenge. Commercially available grafts are typically made from plastics, which have high strength but lack elasticity and present a foreign surface that triggers undesirable biological responses. Tissue engineered grafts, leveraging decellularized animal vessels or derived de novo from long-term cell culture, have dominated recent research, but failed to meet clinical expectations. More effective constructs that are readily translatable are urgently needed. Recent advances in natural materials have made the production of robust acellular conduits feasible and their use increasingly attractive. Here, we identify a subset of natural materials with potential to generate durable, small diameter vascular grafts.

Silk Fibroin Scaffold Architecture Regulates Inflammatory Responses and Engraftment of Bone Marrow-Mononuclear Cells.

Despite being one of the most clinically trialed cell therapies, bone marrow-mononuclear cell (BM-MNC) infusion has largely failed to fulfill its clinical promise. Implanting biomimetic scaffolds at sites of injury prior to BM-MNC infusion is a promising approach to enhance BM-MNC engraftment and therapeutic function. Here, it is demonstrated that scaffold architecture can be leveraged to regulate the immune responses that drive BM-MNC engraftment. Silk scaffolds with thin fibers and low porosity (LP) impairs immune activation in vitro compared with thicker fiber, high porosity (HP) scaffolds. Using the authors' established in vivo bioluminescent BM-MNC tracking model, they showed that BM-MNCs home to and engraft in greater numbers in HP scaffolds over 14 days. Histological analysis reveals thicker fibrous capsule formation, with enhanced collagen deposition in HP compared to LP scaffolds consistent with substantially more native CD68+ macrophages and CD4+ T cells, driven by their elevated pro-inflammatory M1 and Th1 phenotypes, respectively. These results suggest that implant architecture impacts local inflammation that drives differential engraftment and remodeling behavior of infused BM-MNC. These findings inform the future design of biomimetic scaffolds that may better enhance the clinical effectiveness of BM-MNC infusion therapy.

Development of a shear-thinning biomaterial as an endovascular embolic agent for the treatment of type B aortic dissection.

False lumen embolisation is a promising treatment strategy in type B aortic dissection (TBAD) but it is limited by the lack of a disease-specific embolic agent. Our aim was to develop a biomaterial that could be delivered minimally-invasively into the TBAD false lumen and embolise the region. We created 24 shear-thinning biomaterials from blends of gelatin, silicate nanoparticles and silk fibroin, and evaluated their suitability as a false lumen embolic agent in TBAD. We determined the stability of mechanical properties by measuring the compressive modulus of samples stored in physiological conditions over a 21 day period. We quantified injectability by measuring the force required to inject each biomaterial through catheters of varying diameter. We also assessed in vitro degradation rates by measuring weight change over 30 days. Finally, we developed an in vitro experimental pulsatile flow setup with two different anatomically-correct TBAD geometries and performed 78 false lumen occlusion experiments under different operating conditions. We found that the compressive moduli changed rapidly on exposure to 37 °C before stabilising by Day 7. A high silicate nanoparticle to gelatin ratio resulted in greater compressive moduli, with a maximum of 117.6 ±â€¯15.2 kPa. By reducing the total solid concentration, we could improve injectability and biomaterials with 8% (w/v) solids required <80 N force to be injected through a 4.0 mm catheter. Our in vitro degradation rates showed that the biomaterial only degraded by 1.5-8.4% over a 30 day period. We found that the biomaterial could occlude flow to the false lumen in 99% of experiments. In conclusion, blends with high silicate nanoparticle and low silk fibroin content warrant further investigation for their potential as false lumen embolic agents and could be a promising alternative to current TBAD repair methods.

Reducing the gray zone: imaging spectrum of hypoperfusion and hypoxic brain injury in adults.

The purpose of this pictorial essay is to illustrate the computed tomography and magnetic resonance imaging manifestations of hypoperfusion and hypoxic brain injury in adults, a clinical scenario not uncommon in the emergency room setting. The imaging findings can be subtle or marked depending on the type of injury and the time elapsed from injury to imaging. Accurate recognition of the imaging findings in hypoperfusion and hypoxic injury in adults is important for accurate therapy and family-patient counseling.