Tissue engineered vascular grafts are resistant to the formation of dystrophic calcification.

Advancements in congenital heart surgery have heightened the importance of durable biomaterials for adult survivors. Dystrophic calcification poses a significant risk to the long-term viability of prosthetic biomaterials in these procedures. Herein, we describe the natural history of calcification in the most frequently used vascular conduits, expanded polytetrafluoroethylene grafts. Through a retrospective clinical study and an ovine model, we compare the degree of calcification between tissue-engineered vascular grafts and polytetrafluoroethylene grafts. Results indicate superior durability in tissue-engineered vascular grafts, displaying reduced late-term calcification in both clinical studies (p < 0.001) and animal models (p < 0.0001). Further assessments of graft compliance reveal that tissue-engineered vascular grafts maintain greater compliance (p < 0.0001) and distensibility (p < 0.001) than polytetrafluoroethylene grafts. These properties improve graft hemodynamic performance, as validated through computational fluid dynamics simulations. We demonstrate the promise of tissue engineered vascular grafts, remaining compliant and distensible while resisting long-term calcification, to enhance the long-term success of congenital heart surgeries.

Quantification of Skeletal Muscle Perfusion in Peripheral Artery Disease Using 18F-Sodium Fluoride Positron Emission Tomography Imaging.

BACKGROUND: Perfusion deficits contribute to symptom severity, morbidity, and death in peripheral artery disease (PAD); however, no standard method for quantifying absolute measures of skeletal muscle perfusion exists. This study sought to preclinically test and clinically translate a positron emission tomography (PET) imaging approach using an atherosclerosis-targeted radionuclide, fluorine-18-sodium fluoride (18F-NaF), to quantify absolute perfusion in PAD. METHODS AND RESULTS: Eight Yorkshire pigs underwent unilateral femoral artery ligation and dynamic 18F-NaF PET/computed tomography imaging on the day of and 2 weeks after occlusion. Following 2-week imaging, calf muscles were harvested to quantify microvascular density. PET methodology was validated with microspheres in 4 additional pig studies and translated to patients with PAD (n=39) to quantify differences in calf perfusion across clinical symptoms/stages and perfusion responses in a case of revascularization. Associations between PET perfusion, ankle-brachial index, toe-brachial index, and toe pressure were assessed in relation to symptoms. 18F-NaF PET/computed tomography quantified significant deficits in calf perfusion in pigs following arterial occlusion and perfusion recovery 2 weeks after occlusion that coincided with increased muscle microvascular density. Additional studies confirmed that PET-derived perfusion measures agreed with microsphere-derived perfusion measures. Translation of imaging methods demonstrated significant decreases in calf perfusion with increasing severity of PAD and quantified perfusion responses to revascularization. Perfusion measures were also significantly associated with symptom severity, whereas traditional hemodynamic measures were not. CONCLUSIONS: 18F-NaF PET imaging quantifies perfusion deficits that correspond to clinical stages of PAD and represents a novel perfusion imaging strategy that could be partnered with atherosclerosis-targeted 18F-NaF PET imaging using a single radioisotope injection. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03622359.

Successful Orthotopic Liver Transplantation in Mice Utilizing Microcomputed Tomography Angiography.

Microcomputed tomography (microCT) angiography is an invaluable resource to researchers. New advances in this technology have allowed for high-quality images to be obtained of micro-vasculature and are high-fidelity tools in the field of organ transplantation. In this model of orthotopic liver transplantation (OLT) in mice, microCT affords the opportunity to evaluate allograft anastomosis in real time and has the added benefit of not having to sacrifice study animals. The choice of contrast, as well as image acquisition settings, create a high-definition image, which gives researchers invaluable information. This allows for evaluation of the technical aspects of the procedure as well as potentially evaluating different therapeutics over an extended duration of time. In this protocol, we detail an OLT model in mice in a stepwise fashion and finally describe a microCT protocol that can give high-quality images, which aid researchers in in-depth analysis of solid organ transplantation. We provide a step-by-step guide for liver transplantation in a mouse, as well as briefly discuss a protocol for evaluating the patency of the graft through microCT angiography.

Prognostic Value of Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Imaging for Predicting Venous Thromboembolism in Children With Lymphoma.

BACKGROUND: Positron emission tomography (PET)/computed tomography (CT) imaging can detect changes in arterial inflammation, but has not been used to evaluate chemotherapy-induced venous inflammation or assess risk for venous thromboembolism (VTE) in pediatric oncology. Therefore, the purpose of this study was to evaluate the prognostic value of fluorine-18-fluorodeoxyglucose PET/CT imaging of venous inflammation for predicting VTE occurrence in the 12 months after lymphoma diagnosis in pediatric, adolescent, and young adult patients. METHODS: Pediatric, adolescent, and young adult patients with lymphoma diagnoses (n=71) who underwent whole-body PET/CT imaging at initial staging of disease and first therapeutic follow-up were retrospectively evaluated for serial changes in lower extremity venous uptake of fluorine-18-fluorodeoxyglucose. PET/CT images were used to segment and quantify serial changes in fluorine-18-fluorodeoxyglucose uptake for veins of interest (ie, popliteal and femoral). Incidence of VTE was assessed for 12 months after lymphoma diagnosis. RESULTS: PET/CT detected a significantly higher inflammatory response in the femoral (P=0.012) and popliteal (P=0.013) veins of patients who experienced a VTE event compared with those who remained VTE free in the 12 months after diagnosis. The area under the curve values for receiver operator characteristics analyses were 0.76 (femoral vein) and 0.77 (popliteal vein) based on incidence of VTE occurrence. Univariate analyses demonstrated that PET/CT-derived changes in femoral (P=0.008) and popliteal (P=0.002) vein inflammation were significantly associated with VTE-free survival at 12 months after diagnosis. CONCLUSIONS: Fluorine-18-fluorodeoxyglucose PET/CT imaging detects treatment-induced venous toxicity that may provide insight into risk of VTE events in pediatric and adolescent and young adult patients with lymphoma.

Hydrogel-Encapsulated Heterogenous Mesoporous Resin Catalyst for In Situ Anti-Cancer Agent Production under Biological Conditions.

A heterogenous Palladium anchored Resorcinol-formaldehyde-hyperbranched PEI mesoporous catalyst, made by one-pot synthesis, was used successfully for in situ Suzuki-Miyaura cross coupling synthesis of anticancer prodrug PP-121 from iodoprazole and boronic ester precursors. The mesoporous catalyst with the non-cytotoxic precursors were tested in 2D in vitro model with excellent cytocompatibility and a strong suppression of PC3 cancer cell proliferation, underscored by 50% reduction in PC3 cells viability and 55% reduction in cell metabolism activity and an enhanced rate of early and late apoptosis in flow cytometry, that was induced only by successful in situ pro drug PP121 synthesis from the precursors. The 3D gelatin methacrylate hydrogel encapsulated in vitro cell models underscored the results with a 52% reduction in cell metabolism and underscored apoptosis of PC3 cells when the Pd anchored catalyst was combined with the precursors. In situ application of Suzuki-Miyaura cross coupling of non-cytotoxic precursors to cancer drug, along with their successful encapsulation in an injectable hydrogel could be applied for tumor point drug delivery strategies that can circumvent deleterious side effects and poor bioavailability chemotherapy routes with concomitant enhanced efficacy.

Developing Eco-Friendly and Cost-Effective Porous Adsorbent for Carbon Dioxide Capture.

To address the issue of global warming and climate change issues, recent research efforts have highlighted opportunities for capturing and electrochemically converting carbon dioxide (CO2). Despite metal doped polymers receiving widespread attention in this respect, the structures hitherto reported lack in ease of synthesis with scale up feasibility. In this study, a series of mesoporous metal-doped polymers (MRFs) with tunable metal functionality and hierarchical porosity were successfully synthesized using a one-step copolymerization of resorcinol and formaldehyde with Polyethyleneimine (PEI) under solvothermal conditions. The effect of PEI and metal doping concentrations were observed on physical properties and adsorption results. The results confirmed the role of PEI on the mesoporosity of the polymer networks and high surface area in addition to enhanced CO2 capture capacity. The resulting Cobalt doped material shows excellent thermal stability and promising CO2 capture performance, with equilibrium adsorption of 2.3 mmol CO2/g at 0 °C and 1 bar for at a surface area 675.62 m2/g. This mesoporous polymer, with its ease of synthesis is a promising candidate for promising for CO2 capture and possible subsequent electrochemical conversion.

Recent Progress in Iron Oxide Nanoparticles as Therapeutic Magnetic Agents for Cancer Treatment and Tissue Engineering.

The positive response of superparamagnetic iron oxide nanoparticles (SPIONs), in terms of biodegradability, circulation, elimination, toxicity, and manipulation of their structure/activity relationship, has enabled them to find their way into commercialization as an iron supplement, MRI contrast agents, MPI tracers, and hyperthermia and magneto-mechanical actuators. This Review focuses on the most current progress regarding the application of SPIONs as magnetic therapeutic agents for cancer treatment and tissue engineering. Because of their superior magnetic anisotropy, irreversibility of high- and low-field magnetization, and superparamagnetic ordering at corporal temperatures, they exhibit the unique ability to respond to theraputic doses (e.g., in magnetic hyperthermia and targeted drug delivery). This Review discusses the role of SPIONs to enhance chemotherapy and radiotherapy efficiency and specificity and how this enhancement could mitigate some side effects. SPIONs applied as tools for gene delivery, immunotherapy, and tissue engineering are also reviewed in the context of their potential to translational medicine. Lastly, some emerging issues concerning SPION toxicity are summarized and how they are being addressed to achieve success in clinical applications is discussed.

Nano-hydroxyapatite-alginate-gelatin microcapsule as a potential osteogenic building block for modular bone tissue engineering.

To develop osteogenic building blocks for modular bone tissue engineering applications, influence of gelatin as cell adhesive molecule and nano-hydroxyapatite (nHA) as osteoconductive component was examined on alginate-based hydrogel properties and microencapsulated osteoblast-like cell behavior by using factorial experimental design technique. nHA and alginate showed a statistically significant impact on swelling reduction, and improvement of stability and mechanical strength of hydrogels, respectively. Gelatin influence, however, was in a reverse manner. nHA played imperative roles in promoting microencapsulated osteoblastic cell proliferation and function due to its bioactivity and mechanical strength improvement of hydrogels to the modulus range of mineralized bone tissue in vivo. The results and their statistical analysis also revealed the importance of interaction effect of gelatin and nHA. Proliferation and osteogenic function of the cells fluctuated with increasing gelatin concentration of microcapsules in the presence of nHA, demonstrating that hydrogel properties should be balanced to provide an efficient 3D osteoconductive microcapsule. Alginate (1%)-gelatin (2.5%)-nHA (0.5%) microcapsule with compressive modulus of 0.19 MPa ±â€¯0.02, swelling ratio of 52% ±â€¯8 (24 h) and degradation rate of 12% ±â€¯4 (96 h) revealed a maximum performance for the cell proliferation and function, indicating a potential microcapsule composition to prepare building blocks for modular bone tissue engineering.

Patient-Specific Bioinks for 3D Bioprinting of Tissue Engineering Scaffolds.

Bioprinting has emerged as a promising tool in tissue engineering and regenerative medicine. Various 3D printing strategies have been developed to enable bioprinting of various biopolymers and hydrogels. However, the incorporation of biological factors has not been well explored. As the importance of personalized medicine is becoming more clear, the need for the development of bioinks containing autologous/patient-specific biological factors for tissue engineering applications becomes more evident. Platelet-rich plasma (PRP) is used as a patient-specific source of autologous growth factors that can be easily incorporated to hydrogels and printed into 3D constructs. PRP contains a cocktail of growth factors enhancing angiogenesis, stem cell recruitment, and tissue regeneration. Here, the development of an alginate-based bioink that can be printed and crosslinked upon implantation through exposure to native calcium ions is reported. This platform can be used for the controlled release of PRP-associated growth factors which may ultimately enhance vascularization and stem cell migration.

Enhanced mechanical properties and biocompatibility of novel hydroxyapatite/TOPAS hybrid composite for bone tissue engineering applications.

The bioactivity and mechanical properties of hybrid composites of hydroxyapatite (HA) in cyclic olefinic copolymer (COC) also known commercially as TOPAS are investigated, first time, for regeneration and repair of the bone tissues. HA is synthesized to obtain the spherically shaped nanoparticles in the size range of 60±20nm. Various concentrations of HA ranging from 1 to 30wt% are dispersed in TOPAS using sodium dodecyl sulfate (SDS) coupling agent for better dispersion and interaction of hydrophilic HA with hydrophobic TOPAS. Scanning electron microscope shows the uniform dispersion of HA≤10wt% in TOPAS and at higher concentrations >10wt%, agglomeration occurs in the hybrid composites. Tunable mechanical properties are achieved as the compressive modulus and strength are increased around 140% from 6.4 to 15.3MPa and 185% from 0.26 to 0.74MPa, respectively. Such increase in the mechanical properties of TOPAS is attributed to the anchoring of the polymer chains in the vicinity of HA nanoparticles owing to better dispersion and interfacial interactions. In comparison to neat TOPAS, hybrid composites of TOPAS/HA promoted the cell adhesion and proliferation significantly. The cell density and proliferation of TOPAS/HA hybrid composites is enhanced 9 and 3 folds, respectively, after 1day culturing in preosteoblasts cells. Moreover, the morphology of cells changed from spherical to flattened spread morphology demonstrating clearly the migration of the cells for the formation of interconnected cellular network. Additionally, very few dead cells are found in hybrid composites showing their cytocompatibility. Overall, the hybrid composites of TOPAS/HA exhibited superior strength and stiffness along with enhanced cytocompatibility for bone tissue engineering applications.

A microfluidic optical platform for real-time monitoring of pH and oxygen in microfluidic bioreactors and organ-on-chip devices.

There is a growing interest to develop microfluidic bioreactors and organ-on-chip platforms with integrated sensors to monitor their physicochemical properties and to maintain a well-controlled microenvironment for cultured organoids. Conventional sensing devices cannot be easily integrated with microfluidic organ-on-chip systems with low-volume bioreactors for continual monitoring. This paper reports on the development of a multi-analyte optical sensing module for dynamic measurements of pH and dissolved oxygen levels in the culture medium. The sensing system was constructed using low-cost electro-optics including light-emitting diodes and silicon photodiodes. The sensing module includes an optically transparent window for measuring light intensity, and the module could be connected directly to a perfusion bioreactor without any specific modifications to the microfluidic device design. A compact, user-friendly, and low-cost electronic interface was developed to control the optical transducer and signal acquisition from photodiodes. The platform enabled convenient integration of the optical sensing module with a microfluidic bioreactor. Human dermal fibroblasts were cultivated in the bioreactor, and the values of pH and dissolved oxygen levels in the flowing culture medium were measured continuously for up to 3 days. Our integrated microfluidic system provides a new analytical platform with ease of fabrication and operation, which can be adapted for applications in various microfluidic cell culture and organ-on-chip devices.