Aminosilane Functionalized Aligned Fiber PCL Scaffolds for Peripheral Nerve Repair.

Silane modification is a simple and cost-effective tool to modify existing biomaterials for tissue engineering applications. Aminosilane layer deposition has previously been shown to control NG108-15 neuronal cell and primary Schwann cell adhesion and differentiation by controlling deposition of ─NH2 groups at the submicron scale across the entirety of a surface by varying silane chain length. This is the first study toreport depositing 11-aminoundecyltriethoxysilane (CL11) onto aligned Polycaprolactone (PCL) scaffolds for peripheral nerve regeneration. Fibers are manufactured via electrospinning and characterized using water contact angle measurements, atomic force microscopy (AFM), and X-ray photoelectron spectroscopy (XPS). Confirmed modified fibers are investigated using in vitro cell culture of NG108-15 neuronal cells and primary Schwann cells to determine cell viability, cell differentiation, and phenotype. CL11-modified fibers significantly support NG108-15 neuronal cell and Schwann cell viability. NG108-15 neuronal cell differentiation maintains Schwann cell phenotype compared to unmodified PCL fiber scaffolds. 3D ex vivo culture of Dorsal root ganglion explants (DRGs) confirms further Schwann cell migration and longer neurite outgrowth from DRG explants cultured on CL11 fiber scaffolds compared to unmodified scaffolds. Thus, a reproducible and cost-effective tool is reported to modify biomaterials with functional amine groups that can significantly improve nerve guidance devices and enhance nerve regeneration.

A real-world comparison of the clinical and economic utility of OVA1 and CA125 in assessing ovarian tumor malignancy risk.

Aim: This largest-of-its-kind study evaluated the clinical utility of CA125 and OVA1, commonly used as ovarian tumor markers for assessing the risk of malignancy. The research focused on the ability and utility of these tests to reliably predict patients at low risk for ovarian cancer. Clinical utility endpoints were 12-month maintenance of benign mass status, reduction in gynecologic oncologist referral, avoidable surgical intervention and associated cost savings. Materials & methods: This was a multicenter retrospective review of data from electronic medical records and administrative claims databases. Patients receiving a CA125 or OVA1 test between October 2018 and September 2020 were identified and followed for 12 months using site-specific electronic medical records to assess tumor status and utilization outcomes. Propensity score adjustment was used to control for confounding variables. Payer allowed amounts from Merative MarketScan Research Databases were used to estimate 12-month episode-of-care costs per patient, including surgery and other interventions. Results: Among 290 low-risk OVA1 patients, 99.0% remained benign for 12 months compared with 97.2% of 181 low-risk CA125 patients. The OVA1 cohort exhibited 75% lower odds of surgical intervention in the overall sample of patients (Adjusted OR: 0.251, p ≤ 0.0001), and 63% lower odds of gynecologic oncologist utilization among premenopausal women (Adjusted OR: 0.37, p = 0.0390) versus CA125. OVA1 demonstrated significant savings in surgical interventions ($2486, p ≤ 0.0001) and total episode-of-care costs ($2621, p ≤ 0.0001) versus CA125. Conclusion: This study underscores the utility of a reliably predictive multivariate assay for assessing ovarian cancer risk. For patients assessed at low risk of ovarian tumor malignancy, OVA1 is associated with a significant reduction in avoidable surgeries and substantial cost savings per patient. OVA1 is also associated with a significant reduction in subspecialty referrals for low-risk premenopausal patients.

Aligned Polyhydroxyalkanoate Blend Electrospun Fibers as Intraluminal Guidance Scaffolds for Peripheral Nerve Repair.

The use of nerve guidance conduits (NGCs) to treat peripheral nerve injuries is a favorable approach to the current "gold standard" of autografting. However, as simple hollow tubes, they lack specific topographical and mechanical guidance cues present in nerve grafts and therefore are not suitable for treating large gap injuries (30-50 mm). The incorporation of intraluminal guidance scaffolds, such as aligned fibers, has been shown to increase neuronal cell neurite outgrowth and Schwann cell migration distances. A novel blend of PHAs, P(3HO)/P(3HB) (50:50), was investigated for its potential as an intraluminal aligned fiber guidance scaffold. Aligned fibers of 5 and 8 µm diameter were manufactured by electrospinning and characterized using SEM. Fibers were investigated for their effect on neuronal cell differentiation, Schwann cell phenotype, and cell viability in vitro. Overall, P(3HO)/P(3HB) (50:50) fibers supported higher neuronal and Schwann cell adhesion compared to PCL fibers. The 5 µm PHA blend fibers also supported significantly higher DRG neurite outgrowth and Schwann cell migration distance using a 3D ex vivo nerve injury model.

A 90-Day Episode-of-Care Analysis Including Computed Tomography Scans of Robotic-Arm Assisted versus Manual Total Knee Arthroplasty.

In this observational, retrospective study, we performed economic analyses between robotic arm-assisted total knee arthroplasty (RATKA) and manual total knee arthroplasty (MTKA). Specifically, we compared: (1) index costs including computed tomography (CT) scans; (2) 90-day postoperative health care utilization, (3) 90-day episode-of-care (EOC) costs, and (4) lengths of stay between CT scan-based robotically-assisted versus MTKAs. A large national database, Blue Health Intelligence (BHI), was used for RATKAs and MTKAs performed between April 1, 2017 and September 30, 2019. Based on strict inclusion-exclusion criteria, with propensity score matching, 4,135 RATKAs and 4,135 MTKAs were identified and analyzed. Index costs to the payer for RATKA patients were found to be less than those for MTKA patients ($29,984 vs. $31,280, p <0.0001). Overall, 90-day EOC costs for RATKA patients were found to be less than that for MTKA patients in the inpatient and outpatient settings. This also holds true for the use of skilled nursing facilities, pharmacies, or other services. In conclusion, the results from our study show that RATKA were associated with lower costs than MTKAs, even when including the cost of CT scans. These results are of marked importance given the emphasis to contain and reduce health care costs.

Continuous Positive Airway Pressure Adherence and Treatment Cost in Patients With Obstructive Sleep Apnea and Cardiovascular Disease.

Objective: To determine whether continuous positive airway pressure (CPAP) adherence reduces health care-related costs or use in patients with obstructive sleep apnea (OSA) and comorbid cardiovascular disease (CVD). Patients: A total of 23 million patients with CVD were identified in the Medicare fee-for-service database. Of the 65,198 who completed a sleep study between January 2016 and September 2018, 55,125 were diagnosed as having OSA and 1758 were identified in the 5% Medicare durable medical equipment (DME) database. Methods: Patients with DME claims were categorized as adherent (AD, treatment evidenced ≥91 days after CPAP initiation; n=614) or nonadherent (nAD, n=242) to CPAP therapy. In addition, 9881 individuals with CVD who were not diagnosed as having OSA after sleep testing and without CPAP initiation were included as control patients. Propensity score matching balanced the groups for age, sex, and comorbidities (eg, diabetes mellitus), resulting in 241 participants per cohort. Dependent variables included total episode-of-care, inpatient, outpatient, skilled nursing, home health, and DME costs across 12 months. Results: Total episode-of-care costs of AD participants ($6825) were lower than those of nAD ($11,312; P<.05) and control ($8102) participants. This difference (Δ) was attributable to fewer outpatient expenses (Δ$2290; P<.05) relative to the nAD group and fewer inpatient expenses (Δ$745) relative to the control group because skilled nursing costs were comparable between groups (P=.73). Conclusion: Adherence to CPAP treatment reduces annual health care-related expenses by 40% in Medicare patients with CVD and OSA.

Polyhydroxyalkanoates and their advances for biomedical applications.

Polyhydroxyalkanoates (PHAs) are sustainable, versatile, biocompatible, and bioresorbable polymers that are suitable for biomedical applications. Produced via bacterial fermentation under nutrient-limiting conditions, they are uncovering a new horizon for devices in biomedical applications. A wide range of cell types including bone, cartilage, nerve, cardiac, and pancreatic cells, readily attach grow and are functional on PHAs. The tuneable physical properties and resorption rates of PHAs provide a toolbox for biomedical engineers in developing devices for hard and soft tissue engineering applications and drug delivery. The versatility of PHAs and the vast range of different PHA-based prototypes are discussed. Current in vitro, ex vivo, and in vivo development work are described and their regulatory approvals are reviewed.

Cell guidance on peptide micropatterned silk fibroin scaffolds.

Guiding neuronal cell growth is desirable for neural tissue engineering but is very challenging. In this work, a self-assembling ultra-short surfactant-like peptide I3K which possesses positively charged lysine head groups, and hydrophobic isoleucine tails, was chosen to investigate its potential for guiding neuronal cell growth. The peptides were able to self-assemble into nanofibrous structures and interact strongly with silk fibroin (SF) scaffolds, providing a niche for neural cell attachment and proliferation. SF is an excellent biomaterial for tissue engineering. However neuronal cells, such as rat PC12 cells, showed poor attachment on pure regenerated SF (RSF) scaffold surfaces. Patterning of I3K peptide nanofibers on RSF surfaces significantly improved cellular attachment, cellular density, as well as morphology of PC12 cells. The live / dead assay confirmed that RSF and I3K have negligible cytotoxicity against PC12 cells. Atomic force microscopy (AFM) was used to image the topography and neurite formation of PC12 cells, where results revealed that self-assembled I3K nanofibers can support the formation of PC12 cell neurites. Immunolabelling also demonstrated that coating of I3K nanofibers onto the RSF surfaces not only increased the percentage of cells bearing neurites but also increased the average maximum neurite length. Therefore, the peptide I3K could be used as an alternative to poly-l-lysine for cell culture and tissue engineering applications. As micro-patterning of neural cells to guide neurite growth is important for developing nerve tissue engineering scaffolds, inkjet printing was used to pattern self-assembled I3K peptide nanofibers on RSF surfaces for directional control of PC12 cell growth. The results demonstrated that inkjet-printed peptide micro-patterns can effectively guide the cell alignment and organization on RSF scaffold surfaces, providing great potential for nerve regeneration applications.

Mussel Inspired Chemistry and Bacteria Derived Polymers for Oral Mucosal Adhesion and Drug Delivery.

Ulceration of the oral mucosa is common, can arise at any age and as a consequence of the pain lessens enjoyment and quality of life. Current treatment options often involve the use of topical corticosteroids with poor drug delivery systems and inadequate contact time. In order to achieve local controlled delivery to the lesion with optimal adhesion, we utilized a simple polydopamine chemistry technique inspired by mussels to replicate their adhesive functionality. This was coupled with production of a group of naturally produced polymers, known as polyhydroxyalkanoates (PHA) as the delivery system. Initial work focused on the synthesis of PHA using Pseudomonas mendocina CH50; once synthesized and extracted from the bacteria, the PHAs were solvent processed into films. Polydopamine coating was subsequently achieved by immersing the solvent cast film in a polymerized dopamine solution. Fourier Transform Infrared Spectroscopy (FTIR) spectroscopy confirmed functionalization of the PHA films via the presence of amine groups. Further characterization of the samples was carried out via surface energy measurements and Scanning Electron Microscopy (SEM) micrographs for surface topography. An adhesion test via reverse compression testing directly assessed adhesive properties and revealed an increase in polydopamine coated samples. To further identify the effect of surface coating, LIVE/DEAD imaging and Alamar Blue metabolic activity evaluated attachment and proliferation of fibroblasts on the biofilm surfaces, with higher cell growth in favor of the coated samples. Finally, in vivo biocompatibility was investigated in a rat model where the polydopamine coated PHA showed less inflammatory response over time compared to uncoated samples with sign of neovascularization. In conclusion, this simple mussel inspired polydopamine chemistry introduces a step change in bio-surface functionalization and holds great promise for the treatment of oral conditions.

Natural Biomaterials for Cardiac Tissue Engineering: A Highly Biocompatible Solution.

Cardiovascular diseases (CVD) constitute a major fraction of the current major global diseases and lead to about 30% of the deaths, i.e., 17.9 million deaths per year. CVD include coronary artery disease (CAD), myocardial infarction (MI), arrhythmias, heart failure, heart valve diseases, congenital heart disease, and cardiomyopathy. Cardiac Tissue Engineering (CTE) aims to address these conditions, the overall goal being the efficient regeneration of diseased cardiac tissue using an ideal combination of biomaterials and cells. Various cells have thus far been utilized in pre-clinical studies for CTE. These include adult stem cell populations (mesenchymal stem cells) and pluripotent stem cells (including autologous human induced pluripotent stem cells or allogenic human embryonic stem cells) with the latter undergoing differentiation to form functional cardiac cells. The ideal biomaterial for cardiac tissue engineering needs to have suitable material properties with the ability to support efficient attachment, growth, and differentiation of the cardiac cells, leading to the formation of functional cardiac tissue. In this review, we have focused on the use of biomaterials of natural origin for CTE. Natural biomaterials are generally known to be highly biocompatible and in addition are sustainable in nature. We have focused on those that have been widely explored in CTE and describe the original work and the current state of art. These include fibrinogen (in the context of Engineered Heart Tissue, EHT), collagen, alginate, silk, and Polyhydroxyalkanoates (PHAs). Amongst these, fibrinogen, collagen, alginate, and silk are isolated from natural sources whereas PHAs are produced via bacterial fermentation. Overall, these biomaterials have proven to be highly promising, displaying robust biocompatibility and, when combined with cells, an ability to enhance post-MI cardiac function in pre-clinical models. As such, CTE has great potential for future clinical solutions and hence can lead to a considerable reduction in mortality rates due to CVD.

Reactive Inkjet Printing and Propulsion Analysis of Silk-based Self-propelled Micro-stirrers.

In this study, a protocol for using reactive inkjet printing to fabricate enzymatically propelled silk swimmers with well-defined shapes is reported. The resulting devices are an example of self-propelled objects capable of generating motion without external actuation and have potential applications in medicine and environmental sciences for a variety of purposes ranging from micro-stirring, targeted therapeutic delivery, to water remediation (e.g., cleaning oil spills). This method employs reactive inkjet printing to generate well-defined small-scale solid silk structures by converting water soluble regenerated silk fibroin (silk I) to insoluble silk fibroin (silk II). These structures are also selectively doped in specific regions with the enzyme catalase in order to produce motion via bubble generation and detachment. The number of layers printed determines the three-dimensional (3D) structure of the device, and so here the effect of this parameter on the propulsive trajectories is reported. The results demonstrate the ability to tune the motion by varying the dimensions of the printed structures.

Magnetic-silk/polyethyleneimine core-shell nanoparticles for targeted gene delivery into human breast cancer cells.

The lack of efficient and cost-effective methods for gene delivery has significantly hindered the applications of gene therapy. In this paper, a simple one step and cost effective salting-out method has been explored to fabricate silk-PEI nanoparticles (SPPs) and magnetic-silk/PEI core-shell nanoparticles (MSPPs) for targeted delivery of c-myc antisense oligodeoxynucleotides (ODNs) into MDA-MB-231 breast cancer cells. The size and zeta potential of the particles were controlled by adjusting the amount of silk fibroin in particle synthesis. Lower surface charges and reduced cytotoxicity were achieved for MSPPs compared with PEI coated magnetic nanoparticles (MPPs). Both SPPs and MSPPs were capable of delivering the ODNs into MDA-MB-231 cells and significantly inhibited the cell growth. Through magnetofection, high ODN uptake efficiencies (over 70%) were achieved within 20 min using MSPPs as carriers, exhibiting a significantly enhanced uptake effect compared to the same carriers via non-magnetofection. Both SPPs and MSPPs exhibited a significantly higher inhibition effect against MDA-MB-231 breast cancer cells compared to human dermal fibroblast (HDF) cells. Targeted ODN delivery was achieved using MSPPs with the help of a magnet, making them promising candidates for targeted gene therapy applications.

Reactive Inkjet Printing of Functional Silk Stirrers for Enhanced Mixing and Sensing.

Stirring small volumes of solution can reduce immunoassay readout time, homogenize cell cultures, and increase enzyme reactivity in bioreactors. However, at present many small scale stirring methods require external actuation, which can be cumbersome. To address this, here, reactive inkjet printing is shown to be able to produce autonomously rotating biocompatible silk-based microstirrers that can enhance fluid mixing. Rotary motion is generated either by release of a surface active agent (small molecular polyethylene glycol) resulting in Marangoni effect, or by catalytically powered bubble propulsion. The Marangoni driven devices do not require any chemicals to be added to the fluid as the "fuel," while the catalytically powered devices are powered by decomposing substrate molecules in solution. A comparison of Marangoni effect and enzyme powered stirrers is made. Marangoni effect driven stirrers rotate up to 600 rpm, 75-100-fold faster than enzyme driven microstirrers, however enzyme powered stirrers show increased longevity. Further to stirring applications, the sensitivity of the motion generation mechanisms to fluid properties allows the rotating devices to also be exploited for sensing applications, for example, acting as motion sensors for water pollution.

Symmetrical Catalytically Active Colloids Collectively Induce Convective Flow.

Although much attention has focused on self-motile asymmetrical catalytically active "Janus" colloids as a route to enable new fluidic transport applications, the motion of symmetrical catalytically active colloids is less investigated. This is despite isotropically active colloids being more accessible and commonly used as supports for heterogeneous catalysis. Here, we addressed this by systematically investigating the motion of platinum-coated colloids capable of isotropically decomposing hydrogen peroxide. We observed the onset of collective convective flow as the colloidal volume fraction increased above a threshold. The ballistic velocities induced by the collective flow were quantified by particle tracking and were found to increase with the volume fraction. We also determined the associated increase in the Péclet number as evidence of the potential to use convection as a simple method to enhance mass transport rates. By determining the persistence lengths, we were able to correlate the magnitude of convective flow with the overall catalytic activity per unit volume. This suggests that the mechanism for the collective flow is driven by chemical activity-induced local density differences. Finally, we discussed these results in the context of potential new fluidic applications and highlighted the role that activity-induced convection may play in experiments designed to investigate self-motile catalytic systems.

Systematic review and meta-analysis of controlled and prospective cohort efficacy studies of endoscopic radiofrequency for treatment of gastroesophageal reflux disease.

BACKGROUND: The endoscopic radiofrequency procedure (Stretta) has been used for more than a decade to treat patients with gastroesophageal reflux disease (GERD). However, the efficacy of the procedure in improving objective and subjective clinical endpoints needs to be further established. AIM: To determine the efficacy of the Stretta procedure in treating patients with GERD, using a systematic review and meta-analysis of controlled and cohort studies. METHODS: We conducted a systematic search of the PubMed and Cochrane databases for English language clinical studies of the Stretta procedure, published from inception until May 2016. Randomized controlled trials (RCTs) and cohort studies that included the use of the Stretta procedure in GERD patients were included. A generalized inverse weighting was used for all outcomes. Results were calculated by both fixed effects and random effects model. RESULTS: Twenty-eight studies (4 RCTs, 23 cohort studies, and 1 registry) representing 2468 unique Stretta patients were included in the meta-analysis. The (unweighted) mean follow-up time for the 28 studies was 25.4 [14.0, 36.7] months. The pooled results showed that the Stretta reduced (improved) the health-related quality of life score by -14.6 [-16.48, -12.73] (P < 0.001). Stretta also reduced (improved) the pooled heartburn standardized score by -1.53 [-1.97, -1.09] (P < 0.001). After Stretta treatment, only 49% of the patients using proton pump inhibitors (PPIs) at baseline required PPIs at follow-up (P < 0.001). The Stretta treatment reduced the incidence of erosive esophagitis by 24% (P < 0.001) and reduced esophageal acid exposure by a mean of -3.01 [-3.72, -2.30] (P < 0.001). Lower esophageal sphincter (LES) basal pressure was increased post Stretta therapy by a mean of 1.73 [-0.29, 3.74] mmHg (P = NS). CONCLUSIONS: The Stretta procedure significantly improves subjective and objective clinical endpoints, except LES basal pressure, and therefore should be considered as a viable alternative in managing GERD.

Reactive Inkjet Printing of Biocompatible Enzyme Powered Silk Micro-Rockets.

Inkjet-printed enzyme-powered silk-based micro-rockets are able to undergo autonomous motion in a vast variety of fluidic environments including complex media such as human serum. By means of digital inkjet printing it is possible to alter the catalyst distribution simply and generate varying trajectory behavior of these micro-rockets. Made of silk scaffolds containing enzymes these micro-rockets are highly biocompatible and non-biofouling.

Operational Implications of Utilizing 2 Advanced Technologies for Rendering Short-term Hemodynamic Support to Patients Presenting With Cardiogenic Shock: A View Through the Lens of Hospital Readmissions.

PURPOSE: Reducing hospital readmissions for critically ill patients is of concern to payers and providers alike. Patients in cardiogenic shock are often treated with devices to help support the functions of the heart while the patient undergoes treatment. This study compares the readmission experience of Medicare beneficiaries treated for cardiogenic shock (CS) using percutaneous ventricular assist devices (pVADs) vs. extracorporeal membrane oxygenation (ECMO), two types of advanced cardiac support devices. Hospital readmission is a surrogate for quality and cost. DESIGN AND METHODOLOGY: A retrospective comparison of readmission patterns of patients treated for CS using two advanced cardiac support devices during calendar years 2011 and 2012 was captured via the Medicare Inpatient Standard Analytic File (100% census file). A total of 649 eligible cases (pVAD, 517; ECMO, 132) with 90 days of follow-up documentation were included in this analysis. Baseline characteristics were compared, including demographics, admission type, and severity of illness, with the 2 groups generating clinically similar baseline profiles. Primary outcomes include 30- and 90-day readmissions, associated length of stay (LOS), and costs. RESULTS: At 90 days after initial hospitalization, the readmission rates in the pVAD and ECMO cohorts were 38.7% (200/517) and 53.0% (70/132), respectively. Overall, pVAD was associated with a 27.1% reduction in readmission (P = .004). With the use of pVAD, 90-day readmission costs were lower by $12,294 ($32,736 vs $20,442, a reduction of 37.6%, P=.02) and readmission LOS was shorter by approximately 8 days, (20.5 vs. 12.7 days, a 37.9% reduction, P = .002). Similar trends were observed at 30 days; however, only LOS was significantly reduced, by 7.0 days (P < .001). CONCLUSION: In clinically comparable cohorts, pVADs were associated with reduced risk of rehospitalization, lower cost, and shorter LOS, resulting in cost savings for payers and providers. Increased adoption of pVAD, as a technology to support patients in cardiogenic shock, may help hospitals deliver greater value to both government and commercial payers.