Biodegradable branched polycationic polymers as non-viral gene delivery vectors for bone tissue engineering

In this work, biodegradable branched triacrylate/amine polycationic polymers (TAPPs) were synthesized from different amine and triacrylate monomers by Michael addition polymerization and incorporated into a composite scaffold to evaluate these polymers in a bone tissue engineering system. The effects of the hydrophilic spacer lengths in the polymer on characteristics which are important for gene delivery were evaluated by varying the triacrylate monomer used in the synthesis. The results demonstrated that hydrophilic spacers can be incorporated into polycationic polymers to reduce their cytotoxicity and enhance the degradability. The effects of amine basicities in the polymer on characteristics which are important for gene delivery were also evaluated by varying the amine monomers used in the synthesis. The results indicated that polycationic polymers with amines that dissociate above pH 7.4, which are available as positively charged groups for plasmid DNA (pDNA) complexation at pH 7.4, can be synthesized to produce stable polyplexes with increased zeta potential and decreased hydrodynamic size that efficiently transfect cells. TAPP/pDNA polyplexes were then incorporated into a composite containing gelatin microparticles (GMPs) and a porous poly(propylene fumarate) scaffold. The release of pDNA in vitro was not affected by the crosslinking density of the GMPs but depended, instead, on the degradation rates of the TAPPs. Besides the initial burst release of polyplexes not bounded to the GMPs and the minimal release of pDNA through diffusion and dissociation from the GMPs, the pDNA was likely released as naked pDNA or in an incomplete polyplex as fragments of the polymer had to degrade to release the pDNA. The results indicated that polymeric vectors with a lower degradation rate can prolong the release of pDNA from the composite scaffold. Composite scaffolds loaded with TAPP/pDNA polyplexes may not have delivered enough intact polyplexes, as enhanced bone formation was not observed in a critical-size rat cranial defect at 12 weeks postimplantation compared to those loaded with naked pDNA. A gene delivery system consisting of biodegradable polycationic polymers should be designed to release the pDNA in an intact polyplex form

The Dual Delivery of Y15 and Metformin in a PLGA Scaffold for the Treatment of Platinum Resistant Ovarian Cancer

Background: Ovarian cancer is the fifth leading cause of cancer mortality among women in the US. High mortality is linked to resistance to platinum compounds. Currently there is no treatment for platinum resistant ovarian cancer (OCpt). Platinum resistance shows increased activity of focal adhesion kinase (FAK). Y15 is a FAK inhibitor and increases OCpt sensitivity to chemotherapy. Metformin induces apoptosis, has no increased cytotoxicity, and works synergistically with Y15 in OCpt cells. Biomaterial scaffolds deliver drugs locally, maximizing drug concentration and bioavailability while minimizing systemic toxicity. PLGA copolymer has excellent biocompatibility, versatility, and a tailorable degradation rate. The objective of this study is to utilize biomaterials as a dual drug delivery system and investigate if the combined delivery of Y15 and Metformin would result in synergistic effects on cell viability. Methods: A mold-less technique combining PLGA and the drugs in tetraglycol were injected into PBS to form a globular scaffold. An MTT assay was used to analyze cell viability in OCpt OVCAR3 cells at an absorbance of 570 nm with a microplate reader. Results: Metformin and Y15 resulted in cell viabilities of 66% and 54%, respectively. When combined, the viability decreased to 23%. In studies with the fabricated PLGA scaffolds, cell viabilities were 74% and 89% for Metformin and Y15. When combined, cell viability decreased significantly to 5%. Conclusions: The delivery of Y15 and Metformin in a biomaterial scaffold can result in a synergistic effect on cell viability and thus, can be a promising approach for the treatment of OCpt

Liver Cancer: Current and Future Trends Using Biomaterials

Hepatocellular carcinoma (HCC) is the fifth most common type of cancer diagnosed and the second leading cause of death worldwide. Despite advancement in current treatments for HCC, the prognosis for this cancer is still unfavorable. This comprehensive review article focuses on all the current technology that applies biomaterials to treat and study liver cancer, thus showing the versatility of biomaterials to be used as smart tools in this complex pathologic scenario. Specifically, after introducing the liver anatomy and pathology by focusing on the available treatments for HCC, this review summarizes the current biomaterial-based approaches for systemic delivery and implantable tools for locally administrating bioactive factors and provides a comprehensive discussion of the specific therapies and targeting agents to effciently deliver those factors. This review also highlights the novel application of biomaterials to study HCC, which includes hydrogels and scaffolds to tissue engineer 3D in vitro models representative of the tumor environment. Such models will serve to better understand the tumor biology and investigate new therapies for HCC. Special focus is given to innovative approaches, e.g., combined delivery therapies, and to alternative approaches—e.g., cell capture—as promising future trends in the application of biomaterials to treat HCC

Cortisol, Heart Rate, and Perceived Exertion Responses to Different Resistance Training Protocols with and Without Blood Flow Restriction

ABSTRACT PURPOSE: The purpose of this study was to examine the effects of different resistance exercise protocols on cortisol, heart rate, and perceived exertion. METHODS: Eight males and eight females (age = 21.8 ± 2.6) performed three randomly assigned exercise protocols on three separate occasions: low-intensity resistance training (RT) exercises with blood flow restriction (BFR) at 20% of one repetition maximum (1-RM) (BFR20), moderate-intensity RT exercises with BFR at 40% of 1-RM (BFR40), and traditional high-intensity RT exercises at 80% of 1-RM (HI80). Participants completed 2-3 circuits of four sets in the leg press and leg extension machines. Total volume of resistance training (RT) exercises performed was about 25% for the BFR20 session and 50% for the BFR40 session compared to the volume of RT exercises for the HI80 session. Heart rate (HR) and rating of perceived exertion (RPE) were monitored throughout each session. Saliva samples were collected before and immediately after each exercise session. Samples were stored at -80 ℃ and later analyzed with ELISA for salivary cortisol concentrations. RESULTS: No significant differences in cortisol concentrations were noted between conditions, but significant increases in cortisol concentrations were seen from pre- to post-exercise exercise (pCONCLUSION: The cortisol findings may indicate that all three exercise protocols resulted in similar levels of stimuli to the hypothalamic-pituitary-adrenal axis. It should be highlighted that the BFR20 session with lowest training volume and intensity resulted in similar objective (i.e., HR) but significantly lower subjective level of exertion (i.e., RPE) compared to the HI80 session with highest training volume and intensity. The cortisol, HR, and RPE responses to various RT sessions indicate that the findings of the present study may have some clinical and/or practical applications

Effects of solvent used for fabrication on drug loading and release kinetics of electrosprayed temozolomide-loaded PLGA microparticles for the treatment of glioblastoma

Glioblastoma multiforme (GBM) is the most common and invasive form of malignant brain tumors and despite advances in surgery, radiotherapy, and chemotherapy, the survival of patients with GBM still remains poor. Temozolomide (TMZ) is the chemotherapy drug that is most commonly given orally after surgical resection of these tumors. In this study, the effects of solvents (i.e., dichloromethane and acetonitrile) used for the fabrication of electrosprayed TMZ-loaded poly(lactic-co-glycolic acid) (PLGA) on drug loading, loading efficiency, drug release kinetics, surface morphology, and particle size were investigated. The results from this study demonstrated that by using a larger volume of a solvent with higher polarity (i.e., acetonitrile) which allows for a higher amount of hydrophilic TMZ to dissolve into the polymer solution, higher drug loading could be achieved. However, the particles fabricated with high amount of acetonitrile, which has a lower vapor pressure, had large pores and a smaller diameter which led to an initial burst release and high cumulative release at the end of the study. An optimal combination of the two solvents is needed to result in particles with a good amount of loading and minimal initial burst release. The electrosprayed microparticles were able to illicit a cytotoxic response in U-87 MG glioblastoma cells at a lower concentration of drug compared to the free drug. This work indicated that electrospraying is a promising method for the fabrication of TMZ-loaded PLGA microparticles for the treatment of GBM and solvent composition can be altered to control drug loading and release kinetics

Combined Application of Patient-Derived Cells and Biomaterials as 3D In Vitro Tumor Models

Although advances have been made in cancer therapy, cancer remains the second leading cause of death in the U.S. and Europe, and thus efforts to continue to study and discover better treatment methods are ongoing. Three-dimensional (3D) tumor models have shown advantages over bi-dimensional (2D) cultures in evaluating the efficacy of chemotherapy. This commentary aims to highlight the potential of combined application of biomaterials with patient-derived cancer cells as a 3D in vitro model for the study and treatment of cancer patients. Five studies were discussed which demonstrate and provided early evidence to create 3D models with accurate microenvironments that are comparable to in vivo tumors. To date, the use of patient-derived cells for a more personalized approach to healthcare in combination with biomaterials to create a 3D tumor is still relatively new and uncommon for application in clinics. Although highly promising, it is important to acknowledge the current limitations and challenges of developing these innovative in vitro models, including the need for biologists and laboratory technicians to become familiar with biomaterial scaffolds, and the effort for bioengineers to create easy-to-handle scaffolds for routine assessment. View Full-Tex

The Application of Electrosprayed Minocycline-Loaded PLGA For The Treatment Of Glioblastoma

Background: Glioblastoma multiforme (GBM) is one of the most common and aggressive forms of cancer with unfavorable prognosis due to high levels of reoccurrence with around 10,000 patients in the U.S. diagnosed each year. Despite treatment with surgery, radiotherapy, and chemotherapy, survival rate for this disease is around 21 months after diagnosis. Minocycline, a tetracycline-derivative used as an antibiotic, has also demonstrated the ability to inhibit angiogenesis or tumor growth and, presents a possible treatment option for GBM. Methods: Microparticles were fabricated by electrospraying by varying solvent type, distance, flow rate, voltage, and polymer concentration as parameters. The cytotoxicity of endothelial and glioblastoma cells was determined by an MTT assay by determining the absorbance using a spectrophotometer at a wavelength of 350 nm. Scanning electron microscopy (SEM) imaging was used to image the samples to determine microparticle surface morphology and size via an electron beam due to microparticles being sputter coated with gold to generate an electrical conduction. Results: The electrospraying process consists of numerous parameters which directly affect the creation of microparticles. The use of the solvent methanol aids in dissolving minocycline, while the use of DCM is important for the process of electrospraying, due to its higher vapor pressure and ability to dissolve PLGA. Conclusion: In conclusion, electrospraying is a promising method to fabricate drug loaded PLGA microparticles. However, optimization is needed whenever there is a new drug of interest as it can modify the properties of the electrospray solution and result in different effects on the fabrication parameters and particles produced

Effect of drug-to-lipid ratio on nanodisc-based tenofovir drug delivery to the brain for HIV-1 infection

Background: Combination antiretroviral therapy has significantly advanced HIV-1 infection treatment. However, HIV-1 remains persistent in the brain; the inaccessibility of the blood–brain barrier allows for persistent HIV-1 infections and neuroinflammation. Nanotechnology-based drug carriers such as nanodiscoidal bicelles can provide a solution to combat this challenge. Methods: This study investigated the safety and extended release of a combination antiretroviral therapy drug (tenofovir)-loaded nanodiscs for HIV-1 treatment in the brain both in vitro and in vivo. Result: The nanodiscs entrapped the drug in their interior hydrophobic core and released the payload at the desired location and in a controlled release pattern. The study also included a comparative pharmacokinetic analysis of nanodisc formulations in in vitro and in vivo models. Conclusion: The study provides potential applications of nanodiscs for HIV-1 therapy development

Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients