Designing Biomimetic 3D-Printed Osteochondral Scaffolds for Enhanced Load-Bearing Capacity.

Osteoarthritis is a debilitating chronic joint disorder that affects millions of people worldwide. Since palliative and surgical treatments cannot completely regenerate hyaline cartilage within the articulating joint, osteochondral (OC) tissue engineering has been explored to heal OC defects. Utilizing computational simulations and three-dimensional (3D) printing, we aimed to build rationale around fabricating OC scaffolds with enhanced biomechanics.

DeepFreeze 3D-biofabrication for Bioengineering and Storage of Stem Cells in Thick and Large-Scale Human Tissue Analogs.

3D bioprinting holds great promise for meeting the increasing need for transplantable tissues and organs. However, slow printing, interlayer mixing, and the extended exposure of cells to non-physiological conditions in thick structures still hinder clinical applications. Here the DeepFreeze-3D (DF-3D) procedure and bioink for creating multilayered human-scale tissue mimetics is presented for the first time.

Injectable systems for long-lasting insulin therapy.

Insulin therapy is the mainstay to treat diabetes characterizedd by hyperglycemia. However, its short half-life of only 4-6 min limits its effectiveness in treating chronic diabetes. Advances in recombinant DNA technology and protein engineering have led to several insulin analogue products that have up to 42 h of glycemic control.

Nanotechnology in regenerative ophthalmology.

In recent years, regenerative medicine is gaining momentum and is giving hopes for restoring function of diseased, damaged, and aged tissues and organs and nanotechnology is serving as a catalyst. In the ophthalmology field, various types of allogenic and autologous stem cells have been investigated to treat some ocular diseases due to age-related macular degeneration, glaucoma, retinitis pigmentosa, diabetic retinopathy, and corneal and lens traumas. Nanomaterials have been utilized directly as nanoscaffolds for these stem cells to promote their adhesion, proliferation and differentiation or indirectly as vectors for various genes, tissue growth factors, cytokines and immunosuppressants to facilitate cell reprogramming or ocular tissue regeneration.

Design strategies for programmable oligonucleotide nanotherapeutics.

A systematic review on how to design different programmable nanotherapeutics using oligonucleotides as building blocks or as surface and matrix modifiers for controlled and targeted delivery of various therapeutic agents in presented.

Design strategies for chemical-stimuli-responsive programmable nanotherapeutics.

Chemical-stimuli-responsive nanotherapeutics have gained great interest in drug delivery and diagnosis applications. These nanotherapeutics are designed to respond to specific internal stimuli including pH, ionic strength, redox, reactive oxygen species, glucose, enzymes, ATP and hypoxia for site-specific and responsive or triggered release of payloads and/or biomarker detections. This review systematically and comprehensively addresses up-to-date technological and design strategies, and challenges nanomaterials to be used for triggered release and sensing in response to chemical stimuli.

Design strategies for physical-stimuli-responsive programmable nanotherapeutics.

Nanomaterials that respond to externally applied physical stimuli such as temperature, light, ultrasound, magnetic field and electric field have shown great potential for controlled and targeted delivery of therapeutic agents. However, the body of literature on programming these stimuli-responsive nanomaterials to attain the desired level of pharmacologic responses is still fragmented and has not been systematically reviewed. The purpose of this review is to summarize and synthesize the literature on various design strategies for simple and sophisticated programmable physical-stimuli-responsive nanotherapeutics.

Thermoresponsive- co-Biodegradable Linear-Dendritic Nanoparticles for Sustained Release of Nerve Growth Factor To Promote Neurite Outgrowth.

Thermoresponsive and biodegradable linear-dendritic nanoparticles containing poly( N-isopropylacrylamide), poly(l-lactic acid), and poly(l-lysine) dendrons were investigated for sustained release of nerve growth factor (NGF) in response to temperature change. The nanoparticles and their degradants were not cytotoxic to neuron-like PC12 cells for at least one month. The nanoparticles were preferentially taken up by PC12 cells 6-13-times more at temperatures above (37 °C) than below (25 °C) the lower critical solution temperature of the nanoparticles.

Injectable In Situ Forming Depot Systems for Long-Acting Contraception.

Up to date, no long-acting reversible contraceptive (LARC) is developed to be injectable through needles smaller than 18 G and can also provide contraception for more than 3 months after single injection. In this study, injectable polymeric in situ forming depot (ISD) systems are developed to have injectability through 21-23 G needles, and capability of sustained release of levonorgestrel (LNG) for at least 7 months in vitro and in vivo after single subcutaneous injection in rats. The systems are polymeric solutions composed of biodegradable poly(lactide-co-glycolide) and poly(lactic acid) polymers dissolved in a mixture of solvents like N-methyl-2-pyrrolidone and benzyl benzoate or triethyl citrate.

Nanoparticles for drug delivery to the anterior segment of the eye.

Commercially available ocular drug delivery systems are effective but less efficacious to manage diseases/disorders of the anterior segment of the eye. Recent advances in nanotechnology and molecular biology offer a great opportunity for efficacious ocular drug delivery for the treatments of anterior segment diseases/disorders. Nanoparticles have been designed for preparing eye drops or injectable solutions to surmount ocular obstacles faced after administration.

An Accelerated Release Study to Evaluate Long-Acting Contraceptive Levonorgestrel-Containing in Situ Forming Depot Systems.

Biodegradable polymer-based injectable in situ forming depot (ISD) systems that solidify in the body to form a solid or semisolid reservoir are becoming increasingly attractive as an injectable dosage form for sustained (months to years) parenteral drug delivery. Evaluation of long-term drug release from the ISD systems during the formulation development is laborious and costly. An accelerated release method that can effectively correlate the months to years of long-term release in a short time such as days or weeks is economically needed.

Subconjunctivally Implanted Hydrogels for Sustained Insulin Release to Reduce Retinal Cell Apoptosis in Diabetic Rats.

Purpose: Diabetic retinopathy (DR) is a leading cause of blindness in diabetic patients that involves early-onset retinal cell loss. Here, we report our recent work using subconjunctivally implantable hydrogels for sustained insulin release to the retina to prevent retinal degeneration.

Methods: The hydrogels are synthesized by UV photopolymerization of N-isopropylacrylamide and a dextran macromer containing oligolactate-(2-hydroxyetheyl methacrylate) units.

Development and validation of sensitive LC/MS/MS method for quantitative bioanalysis of levonorgestrel in rat plasma and application to pharmacokinetics study.

Rapid, sensitive, selective and accurate LC/MS/MS method was developed for quantitative determination of levonorgestrel (LNG) in rat plasma and further validated for specificity, linearity, accuracy, precision, sensitivity, matrix effect, recovery efficiency and stability. Liquid-liquid extraction procedure using hexane:ethyl acetate mixture at 80:20 v:v ratio was employed to efficiently extract LNG from rat plasma. Reversed phase Luna column C18(2) (50×2.

Long-acting injectable hormonal dosage forms for contraception.

Although great efforts have been made to develop long-acting injectable hormonal contraceptives for more than four decades, few long-acting injectable contraceptives have reached the pharmaceutical market or even entered clinical trials. On the other hand, in clinical practice there is an urgent need for injectable long-acting reversible contraceptives which can provide contraceptive protection for more than 3 months after one single injection. Availability of such products will offer great flexibility to women and resolve certain continuation issues currently occurring in clinics.

Overcoming the blood-brain barrier in chemotherapy treatment of pediatric brain tumors.

Pediatric brain tumors are most common cancers in childhood and among the leading causes of death in children. Chemotherapy has been used as adjuvant (i.e.

β-cyclodextrin-poly(β-amino ester) nanoparticles for sustained drug delivery across the blood-brain barrier.

Novel biodegradable polymeric nanoparticles composed of β-cyclodextrin and poly(β-amino ester) segments have been developed for sustained drug delivery across the blood-brain barrier (BBB). The nanoparticles have been synthesized by cross-linking β-cyclodextrin with poly(β-amino ester) via the Michael addition method. The chemical, physical, and degradation properties of the nanoparticles have been characterized by matrix-assisted laser desoption/ionization time-of-flight, attenuated total reflectance Fourier transform infrared spectroscopy, nuclear magnetic resonance, dynamic light scattering, and atomic force microscopy techniques.

Effect of surface charge of immortalized mouse cerebral endothelial cell monolayer on transport of charged solutes.

Charge carried by the surface glycocalyx layer (SGL) of the cerebral endothelium has been shown to significantly modulate the permeability of the blood-brain barrier (BBB) to charged solutes in vivo. The cultured monolayer of bEnd3, an immortalized mouse cerebral endothelial cell line, is becoming a popular in vitro BBB model due to its easy growth and maintenance of many BBB characteristics over repeated passages. To test whether the SGL of bEnd3 monolayer carries similar charge as that in the intact BBB and quantify this charge, which can be characterized by the SGL thickness (L(f)) and charge density (C(mf)), we measured the solute permeability of bEnd3 monolayer to neutral solutes and to solutes with similar size but opposite charges: negatively charged alpha-lactalbumin (-11) and positively charged ribonuclease (+3).

Quaternary ammonium beta-cyclodextrin nanoparticles for enhancing doxorubicin permeability across the in vitro blood-brain barrier.

This study describes novel quaternary ammonium beta-cyclodextrin (QAbetaCD) nanoparticles as drug delivery carriers for doxorubicin (DOX), a hydrophobic anticancer drug, across the blood-brain barrier (BBB). QAbetaCD nanoparticles show 65-88 nm hydrodynamic radii with controllable cationic properties by adjusting the incorporated amount of quaternary ammonium group in their structure. ATR-FTIR studies confirm the complexation between the QAbetaCD nanoparticles and DOX.

Thermoresponsive and biodegradable linear-dendritic nanoparticles for targeted and sustained release of a pro-apoptotic drug.

Ceramide is a bioactive sphingolipid-derived second messenger that has been demonstrated to induce apoptosis and cell cycle arrest in various cancer cell culture systems. Although in vitro tumor cell culture models have illuminated the potential therapeutic utility of a cell-permeable analog of ceramide, C(6), in vivo delivery is impeded by the extreme hydrophobicity and physical-chemical properties of this bioactive lipid. Previously, we have demonstrated that the incorporation of C(6) into pegylated liposomal vesicles is an effective anti-cancer drug delivery strategy in vitro and in vivo.

Porous thermoresponsive-co-biodegradable hydrogels as tissue-engineering scaffolds for 3-dimensional in vitro culture of chondrocytes.

A new porous, thermoresponsive, partially biodegradable, chemically crosslinked hydrogel system was developed, characterized, and tested as a cartilage tissue-engineering scaffold for in vitro chondrocyte culture over a 4-week period. The hydrogel system was composed of poly(N-isopropylacrylamide), poly(D,L-lactic acid), and dextran segments. Pores in the hydrogels were generated using a salt leaching technique.

Biodegradable thermoresponsive hydrogels for aqueous encapsulation and controlled release of hydrophilic model drugs.

A series of hydrogels with both thermoresponsive and completely biodegradable properties was developed for aqueous encapsulation and controlled release of hydrophilic drugs in response to temperature change. The hydrogels were prepared in phosphate-buffered saline (pH 7.4) through free radical polymerization of N-isopropylacrylamide (NIPAAm) monomer and a dextran macromer containing multiple hydrolytically degradable oligolactate-2-hydroxyethyl methacrylate units (Dex-lactateHEMA).

Thermoresponsive terpolymeric films applicable for osteoblastic cell growth and noninvasive cell sheet harvesting.

A novel multifunctional linear block copolymer, poly(N-isopropylacrylamide-co-acrylic acid)-b-poly( L-lactic acid) (NAL), was synthesized to expand the concept of cell sheet engineering by using its thermoresponsive property and processibility. The chemical structure of synthesized NAL was confirmed by Fourier transform infrared spectroscopy, and its molar mass (103,500 g.mol(-1)) and molar mass distribution were determined by matrix-assisted laser desorption/ionization-time of flight mass spectroscopy.