Designing the new generation of intelligent biocompatible carriers for protein and peptide delivery

Therapeutic proteins and peptides have revolutionized treatment for a number of diseases, and the expected increase in macromolecule-based therapies brings a new set of challenges for the pharmaceutics field. Due to their poor stability, large molecular weight, and poor transport properties,therapeutic proteins and peptides are predominantly limited to parenteral administration. The short serum half-lives typically require frequent injections to maintain an effective dose, and patient compliance is a growing issue as therapeutic protein treatments become more widely available. A number of studies have underscored the relationship of subcutaneous injections with patient non-adherence, estimating that over half of insulin-dependent adults intentionally skip injections. The development of oral formulations has the potential to address some issues associated with non-adherence including the interference with daily activities, embarrassment, and injection pain. Oral delivery can also help to eliminate the adverse effects and scar tissue buildup associated with repeated injections. However, there are several major challenges associated with oral delivery of proteins and peptides, such as the instability in the gastrointestinal(GI)tract, low permeability, and a narrow absorption window in the intestine. This review provides a detailed overview of the oral delivery route and associated challenges. Recent advances in formulation and drugdelivery technologies to enhance bioavailability are discussed, including the co-administration of compounds to alter conditions in the GI tract, the modification of the macromolecule physicochemical properties, and the use of improved targeted and controlled release carriers.

The challenge to improve the response of biomaterials to the physiological environment

New applications of biomaterials often require advanced structures containing synthetic and natural components that are tuned to provide properties unique to a specific application.We discuss how structural characteristics of biomaterials,especially hydrophilic ones,can be used in conjunction with non-ideal thermodynamics to develop advanced medical systems.We show a number of examples of biocompatible,intelligent biomaterials that can be used for organ replacement,biosensors,precise drug delivery over days or weeks,and regenerative medicine.

A microfluidic platform for continuous monitoring of dopamine homeostasis in dopaminergic cells

Homeostasis of dopamine,a classical neurotransmitter,is a key indicator of neuronal health.Dysfunction in the regulation of dopamine is implicated in a long list of neurological disorders,including addiction,depression,and neurodegeneration.The existing methods used to evaluate dopamine homeostasis in vitro are inconvenient and do not allow for continuous non-destructive measurement.In response to this challenge,we introduce an integrated microfluidic system that combines dopaminergic cell culture and differentiation with electroanalytical measurements of extracellular dopamine in real-time at any point during an assay.We used the system to examine the behavior of differentiated SH-SY5Y cells upon exposure to four dopamine transporter ant/agonists(cocaine,ketamine,epigallocatechin gallate,and amphetamine)and study their pharmacokinetics.The IC_(50)values of cocaine,ketamine,and epigallocatechin gallate were determined to be(average±standard deviation)3.7±1.1μM,51.4±17.9μM,and 2.6±0.8μM,respectively.Furthermore,we used the new system to study amphetamine-mediated dopamine release to probe the related phenomena of dopamine transporter-mediated reverse-transport and dopamine release from vesicles.We propose that this platform,which is the first platform to simultaneously evaluate uptake and release,could be useful to screen for drugs and other agents that target dopaminergic neurons and the function of the dopamine transporter.More broadly,this platform should be adaptable for any application that could benefit from high-temporal resolution electroanalysis combined with multi-day cell culture using small numbers of cells.

Re-evaluating the importance of carbohydrates as regenerative biomaterials

Introduction Carbohydrates are the most abundant natural biomaterials in the world.By interacting with cells of a variety of levels,they take part in essential functions of organisms including cellular communication,inflammation,infection development and disease.These carbohydrate–cell interactions occur on a variety of levels through glycoconjugates such as glycolipids,glycosaminoglycans(GAGs),glycoproteins and proteoglycans[1–4].The roles of carbohydrates in biological systems pose them as some of the most sought-after biomaterials.The use of these multifaceted molecules provides the opportunity to tailor desired responses depending on the target application[1–5].

Correction to:A microfluidic platform for continuous monitoring of dopamine homeostasis in dopaminergic cells

Correction to:Microsystems&Nanoengineering(2019)5:10 https://doi.org/10.1038/s41378-019-0049-2 published online:11 March 2019 The legend in Fig.4a in the previously published version of this article contained erroneous units.The correct units are given in the caption–that is,1μM(black),500 nM(red),100 nM(blue),50 nM(cyan),10 nM(pink),and 0 nM(1×PBS solution,brown).

Bone tissue engineering via growth factor delivery:from scaffolds to complex matrices

In recent years,bone tissue engineering has emerged as a promising solution to the limitations of current gold standard treatment options for bone related-disorders such as bone grafts.Bone tissue engineering provides a scaffold design that mimics the extracellular matrix,providing an architecture that guides the natural bone regeneration process.During this period,a new generation of bone tissue engineering scaffolds has been designed and characterized that explores the incorporation of signaling molecules in order to enhance cell recruitment and ingress into the scaffold,as well as osteogenic differentiation and angiogenesis,each of which is crucial to successful bone regeneration.Here,we outline and critically analyze key characteristics of successful bone tissue engineering scaffolds.We also explore candidate materials used to fabricate these scaffolds.Different growth factors involved in the highly coordinated process of bone repair are discussed,and the key requirements of a growth factor delivery system are described.Finally,we concentrate on an analysis of scaffold-based growth factor delivery strategies found in the recent literature.In particular,the incorporation of two-phase systems consisting of growth factor-loaded nanoparticles embedded into scaffolds shows great promise,both by providing sustained release over a therapeutically relevant timeframe and the potential to sequentially deliver multiple growth factors.

Surface hydrolysis-mediated PEGylation of poly(N-isopropyl acrylamide)based nanogels

In this work,poly(N-isopropyl acrylamide-co-acrylamide)[P(NIPAAm-co-AAm)]nanogels were modified by hydrolysis above the lower critical solution temperature(LCST)to localize carboxylic acid functional groups at the surface(surface hydrolysis).PNIPAAm copolymerized with 15%and 20%nominal AAm in the feed were prepared and compared to equivalent hydrogels with acrylic acid.The effect and extent of surface hydrolysis was confirmed by potentiometric titration and zeta potential.These surface modified nanogels were then modified with primary amine functionalized PEG chains.Surface hydrolysis-mediated PEGylation had little effect on the swelling response of the nanogels,while also preventing adsorption of model proteins in physiological relevant conditions.While both 15%and 20%AAm gels both decreased protein adsorption,only the 20%AAm gels resulted in fully preventing protein adsorption.The results presented here point to surface hydrolysis as a new route to passivate nanogels for use in vivo.

Recent advances in glucose-responsive insulin delivery systems:novel hydrogels and future applications

Over the past several decades,there have been major advancements in the field of glucose sensing and insulin delivery for the treatment of type I diabetes mellitus.The introduction of closed-loop insulin delivery systems that deliver insulin in response to specific levels of glucose in the blood has shifted significantly the research in this field.These systems consist of encapsulated glucose-sensitive components such as glucose oxidase or phenylboronic acid in hydrogels,microgels or nanoparticles.Since our previous evaluation of these systems in a contribution in 2004,new systems have been developed.Important improvements in key issues,such as consistent insulin delivery over an extended period of time have been addressed.In this contribution,we discuss recent advancements over the last 5 years and present persisting issues in these technologies that must be overcome in order for these systems to be applicable in patients.

Advanced biomedical hydrogels:molecular architecture and its impact on medical applications

Hydrogels are cross-linked polymeric networks swollen in water,physiological aqueous solutions or biological fluids.They are synthesized by a wide range of polymerization methods that allow for the introduction of linear and branched units with specific molecular characteristics.In addition,they can be tuned to exhibit desirable chemical characteristics including hydrophilicity or hydrophobicity.The synthesized hydrogels can be anionic,cationic,or amphiphilic and can contain multifunctional crosslinks,junctions or tie points.Beyond these characteristics,hydrogels exhibit compatibility with biological systems,and can be synthesized to render systems that swell or collapse in response to external stimuli.This versatility and compatibility have led to better understanding of how the hydrogel’s molecular architecture will affect their physicochemical,mechanical and biological properties.We present a critical summary of the main methods to synthesize hydrogels,which define their architecture,and advanced structural characteristics for macromolecular/biological applications.