抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Spurred by recent progress in materials chemistry and drug delivery, stimuli-responsive devices that deliver a drug in spatial-, temporal- and dosage-controlled fashions have become possible. Implementation of such devices requires the use of biocompatible materials that are susceptible to a specific physical incitement or that, in response to a specific stimulus, undergo a protonation, a hydrolytic cleavage or a (supra)molecular conformational change. In this Review, we discuss recent advances in the design of nanoscale stimuli-responsive systems that are able to control drug biodistribution in response to specific stimuli, either exogenous (variations in temperature, magnetic field, ultrasound intensity, light or electric pulses) or endogenous (changes in pH, enzyme concentration or redox gradients).

Stimuli-responsive nanocarriers for drug delivery

Hydrogel delivery systems can leverage therapeutically beneficial outcomes of drug delivery and have found clinical use. Hydrogels can provide spatial and temporal control over the release of various therapeutic agents, including small-molecule drugs, macromolecular drugs and cells. Owing to their tunable physical properties, controllable degradability and capability to protect labile drugs from degradation, hydrogels serve as a platform in which various physiochemical interactions with the encapsulated drugs control their release. In this Review, we cover multiscale mechanisms underlying the design of hydrogel drug delivery systems, focusing on physical and chemical properties of the hydrogel network and the hydrogel-drug interactions across the network, mesh, and molecular (or atomistic) scales. We discuss how different mechanisms interact and can be integrated to exert fine control in time and space over the drug presentation. We also collect experimental release data from the literature, review clinical translation to date of these systems, and present quantitative comparisons between different systems to provide guidelines for the rational design of hydrogel delivery systems.

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Designing hydrogels for controlled drug delivery.

Tissue engineering applications commonly encompass the use of three-dimensional (3D) scaffolds to provide a suitable microenvironment for the incorporation of cells or growth factors to regenerate ...

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Three-dimensional scaffolds for tissue engineering applications : role of porosity and pore size

Three-dimensional (3D) cell culture systems have gained increasing interest in drug discovery and tissue engineering due to their evident advantages in providing more physiologically relevant information and more predictive data for in vivo tests. In this review, we discuss the characteristics of 3D cell culture systems in comparison to the two-dimensional (2D) monolayer culture, focusing on cell growth conditions, cell proliferation, population, and gene and protein expression profiles. The innovations and development in 3D culture systems for drug discovery over the past 5 years are also reviewed in the article, emphasizing the cellular response to different classes of anticancer drugs, focusing particularly on similarities and differences between 3D and 2D models across the field. The progression and advancement in the application of 3D cell cultures in cell-based biosensors is another focal point of this review.

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Three-Dimensional Cell Culture Systems and Their Applications in Drug Discovery and Cell-Based Biosensors

Methods for culturing mammalian cells ex vivo are increasingly needed to study cell and tissue physiology and to grow replacement tissue for regenerative medicine. Two-dimensional culture has been the paradigm for typical in vitro cell culture; however, it has been demonstrated that cells behave more natively when cultured in three-dimensional environments. Permissive, synthetic hydrogels and promoting, natural hydrogels have become popular as three-dimensional cell culture platforms; yet, both of these systems possess limitations. In this perspective, we discuss the use of both synthetic and natural hydrogels as scaffolds for three-dimensional cell culture as well as synthetic hydrogels that incorporate sophisticated biochemical and mechanical cues as mimics of the native extracellular matrix. Ultimately, advances in synthetic-biologic hydrogel hybrids are needed to provide robust platforms for investigating cell physiology and fabricating tissue outside of the organism.

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Hydrogels as Extracellular Matrix Mimics for 3D Cell Culture

Mechanical cues from the local cellular microenvironment can direct cell fate. Now, experiments with human mesenchymal stem cells cultured on phototunable soft poly(ethylene glycol) hydrogels show that the cells remember past physical environments—with the transcriptional co-activators YAP and TAZ acting as a mechanical rheostat—and therefore that appropriate doses of mechanical cues can be used to manipulate the cells’ fate.

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Mechanical memory and dosing influence stem cell fate.

Medicine relies on the use of pharmacologically active agents (drugs) to manage and treat disease. However, drugs are not inherently effective; the benefit of a drug is directly related to the manner by which it is administered or delivered. Drug delivery can affect drug pharmacokinetics, absorption, distribution, metabolism, duration of therapeutic effect, excretion, and toxicity. As new therapeutics (e.g., biologics) are being developed, there is an accompanying need for improved chemistries and materials to deliver them to the target site in the body, at a therapeutic concentration, and for the required period of time. In this Perspective, we provide an historical overview of drug delivery and controlled release followed by highlights of four emerging areas in the field of drug delivery: systemic RNA delivery, drug delivery for localized therapy, oral drug delivery systems, and biologic drug delivery systems. In each case, we present the barriers to effective drug delivery as well as chemical and mater...

Emerging Frontiers in Drug Delivery

Mouldable hydrogels find a variety of applications in the biomedical industry. Here, Appel et al. show a method to fabricate hydrogels through a self-assembly process based on the interaction between biopolymers and functional nanoparticles for multistage drug delivery in vivo.

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Self-assembled hydrogels utilizing polymer–nanoparticle interactions

We describe a detailed procedure to create photolabile, polyethylene glycol (PEG)-based hydrogels and manipulate material properties in situ. The cytocompatible chemistry and degradation process enable dynamic, tunable changes for applications in two-dimensional (2D) or 3D cell culture. The materials are created by synthesizing an o-nitrobenzylether-based photodegradable monomer that can be coupled to primary amines. In this study, we provide coupling procedures to PEG-bis-amine to form a photodegradable cross-linker or to the fibronectin-derived peptide RGDS to form a photoreleasable tether. Hydrogels are synthesized with the photodegradable cross-linker in the presence or absence of cells, allowing direct encapsulation or seeding on surfaces. Cell-material interactions can be probed in 2D or 3D by spatiotemporally controlling the gel microenvironment, which allows unique experiments to be performed to monitor cell response to changes in their niche. Degradation is readily achieved with cytocompatible wavelengths of low-intensity flood irradiation (365-420 nm) in minutes or with high-intensity laser irradiation (405 nm) in seconds. In this protocol, synthesis and purification of photodegradable monomers take approximately 2 weeks, but the process can be substantially shortened by purchasing the o-nitrobenzylether precursor. Preparation of sterile solutions for hydrogel fabrication takes hours, whereas the reaction to form the final hydrogel is complete in minutes. Hydrogel degradation occurs on demand, in seconds to minutes, with user-directed light exposure. This comprehensive protocol is useful for controlling peptide presentation and substrate modulus during cell culture on or within an elastic matrix. These PEG-based materials are useful for probing the dynamic influence of cell-cell and cell-material interactions on cell function in 2D or 3D. Although other protocols are available for controlling peptide presentation or modulus, few allow manipulation of material properties in situ and in the presence of cells down to the micrometer scale.

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Mark W. Tibbitt

Papers

Hydrogels as Extracellular Matrix Mimics for 3D Cell Culture

Mechanical memory and dosing influence stem cell fate.

Emerging Frontiers in Drug Delivery

Self-assembled hydrogels utilizing polymer–nanoparticle interactions

Synthesis of photodegradable hydrogels as dynamically tunable cell culture platforms