Ultrasound (US) is one of the most frequently used diagnostic methods. It is a non-invasive, comparably inexpensive imaging method with a broad spectrum of applications, which can be increased even more by using bubbles as contrast agents (CAs). There are various different types of bubbles: filled with different gases, composed of soft- or hard-shell materials, and ranging in size from nano- to micrometers. These intravascular CAs enable functional analyses, e.g., to acquire organ perfusion in real-time. Molecular analyses are achieved by coupling specific ligands to the bubbles’ shell, which bind to marker molecules in the area of interest. Bubbles can also be loaded with or attached to drugs, peptides or genes and can be destroyed by US pulses to locally release the entrapped agent. Recent studies show that US CAs are also valuable tools in hyperthermia-induced ablation therapy of tumors, or can increase cellular uptake of locally released drugs by enhancing membrane permeability. This review summarizes important steps in the development of US CAs and introduces the current clinical applications of contrast-enhanced US. Additionally, an overview of the recent developments in US probe design for functional and molecular diagnosis as well as for drug delivery is given.

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Mesenchymal stem cells (MSC) are precursor cells of mesodermal tissue and, because of their trophic phenotype, they are known to play beneficial roles in wound healing. In addition, various tissue engineering strategies are based on MSC/biomaterial constructs. As the isolation and expansion of MSCs is a long-term process, a major goal is to develop an endogenous stem cell recruitment system that circumvents all ex vivo steps generally used for tissue engineering. Therefore collagen and silk fibroin were loaded with hepatocyte growth factor (HGF), a chemoattractant for MSCs. Collagen was mixed with HGF during polymerization, while silk fibroin and HGF were produced as fusion proteins by transgenic silkworms. To demonstrate release of active HGF, enzyme-linked immunosorbent assay, in vitro migration assays and animal studies were performed to demonstrate MSC migration in vivo, followed by detailed examinations of the immunological effects of the biomaterials. Hepatocyte growth factor was released burst-like, both from silk fibroin and collagen during the first 8 h and gradually for up to 168 h in vitro. Directed migration in vitro was demonstrated when MSCs were exposed to HGF. In vivo, HGF-loaded collagen and silk fibroin were tolerated as subcutaneous implants. In addition, it was proved that endogenous MSCs were recruited from the local environment. These results show for the first time recruitment of endogenous MSCs to HGF-loaded collagen (fast degradable) and silk fibroin scaffolds (long-term degradable) in vitro and in vivo. This knowledge could be applied to make off-the-shelf, readily available constructs for use in patients with chronic wound or burns. Copyright © 2016 John Wiley & Sons, Ltd.

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Contrast agents (CA) are routinely used in clinical practice to improve the diagnosis of diseases and to monitor therapy response. The majority of CA comprises small molecules accumulating at pathological sites due to vascular abnormalities, such as changes in perfusion and permeability. For many diseases, high diagnostic accuracy can be achieved with contrast-enhanced imaging. This means that new CA will only succeed in translation if they either show superior performance with respect to diagnostic accuracy, safety and cost, support a new imaging modality, or are directly linked to the refinement of therapy, e.g., as a companion diagnostic. Unfortunately, these basic demands are often not carefully considered by the scientific community, leading to concepts with low chances of clinical translation. Thus, it is not surprising that, despite steadily increasing numbers of publications, there is quite the opposite trend when it comes to the clinical approval of new diagnostics. As a matter of fact, except for PET tracers, in the last decade, only a handful of CA received FDA or EMA approval. Furthermore, several approved products were discontinued by the manufacturers because of low market potential, a competitive own product, suboptimal clinical performance, or safety concerns. This review article discusses the current status of approved diagnostic probes for clinical imaging modalities, with a focus on new trends in CA development. In this context, molecularly targeted diagnostics or probes for emerging fields, such as image-guided surgery, nanomedicine, or theranostics, will be introduced and discussed with regard to their clinical translation. WIREs Nanomed Nanobiotechnol 2017, 9:e1441. doi: 10.1002/wnan.1441 For further resources related to this article, please visit the WIREs website.

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The inside cover image, by Tatjana Opacic et al., is based on the Advanced Review Status and trends in the development of clinical diagnostic agents, DOI: .