Lanthanide-doped upconverting nanoparticles (UCNPs) have emerged as excellent nanotransducers for converting longer wavelength near-infrared (NIR) light to shorter wavelengths spanning the ultraviolet (UV) to the visible (Vis) regions of the spectrum via a multiphoton absorption process, known as upconversion. Here, we report the development of NIR to UV-Vis-NIR UCNPs consisting of LiYF4:Yb(3+)/Tm(3+)@SiO2 individually coated with a 10 ± 2 nm layer of chitosan (CH) hydrogel cross-linked with a photocleavable cross-linker (PhL). We encapsulated fluorescent-bovine serum albumin (FITC-BSA) inside the gel. Under 980 nm excitation, the upconverted UV emission cleaves the PhL cross-links and instantaneously liberates the FITC-BSA under 2 cm thick tissue. The release is immediately arrested if the excitation source is switched off. The upconverted NIR light allows for the tracking of particles under the tissue. Nucleus pulposus (NP) cells cultured with UCNPs are viable both in the presence and in the absence of laser irradiation. Controlled drug delivery of large biomolecules and deep tissue imaging make this system an excellent theranostic platform for tissue engineering, biomapping, and cellular imaging applications.

Efficient control over drug release is critical to increasing drug efficacy and avoiding side effects. An ideal drug delivery system would deliver drugs in the right amount, at the right location and at the right time noninvasively. This can be achieved using light-triggered delivery: light is noninvasive, spatially precise and safe if appropriate wavelengths are chosen. However, the use of light-controlled delivery systems has been limited to areas that are not too deep inside the body because ultraviolet (UV) or visible (Vis) light, the typical wavelengths used for photoreactions, have limited penetration and are toxic to biological tissues. The advent of upconverting nanoparticles (UCNPs) has made it possible to overcome this crucial challenge. UCNPs can convert near-infrared (NIR) radiation, which can penetrate deeper inside the body, to shorter wavelength NIR, Vis and UV radiation. UCNPs have been used as bright, in situ sources of light for on-demand drug release and bioimaging applications. These remote-controlled, NIR-triggered drug delivery systems are especially attractive in applications where a drug is required at a specific location and time such as in anesthetics, postwound healing, cardiothoracic surgery and cancer treatment. In this Perspective, we discuss recent progress and challenges as well as propose potential solutions and future directions, especially with regard to their translation to the clinic.

To design a biodegradable hydrogel as cell support, one should know its in vivo degradation rate. A technique commonly used to track gel degradation is fluorescence spectroscopy. However, the fluorescence from conventional fluorophores quickly decays, and the fluorophores are often moderately cytotoxic. Most importantly, they require ultraviolet or visible (UV-Vis) light as the excitation source, which cannot penetrate deeply through biological tissues. Lanthanide-doped upconverting nanoparticles (UCNPs) are exciting alternatives to conventional fluorophores because they can convert near-infrared (NIR) to UV-Vis-NIR light via a sequential multiphoton absorption process referred to as upconversion. NIR light can penetrate up to few cm inside tissues, thus making these UCNPs much better probes than conventional fluorophores for in vivo monitoring. Also, UCNPs have narrow emission bands, high photoluminescence (PL) signal-to-noise ratio, low cytotoxicity and good physical and chemical stability. Here, we show a nanocomposite system consisting of a biodegradable, in situ thermogelling injectable hydrogel made of chitosan and hyaluronic acid encapsulating silica-coated LiYF4:Yb(3+)/Tm(3+) UCNPs. We use these UCNPs as photoluminescent tags to monitor the gel degradation inside live, cultured intervertebral discs (IVDs) over a period of 3 weeks. PL spectroscopy and NIR imaging show that NIR-to-NIR upconversion of LiYF4:Yb(3+)/Tm(3+)@SiO2 UCNPs allows for tracking of the gel degradation in living tissues. Both in vitro and ex vivo release of UCNPs follow a similar trend during the first 5 days; after this time, ex vivo release becomes faster than in vitro, indicating a faster gel degradation ex vivo. Also, the amount of released UCNPs in vitro increases continuously up to 3 weeks, while it plateaus after 15 days inside the IVDs showing a homogenous distribution of UCNPs throughout the IVD tissue. This non-invasive optical method for real time, live tissue imaging holds great potential for tissue analysis, biomapping and bioimaging applications.

We report a facile method to synthesize highly branched gold nanostars wrapped with nano graphene oxide (nGO) sheets with or without the addition of Raman dyes, as nanoprobes with high SERS activity. Both cysteamine and nGO are added to gold nanostars; the positively charged amino groups help self-assembly of nGO flakes around the nanostars. This increases the Raman signal of nGO by 5.3 folds compared to samples in which nGO is in contact with the nanostars but does not wrap them. We also prepare dye-based SERS nanoprobes by sandwiching a typical Raman reporter such as Rhodamine B (RhB), Crystal Violet (CV) and Rhodamine 6G (R6G) between the nanostars and the nGO coating. The Raman signals of RhB are 5.2 times larger when sandwiched between nGO and nanostars than if the molecules are just adsorbed on the nanostar surface, and similar enhancements are observed for the other dyes. In addition to improving SERS efficiency, the wrapping greatly improves the stability of the dye-based nanoprobes, showing a reproducible Raman signal of RhB for over a week in simulated body fluids at 37 °C. High SERS signal, facile fabrication method and excellent stability make these nanoprobes highly promising for SERS-based biosensing and bioimaging applications.

Perfluorocarbon (PFC) emulsions are capable of absorbing large quantities of oxygen. They are widely used as blood alternates for quick oxygenation of tissues. However, they are unsuitable for applications where sustained oxygen supply is desired over an extended period of time. Here, we have designed a new PFC oxygen delivery system that combines perfluorodecalin with graphene oxide (GO), where GO acts both as an emulsifier and a stabilizing agent. The resulting emulsions (PFC@GO) release oxygen at least one order of magnitude slower than emulsions prepared with other common surfactants. The release rate can be controlled by varying the thickness of the GO layer. Controlled release of oxygen make these emulsions excellent oxygen carriers for applications where sustained oxygen delivery is required e.g. in tissue regeneration and vascular wound healing.