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Biomedical Optics & Medical Imaging

Photothermal therapy used in laser bonding, microsurgery

Gold nanorods are emerging as a powerful solution for various minimally-invasive biomedical applications, including laser bonding of connective tissues.
7 July 2010, SPIE Newsroom. DOI: 10.1117/2.1201006.002890

Near IR (NIR) laser-activatable nanoparticles may become a powerful tool in biomedical optics. Because NIR light penetrates deeply into bodily tissues, specific targets stained with these nanoparticles become exposed to efficient and selective laser interaction that may be exploited for imaging, therapeutics, and sensing.1 Among the alternatives of greatest current interest are gold nanorods.2–4 Their excitation involves plasmon resonances (collective-charge oscillations) at NIR frequencies and activates various processes comprising Rayleigh scattering, near-field enhancement, and intense light absorption. As a reference, about 100pM gold nanorods achieve the same extinction in the NIR range as 100μM indocyanine green (ICG), which is among the most efficient NIR dyes.5 Possible applications for gold nanorods include near-field enhancement for sensing by Raman and luminescence spectroscopy; contrast enhancement for imaging by Rayleigh scattering,6 fluorescence7 and photoacoustics;8 microsurgery by hyperthermia;3 and photoacoustics. The feasibility of these applications depends on reciprocal interactions between the gold nanorods, NIR light, and the biological environment. In turn, these interactions are affected by the size, shape, and surface modification of the nanoparticles, which govern parameters such as the biodistribution, toxicity,9 efficiency of photothermal and photoacoustic conversion, stability, and frequency of the plasmon resonances.2

Colloidal suspensions of gold nanorods may be synthesized by self-assembly and then modified with combinations such as polymers, silicates, and proteins2 to gain additional functionalities. The scientific community is paying special attention to the conjugation of gold nanorods with antibodies due to its potential for active delivery, such as to malignant cells.3,4 Figure 1 gives examples of an extinction spectrum and transmission electron micrographs of different solutions of gold nanorods.10

Figure 1. (top:) extinction spectrum (empty circles) and relevant particle shape distribution (solid circles). (Bottom:) (200 × 200)nm2 transmission electron micrographs of different solutions of gold nanorods. A.U.: Arbitrary unit.

As a model example of photothermal therapy, we tested gold nanorods for laser bonding of connective tissues,5,11 which is emerging as a powerful alternative to conventional surgical suturing where segments of the skin, blood vessels, organ capsules, and the cornea undergo incision.11,12 The edges of a cut were sealed by combining a NIR laser and NIR dye, possibly in conjunction with a solder, to activate various thermal modifications. Laser bonding may give immediate water-tight closure of the cut, with minimal inflammatory response and scar formation. Since NIR chromophores in use are organic dyes such as ICG whose poor stability is a severe constraint, the introduction of gold nanorods may become an enabling breakthrough. As an early proof of concept in ophthalmic surgery, we used gold nanorods to bond patches of porcine eye lens capsules.5,13 Substantial improvement is expected from including gold nanorods in functional biopolymeric formulations. The bio-polymer may exert valuable protection of nanoparticles against the physiological environment, providing great stability, durability, and effectiveness. For instance, nanoparticles may be secured against flocculation (clumping), a critical issue in most physiological fluids. Biopolymers offer additional advantages in manipulation and control over the nanoparticles' density, and they may play an active role post-surgically by promoting tissue repair, decreasing scar formation, and preventing microbial infections. They may even host additional drugs and factors to optimize healing.12 Using biopolymers for tissue repair has gained importance over the last few years.14,15 In particular, polysaccharides, such as hyaluronan and chitosan and their derivatives, are suitable candidates for laser bonding because of their high affinity for bodily tissues, biodegradability, and low cost.

Recently, we engineered a paste of hyaluronan and PEGylated gold nanorods for laser bonding of blood vessels. This formulation maintained the pristine optical features of gold nanorods at least nine months in storage under daylight conditions, and proved suitable to bond 3mm-long incisions through the carotid artery of rabbits in vivo (see Figures 2A-D). No occlusion, blood leakage, or hemorrhage was observed during the intervention. Thirty days after surgery, the animals were sacrificed for histological evaluation (see Figures 2E-F), which demonstrated substantial integrity of the carotid wall, minimal hyalinosis, and regular restoration. Electron microscopy analysis revealed spherical nanoparticles interspersed through the vascular tissue. Thus, gold nanorods underwent transformation into gold nanospheres, which began during the surgery and developed in the 30-day follow-up.

Figure 2. Sequence of a laser-bonding procedure with a hyaluronan-gold nanorods gel. (A) The artery is clamped and a 3mm-longitudinal incision is made. (B) The gel is applied with a spatula. (C) The incision is treated with a laser-diode light. (D) The appearance of the artery immediately after clamp removal. (E) Thirty days after surgery, carotid walls are well preserved (Gomori stain). (F) Transmission electron micrograph (bar = 200nm) revealing spherical nanoparticles interspersed among intact collagen fibers.

In conclusion, we addressed a model photothermal therapy based on gold nanorods by the laser bonding of connective tissues such as ophthalmic capsules and blood vessels. Gold nanorods are ideal NIR chromophores that may be combined with a broad variety of functional formulations, including polysaccharides. While our preliminary tests proved successful both ex vivo and in vivo, issues such as the biocompatibility and the biological fate of gold nanorods require additional investigation.

Roberto Pini, Fulvio Ratto, Paolo Matteini, Francesca Rossi
Institute for Applied Physics
Italian National Research Council (CNR)
Sesto Fiorentino, Italy

Roberto Pini, physicist, heads the Biophotonics and Nanomedicine Lab at the institute and is a professor of biomedical optics at Florence University's Faculty of Medicine. His research focuses on laser-tissue interactions, light excitation of chromophores, and nanoparticles for minimally invasive diagnostics and therapy.

Fulvio Ratto received his MSc in physics from the University of Trieste (Italy) in 2002 and his PhD in materials science from the University of Quebec in Montreal, Canada in 2007. Since 2007 he has held a CNR postdoctoral position. His background is in the development and applications of nanomaterials with advanced electronic and optical functionalities. His present interest is exploring new synergies between nanoplasmonics and biomedical optics.

Paolo Matteini obtained his MSc in chemistry from the University of Florence in 2004 and his PhD in chemical sciences in 2008. Since 2005 he has worked in the field of photothermal therapies and microscopy of biological tissues as a CNR postdoctoral student. Current research interests include the optimization of laser-welding techniques, thermal modifications of biopolymers, and synthesis of new hybrid organic-inorganic nanocomposites.

Francesca Rossi received her MSc in physics in 1996 and her PhD in energetics in 2001, both from the University of Florence. She has been with CNR since 2003. She is studying light-tissue interactions. Her current research interests include experimental and theoretical studies on the temperature dynamics during light irradiations of biotissue.