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The goal of this study is to calibrate a multiscale model of tumor angiogenesis with time-resolved data to allow for systematic testing of mathematical predictions of vascular sprouting. The multi-scale model consists of an agent-based description of tumor and endothelial cell dynamics coupled to a continuum model of vascular endothelial growth factor concentration. First, we calibrate ordinary differential equation models to time-resolved protein expression data to estimate the rates of secretion and consumption of vascular endothelial growth factor by endothelial and tumor cells, respectively. These parameters are then input into the multiscale tumor angiogenesis model, and the remaining model parameters are then calibrated to time resolved confocal microscopy images obtained within a 3D vascularized microfluidic platform. The microfluidic platform mimics a functional blood vessel with a surrounding collagen matrix seeded with inflammatory breast cancer cells, which induce tumor angiogenesis. Once the multi-scale model is fully parameterized, we forecast the spatiotemporal distribution of vascular sprouts at future time points and directly compare the predictions to experimentally measured data. We assess the ability of our model to globally recapitulate angiogenic vasculature density, resulting in an average relative calibration error of 17.7% ± 6.3% and an average prediction error of 20.2% ± 4% and 21.7% ± 3.6% using one and four calibrated parameters, respectively. We then assess the model’s ability to predict local vessel morphology (individualized vessel structure as opposed to global vascular density), initialized with the first time point and calibrated with two intermediate time points. To the best of our knowledge, this represents the first study to integrate well-controlled, experimental data into a mechanism-based, multiscale, mathematical model of angiogenic sprouting to make specific, testable predictions.

Background and Objectives Photothermal therapies have limited efficacy and application due to the poor penetration depth of light inside tissue. In earlier work, we described the development of novel fiberoptic microneedles to provide a means to mechanically penetrate dermal tissue and deliver light directly into a localized target area. This paper presents an alternate fiberoptic microneedle design with the capability of delivering more diffuse, but therapeutically useful photothermal energy. Laser lipolysis is envisioned as a future clinical application for this design. Materials and Methods A novel fiberoptic microneedle was developed using hydrofluoric acid etching of optical fiber to permit diffuse optical delivery. Microneedles etched for 10, 30, and 50 minutes, and an optical fiber control were compared with three techniques. First, red light delivery from the microneedles was evaluated by imaging the reflectance of the light from a white paper. Second, spatial temperature distribution of the paper in response to near-IR light (1,064 nm, 1 W CW) was recorded using infrared thermography. Third, ex vivo adipose tissue response during 1,064 nm, (5 W CW) irradiation was recorded with bright field microscopy. Results Acid etching exposed a 3 mm length of the fiber core, allowing circumferential delivery of light along this length. Increasing etching time decreased microneedle diameter, resulting in increased uniformity of red and 1,064 nm light delivery along the microneedle axis. For equivalent total energy delivery, thinner microneedles reduced carbonization in the adipose tissue experiments. Conclusions We developed novel microscale optical diffusers that provided a more homogeneous light distribution from their surfaces, and compared performance to a flat-cleaved fiber, a device currently utilized in clinical practice. These fiberoptic microneedles can potentially enhance clinical laser procedures by providing direct delivery of diffuse light to target chromophores, while minimizing undesirable photothermal damage in adjacent, non-target tissue. Lasers Surg. Med. 43:914-920, 2011. © 2011 Wiley Periodicals, Inc.

Developing combinatorial treatments involving laser irradiation and nanoparticles require an understanding of the effect of nanoparticle inclusion on tissue thermal properties, such as thermal conductivity. This information will permit a more accurate prediction of temperature distribution and tumor response following therapy, as well as provide additional information to aid in the selection of the appropriate type and concentration of nanoparticles. This study measured the thermal conductivity of tissue representative phantoms containing varying types and concentrations of carbon nanotubes (CNTs). Multi-walled carbon nanotubes (MWNTs, length of 900–1200 nm and diameter of 40–60 nm), single-walled carbon nanotubes (SWNTs, length of 900–1200 nm and diameter

Nanoparticles have significant potential as selective photo-absorbing agents for laser based cancer treatment. This study investigates the use of single walled carbon nanohorns (SWNHs) as thermal enhancers when excited by near infrared (NIR) light for tumor cell destruction. Absorption spectra of SWNHs in deionized water at concentrations of 0, 0.01, 0.025, 0.05, 0.085, and 0.1 mg/ml were measured using a spectrophotometer for the wavelength range of 200-1,400 nm. Mass attenuation coefficients were calculated using spectrophotometer transmittance data. Cell culture media containing 0, 0.01, 0.085, and 0.333 mg/ml SWNHs was laser irradiated at 1,064 nm wavelength with an irradiance of 40 W/cm{sup 2} for 0-5 minutes. Temperature elevations of these solutions during laser irradiation were measured with a thermocouple 8 mm away from the incident laser beam. Cell viability of murine kidney cancer cells (RENCA) was measured 24 hours following laser treatment with the previously mentioned laser parameters alone or with SWNHs. Cell viability as a function of radial position was determined qualitatively using trypan blue staining and bright field microscopy for samples exposed to heating durations of 2 and 6 minutes alone or with 0.085 mg/ml SWNHs. A Beckman Coulter Vi-Cell instrument quantified cell viability of samples treated with varyingmore » SWNH concentration (0, 0.01, 0.085, and 0.333 mg/ml) and heating durations of 0-6 minutes. Spectrophotometer measurements indicated inclusion of SWNHs increased light absorption and attenuation across all wavelengths. Utilizing SWNHs with laser irradiation increased temperature elevation compared to laser heating alone. Greater absorption and higher temperature elevations were observed with increasing SWNH concentration. No inherent toxicity was observed with SWNH inclusion. A more rapid and substantial viability decline was observed over time in samples exposed to SWNHs with laser treatment compared with samples experiencing laser heating or SWNH treatment alone. Samples heated for 6 minutes with 0.085 mg/ml SWNHs demonstrated increasing viability as the radial distance from the incident laser beam increased. The significant increases in absorption, temperature elevation, and cell death with inclusion of SWNHs in laser therapy demonstrate the potential of their use as agents for enhancing photothermal tumor destruction.« less

A new image analysis method called the spatial phantom evaluation of cellular thermal response in layers (SPECTRL) is presented for assessing spatial viability response to nanoparticle enhanced photothermal therapy in tissue representative phantoms. Sodium alginate phantoms seeded with MDA-MB-231 breast cancer cells and single-walled nanohorns were laser irradiated with an ytterbium fiber laser at a wavelength of 1064 nm and irradiance of 3.8 W cm(-2) for 10-80 s. SPECTRL quantitatively assessed and correlated 3D viability with spatiotemporal temperature. Based on this analysis, kill and transition zones increased from 3.7 mm(3) and 13 mm(3) respectively to 44.5 mm(3) and 44.3 mm(3) as duration was increased from 10 to 80 s. SPECTRL provides a quantitative tool for measuring precise spatial treatment regions, providing information necessary to tailor therapy protocols.

Laser-based photothermal therapies for urothelial cell carcinoma (UCC) are limited to thermal ablation of superficial tumors, as treatment of invasive lesions is hampered by shallow light penetration in bladder tissue at commonly used therapeutic wavelengths. This study evaluates the utilization of sharp, silica, fiberoptic microneedle devices (FMDs) to deliver single-walled carbon nanohorns (SWNHs) serving as exogenous chromophores in conjunction with a 1064 nm laser to amplify thermal treatment doses in a spatially controlled manner. Experiments were conducted to determine the lateral and depth dispersal of SWNHs in aqueous solution (0.05 mg/mL) infused through FMDs into the wall of healthy, inflated, ex vivo porcine bladders. SWNH perfused bladder regions were irradiated with a free-space, CW, 1064 nm laser in order to determine the SWNH efficacy as exogenous chromophores within the organ. SWNHs infused at a rate of 50 μL/min resulted in an average lateral expansion rate of 0.36 ± 0.08 cm(2)/min. Infused SWNHs dispersal depth was limited to the urothelium and muscular propria for 50 μL/min infusions of 10 minutes or less, but dispersed through the entire thickness after a 15 minute infusion period. Irradiation of SWNH perfused bladder tissue with 1064 nm laser light at 0.95 W/cm(2) over 40 seconds exhibited a maximum increase of approximately 19°C compared with an increase of approximately 3°C in a non-perfused control. The results indicate that these silica FMDs can successfully penetrate into the bladder wall to rapidly distribute SWNHs with some degree of lateral and depth control and that SWNHs may be a viable exogenous chromophore for photothermal amplification of laser-based UCC treatments.

Cancer is one of the most deadly diseases and leading cause of death. Laser based photothermal therapy can provide a minimally invasive alternative to surgical resection. The selectivity and effectiveness of laser therapy can be greatly enhanced when photoabsorbing nanoparticles such as nanoshells, single walled carbon nanotubes, multi-walled carbon nanotubes, or single wall carbon nanohorns (SWNHs) are introduced into the tissue[1]. Quantitative methods for measuring tumor response to nanoparticle enhanced laser therapies are critical for determining appropriate laser parameters and nanoparticle properties needed to achieve maximum therapeutic benefit. We have previously reported a new method for measuring two dimensional (2D) spatial viability distributions in cell monolayers in response to laser irradiation and nanoparticles. This method has been refined to allow determination of cell viability in three dimensions (3D) within a more physiologically representative tumor volume. This refined method was used to determine the viability of breast cancer cells suspended within sodium alginate tissue phantoms following treatment with SWNHs and external laser irradiation. The tumor treatment volume was accurately quantified in response to varying laser treatment parameters and nanoparticle concentrations. Spatial cellular viability was also measured in ex vivo pig bladders in response to SWNHs and laser irradiation to provide a more anatomically relevant environment. These new measurement methods enable quantification of spatial viability and therapeutic effectiveness, using 3D tumor environments which are more representative than cell monolayers.Copyright © 2012 by ASME

Laser based photothermal therapy is a minimally invasive technique that relies on the absorption of energy by an irradiated tissue sample and results in the deposition of heat to destroy cancerous cells. The inclusion of nanoparticles that act as intense infrared absorbers allows for higher selectivity and additional absorption of laser energy into heat in the desired material. One promising carbonaceous nanoparticle is single walled carbon nanohorns (SWNHs) which have been demonstrated to be effective photoabsorbers [1].Copyright © 2012 by ASME

A major limitation in tissue engineering is the lack of nondestructive methods that assess the development of tissue scaffolds undergoing preconditioning in bioreactors. Due to significant optical scattering in most scaffolding materials, current microscope-based imaging methods cannot “see” through thick and optically opaque tissue constructs. To address this deficiency, we developed a fiber-optic-based imaging method that is capable of nondestructive imaging of fluorescently labeled cells through a thick and optically opaque scaffold, contained in a bioreactor. This imaging modality is based on the local excitation of fluorescent cells, the acquisition of fluorescence through the scaffold, and fluorescence mapping based on the position of the excitation light. To evaluate the capability and accuracy of the imaging system, human endothelial cells (ECs), stably expressing green fluorescent protein (GFP), were imaged through a fibrous scaffold. Without sacrificing the scaffolds, we nondestructively visualized the distribution of GFP-labeled cells through a ∼500 μm thick scaffold with cell-level resolution and distinct localization. These results were similar to control images obtained using an optical microscope with direct line-of-sight access. Through a detailed quantitative analysis, we demonstrated that this method achieved a resolution on the order of 20–30 μm, with 10% or less deviation from standard optical microscopy. Furthermore, we demonstrated that the penetration depth of the imaging method exceeded that of confocal laser scanning microscopy by more than a factor of 2. Our imaging method also possesses a working distance (up to 8 cm) much longer than that of a standard confocal microscopy system, which can significantly facilitate bioreactor integration. This method will enable the nondestructive monitoring of ECs seeded on the lumen of a tissue-engineered vascular graft during preconditioning in vitro, as well as for other tissue-engineered constructs in the future.

Sub-lethal temperature elevations in the tumour incurred during laser cancer therapy can induce heat shock protein (HSP) expression leading to enhanced tumour survival and recurrence. Nanoshells utilised in combination with laser therapy can potentially enable selective heat deposition, greater thermal injury, and diminished HSP expression in the tumour. The study objective was to measure the distribution of temperature and HSP expression in prostate tumours in response to laser therapy alone or with nanoshells to determine if these combinatorial therapies can minimise HSP expression.PC3 cells were inoculated in the backs of CB17-Prkd c SCID/J mice and treated with external laser irradiation (wavelength of 810 nm, irradiance of 5 W/cm(2), spot size of 5 mm, and heating duration of 3 min) alone or in combination with gold nanoshells (diameter of 55 nm and outer gold shell thickness of 10 nm) introduced into the tumour 24 h prior to laser treatment. Magnetic resonance temperature imaging was used to measure the distribution of temperature elevation in the tumours during laser treatment. Tumours were sectioned 16 h following laser treatment, stained for Hsp27 and Hsp70, imaged with a confocal microscope, and HSP expression levels were quantified as a function of depth in the tumours.Maximum temperature elevations at the tumour surface were 28°C for laser treatment only and 50°C for laser heating in combination with gold nanoshells. Laser therapy alone caused significant induction of HSP expression in the first few millimeters of the tumour depth, whereas decreasing HSP expression occurred with greater tumour depth. Tumours treated with laser and nanoshells experienced substantial temperatures (73-78°C) at the tumour surface and temperatures greater than 53°C in the first few millimeters which eliminated HSP expression.Inclusion of nanoshells in laser therapy can provide a mechanism for enhancing heat deposition capable of eliminating HSP expression within a larger tumour region compared to laser heating alone.

Laser-based photothermal therapy can provide a minimally invasive treatment alternative to surgical resection of tumors. The selectivity and effectiveness of laser therapy can be greatly enhanced when photo-absorbing nanoparticles such as multi-walled carbon nanotubes (MWNTs) are introduced into the tissue [1,2]. The effectiveness of nanoparticle enhanced laser treatment can be determined through a combined approach using experimental measurement and computational models. This approach allows ideal laser parameters (e.g. irradiance, pulse duration) and nanoparticle properties (e.g. concentration and delivery method) to be selected to maximize treatment efficacy. We developed a computational model to predict the temperature response of tissue representative phantoms and in vivo murine renal cancer (RENCA) kidney tumors to MWNTs used in combination with external laser irradiation. The accuracy of the computational model prediction of temperature was verified by comparing with experimental measurements of temperature using magnetic resonance thermometry (MRTI). In addition, an image analysis technique is introduced for measuring the spatial viability of cancer cells suspended in tissue phantoms following nanoparticle enhanced laser therapy and correlating cell viability with thermal exposure. Spatial viability and thermal measurements are combined to predict cell death as a function of temperature in tissue phantoms.Copyright © 2011 by ASME

Carbon nanoparticles have the potential to significantly impact the medical field over the next decade. Currently, carbon nanoparticles are being studied for a myriad of applications, including drug delivery, selective laser therapy, imaging, and biosensing. The most common type of carbon particles being investigated are carbon nanotubes (CNTs). CNTs are attractive materials for medical applications because of their physical properties and the ease with which they can be surface modified; however, there is a great deal of controversy over their possible toxicity. A more novel type of CNT that was discovered in 1999 by Iijima et al. is the carbon nanohorn [1]. Individual single-walled nanohorns (SWNHs) are single graphene sheets that roll into a conical open ended structure. The open ends of these cones are then attracted to one another through van der Waals interactions and form a flower-like final structure [2]. SWNHs are more favorable for medical applications because they are produced without the use of metal catalysts abating the concern of toxicity associated with CNTs.Copyright © 2011 by ASME

The degree by which optical properties of tumors are altered following introduction of carbon nanotubes (CNTs) of varying concentration and type is poorly understood, making it difficult to predict the impact of CNT inclusion on the photothermal response to laser therapies. Optical properties were measured of phantoms representative of breast tumor tissue incorporated with multiwalled carbon nanotubes (MWNTs), single-walled carbon nanotubes (SWNTs), and single-walled carbon nanohorns (SWNHs) of varying concentration (0.01–0.1 mg/ml). Tissue phantoms were made from sodium alginate (3 g/ml) incorporated with polystyrene microbeads (3 μm diam and 1 mg/ml) and talc-France powder (40 mg/ml). Absorption (μa) and reduced scattering (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}\mu^\prime _s\end{equation*} \end{document}μs′) coefficients of phantoms containing CNTs were determined by the inverse adding-doubling algorithm for the wavelength range of 400–1300 nm. Optical properties of phantoms without CNTs were in the range of μa = 1.04–0.06 mm−1 and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}\mu^\prime _s\end{equation*} \end{document}μs′ = 0.05–0.07 mm−1 at a wavelength of 900 nm, which corresponds with published data for human breast tumor tissue. Incorporating MWNTs, SWNTs, and SWNHs in phantoms with a concentration of 0.1 mg/ml increased (μa) by 20- to 30-fold, 5- to 6-fold, and 9- to 14-fold, respectively, for the wavelength range of 800–1100 nm with minimal change in \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}\mu^\prime _s\end{equation*} \end{document}μs′ (1.2- to 1.3-fold). Introduction of CNTs into tissue phantoms increased absorption, providing a means to enhance photothermal therapy.

A major barrier for progress in regenerative medicine is the inability to observe the process of tissue regeneration non-destructively, in real time, and with cellular level resolution. In order to overcome this difficult challenge, we have proposed and developed an imaging-bioreactor system based on fiber micro-devices. Our system is based on directly incorporating multiple hollow core fibers (HCFs) into a biocompatible tissue scaffold. By inserting fiber-based micro-mirrors into the HCFs and applying a straightforward scanning-reconstruction algorithm, we have demonstrated an imaging resolution of ∼200 μm through an optically opaque scaffold.

Shallow light penetration in tissue has been a technical barrier to the development of light-based methods for in vivo diagnosis and treatment of epithelial carcinomas. This problem can potentially be solved by utilizing minimally invasive probes to deliver light directly to target areas. To develop this solution, fiber optic microneedles capable of delivering light for either imaging or therapy were manufactured by tapering step-index silica-based optical fibers employing a melt-drawing process. Some of the microneedles were manufactured to have sharper tips by changing the heat source during the melt-drawing process. All of the microneedles were individually inserted into ex vivo pig skin samples to demonstrate the feasibility of their application in human tissues. The force on each microneedle was measured during insertion in order to determine the effects of sharper tips on the peak force and the steadiness of the increase in force. Skin penetration experiments showed that sharp fiber optic microneedles that are 3 mm long penetrate through 2 mm of ex vivo pig skin specimens. These sharp microneedles had a minimum average diameter of 73 μm and a maximum tip diameter of 8 μm. Flat microneedles, which had larger tip diameters, required a minimum average diameter of 125 μm in order to penetrate through pig skin samples. Force versus displacement plots showed that a sharp tip on a fiber optic microneedle decreased the skin’s resistance during insertion. Also, the force acting on a sharp microneedle increased more steadily compared with a microneedle with a flat tip. However, many of the sharp microneedles sustained damage during skin penetration. Two designs that did not accrue damage were identified and will provide a basis of more robust microneedles. Developing resilient microneedles with smaller diameters will lead to transformative, novel modes of transdermal imaging and treatment that are less invasive and less painful for the patient.

Carbon nanotubes (CNTs) are attractive materials for early detection, treatment, and imaging of cancer malignancies; however, they are limited by their inability to be monitored in vitro and in vivo [1]. Unlabeled CNTs are difficult to distinguish using elemental analysis because they are composed entirely of carbon, which is also characteristic of cellular membranes. Although some single walled nanotubes (SWNT) have been found to exhibit fluorescent properties, not all particles in a single batch fluoresce [2]. Additionally, these emissions may be too weak to be detected using conventional imaging modalities [3]. Incorporating fluorescent markers, such as fluorescent proteins or quantum dots, allows the non-fluorescent particles to be visualized. Previously, fluorophores, such as green fluorescent protein (GFP) or red fluorescent protein (RFP), have been used to visualize and track cells or other particles in biological environments, but their low quantum yield and tendency to photobleach generate limitations for their use in such applications.

Cancer remains one of the most deadly diseases today. Laser-induced photothermal therapy can provide a minimally invasive treatment alternative to surgical resection. The selectivity and effectiveness of laser therapy can be greatly enhanced when photoabsorbing nanoparticles such as nanoshells, single walled carbon nanotubes, multi-walled carbon nanotubes, or single wall carbon nanohorns (SWNHs) are introduced into the tissue. Prior studies have effectively used SWNHs combined with near infrared (NIR) laser light to target and destroy microbes [1]. We have previously reported increased tumor cell destruction when SWNHs were used in combination with laser therapy. The present work provides more extensive characterization of cell viability in response to laser therapy alone or in combination with SWNHs. Furthermore, the spatiotemporal temperature and cell viability in vitro in response to combinatorial SWNH-mediated laser therapies is determined using infrared thermometry and a novel viability algorithm, respectively. These new measurements will be critical for planning SWNH-mediated laser treatments where knowledge of the geometric distribution of temperature and cell death are critical to achieving the goal of selectively eliminating a tumor with specific spatial margins with minimal damage to surrounding healthy tissue.

Inclusion of multi-walled carbon nanotubes (MWNTs) into tissue prior to laser therapy has the potential to enhance the selectivity and effectiveness of cancer therapy by providing greater and more controlled thermal deposition. The purpose of this study was to investigate the optical and thermal response of tissue representative phantoms containing MWNTs to optical radiation. Tissue representative phantoms 20 mm in diameter and 1 mm in thickness were created from sodium alginate. Following the inclusion of MWNTs (900 nm in length, 40–60 nm in diameter) in phantoms, the distribution of MWNTs was observed using transmission electron microscopy. A predominantly, evenly dispersed and randomly oriented distribution of MWNTs was observed with a rare presence of MWNT clustering or clumping. In order to characterize the response of MWNT inclusion on optical properties of phantoms, the transmittance and reflectance spectra of phantoms with and without MWNT inclusion were measured with a spectrophotometer over a wavelength range of 200–1400 nm. Inclusion of MWNTs in phantoms dramatically enhanced light absorption across the entire wavelength range as evidenced by a diminished transmittance and reflectance compared with phantoms without MWNTs. In order to evaluate the spatiotemporal temperature distribution associated with laser irradiation of phantoms with and without MWNTs, the temperature was measured at discrete radial distances from the center of the incident laser beam using thermocouples. The rate of temperature increase and peak temperature for phantoms containing MWNTs was much greater compared with phantoms without MWNTs at all measurement locations. In conclusion, MWNT inclusion in tissue phantoms increases the optical absorption and temperature elevation, which may enable more effective photothermal therapies of human disease utilizing lasers.

Non-thermal irreversible electroporation (IRE) is a new, minimally invasive technique that has shown great promise for the ablation of tumors [1]. The procedure involves placing electrodes into or around a targeted tissue and delivering a series of low energy (intense but short) electric pulses for approximately one minute. These pulses induce irreversible structural changes in the cell membranes of the targeted tissue that lead to cell death. Because IRE affects only a single molecular component of the treated area, the cell membrane, it is the first true molecular surgery. IRE has the ability to create complete and predictable cell ablation with a sharp transition between normal and necrotic tissue.Copyright © 2009 by ASME

Laser therapies based on photochemical or photothermal mechanisms can provide a minimally invasive and potentially more effective treatment alternative to conventional surgical resection procedures by delivering prescribed optical/thermal doses to a targeted tissue volume with minimal damage to intervening and surrounding tissues. However laser therapy effectiveness is limited due to nonspecific excitation/heating of target tissue which often results in healthy tissue injury. Nanostructures targeted to tumor cells and utilized in combination with laser excitation can enhance treatment effectiveness by increasing thermal deposition and generating toxic photo-chemical mediators in the form of reactive oxygen species for targeted cell destruction.Copyright © 2009 by ASME

Development of dual diagnostic and therapeutic agents for cancer with heightened sensitivity, selectivity, and lower toxicity could greatly enhance the prognosis of patients suffering from this disease. Recent work by Dr. Harry Dorn of Virginia Tech has resulted in the creation of a novel nanostructure called a carbon nanotube peapod. This structure consists of multiple TNT EMF’s (Trimetallic nitride template endohedral metallofullerenes) contained within a single-walled carbon nanotube (CNT) in the form of a peapod. Using TNT EMFs containing gadolinium, this nanostructure can achieve a 40-fold improvement in magnetic resonance imaging (MRI) contrast enhancement [1]. The CNT component of the peapod can be utilized as a hyperthermia enhancer [2] and an effective platform for drug delivery [3]. This study focuses on the use of carbon nanotube peapods (CNT peapods) to absorb near infrared light and generate therapeutic heat for tumor destruction. With sufficient heating and nanoparticle targeted delivery to tumor cells, CNT peapods can potentially induce selective hyperthermia-mediated toxicity in tumors.

Laser therapies can provide a minimally invasive treatment alternative to surgical resection of tumors. However, the effectiveness of these therapies is limited due to nonspecific heating of target tissue which often leads to healthy tissue injury and extended treatment durations. These therapies can be further compromised due to heat shock protein (HSP) induction in tumor regions where non-lethal temperature elevation occurs, thereby imparting enhanced tumor cell viability and resistance to subsequent chemotherapy and radiation treatments. Introducing multi-walled nanotubes (MWNT) into target tissue prior to laser irradiation increases heating selectivity permitting more precise thermal energy delivery to the tumor region and enhances thermal deposition thereby increasing tumor injury and reducing HSP expression induction. This study investigated the impact of MWNT inclusion in untreated and laser irradiated monolayer cell culture and cell phantom model. Cell viability remained high for all samples with MWNT inclusion and cells integrated into alginate phantoms, demonstrating the non-toxic nature of both MWNTs and alginate phantom models. Following, laser irradiation samples with MWNT inclusion exhibited dramatic temperature elevations and decreased cell viability compared to samples without MWNT. In the cell monolayer studies, laser irradiation of samples with MWNT inclusion experienced up-regulated HSP27, 70 and 90 expression as compared to laser only or untreated samples due to greater temperature increases albeit below the threshold for cell death. Further tuning of laser parameters will permit effective cell killing and down-regulation of HSP. Due to optimal tuning of laser parameters and inclusion of MWNT in phantom models, extensive temperature elevations and cell death occurred, demonstrating MWNT-mediated laser therapy as a viable therapy option when parameters are optimized. In conclusion, MWNT-mediated laser therapies show great promise for effective tumor destruction, but require determination of appropriate MWNT characteristics and laser parameters for maximum tumor destruction.

A scanning-fiber-based method developed for imaging bioengineered tissue constructs such as synthetic carotid arteries is reported. Our approach is based on directly embedding one or more hollow-core silica fibers within the tissue scaffold to function as micro-imaging channels (MIC). The imaging process is carried out by translating and rotating an angle-polished fiber micro-mirror within the MIC to scan excitation light across the tissue scaffold. The locally emitted fluorescent signals are captured using an electron multiplying CCD camera and then mapped into fluorophore distributions according to fiber micro-mirror positions. Using an optical phantom composed of fluorescent microspheres, tissue scaffolds, and porcine skin, we demonstrated single-cell-level imaging resolution (20 to 30 μm) at an imaging depth that exceeds the photon transport mean free path by one order of magnitude. This result suggests that the imaging depth is no longer constrained by photon scattering, but rather by the requirement that the fluorophore signal overcomes the background “noise” generated by processes such as scaffold autofluorescence. Finally, we demonstrated the compatibility of our imaging method with tissue engineering by visualizing endothelial cells labeled with green fluorescent protein through a ∼500 μm thick and highly scattering electrospun scaffold.