Christina R. Inscoe

Physiologically gated microbeam radiation using a field emission x-ray source array

PURPOSE Microbeam radiation therapy (MRT) uses narrow planes of high dose radiation beams to treat cancerous tumors. This experimental therapy method based on synchrotron radiation has been shown to spare normal tissue at up to 1000 Gy of peak entrance dose while still being effective in tumor eradication and extending the lifetime of tumor-bearing small animal models. Motion during treatment can lead to significant movement of microbeam positions resulting in broader beam width and lower peak to valley dose ratio (PVDR), which reduces the effectiveness of MRT. Recently, the authors have demonstrated the feasibility of generating microbeam radiation for small animal treatment using a carbon nanotube (CNT) x-ray source array. The purpose of this study is to incorporate physiological gating to the CNT microbeam irradiator to minimize motion-induced microbeam blurring. METHODS The CNT field emission x-ray source array with a narrow line focal track was operated at 160 kVp. The x-ray radiation was collimated to a single 280 μm wide microbeam at entrance. The microbeam beam pattern was recorded using EBT2 Gafchromic(©) films. For the feasibility study, a strip of EBT2 film was attached to an oscillating mechanical phantom mimicking mouse chest respiratory motion. The servo arm was put against a pressure sensor to monitor the motion. The film was irradiated with three microbeams under gated and nongated conditions and the full width at half maximums and PVDRs were compared. An in vivo study was also performed with adult male athymic mice. The liver was chosen as the target organ for proof of concept due to its large motion during respiration compared to other organs. The mouse was immobilized in a specialized mouse bed and anesthetized using isoflurane. A pressure sensor was attached to a mouses chest to monitor its respiration. The output signal triggered the electron extraction voltage of the field emission source such that x-ray was generated only during a portion of the mouse respiratory cycle when there was minimum motion. Parallel planes of microbeams with 12.4 Gy/plane dose and 900 μm pitch were delivered. The microbeam profiles with and without gating were analyzed using γ-H2Ax immunofluorescence staining. RESULTS The phantom study showed that the respiratory motion caused a 50% drop in PVDR from 11.5 when there is no motion to 5.4, whereas there was only a 5.5% decrease in PVDR for gated irradiation compared to the no motion case. In the in vivo study, the histology result showed gating increased PVDR by a factor of 2.4 compared to the nongated case, similar to the result from the phantom study. The full width at tenth maximum of the microbeam decreased by 40% in gating in vivo and close to 38% with phantom studies. CONCLUSIONS The CNT field emission x-ray source array can be synchronized to physiological signals for gated delivery of x-ray radiation to minimize motion-induced beam blurring. Gated MRT reduces valley dose between lines during long-time radiation of a moving object. The technique allows for more precise MRT treatments and makes the CNT MRT device practical for extended treatment.

Treating Brain Tumor with Microbeam Radiation Generated by a Compact Carbon-Nanotube-Based Irradiator: Initial Radiation Efficacy Study

Microbeam radiation treatment (MRT) using synchrotron radiation has shown great promise in the treatment of brain tumors, with a demonstrated ability to eradicate the tumor while sparing normal tissue in small animal models. With the goal of expediting the advancement of MRT research beyond the limited number of synchrotron facilities in the world, we recently developed a compact laboratory-scale microbeam irradiator using carbon nanotube (CNT) field emission-based X-ray source array technology. The focus of this study is to evaluate the effects of the microbeam radiation generated by this compact irradiator in terms of tumor control and normal tissue damage in a mouse brain tumor model. Mice with U87MG human glioblastoma were treated with sham irradiation, low-dose MRT, high-dose MRT or 10 Gy broad-beam radiation treatment (BRT). The microbeams were 280 μm wide and spaced at 900 μm center-to-center with peak dose at either 48 Gy (low-dose MRT) or 72 Gy (high-dose MRT). Survival studies showed that the mice treated with both MRT protocols had a significantly extended life span compared to the untreated control group (31.4 and 48.5% of life extension for low- and high-dose MRT, respectively) and had similar survival to the BRT group. Immunostaining on MRT mice demonstrated much higher DNA damage and apoptosis level in tumor tissue compared to the normal brain tissue. Apoptosis in normal tissue was significantly lower in the low-dose MRT group compared to that in the BRT group at 48 h postirradiation. Interestingly, there was a significantly higher level of cell proliferation in the MRT-treated normal tissue compared to that in the BRT-treated mice, indicating rapid normal tissue repairing process after MRT. Microbeam radiation exposure on normal brain tissue causes little apoptosis and no macrophage infiltration at 30 days after exposure. This study is the first biological assessment on MRT effects using the compact CNT-based irradiator. It provides an alternative technology that can enable widespread MRT research on mechanistic studies using a preclinical model, as well as further translational research towards clinical applications.

Nanotube x-ray for cancer therapy: a compact microbeam radiation therapy system for brain tumor treatment

Microbeam radiation therapy (MRT) is a promising preclinical modality for cancer treatment, with remarkable preferential tumoricidal effects, that is, tumor eradication without damaging normal tissue functions. Significant lifespan extension has been demonstrated in brain tumor-bearing small animals treated with MRT. So far, MRT experiments can only be performed in a few synchrotron facilities around the world. Limited access to MRT facilities prevents this enormously promising radiotherapy technology from reaching the broader biomedical research community and hinders its potential clinical translation. We recently demonstrated, for the first time, the feasibility of generating microbeam radiation in a laboratory environment using a carbon nanotube x-ray source array and performed initial small animal studies with various brain tumor models. This new nanotechnology-enabled microbeam delivery method, although still in its infancy, has shown promise for achieving comparable therapeutic effects to synchrotron MRT and has offered a potential pathway for clinical translation.

An update on carbon nanotube-enabled X-ray sources for biomedical imaging

A new imaging technology has emerged that uses carbon nanotubes (CNT) as the electron emitter (cathode) for the X-ray tube. Since the performance of the CNT cathode is controlled by simple voltage manipulation, CNT-enabled X-ray sources are ideal for the repetitive imaging steps needed to capture three-dimensional information. As such, they have allowed the development of a gated micro-computed tomography (CT) scanner for small animal research as well as stationary tomosynthesis, an experimental technology for large field-of-view human imaging. The small animal CT can acquire images at specific points in the respiratory and cardiac cycles. Longitudinal imaging therefore becomes possible and has been applied to many research questions, ranging from tumor response to the noninvasive assessment of cardiac output. Digital tomosynthesis (DT) is a low-dose and low-cost human imaging tool that captures some depth information. Known as three-dimensional mammography, DT is now used clinically for breast imaging. However, the resolution of currently-approved DT is limited by the need to swing the X-ray source through space to collect a series of projection views. An array of fixed and distributed CNT-enabled sources provides the solution and has been used to construct stationary DT devices for breast, lung, and dental imaging. To date, over 100 patients have been imaged on Institutional Review Board-approved study protocols. Early experience is promising, showing an excellent conspicuity of soft-tissue features, while also highlighting technical and post-acquisition processing limitations that are guiding continued research and development. Additionally, CNT-enabled sources are being tested in miniature X-ray tubes that are capable of generating adequate photon energies and tube currents for clinical imaging. Although there are many potential applications for these small field-of-view devices, initial experience has been with an X-ray source that can be inserted into the mouth for dental imaging. Conceived less than 20 years ago, CNT-enabled X-ray sources are now being manufactured on a commercial scale and are powering both research tools and experimental human imaging devices. WIREs Nanomed Nanobiotechnol 2018, 10:e1475. doi: 10.1002/wnan.1475 This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

Contrast enhanced imaging with a stationary digital breast tomosynthesis system

Digital breast tomosynthesis (DBT) captures some depth information and thereby improves the conspicuity of breast lesions, compared to standard mammography. Using contrast during DBT may also help distinguish malignant from benign sites. However, adequate visualization of the low iodine signal requires a subtraction step to remove background signal and increase lesion contrast. Additionally, attention to factors that limit contrast, including scatter, noise, and artifact, are important during the image acquisition and post-acquisition processing steps. Stationary DBT (sDBT) is an emerging technology that offers a higher spatial and temporal resolution than conventional DBT. This phantom-based study explored contrast-enhanced sDBT (CE sDBT) across a range of clinically-appropriate iodine concentrations, lesion sizes, and breast thicknesses. The protocol included an effective scatter correction method and an iterative reconstruction technique that is unique to the sDBT system. The study demonstrated the ability of this CE sDBT system to collect projection images adequate for both temporal subtraction (TS) and dual-energy subtraction (DES). Additionally, the reconstruction approach preserved the improved contrast-to-noise ratio (CNR) achieved in the subtraction step. Finally, scatter correction increased the iodine signal and CNR of iodine-containing regions in projection views and reconstructed image slices during both TS and DES. These findings support the ongoing study of sDBT as a potentially useful tool for contrast-enhanced breast imaging and also highlight the significant effect that scatter has on image quality during DBT.

Stationary intraoral tomosynthesis for dental imaging

Despite recent advances in dental radiography, the diagnostic accuracies for some of the most common dental diseases have not improved significantly, and in some cases remain low. Intraoral x-ray is the most commonly used x-ray diagnostic tool in dental clinics. It however suffers from the typical limitations of a 2D imaging modality including structure overlap. Cone-beam computed tomography (CBCT) uses high radiation dose and suffers from image artifacts and relatively low resolution. The purpose of this study is to investigate the feasibility of developing a stationary intraoral tomosynthesis (s-IOT) using spatially distributed carbon nanotube (CNT) x-ray array technology, and to evaluate its diagnostic accuracy compared to conventional 2D intraoral x-ray. A bench-top s-IOT device was constructed using a linear CNT based X-ray source array and a digital intraoral detector. Image reconstruction was performed using an iterative reconstruction algorithm. Studies were performed to optimize the imaging configuration. For evaluation of s-IOT’s diagnostic accuracy, images of a dental quality assurance phantom, and extracted human tooth specimens were acquired. Results show s-IOT increases the diagnostic sensitivity for caries compared to intraoral x-ray at a comparable dose level.

Minibeam radiotherapy with small animal irradiators; in vitro and in vivo feasibility studies

Minibeam radiation therapy (MBRT) delivers an ultrahigh dose of x-ray (⩾100 Gy) in 200-1000 µm beams (peaks), separated by wider non-irradiated regions (valleys) usually as a single temporal fraction. Preclinical studies performed at synchrotron facilities revealed that MBRT is able to ablate tumors while maintaining normal tissue integrity. The main purpose of the present study was to develop an efficient and accessible method to perform MBRT using a conventional x-ray irradiator. We then tested this new method both in vitro and in vivo. Using commercially available lead ribbon and polyethylene sheets, we constructed a collimator that converted the cone beam of an industrial irradiator to 44 identical beams (collimator size  ≈  4  ×  10 cm). The dosimetry characteristics of the generated beams were evaluated using two different radiochromic films (beam FWHM  =  246  ±  32 µm; center-to-center  =  926  ±  23 µm; peak-to-valley dose ratio  =  24.35  ±  2.10; collimator relative output factor  =  0.84  ±  0.04). Clonogenic assays demonstrated the ability of our method to induce radiobiological cell death in two radioresistant murine tumor cell lines (TRP  =  glioblastoma; B16-F10  =  melanoma). A radiobiological equivalent dose (RBE) was calculated by evaluating the acute skin response to graded doses of MBRT and conventional radiotherapy (CRT). Normal mouse skin demonstrated resistance to doses up to 150 Gy on peak. MBRT significantly extended the survival of mice with flank melanoma tumors compared to CRT when RBE were applied (overall p  <  0.001). Loss of spatial resolution deep in the tissue has been a major concern. The beams generated using our collimator maintained their resolution in vivo (mouse brain tissue) and up to 10 cm deep in the radiochromic film. In conclusion, the initial dosimetric, in vitro and in vivo evaluations confirmed the utility of this affordable and easy-to-replicate minibeam collimator for future preclinical studies.Minibeam radiation therapy (MBRT) delivers ultrahigh dose of X-ray (≥100 Gy) in 200-1000 μm beams (peaks), separated by wider non-irradiated regions (valleys) usually as a single temporal fraction. Preclinical studies performed at synchrotron facilities revealed that MBRT is able to ablate tumors while maintaining normal tissue integrity. The main purpose of present study was to develop an efficient and accessible method to perform MBRT using a conventional X-ray irradiator. We then tested this new method both in-vitro and in-vivo. Using commercially available lead ribbon and polyethylene sheets, we constructed a collimator that converts the cone beam of an industrial irradiator to 44 identical beams (Collimator size ≈ 4×10 cm). The dosimetry characteristics of the generated beams were evaluated using two different radiochromic films (beam FWHM = 246±32 μm; center-to-center = 926±23 μm; peak-to-valley dose ratio = 24.35±2.10; collimator relative output factor = 0.84±0.04). Clonogenic assays demonstrated the ability of our method to induce radiobiological cell death in two radioresistant murine tumor cell lines (TRP = glioblastoma; B16-F10 = melanoma). Radiobiological equivalent dose (RBE) was calculated by evaluating the acute skin response to graded doses of MBRT and conventional radiotherapy (CRT). The normal mouse skin demonstrated resistance to doses up to 150 Gy on peak. MBRT significantly extended the survival of mice with flank melanoma tumor compared to CRT when RBE were applied (overall p<.001). Loss of spatial resolution deep in the tissue has been a major concern. The beams generated using our collimator maintained their resolution in-vivo (mouse brain tissue) and up to 10cm deep in the radiochromic film. In conclusion, the initial dosimetric, in-vitro and in-vivo evaluations confirmed the utility of this affordable and easy-to-replicate minibeam collimator for future preclinical studies.

Estimating scatter from sparsely measured primary signal

Abstract. Scatter radiation severely degrades the image quality. Measurement-based scatter correction methods sample the scatter signal at sparsely distributed points, from which the scatter profile is estimated and deterministically removed from the projection image. The estimation of the scatter profile is generally done through a spline interpolation and the resulting scatter profile is quite smooth. Consequently, the noise is intact and the signal-to-noise ratio is reduced in the projection image after scatter correction, leading to image artifacts and increased noise in the reconstruction images. We propose a simple and effective method, referred to as filtered scatter-to-primary ratio (f-SPR) estimation, to estimate the scatter profile using the sparsely sampled scatter signal. Using the primary sampling device and the stationary digital tomosynthesis systems previously developed in our lab, we evaluated and compared the f-SPR method in comparison with existing methods in terms of contrast ratio, signal difference-to-noise ratio, and modulation transfer function. A significant improvement in image quality is observed in both the projection and the reconstruction images using the proposed method.

Stationary digital intraoral tomosynthesis: Demonstrating the clinical potential of the first-generation system

Stationary intraoral tomosynthesis (sIOT) is an experimental imaging approach using a fixed array of carbon nanotubeenabled x-ray sources to produce a series of projections from which three-dimensional information can be reconstructed and displayed. Customized to the dental workspace, the first-generation sIOT tube is compact, easy-to-operate, and designed to interface with standard digital intraoral detectors. The purpose of this work was to explore the utility of the sIOT device across a range of dental pathologies and thereby identify limitations potentially amenable to correction through post-acquisition processing. Phantoms, extracted human teeth, and cadaveric specimens containing caries, fractures, and dilacerated roots, often associated with amalgam restorations, were imaged using tube settings that match the kVp and mA used in conventional clinical 2D intraoral imaging. An iterative reconstruction approach generated a stack of image slices through which the reader scrolls to appreciate depth relationships. Initial experience demonstrated an improved ability to visualize occlusal caries, interproximal caries, crown and root fractures, and root dilacerations when compared to 2D imaging. However, artifacts around amalgam restorations and metal implants proved problematic, leading to the incorporation of an artifact reduction step in the post-acquisition processing chain. These findings support the continued study of sIOT as a viable limited-angle tomography tool for dental applications and provide a foundation for the ongoing development of image processing steps to maximize the diagnostic utility of the displayed images.

Initial clinical evaluation of gated stationary digital chest tomosynthesis

High resolution imaging of the chest is dependent on a breath hold maintained throughout the imaging time. However, pediatric and comatose patients are unable to follow respiration commands. Gated tomosynthesis could offer a lower dose, high in-plane resolution imaging modality, but current systems are unable to prospectively gate in a reasonable scan time. In contrast, a carbon nanotube (CNT) based linear x-ray source array offers both the angular span and precise control necessary to generate x-ray projections for gated tomosynthesis. The goal of this study was to explore the first clinical use of the CNT linear x-ray source array for gated clinical chest imaging. Eighteen pediatric cystic fibrosis patients were recruited for this study, with 13 usable image sets. The s-GDCT system consists of a CNT linear x-ray source array coupled with a digital detector. A respiration signal derived from a respiratory belt served as a gating signal with sources fired sequentially when the imaging window and maximum inspiration window coincided. Images were reconstructed and reviewed for motion blur and ability to identify major anatomical structures. Image quality was highly dependent on quality of the respiration gating signal, and a correlation was found between qualitative image quality and height of the respiration peak. We demonstrate the first prospectively gated evaluation of the stationary digital chest tomosynthesis patients in pediatric patients. Though further refinements in projection selection and respiratory gating approaches are necessary, this study demonstrates the potential utility of this low dose imaging approach.