DOSIEâ„¢
An essential treatment planning medical device to enable predictable and repeatable PDT in treating advanced cancers
Dosieâ„¢ is an integrated computational device that combines accurate simulations of light distribution and light drug toxicity to give oncologists and medical physicists an essential treatment planning tool to prepare a healing dose, uniquely tailored to each patient, to be delivered by Photodynamic therapy in treating certain advanced types of cancers. Dosieâ„¢ is a complex device requiring years to complete and validate at a cost of a few million dollars.
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Similar to the advanced x-ray treatment planning platforms, Dosie uses advanced mathematical methods, including Monte Carlo, Finite Elements, and adaptive embedded iterations, to simulate not only conventional light dose for Intracavitary PDT (icav-PDT), Interstitial PDT (I-PDT), and External Beam or Superficial PDT, but also the promising experimental PDT dose and photoactivated singlet oxygen dose that recently proved in pre-clinical trials to be the better predictors of successful outcomes.
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To complete the simulation in a reasonable time, during the pre-treatment phase and in OR, the Dosie's advanced numerical code takes advantage of multi-core CPU architecture as well as massive parallel GPU architecture, making it possible to complete certain cases even on a laptop. The in-house numerical simulation code and the hardware configuration are kept as the company's trade secret.
Why DOSIE?
A reliable, simulation-based, treatment planning for PDT is needed to make PDT as commonplace as x-ray radiation therapy is today. Unfortunately, a commercially available treatment planning software or device that includes all variables and can accurately predict the PDT outcome did not exist until now. One commercial software product, IDOSE®, from SpectraCure (www.spectracure.com), calculates the light dose in the tumor (prostate cancer only) but neglects the light-drug and drug-oxygen interactions without which the effectiveness of PDT* cannot be accurately determined. According to the recent (2017-18) pre-clinical studies neglecting photosensitizer and molecular oxygen may result in incorrect values for the treatment light dose and treatment time, which are insufficient to kill all the cancer cells.
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Because we are the first to include all variables in the commercial product, our technology is the only one that can truly enable PDT to treat different types of cancers. This advancement was made possible by combining the expertise of optical physicists, mathematicians, and computer scientists with that of biologists, medical physicists, medical clinicians, and surgeons.
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*) During such interactions, the activated drug converts molecular oxygen into reactive singlet oxygen, i.e. the cytotoxic agent.
How DOSIE does it?
Dosie supports modeling 3 types of doses, which determine the effectiveness of PDT:
A conventional light dose,
PDT dose, and
(Reacted) singled oxygen dose.
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While the first two doses reflect on how well the photosensitizer (light-drug) is activated, the last one characterizes how well the activated light-drug excites the oxygen, thus creating the cancer cell killing agent.
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Dosie input consists of patient-specific parameters:
the shape of the tumor and surrounding tissue,
the optical parameters of all tissues,
initial oxygen concentration,
initial photosensitizer concentration
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as well as PDT-specific parameters:
the parameters of the photosensitizer (e.g. all decay times, absorption coefficient, intersystem transfer, oxygen absorption and decay time, photobleaching rate)
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The optimization parameters include:
type of light source
number and location of light sources
light wavelength
duration of treatment
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Dosie calculations start with the light propagation throughout the tumor to estimate light distribution at all points in the tumor. User can choose a ray-based Monte Carlo method or light-diffusion Finite Element method to estimate the light distribution map (fluence or fluence rate) on a sub-millimeter basis within the tumor target translucent region during a PDT session.
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The calculations that follow include PDT photokinetics that estimate PDT dose (e.g. the product of the light fluence rate and the PS concentration, integrated in time), and the reacted singlet oxygen dose [1O2]rx at every microscopic spatial point for every time interval. One of the major developments at Simphotek is for its commercial PDT Medical Devices to reduce the computational time to a minute or two, making it feasible for near real-time simulations in the clinic or operating room.
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Dosie GUI is a proprietary system that supports 2D and 3D visualization and interaction with the resulting dose maps and the patient’s scanned tumor and surrounding tissue geometry. By setting the critical thresholds, the user (medical physicist or treating physician) will be able to quickly spot under- and over-treated areas, within the target volume as well as its margins.
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Volume rendering is supported to visualize 3D maps in the upper left view, while other views show the standard three 2D slices of the maps – sagittal, coronal, and transverse views. The resulting dose maps calculated by Dosie can be overlaid with patient’s CT/MRI scans and STL meshes (see below).
Critical modules
The main Dosie’s modules are
GUI
Light transport solver with Monte Carlo
Light transport solver with Finite Element Method
Photokinetics solver with Adaptive Embedded method
MC (Light Transport module)
Dosie™ Monte Carlo light transport module supports simulation of light distribution within living tissue. The target tissue volume that contains regions with cancer cells is discretized by a 3D regular grid of even voxels. Each voxel is assigned a set of optical properties (i.e., absorption coefficient, scattering coefficient, anisotropy factor, refractive index) and can represent healthy tissue, cancer cells, or an air pocket. Packets of photons are launched from a point or broad area light source and propagated through and absorbed within the voxels according to their optical properties and anisotropy factors.
FE (Light transport module)
Finite Element (FE)  Light Transport is a Dosie’s tool that solves the time-dependent light diffusion equation using a variant of an FE solver. The target region is represented by a tetrahedral FE-mesh. The user labels those elements that belong to the light sources and the target region boundary.
PKÂ (Photokinetics module)
Dosie's PK simulation module solves photokinetics equations by applying the company’s variant of the Runge-Kutta mathematical method, adopted to accurately estimate molecular concentrations of all the species involved in PDT process, including the electronic ground state of the photosensitizer (PS) molecules (S0), the ground state oxygen molecules (O2), and the Target (cancer cells).
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Dosie PK module simulates for all the molecules the following processes (these and other processes are shown as transitions on the PDT energy level diagram):
light excites a PS molecule that undergoes intersystem crossing from a singlet excited state (S1) to a triplet state (T1).
excited PS triplet state transfers energy to O2, causing the oxygen molecule to be excited from its triplet ground state (3O2) to an excited singlet state (sOxy or 1O2).
sOxy is highly reactive and can attack target molecules in nearby cancer cells and subsequently kill the cancer cells.
photobleaching is also possible when sOxy molecules attack and neutralize the PS molecules in an undesirable side reaction. But this occurs at a slower rate than the desired therapeutic rate.
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Dosie has been developed to be compliant with standards in SDLC (Software Development Life Cycle) for medical instruments.