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A miniature Bio-photonics Companion Diagnostics platform for reliable cancer diagnosis and treatment monitoring.

Periodic Reporting for period 1 - BIOCDx (A miniature Bio-photonics Companion Diagnostics platform for reliable cancer diagnosis and treatment monitoring.)

Reporting period: 2017-01-01 to 2018-06-30

In the medical diagnostics industry, there is an ever-increasing need for the development of robust, reliable, accurate and fast devices for early diagnosis, screening and monitoring of diseases allowing for the presently emerging paradigm shift of Personalized Medicine and Companion Diagnostics. There is a special interest in cancer.
BIOCDx aims to develop a miniaturized, ultra-sensitive and reliable Point-of-Care (PoC) device with disposable microfluidic cartridge for the monitoring of cancer biomarkers in body fluids and specifically in whole blood samples. The proposed PoC device will aid primary tumour and metastases detection, as well as monitoring of drug efficacy as a companion diagnostic. It will provide clinicians, caretakers and patients with a more sensitive, robust and selective tool for improved clinical decisions through the early and fast diagnosis of the disease, as well as monitoring of therapeutic response, reducing the cost of the healthcare system. Besides the obvious health benefit for the patient, it will contribute to the sustainability of the European health care system by decreasing the expenditure associated with pharmaceutical treatments and with hospitalization.
One of the scientific breakthroughs of BIOCDx is the development of a “cancer stem cells” detection platform by virtue of expression of the cancer stem cell-specific transcription factor TWIST1, which controls the expression of the bloodstream circulating biomarkers like the periostin (POSTN) protein. Cancer stem cells represent the most aggressive/tumorigenic cell compartment within tumours and are known to support primary tumour growth and to migrate to distant tissues and establish secondary tumours (metastases). They are also believed to survive chemotherapy and upon completion of treatment, they grow back leading to tumour recurrence. These recurrences evolve to ever more resistant tumours with fatal outcome.
To do so, BIOCDx will combine advanced concepts from the photonic, nano-biochemical and fluidic parts and reader/packaging platforms aiming to overcome limitations related to detection reliability, sensitivity, specificity, compactness and cost issues. BIOCDx will use ultrasensitive, photonic elements based on an array of 8 asymmetric MZI waveguides fabricated by TriPlex technology on silicon nitride substrates and aiming to achieve a 100 fold improvement of the sensitivity (<10-8 RIU) with respect to current technologies. A sandwich assay, enhanced with nanoparticles, will be developed, based on the use of two antibodies per protein, to detect all three circulating proteins. This will enhance the limit of detection (LOD) close to femtomolar. BIOCDx photonic, nano-biochemical, fluidics and packaging platforms will be integrated into a POC device which will be validated in preclinical and clinical settings for three cancer types: breast cancer, hormone-independent prostate cancer and melanoma.
The highlights of the considered reporting period are summarized below:
• Complete characterisation of the biological elements was performed to set up sandwich assays.
• The filter test cartridge was developed and used in order to test several filter materials, filter sizes and shapes to be able to generate plasma from whole blood.
• For the sandwich assay, enhanced with nanoparticles, simulation studies have been performed.
• The laser-based printing technique (LIFT) was successfully implemented with chemical functionalization approaches. Furthermore, the direct laser immobilization approach has also been successfully tested.
• Four different types of passive measurement chips was designed and produced. A simulation study was performed to select the most promising MMI coupler designs. Several types of MMI test structures were fabricated and characterized. An alignment chip holder was developed and a new approach for chip fabrication is introduced with the use of an extra silicon layer. The mask design of the new generation of chips was completed along with a measurement system for the characterization of the biophotonic chips and for the validation experiments.
• For the fabrication of the cartridge, selection of the material was performed and the verification of the plasma generation from whole blood using a filter membrane was achieved. A protective frame for the fragile electronic components and the functionalized sensor surface will be included. Two bread board versions have been realized. The final bread board contains parts of the final instrument and operates the final cartridge with its on-cartridge syringes and on-cartridge valves. The bread boards together with the cartridges have been fluidically verified.
• The definition of the BIOCDx system design has been completed. The instrument requirements are defined and will be refined according to further results. The instrument development started by designing the measurement system. The design is partly realized in breadboard comprising the full mechanical interface to the cartridge and the electronic hardware for fluidic control including firmware. The breadboard can be used with a PC tool. The final steps for finishing the measurement system are the full implementations of the data acquisition, data analysis and heating. The work on all these items has already started.
• A Biobank has been set up in collaboration with HORG that already measures samples from patients and volunteers and is being constantly enriched. Xenograft mouse models for all of the human cancer cell lines were generated (selected on the basis of data provided on the expression the biomarkers of interest). These mice are already being treated with chemotherapeutic drugs.
• A cost analysis of the BIOCDx device has been performed. A preliminary market analysis has been completed as well. The positioning of the BIOCDx device with respect to cancer and purpose has been established. Information regarding the path to commercialization has been collected as well.
• BIOCDx consortium performed a number of dissemination activities (5 press-releases, participation to international conferences, workshops and EU events (15 participations in total) and design of BIOCDx leaflet brochure).
• All the relevant procedures and protocols with regards to human sample collection and processing as well as with the work with animal models have been defined. The established protocols have been approved by the IECs of the collaborating hospitals, the DPO appointed by HORG and BRFAA’s ethics committee.
The progress beyond the state of the art achieved so far for the 1st period of the project includes the:
- Design and fabrication of new generations of MZI waveguides.
- Testing of the individual approaches that lead to further increase of the sensors’ sensitivity.
- Novel functionalization approaches for the immobilization of the biomaterials on the aMZIs.
- Design of the complete hybrid integration of laser, biosensor and detectors in a system-on-chip, allowing for a cost-effective solution in production.
- Design and testing of materials for the fabrication of a disposable, miniaturized, low-cost microfluidics cartridge with integrated sensor and blood filtering module. this cartridge a reduced volume of sample will be used and the manual steps needed up to now for sample preparation will be eliminated.
Overall Concept of BIOCDx Project