Cancer remains a leading cause of death globally, with conventional treatments like surgery, radiation, and chemotherapy presenting significant side effects. Photodynamic therapy (PDT) offers a promising alternative due to its high selectivity for cancer cells and reduced side effects. PDT involves injecting a photosensitizer, which upon light activation, generates reactive oxygen species that destroy tumor cells. However, conventional PDT systems using lasers and endoscopes have limitations, including shallow penetration depth, rapid photodynamic reactions, poor accessibility, and high cost. Recently, wireless implantable PDT systems have been developed to address these limitations. However, these systems often lack features like light intensity modulation and tumor-related measurements. Hyperthermia, another cancer treatment method, involves exposing cancerous tissue to high temperatures. While effective, it can damage healthy tissues. Localized hyperthermia techniques aim to minimize this damage. Continuous monitoring of cancer progression is crucial for evaluating treatment effectiveness, but current methods like CT scans and bioluminescence lack the necessary temporal resolution. This paper proposes a flexible, fully implantable, battery-free optoelectronic system that combines PDT with hyperthermia and real-time tumor size monitoring. The system uses a µ-LED probe inserted into the tumor for light delivery and heat generation, and an external phototransistor for monitoring the light scattered by the tumor, indicating its size. A wireless communication system enables control of light intensity and data acquisition via a smartphone application. Biocompatible materials ensure long-term operation and biocompatibility. The study aims to demonstrate the efficacy of this combined approach in vitro and in vivo.

The introduction provides a comprehensive literature review highlighting the limitations of existing cancer treatments and the advantages of PDT. It discusses the drawbacks of conventional PDT systems, the development of implantable systems, and the challenges of combining PDT with hyperthermia. The limitations of current tumor monitoring techniques are also addressed, setting the stage for the proposed innovative system. The review cites relevant studies on PDT mechanisms, implantable devices, hyperthermia, and tumor monitoring.

The methodology section details the fabrication of the implantable device, including the design and assembly of the flexible printed circuit board (FPCB) with its components (µ-LED, phototransistor, Bluetooth Low Energy (BLE) system). The multi-layered encapsulation process using Parylene-C, SiO2, and biocompatible black PDMS is described to ensure long-term operation and biocompatibility in vivo. The design and functionality of the smartphone application for wireless control and data acquisition are explained. The optical simulation methods, using ray-tracing simulations based on the Monte-Carlo method with OpticStudio 16.0 software, are outlined, considering optical properties of human colon tumors. In vitro experiments used an HCT-15 cell-based tumor-mimicking tissue model to assess PDT efficacy. The cell viability was evaluated using a LIVE/DEAD assay. In vivo experiments utilized a human colorectal cancer cell (HCT-15)-based xenograft mouse model, where the device was implanted subcutaneously, and the µ-LED was activated wirelessly for PDT with hyperthermia. Tumor volume, body weight, and histological analysis (H&E staining, immunofluorescence staining for caspase 3, vWF, and Ki67) were performed to assess treatment efficacy. The in vitro cytotoxicity of the device materials was assessed using NIH-3T3 cells.

In vitro experiments demonstrated significant cell death (14.38-15.69% viability) in the 5-ALA/device (+) group (with µ-LED light) compared to the control group (90.83-91.95% viability). Ray-tracing simulations showed that the black PDMS encapsulation effectively reduced light noise and enhanced tumor size monitoring accuracy. The system allowed for precise control of µ-LED intensity via pulse width modulation (PWM), with demonstrable differences in cell viability observed at different intensities. Ex vivo experiments using HCT-15 tumors of varying sizes showed a clear correlation between phototransistor voltage (VPD) and tumor volume, validating the tumor size monitoring capabilities. In vivo studies with the xenograft mouse model demonstrated that the system successfully monitored tumor growth over three weeks. The normalized VPD values correlated well with the normalized tumor size. The combined PDT and hyperthermia treatment significantly reduced tumor volume and improved body weight compared to control and other treatment groups. Histological analysis revealed increased apoptosis (caspase 3 expression), reduced angiogenesis (vWF expression), and decreased cell proliferation (Ki67 expression) in the 5-ALA/device (+) group, confirming the efficacy of the combined therapy.

The findings demonstrate the successful development and validation of a fully implantable, battery-free wireless optoelectronic system for combined PDT and hyperthermia treatment, along with real-time tumor monitoring. The system effectively addresses the limitations of existing cancer treatment and monitoring methods by enabling precise control of light intensity, efficient heat generation, and continuous monitoring of tumor size. The in vivo results confirm the therapeutic efficacy and reliable tumor growth monitoring capabilities. The combination of PDT and hyperthermia appears synergistic in achieving better cancer cell elimination. The system's portability and user-friendliness through smartphone control make it a potentially transformative tool in cancer treatment.

This study successfully demonstrated a fully implantable, battery-free, and wireless optoelectronic system for modulable cancer therapy (PDT with hyperthermia) and real-time monitoring. The system showed significant therapeutic efficacy and accurate tumor size tracking in both in vitro and in vivo models. Future studies should focus on using lower-intensity light, independent control of light and heat, and investigation of therapeutic effects in deeper tumors and different cancer types. This technology offers the potential to revolutionize cancer treatment and monitoring, providing personalized and efficient therapeutic approaches.

The study was limited to subcutaneous tumors in a mouse model. The generalizability to other tumor types and locations within the body requires further investigation. While the device was sutured in place, slight variations in µ-LED position within the tumor could have affected the accuracy of tumor size measurements. Long-term biocompatibility studies over extended periods are needed to fully assess the device’s safety and durability. The use of a larger animal model might provide more robust in vivo data.