A biodegradable, flexible photonic patch for in vivo phototherapy

Optical illumination of internal organs and tissues is crucial for optical diagnosis, laser surgery, and light-activated therapies. However, current in vivo illumination methods struggle to meet the diverse requirements of depth, area, wavelength, and power across various scenarios, especially for large-area illumination of deep targets. External light sources are limited by photon absorption, scattering, and autofluorescence, even within the near-infrared windows. Therefore, placing light sources directly onto the target tissue in vivo is a preferred approach. While implantable light-emitting diodes and upconversion nanoparticles show promise, their illumination intensity is limited by energy-transferring efficiency or light penetration and quantum-transferring efficiencies. Optical fiber devices, fabricated from biocompatible materials, offer advantages in precise, wide-spectrum, high-power waveguiding. Integrated with endoscopes or guided by imaging techniques, they enable minimally invasive placement. However, inserting optical fibers into tissues carries risks of impairing tissue function. Existing strategies to manipulate optical energy distribution, such as surface etching, side polishing, and attaching planar waveguides, yield only limited improvements. Large-area, deep, non-destructive illumination with controllable parameters remains challenging, particularly for moving targets like the heart. This study introduces a novel biodegradable, flexible photonic device, iCarP, designed to overcome these limitations and enable more effective and safe in vivo phototherapy.

The existing literature highlights the challenges in achieving effective in vivo illumination for various medical applications. While implantable LEDs and upconversion nanoparticles offer potential solutions, they are constrained by factors such as energy transfer efficiency and light penetration. Optical fibers provide superior control over light delivery but their use is often limited by invasive insertion into the target tissue. Modifications such as surface etching and waveguide attachments have been attempted to improve the illumination area, but the results remain insufficient for large-area deep tissue illumination, especially in dynamic organs. This gap in technology necessitates the development of a novel device capable of providing large-area, deep, non-invasive illumination, which is the primary focus of this research.

The study designed and fabricated iCarP, a biodegradable and flexible photonic device. iCarP comprises a tapered optical fiber (TOF) embedded in a biodegradable, transparent polyester (PMCL) patch, with a micrometer-thin air gap between the TOF tip and the PMCL. The fabrication process involves tapering the optical fiber, plasma cleaning and silanization, PMCL patch forming, and UV light curing. The light scattering properties of iCarP were evaluated in vitro and in silico. The in vitro assessment involved measuring light divergence angles and simulating electric field intensity distributions using the Beam Propagation Method (BPM). In vivo experiments utilized a rat model for photothermal and photodynamic therapy of subcutaneous tumors and a rat myocardial infarction (MI) model for in situ photosynthesis treatment. Different photosensitizers (gold nanorods, FITC, and Chlorella) were used to assess iCarP's compatibility with various phototherapies. The device's stability on beating hearts was evaluated in vivo. Minimally invasive implantation compatibility was tested in a canine thoracoscopy surgery. Various analyses including infrared thermal imaging, TUNEL and H&E staining, Masson's trichrome staining, immunofluorescence staining, RNA-seq, and echocardiography were performed to assess therapeutic efficacy and safety.

iCarP demonstrated superior light scattering capability compared to conventional optical fibers and other devices. The combination of the tapered optical fiber tip, the air gap, and the PMCL patch effectively scattered light into a bulb-like illumination pattern, achieving a significantly larger illumination area and improved penetration depth. In vitro experiments showed a 10% increase in oxygen production from Chlorella compared to a tapered fiber alone, highlighting the enhanced light scattering and photosynthesis. In vivo studies in rats demonstrated iCarP's ability to deliver various wavelengths of light (405 nm, 520 nm, 660 nm, 808 nm) with precise intensity and temporal control (continuous or pulsatile). In subcutaneous tumor photothermal therapy, iCarP achieved a higher peak temperature (56°C) and larger heated area compared to a flat-end optical fiber (49°C), leading to greater tumor ablation. In photodynamic therapy, iCarP also showed significantly better tumor growth inhibition. In a rat MI model, iCarP, with or without light illumination, significantly reduced cardiomyocyte apoptosis and myocardial fibrosis. Light-triggered photosynthesis further enhanced the therapeutic effect, improving ejection fraction. Finally, the successful minimally invasive implantation of iCarP in a canine model validated its clinical potential.

The results demonstrate iCarP's efficacy as a novel photonic device for in vivo phototherapy. The key to its success is the innovative design featuring the micrometer-scale air gap, which effectively redirects light from the forward direction into lateral directions, achieving large-area, deep penetration without tissue damage. The air gap's low refractive index is crucial for this scattering effect. The biodegradable and flexible nature of the device further enhances its safety and applicability. The in vivo studies clearly show the therapeutic benefits of iCarP across different phototherapy modalities and disease models. The results suggest that iCarP can significantly improve treatment outcomes by enhancing light delivery to the target tissue. The successful minimally invasive implantation highlights its potential for clinical translation.

This study introduces iCarP, a flexible, biodegradable photonic device that overcomes the limitations of current in vivo illumination technologies. Its innovative design, incorporating a micrometer-scale air gap, allows for large-area, deep penetration of light without tissue damage. The preclinical studies demonstrate its therapeutic potential in various applications, particularly in photothermal and photodynamic therapies, and in myocardial infarction treatment. Future studies should focus on long-term biocompatibility and efficacy assessments, as well as exploring its use in other light-based therapies and diagnostic procedures.

The study has some limitations. Long-term foreign body responses of iCarP were not comprehensively investigated. The relatively slow degradation of the PMCL patch may need further consideration. The illumination time in the rat studies was limited by anesthesia duration; the effects of extended illumination require further exploration. Light scattering occurs on both sides of iCarP, and a reflective coating may be necessary to improve target-specific light delivery. Further investigation into the long-term effects and potential toxicity of the device is also necessary before clinical translation.