Fully implantable and battery-free wireless optoelectronic system for modulable cancer therapy and real-time monitoring

The study addresses limitations of conventional cancer therapies (surgery, radiotherapy, chemotherapy) due to side effects and morbidity, and of conventional laser-based PDT due to shallow light penetration, high-intensity damage, bulkiness, and cost. Prior wireless implantable PDT systems improved accessibility but often were not fully implantable or used rigid form factors, lacked active control of light intensity and on-board sensing/communication, and suffered from poor long-term encapsulation. Hyperthermia is a complementary modality but conventional methods risk damage to healthy tissue. Continuous cancer treatment requires concurrent, frequent monitoring, yet CT/bioluminescence lack temporal resolution and are resource-intensive. Existing flexible strain sensors can monitor tumor growth but do not treat, and externally monitored photosensitizers still rely on separate imaging. The research aims to develop a fully implantable, battery-free, flexible optoelectronic system that enables modulable PDT with concomitant hyperthermia and real-time tumor size monitoring inside the body, overcoming prior limitations in functionality, biocompatibility, and long-term operation.

The paper reviews: limitations of conventional PDT using lasers/endoscopes (penetration <1 cm, high coherence intensity reducing therapeutic effect, bulky/non-portable systems). Prior wireless or implantable PDT devices improved accessibility but remained partially implantable or rigid, lacked active modulation and sensing due to passive electronics, and had insufficient encapsulation for multi-week stability in vivo. Hyperthermia techniques (focused ultrasound, nanoparticle-mediated) aim for localized heating but still face challenges. Monitoring approaches such as CT/bioluminescence offer low temporal resolution and toxicity/cost constraints; a flexible strain sensor can monitor tumor regression but cannot treat. Recent photosensitizers enable external real-time monitoring, yet a fully integrated system performing PDT and on-board tumor monitoring simultaneously without external imaging had not been reported.

Device/system: A fully implantable, flexible, battery-free optoelectronic device comprising a µ-LED probe (624 nm), a silicon phototransistor, BLE SoC (nRF52832), wireless power receiver (13.56 MHz planar coil, full-bridge rectifier with Schottky diodes, LTC3255 regulator to 3.3 V), and user interface via custom Android app. The µ-LED intensity is controlled via pulse width modulation (PWM) at 1 kHz with duty factor 0–100% set wirelessly. The phototransistor emitter voltage (V_PD) is digitized by SAADC on the SoC for real-time monitoring. Encapsulation: Flexible PCB (Cu/PI/Cu: 18/25/18 µm) with via-connected bilayer metal lines. Multilayer encapsulation PDMS/SiO2/parylene-C applied on both sides for biostability. To block total internal reflection causing optical crosstalk, a black PDMS layer (PDMS + edible black dye) is inserted between µ-LED and phototransistor, validated by ray-tracing simulations and phototransistor current measurements. Smartphone app: Kotlin/Android Studio; BLE GATT connection for control and data logging to text files; real-time UI. Ray-tracing optical simulations: Monte Carlo (OpticStudio/ZEMAX). Source: 0.80 × 0.35 mm, λ≈632 nm, 0.5 lm. Detector: 1.7 × 0.8 mm (30×30 pixels). Material indices: PDMS 1.4, PI 1.5, black PDMS transmittance ~0.001%. Tumor optical properties from human colon tumor literature (μs′ ~120 cm−1, μa ~1 cm−1). 5×10^7 rays. Simulated tumor diameters D=4, 8, 11 mm to assess light scatter to the phototransistor vs. tumor size and effect of black PDMS. In vitro PDT efficacy: Tumor-mimic hydrogel model embedding HCT-15 human colorectal cancer cells (1×10^7 cells/mL) in 1:1 collagen I (3 mg/mL) and fibrinogen (3 mg/mL), gelled with thrombin (2 U/mL), pH 7.0, 3 cm diameter × 5 mm height. PpIX absorbance measured (450–700 nm) to select 624 nm µ-LED. Treatment groups: Control, 5-ALA only (1 mM), 5-ALA with device but LED off, 5-ALA with device LED on (5 mW, 30 min). Live/dead assay imaging at distances 0, 7, 15 mm from center; analysis with ImageJ. Thermal characterization of µ-LED heating at intensities 0%, 30%, 70%, 100% using thermal imaging. Intensity-dependent PDT: With 5-ALA, µ-LED intensities 0%, 30%, 70%, 100%; assess cell viability at 0, 5, 10, 15 mm. Ex vivo tumor monitoring: Excised HCT-15 xenograft tumors of volumes 57, 163, 199, 941, 1671 mm^3. Insert µ-LED probes from three devices to reach tumor centers at different insertion sites; measure phototransistor emitter voltage V_PD across load resistor using emitter follower circuit; evaluate correlation with volume and sensitivity to off-center LED positioning. In vivo xenograft model: BALB/c nude mice (7-week-old), subcutaneous injection of 1×10^7 HCT-15 in 200 µL PBS into dorsal flanks. Start when tumors reach 5–7 mm (~2 weeks post-injection). Implant device subcutaneously; insert µ-LED probe into tumor; suture fascia and skin. Wireless power via external 13.56 MHz coil (function generator 10 V, 13.56 MHz). PDT with hyperthermia protocol: 5-ALA 250 mg/kg i.p.; 4 h later, LED on at 100% for 30 min; repeated weekly for 3 weeks. Monitoring cohort: weekly V_PD measurements with LED at 50% for 1 min over up to 3 weeks. Tumor dimensions measured with calipers; volume=(width^2×length)/2. Body weight monitored. Endpoint histology 3 days after last treatment: H&E, immunofluorescence for apoptosis (caspase 3), angiogenesis (vWF), proliferation (Ki67); DAPI nuclei. Biocompatibility assessed in SD rats with subcutaneous implantation, explant at days 5 and 14 for histology. Statistics: Data mean ± SEM; one-way ANOVA with Tukey post hoc; p<0.05 significant (Origin 2022).

- Black PDMS optical isolation: Ray-tracing and measurements showed black PDMS significantly reduced internally reflected light reaching the phototransistor, enabling sensitive tumor-size-dependent signals. Phototransistor emitter current dropped markedly with black PDMS compared to clear encapsulation when LED was on in darkness, consistent with simulations. - Programmable LED control: PWM allowed precise intensity modulation (0–100%). LED heating at 36.5 °C baseline increased temperature by <1 °C (30% intensity), ~4 °C (70%), and ≥7–8 °C (100%), supporting potential for controlled hyperthermia. - In vitro PDT efficacy: In the 5-ALA/device(+) group, cell viability was ~14.38% (0 mm), 15.19% (7 mm), 15.69% (15 mm), which were 6.91×, 6.52×, and 6.33× lower than control, respectively. 5-ALA only and 5-ALA/device(−) groups showed high viabilities (>85–94%), indicating minimal device material cytotoxicity and only low-level ambient activation of PpIX. - Intensity dependence: Cell viability decreased with higher LED intensity. At 100% intensity, viability ≈15% across distances; at 70%, increased viability at 10 and 15 mm (2.86× and 6.39× higher than 100%); at 30%, viability higher still; at 0%, ≈98% viability. This supports tunable therapy to maximize tumor killing while sparing surrounding tissue. - Ex vivo tumor monitoring: V_PD increased proportionally with tumor volume across tumors of 57–1671 mm^3. While µ-LED off-center placement caused minor V_PD variation, tumor-size-dependent scattering dominated, enabling reliable size discrimination. - In vivo tumor growth monitoring: In untreated-growth monitoring over up to 3 weeks (n=4), normalized V_PD correlated with normalized tumor volume within each mouse; minimal tumor growth corresponded to minimal V_PD change, whereas rapid growth showed proportional V_PD increases. - In vivo therapeutic efficacy (HCT-15 xenografts): Across groups (Cont, 5-ALA, Device(−), Device(+), 5-ALA/Device(+)), the 5-ALA/Device(+) group exhibited the smallest tumor volume ratios by day 17, significantly smaller than control (p=0.028). Body weight change after 17 days: Cont −15.4%, 5-ALA −0.06%, Device(−) −0.05%, Device(+) +2.07%, 5-ALA/Device(+) +8.68%. - Histology/immunofluorescence: 5-ALA/Device(+) showed marked reduction in cellularity, highest apoptosis (caspase 3+ area highest among groups). Device(+) alone showed central apoptosis likely from hyperthermia; 5-ALA alone showed surface apoptosis only (ambient light activation). vWF-positive area was remarkably lower in 5-ALA/Device(+) than all other groups (reported reduced to 91.46% of control). Ki67-positive area lowest in 5-ALA/Device(+) at 2.11 ± 0.56%, versus highest in control at 33.86 ± 1.68%. Overall indicates enhanced apoptosis and suppressed angiogenesis and proliferation with combined PDT + hyperthermia.

The integrated, fully implantable, battery-free optoelectronic system achieved simultaneous, wirelessly controlled PDT with hyperthermia and real-time tumor size monitoring. By embedding a programmable µ-LED within the tumor and an external phototransistor isolated by black PDMS, the device provided adjustable therapeutic light dosing while accurately sensing tumor-size-dependent scattered light, enabling longitudinal assessment without external imaging. In vitro and ex vivo data established optical isolation, intensity-dependent cytotoxicity, and correlation between V_PD and tumor volume. In vivo, the system reduced tumor growth and improved body weight when combining 5-ALA with LED activation, and histology confirmed increased apoptosis and decreased angiogenesis and proliferation. The results address prior limitations of implantable PDT systems by adding active modulation, sensing, wireless power/communication, and long-term encapsulation, underscoring the potential for portable, patient-tailored cancer therapy with concurrent monitoring.

This work presents a flexible, fully implantable, battery-free wireless optoelectronic platform that unifies modulable PDT, local hyperthermia from µ-LED heating, and on-board tumor size monitoring. The system demonstrates multi-week in vivo operation, smartphone-based control, and significant antitumor effects alongside reliable monitoring in a mouse xenograft model. Future directions include: integrating an independent heater to decouple light and heat control; optimizing low-intensity light regimens; enhancing fixation and alignment to reduce positional variability; and extending to deeper or non-subcutaneous tumors and larger animal models to validate clinical translation.

- In vivo experiments were conducted in subcutaneous xenograft mouse models; applicability to deep-seated or orthotopic tumors requires further validation. - Potential positional shifts of the µ-LED probe over time despite suturing introduced variability in V_PD-tumor size slopes between animals; larger animal models and improved fixation could reduce this. - Occasional early termination in some animals due to excessive tumor growth or device operation stability challenges indicates need for further robustness optimization. - Hyperthermia and PDT effects are coupled through the µ-LED; a separate heater is needed to independently control thermal and photodynamic contributions. - Long-term operation demonstrated over ~2–3 weeks; longer durations and chronic biocompatibility beyond this window were not assessed.