1. Background
The increasing global aging population has led to a steady rise in the demand for titanium orthopedic implants. However, titanium's biological inertness limits its ability to prevent bacterial adhesion and infection, especially for persistent biofilm-related infections. Once infections form, they are often resistant to standard antibiotic treatments. Additionally, prolonged and excessive antibiotic use worsens bacterial resistance, placing a heavy burden on patient outcomes and healthcare systems.
Photodynamic therapy (PDT), which generates reactive oxygen species (ROS) via photosensitizers activated by specific light wavelengths, offers a novel non-antibiotic-dependent strategy for controlling implant-associated infections. Compared with traditional antibacterial coatings or surface antifouling modifications, PDT offers distinct advantages, including broad-spectrum antibacterial activity, low propensity to induce resistance, and spatiotemporal control. Nevertheless, its practical application to titanium implants faces critical challenges, including the selection and stable loading of photosensitizers, optimization of illumination parameters, and insufficient biocompatibility assessment. Recently, the team led by Professor Jinzhong Ma and Tao Wang at Shanghai General Hospital, in collaboration with Professor Guoqing Pan at Jiangsu University, conducted a systematic review on this topic, comprehensively summarizing the latest advances and advancing the development and application of photodynamic antibacterial strategies for titanium implants.

2. Research Progress
2.1. In-depth elucidation of Photodynamic Reactions and Antibacterial Mechanisms
The team systematically elaborates on the fundamental reaction processes of PDT and its antibacterial mechanisms (Fig. 1). Starting from the energy level transitions (S₀→S₁→T₁) of photosensitizers upon light excitation, it clearly distinguishes between Type I and Type II reaction pathways: Type I reactions generate radicals such as ·OH, O₂·⁻, and H₂O₂ via electron transfer or hydrogen transfer, exhibiting stronger adaptability to hypoxic environments; Type II reactions produce singlet oxygen (¹O₂) through energy transfer, with efficiency highly dependent on oxygen concentration.

Furthermore, the authors reveal the multi-target antibacterial mechanisms mediated by ROS at the molecular level, including disruption of cell membranes, oxidative inactivation of proteins, inhibition of metabolic processes, and damage of nucleic acid, thereby demonstrating the broad-spectrum and high-efficiency bactericidal properties of PDT. Importantly, the team highlighted the pivotal role of PDT in immunomodulation, an aspect often neglected in prior research. Beyond directly killing bacteria, PDT amplifies the host's anti-infection response by promoting the release of inflammatory factors, enhancing immune cell recruitment, and improving antigen-presenting capabilities. Particularly in biofilm infections, PDT not only disrupts the extracellular polymeric substance matrix but also reverses the immunosuppressive microenvironment, providing novel therapeutic insights for the complete eradication of biofilm infections

2.2. Framework for Photosensitizers Applied to Titanium Implants
The team systematically categorizes photosensitizers suitable for titanium implant surfaces, establishing a clear classification framework primarily comprising organic and inorganic photosensitizer systems (Fig. 2).

Organic Photosensitizers: Phenothiazine dyes (e.g., methylene blue and toluidine blue O) offer good water solubility and established clinical foundations. Cyanine dyes (e.g., indocyanine green and derivatives) provide near-infrared (NIR) responsiveness and enhanced tissue penetration, though their relative instability often necessitates performance optimization via nanocarriers or composite strategies. Natural photosensitizers (e.g., curcumin, riboflavin, chlorins) exhibit excellent biocompatibility but are limited by photostability and penetration depth.

Inorganic Photosensitizers: TiO₂ is a prominent, FDA-approved material for clinical implants. However, its application in PDT is constrained by its wide bandgap, narrow absorption range, and high recombination rates of photogenerated charge carriers. To address these limitations, the team summarized various optimization strategies (Fig. 3), including upconversion strategies, ion doping, heterojunction formation, oxygen-vacancy introduction, and surface nanomorphology engineering, to enhance NIR response and carrier-separation efficiency. Emerging materials such as carbon-based nanoparticles, MXenes, metal-organic frameworks (MOFs), and black phosphorus also demonstrate significant application potential.

2.3. Innovative Strategies Enhancing Photodynamic Therapy Performance
Centering on critical issues, including hypoxia within the infection microenvironment, limitations of photosensitizer performance, and insufficient efficacy of monotherapy, the team summarized recent multi-dimensional optimization strategies:
• Nanoplatform Engineering: Developing nanoscale PDT systems allows for precise control of photosensitizers. Interfacial engineering with polydopamine and mesoporous carriers greatly improves photosensitizer stability, biocompatibility, and targeted enrichment, laying the groundwork for the synergistic enhancement of effectiveness and safety.
• Novel Photosensitizer Design: The introduction of aggregation-induced emission (AIE) photosensitizers effectively overcomes the "aggregation-caused quenching" problem inherent in traditional photosensitizers. AIEgens maintain efficient ROS generation even in highly aggregated states and enable integrated imaging and therapy, facilitating precise visualized intervention in infected areas.
• Microenvironment Modulation: To counter hypoxia prevalent at infection sites, strategies involving oxygen carrier delivery or catalytic oxygen-generation systems provide sustained local oxygen supply, markedly boosting PDT efficiency and offering a key solution to overcome oxygen limitations.
• Multimodal Synergistic Therapy: The emergence of synergistic treatment approaches greatly broadens PDT's antibacterial capabilities. Combining PDT with photothermal therapy (PTT), sonodynamic therapy (SDT), or gas therapy results in more effective and comprehensive anti-infection outcomes through multiple mechanisms.

3. Future Prospects
To advance the clinical translation of PDT in titanium implant infection management, more systematic and standardized research is imperative:
• Unified Evaluation System: Develop standardized protocols to systematically compare the physicochemical properties and antibacterial effectiveness of different photosensitizers under various illumination parameters (dose, power density, frequency, irradiation time). This will help identify clinically viable candidate systems and establish optimal therapeutic windows.

• Engineering Scalable Functionalization: Developing simple, scalable, and cost-effective surface functionalization strategies is crucial. Achieving stable immobilization and long-term controlled release of photosensitizers on implant surfaces is the core prerequisite for clinical application.

• Comprehensive Biosafety Assessment: Current research shows major gaps in biosafety evaluation, especially the absence of long-term toxicological studies. Future work must focus on the metabolic pathways, biodistribution, and degradation behavior of photosensitizers and their nanocarriers in vivo, systematically examining their potential effects on local tissues and systemic organs to provide reliable safety data for clinical application.

Currently, research is shifting toward multifunctional implant systems. By incorporating osteoactive molecules, immunomodulatory factors, and pro-angiogenic signals, PDT platforms can inhibit bacterial colonization while simultaneously promoting osseointegration and tissue repair (Fig. 4). This enables dynamic regulation from an antibacterial/pro-inflammatory phase to an anti-inflammatory/pro-regenerative microenvironment conducive to osseointegration. Coupled with light-responsive control strategies, this approach allows spatiotemporally precise modulation of the therapeutic process, driving the evolution of titanium implants from passive structural supports into functional, bioactive, and intelligent therapeutic platforms.

The complete study is accessible via DOI:10.34133/research.1092