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We developed a heat-sensitive microbubble (HSM) agent for intraoperative assessment of thermal ablation margins in cancer ablation therapies. The HSM agent, comprising a core of liquid perfluorocarbon (PFC) compound and a shell of biodegradable poly lactic-coglycolic acid (PLGA), was fabricated using an emulsion evaporation method. In our previous study, significant increase of ultrasound contrast was observed after heat activation of HSMs. In this study, intraoperative ultrasonic assessment of thermal ablation margins by HSMs was demonstrated in vivo in a pig model. HSMs were delivered to the pig liver by portal vein injection. Liver ablation was done using a RF ablation probe. Intraoperative ultrasound imaging with HSMs clearly delineated the ablation margin. Fluorescence images of liver tissue samples confirmed the existence and activation of HSMs. This result demonstrated that the HSM agent can be potentially utilized as a multimodal contrast agent for intraoperative ultrasonic and fluorescence assessment of thermal ablation margins in cancer ablation therapies.

Bevacizumab (Avastin) has been used as one of the anti-VEGF therapies to manage neovascular age-related macular degeneration (AMD). The drug delivery system for bevacizumab needs to be improved in order to decrease the frequency of injection and reduce the adverse effects. In our study, bevacizumab was conjugated with poly (lactic-co-glycolic acid) (PLGA) microbubbles by activating carboxyl functional groups. The averaged size of microbubbles was estimated 1.055±0.258μm, allowing for ultrasound guided drug delivery. The binding efficiency between bevacizumab and microbubbles was evaluated in an enzyme-linked immunosorbent assay plate. The test results demonstrated the potential of using PLGA microbubbles to deliver bevacizumab with imaging guidance.

Background: Accurate assessment of tumor boundaries and intraoperative detection of therapeutic margins are important oncologic principles for minimal recurrence rates and improved long-term outcomes. However, many existing cancer imaging tools are based on preoperative image acquisition and do not provide real-time intraoperative information that supports critical decision-making in the operating room. Method: Poly lactic-co-glycolic acid (PLGA) microbubbles (MBs) and nanobubbles (NBs) were synthesized by a modified double emulsion method. The MB and NB surfaces were conjugated with CC49 antibody to target TAG-72 antigen, a human glycoprotein complex expressed in many epithelial-derived cancers. Multiple imaging agents were encapsulated in MBs and NBs for multimodal imaging. Both one-step and multi-step cancer targeting strategies were explored. Active MBs/NBs were also fabricated for therapeutic margin assessment in cancer ablation therapies. Results: The multimodal contrast agents and the cancer-targeting strategies were tested on tissue simulating phantoms, LS174 colon cancer cell cultures, and cancer xenograft nude mice. Concurrent multimodal imaging was demonstrated using fluorescence and ultrasound imaging modalities. Technical feasibility of using active MBs and portable imaging tools such as ultrasound for intraoperative therapeutic margin assessment was demonstrated in a biological tissue model. Conclusion: The cancer-specific multimodal contrast agents described in this paper have the potential for intraoperative detection of tumor boundaries and therapeutic margins.

Accurate assessment of wound oxygenation and perfusion is important for evaluating wound healing/regression and guiding following therapeutic processes. However, many existing techniques and clinical practices are subjective and qualitative due to background bias, tissue heterogeneity, and inter-patient variation. To overcome these limitations, we developed a dual-modal imaging system for in vivo, non-invasive, real-time quantitative assessment of wound tissue oxygenation and perfusion. The imaging system integrated a broadband light source, a high-resolution CCD camera, a highly sensitive thermal camera, and a liquid crystal tunable filter. A user-friendly interface was developed to control all the components systematically. Advanced algorithms were explored for reliable reconstruction of tissue oxygenation and appropriate co-registration between thermal images and multispectral images. Dual-mode oxygenation and perfusion imaging was demonstrated on both benchtop models and human subjects, and compared with measurements using other methods, such as Laser Doppler and tissue oximeter. The test results suggested that the dual-modal imaging system has the potential for non-contact real-time imaging of wound tissue oxygenation and perfusion.