By Clinical Research News Staff 

August 5, 2025 | Researchers are making significant strides in fluorescence-guided surgery, with dozens of glowing molecular probes currently under investigation in clinical trials to help surgeons better visualize tumor margins during operations. The technology could revolutionize surgical precision and eventually enable autonomous robotic surgery. 

Dr. Eric Henderson, an orthopedic surgeon at Dartmouth Health and sarcoma specialist, recently completed a promising phase 0/1 clinical trial using a synthetic fluorescent probe called ABY-029 in 12 soft-tissue sarcoma patients. The study, published in Molecular Cancer Therapeutics, demonstrated a high correlation between the fluorophore and epidermal growth factor receptor (EGFR) expression, with contrast values encouraging enough for clinical translation. 

The trial employed a dose-escalation design, starting with FDA-defined microdoses and increasing to three and six times that amount. Notably, the synthetic affibody peptide achieved performance comparable to antibody-based agents while dramatically reducing the time between imaging and surgical resection. 

Expanding Clinical Applications 

Henderson's team conducted parallel trials using ABY-029 for glioblastoma and head and neck cancers, which also commonly overexpress EGFR. Additional ongoing studies include testing a nerve-specific molecule for diagnosing necrotizing soft-tissue infections and evaluating cartilage health during arthroscopy procedures. 

The research earned significant federal recognition, with a $31 million Moonshot award from the Advanced Research Projects Agency for Health (ARPA-H) to test combination fluorophore approaches in human studies. The project will use multiple light wavelengths to simultaneously assess tissue properties and distinguish between cancers, blood vessels, and nerves. 

Addressing Critical Clinical Needs 

The clinical value becomes evident when considering that soft-tissue sarcomas represent approximately 15,000-16,000 annual cases in the United States. While some sarcomas have clean margins and can be cured through complete removal, aggressive types like myxofibrosarcoma can send microscopic extensions into surrounding tissues that are invisible to surgeons. 

Current practice requires surgeons to visually identify suspicious areas and send tissue samples for frozen section microscopy analysis, a process taking 25-35 minutes per section while patients remain under anesthesia. Fluorescence guidance aims to detect microscopic tumor presence in real-time, preventing positive margins discovered weeks later or local recurrence years after surgery. 

Regulatory and Development Challenges 

The FDA has approved only six fluorescent surgical agents to date, with most having decades-old approvals. The regulatory pathway is complicated because fluorescence-guided surgery requires both a pharmaceutical probe and compatible imaging device, each with distinct regulatory requirements. 

Henderson, who served as a reviewer on recent FDA draft guidance for optical imaging drugs, notes that contrast agents must be given at the lowest effective dose without therapeutic effects. The challenge extends to hardware compatibility, as fluorophores have specific excitation and emission peaks that must match available imaging systems. 

Future Implications 

While fluorescence-guided surgery is gaining adoption across surgical disciplines—particularly in neurosurgery for glioblastoma—Henderson envisions broader applications leading toward autonomous robotic surgery. The technology's ability to help machines identify different tissue types could enable surgical robots to operate with greater independence, potentially delivering advanced surgical care to underserved regions worldwide. 

The multi-institutional collaboration spanning Sweden, Switzerland, Alabama, and New Hampshire demonstrates the international scope of this emerging field, with true phase 1 studies of ABY-029 planned while researchers continue exploring additional fluorescent probe candidates. 

Read Deborah Borfitz’s full story at Diagnostics World.