Keywords: fluorescence enhancement, false negatives, false positives, early diagnostics, molecular diagnostics
Summary:In vitro diagnostics (IVD) are indispensable tools for patient management, enabling early-stage disease intervention. A critical problem with IVD is the high level of false negatives (40-80%) and false positives (5-10%) when bio-marker concentrations are low, as in early stages of a disease. Last year 86,000 new cases of cancer were misdiagnosed in the USA. The problem is significantly worse in China where 45 million new cases of cancer are diagnosed each year. False results have multiple causes, including operator error during sample extraction and handling, expired or poorly validated reagents (antibodies, blocking agents) as well as low sensitivity or low specificity. Can advanced materials provide a point solution that works across a wide range of IVD assays? The answer is YES when 1) the assay involves fluorescence, 2) false results are related to low sensitivity and/or low specificity. One of these advanced materials is nano-structured ceramics. As compared to passive, non-porous glass surfaces, recently developed nano-structured ceramic films are capable of providing active photo-physical means to enhance fluorescence signals to high levels (300%-1000% depending on the bio-assay), providing unprecedented signal to noise ratios. This has been achieved without adding undue complexity to any given IVD. For example, the enhanced fluorescent activity has been achieved with commercially available fluorescence compounds used with antibodies, fusion proteins, oligonucleotides, oligo-peptides, and amino acids. Superior performing IVD are being developed using these materials as substrates without any additional modification, adding off the shelf fluorescent labels and probes, or with genetically engineered fluorescent probes and natural auto-fluorescent bio-molecules. In addition, the technology can be used to enhance the exquisite high specificity of monoclonal antibodies by drastically reducing the fluorescent tag ratios down to a single fluorescent tag. The fundamental principles of the enhancement are well understood at the atomic level. Extreme care has been taken to make these material bio-compatible. Thus, these advanced “photonic” materials can readily be vertically integrated with new or existing FDA approved IVD kits, without major re-tooling, without new chemistries or additional consumables, and more importantly without extensive R&D. Existing IVD manufacturers must consider going beyond "in vitro" ("on glass" in Latin), exploring the advantages of “photonic” active materials over glass. The technology is compatible with precision medicine tools, reducing false positives and false negatives and the amount of IVD consumables. Government regulatory agencies may eventually adopt these materials for a new gold standard in IVD. All that is needed is to go beyond in vitro. In this presentation we will discuss the general principles behind this breakthrough, its technology readiness level (TRL), the successful efforts to make these advanced nano-structured ceramics non-cytotoxic, the general costs of these material, and the new methods to produce them in large scale, suitable for vertical integration into existing IVD manufacturing lines.