Unpacking the packaged optical fiber bio-sensors: understanding the obstacle for biomedical application.

A biosensor is a promising alternative tool for the detection of clinically relevant analytes. Optical fiber as a transducer element in biosensors offers low cost, biocompatibility, and lack of electromagnetic interference. Moreover, due to the miniature size of optical fibers, they have the potential to be used in microfluidic chips and in vivo applications. The number of optical fiber biosensors are extensively growing: they have been developed to detect different analytes ranging from small molecules to whole cells. Yet the widespread applications of optical fiber biosensor have been hindered; one of the reasons is the lack of suitable packaging for their real-life application. In order to translate optical fiber biosensors into clinical practice, a proper embedding of biosensors into medical devices or portable chips is often required. A proper packaging approach is frequently as challenging as the sensor architecture itself. Therefore, this review aims to give an unpack different aspects of the integration of optical fiber biosensors into packaging platforms to bring them closer to actual clinical use. Particularly, the paper discusses how optical fiber sensors are integrated into flow cells, organized into microfluidic chips, inserted into catheters, or otherwise encased in medical devices to meet requirements of the prospective applications.

Dynamic Measurement of a Cancer Biomarker: Towards In Situ Application of a Fiber-Optic Ball Resonator Biosensor in CD44 Protein Detection.

The accuracy and efficacy of medical treatment would be greatly improved by the continuous and real-time monitoring of protein biomarkers. Identification of cancer biomarkers in patients with solid malignant tumors is receiving increasing attention. Existing techniques for detecting cancer proteins, such as the enzyme-linked immunosorbent assay, require a lot of work, are not multiplexed, and only allow for single-time point observations. In order to get one step closer to clinical usage, a dynamic platform for biosensing the cancer biomarker CD44 using a single-mode optical fiber-based ball resonator biosensor was designed, constructed and evaluated in this work. The main novelty of the work is an in-depth study of the capability of an in-house fabricated optical fiber biosensor for in situ detection of a cancer biomarker (CD44 protein) by conducting several types of experiments. The main results of the work are as follows: (1) Calibration of the fabricated fiber-optic ball resonator sensors in both static and dynamic conditions showed similar sensitivity to the refractive index change demonstrating its usefulness as a biosensing platform for dynamic measurements; (2) The fabricated sensors were shown to be insensitive to pressure changes further confirming their utility as an in situ sensor; (3) The sensor's packaging and placement were optimized to create a better environment for the fabricated ball resonator's performance in blood-mimicking environment; (4) Incubating increasing protein concentrations with antibody-functionalized sensor resulted in nearly instantaneous signal change indicating a femtomolar detection limit in a dynamic range from 7.1 aM to 16.7 nM; (5) The consistency of the obtained signal change was confirmed by repeatability studies; (6) Specificity experiments conducted under dynamic conditions demonstrated that the biosensors are highly selective to the targeted protein; (7) Surface morphology studies by AFM measurements further confirm the biosensor's exceptional sensitivity by revealing a considerable shift in height but no change in surface roughness after detection. The biosensor's ability to analyze clinically relevant proteins in real time with high sensitivity offers an advancement in the detection and monitoring of malignant tumors, hence improving patient diagnosis and health status surveillance.

All-fiber label-free optical fiber biosensors: from modern technologies to current applications [Invited].

Biosensors are established as promising analytical tools for detecting various analytes important in biomedicine and environmental monitoring. Using fiber optic technology as a sensing element in biosensors offers low cost, high sensitivity, chemical inertness, and immunity to electromagnetic interference. Optical fiber sensors can be used in in vivo applications and multiplexed to detect several targets simultaneously. Certain configurations of optical fiber technology allow the detection of analytes in a label-free manner. This review aims to discuss recent advances in label-free optical fiber biosensors from a technological and application standpoint. First, modern technologies used to build label-free optical fiber-based sensors will be discussed. Then, current applications where these technologies are applied are elucidated. Namely, examples of detecting soluble cancer biomarkers, hormones, viruses, bacteria, and cells are presented.

Ultra-wide, attomolar-level limit detection of CD44 biomarker with a silanized optical fiber biosensor.

Measuring cancer biomarkers at ultralow detection limit and high sensitivity could be a promising tool for early diagnosis, monitoring treatment and post-treatment recurrence. Soluble CD44 is a promising diagnostic and prognostic biomarker in several types of cancer including gastric, colon and breast cancer. Several highly sensitive biosensors have been built to measure this important biomarker. However, they did not reach attomolar level of detection. The aim of this work was to build a biosensor capable of detecting CD44 concentrations down to attomolar (aM) level while measuring it in a wide concentration range. Herein, we demonstrate a biosensor that offers 4 key advantages over existing platforms for CD44 detection: 1) detection of CD44 was carried out in a diluted serum down to attomolar level (4.68 aM) which is about 6 orders of magnitude lower than that of a traditional ELISA; 2) fabrication of the sensor is done in a fast way using inexpensive materials making it a disposable fiber optic biosensor; 3) detection of CD44 was performed in a wide dynamic range previously not shown in other similar biosensors; 4) a proof-of-concept experiment was performed using the biosensor to embed it in a catheter to measure the protein in flow conditions.

Label-free fiber-optic spherical tip biosensor to enable picomolar-level detection of CD44 protein.

Increased level of CD44 protein in serum is observed in several cancers and is associated with tumor burden and metastasis. Current clinically used detection methods of this protein are time-consuming and use labeled reagents for analysis. Therefore exploring new label-free and fast methods for its quantification including its detection in situ is of importance. This study reports the first optical fiber biosensor for CD44 protein detection, based on a spherical fiber optic tip device. The sensor is easily fabricated from an inexpensive material (single-mode fiber widely used in telecommunication) in a fast and robust manner through a CO2 laser splicer. The fabricated sensor responded to refractive index change with a sensitivity of 95.76 dB/RIU. The spherical tip was further functionalized with anti-CD44 antibodies to develop a biosensor and each step of functionalization was verified by an atomic force microscope. The biosensor detected a target of interest with an achieved limit of detection of 17 pM with only minor signal change to two control proteins. Most importantly, concentrations tested in this work are very broad and are within the clinically relevant concentration range. Moreover, the configuration of the proposed biosensor allows its potential incorporation into an in situ system for quantitative detection of this biomarker in a clinical setting.

Optical Fiber Ball Resonator Sensor Spectral Interrogation through Undersampled KLT: Application to Refractive Index Sensing and Cancer Biomarker Biosensing.

Optical fiber ball resonators based on single-mode fibers in the infrared range are an emerging technology for refractive index sensing and biosensing. These devices are easy and rapid to fabricate using a CO2 laser splicer and yield a very low finesse reflection spectrum with a quasi-random pattern. In addition, they can be functionalized for biosensing by using a thin-film sputtering method. A common problem of this type of device is that the spectral response is substantially unknown, and poorly correlated with the size and shape of the spherical device. In this work, we propose a detection method based on Karhunen-Loeve transform (KLT), applied to the undersampled spectrum measured by an optical backscatter reflectometer. We show that this method correctly detects the response of the ball resonator in any working condition, without prior knowledge of the sensor under interrogation. First, this method for refractive index sensing of a gold-coated resonator is applied, showing 1594 RIU-1 sensitivity; then, this concept is extended to a biofunctionalized ball resonator, detecting CD44 cancer biomarker concentration with a picomolar-level limit of detection (19.7 pM) and high specificity (30-41%).