Enabling Technologies to Accelerate Development of Oral Biodevices

Objectives

The purpose of this initiative is to encourage research in transformative engineering solutions for system-level challenges that significantly improve the evaluation, monitoring, and management of oral and overall health using multi-functional oral biodevices. These efforts may include systematic engineered approaches to accelerate progress in the interface and integration of electronic, physical, and biological systems into biodevices intended for detection, diagnosis and treatment of oral and systemic disease. The long-term goal is to pave the way for acceleration of technical development and clinical translation of innovative oral biodevices that are highly sensitive and specific for maintaining wellness and timely management of disease and disease risks. These novel integrated oral biodevice systems would help facilitate incorporation of precision medicine-based approaches into clinical practice.

Background

Diagnosis of clinical disease relies on a variety of laboratory-based tests including microscopy, tissue and microbial culture, immunoassays and nucleic-acid amplification. While widely used, standard diagnostics have well-recognized shortcomings, including time delay and a snapshot of physiology only at the time of biospecimen collection. These inherent inefficiencies with standard of care diagnostics can complicate timely delivery of evidence-based care.

Advances in engineering science and biomedical research are leading to the development of next generation diagnostics with the possibility to combine simplicity, speed, and reliability into integrated miniaturized systems. Recent innovations in materials, manufacturing processes, and nanotechnology provide new opportunities to further advance biosensor technologies capable of real-time, continuous and noninvasive quantification of specific biological, chemical, and physical processes that allow for health surveillance, rapid disease detection, and prediction and monitoring of effective treatment. Amperometric, optical, surface plasmon resonance- , enzymatic-, DNA-, Phage-, and bacterial- based biosensors have shown great promise in the detection of a broad spectrum of biological analytes in medical laboratories, food bioanalysis, microbial detection, etc. Increasingly, biosensors are also being used to augment targeted therapies in precision medicine and increase the effectiveness of drugs by strengthening patient compliance.

As biosensor technologies continue to advance towards smaller devices that are integratable, wearable, and embeddable, development of more reliable, accurate and application specific biodevices will facilitate the assessment of clinically relevant outputs and endpoints that are indicative of health status, disease progression, and patients’ compliance with treatment regimen.

Gaps and Opportunities

While the oral cavity offers unique opportunities for development of biodevices designed for real-time, continuous, noninvasive, physiological measurements indicative of oral/dental and overall health status, there are multiple challenges in their development and implementation to ensure safety and efficacy. A systems engineering approach is needed to properly identify risks, design criteria and fabrication methods that address the challenges imposed by the oral environment, including: mastication forces, varying pH levels and temperatures, oral flora, adhesion to wet intraoral tissues, interference with speech, breathing and nutritional intake, and material biocompatibility.

Adoption of human factors engineering (HFE) and usability engineering (UE) principles in the development process can ensure devices are safe and effective for intended device users, uses, and use environments while maximizing ease-of-use, efficiency, and user satisfaction. HFE/UE considerations can ensure that the device user interface is designed such that unintended errors that could cause harm or degrade medical treatment are either eliminated or reduced to the greatest extent possible. Implementation of risk mitigation strategies that appropriately address potential safety and effectiveness concerns with device use is essential during device development to reduce possible design-related problems, and maximize the functionality and clinical translation of intraoral biodevices. Novel oral biodevices should build upon technical advances of current state-of-the-science biosensors, including, but not limited to: improved biocompatible materials, material surface modifications to prevent or minimize biofouling, enhanced low-power/miniaturized/flexible electronics, long-term power generation capability/cycle life or rechargeability of power cell, systems integration of biosensor with implantable device and/or digital health system, methods and means of delivery and/or implantation and programmability or ability to upgrade residing software/firmware, reliable adhesion to wet intraoral tissues, and secure wireless data transmission.

Additionally, the oral cavity has many properties which makes it an attractive site for the development of integrated drug delivery systems that would not only improve the treatment of many oral diseases but also enable the systemic delivery of therapies in a more effective and patient acceptable manner. However, pairing of pharmaceutical products with delivery devices requires close attention to the design, function, and efficacy of integrated delivery systems. A successful integrated oral biodevice with combined sensing and drug delivery features must consider many different factors including patient acceptance, drug release profile, as well as practical and performance requirements attributed to the oral environment. Determination of the exact release profile (sustained delivery versus repeat administration) should depend on the condition being treated, and consider variations in patient’s metabolism, genetics, epigenetics, diet, and other medication intake. Development of oral biodevices that couple sensor and drug delivery systems offers unprecedented opportunities to monitor treatments and enable precise dosing of medications. Integration of a biosensor monitoring device with automated drug delivery systems, or a mobile device notification system, would enhance medication compliance, and reduce complications caused by forgetting a dose or not completing a full cycle of a medication.

Advancements in enabling technologies for biosensors and integrated biodevices will capitalize on the use of the oral cavity as sensing site for noninvasive, dynamic, continuous, real-time monitoring of physiological processes, and provide effective indicators of oral and systemic health. These and other applications of oral biodevices are likely to generate new health surveillance and therapeutic paradigms for effective, economical and low-morbidity precision medicine approaches that will greatly benefit diverse patient populations.

Specific Areas of Focus

The scope of this initiative includes, but is not limited, to enabling technologies and systems integration to accelerate development and clinical translation of intraoral biodevices:

Enabling Technologies

Development of sensitive and selective biodevices utilizing efficient transducing elements and specific biosensing recognition materials to detect small quantities of biomolecules.
Development of biodevices at micro/nanoscale level utilizing novel nano/materials for single biomolecule detection and/or detection of single events originated from enzymatic reactions.
Development of high fidelity self-powered, stand-alone, biodevices with secure wireless data transmission for long-term, real-time, quantitative measurements and analysis.
Development of label-free affinity biosensors with demonstrated selectivity, reproducibility and accuracy to chosen analyte(s) tailored to specific applications.
Optimization of electrode form factor, interaction between nanomaterials and biomolecules on surface of electrodes, and implementation of biosensor arrays to improve reproducibility and accuracy of single molecule detection or simultaneous detection of multiple validated biomarkers.
Robust solutions to ensure biocompatibility of fabrication processes and materials, device reusability, minimization of device biofouling, enhancement of the shelf-life and improvement of device adhesion to wet intraoral tissues.

Systems Integration and Interoperability

Development and validation of fully integrated biosensor-based systems that bring together components of sample preparation and analyte detection with interoperable digital health systems / internet-of-things (IoT) platforms / drug delivery systems, and end-user functionality.
Establishment of validated biological and engineering solutions for system-level tasks in sensing, interfacing, and designing control processes that significantly improve performance of multi-functional sensors for intra oral applications.
Development of novel control strategies with smart, dynamically interfaced intraoral biosensors and actuators that can control drug release, electrical stimulation and other therapeutic outputs by combining intelligent feedback control with secure global wireless interconnectivity.
Overcoming fundamental technological gaps in implementation of feedback control for intelligent decision-making of fully integrated, self-powered, autonomous engineered devices capable to assess medical conditions and prompt early and effective interventions.
Integration and validation of biosensors and processing technologies in embedded, continuous, intraoral diagnostic systems with individualized signal conditioning components for diagnostic and trend-detecting algorithms.
Miniaturization and integration of biosensor components within enclosure or a framework adequately designed to conform comfortably to the oral cavity.

Feasibility and Timeliness

This initiative is feasible and timely because recent progress in wearable biosensor technologies have paved the way to allow for continuous and noninvasive detection of complex clinically-relevant analytes in real-time. Parallel advances in digital health technologies, data and software platforms and drug delivery instrumentation offer unique opportunities for systems integration of biosensors into application-specific oral biodevices and systems with the potential to enhance current capabilities to evaluate, monitor and manage oral and overall health with high precision.

Since the oral cavity serves as the main entryway for many inputs in the body, this initiative will provide NIDCR a unique opportunity to impact both oral/dental and overall health. These oral biodevices will have the capacity to dynamically and non-invasively monitor in real time oral and systemic conditions that can be precisely integrated with drug delivery systems to enable preventative and therapeutic approaches to improve health.

Current NIDCR/NIH Portfolio

The NIDCR Dental Materials and Biomaterials Program currently supports several SBIR/STTR projects through its “Imaging Diagnostics of Dental Diseases and Conditions” FOA (PA12-193 and PA12-195), which are focused on diagnosis of cracks, dental caries, and measuring pulp vitality with hand held devices that utilize signal inputs and feedback. However, these devices do not employ wireless approach and do not provide continuous, real-time analysis.

Additionally, the Program also supports several R01 and R21 projects through its “Biosensors in the Oral Cavity” Funding Opportunity Announcement (RFA-DE-17-004 and RFA-DE-17-005), which are focused on development of biosensors to assess health and disease states by receiving and analyzing signals from oral fluids, oral and dental tissues, cells and microorganisms, and compounds found in or passing through the oral cavity.

Alignment with NIDCR Strategic Plan

Goal 1, Objective 3: Conduct translational and clinical investigations to improve dental, oral, and craniofacial health

Goal 2, Objective 1: Support research toward precise classification, prevention, and treatment of dental, oral, and craniofacial health and disease

NIDCR 2030 Goals: Oral Biodevices, Oral Health and Overall Health, and Precision Health

Bibliography

Ali J, Najeeb J, Ali MA, Aslam MF, Raza A. Biosensors: Their fundamentals, designs, types and most recent impactful applications: A review. J Biosensors & Bioelectron. 2017; 8:1. doi: 10.4172/2155-6210.1000235.

https://www.hilarispublisher.com/open-access/biosensors-their-fundamentals-designs-types-and-most-recent-impactful-applications-a-review-2155-6210-1000235.pdf

Neethirajan S, Ahmed SR, Chand R, Buozis J, Nagy E. Recent advances in biosensor development for foodborne virus detection. Nanotheranostics. 2017; 1(3): 272-295. doi: 10.7150/ntno.20301.
https://www.ncbi.nlm.nih.gov/pubmed/29071193

Vigneshvar S, Sudhakumari CC, Senthilkumaran B and Prakash H. Recent advances in biosensor technology for potential applications – An overview. Front. Bioeng. Biotechnol. 2016; 4:11. doi: 10.3389/fbioe.2016.00011.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754454/

Daniels JS and Pourmanda N. Label-free impedance biosensors: opportunities and challenges. Electroanalysis. 2007; 19(12): 1239–1257. doi: 10.1002/elan.200603855.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2174792/

Sin ML, Mach KE, Wong PK, and Liao JC. Advances and challenges in biosensor-based diagnosis of infectious diseases. Expert Rev Mol Diagn. 2014; 14(2): 225–244. doi:10.1586/14737159.2014.888313.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104499/

Guha S, Jamal FI and Wenger C. A review on passive and integrated near-field microwave biosensors.

Biosensors. 2017; 7(4): 42; doi:10.3390/bios7040042.
https://www.ncbi.nlm.nih.gov/pubmed/28946617

Mehrotra P. Biosensors and their applications – A review. Journal of Oral Bio and Cranio Res. 2016; 6(2): 153–159.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862100/

Kim J-W and Tung S. Bio-hybrid micro/nanodevices powered by flagellar motor: Challenges and strategies. Front. Bioeng. Biotechnol. 2015; 3: 100. doi: 10.3389/fbioe.2015.00100.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515596/

Lim JW, Ha D, Lee J, Lee SK and Kim T. Review of micro/nanotechnologies for microbial biosensors. Front. Bioeng. Biotechnol. 2015; 3:61. doi: 10.3389/fbioe.2015.00061.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426784/

Goda T, Tabata M and Miyahara Y. Electrical and electrochemical monitoring of nucleic acid amplification. Front. Bioeng. Biotechnol. 2015; 3:29. doi: 10.3389/fbioe.2015.00029
https://www.ncbi.nlm.nih.gov/pubmed/25798440

Achyuthan K. Whither commercial nanobiosensors? J Biosens Bioelectron. 2011; 2:102e. doi:10.4172/2155-6210.1000102e.
https://www.omicsonline.org/whither-commercial-nanobiosensors-2155-6210.1000102e.php?aid=495

Hearnden V, Sankar V, Hull K, Juras DV, Greenberg M, Kerr AR, Lockhart PB, Patton LL, Porter S, Thornhill MH. New developments and opportunities in oral mucosal drug delivery for local and systemic disease. Adv Drug Deliv Rev. 2012; 64(1): 16-28. doi: 10.1016/j.addr.2011.02.008. https://www.ncbi.nlm.nih.gov/pubmed/21371513

Applying human factors and usability engineering to medical devices. U.S. Food and Drug Administration Guidance for Industry and FDA Staff. 2016
https://www.fda.gov/media/80481/download

Last Reviewed

February 2024