Implantable Biosensors for Musculoskeletal Health

Introduction

A healthy musculoskeletal system requires complex functional integration of bone, muscle, cartilage and connective tissues responsible for bodily support, motion, and the protection of vital organs. Conditions or injuries to musculoskeletal tissues can devastate an individual’s quality of life. Some conditions that are particularly disabling include severe bone and muscle injuries to the extremities and amputations resulting from unmanageable musculoskeletal conditions or injuries. Monitoring and managing musculoskeletal health is intricate because of the complex mechanobiology of these interconnected tissues ^1,2. Novel implantable biosensors capable of tracking biophysical parameters in vivo are highly relevant to musculoskeletal health because of their ability to collect clinical data relevant to medical decisions, complex trauma treatment, and the performance of osseointegrated prostheses. This review focuses on implantable biosensors related to clinical data of the musculoskeletal system, therapeutics for complex bone injuries, and osseointegrated prosthetics as example applications. A brief summary of biosensor technologies is provided along with review of noteworthy biosensors and future developments needed to fully realize the translational benefit of biosensors for musculoskeletal health.

Musculoskeletal Health

Complex bone injuries or musculoskeletal trauma

Within the scope of musculoskeletal injuries, complex bone injuries are particularly devastating and often impact several musculoskeletal tissues including bone, vasculature, and musculature in the extremities. Conditions that cause or leave patients susceptible to these injuries include accident or combative traumas, tumor resection surgeries, or other congenital disorders such as diabetes ³. Complicated surgeries and long-term rehabilitation are often required for these injuries, which worsens the financial burden for patients ^4–6. Preclinical and clinical investigations have struggled to create a clinical standard for treating severe musculoskeletal injuries that often exhibit high complications rates and poor functional recovery because of their complex, multi-tissue nature ^7–9. Rehabilitation is a key part of recovery since restoration of injured musculoskeletal tissue is potently influenced by mechanical stimulus ^1,2, but rehabilitation remains highly subjective with no current method to monitor the stability of the reconstructed tissues throughout healing. Implantable biosensors can address this limitation by longitudinally monitoring biophysical conditions that are indicative of stability. Additionally, these technologies can monitor patient-specific and real-time data that may inform feedback-controlled rehabilitation and predict healing complications using multivariate computational models. All of this warrants the consideration of implantable biosensors to aid in clinical decisions and rehabilitation by better analyzing patient-specific healing parameters in “hard to reach” places.

Amputation

Another consideration of musculoskeletal health includes amputations, or the intentional removal of a limb or body part, which are commonly performed to remove diseased tissues or relieve pain. These procedures are applicable to severe injuries or disease states that were not effectively treated with other therapeutics or surgical interventions. Implications for amputation include gangrene, peripheral vascular disease, musculoskeletal trauma, tumors, infection, or other uncontrolled congenital limb anomalies ¹⁰. In the event of limb amputation, patients are left with profound economic, social, and psychological effects, on top of the obvious physical struggles ¹⁰. Typically, surgeons view amputations as the last resort and are thus considered a treatment failure. Better assessment of musculoskeletal tissue after injury or while in a diseased state could help improve limb salvage efforts and prevent amputations.

When amputation is required, osseointegration may improve prostheses outcome in terms of functionality, fit, and patient satisfaction. Osseointegration of prosthetics is an innovative surgical method that anchors the metal prosthetic directly into the host bone of residual limbs via screw, compression, and press fit implantation (Fig. 1). This procedure can be advantageous to traditional prosthetics as it improves mobility, control, and proprioception of the prosthetic limb, reduces nerve pain, and increases comfort which can eliminates common socket-associated problems ¹¹. Despite these advantages, osseointegrated prostheses face several challenges including high incidence of tissue infection, potential for implant loosening, host bone fractures, and a lack of quantitative assessment of when an osseointegrated prosthetic can withstand loading ¹². Implantable biosensors may help address issues related to implant loosening and host bone fractures by monitoring in vivo loads and the resulting host bone conditions after surgery ^12,13.

Fig. 1.

Three types of osseointegration ⁷⁷ (A) graphic of x-ray differences between socket based prosthetics and osseointegrated prosthetics (B) screw osseointegration with the fixture that holds the abutment and supporting abutment screw (C) Compression osseointegration with an anchor plug and transverse pins to withstand the strains from this method (D) press fit osseointegration with supporting hardware. Created with BioRender.com

Biosensors impact on musculoskeletal health

As technology and analytic capabilities continue to advance, our healthcare system has become increasingly data-driven and less dependent on in-person physician examinations. As a result, biosensors, among other technologies such as mobile devices, are playing an increasing role in healthcare because they can quantitatively track physiological events to aid in clinical outcomes and individual health management ¹⁴. Current biosensors include wearable or implantable devices that can communicate with external devices through USB (wearable devices) or wireless communications (both wearable and implantable devices) such as Bluetooth or Wi-Fi (Fig. 2). Figure 2 includes some examples of implantable technologies for monitoring musculoskeletal health, as well as wearable sweat patches and benchtop biochemical sensors, which may evolve into implantable applications upon future development. Wearable devices have an undeniable place in healthcare because of their potential to minimize pain and discomfort, exhibit fast implementation, bypass biocompatibility considerations, and exhibit easy point-of-care access. However, implantable biosensors are also crucial, as they allow for translatable knowledge of “hard to reach” places and avoid the low signal-to-noise ratio that often hinders wearable devices and stems from poor sensor-skin contact or patient movement. In addition, implantable biosensors can allow for longitudinal analysis of the local environment within preclinical models to help understand and facilitate novel translatable treatments for musculoskeletal injuries or disease. Overall, implantable devices have the potential to aid in clinical understanding of disorders, medical decisions, injury prevention, and post-injury treatment ^14–16.

Fig. 2.

Schematic of biosensors used to monitor musculoskeletal health. (A) microanalytic technique ^78,79 (B) wearable sweat patches ^80–82 (C) thermal analysis ^83,84 (D) in vivo strain measurements ^41,85,86 (E) biomechanics analysis using optics ^87–91 (F) biochemical monitoring ^49,92–95. Created with BioRender.com

Part of the data-driven evolution of healthcare includes implantable biosensors, which are predominantly biophysical sensors, but future advancements may elucidate future applications for implantable biochemical sensors. Biosensors can be defined as analytical devices that convert either a physical or biological response into a quantifiable electrical signal ¹⁷. The first implantable biosensor originated in 1960 as a cardiac pacemaker to address arrhythmias. Since then, biosensors have expanded to intricate pacemakers, defibrillators, and implantable devices that stimulate and monitor physiologically relevant processes. The drastic growth in biosensor technologies has affirmed biosensors as crucial in reliable diagnostics and treatment options for millions of patients ¹⁴. The first implantable devices were all battery powered, controlled by programmable circuits, and reliant on biocompatible electrodes and wires ¹⁴. Since then, biosensors have expanded in their means of power, electrical components, and wireless capabilities. This review dives into the growing application of implantable biosensors for musculoskeletal health by providing an overview of biosensor technologies and how they have helped translatable knowledge of musculoskeletal biomechanics, post-injury recovery, and amputation management.

Overview of implantable biosensors

The development of biosensors relies on multidisciplinary knowledge and collaboration because of the breadth in required components and functionality. These complex devices also require proactive organization and understanding of what the biosensor will detect, crucial components for fabrication, and the necessary functionalities throughout all design iterations. The following section will outline relevant parameters to detect for musculoskeletal health, ubiquitous components of biosensors, and key considerations for implantable biosensors.

Parameters relevant to musculoskeletal health

Biosensors can detect unique parameters related to the biological or physical conditions. For example, biophysical sensors can quantify the biomechanical environment by monitoring physical parameters such as compressive, shear, or tensile strain as well as temperature or pressure in vivo ^18–21. Conversely, biochemical sensors often monitor the presence or concentration of specific biomarkers including cells, molecules, cytokines, or proteins ²². Due to the intricacies of biochemical sensors, they are currently limited to wearable or benchtop technologies that often rely on fluid extraction and subsequent analysis. Common bodily fluids used for biochemical sensors include urine, sweat, blood serum, or local fluid around musculoskeletal tissues such as synovial fluid near knee joints susceptible to osteoarthritis, a degenerative disease of joint cartilage and underlying bone. Quantification of these parameters requires in-depth investigation of the biosensor’s reliability, sensitivity, specificity, and selectivity in vivo. Biochemical and biophysical parameters are relevant to musculoskeletal health because mechanical conditions influence the biological cascades that control tissue regeneration and remodeling crucial for injury prevention, healing, and degeneration management. Similarly, dysregulated analytes may hinder the physiological state of musculoskeletal tissues. Overall, the mechanobiology of musculoskeletal tissues is highly dynamic, so reliable analysis of local biophysical and biochemical conditions has potential to inform medical decisions and treatment outcomes.

Functional components of implantable biosensors

In short, the basic functionality of biosensors relies on five key components: a power source, bioreceptor, transducer, supporting circuitry, and a reliable interface for data transmission as shown in Figure 3 ²². Once powered, biosensors rely on a sensing mechanism in the form of either a bioreceptor that specifically binds to the analyte of interest or a detection apparatus that reliably gauges physical parameters. Some examples of sensing elements include chemical/biological recognition elements such as enzymes and immobilized antibodies. The functionality of a biosensor also requires a transducing element that converts the sensed parameter into a usable electrical response for quantification as well as supporting circuitry that controls the measurement process of the sensor and modulates the power for the electrical components. A common example of transducers for biophysical parameters is the strain gauge that converts applied forces, pressures, torques, etc. into changes in electrical resistance. Main function of the supporting circuitry include providing the needed voltage and control for the transducer to operate, digitizing the output data for further processing or transmission. Lastly, data collected by biosensors are transmitted to an external device via custom wireless communication protocol or common protocols such as Bluetooth or WiFi. Advancements in these foundational components have led to novel biosensors with potential for broad clinical application.

Fig. 3.

Diagram of functional components of biosensors including reception components to detect an analyte (bioreceptors specific to biochemical sensors), transducers to convert input signal to quantifiable data output, supporting circuitry to allow for specific functionality, and data transmission to capture outputted data. Created with BioRender.com

The general performance of biosensors largely depends on the sensing element that detects either a biochemical or biophysical parameter, often at nanoscale quantities ²². When developing a biosensor, the design or implementation of various transducers such as strain gauges or temperature gauges, or biological recognition elements such as immobilized bioreceptors are key considerations. For biophysical sensors, the sensitivity, measurement of hysteresis, and signal drift are crucial for reliable and accurate detection. Furthermore, sensor performances are often impacted by electrical noise from the power supply or vibrational noise from the environment ²². When disruptive acoustic waves are present, many biophysical sensors will detect them as vibrations, which will affect the accuracy of detection. Therefore, to minimize noise, one must consider biosensor placement and external conditions to better discern relevant signals from noise.

Beyond the sensing element, supporting circuitry is also needed for the functionality of biosensors. Supporting circuitry typically includes an electrical circuits with appropriate power supply. Depending on the circuit function, typical circuitry for biosensing includes common electrical and electronic components such as capacitors, resistors, transistors, or amplifiers. Additionally, many biosensors also rely on microcontrollers to control the functionality of the device, as well as data transmission components needed for USB, WiFi, or Bluetooth communication with external devices. When incorporating a microcontroller, the functionality of the supporting circuitry, such as power management, sensing functions, data transmission, and calibration, can be customized or even optimized on the fly with programming codes or scripts.

Key considerations for implantable biosensors

Implantable biosensors are particularly fitting for musculoskeletal applications because many conditions or injuries already require a surgical procedure and would benefit from longitudinal monitoring throughout recovery. However, compared to wearable technologies, implantable biosensors come with additional risk to local tissue and systemic complications. Issues such as safety, tissue response, and in vivo interference are important practical considerations during the development of implantable biosensors.

When investigating the potential application of implantable biosensors, one must consider potential implications of the invasive approach during delivery and possible later removal of the biosensor. When the body recognizes a foreign implant, a complex response occurs (e.g. fibrotic encapsulation) in both the short and long term, which can adversely affect both the function of the implant and health of the local tissue ^23–28. Proactive measures related to biocompatibility and sterilization can help minimize the response to the implant. In addition, careful selection of biocompatible materials or coatings (e.g. high molecular weight polyermers such as polyethylene glycol/PEG, polydimethylsiloxane/PDMS, or parylene- C ²⁹) can help minimize the local tissue response. Localized heating caused by power dissipating and unintended stimulation can also cause harmful damage to local tissue, so biosensors should use a low-frequency carrier wave with frequencies still above physiological thresholds ²³. Biocompatibility is achieved when an implanted biosensors can function in vivo without eliciting detrimental local or systemic responses in the body. To promote biocompatibility, biosensors can be coated with certain materials that can minimize the host tissue’s reaction around the sensor. For example, biosensors have been coated with porous polylactic acid (PLA) to reduce fibrosis (thickening and/or scarring of connective tissue) ³⁰. In addition, anti-inflammatory agents (e.g. dexamethasone) have been delivered at the site of implantation in an attempt to suppress inflammation and avoid host tissue rejection of the implanted biosensor ³¹. Sterilization of the device can also help avoid a harmful immune response, but certain forms of sterilization may hinder biosensor functionality (temperatures from dry heat or steam can damage components of sensors), so biosensor performance must be tested both before and after sterilization. Some established forms of sterilization include ethylene oxide, radiation, dry heat or steam, hydrogen peroxide (H₂O₂), and ozone, while more novel forms include peracetic acid, ultraviolet light, microwave, sound waves, and pulsed light ³².

To avoid harmful complications and wasted resources, the functionality of the biosensor in an environment comparable to living tissue must be rigorously tested prior to implantation. This environment will entail bodily fluids with a controlled temperature and pH level. To preserve functionality, the core components must be enclosed by a durable, yet biocompatible material to limit biological fluid leakage and vibrational noise. Once the device is ready for implantation, one needs to consider the approach of delivering and removing the biosensor in terms of placement, size, damage to local tissue, and patient comfort. In addition, implantable biosensors are prone to implant migration which can lead to healing complications ¹⁸. Therefore, the biosensor’s susceptibility to physical migration during ambulation and mundane activities for both short and long term care needs to be minimized. Implantations come with several risks related to sensor attrition and physiological complications, so extensively testing in relevant in vitro and in vivo environments is paramount to clinical success.

Exemplary biosensors utilized for musculoskeletal health

History of biosensors for clinical data of the musculoskeletal system

Beyond biosensors for diagnostic or treatment purposes, implantable biosensors have also provided decades worth of clinical data about the biomechanics of the musculoskeletal system. The use of implantable biophysical sensors for clinically relevant research started as early as 1966 when Rydell analyzed forces acting on implanted femoral components using strain gauges and temporary percutaneous wire that connected the permanent implant ³³. From the well-received significance of in vivo data for musculoskeletal behavior, later researchers continued to fabricate and implement biosensors for bone and joint analysis including Lanyon and colleagues who measured bone strain in 1975 using a strain gauge attached to the midshaft of a man’s tibia ³⁴. These two early implantable biosensors continued to motivate additional applications such as measuring strain in fracture fixation, pressure in cartilage, forces in the spine, and forces within the knee, hip, and shoulder joints ³⁵. In summary, implanted biosensors have yielded in vivo quantification of force, torque, strain, displacement, pressure, and temperature ^36,37. Recent advancements in microfabrication, wireless capabilities, and reduction in cost allow these sensors to be incorporated into implants with minimal alterations to the host implant. Orthopedic smart implants are a specific category of biosensors mainly used for research. These implantable devices are incorporated into implants to measure physical parameters inside the body, and their data have led to the refinements of implant design, surgical technique, postoperative care, and rehabilitation. Implantable biophysical sensors embedded in the body or implants benefit the research community the most as the sensors data can immediately aid in testing, validating, and generating relevant insight into the behaviors of musculoskeletal tissues in response to injury, surgical repair, degeneration, and healing. Further, these biosensors are valuable to companies for medical devices, implants, and prosthetics as they allow for clinically relevant improvements to the design and implementation. Lastly, the future of these biosensors has potential to inform feedback-controlled rehabilitation or therapeutics by integrating the longitudinal data into personalized models that inform clinical decisions. Clinical knowledge starts with research, and implantable biosensors have been the cornerstone for comprehensive knowledge of the in vivo biomechanics of musculoskeletal tissue. Now the challenge is translating these research tools into clinical resources to aid in diagnostics, management, and treatment of musculoskeletal injuries and disorders.

Biophysical sensors for musculoskeletal injury management

Stress and strain are critical parameters for the growth, remodeling, and repair of musculoskeletal tissues. Therefore, in vivo knowledge of these forces and any resulting deformities provide critical insight into the tissue’s response to injury or disease. Several implantable biophysical sensors have been used to directly measure biomechanics including strain in several musculoskeletal tissues and have seen a promising impact on clinical applications. For example, in the early 1970s Burney and coworkers used percutaneous leads to measure loads during fracture healing by instrumenting external fracture plates with strain gauges ³⁸. Later, Schneider et al. instrumented a femoral intramedullary nail with a biosensor and telemetry system to monitor femoral forces throughout healing ³⁹. Their analysis found a 50% decrease in loading over the first 6 months of healing. They reasoned that the decrease in loading and the increase in bone stiffness was a result of tissue healing. This correlation between stiffness and healing supports biophysical sensors that longitudinally measure stiffness and thus monitor healing throughout treatment. In addition, other implantable biophysical sensors for musculoskeletal injury management have been outlined in D’Lima et al. review article that includes sensors to measure strain in bone, fracture fixation, cartilage, the spine, and major joints like the hip and shoulder ³⁵.

More recently, Klosterhoff et al. deployed an implantable strain biosensor platform to examine the biomechanical cues in a critical-sized segmental bone defect in rat femurs during treadmill rehabilitation. This defect model was treated with BMP-2 and stabilized by either a stiff (made of polysulfone) or compliant (made of ultra-high molecular weight polyethylene) internal fixation plate instrumented with a strain gauge that connects to a transceiver pack via a subcutaneous wire (Fig. 4). This biosensor platform deploys Bluetooth wireless communication to transmit the strain induced within the regenerative niche to nearby monitors in real-time (Fig. 4). The biosensor technology monitors longitudinal strain, providing the opportunity to guide weekly revisions to rehabilitation. These revisions can be informed by biofeedback mechanisms understood through patient-specific data collected in real-time. This model emulates complex bone injuries that face high complication rates and devastating long-term disabilities, which motivates therapeutic strategy that synergistically combines regenerative and rehabilitative treatments. The preclinical work by Klosterhoff et al. found that compliant plates allowed a two-fold increase in deformation magnitude than the stiff fixation plates, which led to a subsequent three-fold increase in mineralized bridging and over 60% increase in bone formation ⁴⁰. They further showed that early strains, just one week post-injury, and well before radiographic evidence of healing, correlate with altered local biological responses and long-term healing outcomes ^41,42. These findings support their implantable strain biosensor platform for non-invasive readouts of healing in a personalized, real-time manner. Further, their findings exemplify the clinical relevance of quantifying mechanical loads in musculoskeletal tissues to monitor healing or disease progression, with potential to accelerate functional recovery of complex musculoskeletal injury via personalized, feedback-controlled rehabilitation. Implantable biosensors for future clinical treatment of complex traumas would benefit from additional advancements in biosensor technologies, including elimination of internal batteries and miniaturization, as well as integration with machine learning algorithms to predict and optimize patient functional recovery.

Fig. 4.

(A) Still image of rat from high-speed x-ray video. Note the fixator plate and transceiver pack both outlined in red (B) Biosensor output depicting cyclic strain amplitudes corresponding to discrete steps.

Biophysical sensors to aid in osseointegrated prosthetics

Since the 1990s, osseointegrated prosthetics have leveraged bone ingrowth into metal implants to improve prosthetics for applicable patients ⁴³. Although osseointegration has seen promising results, this procedure is still challenged with host bone fractures, infection, and insufficient knowledge of when osseointegrated prosthetics can handle loads. To address this shortcoming, recent developments have focused on implantable biosensors to monitor the in vivo bone strain and growth. Recent advances in technology and growing interest in sensor-laden implants that provide clinical data related to the performance of implants, has led to the application of implantable biosensors to monitor and improve osseointegrated prosthetics.

As a noteworthy example, Burton et al. recently developed a biocompatible wireless sensor system to monitor the growth and strain response of bone after implantation ¹³. Their thin-film sensor is intended to wrap around the circumference of the host bone during surgical implantation and consists of a two resistor-inductor-capacitor (RLC) circuits. One circuit measures axial strain in bone and the other tracks bone hoop strains in comparison to known target hoop strain to monitor bone growth ¹³. Upon initial characterization of the circuit components, their passive strain sensing system agreed closely with theory ¹³. Subsequent simulation and experiments also validated their ability to detect bone strains expected during compressive osseointegration, as well as the proposed hoop strain-sensing system to quantitatively monitor bone growth within the osseointegrated implant. Although these authors were able to develop and validate this sensing system, they have not translated their sensor system to in vivo animal models. After testing in animal models their system may encounter complications which will require system revisions. In addition, their sensing mechanism focuses on low levels of strain which may limit the application to humans. The expanding focus on implantable biosensors for osseointegrated prosthetics has deviated from other external sensor systems, such as the external apparatus mounted on the abutment of osseointegrated prosthetics done by Frossard et al, in hopes of detecting bone integration earlier and improving rehabilitation ^44,45.

The field of osseointegration continues to evolve and recent advancements in biosensor technology have led to the consideration of implantable biosensors for this application. Wireless biosensors implanted with osseointegrated prosthetics to monitor strain and bone integration has potential to transform clinical understanding and overall outcomes of osseointegrated prosthetics. More specifically, advancements with these biosensors have potential to inform data-driven loading in terms of magnitude and timing for osseointegration patients, as well as minimize current osseointegration complications such as loosening and host bone fractures.

Clinically available biosensors

Although increasing research has focused on implantable biosensors for musculoskeletal health, they are often confined to research applications with few products commercially available. One notable biophysical sensor in the market is the open eDisk developed by Theken Disc, LLC for measuring motion and loads within a spinal disc implant. This was the first artificial spinal disc with an integrated microelectronics module to reduce post-operative complications and accelerate recovery and return to work. The force monitoring capability of this implanted disc allows for real-time and personalized data that assesses whether a patient is able to return to work, while the microelectronic module monitors any dynamic high-load events to immediately alert the patient via a wireless signal to a worn audible alert unit ⁴⁶. In addition, the FDA recently granted de novo classification for the Persona IQ smart knee implant, which is the only smart knee implant cleared by the FDA for total knee replacement surgery to date ⁴⁷. This technology records and wirelessly transmits a wide range of gait data to a patient’s personal base station at home before data are securely delivered to surgeons, via a FDA regulated and HIPPA-compliant cloud-based platform, to assess post-surgery recovery. The smart implant consists of a cemented tibial plate and tibial extension, and the biosensing is enabled through the stem that is instrumented with internal motion sensors (3D accelerometer and gyroscope). Proprietary algorithms convert the raw data into clinically relevant gait metrics that allows easy post-operative monitoring by both the patient and healthcare providers. One of the most striking aspects of this clinically available smart implant is the ability to monitor patient’s gait daily through one year of recovery, with potential for 20 years of longitudinal data collection if data collection is less frequency after the first year ⁴⁷. Biosensors for treatment of musculoskeletal tissues are not clinically available, but further validation of implantable technologies in preclinical and clinical models may encourage future translation. Some of the challenges associated with implementing biosensors include safety regulations, cost issues, lack of long-term research, biocompatibility as well as privacy and security concerns due to wireless signal transmission ¹⁹. Besides these challenges, the future is promising for implantable biosensors due to the rapid developments in associated technologies to help address some of the current limitations with preclinical biosensors.

Future directions

Biochemical sensors for osteoarthritis and the potential for future implantable applications

Osteoarthritis (OA) is a progressive joint degenerative disease that involves gradual molecular, cellular, and tissue modifications that no physical therapy or drug has effectively treated ^48,49. The current method of diagnosing this degenerative disease is through clinical examinations and imaging only during late stages. Similarly, the current method to assess biomarkers related to OA often involves Enzyme-Linked Immunosorbent Assays (ELISA), which are generally costly as they require highly skilled workers, expensive laboratory equipment, and long analysis time ⁵⁰. However, biochemical sensors that measure biomarkers released by joint metabolism may provide an advantageous way to diagnose and monitor the disease progression since reliable detection of biomarkers is critical for understanding patients’ condition. The current biosensors used for OA applications include several wearable biosensors to characterize gait for OA patients ^51–53 as well as microfluidic biosensors to analyze immune cells of interest ⁵⁴. The biophysical gait sensors study the impact of physical therapy on the management of OA, while the biochemical microfluidic sensors monitor immune biomarkers with potential to target and analyze markers relevant to OA pathogenesis ⁵⁵. Biochemical sensors have potential for broad clinical impact, because of their potential to monitor a plethora of biomarkers that are relevant to various disease or injury conditions. These biosensors involve wearable technologies which help avoid common biochemical laboratory analysis that requires expensive laboratory equipment, time intensive analysis, and trained personnel. However, these wearable biochemical sensors are limited to systemic biomarkers analysis and require painful fluid extraction and dilution steps for local analysis. Implantable biochemical sensors could provide longitudinal data with just one procedure, as opposed to the multiple painful synovial fluid extractions. Longitudinal data could be useful for injury or disease management, especially for musculoskeletal cases that already require surgical intervention. Advancement into implantable biochemical technologies could also avoid fluid dilution steps and allow for local analysis of relevant biomarkers. Overall, advancements to the current wearable technology and potential future implantable applications may allow for proactive diagnosis, patient-specific data to inform clinical decisions, and translatable knowledge for future therapeutics.

Power management and miniaturization strategies

Although implantable biosensors continue to play an increasing role in healthcare, they still face challenges in terms of power efficacy, size, and biocompatibility for long-term monitoring. Furthermore, the lack of standardization in clinical implantable biosensors result in confusion and miscommunication between the biosensor developers and physicians, ultimately slowing down the translation process ⁵⁶.

The power supply is usually a limiting factor for implantable biosensors and they are traditionally battery operated, so maximizing the battery or power budget is particularly important for implantable applications ²³. The method of powering implantable devices depends on the circuit energy consumption rate, operational period, size constraints, and implantable safety considerations ¹⁵. Battery power avoids external wires that connect the implant with external circuitry, which can help avoid surgical complications including wire breakage, infection, and electrical noise, but they are larger in size and have limited operation lifetime ²³. Therefore, batteries require a carefully planned power budget. Progress in several low-power or power-saving circuits have helped prolong battery life in fabricated biosensors ^23,57. Alternatively, wireless power strategies that generate and harvest energy from mechanical, thermal, or kinetic forces surrounding implants have been investigated ^15,16. For example, energy in the form of heat or movement can generate electricity using thermoelectric generators ¹⁶. In addition, novel technologies are utilizing bio-fuel cells such as glucose or amylum to generate electric power from renewable biodegradable materials ^58,59. Other battery-free methods to power implantable biosensors include energy coupling through electromagnetic fields or acoustic waves, or energy-passive elements such as magnetic materials or passive electronic components. For example, magnetoelastic sensors convert magnetic energy to mechanical energy and vice versa, have no active circuitry, and do not require an internal power source like a battery or energy harvesting system ⁶⁰. Implantable biosensors rely on permanent and sufficient power supply to ensure proper operation, so investigating reliable, sustainable, and continuous methods to power biosensors will be in constant demand.

Wireless biosensors can be powered through passive or active means, where passive devices are often powered though wireless energy coupling with external sources (e.g. interrogator), while active devices rely on an internal power source (e.g. battery or energy harvesting system) ¹⁵. Passive biosensors often have a simpler design and smaller size, but are limited to brief snippets, depend on remote power to operate, and often require a reader device to remain in close proximity which restricts the potential for continuous data acquisition throughout daily activity ⁶¹. One advantage of passive power is an operation lifetime that is not limited by batteries. On the other hand, active biosensors often contain electrical components such as microcontrollers and battery powered transducers that allow for remote monitoring and continuous data recording, but the operation lifetime and footprint of the biosensors are hindered by the battery ¹⁵. The decision on the powering method for particular biosensors depend on the required size, functionality, and placement. Passive biosensors are particularly useful for prototyping new technologies because of their simple design, robustness, and long operational lifetime without loss of power, making them ideal for long-term implantable applications where retrieval of sensors are not needed ¹⁵. In contrast, active biosensors are useful for their complex functionality, and ability for remote and continuous data acquisition. Overall, both passive and active powering methods are important for biosensors to monitor musculoskeletal health as they both provide custom and multiplexed measurements, which is of increasing importance in our evolving healthcare.

To avoid patient discomfort and large costs, size is also a crucial consideration for implantable devices. Devices that are battery operated have limited miniaturization potential since batteries are often bulky and account for most of the sensor volume. Other battery-free power sources include energy harvesting technologies, wireless power transfers such as near, mid, and far field effect, inductive coupling, capacitive coupling, and ultrasound ⁶². Careful design of printed circuit boards (PCB) can also aid in miniaturization. Flexible and rigid-flex PCBs are particularly interesting for miniaturization as they reduce the number of connectors and allow folding to complex shapes instead of the previous titanium or ceramic bulky housing units to seal electronic components. Flexible electronics were initially developed for wearable applications but have expanded to implantable applications as small, flexible components for easier and more sustainable implantation ⁶³. Further, soft, stretchable, and flexible electronics are now utilized for implantable biosensors since they reduce the number of connectors to promote miniaturization and they can conform to soft, curvilinear, and elastic tissues while supporting multimodal functions ⁶⁴. Three-dimensional printing technology has also allowed these flexible PCBs and electronics to be stored in geometrically unique housing units to further ease implantation of biosensors.

Multiplexed biosensors

Multiplexed biosensors could drastically advance clinical management of diseased or injured musculoskeletal tissue. The complex mechanobiology of musculoskeletal health warrants the simultaneous monitoring of multiple parameters allowed by multiplexed biosensors. Multiplexed biochemical sensors could simultaneously detect several proteins, cytokines, hormones, etc. to better elucidate the cellular mechanism driving physiological changes to musculoskeletal tissue. On the other hand, multiplexed biophysical sensors could detect several biomechanical properties to better understand the mechanobiology of musculoskeletal tissue. Implantable multiplexed biosensors have yet to be utilized for musculoskeletal applications, but these devices still exhibit increased clinical relevance as they would provide knowledge that better simulates physiological events. The delayed development into implantable applications is largely due to the complex functionality as well as the increased cost, risk, and efforts required to sense multiple parameters and bring this technology to market.

Biodegradable devices

In hopes of minimizing biocompatibility limitations (e.g. fibrous encapsulation and inflammation) as well as avoid secondary removal surgeries, increasing interest has evaluated biodegradable sensors for either short or long term in vivo monitoring ^65,66. These devices rely on biodegradable metals (Mg, Fe) or polymers (PLLA, PCL, and PPy) that break down into non-toxic components after a predetermined functional lifetime ¹⁸. In addition to the improved biocompatibility, biodegradable sensors are advantageous because they avoid removal surgeries altogether ⁶⁷. One example of a recent biodegradable biosensor is the passive pressure sensor developed by Luo and coworkers ⁶⁸. The structural and dielectric material for these wireless biosensors was made of PLLA and PCL, while the conductive portion was made of Zinc and Iron bilayers. Although implanted biodegradable sensors help minimize post-surgery complications, they are all passively powered due to the lack of biodegradable batteries. However, novel advancements in biodegradable batteries have increased the potential of actively powered biodegradable sensors. For example, Tsang et al. developed a magnesium/iron battery in PCL that exhibited adequate energy density and reduced size ⁶⁹. Additionally, biodegradable electronics such as iron microparticle and PCL interconnected system developed by Zhang et al. ⁷⁰, and silk fibroin substrate fabricated by Kim et al. ⁷¹, have advanced the possibility of a fully biodegradable implantable biosensor. These biodegradable technologies are still in their preliminary stages and will require rigorous bench top testing and in vivo monitoring before they are clinically deployed.

Personalized health

The lack in clinical standards and slow translation of emerging technologies have resulted in tremendous variability in musculoskeletal treatment approaches. However, technology for personalized health has been rapidly evolving as each generation exhibits better sensitivity and selectivity while being more resource conscious. Deploying implantable biosensors to examine the variability of musculoskeletal tissue response to disease, injury, and subsequent treatments can help inform personalized clinical treatment ^72–75. For example, the patient-specific data collected by implantable biosensors can provide the inputs for predictive computational models that can aid in clinical treatment decisions. Utilizing implantable biosensors can revolutionize healthcare, since treatment can rely on biofeedback mechanisms enabled by these implantable biosensors and predictive models. Further, personalized health can account for confounding factors such as genetic predisposition which may influence a patient’s condition, prescribed treatment protocol, and response to medical intervention ⁷⁶. To help advance the ability to monitor musculoskeletal health, multidisciplinary projects should utilize implantable biosensors to allow for evidence-based guidelines that allow patient-specific treatment.

Conclusion

Implantable biosensors have exhibited promising potential to advance the knowledge and management of musculoskeletal health. For example, extensive research has allowed the deployment of biophysical sensors to monitor complex injuries, prostheses functionality, and the overall biomechanics of musculoskeletal tissue. Wearable biosensors have dramatically increased in development and use for several clinical applications, while implantable biosensors are much earlier in development and translation. Despite this delay, implantable biosensors still exhibit tremendous potential to impact musculoskeletal healthcare because of the recent advancements in wireless technologies, flexible electronics, biodegradable materials, and energy harvesting techniques. Future work will continue to modify and validate implantable intricate biosensors with hopes of clinical translation to further advance data-driven healthcare.