Articles About Biomechanical Compatibility

Importance of Medical Device Biomechanical Compatibility

Christopher Cheng, Ph.D., Valerie Merkle, Ph.D.

Function and Accommodation

Cardiovascular medical devices are invented and used for a myriad of reasons.  They maintain blood vessel flow lumens, exclude aneurysms and dissections, close orifices and communications, and even completely replace the function of valves, vessels, and membranes.  However, with focused attention on the implant’s primary functions, it is easy forget that an implant also has secondary objectives – to do no harm and stay intact.  While loss of device integrity may not lead to immediate clinical sequelae, the potential risk for such events may increase over the lifetime of the device.  Ultimately, each device is designed to do something, but it can only keep performing its primary function if it adequately accommodates its environment.

 

Interactions between Device and Environment

Implants come in many forms, making their interactions with the human body as varied as physiologic phenomena and the patient population.  Devices need to pulse with the cardiac cycle, conform and flex with respiration, and stretch, shorten, crush, bend, and twist with joint motion and muscular contraction.  We know a lot about how implants behave in some anatomies through decades of research, such as stents in the coronary and superficial femoral arteries.  However, we know very little about how devices interact with their environment in novel applications, such as devices that occupy veins or cross between chambers of the heart.  For these novel applications, it is even more important to complete appropriate research to develop a greater understanding of the in vivo environments to which the devices will be exposed.

 

The Tripod – Loading Conditions, Computational Modeling, Benchtop Testing

Loading conditions come in different flavors: displacement-controlled, force-controlled, and mixed.  A displacement-controlled loading condition will deform any device agnostically regardless of its mechanical properties, while a force-controlled condition will cause deformation commensurate with device stiffness.  The human cardiovascular system tends to mix these two types of conditions, making device deformations difficult to predict.  However, with focused preclinical, cadaver, or clinical observations, realistic loading conditions can be developed and used to properly predict stress and strain through computational modeling, and then confirm and interpret those stresses and strains using benchtop testing and materials science concepts.  The result is an evaluation of mechanical durability.

 

Mechanical Durability vs. Biomechanical Harmony

Besides mechanical durability, the other piece of biomechanical compatibility is biomechanical harmony.  An implant can be designed to be so stiff that it would not deform due to any physiologic motion.  Without deformation, there can be no stress or strain (at least in normal circumstances in the body), so there can be no mechanical fatigue.  However, this type of rigid device could cause tissue trauma or irritation, e.g. a rigid stent could cause vessel kinking at the transition between the stent and the native vessel, which could lead to restenosis, dissection, aneurysm, or rupture.  Every device will impact the mechanical environment of the anatomy where it resides, and considerations to the intended in vivo environment should be made to minimize adverse events to the patients receiving the device. 

 

Importance of Mechanical Durability

Mechanical durability that addresses relevant loading modes is an important aspect of a device evaluation strategy.  While clinical study data provides a real assessment of mechanical durability in the intended conditions of use, clinical studies to support marketing approval or clearance are generally designed with the primary analysis at shorter-term implant durations (e.g., 1 year).  Therefore, the mechanical durability evaluation provides insights into the long-term fatigue performance of the device to further support placing it on the market.

 

The What, The How, The Why

Designers of any device, medical or otherwise, need to know WHAT they are building.  The deeper question of HOW they build it sets them apart from their competitors by being able to manufacture better products, and perhaps even make a profit in the meantime.  But the deepest question of WHY they are building their device reveals what truly distinguishes outstanding products from others.  One of the reasons why all of us participate in the healthcare industry is to help improve and save lives.  We do not treat disease; we treat patients.  Great medical devices do not only treat ailments – they also function for a lifetime and interact with the body harmoniously.

Biomechanical Compatibility as Part of Device Development

Christopher Cheng, Ph.D., Valerie Merkle, Ph.D.

 

Starting Too Late

Let’s start with a hypothetical.  A company spends three years building a team, iterating designs, screening materials, constructing a supply chain, conducting preliminary preclinical and functional evaluations, and building the bones of a design history file for an improved version of an existing medical device.  Now it is time to freeze the design and launch costly good laboratory practice (GLP) evaluations necessary for getting approval for a pivotal clinical study.  This includes biocompatibility, acute and/or chronic animal safety studies, simulated use, mechanical durability, package integrity, and sterility testing, among other things.  Then, the company spends the next two years completing these activities and obtaining approval of an investigational device exemption (IDE), only to learn that the existing marketed device causes intimal hyperplasia and occlusion due to blood vessel kinking.  While this company spent millions of dollars going through design input, design output, and design verification phases, it turns out they had not adequately defined the design inputs in the first phase.  By the way, about the hypothetical assumption of only spending five years to get an IDE for a Class III permanent implant … it’s often far longer than that.

 

Biomechanics as a Design Input

Biomechanical compatibility and durability is often an afterthought to medical device design – in fact it should to be one of the starting points.  As the first article of this series described, a device needs to perform its primary function while surviving and accommodating its environment.  For example, a iliofemoral venous stent not only needs to maintain luminal area in order to promote adequate venous return, it also needs to survive radial pulsatility, resist diametric compression from the pubis bone, and bend with hip flexion without causing trauma at the end of the stent (Figure).  A failure to account for these biomechanical factors during the design input phase could cause serious, and costly, delays during development.

Figure. Lateral images of iliofemoral venous stents with 0, 45, 75, 105, and 135 degrees of hip flexion (top row), and 3D models of stents, L5 vertebral body, and inguinal ligament paths corresponding to 0 (gray), 45 (red), 75 (green), 105 (blue), and 135 (purple) degrees of hip flexion (bottom row). From Cheng et al., J Vasc Surg Venous Lymphat Disord 2020, doi:10.1016/j.jvsv.2020.01.022

 

Leverage Existing Devices and Obligatory Development Activities

Much of determining design inputs with respect to biomechanical accommodation may be gleaned from data of existing devices.  For example, let’s say you are developing the first stent with an inferior vena cava (IVC) indication in the United States (none currently exist).  Even without any approved predicate devices, stents and IVC filters have been implanted into the IVC for decades, and can inform how breathing and Valsalva maneuvers may deform the new device.  The deformation of an existing device can be tracked on medical images, essentially playing the role of a strain gauge, and used to predict deformations of the new device by comparing the mechanical properties between the two.  Furthermore, obligatory development activities to test safety and function, such as animal and cadaver studies, can often be leveraged to investigate biomechanics with some protocol tweaks.

 

Can Be Small Incremental Cost and Effort

Early studies to understand biomechanics do not need to be expensive.  For developing loading conditions, pre-GLP and pre-clinical trial studies cost a fraction of the later, more-structured activities that will form the bulk of the eventual regulatory submission.  For computational simulation and fatigue benchtop testing, shorter, less-structured, and cheaper studies will do the trick early in the development cycle, especially before design freeze.  From the perspective of the entire development path, these scoping activities will only add small incremental costs and effort, and dramatically reduce development risk.

 

Penny Wise and Pound Foolish

Effort and costs increase with each stage of medical device development, with big jumps at design freeze, clinical study, and market rollout.  This means that delays due to unexpected development activities get more costly the later they occur.  A well-designed device evaluation strategy reduces costly errors during verification and validation testing by identifying the right testing to do at the right time.  The strategy ideally takes into consideration relevant device attributes, potential failure modes, clinical effects of failure, and clinical mitigation strategies.  When executed correctly, it will provide valuable insights into device safety and performance, with appropriate levels of testing to support each milestone (e.g., early feasibility study, pivotal study, marketing approval/clearance) beginning early in the product development process and iterating as new information is obtained.  To avoid costly errors, a device evaluation strategy should not be based on the minimum regulatory requirements to support each milestone, but rather on the testing needed to further the understanding of the device and its performance throughout product development.

Device Durability Evaluation for Initiating Clinical Studies

Christopher Cheng, Ph.D., Valerie Merkle, Ph.D.

 

It’s All Fun and Games Until

During the medical device development process, the stakes rise with every stage, transitioning from concept discovery, to design iteration, preclinical testing, clinical testing, and finally, market launch.  These stages often cross and blend together, but there is no denying that a major nail-biting moment is moving into initial clinical evaluation.  This is the first time human lives may be at stake. Sufficient information, including evidence related to device durability, must be generated to support that the device is unlikely to cause undue morbidity or mortality.  This does not mean that all device fatigue risk must be driven out – that is an impossible task.  However, enough fodder must be gathered to justify the leap to subjecting a small number of patients to unknown risks in the effort to help the larger patient population. 

 

Clinical Indication and Clinical Study Phase

The burden of proof related to mechanical durability to initiate a clinical study is highly dependent on the clinical indication.  Is the device part of an acute treatment or something that needs to last a lifetime?  Are the patients elderly with limited mobility and a short life expectancy, or are they children with treatable congenital heart defects who may live 90 years and will someday do an Ironman Triathlon?  Are the patients seeking a last resort after all other options have been exhausted, or are there reasonable treatment alternatives available?  The scope of durability evaluation depends on these factors of dwell time, loading magnitudes, and the safety of other treatment options.  Another major factor in determining the burden of proof is the phase of the clinical study. 

 

Appropriate Evaluation at the Appropriate Stage

Often, the primary goals of a clinical study are to collect safety and effectiveness information of a device, however, critical data on design weaknesses can also be gleaned.  The earlier in the device development process, that is, the more a device has yet to be optimized, the leaner the durability assessment often is.  While fatigue evaluation must still de-risk the device enough to warrant exposure to patients, there is no need to complete market approval-levels of evaluation in early studies because the clinical experience may yield information that leads to substantial design changes.  The amount of investment that should be dedicated to these appropriately supportive, but as yet inexhaustive, fatigue evaluations are also dependent on knowledge of the device category at large.  A device that is an iterative improvement on existing devices may be able to leverage existing durability data while a truly breakthrough device may require more evaluation before clinical exposure.  Regarding investment level, manufacturers must also consider the amount of development risk (i.e. potential time and cost of changing design) and regulatory risk (e.g. need for additional data and regulatory reviews) to take at each stage.

 

Clinical Data is Part of Biomechanical Evaluation

A concept that bears highlighting is that a clinical study can itself generate biomechanical boundary conditions that lay the groundwork for realistic durability evaluation.  This means that device durability evaluation should not be relegated as an inconvenient input prior to clinical studies, but clinical studies may in fact generate critical outputs that aid in durability assessment.  Thus, there are prudent opportunities to leverage costly clinical studies to generate necessary engineering data with low incremental investment.  While device-specific in vivo data may not be necessary for pure force-controlled or displacement-controlled loading conditions, devices that exist in complex environments with mixed loading conditions can benefit from dedicated clinical investigation.  For example, while an isolated, short arterial stent may be fatigued predominantly by radial deformation from blood pressure pulsatility, a bridging stent in complex endovascular aortic repair is subject to bending forces as a result of complex interactions between the bridging stent, main endograft, and diaphragmatic and visceral organ translation due to respiration (Figure). 

Figure. Respiratory-induced deformation of the renovisceral arteries for examples of snorkel- (SN-EVAR) and fenestrated- (F-EVAR) endovascular aortic repair.  Vessels at inspiration (gray) and expiration (yellow) are superimposed with the bridging stents (red).  Respiratory-induced end-stent angle changes are highlighted with blue circles. Adapted from Ullery et al., J Vasc Surg 2015, 61(4), 875-884, Figure 3.

 

Teamwork

Device manufacturers can work hand in hand with their clinical investigators and clinical research organization (CRO) to generate the biomechanical data needed to optimize devices and device evaluation.  Working with the FDA to come up with a plan for the right testing at the right time, and protecting patient safety while collecting informative biomechanical data is critical to reduce both financial and patient risks.  Additionally, it is imperative to communicate with the FDA through a well-written pre-submission and incorporate. This will improve the likelihood that the costly and time-consuming durability evaluations to support regulatory submissions will meet the expectations of the FDA reviewers.  Finally, remember that the ultimate goal of timely and robust fatigue evaluation is to improve patient care. 

Device Durability Evaluation for Market Approval

Christopher Cheng, Ph.D., Valerie Merkle, Ph.D.

 

Prepare to Enter the Wild

The leap from preclinical to clinical evaluation is a critical one, exposing patients to potential morbidity and mortality.  However, the transition from clinical study to market release is equally serious, with a much larger risk profile.  The risks are not limited merely to the increase in the number of patients that may be treated by the device.  Clinical studies typically operate under tight control, whereas commercialization releases a product into relatively unrestricted use.  While instructions for use (IFU) are meticulously written to guide physicians on proper patient selection, treatment, and care, it is not uncommon for the device to be used outside of the IFU as part of the practice of the medicine.  Furthermore, while insights into device durability, including computational, benchtop, and early clinical data, are captured during product evaluation to support regulatory approval, real-time in vivo implantation of greater than 1-3 years is often realized for the first time after market release.

 

Durability Prediction

Since real-time in vivo evaluation of the maximum dwell time of a device in a patient could exceed 10 or even 20 years, it is not reasonable to expect real-time fatigue evaluation prior to market approval.  If this were required, countless patients could be precluded from safe and effective therapies, with this risk greatly outweighing the risk of treatment.  This is precisely why non-clinical fatigue evaluation must be performed in a robust and comprehensive manner.  Since fatigue is known to be a logarithmic phenomenon, that is, the risk of fracture increases less as the number of fatigue cycles increase, devices may not need to be tested out to the maximum theoretical life span of the patient.  Thus, regulatory bodies typically recommend aortic and peripheral vascular devices be evaluated to 10 years of equivalent life, and heart valve devices to 15 equivalent years due to their more critical and dynamic nature (Figure).  The precision of the of non-clinical fatigue evaluation may also be influenced by: a) the amount of information available to characterize the in vivo environment, b) expected patient population, and c) the level of understanding of the device interactions with the cardiovascular system.

Figure. Examples of percutaneous heart valve fatigue evaluation. Left: Fatigue evaluation using in vivo deformation analysis from medical imaging and computational simulation (adapted from https://slideplayer.com/slide/4236293/, Slide 10).  Right: Benchtop durability evaluation of accelerated wear and metallic frame fatigue (adapted from Cribier, Global Cardiology Science & Practice 2016: 32 http://dx.doi.org/10.21542/gcsp.2016.32, Figure 5).

 

Many Paths to the Summit

Each round of regulatory review consumes valuable time before commercialization and revenue generation.  Providing iterative levels of mechanical durability data through a series of regulatory communications may involve a longer review process.  Conversely, providing thorough durability evidence early may reduce the review timeline, but is likely to require more upfront investment in generating robust loading conditions, computational simulations, and benchtop testing.  Investment in durability evaluation must be balanced with the other submission components; however, the cost of durability assessment is usually dwarfed by the costs of appraising clinical safety and effectiveness.  The paths to the end goal are numerous and highly variable because fatigue assessment guidance is limited, and loading conditions, methodology, and acceptance criteria are all up to the sponsor to define and justify.  Sometimes, rationale can be used to reduce the burden for test data, but only when accompanied by clear arguments that demonstrate deep understanding of fatigue mechanisms.  Working with regulatory agencies from the outset, thereby minimizing incorrect assumptions, will decrease the risk of falling short or wasting resources on superfluous analysis.  Importantly, durability evaluation plan must be carefully considered not merely for the purpose of satisfying regulatory agencies, but for truly addressing the clinical situation. 

 

Life After Market Approval

A post-market study may be required by a regulatory body to evaluate longer-term clinical performance, initiated by the manufacturer to study real-world use (e.g. use of a registry) and/or performed by independent investigators.  These clinical studies, if deliberately designed, may potentially provide insight into the performance of the device not gleaned from the shorter-term feasibility and pivotal studies where there was strict adherence to study protocols.  Further, these post-market studies can be important for informing future durability assessments if information is obtained in the clinical study with respect to critical boundary conditions.  Quality durability data can also have marketing benefit by way of presentations and peer-reviewed publications.

 

Regulatory Strategy is Key

Efficiency through the regulatory process can be obtained by a well-defined regulatory strategy.  This begins with defining the end goals for the device early in the product development process, for example, including a broad indications for use statement and/or multiple procedural options for use of the device.  The clinical and engineering data needed to support the desired labeling, including the data to support any potential interim milestones, should be outlined in the regulatory plan.  For example, presenting a prospectively-defined and well-justified plan to the FDA through pre-submission interactions provides a manufacturer opportunities to collaborate with the Agency on an appropriate path forward.  It is important to remember that the ultimate goal of an efficient regulatory strategy is to provide patients with timely access to safe and effective medical devices.

The Promise of Biomechanical Compatibility

Christopher Cheng, Ph.D., Valerie Merkle, Ph.D.

 

Fracture Does Not Equal Failure

There is a tendency for negative visceral reaction when the topic of device fracture arises.  Indeed, device fracture is usually an indication of fatigue failure; however, it has been shown that fracture does not always lead to clinical sequelae.  In fact, some devices are designed to preferentially fracture as part of their normal operation, and others that do not fracture may actually indicate excessive stiffness and be the cause of clinical consequences (Figure).  Therefore, fracture, defined as breaking a continuous structure into discontinuous portions, is not necessarily a sign of impending adverse clinical outcomes or even a design flaw.  Sometimes, the problem can be fixed just by understanding the underlying vascular biomechanics and altering intervention strategies.  For example, in the case of femoropopliteal artery stents, the incidence of device fracture was dramatically reduced by avoiding placing stiffer stents in regions susceptible to extreme kinking at the adductor hiatus near the knee.  Even well-designed devices can fracture and may contribute to subsequent clinical sequelae.  However, the overall benefits to patients may still far outweigh the risks of fracture.

Figure. Left: The Stentys coronary bifurcation stent was designed to fracture at certain bridges in order to open up into a branch ostium (adapted from Laborde et al., Eurointervention 2007, 3(1):162-165 and Mishra, Indian Heart J, 68(6):841-850).  Right: Some peripheral stents exhibit high axial and bending stiffness which can cause arterial kinking distal to the stent in the femoropopliteal artery due to knee flexion, which can lead to thrombosis or restenosis (adapted from Gokgol et al., Biomech Model Mechanobiol 2019, 18(6):1883-1893).

 

Understanding Will Lead to Better Products

The impact of biomechanical compatibility is usually only revealed over the long term, requiring clinical studies and a deep understanding of how biomechanics affect biology and clinical outcomes.  However, there is no debate that increased understanding of these interactions will lead to more precise product development, which should yield better devices with less ambiguity during the development cycle.  One of the mechanisms for this is more precise and comprehensive standards and guidance for biomechanical evaluation.  For example, while there is guidance about radial pulsatile testing in arteries, there is a dearth of consensus about axial, bending, crush, and twisting deformations for structural heart, coronary, aortic, peripheral artery, venous, and neurovascular devices. 

 

Biomechanical Compatibility Is in Its Infancy

Evaluation of fatigue (how the dynamic anatomy affects the device) is often treated like an inconvenient but necessary portion of device development, and biomechanical harmony (how the device affects the dynamic anatomy) is rarely considered.  There is good reason for this lack of attention: biomechanics is not enticing.  Would an engineer rather be acknowledged for inventing and designing a novel device, or merely for confirming that that device will survive for 10 years in vivo?  Probably the former.  Would a company rather invest in producing more products that can generate more revenue, or spend time and money optimizing biomechanical compatibility?  Definitely the former.  However, it is now recognized that biomechanical compatibility is critical to device design, evaluation, and ultimately patient safety.  As an industry, we are just beginning to pay attention to biomechanical compatibility and learn how it impacts device performance and clinical outcomes.

 

A Call to Action

As some device categories become more mature, we should be working together as an industry to develop more defined guidance around biomechanical compatibility, including loading conditions, computational modeling, and physical testing.  For newer device categories, especially for those addressing lower-risk patients who may be healthier, more active, and younger, we must challenge the conventions of using “normal” loading conditions for 10 years of life.  For example, replacement heart valves are already tested for 15 years, and as iliofemoral vein stents and structural heart devices get used on healthier, younger patients, perhaps 20-30 years of cycling in more compliant vessels is more appropriate.  This can be accomplished either at each respective manufacturer or external to the manufacturer, potentially through non-profit organizations such as Cardiovascular Implant Durability (cvidconference.org).  Furthermore, understanding the dynamic behavior of blood vessels goes far beyond medical devices.  Measurement of vascular motion can be a critical diagnostic tool.  Vessel elasticity and motion, for example, have been shown to correlate with cardiovascular health, and may play roles in diagnostics, treatment planning, and development of pharmaceutical or genetic therapies.

 

Partnering with Regulatory Bodies

To further the field and include regulatory considerations, it is helpful to include the FDA and other regulatory bodies in industry-wide efforts.  For example, when communication between regulators and companies is collaborative, device fractures identified during a pivotal study may not preclude commercial approval.  Consideration is given to the severity, location, frequency, timing, and clinical relevance of fractures, as well as the overall benefit-risk profile of the device for its labelled indication.  Manufacturers should work collaboratively with regulators when fractures are first observed in order to ensure study subjects are adequately protected through root cause analyses.  Manufacturers and regulators have the same ultimate goal: to provide patients with timely access to safe and effective medical devices.