Pediatric Medical Devices: History
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Subjects: Health Care Sciences & Services
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Nunzio Denora

Children represent the future, and ensuring their physical, socio-emotional, language, and cognitive development is integral to health technology development. The development of a child from term or preterm neonate to a fully mature individual relies on complex physiological, anatomical, developmental, and social changes. Understanding the inter- and intra-population differences within the pediatric subpopulations is necessary to address the existing challenges and break down some of the long-recognized barriers. There is thus a clear need for research infrastructure and networks with the depth of expertise to support pediatric device development through collaboration across the life sciences sector. 

  • medical devices
  • pediatrics

1. The Complexities in the Development of Medical Devices for Children

Children undergo dynamic changes in anatomy, physiology, and development from the neonatal period through childhood into adolescence. For example, heart rate and respiratory rate reduce, and blood pressure increases as children grow (Table 1), meaning that digital platforms or wearables monitoring these parameters and others need to be capable of addressing these dynamic changes and respond appropriately to pathophysiological changes [1].
Table 1. Ranges of blood pressure, pulse, and respiratory rate in relation to age of child [2].
Age Approximate Weight (kg) Systolic Blood Pressure (mmHg) Heart Rate (Beats per Minute) Respiratory Rate (Breath per Minute)
Term 3.5 60–105 110–170 25–60
3 months 6 65–115 105–165 25–55
6 months 8 65–115 105–165 25–55
1 year 10 70–120 85–150 20–40
2 years 13 70–120 85–150 20–40
4 years 15 70–120 85–150 20–40
6 years 20 80–130 70–135 16–34
8 years 25 80–130 70–135 16–34
10 years 30 80–130 70–135 16–34
12 years 40 95–140 60–120 14–26
14 years 50 95–140 60–120 14–26
17 years + 70 95–140 60–120 14–26
Clinical evaluation of these devices may require stratification by age, posing challenges in assessing large, stratified populations of children to appropriately power studies. Changes in anatomy will mean that versatility in device development should play an integral part in addressing the needs of the pediatric population. In this respect, technology approaches such as 3D body or facial scanning and 3D printing have led to the development of medical devices that can be adapted as anatomical changes occur with growth [3][4][5]. As children mature, there is a shift from parental dependence to independence during adolescent years, by which children move from being dependent on parental nurturing and support, to becoming young people gaining autonomy and with the ability and cognition to engage directly with medical devices without the need for parental direction. CYP with long-term conditions are surviving longer and often well into adulthood with the need to gain independent control of their condition and health, yet in Europe, less than 25% of countries allow adolescents access to health services on the basis of maturity without parental consent. Depression and anxiety disorders are among the top five causes of the disease burden, and suicide is one of the leading causes of death among adolescents, indicating that young people need access to alternative technologies to support their mental as well as physical health and wellbeing [6][7]. Thus, medical device developers need to overcome the challenge of developing devices that may initially be used by parents with their children, but in-turn meet the independent needs of adolescents with the same medical condition.
In general, there has been a significant shift in attitude to the delivery of healthcare, with a move away from a hospital-centric approach towards community or home settings with the support and integration of medical devices and a greater emphasis on self-management. This will inevitably improve the quality of life for children with long-term conditions, leaving them with more time for education and social integration, whilst reducing the number of workdays missed by parents. Improving health of CYP and the delivery of their healthcare leads to an improvement in educational attainment. In contrast, where poor school attendance and poor achievement are present, the risk of ill-health is 4.5 times higher in adulthood with 31% of school pupils aged 11–15 years reporting that their long-term condition or disability negatively impacted on their ability to participate in education [8][9]. Thus, the situational context of healthcare delivery for children, young people, and their families must be factored into the development of novel MDs to minimize disruption to their lives and limit the number of hospital attendances.

2. Addressing the Market Need for Pediatric Medical Devices

The need for new and innovative approaches for the development of medical devices to support CYP with acute and long-term health conditions is matched by a compelling argument to support novel technologies for prevention in childhood to ensure that our population of CYP remains healthy well into adult life. Major adult health conditions such as heart disease, stroke, hypertension, obesity, and chronic liver disease have their origins in childhood [10][11][12], yet health expenditure is typically focused on the treatment rather than prevention of these problems. This needs to be matched with funding calls focusing specifically on the development of medical devices for children to ensure targeted medical device development. To boost pediatric medical device development, pediatric child health technology networks, established to support multi-professional stakeholder collaborations involving children and their families [13][14], will accelerate the development and spread of new medical devices for pediatrics, providing a scalable offering to the commercial sector [13]. Aligned with this is the need to dispel outdated opinions that the pediatric devices market is small compared to the adult healthcare market. The global pediatric healthcare market was valued at approximately USD 11,881 million in 2018 and is expected to generate around USD 15,984 million by 2025 [15]. Europe was second to the United States in the global pediatric healthcare market in 2018, due to the increasing demand for treatments in long-term conditions and increasing healthcare infrastructure [15]. The United Kingdom is estimated to be growing rapidly over the same forecast timeframe. Germany dominated the European market with a major revenue share in 2018, due to the increasing adoption of advanced medical treatments [15]. Given the rapidly expanding pediatric healthcare market, as well as the advances in digital healthcare and data-analytics, this provides an opportunity to collect large volumes of meaningful national and international data to provide clarity about childhood growth, development, and disease in environments that will exceed traditional healthcare boundaries as the opportunities for self-management and technology-driven home-based therapies increases.
As the medical device market for pediatrics grows, industry, academics, and clinicians will be faced with the formidable challenge of how to impact upon the hard to reach and vulnerable populations. Addressing social determinants of child health and child health inequalities in large populations will be blighted by socioeconomic factors that limit technology reach. The application of novel technologies to implement change where needed most will require collaborative working between health, the life sciences industry, social care, education, and policymakers. Different processes, terminology, and cultures alongside sometimes contradictory goals and timescales can each make these collaborations a challenging venture [16][17]. Despite this, collaborative research within a triad of industrial–academic–clinical collaboration enables a fusion of diverse perspectives and expertise, often unlocking the ability to solve complex social-economic or technical problems. Driven by the emergence of combination technologies to support the development of medical devices, expertise drawn from across a range of disciplines is required [18], with universities and industry partners unlocking a range of expertise across multiple disciplines and clinicians bringing expertise relating to real-world context and integration, but importantly providing access to end-users, as either consumers or providers of healthcare.

3. Addressing the Regulatory Needs for Pediatric MDs

Since the early 1990s, the European Community has harmonized national regulatory frameworks to provide regulatory guidance for the classification of MD that are placed on the markets of the European Economic Area (EEA). Currently, MD designed for children must fulfil the same regulatory framework as MD for adults to enter the commercial market. Different directives and regulations have been issued to regulate MD [19], active implantable MD [20], and in vitro diagnostic MD [21]. In 2017, following the convergence of national regulatory frameworks on MD, the Regulation (EU) 2017/745 was published [22]. The regulation states specific provisions need to be in place to protect vulnerable patients, including CYP, which is fulfilled by the need to conduct clinical trials in these populations. Any clinical trial involving CYP must be able to initially demonstrate a potential benefit from their participation and must include their informed consent according to their age and maturity. However, unlike the FDA that has released guidance specifically for the development of pediatric MD assessment [23], no specific European guidance exists to manage research on MD in children or other vulnerable populations. Guidelines on clinical investigation and clinical evaluation (MEDDEV (MEDical DEVices) guideline 2.7/1 rev. 4, MDCG (Medical Device Coordination Group) guidelines from 2020-5 to 2020-13) [24][25] merely emphasize the need for establishing protocols able to assess the clinical evidence on the device efficacy and safety on the basis of the peculiarities of target population groups (e.g., pediatric populations). Similarly, few ISO standards are available for the development of MD in children [26]. In this context, it is noteworthy that article 106 of Regulation (EU) 2017/745 allows the European Commission, in consultation with the MDCG, to address these existing gaps by designating expert panels and laboratories on the basis of their up-to-date clinical, scientific, or technical expertise in the field to contribute to the development of appropriate guidance and common specifications on specific topics (e.g., clinical investigations, performance studies, biocompatibility) for specific devices in specific populations.

4. 3D Printing for Pediatric MD

3D printing (3DP) is a process of making three-dimensional solid objects from a digital file, by which a wide range of materials can be laid down in successive layers to form a three-dimensional object, a process referred to as additive manufacturing. Thus, 3DP provides opportunities to produce custom-made and bespoke medical products and equipment. The application of 3DP in pediatric healthcare has already been applied in specialties such as surgery, dentistry, drug delivery, orthotics and prosthetics, organs and tissues, ventilation masks, and interactive interfaces for robots and manipulators. One of the major advantages of 3DP in pediatrics is the ability to provide a bespoke product that aligns with the need for versatile manufacturing in relation to increasing body size and anatomical changes with growth. An example of this is the recent development of 3D custom-made masks for non-invasive ventilation that can accommodate the anatomical facial changes associated with growth (Figure 1) [3]. 3DP can be inexpensive, less time-consuming, and more controllable than traditional manufacturing techniques for custom-made devices—costs for molds and waste produced in machining by chip removal are reduced; milling, forging, and finishing phases are not necessary; less manual handwork is needed; and human error is reduced [27][28].
Pharmaceutics 13 02178 g001 550
Figure 1. Facial mapping to develop a 3 dimensional model of a framework for a mask that will fit directly onto child’s face for non-invasive ventilation (left). 3D printed bespoke non-invasive ventilation mask (right) [3]. Pictures courtesy of Professor Heather Elphick, Sheffield Children’s NHS Foundation Trust UK.
One of the earliest uses of 3DP was in the production of patient-specific anatomical models, reconstructed from the medical images derived from computerized tomography (CT scans) and magnetic resonance (MRI) for surgical planning. The same models were also be used for explaining the surgery to the patients and their families in a more effective way and for education and training [29]. Subsequent applications of 3DP in pediatric surgery include the development of customized bespoke products for implantation in growing children [30]. Orthotics and prosthetics manufacturing is one of the most active areas of 3DP technologies in CYP. Prototypes and final external devices have been developed using 3DP for interface parts (e.g., prosthetic sockets), for the whole product (e.g., ankle–foot orthoses, wrist splints, or spinal braces) [27][31] and for covering metal implantable prostheses (e.g., hip and knee prostheses or skull plates) [29]. The use of 3DP to customize prosthetic and implants provides value for both patients and healthcare professionals, as prosthetics can be produced quickly and cheaply compared to traditional manufacturing methods [32] and reduced polymer cost provides developing countries with greater access to advanced treatments [33]. Other applications of 3DP in the healthcare of CYP include dentistry, drug development, and drug delivery, creating opportunities for improving the safety, efficacy, delivery, and accessibility of medicines, as well as the creation of assistive devices for those with restricted movement [5][34][35][36].

5. New Materials for Pediatric Medical Devices

Novel approaches have been recently adopted to develop materials specifically for pediatric healthcare. Underpinning the development of new materials for CYP is the need to ensure that materials meet biocompatibility standards. Biocompatibility is defined as the ability of a material to perform with an appropriate host response in a specific application [37]. Biocompatibility assessment has to be done under conditions similar to the clinical setting, and usually includes in-vitro and in-vivo tests for cytotoxicity, sensitization, intracutaneous reactivity, systemic toxicity (acute), sub-chronic toxicity (sub-acute), genotoxicity, implantation (to mitigate the risk of local intolerance), and hemocompatibility [38]. For nanoparticulate components, it is critical to test interactions with biological substances at the nanoscale, where contact areas are highly expanded. Even if a particular material is known to be highly biocompatible at the macroscale, if used in a nanostructure, it should be re-tested [39]. The components of medical devices can be natural, nature-based semi-synthetic, or completely synthetic substances. After placement, MDs potentially come into contact with biological media, cells, and tissues, and may interact with them in different ways. It is of particular importance that this contact does not result in adverse reactions or toxicity. Before any MD is approved, its biological compatibility should be appropriately assessed, depending on its intended use including any potential for foreseeable misuse. The issue of “misuse” is particularly important in CYP, where age-related risks will change during growth and development. For example, a recent study reported that 33% of total pediatric MD adverse events involved ophthalmic devices, and more than 20% involved contact lenses. Greater than 40% of cases were due to non-compliant behaviors, such as wearing soft contact lenses while in shower or sleeping [40].
Although many differences apply between MDs for adult and pediatric use, no special requirements are mentioned in the European MDR (Medical Device Regulations) [22] or in relevant ISO standards, regarding safety/biocompatibility assessment of pediatric MD. Special mention of children or minors only relates to the presence of CMR (carcinogenic, mutagenic, or toxic to reproduction) and/or endocrine-disrupting substances in MD relating to specific treatments or device labelling [22]. Similarly, the FDA makes no distinction in assessing biocompatibility safety and effectiveness of MD in pediatric populations and uses the same regulatory bases and processes used to assess adult devices, but does consider MD risk assessment in relation to the age and physiological maturity of patients, the nature of the pathology, the planned duration of MD use, and exposure and the impact of the MD on growth and development [23]. In the future, regulations relating to the development of new materials in CYP need to consider their longer duration of use, the risks in the context of physiological and psychosocial maturity, and the potential differences in biocompatibility in the in-vivo environment that changes and evolves with growth and development. Many devices need to be replaced or updated as pediatric patients grow, requiring additional or different procedures to test their biocompatibility and safety, with regards to their intended duration of use, their components, and dimensions.
An example of these potential challenges is in patients with cardiac anomalies that may require use of a wide range of cardiovascular devices including synthetic heart valves, which are implanted during infancy or early childhood. As the cardiovascular anatomy is substantially modified from early infancy to adolescence, the diameters of cardiac valves increase by three times, requiring a change in valve to meet the needs of the developing patient [41]. Another application to using novel materials in CYP is microneedle (MN) technology, which provides a new opportunity for drug delivery across the skin through considerable advances in the key materials from which medical devices are manufactured, including ceramics, glasses, polymers, metals, sugars, and proteins [42]. Patch devices containing many needles less than 1 mm in length can be applied to the skin without causing bleeding or pain. Hydrogel-forming and dissolving patches can be used for drug delivery and vaccination, having potential for easy administration by children or caregivers [43].

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics13122178

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