Home > Advancing MedTech Histopathology: Expanding Capabilities at SeqMatic

Advancing MedTech Histopathology: Expanding Capabilities at SeqMatic

Figure 1: Implantable medical devices are used across a wide range of disorders. This includes deep brain stimulators to treat Parkison’s, Cochlear implants to treat hearing loss, gastric stimulators to treat gastroparesis, pacemakers to treat heart failure, insulin pumps to treat Diabetes, and foot drop implants to treat gait impairments5
Figure 1: Implantable medical devices are used across a wide range of disorders. This includes deep brain stimulators to treat Parkison’s, Cochlear implants to treat hearing loss, gastric stimulators to treat gastroparesis, pacemakers to treat heart failure, insulin pumps to treat Diabetes, and foot drop implants to treat gait impairments5

In the rapidly evolving field of medical technology, the histopathological evaluation of implanted medical devices stands as a crucial pillar of preclinical research, serving as a gateway to ensuring the safety and efficacy of such innovations before they advance to clinical trials. At SeqMatic, we specialize in facilitating the intricate journey of medical device development, from conceptualization to clinical application, through our expert histopathological assessments and advanced imaging techniques. This meticulous process sheds light on the body’s response to foreign objects, offering a glimpse into the potential for both the long-term success and the possible failure of the implant. Groundbreaking devices, such as the continuous glucose monitors from Dexcom1 and Eversense2, have revolutionized diabetes management by offering continuous measurement of glucose levels and informing insulin pumps of the necessary dosages. Similarly, cochlear implants by Cochlear3 have transformed lives by converting sounds into electrical signals, enabling those with hearing impairments to perceive sound (see Figure 1). These advancements, including the pioneering brain-computer interface by Medtronic4, exemplify the transformative potential of medical devices, highlighting the indispensable role of histopathological evaluation in their development.

Figure 1 above: Implantable medical devices are used across a wide range of disorders. This includes deep brain stimulators to treat Parkison’s, Cochlear implants to treat hearing loss, gastric stimulators to treat gastroparesis, pacemakers to treat heart failure, insulin pumps to treat Diabetes, and foot drop implants to treat gait impairments5.

Leading Use Cases For MedTech Histopathology

As these innovations journey from conception towards FDA approval, the intricate dance between innovation, safety, and the promise of enhancing human health becomes evident. Histopathological evaluations illuminate the complex interactions between medical devices and the human body, focusing on crucial aspects such as implant location, device function, potential failures, and the biological response to the device. This rigorous analysis ensures the device’s placement within targeted tissues, checks for any unwanted migration, and measures how well the device operates within the biological milieu. Furthermore, it reveals issues such as impedance rise due to fibrotic encapsulation, mechanical damage, or material degradation due to oxidative stress. Such detailed examinations provide invaluable feedback, guiding researchers and developers in refining device designs to enhance safety, functionality, and patient outcomes. One common medical implant that requires all four leading use cases for conducting histopathology are brain computer interfacing implants (Figure 2).

Figure 2: Brain computer interfacing implants, such as the Utah Array, can typically require histopathological assessment of all leading use cases. This includes assessing the brain region that the device was implanted into (A)6, assessing whether neurons were activated post-stimulation of the device using a c-Fos immunohistochemical stain (B)6, assessing electrode impedance may be due accumulation of fibrosis (C)7, and most importantly assessing what biological response is toward this foreign body material (D)8.

Device Classification of ISO 10993-1

Moreover, assessing the safety risk associated with medical devices is fundamental to their development and approval process. The International Organization for Standardization (ISO) 10993-19 categorizes devices into different classes based on potential risk, from Class I devices like Band-Aids and toothbrushes to Class III devices such as knee implants, stents, and neural probes (see Figure 3). This classification system underscores the importance of conducting rigorous testing and evaluation, including histopathological assessments, to ensure devices are safe for their intended use. It directs the path toward safe and effective medical device innovation, ensuring that they meet the highest standards of patient safety before market release.

Figure 3: Prior to a medical device being placed on the market, the device needs to be assessed for its classification10, 11. This includes Class 1 devices which are of low risk, such as a bandaid, and may even be exempt from receiving a 510 (k) clearance. Class II devices, which are moderately risky, such as a continuous subcutaneous infusion set and will typically require a 510 (k) approval from the FDA. Class III devices, which are highly risky, such as a cardiac stent, and will more than likely require premarket approval. Lastly, for novel devices, such as a non-invasive low intensity focal ultrasound used for modulating activity in the brain that may fall under an alternative pathway for the FDA to try and structure receiving approval.

Use-Case of Histopathology Within ISO Guidelines

Throughout the research and development (R&D) phase, histopathology readouts serve as a pivotal tool in screening materials to discern those that are compatible with tissue from those that are not, effectively bridging the gap between early experimentation and clinical readiness. From tissue damage and regeneration to the foreign body response, including inflammation, each reaction must be meticulously evaluated. As these medical devices transition from the bench to bedside, adherence to ISO guidelines becomes paramount, ensuring a standardized approach to evaluating potential risks and ensuring biocompatibility. These guidelines, such as ISO 10993-3 for carcinogenic and developmental toxicity, ISO 10993-6 for local effects, ISO 10993-10 for skin irritation and sensitization, and ISO 10993-11 for systemic effects, provide a comprehensive framework for assessing the safety of medical devices (Figure 4). This meticulous evaluation process is particularly crucial for materials that may extract or leach out of implantable devices, posing potential risks to patients.

Figure 4: Table A.1 of the ISO 10993-1 document presents a comprehensive table designed to guide manufacturers in selecting the appropriate biological evaluation tests for their medical devices9. This table is crucial for determining the necessary assessments based on the nature and duration of contact between the medical device and the body. It categorizes devices according to the type of body contact (e.g., skin, blood, or tissue) and the duration of exposure (limited, prolonged, or permanent), recommending specific tests for cytotoxicity, sensitization, irritation, or systemic toxicity, among others. This structured approach helps ensure that all potential biological risks are thoroughly evaluated, facilitating the development of safer medical devices by providing a clear roadmap for compliance with regulatory standards and protecting patient health.


The imperative for evaluations to be conducted under Good Laboratory Practices (GLP)12, as part of a broader suite of Good Practice (GxP) quality guidelines which include Good Clinical Practice (GCP)13 and Good Manufacturing Practice (GMP)14, and in alignment with Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathologists (CAP) standards, is fundamental to ensuring the reliability and integrity of safety data within the medical device industry. GxP compliance, along with adherence to CLIA15 and CAP16 standards, ensures that evaluations are executed systematically, following standardized, auditable, and reproducible procedures. This multi-layered approach offers a comprehensive foundation for safety assessment, integrating the rigors of laboratory testing with clinical and manufacturing quality assurance.

Integral to this rigorous process is the meticulous documentation of histopathology training records, affirming that personnel are not only proficient in their tasks but also compliant with the wide spectrum of GxP, CLIA, and CAP requirements. This is further supported by the adherence to part 1117 compliance for electronic data, which safeguards data integrity and ensures the accessibility of data over time. All study data generated should adhere to an ALCOA-plus method18 (Attributable, Legible, Contemporaneous, Original, Accurate, and the plus factors: Complete, Consistent, Enduring, and Available) to data integrity, embodying the principles of thoroughness and accountability in data management and documentation (see Figure 5).

Figure 5: The ALCOA principles, a cornerstone of data integrity in the scientific and regulatory fields, highlight the essential criteria for ensuring that data are Attributable, Legible, Contemporaneous, Original, and Accurate.

Additionally, the development and conscientious maintenance of histopathology Standard Operating Procedures (SOPs) are paramount, necessitating regular reviews and updates to mirror the evolving landscape of best practices, technological advancements, and regulatory standards. This dynamic approach to SOP management, underpinned by GxP, CLIA, and CAP principles, ensures that the procedures governing histopathological evaluations are not only scientifically robust but also aligned with the highest quality and safety standards. By embracing these comprehensive guidelines, the medical device industry upholds its commitment to patient safety, regulatory compliance, and the continual advancement of medical technology, setting a gold standard for the development and evaluation of medical devices.

Equally important is the stringent management of samples and reagents, which must be properly stored with detailed labeling that includes the sample type, species, date of storage, the reagent used, expiration date, and the initials of the handler19. This comprehensive approach ensures traceability, accountability, and the maintenance of sample integrity over time (see Figure 6). By integrating these rigorous practices during the R&D phase and extending them through clinical trials, the medical device industry demonstrates a profound commitment to patient safety, regulatory compliance, and the advancement of medical technology. The seamless transition from histopathological evaluations in the laboratory to the adherence to ISO guidelines and GxP standards underscores a disciplined and thorough approach necessary for bringing safe, effective, and innovative medical devices to market, thereby enhancing patient care and propelling the field of medical technology forward.

Figure 6: A GxP compliant reagent label typically includes critical information such as the reagent name, concentration, preparation date, expiration date, and storage conditions, ensuring traceability and quality control in regulated environments.

Finding the Right Preclinical Model

The methodology involved in processing implant sites is meticulously designed to achieve a detailed cross-section of the material-tissue interface, particularly when conducting local assessments. This step is critical in preclinical evaluations, where identifying the appropriate biological model plays a pivotal role in simulating the interaction between the medical device and biological tissues. The spectrum of preclinical assessment spans from in vitro methods, which include 2D cell cultures, organoids, cell pellets, and cytotoxicity testing, to ex vivo techniques 20, 21, which provides a closer approximation of in vivo conditions without the ethical and logistical complexities of live animal models (Figure 7).

Figure 7: Skin explant procedures involve the cultivation of human skin tissue samples ex vivo to maintain their physiological properties and functionality for experimental use. Companies like QIMA Life Sciences and GenoSkin specialize in creating these explant models, which replicate the complex environment of human skin, allowing for the detailed assessment of biological responses to foreign implanted materials. Through these models, researchers can evaluate the skin's reaction to implants, including inflammation, healing processes, and potential adverse effects, providing invaluable insights for the development of safer and more compatible medical devices.

In vivo studies, utilizing a range of animal models such as rodents, swine, ovine, and non-human primates (NHP), offer invaluable insights into how a device functions within a living organism. These models are critical for evaluating the biocompatibility and safety of medical devices, employing a variety of control comparisons to ensure rigor and reliability in the findings. This includes comparisons between the implant and various controls: dummy (an inert device), sham (surgery performed but no device implanted), no device, and explant controls, each serving a specific purpose in elucidating the device’s effects.

Figure 8: Sheep can serve as valuable models to assess the functionality of low-intensity focal ultrasound targeting the motor cortical and thalamic areas of the brain by allowing for in vivo evaluation of neuromodulation effects and therapeutic potential in a complex biological system22.

Timing the harvesting of tissue post-implantation or explantation is another vital consideration, with tissue samples collected at acute, sub-acute, sub-chronic, and chronic time points to assess the progression and resolution of biological responses over time. Such comprehensive and systematic evaluation methods are essential for understanding the complex dynamics at the material-tissue interface, ultimately guiding the development of safer and more effective medical devices.

Finding the Right Histopathology Pipeline

The histopathology pipeline, a critical component of the preclinical evaluation of medical devices, encompasses a series of meticulous steps designed to analyze the biological response to implanted materials. This process begins with necropsy, targeting both tissues intended for clinical implantation (target tissue) and those not directly impacted by the device (non-target tissue). Non-target tissues, including regional lymph nodes, the five major organs, and all organs specified in annex E of ISO 10993-11, are collected to meet regulatory requirements and to observe any potential systemic effects or abnormalities. Preparation for a perfusion may also be considered at this stage if deemed necessary.

The next step, grossing, involves the trimming or “breadloafing” of the collected tissues, which may also undergo decalcification if the implant is in contact with bone, utilizing one of several agents such as formic acid, hydrochloric acid, or EDTA. This step ensures that the tissues are properly prepared for subsequent processing and analysis.

histopathological staining and microscopic imaging of the implant site then follow, employing one of three main embedding methods: paraffin, which involves alcohol dehydration and xylene clearing before sectioning with a microtome; frozen, utilizing cryoprotectants and OCT (optimal cutting temperature compound) for sectioning in a cryostat; and plastic embedding, where resin is used and sections are cut with an ultramicrotome for ultrastructural analysis. Each method is selected based on the specific requirements of the study and the nature of the tissues and devices being examined.

The final step involves staining the prepared sections for visualization under a microscope. Hematoxylin and eosin (H&E) staining is commonly used for general tissue morphology, while special stains and immunohistochemistry (IHC) provide detailed insights into specific tissue components and cellular responses. Examples of special stains include Trichrome for connective tissue and Luxol Fast Blue for myelin, and IHC stains such as GFAP for astrocytes and Iba-1 for microglia, offering a deeper understanding of the tissue’s response to the implanted device (see Figure 9). Through this comprehensive histopathology pipeline, researchers can obtain a detailed view of the device-tissue interaction, guiding the development of safer and more effective medical technologies.

Figure 9: This figure presents an immunofluorescent image of a brain sample implanted with different neural electrodes, stained for markers Iba-1 and GFAP, to analyze the immune response elicited by each electrode type. By comparing the intensity and distribution of Iba-1, a microglia/macrophage marker, and GFAP, an astrocyte marker, the figure highlights variations in glial activation and neuroinflammatory responses associated with each electrode. The analysis aims to determine which electrode design is less reactive to the immune system, providing insights into developing neural interfaces with minimized gliosis and enhanced biocompatibility23.

Finding the Right Data to Generate

The data generated from the histopathology pipeline provides a comprehensive assessment of the medical device’s impact on the tissue, encompassing a wide array of imaging and analysis techniques. Gross images serve as the initial step, helping to identify the stereo offset of the device in contact with the tissue, any mechanical damages or degradation of the material, and the gross severity of the implant site. These images are crucial for recording abnormalities that could be systematically related to the extractables and leachables from the device, offering an early indication of potential issues.

Advancements in digital imaging allow for the creation of whole slide images, captured using a digital microscope slide scanner. These images can be analyzed through various modalities, including brightfield, fluorescent, and polarized light, providing detailed insights into the tissue-device interface. Complementary imaging read-outs further enhance the evaluation, incorporating techniques such as radiographic imaging (MRI, uMRI, CT, uCT, PET), electron microscopy, high-frequency ultrasound, elemental analysis (MaltiToF), and spatial transcriptomics (10x Visium), each offering unique perspectives on the device’s impact.

Image analysis (IA) quantitatively assesses the presence of the implanted material and the extent of pathology, including necrosis, tissue-specific cell loss, chronic inflammation, and fibrosis. This quantification allows for an objective assessment of the device’s safety and effectiveness.

The culmination of this process is the pathology report, a critical, unbiased document that assesses the device’s safety preclinically. It synthesizes surgical pathological reports, clinical observations, necropsy findings, and microscopic slide data to summarize any severe pathology that may have arisen due to contact with the device. Tissues are typically stained hematoxylin and eosin (H&E) and scored semi-quantitatively on a severity scale ranging from 0 to 4, providing a clear, standardized measure of the device’s biological impact. This comprehensive approach ensures a thorough evaluation of the medical device’s safety, guiding future development and regulatory approval processes.

Figure 10: This figure illustrates the foreign body response to steel and Teflon cannulas used in continuous subcutaneous insulin infusions, visualized over various time points using H&E staining. It highlights the differences in tissue reaction, such as inflammation and fibrosis, around the area that the cannulas were implanted, providing insight into the biocompatibility and long-term viability of these materials for insulin delivery24.
Figure 11: Representative photomicrographs of BMS (a, e)25.

Advancing MedTech Histopathology: Expanding Capabilities at SeqMatic

At SeqMatic, we specialize in facilitating the intricate journey of medical device development, from conceptualization to clinical application, through our expert histopathological assessments and advanced imaging techniques. Our methodologies delve deep into the device-tissue interaction, providing essential insights into the safety and efficacy of medical technologies. Adhering to rigorous standards, including GxP compliance and ISO guidelines, we ensure that each product undergoes a comprehensive evaluation, safeguarding patient health while propelling the medical technology field forward. Our services cover the entire spectrum of evaluation, from gross imaging to detailed pathology reports, demonstrating our commitment to innovation, safety, and improving patient care. Partnering with SeqMatic not only advances the refinement of evaluation techniques but also promises enhanced therapeutic outcomes and the ongoing evolution of healthcare.

DISCLAIMER: Images featured in this whitepaper article include assets that have been adapted for the post. Original images are credited to their corresponding cited references. Refer to citation links for publication and author’s scientific context.


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