Developing clinically successful biomedical devices by understanding the pathophysiology of the target tissue: insights from over 25 years at the microscope

Volumetric conductive-convective heat sources, microwave and radiofrequency energy sources, high intensity focused ultrasound (HIFU), laser irradiation and other non-ionizing irradiation sources can be used to generate hyperthermic tissue injury in a variety of clinical settings with therapeutic temperature gradients ranging from 40 to over 90°C. On the opposite side, cryotherapy can be used to freeze tissues with negative therapeutic temperature gradients. The development of a successful thermal therapy using any one of these devices requires a precise understanding of the desired clinical end point in terms of 1) diagnosis vs. therapy, 2) cure vs. palliative intent, 3) dysfunctional vs. malignant tissue and 4) long-term monitoring issues. The effects of a specific thermal exposure depend on the architecture of the heat source and overall thermal history. During initial treatment before heat generation or cooling becomes dominant, tissue interactions with the delivered treatment may affect the geometry of the treatment effect and body's healing response. These two parameters are also affected by tissue anatomy, blood supply and protein vs. lipid content. The thermal lesion and final clinical outcome represent the sum of direct primary and secondary short and long term delayed injury. The latter occurs primarily from host responses producing ischemia, inflammation and wound healing followed by possible regeneration and/or scar formation. Once the thermal insult has been deployed, the resulting lesions can be broadly divided into two major zones: 1) a complete tissue ablation with lethal tissue injury closer to the device and 2) a peripheral transition zone of partial injury. Hyperthermic complete ablation zones can have two sub-regions: 1) thermal fixation from direct denaturation of cellular and tissue components and 2) coagulative necrosis due to direct injury and delayed secondary host responses. With a variety of special techniques, direct cellular injury can be studied at post-therapy intervals of less than 12 hours. At 1-5 days, the acute effects of direct and secondary injury can be assessed with hematoxylin and eosin staining and other techniques. While early healing changes can be studied around 7-10 days, chronic changes are best assessed at variable intervals between 1-9 months. A thorough understanding of the interval dynamics of direct and delayed tissue responses after treatment is critical when choosing appropriate post-treatment times to assess the results. Since many preclinical studies represent "snap shots" in time, care needs to be taken when using acute experimental results to develop mathematical models to predict chronic clinical outcomes. Recent collaborative studies indicate that many pathologic effects can act as direct markers of clinical efficacy when combined with various imaging modalities. In addition, both animal and human studies are performed to establish safety and efficacy; therefore, understanding species differences and the appropriate selection of pathology techniques is critical when designing these studies. In summary, effective biomedical instrument development requires close cooperation among engineers, physiologists, internists, pathologists and radiologists from conceptualization through instrument development, validation and refinement.