Our scientific program began with cryosurgery, a focal therapy used to treat cancer and cardiovascular disease, where we investigated the mechanisms of freezing injury within tissues. While cryosurgery is rooted in cryobiology, it differs fundamentally from cryopreservation in that the goal is to accentuate, rather than avoid, both ice formation and solute-driven cellular dehydration. We demonstrated that ice forms first in the extracellular compartment and then propagates along the vasculature, dehydrating cells within the tissue. By quantifying the location and extent of ice formation and the resulting cellular and tissue injury, we identified vascular injury as a dominant mechanism of in vivo freeze injury. We further demonstrated that these injury mechanisms can be enhanced using eutectic-forming salts and vasoactive adjuvants, including vascular-disruptive agents, shifting the threshold for tissue injury from approximately −40 °C to just below the phase-change temperature at the iceball edge. These findings have important implications for cryosurgical protocol development and the definition of surgical margins. More recently, we have contributed to the development of cryotherapy protocols for treatment of the pulmonary veins in atrial fibrillation and to the development of a cryoprotective gel designed to preserve nerves and reduce complications during prostate cryosurgery.
Building on this long-standing program in cryosurgery, we developed methods to assess focal-therapy-induced injury at both the cellular and tissue levels in vitro and in vivo. These approaches have been extended with collaborators to investigate a broad range of focal therapies, including heat-based modalities such as radiofrequency (RF), microwave, and high-intensity focused ultrasound (HIFU), as well as irreversible electroporation (IRE) and thermochemical therapies. Across these modalities, our work focuses on connecting specific thermodynamic perturbations—thermal, electrical, or chemical—to the ultimate mechanisms of cellular and tissue destruction, with particular emphasis on responses at the cellular and vascular levels. Examples include demonstrating that thermal effects are negligible during IRE in vivo, linking protein denaturation to cellular injury during heating in vitro, and demonstrating that antigen release following IRE can enhance anti-tumor immune responses. This work has further expanded into cancer immunotherapy, where collaborations with several large companies have supported the development of treatment protocols combining focal therapies with immune checkpoint inhibitors, including anti-CTLA-4 and anti-PD-1 therapies, with the goal of optimizing antigen release and synergistically improving cancer control.
Publications
Selected publications for Cryosurgery:
Pazhayannur P, Bischof JC. Measurement and simulation of water transport during freezing in mammalian liver tissue. ASME J Biomech Eng. 1997;119(3):269-77. (Fundamental study of tissue freezing. Best paper award in Journal that year)
Devireddy RV, Smith DJ, Bischof JC. Effect of microscale mass transport and phase change on numerical prediction of freezing in biological tissues. ASME J Heat Transfer. 2002;124(2):365-74. (Fundamental numerical study of tissue freezing. Best paper award in Journal that year)
Rupp CC, Hoffmann NE, Schmidlin FR, Swanlund DJ, Bischof JC, Coad JE. Cryosurgical changes in the porcine kidney: histologic analysis with thermal history correlation. Cryobiology. 2002;45:167-82. (A study which outlined the differences between in vitro and in vivo injury after cryosurgical insult in tissues. This became an important paper in demonstrating the impact of microvascular injury during cryosurgery).
Jiang J, Goel R, Schmechel S, Vercellotti G, Forster C, Bischof JC. Pre-conditioning cryosurgery: Cellular and molecular mechanisms and dynamics of TNF-α enhanced cryotherapy in an in vivo prostate cancer model system. Cryobiology. 2010;61(3):280-8. (Demonstrates the use of a vascular disruptive agent – TNF-α - to pre-inflame vasculature thereby enhancing microvascular injury and making overall injury more predictive).
Shenoi MM, Iltis I, Choi J, Koonce NA, Metzger GJ, Griffin RJ, Bischof JC. Nanoparticle Delivered Vascular Disrupting Agents (VDAs): Use of TNF-alpha conjugated Gold Nanoparticles for Multimodal Cancer Therapy. ACS Mol Pharm. 2013;10(5):1683-94. (Shows that TNF-α can be delivered intravascularly by gold nanoparticles to achieve pre-inflammation and enhanced and predictable injury at the microvascular and tissue level).
Goff RP, Quallich SG, Buechler RA, Bischof JC, Iaizzo PA. Determination of cryothermal injury thresholds in tissues impacted by cardiac cryoablation. Cryobiology. 2017 Apr;75:125-133. (Example extension of work on cancer injury thresholds into cardiac systems for atrial fibrillation treatment. Study was sponsored by Medtronic).
Ranjbartehrani P, Ramirez DA, Schmidlin F, Etheridge M, Iaizzo PA, Shao Q, Bischof J. Nerve Protection During Prostate Cryosurgery. Ann Biomed Eng. 2023;51(3):538-549 (The cryoprotective nerve sparing gel from this work is being patented and commercialized by Everest Medical in Switzerland).
Selected publications for other focal ablation modalities (heat, electroporation):
Shao Q, O'Flanagan S, Lam T, Roy P, Pelaez F, Burbach BJ, Azarin SM, Shimizu Y, Bischof JC. (2019). Engineering T cell response to cancer antigens by choice of focal therapeutic conditions. Int J Hyperthermia. 2019;36(1):130-138.. (*Shows a dramatic in vitro difference in the ability of electroporation, over cryosurgery or heat, to release antigens which T cells respond to. Best Paper Award in Biology for the Journal 2019)
Jiang, M., Shao, Q., Vallin, J., Shimizu, Y., Burbach, B., Azarin, S., & Bischof, J. (2026). Focal therapeutic conditions matter: How energy affects antigen presentation and T cell activation. Bioengineering & Translational Medicine, e70152. (Building on Shao et al’s work, this study used a model antigen to identify electroporation as the most immunogenic focal therapy condition in our system, despite not producing the most antigen, highlighting the interplay among antigen release, adjuvant signals, and immune processing in driving antitumor immunity.)
Burbach BJ, O’Flanagan SD, Shao Q, Young K, Slaughter J, Rollins MR, Granger V, Olson TJ, Beura LK, Azarin SM, Ramadhyani S, Forsyth B, Bischof JC, Shimizu Y. Irreversible electroporation augments checkpoint immunotherapy and promotes tumor antigen-specific tissue-resident memory CD8+ T cells. Nature Communications 2021:12(1);1-16. (This study demonstrated that electroporation enhances checkpoint immunotherapy in prostate cancer by promoting tumor antigen-specific tissue-resident memory CD8⁺ T cells, providing a potential mechanism for durable local and systemic antitumor immunity.)
Jiang, M., Shao, Q., Slaughter, J., & Bischof, J. (2024). Irreversible electroporation has more synergistic effect with anti‐PD‐1 immunotherapy than thermal ablation or cryoablation, in a colorectal cancer model. Advanced Therapeutics, 7(9), 2400068. (This study was among the first to directly compare electroporation, thermal ablation, and cryoablation in a colorectal cancer model and demonstrated that IRE produced the strongest synergy with anti-PD-1 immunotherapy.)
Bhowmick P, Coad JE, Bhowmick S, Larson T, de la Rosette J, Pryor JL, Bischof JC. In vitro assessment of the efficacy of thermal therapy in human nodular prostatic hyperplasia. Int J Hyperthermia. 2003;20(4):421-440. (First study to map the thermal thresholds of injury in human prostate tissue. This was supported by, and followed closely by multiple companies in the prostate therapy space).
He X, Bischof JC. Quantification of Temperature and Injury Response in Thermal Therapy and Cryosurgery. Crit Rev Biomed Eng. 2003;31(5&6):355-422. (Highly cited review of principles which govern thermal and biophysical responses that govern tissue injury).
He X, McGee S, Coad JE, Schmidlin F, Iaizzo PA, Swanlund DJ, Kluge S, Rudie E, Bischof JC. Investigation of the thermal and tissue injury behavior in microwave thermal therapy using a porcine kidney model. Int J Hyperthermia. 2004 Sep;20(6):567-93. (Highly cited companion paper to Rupp et al in Cryobiology showing differences in in vitro and in vivo injury after thermal insult in porcine kidney that are microvascular in origin).
Jiang C, Davalos R, Bischof JC. A Review of Basic to Clinical Studies of Irreversible Electroporation Therapy. IEEE TBME. 2015;62(1):4-20. (Highly cited invited review of the field of Irreversible Electroporation for cancer treatment).