Lung Recovery and Bioengineering Laboratory
Brandon A. Guenthart Lab
The Laboratory for Lung Recovery and Bioengineering is a collaborative research group working on expanding the pool of donor lungs and developing novel therapeutics to alleviate end-stage lung disease. Working to advance the field of ex vivo lung perfusion and advanced mechanical support, Dr. Guenthart and his colleagues have developed systems capable of prolonged normothermic organ support by harnessing the systemic regulation of the body. This radical advance allows for interventional therapies, functional recovery, cellular regeneration, and whole organ bioengineering.
With the bold vision to address the challenges and limitations in organ transplantation and regenerative medicine, the lab explores bioengineered solutions inspired by nature. Current work is focused on investigating cell-based therapeutics and extracellular matrix biomaterials in human ex vivo platforms and large animal models. Through this work, additional enabling technologies have been developed, including an airway cell replacement device, biomimetic lung sealant, and non-invasive lung imaging diagnostics.
Life Science Research Professional
Moeed graduated from the University of Oklahoma this past May with a B.S. in Chemical Biosciences. He worked as an EMT in Oklahoma City for the last three years and as a volunteer firefighter for two years. In addition, he worked as a Research Technician at the University of Oklahoma's Health Science Center. During his undergrad years, he was a part of OU's Racing Team and Men's Rowing Club.
Joe Simmons, NP, ACNPC, CCNS, RNFA
Lead APP Surgical MCS/Heart and Lung Transplant Inpatient Team
Joe graduated from the University of Tennessee Knoxville in 2004, president of his class, receiving a Bachelors of Science in Nursing. He worked as a nurse, nurse manager, educator and case manager for 8 years in Cardiac Surgery/Interventional Cardiology/Heart Failure and Heart Transplant. In 2012 he completed his Masters of Science at the University of California San Francisco and Post Masters Certificate to complete his education as a Critical Care Trauma Clinical Nurse Specialist and Acute Care Nurse Practitioner. He completed his Registered Nurse First Assist program at the University of California Los Angeles in 2015. Joe has worked for the department of Cardiovascular Health at Stanford for the last 10 years as an APP in Cardiac Surgery and most recently was Lead APP for the Surgical MCS/Heart and Lung Transplant Inpatient Team. For the past 4 years, he has also concurrently held a position as Assistant Clinical Professor in the Department of Physiological Nursing at the University of California San Francisco where he enjoys developing nurses to become nurse practitioners by teaching Advanced Health Assessment Techniques and a Clinical Practicum.
Technique for xenogeneic cross-circulation to support human donor lungs ex vivo.
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
Kelly Wu, W., Guenthart, B. A., O'Neill, J. D., Hozain, A. E., Tipograf, Y., Ukita, R., Stokes, J. W., Patel, Y. J., Pinezich, M., Talackine, J. R., Cardwell, N. L., Fung, K., Vunjak-Novakovic, G., Bacchetta, M.
Xenogeneic cross-circulation (XC) is an experimental method for ex vivo organ support and recovery that could expand the pool of donor lungs suitable for transplantation. The objective of this study was to establish and validate a standardized, reproducible, and broadly applicable technique for performing xenogeneic XC to support and recover injured human donor lungs ex vivo.Human donor lungs (n = 9) declined for transplantation were procured, cannulated, and subjected to 24 hours of xenogeneic XC with anesthetized xeno-support swine (Yorkshire/Landrace) treated with standard immunosuppression (methylprednisolone, mycophenolate mofetil, tacrolimus) and complement-depleting cobra venom factor. Standard lung-protective perfusion and ventilation strategies, including periodic lung recruitment maneuvers, were used throughout xenogeneic XC. Every 6 hours, ex vivo donor lung function (gas exchange, compliance, airway pressures, pulmonary vascular dynamics, lung weight) was evaluated. At the experimental endpoint, comprehensive assessments of the lungs were performed by bronchoscopy, histology, and electron microscopy. Student's t-test and 1-way analysis of variance with Dunnett's post-hoc test was performed, and p < 0.05 was considered significant.After 24 hours of xenogeneic XC, gas exchange (PaO2/FiO2) increased by 158% (endpoint: 364 ± 142 mm Hg; p = 0.06), and dynamic compliance increased by 127% (endpoint: 46 ± 20 ml/cmH2O; p = 0.04). Airway pressures, pulmonary vascular pressures, and lung weight remained stable (p > 0.05) and within normal ranges. Over 24 hours of xenogeneic XC, gross and microscopic lung architecture were preserved: airway bronchoscopy and parenchymal histomorphology appeared normal, with intact blood-gas barrier.Xenogeneic cross-circulation is a robust method for ex vivo support, evaluation, and improvement of injured human donor lungs declined for transplantation.
View details for DOI 10.1016/j.healun.2022.11.002
View details for PubMedID 36456408
Type A Aortic Dissection With Concurrent Aortic Valve Endocarditis, Subarachnoid Hemorrhage, and Disseminated Intravascular Coagulation.
JACC. Case reports
Elde, S. F., Guenthart, B. A., de Biasi, A., Dalal, A. R., Casselman, K. G., Hiesinger, W., Burton, E. C.
2022; 4 (14): 839-843
We describe surgical repair of a Stanford Type A aortic dissection with concurrent aortic valve Streptococcus equi endocarditis in the setting of subarachnoid hemorrhage and disseminated intravascular coagulation. Multidisciplinary collaboration among specialists from a variety of disciplines is essential when treating acutely ill cardiovascular patients with multisystem involvement. (Level of Difficulty: Beginner.).
View details for DOI 10.1016/j.jaccas.2021.05.008
View details for PubMedID 35912321
Half of Anastomotic Leaks after Esophagectomy are Undetected on Initial Postoperative Esophagram.
The Annals of thoracic surgery
Elliott, I. A., Berry, M. F., Trope, W., Lui, N. S., Guenthart, B. A., Liou, D. Z., Whyte, R. I., Backhus, L. M., Shrager, J. B.
The sensitivity of fluoroscopic esophagrams with oral contrast to exclude anastomotic leak after esophagectomy is not well-documented, and the consequences of missing a leak in this setting have not been previously described.We performed a retrospective cohort study of a prospectively maintained institutional database of patients undergoing esophagectomy with esophagogastric anastomosis 2008-2020. Relevant details regarding leaks, management, and outcomes were obtained from the database and formal chart review. Statistical analysis was performed to compare patients with and without leaks, and those with false negative versus positive esophagrams.There were 384 patients who underwent esophagectomy with gastric reconstruction: the majority were Ivor-Lewis (82%), and 51% were wholly or partially minimally-invasive. Using a broad definition of leak, 55 patients (16.7%) developed an anastomotic leak. Twenty-seven of the 55 patients (49%) who ultimately were found to have a leak initially had a negative esophagram (performed on average on postoperative day 6). Those with a negative initial esophagram were more likely to have an uncontained leak (81% vs. 29%, p<0.01), require unplanned readmission (70% vs. 39%, p=0.02), and undergo reoperation (44% vs. 11%, p<0.01).Early postoperative esophagrams intended to evaluate anastomotic integrity have a low sensitivity of 51%, and leaks missed on initial esophagram have greater clinical consequences than those identified on initial esophagram. These findings suggest a high index of suspicion must be maintained even after a normal esophagram and calls into question the common practice of using this test to triage patients for diet advancement.
View details for DOI 10.1016/j.athoracsur.2022.04.053
View details for PubMedID 35618049
Pathological remodeling of distal lung matrix in end-stage cystic fibrosis patients.
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
Pinezich, M. R., Tamargo, M. A., Fleischer, S., Reimer, J. A., Hudock, M. R., Hozain, A. E., Kaslow, S. R., Tipograf, Y., Soni, R. K., Gavaudan, O. P., Guenthart, B. A., Marboe, C. C., Bacchetta, M., O'Neill, J. D., Dorrello, N. V., Vunjak-Novakovic, G.
Manifestations of cystic fibrosis, although well-characterized in the proximal airways, are understudied in the distal lung. Characterization of the cystic fibrosis lung 'matrisome' (matrix proteome) has not been previously described, and could help identify biomarkers and inform therapeutic strategies.We performed liquid chromatography-mass spectrometry, gene ontology analysis, and multi-modal imaging, including histology, immunofluorescence, and electron microscopy for a comprehensive evaluation of distal human lung extracellular matrix (matrix) structure and composition in end-stage cystic fibrosis.Quantitative proteomic profiling identified sixty-eight (68) matrix constituents with significantly altered expression in end-stage cystic fibrosis. Over 90% of significantly different matrix peptides detected, including structural and basement membrane proteins, were expressed at lower levels in cystic fibrosis. However, the total abundance of matrix in cystic fibrosis lungs was not significantly different from control lungs, suggesting that cystic fibrosis leads to loss of diversity among lung matrix proteins rather than an absolute loss of matrix. Visualization of distal lung matrix via immunofluorescence and electron microscopy revealed pathological remodeling of distal lung tissue architecture and loss of alveolar basement membrane, consistent with significantly altered pathways identified by gene ontology analysis.Dysregulation of matrix organization and aberrant wound healing pathways are associated with loss of matrix protein diversity and obliteration of distal lung tissue structure in end-stage cystic fibrosis. While many therapeutics aim to functionally restore defective cystic fibrosis transmembrane conductance regulator (CFTR), drugs that target dysregulated matrix pathways may serve as adjunct interventions to support lung recovery.
View details for DOI 10.1016/j.jcf.2022.04.016
View details for PubMedID 35525782
- Sound-guided assessment and localization of pulmonary air leak BIOENGINEERING & TRANSLATIONAL MEDICINE Pinezich, M. R., Mir, S., Reimer, J. A., Kaslow, S. R., Chen, J., Guenthart, B. A., Bacchetta, M., O'Neill, J. D., Vunjak-Novakovic, G., Kim, J. 2022 Hide More
Imaging-Guided Bioreactor for Generating Bioengineered Airway Tissue.
Journal of visualized experiments : JoVE
Mir, S. M., Chen, J., Pinezich, M. R., O'Neill, J. D., Guenthart, B. A., Vunjak-Novakovic, G., Kim, J.
Repeated injury to airway tissue can impair lung function and cause chronic lung disease, such as chronic obstructive pulmonary disease. Advances in regenerative medicine and bioreactor technologies offer opportunities to produce lab-grown functional tissue and organ constructs that can be used to screen drugs, model disease, and engineer tissue replacements. Here, a miniaturized bioreactor coupled with an imaging modality that allows in situ visualization of the inner lumen of explanted rat trachea during in vitro tissue manipulation andculture is described. Using this bioreactor, the protocol demonstrates imaging-guided selective removal of endogenous cellular components while preserving the intrinsic biochemical features and ultrastructure of the airway tissue matrix. Furthermore, the delivery, uniform distribution, and subsequent prolonged culture of exogenous cells on the decellularized airway lumen with optical monitoring in situ are shown. The results highlight that the imaging-guided bioreactor can potentially be used to facilitate the generation of functional in vitro airway tissues.
View details for DOI 10.3791/63544
View details for PubMedID 35467661
- Exvivo aortic valve replacement before orthotopic heart transplantation. JTCVS techniques Elde, S. F., Guenthart, B. A., Shudo, Y., Woo, Y. J. 2022; 12: 118-120 Hide More
- Cannulation Strategies in Ex Vivo Lung Perfusion. ASAIO journal (American Society for Artificial Internal Organs : 1992) Guenthart, B. A., O'Neill, J. D., Bacchetta, M. 2021 Hide More
Homogeneous Distribution of Exogenous Cells onto De-epithelialized Rat Trachea via Instillation of Cell-Loaded Hydrogel.
ACS biomaterials science & engineering
Chen, J., Mir, S. M., Pinezich, M. R., O'Neill, J. D., Guenthart, B. A., Bacchetta, M., Vunjak-Novakovic, G., Huang, S. X., Kim, J.
Injured or diseased airway epithelium due to repeated environmental insults or genetic mutations can lead to a functional decline of the lung and incurable lung diseases. Bioengineered airway tissue constructs can facilitate in vitro investigation of human lung diseases and accelerate the development of effective therapeutics. Here, we report robust tissue manipulation modalities that allow: (i) selective removal of the endogenous epithelium of in vitro cultured airway tissues and (ii) spatially uniform distribution and prolonged cultivation of exogenous cells that are implanted topically onto the denuded airway lumen. Results obtained highlight that our approach to airway tissue manipulation can facilitate controlled removal of the airway epithelium and subsequent homogeneous distribution of newly implanted cells. This study can contribute to the creation of innovative tissue engineering methodologies that can facilitate the treatment of lung diseases, such as cystic fibrosis, primary ciliary dyskinesia, and chronic obstructive pulmonary disease.
View details for DOI 10.1021/acsbiomaterials.1c01031
View details for PubMedID 34874712
Extended Static Hypothermic Preservation In Cardiac Transplantation: A Case Report.
Guenthart, B. A., Krishnan, A., Koyano, T., La Francessca, S., Chan, J., Alassar, A., Macarthur, J. W., Shudo, Y., Hiesinger, W., Woo, Y. J.
BACKGROUND: The donor shortage poses a major limitation to use of heart transplantation. Novel strategies such as use of expanded-criteria donors with prolonged ischemia times are being employed to address this need. Recent developments in static hypothermia have allowed for the safe use of cardiac allografts with prolonged ischemic times.CASE REPORT: We present the case of a 68-year-old woman with valvular cardiomyopathy refractory to medical therapy who underwent orthotopic heart transplantation with a cardiac allograft exposed to elevated ischemic times. This was achieved through use of the federally approved SherpaPak Cardiac Transport System for transportation of the allograft. This method of static hypothermic organ preservation allowed for a 330-minute total ischemic time, including 283 minutes of storage within the preservation system. The patient tolerated the procedure well and was discharged on postoperative day 10, with excellent graft function and no evidence of rejection 3 months postoperatively.CONCLUSIONS: Though traditionally ischemic times of 240 minutes or less are recommended for cardiac allografts, we demonstrate, to our knowledge, the longest reported ischemic time of 330 minutes via use of a novel method of static hypothermia for organ preservation. The recipient had an excellent outcome postoperatively, demonstrating the potential for this new organ preservation system to expand the donor pool and improve access and use of heart transplantation.
View details for DOI 10.1016/j.transproceed.2021.08.021
View details for PubMedID 34521542
This Heart is Not Human
Oct 13, 2022
A pig heart in a human? Before this year, a heart transplant surgery like this seemed unlikely, but over 50 years of innovations have made it possible. Because of the low availability of human organs for transplants, doctors have looked into xenotransplantation as the answer. WIRED spoke with Dr. Brandon Guenthart to understand exactly how this surgery works, and why the future of surgery might look similar.