MEMP PhD Thesis Defense: Brandon Krupczak

Cell Therapy Manufacturing for Reduced Heterogeneity and Enhanced Therapeutic Efficacy in Treatment of Acute Respiratory Distress Syndrome

Cell therapy—the use of living cells as medicine—is an emerging therapeutic modality with great potential to address unmet medical needs. Mesenchymal Stem/Stromal Cells (MSCs) represent a promising entrant to this field but face two key barriers to clinical translation: (1) phenotypic heterogeneity of the cellular product foments inconsistent batch-to-batch quality attributes, leading to inconsistent patient response and challenges identifying appropriate release criteria; (2) insufficient therapeutic efficacy in vivo, leaving critical patient needs unmet. This thesis work comprises our efforts to address these barriers to clinical translation using a unified microcarrier-microbioreactor manufacturing strategy that simultaneously reduces inter-batch phenotypic heterogeneity and putatively enhances aggregate therapeutic efficacy.

In order to guide our investigations, we identified an archetypal clinical indication to provide a defined treatment objective: Acute Respiratory Distress Syndrome (ARDS). ARDS is a critical (progression in hours to days), prevalent (> 200,000 annual cases in the US), and deadly indication (27%-46% mortality, depending on the grade of severity) for which there are no available pharmacological interventions to reduce mortality risk in the majority of patients. There is a critical unmet need for enhanced MSC therapies with sufficient therapeutic consistency and potency to improve outcomes for patients.

Motivated by this goal, we explored a multifaceted strategy to produce enhanced MSCs, integrating advances in materials science, bioprocessing, biochemical regulation, and cell biology. First, we process engineered reliability improvements to our in-house gelatin microcarrier manufacture procedure, achieving production scale and reproducibility suitable for bioreactor-based cell manufacture. Next, we modified a commercially available microbioreactor system to enable anchorage-dependent MSC manufacture at benchtop scale, showcasing definitive improvements in resource consumption, cell yield, and putative therapeutic efficacy relative to conventional flask-based manufacturing approaches. We then explored iterative process parameter modifications to further enhance resultant MSC therapeutic potency and characterized improvements in therapeutic efficacy with multiple in vitro assays and models. Finally, we evaluated the impact of our microcarrier-microbioreactor manufacturing strategy on MSC heterogeneity, determining that our enhanced manufacturing approach yields a more consistent phenotypic product relative to the conventional gold-standard across multiple batches and unique donor identities. 

Collectively, these results identify key bottlenecks restraining clinical translation of an important emerging modality with great potential to address unmet medical needs, suggest countermeasures to overcome these bottlenecks that show critical signs of early promise, and highlight mechanisms governing phenotypic heterogeneity with broad applicability to the larger scientific and clinical domains.

Thesis Supervisors:
Krystyn J. Van Vliet, Ph.D.
Vice President for Innovation and External Engagement Strategy, Cornell University
Professor of Materials Science & Engineering and Biomedical Engineering, Cornell University

Paula T. Hammond, Ph.D.
Institute Professor, Massachusetts Institute of Technology
Dean, School of Engineering, Massachusetts Institute of Technology

Thesis Committee Chair:
Alex K. Shalek, Ph.D.
Director, Institute for Medical Engineering & Science
Director, Health Innovation Hub
J.W. Kieckhefer Professor, IMES, Chemistry, Massachusetts Institute of Technology

Thesis Reader:
Kathryn A. Hibbert, M.D.
Vice-Chief of Critical Care, Massachusetts General Hospital
Director, Medical Intensive Care Unit, Massachusetts General Hospital
Assistant Professor of Medicine, Harvard Medical School

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Topic: Brandon Krupczak MEMP PhD Thesis Defense
Time: Wednesday, April 8, 2026, 3:00 PM Eastern Time (US and Canada)

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