Ann Rundell

Purdue University, Weldon School of Biomedical Engineering, Faculty Member

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Estimation of Likely Cancer Cure Using First and Second-Order Product Densities of Population Balance Models

Annals of Biomedical Engineering, 2007

The objective of chemotherapy is to eradicate all cancerous cells. However, due to the stochastic... more The objective of chemotherapy is to eradicate all cancerous cells. However, due to the stochastic behavior of cells, the elimination of all cancerous cells must be discussed probabilistically. We hypothesize, and demonstrate in the results, that the mean and standard deviation of a cancer cell population, derived through the probabilistic interpretation of population balance equations, are sufficient to estimate the likelihood of cancer eradication. Our analysis of a binary cell division model reveals that an expected cancer population that is six standard deviations less than one cell provides a good estimate for the treatment durations that nearly ensures treatment successes. This approximation is evaluated and tested on two other physiologically likely scenarios: variable patient response to chemotherapy and the presence of a dormant population. We find that early identification of individual patient susceptibility to the chemotherapeutic agent is extremely important to all patients as treatment adjustments for non-responders greatly enhances their likelihood of cure while responders need not be subjected to needlessly harsh treatments. Presence of a dormant population increases both the required treatment duration and population variability, but the same estimation method holds. This work is a step toward using stochastic models for a quantitative evaluation of chemotherapy.

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Analytically derived material properties of multilaminated extracellular matrix devices using the ball-burst test

Biomaterials, 2005

Xenogeneic extracellular matrices (ECMs) have been shown to be effective as naturally occurring s... more Xenogeneic extracellular matrices (ECMs) have been shown to be effective as naturally occurring scaffolds for soft-tissue repair. As acellular tissue substitutes at the time of surgical implantation, ECMs are subjected to the mechanical forces and microenvironmental conditions representative of the anatomical location in which they are placed. Ideally such natural scaffolds would possess mechanical properties that allow for normal tissue function in and around the implant site. The ball-burst test was used to simulate biaxial forces and to determine the strength of the ECM scaffold under a relevant physiological loading condition. The ballburst test, in itself, does not quantify intrinsic mechanical properties and therefore a methodology was developed to determine the maximum stress resultant tangent modulus (MSRTM) or the maximum stress tangent modulus (MSTM), stress to failure ðs f Þ; failure stress resultant ðN f Þ, ball-burst pressure ðPÞ; and maximum elongation ðl max Þ from the raw ball-burst data obtained at a constant-rate of transverse. The analytical methodology was compared to finite element simulations and showed good correlation with the analytical solution presented. The proposed approximations were used to compute biaxial failure properties for a variety of multilaminate ECM devices with varying number of layers, disinfection and sterilization, and organ origin. r

format_quote2-layer PAA treated devices exhibited lower ball-burst pressure than 4-layer devices, highlighting treatment effects on structural performance.format_quote

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Biaxial strength of multilaminated extracellular matrix scaffolds

Biomaterials, 2004

Xenogeneic extracellular matrix (ECM) can be harvested and configured to function as a bioscaffol... more Xenogeneic extracellular matrix (ECM) can be harvested and configured to function as a bioscaffold for tissue and organ reconstruction. The mechanical properties of the ECM vary depending upon the tissue from which it is harvested. Likewise, the manufacturing steps required to develop ECMs into medical grade devices will affect the surface morphology and the mechanical properties of the bioscaffold; important properties for constructive tissue remodeling. The present study compared the ball-burst strength of five different ECM scaffolds before and after treatment with peracetic acid (PAA): porcine small intestinal submucosa (SIS), porcine urinary bladder submucosa (UBS), porcine urinary bladder matrix (UBM), a composite of UBS+UBM, and canine stomach submucosa (SS). This study also compared the mechanical properties of 2-and 4-layer ECM scaffolds. Results showed 2-layer SS devices had the highest ball-burst value of all 2-layer ECM devices. Moreover, all 4-layer ECM devices had similar ballburst strength except for 4-layer UBM devices which was the weakest. PAA-treatment decreased the ball-burst strength of SS and increased the ball-burst strength of UBS 2-layer devices. This study showed the material properties of the ECM scaffolds could be engineered to mimic those of native soft tissues (i.e. vascular, musculotendinous, etc) by varying the number of layers and modifying the disinfection/sterilization treatments used for manufacturing. r

$Fig. 6. SEM images of fracture edge of: (A) 750x magnification of a portion of the fracture edge of a PAA-treated 4-layer SIS device. (B) 270 x magnification of fracture edge of a PAA-treated 4-layer SIS device. (C) 500 x magnification of a PAA-treated 2-layer SIS device.$

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Rhythmic abdominal compression CPR ventilates without supplemental breaths and provides effective blood circulation

Resuscitation, 2008

Standard chest-compression CPR has an out-of-hospital resuscitation rate of less than 10% and can... more Standard chest-compression CPR has an out-of-hospital resuscitation rate of less than 10% and can result in rib fractures or mouth-to-mouth transfer of infection. Recently, we introduced a new CPR method that utilizes only rhythmic abdominal compressions (OAC-CPR). The present study compares ventilation and hemodynamics produced by chest and abdominal compression CPR. Twelve swine (29-34kg) were anesthetized, intubated and allowed to breathe spontaneously. Physiologic dead space, resting tidal volume, compression-induced lung air flow, and blood pressures were recorded. Ventricular fibrillation (VF) was electrically induced and subjects were treated with either standard CPR or OAC-CPR at various force and rate settings. Minute alveolar ventilation (MAV) and mean coronary perfusion pressure (CPP) were compared. For OAC-CPR, ventilation per compression tended to increase with increasing force and decreasing rate. Chest only compressions produced no MAV, while OAC-CPR at 80cycles/min or less, matched the MAV for spontaneous respiration. For all rates, abdominal compressions met, or exceeded, the CPP of chest compressions performed at 100lbs. OAC-CPR generated ventilatory volumes significantly greater than the dead space and produced equivalent, or larger, CPP than with chest compressions. Thus, OAC-CPR ventilates a subject, eliminating the need for mouth-to-mouth breathing, and effectively circulates blood during VF without breaking ribs. Furthermore, this technique is simple to perform, can be administered by a single rescuer, and should reduce bystander reluctance to administer CPR.

A new cardiopulmonary resuscitation method using only rhythmic abdominal compression

American Journal of Emergency Medicine, 2007

This article introduces 2 new cardiopulmonary resuscitation (CPR) concepts: (1) the use of only r... more This article introduces 2 new cardiopulmonary resuscitation (CPR) concepts: (1) the use of only rhythmic abdominal compression (OAC) to produce blood flow during CPR with ventricular fibrillation and (2) a new way of describing coronary perfusion effectiveness, namely, the area between the aortic and right atrial pressure curves, summed over 1 minute, the units being millimeters of mercury per second. We call this unit the coronary perfusion index (CPI). True mean coronary perfusion pressure is CPI/60. We also relate CPI during CPR with ventricular fibrillation to the CPI for the normally beating heart in the same animal, obtained before each experiment. This 11-pig (25-35 kg) study compares the CPI for standard chest-compression CPR and that obtained with OAC-CPR. The coronary perfusion ratio for OAC-CPR compared with standard chest-compression CPR was 1.6 ± 0.73 (P = .024). In other words, OAC-CPR produced 60% more coronary perfusion than standard chest-compression CPR, with no damage to visceral organs.

format_quoteOAC-CPR eliminates the risk of rib fractures associated with standard CPR without sacrificing perfusion effectiveness.format_quote

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The natural biochemical changes during ventricular fibrillation with cardiopulmonary resuscitation and the onset of postdefibrillation pulseless electrical activity

American Journal of Emergency Medicine, 2006

Objective: The objective of this study was to document the biochemical changes during ventricular... more Objective: The objective of this study was to document the biochemical changes during ventricular fibrillation (VF) with cardiopulmonary resuscitation (CPR), and to identify factors associated with postdefibrillation pulseless electrical activity (PD-PEA). Background: It has been reliably estimated that as much as 60% of out-of-hospital sudden cardiac death can be attributed to the onset of PD-PEA Niemann JT, Cruz B, Garner D et al. Immediate countershock versus CPR before countershock in a 5-minute swine model of ventricular fibrillation arrest. Ann Emerg Med 2000;36:543-6). Previous attempts to treat reversible causes of pulseless electrical activity have not been successful clinically (Niemann JT, Stratton SJ, Cruz B, Lewis RJ. Outcome of out-of-hospital postcountershock asystole and pulseless electrical activity versus primary asystole and pulseless electrical activity. Crit Care Med 2001;29:2366-70).

format_quotePotassium increased by nearly 10% per minute during VF with CPR, a critical factor for post-defibrillation outcomes.format_quote

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Sustained abdominal compression during CPR raises coronary perfusion pressures as much as vasopressor drugs

Resuscitation, 2007

This study investigated sustained abdominal compression as a means to improve coronary perfusion ... more This study investigated sustained abdominal compression as a means to improve coronary perfusion pressure (CPP) during cardiopulmonary resuscitation (CPR) and compared the resulting CPP augmentation with that achieved using vasopressor drugs. During electrically induced ventricular fibrillation in anesthetized, 30kg juvenile pigs, Thumper CPR was supplemented at intervals either by constant abdominal compression at 100-500mmHg using an inflated contoured cuff or by the administration of vasopressor drugs (epinephrine, vasopressin, or glibenclamide). CPP before and after cuff inflation or drug administration was the end point. Sustained abdominal compression at &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;200mmHg increases CPP during VF and otherwise standard CPR by 8-18mmHg. The effect persists over practical ranges of chest compression force and duty cycle and is similar to that achieved with vasopressor drugs. Constant abdominal compression also augments CPP after prior administration of epinephrine or vasopressin. During CPR noninvasive abdominal compression with the inflatable contoured cuff rapidly elevates the CPP, sustains the elevated CPP as long as the device is inflated, and is immediately and controllably reversible upon device deflation. Physical control of peripheral vascular resistance during CPR by abdominal compression has some advantages over pharmacological manipulation and deserves serious reconsideration, now that the limitations of pressor drugs during CPR have become better understood, including post-resuscitation myocardial depression and the need for intravenous access.

Experimental strategies to improve in vitro models of renal ischemia

Experimental and Molecular Pathology, 2007

Ischemia has elicited a great deal of interest among the scientific community due to its role in ... more Ischemia has elicited a great deal of interest among the scientific community due to its role in life-threatening pathologies such as cancer, stroke, acute renal failure, and myocardial infarction. Oxygen deprivation (hypoxia) associated with ischemia has recently become a subject of intense scrutiny. New investigators may find it challenging to induce hypoxic injury in vitro. Researchers may not always be aware of the experimental barriers that contribute to this phenomenon. Furthermore, ischemia is associated with other major insults, such as excess carbon dioxide (hypercapnia), nutrient deprivation, and accumulation of cellular wastes. Ideally, these conditions should also be incorporated into in vitro models. Therefore, the motivation behind this review is to: i. delineate major in vivo ischemic insults; ii. identify and explain critical in vitro parameters that need to be considered when simulating ischemic pathologies; iii. provide recommendations to improve experiments; and as a result, iv. enhance the validity of in vitro results for understanding clinical ischemic pathologies. Undoubtedly, it is not possible to completely replicate the in vivo environment in an ex vivo model system. In fact, the primary goal of many in vitro studies is to elucidate the role of specific stimuli during in vivo pathological events. This review will present methodologies that may be implemented to improve the applicability of in vitro models for understanding the complex pathological mechanisms of ischemia. Finally, although these topics will be discussed within the context of renal ischemia, many are pertinent for cellular models of other organ systems and pathologies.

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Ischemia’s Proliferative and Morphological Effects: Analyzing the Roles of Hypoxia, Hypercapnia, and Glucose

Cellular and Molecular Bioengineering, 2010

In ischemic tissues, oxygen (O2) and glucose become depleted while cells concomitantly promote ca... more In ischemic tissues, oxygen (O2) and glucose become depleted while cells concomitantly promote carbon dioxide (CO2) and waste accumulation. Hypoxia has become a topic of great interest. Notably, these insults, including hypoxia, do not exist in isolation during ischemia in vivo; their simultaneous presence may influence pathological mechanisms. We hypothesized that low O2 (hypoxia), elevated CO2 (hypercapnia), and glucose deprivation each have a statistically significant main effect and interact in a non-additive manner, leading to decreased cellular proliferation and altered (i.e., increased) morphological measurements. Renal LLC-PK1 cells were subjected to: (i) hypoxia (2/5%CO2); (ii) hypercapnia (20%O2/20%CO2); or (iii) hypoxia + hypercapnia (2/20%CO2). Two levels of media glucose were used to investigate glucose depletion. Additionally, a recovery period was simulated with and without fresh media to explore post-insult reperfusion responses. Statistical analyses identified significant main effects and insult interactions. Several interactions occurred between hypoxia, hypercapnia, and/or glucose, thereby producing decreased cellular proliferation and atypical morphologies. Hypoxia-induced changes in proliferation were moderated by hypercapnia. Moreover, reoxygenation and nutrient replenishment were essential to increase cell density during simulated post-ischemia reperfusion. Multiple insults may exert main effects and interact during ischemia-induced morphological and proliferative changes. To promote clinical relevance, future studies targeting ischemic mechanisms should examine multiple insults and consider the implications of insult interactions.

Investigating the Role of Ischemia vs. Elevated Hydrostatic Pressure Associated with Acute Obstructive Uropathy

Annals of Biomedical Engineering, 2009

Obstructive uropathy can cause irreversible renal damage. It has been hypothesized that elevated ... more Obstructive uropathy can cause irreversible renal damage. It has been hypothesized that elevated hydrostatic pressure within renal tubules and/or renal ischemia contributes to cellular injury following obstruction. However, these assaults are essentially impossible to isolate in vivo. Therefore, we developed a novel pressure system to evaluate the isolated and coordinated effects of elevated hydrostatic pressure and ischemic insults on renal cells in vitro. Cells were subjected to: (1) elevated hydrostatic pressure (80 cm H2O); (2) ischemic insults (hypoxia (0% O2), hypercapnia (20% CO2), and 0 mM glucose media); and (3) elevated pressure + ischemic insults. Cellular responses including cell density, lactate dehydrogenase (LDH) release, and intracellular LDH (LDHi), were recorded after 24 h of insult and following recovery. Data were analyzed to assess the primary effects of ischemic insults and elevated pressure. Unlike pressure, ischemic insults exerted a primary effect on nearly all response measurements. We also evaluated the data for insult interactions and identified significant interactions between ischemic insults and pressure. Altogether, findings indicate that pressure may sub-lethally effect cells and alter cellular metabolism (LDHi) and membrane properties. Results suggest that renal ischemia may be the primary, but not the sole, cause of cellular injury induced by obstructive uropathy.

SBML-SAT: a systems biology markup language (SBML) based sensitivity analysis tool

BMC Bioinformatics, 2008

Background: It has long been recognized that sensitivity analysis plays a key role in modeling an... more Background: It has long been recognized that sensitivity analysis plays a key role in modeling and analyzing cellular and biochemical processes. Systems biology markup language (SBML) has become a well-known platform for coding and sharing mathematical models of such processes. However, current SBML compatible software tools are limited in their ability to perform global sensitivity analyses of these models.

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Targeting a fixed percentage of granulocyte differentiation using experiments designed via nonlinear model predictive control

Previous efforts to control cellular differentiation have been largely experimental. Although som... more Previous efforts to control cellular differentiation have been largely experimental. Although some mathematical models for this process exist, rarely has a quantitative approach been employed to design experiments that predictably direct the cell fate. As an initial step towards this aim, a control strategy for sustaining a desired constant level of differentiated human promyelocytic leukemia (HL60) cells is proposed. Nonlinear model predictive control is applied using a model of HL60 cell differentiation which reflects the dominant observable cell states along the known granulocyte/monocyte differentiation pathway. After implementing changes identified by a preliminary experimental trial, the experimental realization of the controller successfully achieved the target differentiation level and demonstrated the need for a quantitative approach to experiment design.

Applications of sparse grid interpolation: sensitivity analysis and experiment design

Procedia - Social and Behavioral Sciences, 2010

We use adaptive sparse grid interpolation to produce accurate and efficient estimates of the sens... more We use adaptive sparse grid interpolation to produce accurate and efficient estimates of the sensitivity coefficients of Sobol' and to guide the design of experiments based on model output. We illustrate this method on two models of the mitogen-activated protein kinase cascade, one with 3 uncertain parameters and one with 18 uncertain parameters.

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Application of stochastic equations of population balances to sterilization processes

Chemical Engineering Science, 2009

... Mathematical modeling of the expected population dynamics has aided in the understanding and ... more

Biosensor immunosurface engineering inspired by B-cell membrane-bound antibodies: modeling and analysis of multivalent antigen capture by immobilized antibodies

IEEE Transactions on Nanobioscience, 2003

Immobilized antibodies are used by many biosensors and diagnostic tests as specific receptors for... more Immobilized antibodies are used by many biosensors and diagnostic tests as specific receptors for the presence of targeted substances in clinical, biological, or environmental samples. The antibodies used in these devices are the soluble form of the antibodies presented on the B-cell membrane: they have the same specificity, but they may differ from those presented on the B cell in orientation, flexibility, mobility, and support-membrane properties. These properties influence the formation of noncovalent bonds between the pathogen antigenic determinants (epitopes) and the amino acids of the antibodies. This paper extends the theoretical modeling foundation addressing multivalent antigen binding to cell surface receptors to account for local and far-field antibody surface density effects, immobilized antibodies, and the flexibility and range of motion of immobilized antibodies. An analysis of the derived model provides insight into the design of biosensor immunosurfaces to enhance pathogen capture capability.

Using adaptive model predictive control to customize maintenance therapy chemotherapeutic dosing for childhood acute lymphoblastic leukemia

Journal of Theoretical Biology, 2010

Acute lymphoblastic leukemia (ALL) is a common childhood cancer in which nearly one-quarter of pa... more Acute lymphoblastic leukemia (ALL) is a common childhood cancer in which nearly one-quarter of patients experience a disease relapse. However, it has been shown that individualizing therapy for childhood ALL patients by adjusting doses based on the blood concentration of active drug metabolite could significantly improve treatment outcome. An adaptive model predictive control (MPC) strategy is presented in which maintenance therapy for childhood ALL is personalized using routine patient measurements of red blood cell mean corpuscular volume as a surrogate for the active drug metabolite concentration. A clinically relevant mathematical model is developed and used to describe the patient response to the chemotherapeutic drug 6-mercaptopurine, with some model parameters being patient-specific. During the course of treatment, the patient-specific parameters are adaptively identified using recurrent complete blood count measurements, which sufficiently constrain the patient parameter uncertainty to support customized adjustments of the drug dose. While this work represents only a first step toward a quantitative tool for clinical use, the simulated treatment results indicate that the proposed mathematical model and adaptive MPC approach could serve as valuable resources to the oncologist toward creating a personalized treatment strategy that is both safe and effective.

Exploring antigen valency and size effects on capture by immuno-surfaces through analysis and experimentation

Abstract Experimental exploration and model development is being pursued for analytical determina... more

Modeling and analysis of early events in T-lymphocyte antigen-activated intracellular-signaling pathways

Journal of Computational and Applied Mathematics, 2005

The T-cell antigen-activated signaling pathway is a highly regulated intracellular biochemical sy... more The T-cell antigen-activated signaling pathway is a highly regulated intracellular biochemical system that is crucial for initiating an appropriate adaptive immune response. To improve the understanding of the complex regulatory mechanisms controlling the early events in T-cell signaling, a detailed mathematical model was developed that utilizes ordinary differential equations to describe chemical reactions of the signaling pathway. The model parameter values were constrained by experimental data on the activation of a specific signaling intermediate and indicated an initial rapid cascade of phosphorylation events followed by a comparatively slow signal downregulation. Nonlinear analysis of the model suggested that thresholding and bistability occur as a result of the embedded positive and negative feedback loops within the model. These nonlinear system properties may enhance the Tcell receptor specificity and provide sub-threshold noise filtering with switch-like behavior to ensure proper cell response. Additional analysis using a reduced second-order model led to further understanding of the observed system behavior. Moreover, the interactions between the positive and negative feedback loops enabled the model to exhibit, among a variety of other feasible dynamics, a sustained oscillation that corresponds to a stable limit cycle 321 in the two-dimensional phase plane. Quantitative analysis in this paper has helped identify potential regulatory mechanisms in the early T-cell signaling events. This integrated approach provides a framework to quantify and discover the ensemble of interconnected T-cell antigen-activated signaling pathways from limited experimental data.

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Modeling Mitochondrial Bioenergetics with Integrated Volume Dynamics

PLOS Computational Biology, 2010

Mathematical models of mitochondrial bioenergetics provide powerful analytical tools to help inte... more Mathematical models of mitochondrial bioenergetics provide powerful analytical tools to help interpret experimental data and facilitate experimental design for elucidating the supporting biochemical and physical processes. As a next step towards constructing a complete physiologically faithful mitochondrial bioenergetics model, a mathematical model was developed targeting the cardiac mitochondrial bioenergetic based upon previous efforts, and corroborated using both transient and steady state data. The model consists of several modified rate functions of mitochondrial bioenergetics, integrated calcium dynamics and a detailed description of the K + -cycle and its effect on mitochondrial bioenergetics and matrix volume regulation. Model simulations were used to fit 42 adjustable parameters to four independent experimental data sets consisting of 32 data curves. During the model development, a certain network topology had to be in place and some assumptions about uncertain or unobserved experimental factors and conditions were explicitly constrained in order to faithfully reproduce all the data sets. These realizations are discussed, and their necessity helps contribute to the collective understanding of the mitochondrial bioenergetics. PLoS Computational Biology | www.ploscompbiol.org 1 January 2010 | Volume 6 | Issue 1 | e1000632 Mitochondrial Reactions J PDH Pyruvate dehydrogenase PYR + CoASH + NAD + H 2 O « CO 2 + SCOA + NADH J CS Citrate synthase OAA + AcCoA + H 2 O « CoASH + CIT J ACH Aconitase CIT « ISOC J IDH Isocitrate dehydrogenase NAD + ISOC + H 2 O « aKG + NADH + CO 2 J aKGDH a-Ketoglutarate dehydrogenase aKG + CoASH + NAD + H 2 O « CO 2 + SCoA + NADH J SCoAS Succinyl CoA synthase SCoA + GDP + Pi « SUC + GTP + CoASH J SDH Succinate dehydrogenase SUC + UQ « UQH 2 + FUM J FH Fumarate hydratase FUM + H 2 O « MAL J MDH Malate dehydrogenase NAD + MAL « OAA + NADH J NDK Nucleoside diphosphokinase GTP + ADP « GDP + ATP J GOT Glutamate oxaloacetate transaminase ASP + aKG « OAA + GLU J CI Complex I NADH + UQ « NAD + UQH 2 J CIII Complex III UQH 2 + 2Cytc 3+ « UQ + 2Cytc 2+ J CIV Complex IV 2Cytc red + KO 2 « 2Cytc ox + H 2 O J F1FO F 1 F O ATP synthase ADP + Pi « ATP + H 2 O J AK Adenylate Kinase 2ADP « ATP + AMP Exchangers and Ion Channels J GAE Glutamate-aspartate exchanger GLU ims + H + ims + ASP mtx « GLU mtx + H + mtx + ASP ims J OME a-Ketoglutarate-malate exchanger aKG ims + MAL mtx « aKG mtx + MAL ims J PYRH Pyruvate-proton cotransporter PYR ims + H + ims « PYR mtx + H + mtx J GLUH Glutamate-proton cotransporter GLU ims + H + ims « GLU mtx + H + mtx J CITMAL Tricarboxylate carrier CIT ims + MAL mtx « CIT mtx + MAL ims J ISCOMAL Tricarboxylate carrier ISOC ims + MAL mtx « ISOC mtx + MAL ims J SUCPi Dicarboxylate carrier SUC mtx + Pi ims « SU C ims + Pi mtx J MALPi Dicarboxylate carrier MAL mtx + Pi ims « MAL ims + Pi mtx J ANT Adenine nucleotide transporter ATP mtx + ADP ims « ATP ims + ADP mtx J PIC Inorganic phosphate carrier Pi ims + H + ims « Pi mtx + H + mtx J mHleak Proton leak H + ims « H + mtx

format_quoteThe model aligns simulation results of mitochondrial bioenergetics with multiple datasets, encompassing inorganic phosphate and matrix dynamics validations.format_quote

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Achieving targeted granulocyte differentiation through the use of interpolation and optimization techniques

Cellular differentiation is a complex process for which systematic design of control strategies h... more Cellular differentiation is a complex process for which systematic design of control strategies has not been widely investigated. As a first step towards this aim, a control strategy for achieving a desired percentage of differentiating cells is proposed. A population balance model structure parallels the known granulocyte/monocyte differentiation pathway. Transition rate functions that characterize the movement of cells from one differentiation state to the next were identified from experimental data obtained via flow cytometry. An additional experiment demonstrates the efficacy of the proposed model and control strategy.

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