Precession-Based Stem Cells Harvesting Device
Segment: Academic Country: Singapore
Author(s): Tang Kok Zuea
Products:
NI cDAQ-9174 with module NI 9215 (Analog input module) NI 9401 (digital I/O module)
NI 9472 (digital output-relay switch)
(In the process of replacing cDAQ with CompactRIO NI-cRIO 9022 with chassis NI-cRIO 9111)
Challenge:
The human placenta provides a rich source of stem cells (HSCs) for many clinical uses with advantages over traditional sources. However, the current constraint with this source is the inadequate number of HSCs cells which can be harvested in a single collection using current approaches for transplantations.
Solution:
A precession-based device (i.e. amenable to be readily deployable in the delivery wards) that improves the harvest of stem cells is developed, integrating the various mechanical and electrical components on a single platform. This takes into consideration the needs of the various stakeholders.
Abstract
This invention is awarded the 2013 bed-to-beside innovation grant from the university, with strong collaborations from the Yong Loo Lin School of Medicine (NUS), the Design-Centric Program Team (NUS) and the biomedical incubator at the Biofactory (Singapore). The user-centric approach is adopted in this project to tackle the social and technical issues related to the harvesting of HSCs. In addition, a novel device (i.e. amenable to be readily deployable in the delivery wards) that will improve the harvest of stem cells is developed. Initial results have provided good motivation to proceed with the full scale development of the device.
Preliminaries
After discussions with the collaborating clinicians and doctors, a more in-depth understanding of the concepts of the anatomical structures related to stem cells is obtained. Given the level of fluid content within the placenta structure, the viscosity of the fluid, and the presence of the other complex bodies within the structure, a fluidic vortex flow could be created. Although this may cause the deviation or breakdown of the azimuthal circulation generated in the rotating body, such instabilities are some of the mechanisms of elliptic instability present in the system. With the inviscid fluid, it can be shown that there exists a class of solution with uniform vorticity whose direction rotates around the precession axis based on the linear inviscid theory [1]. This may eventually lead to more flow via the umbilical
cord. Precession could be applied to the placenta in a smaller footprint device. The precession technique will harness the restoring forces to drive fluid from the branched networks of vessels, through the flat chorionic plate & cord and into the collection vessel.
In developing a novel technique to extract stem cells, a detailed study of current available devices is conducted. The search is expanded to include publications as well as patents. This search yields several results. There are a few patents granted in the area of applying pressure to placental cord blood. They are as follows:
Paderni V. et al., Appartus for Extracting Fluids, 1999 [2].
Tan K.K. et al., Umbilical Cord Blood Collection Apparatus, 2006 [3].
For the work by Paderni V et al., one of the main shortcomings of this approach is the difficulty of the placenta to maintain a pressure that allows the placental blood to flow out due to the loss of the maternal pressure. Though, in Tan K.K. et al., efforts are made to mimic the maternal pressure on the placenta in the ex-utero setting, this approach do not ensure that the HSCs in the second and third order villi are able to flow out of the placenta network and eventually via the umbilical cord. In the proposed approach, the precession effect that creates coriolis forces on the primitive HSCs in the second and third order villi is utilized. This generated force tends to concentrate towards the central axis that runs through the umbilical cord.
The other current approaches [4-6] to UCB collection are predominantly in-utero, with the blood extracted with a syringe from the umbilical cord while the placenta is still in the maternal womb. Due to the time and space constraints, the blood collected this way is limited in volume (about 50mL) and thus, the number of HSCs to be harvested is correspondingly low, thus restricting the use of these HSCs mainly to pediatric treatment as only 25% of collections will meet the threshold required by 50kg adults.
There are a few recent methods that were developed over the last few years which aim to increase the yield of the collection of umbilical cord blood. These recent reported efforts are by teams from the Madrid Cord Blood bank and also the Department of Obstetrics and Gynecology at Haddassah University Hospital based in Jerusalem Israel [7]. It is noted that trained personnel is needed to execute the steps reported for the collection of the HSCs. It would be desirable if the collection system can be easily operated by the medical staff in the delivery wards. This will allow the collection process to be more seamlessly integrated into the whole flow after the harvesting of the placenta.
In view of the ethnography study and the review of the current approaches, an ex-utero approach that results in a compact and easy to operate device would be an amenable solution to be deployable in the delivery wards. This proposed approach will implement the precession effect that will lead to the dislodging of the primitive HSCs in the complex anatomical structure of the placenta. Subsequent cell verification work will be carried out to ensure the effectiveness of the proposed approach.
Architecture of the Prototype
Taking into considerations the needs of the various stakeholders and the current conditions in the delivery wards, an initial design of the HSCs harvesting device is developed. Considerations aside from usability and ergonomics consist of:
Able to withstand rotational speed of the placenta when the placenta is placed on the proposed device
Minimum frictional forces of the various rotating parts as non-linearity of such forces makes control difficult
Real-time and independent adjustments of control parameters in the device
The use of precession overcomes some of the concerns raised about the centrifugation technique. Precession could be applied to the placenta in a smaller footprint device. This will allow adoption by users who face space constraint.
The device could allow longer cord length due to the different possible design of the placenta holder without sacrificing size.
The precession technique will harness coriolis or the restoring forces to drive fluid from the branched networks of vessels, through the flat chorionic plate & cord and into the collection vessel.
After several rounds of design iteration/refinements, a preliminary design is implemented on a computer aided design (CAD) model as shown. The model and pictorial view of the prototype are shown in Figures 1 and 2. The prototype comprises of the following three components:
A placenta bowl with umbilical cord positioner,
An air-tight chamber with a controlled rotational application system,
An open-architecture software control system fulfilling the functionalities of the overall system.
These three components are modular in nature so that each can be modified or replaced, while the other components remain in use. This feature facilitates repeated operations using the same device. Collectively, the three components form an electro-mechanical apparatus which is able to manipulate the placenta via a combination of rotational forces, to maximize the flow of blood from the placenta to a collection tube. In addition, all the key components which may be directly or indirectly in contact with the placenta can be readily sterilized and are also designed to filter contaminants from the collected blood.
For the realization of the precession effect [1], the designs must allow for the manipulation of the rotation frequency about the principal axis w2, rotation frequency of the placental holder axis w1 and the tilt angle θ.
Hierarchical Control Structure
In view of the multi-dimensional and multi-variable nature of the precision control of complex motion structures, the hierarchical control structure is proposed as a framework that performs two main tasks:
Map from one system state to another
Online learning of the mapping using the existing states of the system
The proposed controller is hierarchical in nature. The higher level controllers combine the behavioral criteria from the lower level controller. In many cases, the low level behavioral criteria can be expressed in mathematical forms. The root level (i.e., first level) controller abstracts the desired behavioral criteria of some tuned (i.e., using well known theories like Ziegler Nicholas tuning criteria) controllers.
Individually, the states-based equation modeling the system of placenta holder motor (i.e. to manipulate the main axis w1 and the turn table motor (i.e. to manipulate the secondary axis w2) would be
(1)
(2)
where A= , B= , C=[1 0 0] , D= , and J are motor constants.
Let Ap be the matrix A in the states space equation of (1) of the placenta holder motor (i.e. to manipulate w1), Ab be the matrix A in the states space equation of (1) of the turn table motor (i.e. to manipulate w2). The overall equation of the system would be
(3)
The matrix p and b are both non zero matrices due to the interaction effects between the two axis. This gain-based controlled is implemented using NI LabVIEW (Figure 3) to control sequentially the various hardware components and off-the-shelf medical components.
Figure 1: Model of the prototype.
Figure 3: Closed-loop control of each axis of the motor. Initial Prototype Testing
The initial prototype is fabricated using common light-weight materials, like acrylic and aluminum. From reported literature [8], the current ways of collection typically recovers 40 to 200mL, and small volumes of only 20 to 40 mL are not infrequent. The prototype has been tested on 5 placenta units to-date. It is shown that even after the usual collection via the manual syringe method; the prototype is able to collect an incremental 30% of blood. It can be noted that with the fine-tuning of the various system parameters, the proposed approach will be able to perform even better.
Conclusion
In this paper, the preliminary results from the proof-of- concept for the development of a hematopoietic stem cells harvesting device are presented. The insights from the ethnographic study and the initial experiments help to understand the problem more. Further feasibility studies will be conducted to fine-tune the system.
References:
[1] J.J. Kobine, “Inertial wave dynamics in a rotating and precessing cylinder,” J. Fluid Mech., 303(1), 1995, pp. 233-252.
[2] V: Paderni, WO 98/07460 A1 (1998)
[3] K.Z. Tang and K.K. Tan, “Development of an automated umbilical cord blood collection system,” Artificial Cells, Blood Substitutes and Biotechnology, 34(1), 2006, pp. 75-88.
[4] H. Lazarus and M. Laughlin, Eds., Allogeneic Stem Cell Transplantation, Humana Pr Inc, 2009. [5] S. V. Rudmann, Eds., Textbook of blood banking and transfusion medicine, W B Saunders Co, 2005.
[6] B. Michael, B. Karen and M. Martin, “Cord Blood Unit Access and Selection: 2010 and Beyond: Best Practices and Emerging Trends in Cord Blood Unit Selection,” Biology of Blood and Marrow Transplantation, 17(1), 2011, pp. S46-S51.
[7] R. Bornstein and et al., “A modified cord blood collection method achieves sufficient cell levels for transplantation in most adult patients,” Stem Cells, 23(3), 2005, pp. 324-334.
[8] J. McCullough, G. Herr, and S. Lennon, “Factors influencing the availability of umbilical cord blood for banking and transplantation,” Transfusion, 38(3), 1998, pp. 508-510.
Author Information: Tang Kok Zuea
National University of Singapore Blk E1A, 1 Engineering Drive 2 Singapore 117576
