Mechatronics design principles forbiotechnology product developmentCarl-Fredrik Mandenius1 and Mats Bjorkman2

1 Division of Biotechnology/IFM2 Division of Assembly Technology /IEI, Linkoping University, S-581 83 Linkoping, Sweden

Opinion

Glossary

Active environment (AEnv): the unknown environmental effects that exert

unanticipated influences on the transformations.

Biological systems (SBioS): all biological systems, including cells and

biomolecules, which intentionally affect the transformations and may or may

not be consumed.

Management and goals systems (SM&GS): management activities and set

goals necessary for carrying out the transformations. This includes a set-point

of controllers and statistical process control methods.

Human systems (SHuS): the individuals involved in carrying out the

transformations, such as plant operators at the manufacturing site or

customers using the final product.

Information systems (SIS): information devices or software methods for

monitoring and controlling the transformations.

Ingoing operands (SOdIn): the input materials and/or information that are to

be transformed to final product. Examples are raw material components or

data.

Outgoing operands (SOdOut): the outgoing materials and/or information.

These are results of the transformations and are parts of the final product(s).

Secondary inputs (SecIn): secondary input materials and/or information that

are necessary for transforming the input operands, but are not included in the

final product(s).

Transformation process (TrP): the process which converts, reacts, or

rearranges the input operands, resulting in a final product. The TrP is a result

of the actions and effects caused by all of the systems involved.

Technical systems (STS): technical systems necessary for carrying out the

Traditionally, biotechnology design has focused on themanufacture of chemicals and biologics. Still, a majorityof biotechnology products that appear on the markettoday is the result of mechanical–electric (mechatronic)construction. For these, the biological components playdecisive roles in the design solution; the biological enti-ties are either integral parts of the design, or are trans-formed by the mechatronic system. This article explainshow the development and production engineeringdesign principles used for typical mechanical productscan be adapted to the demands of biotechnology pro-ducts, and how electronics, mechanics and biology canbe integrated more successfully. We discuss three emer-ging areas of biotechnology in which mechatronicdesign principles can apply: stem cell manufacture, arti-ficial organs, and bioreactors.

Conceptual design in mechanical engineeringIndustrial development and manufacturing of complexelectro-mechanical (mechatronic) products encompass awide variety of complex engineering achievements, ran-ging from large-scale applications, such as aircraft vehiclesand power plants, to highly miniaturized devices, such ascell phones and digitalized home electronics. Many bio-technological instruments and devices are inherently com-plex, and the incorporation of biological molecules andcells, which are responsible for achieving core device func-tions, as in biosensors, or are transformed within thedevices, as in bioreactors, adds to that complexity [1].

In mechanical engineering, the design methodology iswell-recognized and is used for training at engineeringschools throughout the world [2]. The two key elementsare: (i) the generation of conceptual solutions to thedesign problem; and (ii) the analysis of functions andstructures for alternative solutions. One of the recognizedmethods for generating and analyzing design solutions isthe Hubka–Eder theory for conceptual design [3,4]. It isbased on a careful description of the transformation thatwill be carried out by the designed machine, where theinputs are consumed and the outputs are created. Thesubparts are identified and described, and the entiretransformation process is divided into sequential and/or parallel steps that all contribute to its realization. Toachieve transformation, a variety of different systems arerequired; these different technical, human, information,management and control systems are all required for

Corresponding author: Mandenius, C.-F. (cfm@ifm.liu.se).

230 0167-7799/$ – see front matter � 2010 Elsevier

creating a desired transformation (Box 1). When Hubkaand Eder formed their theory in the 1980 s, they prim-arily envisioned product design for the mechanical indus-try [3], which typically included consumer products likecoffee machines and automobiles, as well as business-to-business products, such as electric turning lathes andheavy trucks. At that time, biotechnology products werenot considered.

However, the generic transformation process could beadopted by every bioengineer and adapted to transform-ations caused by biomolecules, enzymes or cells. In so doing,the inherent efficiency of the mechatronic design method-ology could be applied to biotechnology products. Thus, thebiological systems could be considered as parts of the tech-nical systems, or perhaps better, a systems entity of theirown [5]. For example, a laboratory bioreactor can berepresented in the Hubka–Eder model with its transform-ation of nutrients and media into biologics. The cell cultureinoculum is the active biological system and the reactorvessel with pumps and impeller comprise the technicalsystems. Electrodes and flow meters form the informationsystems. The control software with the operator interface isthe management system and the operators serve as thehuman systems (Figure 1).With this systematic structuringof the design parts and functions, the various design

transformations. This may include manufacturing machines, such as a motor,

in the final product. Formally, the TS are not consumed by the TrP.

Ltd. All rights reserved. doi:10.1016/j.tibtech.2010.02.002 Available online 23 March 2010

Box 1. Hubka–Eder theory

The Hubka–Eder theory for conceptual design was first presented in

1988 by Vladimir Hubka and Ernst Eder [3]. Figure 1 illustrates the

principle. Its fundament is the TrP with three recurring phases:

the preparation phase, the execution phase and the finishing phase.

The TrP is fed by primary input operands (SOdIn) – those inputs of

materials, energy or anything else that will be directly transformed –

and the secondary inputs (SSecIn) – those that are needed, but not

taken up by or in the final product. The primary output operands

(SOdOut) are the expected results of the transformation (i.e. a pure

protein, a produced recombinant protein or an analytical result), and

the secondary or residual outputs (SSecOut) are those that are not

included in the main products (by-products or un-used nutrients) [11].

To carry out the TrP, several technical systems (STS) are required

for realizing the phases of the TrP. In general terms, each TS causes a

decisive effect on the TrP, and their functionality, or ability to cause

the effect, is of vital interest for the design concept. Normally, the

number of STS is fairly large, but they can also be subdivided into

smaller parts that simplify the analysis at the expense of enlarging the

complexity of the STS.

The TrP and the STS require humans for operation. Normally,

several individuals with specific expertise are involved. Together,

they form the humans systems (SHuS) and are interdependent,

and exert their effects in unique ways. The STS and SHuS are

further supported by the information systems (SIS). These observe

the TrP and the effects of the STS. The SIS affect operation and

decision-making based on management and goal systems

(SM&GS); that is, set procedures on how to proceed or behave in

defined situations or according to established or regulatory

approved standards.

Finally, the Hubka–Eder theory introduces the active environment

(AEnv), which refers to the unpredictable variations that affect the

TrP and the systems in an unexpected way. This is recognized in

biotechnical systems as the ‘‘biological variation,’’ but might occur

in any technical systems (i.e. weather conditions). It is possible to

add the biological systems (SBioS) to the Hubka–Eder theory [6,12].

This could be justified especially for cells in biological media in

which the interactions and effects on the TrP and the other systems

described above deserve special attention and are intrinsically

complex to disentangle. Analyzing these effects in both directions;

how the SBioS are affected by the choice of STS alternatives, for

example, could be an important success factor for a biotechnology

product design.

Opinion Trends in Biotechnology Vol.28 No.5

concepts are amassed and analyzed (Box 1). In theory, anybiotechnology machine or apparatus can be reflected in thisprinciple, regardless of whether it is a protein purificationsystem,anaffinitybiosensor, ora spottedmicroarray instru-ment.

An alternative approach for advancing the mechatronicdesign methodology for biotechnological products and pro-duction design is the Ulrich–Eppinger method [6]. Itsstarting point is the identification of the users’ (or custo-mers’) needs for the ultimate product (Figure I in Box 2).The needs are specified in detail and the target values areset. With these boundary conditions, a multitude of con-ceptual design solutions are suggested. The solutions areevaluated and scored, with a few selected for final evalu-ation and further systematic testing and prototyping. Themanufacturing requirements can be superimposed ontothe scoring of the design concept so that the manufactur-ability aspects become decisive for the selection of altern-atives (Box 2). User needs are typically identifiable formost biotechnology devices and can be described withseveral target values, including purity, bioactivity, yieldand analytical sensitivity.

Both the Ulrich–Eppinger and Hubka–Eder approachesare highly applicable to any biotechnology product design.Here, we emphasize three mechatronic biotechnology pro-ducts that are complex, yet are the most relevant tobiotechnology today, and also the most demanding toanalyze.

Bioreactor designBioreactor design has experienced significant developmentduring the 1980s and 1990s. Key achievements have beendesigns for adherent cells, suspension cultures, scaling up,and coping with safety and regulatory restrictions.Changes to conditions and the market have influenced,and sometimes hampered, efficient development. In recentyears, much focus has been dedicated to analytical, high-throughput, micro-bioreactor devices [7–9], bioreactors formammalian and tissue cultures [10,11], and human stemcell culturing [12]. Development of these devices could be

substantially improved and facilitated if integrated into adesign process, such as the conceptual mechatronic designmethodology described herein.

The identification of the critical transformation process(TrP) and acting systems, according to the Hubka–Edertheory for the bioreactor shown in Figure 1, requires moredetail to serve as truly efficient design tools. This is done bydividing the systems into subsystems and even sub-sub-systems. When retrospectively analyzing a typical bio-reactor set-up, the exercise becomes transparent. Theidentification of the functional requirements for pumpsand valves (heating/cooling, gassing, sterilization, agita-tion) control loops, and pH and dissolved oxygen electrodesare critical for efficient operation of the entire system [13].This functional analysis benefits considerably if beingconsidered in the Hubka–Eder framework. However, whenthe first modern bioreactors were designed, many altern-atives were overlooked or, at least, not thoroughly con-sidered. Also, the functional analysis would have failed toanticipate and adapt more rapidly to changing conditionsconcerning preferred cell lines and increasing regulatorydemands. The considerable time lapse between the firstcontinuous stirred bioreactors and the wave bioreactormost likely could have been reduced with a more systema-tic design methodology.

As noted in Figure 1 and Figure 2, the functions of thetechnical systems (STS) are identified, but neither thedevices nor units carrying out the functions. Thus, thesame function can mostly be attained by more than onedevice or combination of devices. The Hubka–Eder methoddistinguishes between functional and anatomical (i.e.physical device) design charts. The generation of conceptsshould follow that order and the alternatives should beranked systematically to screen for the best alternative foraccomplishing the designed product specification [4]. Inthis way, design efficiency is strengthened.

Also useful in the design work are design effect matricesin which the cross-effects between the TrP phases and/orsystems and subsystems are compared (Figure 2). Impor-tantly, the diagonal line in the matrix is not a mirror; the

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Figure 1. The Hubka–Eder methodology applies to typical mechatronic products, such as a coffee machine, and to biotechnology products, such as a bioreactor. The basic

steps in the methodology are illustrated, including the identification of inputs and outputs, transformation stages and system functions. The basic steps are followed by

effect analysis and ranking of importance.

Opinion Trends in Biotechnology Vol.28 No.5

effects represented in the matrix are asymmetric on theopposite sides of the diagonal because effects in a designnormally exert different direction-dependent strengths.For example, the information systems in Figure 2 (e.g.pH or oxygen electrodes) do not affect the cell culture,whereas the cell culture affects the information of theelectrodes (which might also include drift and longerresponse effects). The Figure 2 matrix for the bioreactorsubsystems illustrates how to identify the crucial designissues, and indicates where special efforts should be dedi-cated. Different design concepts and solutions can be com-pared more easily via the design effect matrices in whichstrengths and weaknesses become apparent. A second, andeven a third, level of subsystems can then be added to thematrix.

Comparison of the wave bioreactor and the stirred tankbioreactor highlights the function of sterilization, by eitherpre-sterilized, single-use reactor bags or in situ, steriliz-able steel vessels. The function to maintain sterility for adefined time period, according to the users’ needs, can beachieved with both designs. The function of controlling pHcan be achieved either by a buffer medium or by infusing

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base or acid under agitation (wave motion or vigorousshaking/agitation by a turbine) to obtain a set range ofgas transfer values. The matrix exemplified in Figure 2should rank the impact of the design alternatives and, atan early stage, reveal the strengths and weaknesses of thebioreactor alternatives.

Artificial liver deviceRelated to bioreactor design is the engineering of artificialorgan devices [14,15]. Significant attention has been paidin the field of biomedical engineering to artificial liverconstructs, propelled by such applications as transplan-tation surgery and drug development and testing [16].Application of the Ulrich–Eppinger approach to the users’needs for an artificial liver device, from either a clinical or apharmacological standpoint, reveals the differences indesign requirements (Table 1) [14]. Setting target specifi-cations for these two applications illustrates the utility ofusing the Ulrich–Eppinger approach, which has seldombeen done systematically. As seen in Table 1, the rangesand values deviate much between the applications and, asa consequence, fundamentally influence the concept

Box 2. Ulrich–Eppinger approach

Karl Ulrich and Steven Eppinger at Massachusetts Institute of

Technology uncovered another approach for mechanical engineering

design in the early 1990 s [6], which can be applied to an engineering

team at any firm involved in product development. The Ulrich–

Eppinger approach presupposes that the team design mission is to

establish and manufacture a new product. Success on the market is a

key consideration. Thus, the design process starts with the identifica-

tion of the customers’ needs from all aspects: market, users and

manufacturing requirements. The needs are normally verbal and

qualitative. The next step is to specify the needs in detail and try to

apply metrics to them. At this stage it is difficult to assess the realism

of the specifications, but target values are set for the attributes

qualitatively or in ranges. The target specification directs the activity

in the third step, the concept generation, when a large number of

concepts is generated based on known techniques and material

properties. It is unrealistic to test and prototype all concepts,

therefore, these are screened towards criteria derived from the target

specification and are subsequently scored, or assessed, according to

target values (Figure I). With one or two concepts remaining after the

scoring assessment, prototypes are built and tested in thorough

testing programs.

Of particular interest is the integration of manufacturing require-

ments into the design, so-called Design-for-Manufacturing (DFM). The

aim of DFM is to ensure that those design concepts that are more

feasible for manufacturing become favored in the screening and

assessment process. For biotechnological products, it is important

that the biological attributes and relevant criteria for manufacture are

carefully considered when they are listed in the target specification.

These criteria should also be ranked high when scoring the

manufacturing alternatives. Thus, the biological experts of the team

must identify the biology-related manufacturing requirements early

and, if possible, also anticipate their cost effects.

Figure I. The main steps in the Ulrich–Eppinger approach are depicted sequentially, but are actually applied iteratively [6]. The selection of concepts is also a stepwise

iterative procedure with an initial screening of alternative courses followed by a detailed scoring and ranking.

Opinion Trends in Biotechnology Vol.28 No.5

generation step. For example, the user time for the sur-gical device is typically less than 48 h [17], while weeksare required for evaluating the long-term effects of drugs[18]. This has obvious consequences for the design free-dom. For transplant surgery, typically 600–1000 g of livertissue are required in each device to reach the capacity of ahuman liver organ; whereas for drug testing, the numberof hepatic cells required could be limited to only 103–104

cells per device, provided these cells adequatelymimic the3D behavior of the liver tissue. The need for paralleldevices is critical for achieving high-throughput function-ality and reducing cost during drug testing, whereastransplantation surgery requires one device only. Newconcepts and design solutions based on, for example,microfluidics [19], nano-scale arrays [16,20], ‘lab-on-a-chip’ devices [21] and sophisticated micro-scaffold struc-tures [17], rarely systematically evaluate the specifiedcriteria shown in Table 1. Systematic comparison byapplying the Hubka–Eder or Ulrich–Eppinger method-ology could facilitate the design process and improvethe design at earlier stages.

Design concepts are generated based on the differenttarget values set in the specification. The number of gener-ated ideas can, at this stage, be overwhelming. However, acritical selection procedure based on screening and scoringassessments derived from the criteria in the target specifi-cation can significantly reduce the number of design con-cepts. This is followed by ranking based on experimentsusing prototypes with different architectures and materialoptions. Scrutiny of several published design alternatives inthe literature might give the impression that a systematicdesign methodology is seldom (or never) applied for thedemonstrated stand-alone solutions. However, theseremarks should not be viewed as criticism; the efforts,sometimes accomplished with limited financial resources,have undoubtedly provided the science with inspired andinventive solutions which, in a more evolutionary manner,havebeenrefinedwithvaluablefinal results.Thestructuredand holistic approaches of the Hubka–Eder and Ulrich–

Eppinger methodologies could be of decisive importancein uncovering interactions that would be otherwise unrec-ognized in a traditional engineering design approach.

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Figure 2. A design effect matrix for the involved systems and subsystems of a bioreactor. Effect strengths are ranked for revealing which design solution components are

the most sensitive or decisive for the product. The X and Y arrows show the directions of the effects (i.e. the effect of cell growth on metabolic conversion, gene expression,

etc. is seen along the x-axis, and the effect of metabolic conversion on cell growth, gene expression, etc. is seen along the y-axis). Colors indicate strength of effect.

Opinion Trends in Biotechnology Vol.28 No.5

Stem cell manufactureAnother novel biotechnology application that exemplifiesthe combined complexity of mechanics, electronics andbiological transformations is the automated productionof stem cell-derived tissue and organ cells. Given that stemcell technology is still in its infancy and new and improveddifferentiation procedures are constantly emerging, itcould be regarded as premature to try to settle manufac-turing principles at this stage. Nonetheless, this sectioncovers a number of issues that must be addressed system-atically in the design of manufacturing systems; severalcrucial steps include the expansion stage of the production[22], control of differentiation [23], analysis and in-processcontrol [24], and automation and scale-up [25]. Addition-ally, if manufacturing demands can influence the ingenuityof the technology positively and generate procedures betterequipped to manufacture stem cells on a large scale, thenthis would be a marked accomplishment, and would alsocomply with the Design-for-Manufacturing (DFM) conceptmentioned in Box 2 [26].

A simplified overview scheme for stem cell productionfrom embryos to target organ cells, including some of the

Table 1. Examples of target specifications for artificial liver device

Specification attributes Applications

Clinical measurements fo

surgery support

Amount of liver cells required per device 600–1000 g liver tissue

Temperature range 37�0.2 8C3D tissue structure Liver-like at steady-state

Expression of select biomarkers CYP1A2, CYP2A6, CYP3A4

Acceptable construction materials Silicone, acrylic polymers

Oxygen/carbon dioxide exchange rate 0.10–0.20 mg/g cells/min

Sterility requirement > 48 h

Stability requirement Stable for 48 h

Analytical capacity None required

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technical equipment needed along the differentiation route,is illustrated inFigure3a.Ofnote is the long scale-up timeof3–4 weeks from start to finished product. The TrP, withinputs of embryonic stem cells, media, feeder cells, andgrowth and differentiation factors, are clearly identifiable[23]. The technical systems required for handling the TrP,such as robots, micro-manipulators and cryopreservationequipment, are complex and sophisticated components,which, when merged into a larger system, make the man-ufacturing even more complex. The important role of theinformation systems (SIS) is to monitor, verify and controlthe quality of the stemcells at thedifferent process stages byusing imaging methods, PCR analysis, and various immu-nofluorescence detection instruments and software. Also,the SISmonitors the operations of the STS. In this way, theSIS aims to interpret data and is the key to successfulproduction. In the SM&GS, the Good Manufacturing Prac-tice and Standard Operation Procedure protocols for theproduction facility are included. The human systems(SHuS) that carry outmanyof themanual operationsduringprocessing are more important than in other bioprocessesthat are more easily automated. After identifying the

s for different applications

r Pharmacological measurements for

toxicity testing

103–105 hepatic cells

32–37 8CLiver-like at steady-state

CYP1A2, CYP2A6, CYP3A4, GSTA1-1, OATP-B

and polysulfone Acrylic polymers and steel

0.10–0.20 mg/g cells/min

> 3 weeks

Stable for 2 weeks

100–400 samples per day

Figure 3. (a) Stem cell differentiation procedures are highly complex in a manufacturing scenario, especially when analyzing interactions with involved analytical, robotic,

regulatory and human systems. (b) When correctly applied, the Hubka–Eder methodology and its supporting techniques provide a convenient tool for stem cell

manufacture analysis.

Opinion Trends in Biotechnology Vol.28 No.5

systems, a Hubka–Eder representation of the process isdeveloped (Figure 3b) Again, the cross-effects and inter-actions between the required functions need to be assessedand alternative solutions considered. The design effectmatrix becomes a useful tool for this, as shown in Figure 2.

Concluding remarksMechatronic design principles have great potential forimproving product development in biotechnology. Theestablished mechatronic design methodology, such asthe Ulrich–Eppinger and Hubka–Eder methods, can easily

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Opinion Trends in Biotechnology Vol.28 No.5

be adapted to biotechnology applications. The threeexamples described in this review serve as elucidatingexamples of how the analysis of design concepts can bebetter structured for biotechnology products. This leads toseveral advantages of the design process: it is simplified,it follows a settled procedure, and it allows continuous(re)evaluation.

In industrial practice, the design work is a team activitythat is iterated over a period of time. Gradually, the level ofdetail in the designwork becomes dense and complex itself,which reveals the advantages of following an establishedand transparent methodology that is proven to work and iswidely accepted. Also, the work is significantly facilitated ifit is communicated and managed with the support of awell-structured design methodology [27]. Especially forcompanies with limited resources, a streamlined method-ology for development is advantageous since it reducesupfront costs and shortens time-to-market. It is difficultto verify completely the utility of the mechatronic designmethodology in industrial practice because product devel-opment spans over long periods during which conditionsfrequently change. An example of successful industrialproduct development is the surface plasmon resonancebiosensor for which substantial portions of the Ulrich–

Eppinger design methodology were identified [5]. Appli-cation of the Hubka–Eder and Ulrich–Eppinger method-ologies seems especially appropriate for areas in earlystages of industrial development, such as artificialorgan-simulating devices and embryonic stem cell manu-facturing. Process Analytical Technology and Quality-by-Design application to biotechnology manufacturing areexamples of other emerging areas in which the mechatro-nic methodology can facilitate the design of complex pro-duction systems [28,29].

The main purpose of the mechatronic conceptual designtheory is to accelerate the work process and to improveoverall product quality. This is a common goal for allengineering design. By applying the mechatronic method-ology to biotechnological product design, greater develop-ment efficiency is expectedwith decreased time and cost forindustrial exploitation.

AcknowledgementsThe authors would like to thank the Swedish Governmental Agency forInnovation Systems (VINNOVA) for financial support.

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