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3 Requirements for Validation of Single Organ/Tissue Bioreactors

3 Requirements for Validation of Single Organ/Tissue Bioreactors

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substantially, pathway and group of chemicals studied. Importantly, it is mandatory

that the data collected by in vitro culture in bioreactors is correlated to existent in

vivo data and that the new standards generated for validation are based on this correlation regarding levels of activity, rates of perfusion, doses, etc. The new standards

generated for validation should not only encompass general features, such as basic

integrity and metabolic activity, but should also be directed at specific modes of

action for groups of chemicals. This implies that a combination of data from multiple tests is performed by the use of chemical categories/grouping using “Integrated

Testing Strategies”, as has been proposed by experts in toxicology and gradually

accepted by the regulatory agencies (Lilienblum et al. 2008; Hartung et al. 2013).

The significant progress in bioreactor-based single organ modelling at ever

decreasing scale “first in history” provides a basis for organ integration into systems

of true organismal complexity. Being developed in this way, such “human-on-achip” systems might mark a translational paradigm shift in safety and efficacy

assessment in the future, eventually enabling mode of action analysis and adverse

outcome pathway assessment at a level currently reserved for animal testing and

clinical trials in man. These novel “human-on-a-chip” strategies are overviewed in

the next section of this chapter.



2

2.1



Human-on-a-Chip Devices for Chemical Safety Assessment

Introduction



Strategies to develop “human-on-a-chip” technologies are applying microphysiological systems towards the in vitro combination of miniaturized human

organ equivalents into functional human micro-organisms. These aim to replace

systemic toxicity testing and efficacy assessment of therapeutic agents, food additives, chemicals, or environmental pollutants in laboratory animals and might generate predictive data to humans safety and efficacy evaluation prior to substance

exposure to humans. Therefore, the technologies need to functionally represent

normal and diseased human biology at the smallest possible scale at reproducible

and viable operation under physiological or pathological conditions over long periods of time. If these are generated from the respective donor or patient tissue

sources, they bear the capacity for the representation of normal and disease phenotypes and population diversity. Finally, they are amenable to high-content screening due to their small size. Such “human-on-a-chip” technologies are at an early

stage of development, but a prime top-down US initiative between DARPA

(Defence Advanced Research Projects Agency), NIH (National Institutes of

Health) and the FDA (Food and Drug Administration), with more than USD 140

million investment into respective developments (http://www.ncats.nih.gov/

research/reengineering/tissue-chip/funding/funding.html) and a number of significant development investments in Europe, has initiated an irreversible process

toward success in this area.



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2.2



S.P. Rebelo et al.



Historical Sketch (Toward Organismal Engineering)



Over the last hundred years, scientists have been trying to emulate human tissue architecture and microenvironment in vitro in order to gain mechanistic knowledge and to

assist with the development of new medicines. Interestingly, as early as 1912, Alexis

Carrel (Rockefeller Institute for Medical Research, New York) said “On the permanent life of tissues outside of the organism” (Carrel 1912), that some in vitro “cultures

could be maintained in active life for 50, 55 and even for 60 days”. These results

demonstrated that the early death of tissues cultivated in vitro was preventable and

“therefore that their permanent life was not impossible”. At that time, synthetic cell

culture media, antibiotics, disposable tissue culture flasks, aseptic techniques, and

bioreactors were not available. About two decades later, an avian bone more than

7 mm long and with clear signs of calcification could be produced in vitro from

embryonic cells (Fell and Robison 1929). Interestingly, some of the early human histotypic cultures, such as Dexter and Lajatha’s culture of human haematopoietic SCs

on feeder layers, demonstrated the crucial importance of the interaction of different

primary human cell types with each other to form human-like growth and functionality (Dexter and Lajtha 1974). It took more than half a century to recognise that static

tissue cultures in flasks or petri dishes with media levels higher than 1.2 mm generate

a non-physiological low level of oxygen supply for primary liver cells from humans

and rodents (McLimans et al. 1968). It became obvious that true emulation of human

biology in vitro needs to be established on primary human cells, carrying the genotypic information of their respective donors. Furthermore, embryonic SCs give rise to

ectoderm, mesoderm and endoderm early in human embryonic development. Rapid

pluripotent SC proliferation and cell differentiation into various tissues, which is

induced by local microenvironments, continues from fertilization to beyond adolescence, during which organs mature at different rates before functional homeostasis is

reached. Should a xenobiotic cause organ or tissue damage, regenerative processes

attempt to restore this homeostasis by the renewal of damaged tissue. Thus, biological

substrates from the early development of human individuals might provide a valid cell

source for the in vitro modelling of organ functionality and organ regeneration. Human

embryonic SC technologies (Ben-David et al. 2012), and, more recently, induced pluripotent SC technologies (Takahashi et al. 2007; Inoue et al. 2014) have provided

nearly unlimited access to human tissues for the in vitro emulation of organs. First

impressive results of human organoid self-assembly from embryonic SC sources are

demonstrated in literature, for example, for the generation of miniaturized gut equivalents (Spence et al. 2011) and human mini-brains (Lancaster et al. 2013).

In a next step, it has become clear that, in addition to efficient oxygen and nutrient

supply, a local microenvironment with appropriate mechanicochemical coupling

achieved by regulating interstitial flow or applying external stresses is a crucial prerequisite for mimicking the in vivo biology of individual organs at stable homeostasis over

long periods (Griffith and Swartz 2006). Finally, in vitro-generated individual organs

should be interconnected properly to represent the functionality of a human organism.

First attempts to interconnect different cell types or tissues at a miniaturized chip scale

through microchannels, applying microsystem technologies were reported in literature



12 Validation of Bioreactor and Human-on-a-Chip Devices…



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(Hwan et al. 2009; Zhang et al. 2009; Sung et al. 2010; Imura et al. 2010). A long-term

stable homeostasis between human 3D liver spheroids and skin biopsies on a chip were

demonstrated recently (Wagner et al. 2013). In the human body, organs are interconnected by a vascular network entirely lined by human endothelial cells, representing

nature’s blood-tissue barrier. The endothelial cell layer communicates with the tissue

and signals into the blood stream to recruit, for example, leucocytes into a region of local

damage in the organism. Finally, a closed endothelial cell layer prevents blood cells

from bleeding into tissue and clotting. Different approaches to establish human vasculature in vitro at a mini-scale through the so-called BioVaSc technology (Mertsching et al.

2009; Schanz et al. 2010; Scheller et al. 2013) and at microscale on chips (Yeon et al.

2012; Kim et al. 2013; Schimek et al. 2013; Lee et al. 2014) have been published in the

past. Summarizing the historical developments: After more than 100 years of in vitro

cell cultures, all technological prerequisites to emulate a human organism at miniature

scale are in place. The question remains how many organs are necessary to achieve

organismal complexity and how small can we go?



2.3



Human-on-a-Chip Systems: The Concept



Nowadays, systemic single and repeated dose safety assessment, disease modelling,

systemic testing, and efficacy evaluation of substances are carried out on laboratory

animals and in humans due to the lack of predictive alternatives. Relevant international guidelines for chemical testing—OECD test guidelines 407, 408, 410–413,

419, and 453—demand 28-day, 90-day and 12 month test durations, and oral, dermal

and inhalation exposure routes in groups of 25–50 animals per substance for safety

assessment. The toxicity testing of pharmaceuticals often adheres to approximately

the same number and species of animal per drug candidate, and lasts from weeks to

months, whilst safety testing in humans usually requires 60–100 healthy volunteers

who are exposed over days and weeks. Notably, the use of animal disease models for

the efficacy evaluation of drug candidates has increased rapidly over the last decade.

Once an animal model is accepted as a suitable representation of a specific human

disease, substance testing is commonly carried out over weeks and months in groups

of several hundred animals, similar to human patients in clinical phase 2 trials. A

translational alternative to these tests and trials should ideally narrow down the phylogenetic distance between laboratory animals and human beings, and close the biosimilarity gap between the current single “organ-on-a-chip” and human beings.

The definition of spatial-temporal biological levels is of outstanding importance

for “human-on-a-chip” concepts, due to the biological fidelity of a human individual during their lifespan. It is evident in substance testing and disease modelling

arenas, that prenatal development, childhood and adulthood, at gender level are discrete phases of human biology in an individual’s lifespan. Considering the everincreasing human lifespan, senescence is envisaged as a new category which can

hardly be modelled using laboratory animals. In addition, the period of pregnancy

is also a category to be considered. Current “human-on-a-chip” developments focus

on the emulation of non-pregnant adulthood, as this time span has the largest



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numeric relevance for safety and efficacy testing. Steadily improving concepts

towards the “human-on-a-chip” have been reviewed in literature (Huh et al. 2011;

Shuler 2012; Marx et al. 2012; van de Stolpe and den Toonder 2013). The aforementioned DARPA-NIH-FDA US initiative has postulated, that organs from the

following ten systems should be interconnected in a biological manner to gain

human organismal homeostasis in vitro: circulatory, endocrine, gastrointestinal,

immune, integumentary, musculoskeletal, nervous, reproductive, respiratory, and

urinary. With regard to the scale of chip-based organisms, the first approaches to

calculate a biologically representative scale-down of human organs have been published (Moraes et al. 2013; Wikswo et al. 2013). We have recently published a possible design of such a “human-on-a-chip” with a scaling mechanism, taking into

account the organoid structure of each and every organ (Giese and Marx 2014).



2.4



A Validation Roadmap for Upcoming “Human-on-a-Chip”

Solutions



Once “human-on-a-chip” concepts turn into solutions capable of replacing systemic

substance testing in animals, their qualification and validation strategies should

adhere to the latest standards of qualification and validation and might be compared

to those laboratory animal tests, which they aim to replace. There are two procedural pathways aiming at the validation of a “human-on-a-chip” based test assay

within the current regulatory landscape in US and Europe.

Firstly, if the “human-on-a-chip” based model aims to replace the animal model qualified through the new US FDA validation strategy of Drug Development Tools (DDT), the

validation programme should adhere to exactly the same criteria. The aforementioned

FDA DDT Qualification Programme involves a “fit-for-purpose” qualification. Once an

animal model is qualified for a specific context of use as a DTT, industry can use the tool

for the qualified purpose during product development, and FDA reviewers can be confident in applying the DDT without the underlying supporting data. Qualification of an

animal model according to this Animal Model Qualification Programme of the FDA is

voluntary (i.e. not required for product approval or licensure under the Animal Rule). The

qualification process is limited to animal models used for product approval under the

Animal Rule. A qualified model may be used for efficacy testing in development programmes for multiple investigational drugs for the same disease or condition targeted.

Such animal models are considered to be product-independent (i.e. not linked to a specific

drug). The regulatory pathway above mentioned should apply equally to a “human-on-achip” solution, replacing the respective animal model and, therefore, should be a possible

and reliable road map leading towards fast and pragmatic validation.

Secondly, for the validation of “human-on-a-chip” models aiming to replace the

animal models used in the aforementioned OECD guidelines in chemical safety

assessment, the adherence to existing OECD Guidance Document on Validation of

test methods for hazard assessment (OECD 2005), the EMA guideline on regulatory

acceptance of 3R methods and qualification of novel methodologies for drug development (EMEA/CHMP/SAWP/72894/2008 Corr1), via the EMA Scientific Advice



12 Validation of Bioreactor and Human-on-a-Chip Devices…



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Working Party (SAWP) and the recommendation of the ICH Safety Topic

Recommendation Working Group could be instrumental. In other words, the following validation principles should apply to validate a “human-on-a-chip” based assay,

for example, to replace the current technical guideline OECD TG 410 on “Repeated

Dose Dermal Toxicity: 21/28-day Study” in adult rat, rabbit or guinea pigs:

1. Bioreactor equipment operating the “human-on-a-chip” solutions should be

qualified according to standard IQ, OQ and PQ procedures (installation-, operation- and performance qualification).

2. Test design should address the endpoints covered by the existing test guidelines

3. Representative groups of substances for validation should be used with prior coordination with the respective regulatory agency.

In addition, the validation process should consider the recommendations of the

aforementioned sources.

As of today, a subsequent combination of the two validation pathways, as shown

in Fig. 12.1, seems to be the most efficient road map toward validation of upcoming

“human-on-a-chip” solutions.



Fig. 12.1 A possible stepwise validation roadmap for upcoming human-on-a-chip solutions



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Acknowledgement The authors acknowledge Fundaỗóo para a Ciờncia e Tecnologia, Portugal,

for the financial support provided by the grants PTDC/EBB-BIO/112786/2009 and SFRH/

BD/70264/2010.



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Chapter 13



Integrated Approaches to Testing

and Assessment

Andrew P. Worth and Grace Patlewicz



Abstract In this chapter, we explain how Integrated Approaches to Testing and

Assessment (IATA) offer a means of integrating and translating the data generated

by toxicity testing methods, thereby serving as flexible and suitable tools for toxicological decision making in the twenty-first century. In addition to traditional in vitro

and in vivo testing methods, IATA are increasingly incorporating newly developed

in vitro systems and measurement technologies such as high throughput screening

and high content imaging. Computational approaches are also being used in IATA

development, both as a means of generating data (e.g. QSARs), interpreting data

(bioinformatics and chemoinformatics), and as a means of integrating multiple

sources of data (e.g. expert systems, bayesian models). Decision analytic methods

derived from socioeconomic theory can also play a role in developing flexible and

optimal IATA solutions. Some of the challenges involved in the development, validation and implementation of IATA are also discussed.

Keywords Integrated approach to testing and assessment (IATA) • Integrated testing strategy (ITS) • Predictive toxicology • Adverse outcome pathway • Chemical

safety assessment



A.P. Worth (*)

European Commission, Joint Research Centre (JRC), Ispra, Italy

e-mail: andrew.worth@ec.europa.eu

G. Patlewicz

Dupont Haskell Global Centers for Health and Environmental Sciences, Newark, DE, USA

National Center for Computational Toxicology (NCCT), US Environmental Protection

Agency (EPA), Research Triangle Park, NC 27711, USA

© Springer International Publishing Switzerland 2016

C. Eskes, M. Whelan (eds.), Validation of Alternative Methods for Toxicity Testing,

Advances in Experimental Medicine and Biology 856,

DOI 10.1007/978-3-319-33826-2_13



317



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