**4. Organoid cell atlas**

Organoids holds promise as a propitious platform in biomedical research and applications for many decades to come. Human organoids currently have a few limitations that require to be circumvented to appreciate their full potential. Some technical and conceptual limitations may be addressed using single-cell sequencing and spatial profiling. Single-cell transcriptome/ epigenome sequencing and spatial profiling can provide a thorough idea about the composition of cells and the state of cells present within the organoids, which may help develop organoids as futuristic models of human biology. In combination with the Human organoids and single-cell technology, a pilot project has been launched within the Human Cell Atlas (HCA) as a "Biological network" (https://www.humancellatlas.org/euh2020/) [54]. HCA is a revolutionary global collaborative initiative aiming at advancing biomedical research opportunities and therapy using single-cell technologies (https://hca-organoid.eu/). This pilot project, under HCA, focuses on the single-cell characterization of organoids and other complex *in vitro* systems. It has been established to foster the assembly, internal control, dissemination, utilization, and linking of such big human organoidassociated datasets [54–56].

It is one of the six pilot projects funded by the European Union (EU) Horizon 2020 Framework Programme, which will be helpful in developing the first version of the Organoid Cell Atlas, which may be used as a nucleus for a broader, collaborative, global initiative. The HCA-Organoid association has eight partner Institutions, including EMBL's European Bioinformatics Institute institutions having experts in organoid technology, single-cell profiling, advanced imaging, and bioinformatics from Austria, Germany, the Netherlands, and Switzerland, and received €5 million by EU funding, as a part of the European contribution to the HCA project. Currently, the project mainly focuses on generating single-cell transcriptome, epigenome maps, and detailed imaging data in a selection of human organoids. The initial objective of the funded project is to derive and characterize two organoids, colon and brain, from 100 whole-genome-sequence individuals each, to have a record of normal population variation and have a reference for disease-centric research [56].

The colon and brain organoids were one of the first organs to which organoids were demonstrated, so comparatively, more advanced protocols for the two are available with HCA [2, 23]. Apart from this, the colon organoids are derived from adult stem cells while the brain is from the iPSCs, thus spanning the two primary sources of organoid derivation. Both of them have primarily been used for disease-centric studies. If the single-cell characterization of these organoids is done for many individuals, this can help facilitate various biomedical applications. Beyond the initial target, most of the data information in the project is generalized in a way to be applicable to various other types of human organoids. The HCA has also spoken about the possibility that they can collaborate with other institutes for different projects, which can pursue systematic single-cell profiling in other types of human organoids, to explore the possibility of interrelation with the Organoid Cell Atlas [56].

The main aim of the EU H2020 HCA-Organoid project is to build an Organoid cell atlas portal that may be equipped with the computational infrastructure and a web-based front end that makes the data easily accessible and analyzed. Some of the organoid-specific features that have been focused on while developing an Organoid portal include the interactive exploration of human organoid data, data-driven selection of organoids for functional experiments, and comparison of disease-specific organoids against reference collections of normal organoids.

This portal also focuses on providing the data of the corresponding primary tissues available in the HCA and also will work on showing interactive mappings between single-cell profiles of human organoids. These may be achieved using the algorithms that enable cell-cell alignments between these datasets. This portal is supposed to facilitate the use of organoids in biomedical experiments and encourage the use of organoids as models in various experiments like precision medicine, drug development, disease modeling, etc. Mapping and data integration may detect normal variation between individuals in an interactive manner showcasing organoid as the capable model for the corresponding variation in primary tissues. The analysis and interpretations of disturbances in the human organoids related to the primary tissues will be performed using cell-cell alignments [56].

A set of strategies have been laid to develop the atlas to be most productive and of high quality. Initially, it was thought to invest in validation and standardization for organoid-related research. Later, a contribution towards the HCA to establish community standards and software infrastructure for data processing and data annotation was strategized. Then the development and validation of computational methods for the comparison of cells between organoids and corresponding primary tissues and their flexible alignments were implemented. Finally, the implementation of interactive visualization tools that helps in establishing user-friendly quality control and exploratory analysis of single-cell organoid datasets contributed to the Organoid Cell Atlas [55].

## **5. Commercialization of organoids**

With the development and successful commercialization of organoids, the most demanded sector in treating patients and pre-clinical trials in pharmaceutical industries will give a slanting graph in the market in the future [57]. In this present era, many specific and most suitable techniques have been developing over the years for organoid research, leading to competition among industries worldwide. The annual cost of treating brain diseases in Europe is \$798 billion, and globally it amounts to \$3 *Organoids and Commercialization DOI: http://dx.doi.org/10.5772/intechopen.104706*

trillion. Over 90% of novel drugs that are being developed for brain diseases fail during the developmental process, which further reinforces the scope and opportunities for organoids [2]. The development of the living human brain (LHB) enables culturing of human-derived brain organoids from the cells of any individual; the University of Helsinki provides a new technical idea for preclinical trials of drugs in this area. Helsinki Innovation Services Ltd (HIS) supports the commercialization projects of the University of Helsinki from the funding application stage to completion.

Many startups such as XILIS, CELLESCE, SYSTEM1 BIOSCIENCES, 3DYNAMICS, PATH BIOANALYTICS, KNOWN MEDICINE, CYPRE, DYNOMICS are currently working in the domain of organoid technology. XILIS is developing a patient-derived miniature organoid technology to upgrade precision medicine and pharmaceutical drug discovery; their needed materials lead to 30× speed, 50× throughput, and 300× cost-saving (Hans Clever includes in the founding team of XILIS). CELLESCE is a UK-based startup that invented a bio-processing technology intended to grow and expand organoids in drug discovery and regenerative medicine. \$25 million of Series A venture funding is raised in SYSTEM1 BIOSCIENCES incorporation with Charles River Ventures and Pfizer Ventures, upgrading neuro drug discovery through the combined action of human brain models, scaled biology, and machine learning to interpret brain disease from genetics to neural computation. Also, KNOWN MEDICINE raised a total of \$2.4 M from Khosla, Cota Capital, and Y-Combinator, offering cutting-edge biology research and the latest AI techniques, giving oncologists an easy spot for treating patient's tumors with the best suitable drug. PATH BIOANALYTICS does bioanalysis of Phenotypic drug discovery and development. CYPRE is developing a tumor model platform intended for transformative 3D cellular research and clinical testing of cancer patients with seed funding from Hemi Ventures and others. DYNOMICS received \$500K in pre-seed funding from Boost VC. The details of the organoid-specific startups are presented in **Table 1**. These different startups contribute a vast platform to save millions of people's life [58]. Several companies are also operational in the tumor organoid domain, like Charles River and CROWNBio.


#### **Table 1.**

*The current leaders in the commercialization of organoids, their geographical location, and application areas.*

Despite using pre-clinical trials in animal models, concerns are raised about whether the animals will be extinct if used over the years. This will lead to the depletion of species and a significant effect on the ecosystem. Moreover, they may lead to harmful effects on the environment once mutated and released. The Animal Welfare Act of 1970 was implemented in the United States and set standards for animal use and care in research. Three principles of the Act are (1) experiments must be proven necessary for instruction or to save or prolong human life, (2) animals must be appropriately anesthetized, (3) animals must be killed as soon as the experiment is over. Much to our intrigue, different types of organoids such as kidney organoids, lung organoids, liver organoids, intestine organoids, brain organoids, etc., can substitute such animal models in preclinical trials for drug discovery and precision medicine. Even self-organ plantation may occur with the continuous development of organoids.

Globally, the expenses of organ transplantation and post-transplantation maintenance treatment are quite expensive but varies according to variables such as geographical location, medical facility, transplant organ type, and access to insurance coverage [59]. Private hospitals in India now charge around INR 10 lakh to INR 30 lakh for a heart transplant, while in USA, the charges can be very high ~\$1,664,800.00 (https://www.statista.com/statistics/808471/organ-transplantation-costs-us/). While the cost of a kidney transplant goes from INR 5 lakh to INR 20 lakh, while in USA it can be around ~\$442,500.00. The cost of a liver transplant runs from INR 15 lakh to INR 35 lakh, and ~\$878,400.00 in the USA. The eventuality of the unaffordability of such expensive treatment modalities led to the demise of a multitude. Furthermore, organ transplants from other donors are sometimes associated with organ rejection and the onset of auto-immune disease. It is not only the high cost of transplant but also the availability and transport of organs is a major issue in many countries. Though the number of donors have increased but the needs have also reached new heights [59]. One-third of all organ transplants fail due to rejection due to multiple reasons including HLA mismatch and alloantibodies [60]. While modern medicine has halted acute rejection but chronic rejection is a major challenge. The organoid technology may provide a realistic patform to design transplantable tissues in a dish thereby catering to the transplant problem in the near future as current limitation prevent organoids from meeting these expectations.

Another recent scientific area where organoids showed great potential was during the COVID-19 pandemic caused by the SARS-CoV-2 coronavirus. SARS-CoV-2 causes respiratory illness and multi-organ dysfunction. Scientists were scrambling to test experimental COVID-19 systemic medicines. Organoids were used to study the adverse effects of SARS-CoV-2 infection on human tissues and for the investigation of prospective therapeutic approaches. With the recent work on mini lungs organoids, a few of the drugs stemmed from the infection of the organoid models, representing a handful of possible treatments for COVID-19 [26]. Scientists must still develop methods to produce more complicated systems, such immune cells and blood arteries, to fully harness the technology [26]. Scientists must also find a way to swiftly and inexpensively produce thousands of identical organoids. Bioprinting is a potential new fast prototyping method that prints cells and accompanying matrices in 3D. Organoid bioprinting uses hydrogel-based bioinks to deposit various cell types that stimulate physiological signaling and can help commercialize the platform faster [61].

According to a study published by Fior Markets, the global organoids, and spheroids market is predicted to increase from USD 502.92 million in 2019 to USD 2794.79 million in 2027, with a CAGR of 23.91% from 2020 to 2027 [57, 62]. Till now, 19 companies are having an interest in organoid commercialization. Some of them

#### *Organoids and Commercialization DOI: http://dx.doi.org/10.5772/intechopen.104706*

are Thermo Fisher Scientific (Waltham, MA, USA), Merck (Kenilworth, NJ, USA), Corning (Corning, NY, USA), STEMCELL Technologies (Vancouver, Canada), Lonza (Basel, Switzerland), Prellis Biologics (San Francisco, CA, USA), Amsbio (Abingdon, UK), Cellesce (Cardiff, UK), DefiniGEN (Cambridge, UK), OcellO B.V. (Leiden, Netherlands), HUB Organoid Technology (Utrecht, Netherlands), 3Dnamics Inc. (Baltimore, MD, USA), Organoid Therapeutics (Pittsburgh, PA, USA), InSphero (Schlieren, Switzerland), etc. Organome (Baltimore, USA) and HUB (Hubrecht Organoid Technology) are dedicated to organoid biobanking, and other companies aim at manufacturing, organoid marketing, other related technologies. SUN Biosciences (Lausanne, Switzerland) and System1 Biosciences (San Francisco, CA, USA) use robotic automation tools for organoid generation. The semi-automated process enabled researchers to make retinal organoid production and selection faster using the algorithm. The MIMETAS (Leiden, Netherlands)—the organ-on-a-chip company, offers the second-best cell-based model after humans, using human cells growing in three-dimensional structures called Mimetas'OrganoPlates (microfluidics-based culture plates allowing culturing and screening of a range of organ and tissue models), which are affordable and available for nonspecialized end-users. With a consumption market share of about 46% in 2019, North America is the most important consumer of organoids, with Europe in second place. Key manufacturers of the global organoids market are Thermo Fischer Scientific, Merck, and Corning. The top three players took up a market share of about 75% in 2019. Byers of the report can access verified and reliable market forecasts, including those for the overall size of the global organoids' market in terms of revenue. The Organoids' market is segmented into 3D Organoid Culture and Biochemical Cues. In the case of Organoids application, the leading players are Biopharmaceutical Companies, Contract Research Organizations, Academics, and Research Institutes. The regional analysis covers North America (USA, Canada, and Mexico), Europe (Germany, France, UK, Russia, and Italy), Asia-Pacific (China, Japan, Korea, India, and Southeast Asia), South America (Brazil, Argentina, Columbia, etc.), Middle East and Africa (Saudi Arabia, UAE, Egypt, Nigeria, and South Africa) and predicts an upsurge in the usage of organoid technology across the globe in future.

Organoid Biobank is like a commercial bank with a similar modus operandi. In organoid biobank, collected samples from different sources such as stem cells, primary tissues, and biopsies were made into organoids and stored. The organoid samples can be taken from a healthy individual and a patient. These stored organoids are ready to use for different purposes. Organoid biobanks manage the database of organoids and a registry with all the patient details. These stored organoids can be tracked and used for wireless phenotyping with the help of radio-frequency identification (RFID) ultracompact chips inserted within them. The organoid biobanks store and transport organoids using liquid nitrogen.
