Three-dimensional modelling of ovarian cancer: from cell lines to organoids for discovery and personalized medicine

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

To date, there have been no reports of using decellularized ovary ECM for the study of ovarian cancers.

“To date, there have been no reports of using decellularized ovary ECM for the study of ovarian cancers.”

Probably not a substantial claim: may not pass S4 (based).

Modelling interactions with the tumor microenvironment, including the surface of organs in the peritoneal cavity that support metastatic growth of ovarian cancer, will improve the power of these models.

“Additionally, modelling interactions with the tumor microenvironment, including the surface of organs in the peritoneal cavity that support metastatic growth of ovarian cancer, will improve the power of these models.”

• AssumptionRests on an assumption: Traditional 2D in vitro cell culture of ovarian cancer lacks critical cell-to-cell interactions afforded by culture in three dimensions.

May combine two claims.

Reasons not all genomic scar tumors respond to PARP inhibitors include reversion of a BRCA mutation, occurrence of a secondary mutation that restores wild-type function, or changes in methylation patterns of an HRR gene that functionally restores HRR but the genomic scar remains.

“Reasons for this include reversion of a BRCA mutation, occurrence of a secondary mutation that restores wild-type function or changes in methylation patterns of an HRR gene that in effect functionally restores HRR but the genomic scar remains (Patch et al., 2015).”

• cites Patch et al., 2015Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Ovarian cancer classification includes distinct histological subtypes with varied sites of origin underpinned by defining molecular events affecting tumor suppressors and oncogenes.

“The classification of ovarian cancer includes distinct histological subtypes with varied sites of origin underpinned by defining molecular events affecting tumor suppressors and oncogenes.”

Probably not a substantial claim: may not pass S4 (based).

Ovarian cancer histotypes have differing responses to platinum-based drugs.

“These histotypes have differing responses to platinum-based drugs that have been the mainstay of therapy for ovarian cancer for decades.”

Classified as probably not a substantial claim.

Predictive molecular testing involving identification of a genomic scar and/or germline or somatic BRCA1 or BRCA2 mutation is in clinical use to inform likely success of a PARP inhibitor.

“While predictive molecular testing involving identification of a genomic scar and/or the presence of germline or somatic BRCA1 or BRCA2 mutation are in clinical use to inform the likely success of a PARP inhibitor”

Classified as probably not a substantial claim.

Molecular events in ovarian cancer drive specific patterns of clinical behavior characteristic of histotypes, including response to chemotherapeutic agents and molecular target drugs.

“These events drive specific patterns of clinical behavior characteristic of histotypes, including response to chemotherapeutic agents and molecular target drugs.”

Probably not a substantial claim: may not pass S4 (based).

No similar tests are available to identify women likely to respond to bevacizumab.

“no similar tests are available to identify women likely to respond to bevacizumab.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

For histotypes that initially respond to carboplatin and paclitaxel, such as high-grade serous ovarian cancer, development of chemoresistance is common and underpins incurable disease.

“For histotypes that initially respond to a chemotherapeutic regime of carboplatin and paclitaxel such as high-grade serous ovarian cancer, the development of chemoresistance is common and underpins incurable disease.”

May combine two claims.

As a predictive DNA marker of defective homologous recombination repair, genomic scars are helpful, but not all tumors with a genomic scar will respond to a PARP inhibitor.

“As a predictive DNA marker of defective HRR, genomic scars are helpful, but not all tumors with a genomic scar will respond to a PARPi.”

Probably not a substantial claim: may not pass S3 (load-bearing).

PARP inhibitors are in clinical use for ovarian cancers defective in homologous recombination repair.

“Recent discoveries have led to the clinical use of PARP (poly ADP ribose polymerase) inhibitors for ovarian cancers defective in homologous recombination repair, as well as the anti-angiogenic bevacizumab.”

Probably not a substantial claim: may not pass S2 (checkable).

Three-dimensional modelling systems, from cell lines to organoid or tumoroid cultures, represent enhanced starting points from which improved translational outcomes for women with ovarian cancer will emerge.

“Three-dimensional (3D) modelling systems, from cell lines to organoid or tumoroid cultures, represent enhanced starting points from which improved translational outcomes for women with ovarian cancer will emerge.”

• AssumptionRests on an assumption: Traditional 2D in vitro cell culture of ovarian cancer lacks critical cell-to-cell interactions afforded by culture in three dimensions.

Probably not a substantial claim: may not pass S4 (based).

Being able to reliably grow primary tumoroid cultures of ovarian cancer will improve the ability to recapitulate tumor heterogeneity.

“Being able to reliably grow primary tumoroid cultures of ovarian cancer will improve the ability to recapitulate tumor heterogeneity.”

• AssumptionRests on an assumption: Traditional 2D in vitro cell culture of ovarian cancer lacks critical cell-to-cell interactions afforded by culture in three dimensions.

May combine two claims.

Ovarian cancers with germline or somatic mutation of BRCA1 or BRCA2, mutation of RAD51C or RAD51D, methylation of BRCA1, or high loss of heterozygosity have all been reported to respond to PARP inhibition.

“Ovarian cancers with germline or somatic mutation of BRCA1 or BRCA2, mutation of RAD51C or RAD51D, methylation of BRCA1, or high LOH have all been reported to respond to PARP inhibition (Audeh et al., 2010; Wang et al., 2012; Ledermann J. et al., 2014; Kondrashova et al., 2017; Swisher et al., 2017; Moore et al., 2018).”

• cites Audeh et al., 2010 sourceNot checked yet

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• cites Wang et al., 2012Not checked yet

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• cites Ledermann J. et al., 2014Not checked yet

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May combine two claims.

Mucinous ovarian cancer has previously been reported as originating from metastatic deposits of primary tumors of the colon, stomach, pancreas and uterus, but evidence now shows that these tumors arise in the ovary following a progression model commencing with benign and borderline precursor lesions.

“While MOC has previously been reported as originating from metastatic deposits of primary tumors of the colon, stomach, pancreas and uterus, evidence now shows that these tumors do in fact arise in the ovary following a progression model commencing with benign and borderline precursor lesions (Ledermann J. A. et al., 2014; Cheasley et al., 2019).”

• cites Ledermann J. A. et al., 2014Not checked yet

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• cites Cheasley et al., 2019Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Loss of RAD51C methylation has recently been implicated as a mechanism of PARP inhibitor resistance.

“Furthermore, loss of RAD51C methylation has recently been implicated as a mechanism of PARPi resistance (Nesic et al., 2021).”

• cites Nesic et al., 2021Not checked yet

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May combine two claims.

Many ovarian cancer cell lines have been well characterized morphologically and molecularly and, when able to be tested, maintain unique features of their derivative sample.

“Many cell lines have been well characterized morphologically and molecularly and, when able to be tested, maintain unique features of their derivative sample.”

May combine two claims.

The majority of women with high-grade serous ovarian cancer will respond initially to carboplatin, although some tumors display innate platinum resistance.

“The majority of women with HGSOC will respond initially to carboplatin, although some tumors display innate platinum resistance (Davis et al., 2014).”

• cites Davis et al., 2014Not checked yet

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May combine two claims.

There are no robust markers to predict response to platinum drugs, including through the development of acquired chemoresistance, although defects in homologous recombination repair in primary tumors have been associated with a more favorable response.

“There are no robust markers to predict response to platinum drugs, including through the development of acquired chemoresistance, although defects in HRR in primary tumors have been associated with a more favorable response (Konstantinopoulos et al., 2010; Muggia and Safra, 2014).”

• cites Konstantinopoulos et al., 2010Not checked yet

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• cites Muggia and Safra, 2014Not checked yet

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May combine two claims.

Ovarian cancer cells detach from the primary tumor and are attracted to adipose-rich omental tissue.

“Ovarian cancer cells detach from the primary tumor and are attracted to adipose-rich omental tissue.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The A2780/A2780VeliR lines were made resistant in vitro to the PARP inhibitor veliparib.

“The A2780/A2780VeliR lines were made resistant in vitro to the PARPi veliparib (Dickson et al., 2021).”

• cites Dickson et al., 2021Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Other ovarian cancer cell lines have been made resistant to cisplatin in vitro, including A2870/A2780CisR, TYK-nu/TYK-nu.CP-r and CaOV3/CaOV3CisR.

“Other ovarian cancer cell lines have been made resistant to cisplatin in vitro, including A2870/A2780CisR (Behrens et al., 1987), TYK-nu/TYK-nu.CP-r (Yoshiya et al., 1989) and CaOV3/CaOV3CisR (Joshi et al., 2021).”

• cites Behrens et al., 1987Not checked yet

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• cites Yoshiya et al., 1989Not checked yet

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• cites Joshi et al., 2021Not checked yet

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Probably not a substantial claim: may not pass S4 (based).

To date, the majority of in vitro studies in ovarian cancer have relied on the use of 2D cell culture of immortalized cell lines derived from primary ovarian cancers, pleural effusion, ascitic fluid from the peritoneal cavity or a distant metastatic site.

“To date, the majority of in vitro studies in ovarian cancer have relied on the use of 2D cell culture of immortalized cell lines derived from primary ovarian cancers, pleural effusion, ascitic fluid from the peritoneal cavity or a distant metastatic site.”

May combine two claims.

Only 11-27% of ovarian clear cell carcinoma respond initially to platinum therapy, dropping to only 1-2% response rates in recurrent disease.

“Only 11–27% of OCCC respond initially to platinum therapy, dropping to only 1-2% response rates in recurrent disease (Sugiyama et al., 2000; Mabuchi et al., 2016; Tan et al., 2019).”

• cites Sugiyama et al., 2000Not checked yet

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• cites Mabuchi et al., 2016Not checked yet

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• cites Tan et al., 2019Not checked yet

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May combine two claims.

The PEO4 cell line represents malignant cells after the patient developed chemoresistance, having a secondary BRCA2 reversion mutation which restores wild-type BRCA2 function.

“The PEO4 cell line represents malignant cells after the patient developed chemoresistance, having a secondary BRCA2 reversion mutation which restores wild-type BRCA2 function.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Ovarian clear cell carcinoma and endometrioid ovarian cancer have been associated with endometriosis.

“OCCC and EnOC have been associated with endometriosis (Samartzis et al., 2020).”

• cites Samartzis et al., 2020Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Granulosa cell tumors arise in granulosa cells that produce estrogen.

“the sex cord stromal tumor GCT arise in granulosa cells that produce estrogen (Jamieson and Fuller, 2012).”

• cites Jamieson and Fuller, 2012Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

There remain conflicting reports in the field as to the accuracy of some ovarian cancer cell lines.

“Still, there remains conflicting reports in the field as to the accuracy of some ovarian cancer cell lines.”

Classified as probably not a substantial claim.

Given the advances seen in progression-free survival and overall survival of some women receiving bevacizumab, development of functional assays to predict the likelihood that a woman will respond to bevacizumab would represent a major advance.

“Given the advances seen in PFS and OS of some women receiving this monoclonal antibody that targets vascular endothelial growth factor (VEGF), development of functional assays to predict the likelihood that a woman will respond to bevacizumab would represent a major advance (Burger et al., 2011; Perren et al., 2011; Oza et al., 2015).”

• cites Burger et al., 2011Not checked yet

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• cites Perren et al., 2011Not checked yet

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• cites Oza et al., 2015Not checked yet

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May combine two claims.

Ovarian tumoroid cultures have been established from both ascitic fluid and primary tumors, to date primarily from high-grade serous ovarian cancer but also from low-grade serous ovarian cancer, mucinous ovarian cancer, ovarian clear cell carcinoma, and endometrioid ovarian cancer.

“Ovarian tumoroid cultures have been established from both ascitic fluid and primary tumors, to date primarily from the more common HGSOC but also from LGSOC, MOC, OCCC, and EnOC (Hill et al., 2018; De Witte et al., 2020; Nanki et al., 2020).”

• cites Hill et al., 2018 sourceNot checked yet

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• cites De Witte et al., 2020Not checked yet

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• cites Nanki et al., 2020Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Some molecular events, such as those in the homologous recombination repair pathway, are already being targeted clinically by FDA-approved PARP inhibitors.

“Some molecular events, such as those described in the HRR pathway, are already being targeted clinically by FDA-approved PARPis.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Inclusion of scaffolds in 3D multicellular in vitro models of ovarian cancer adds another level of model complexity, allowing for the recreation of the physical and mechanical tumor microenvironment that can influence ovarian cancer cell behavior.

“Inclusion of scaffolds in 3D multicellular in vitro models of ovarian cancer adds another level of model complexity, allowing for the recreation of the physical and mechanical tumor microenvironment that can influence ovarian cancer cell behavior.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The major constituents of Matrigel are laminins, collagen IV, entactin, and the heparin sulfate proteoglycan perlecan, though ratios often differ by batch, raising the need for caution when interpreting results of cells cultured in Matrigel.

“The major constituents of this ECM are laminins, collagen IV, entactin, and the heparin sulfate proteoglycan perlecan (Hughes et al., 2010), though ratios often differ by batch, raising the need for caution when interpreting results of cells cultured in Matrigel (Vukicevic et al., 1992).”

• cites Hughes et al., 2010Not checked yet

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• cites Vukicevic et al., 1992Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Efforts towards creation of high-throughput in vitro and ex vivo models for drug screening have been a focus in recent years, and will eventually replace 2D cultures.

“Further, efforts towards creation of high-throughput in vitro and ex vivo models for drug screening have been a focus in recent years, and will eventually replace 2D cultures.”

• AssumptionRests on an assumption: Two-dimensional growth of cancer cells as monolayers may fail to recapitulate aspects of the derivative cell behavior and morphology.
• AssumptionRests on an assumption: Differential drug responses in 2D versus 3D cultures have been observed in many in vitro models of cancer, including ovarian cancers.

May combine two claims.

Platinum resistance has been found to predict PDX engraftment success, with successful engraftment correlating with shorter progression-free survival and overall survival of the derivative patient.

“Platinum resistance has also been found to predict PDX engraftment success, with successful engraftment correlating with shorter PFS and OS of the derivative patient (Heo et al., 2017).”

• cites Heo et al., 2017Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Naturally derived ECM hydrogels such as Matrigel, collagens, alginate, and agarose have been favored in 3D cell culture models due to their history of high biocompatibility with various cell types, including ovarian cancer cell lines and tumor organoids, although they are limited in their mechanical tunability and composition consistency.

“Naturally derived ECM hydrogels such as Matrigel, collagens, alginate, and agarose have been favored in 3D cell culture models due to their history of high biocompatibility with various cell types, including ovarian cancer cell lines and tumor organoids, although they are limited in their mechanical tunability and composition consistency.”

May combine two claims.

These hanging drop models are limited to short-term culture and require frequent attention.

“These models are therefore limited to short-term culture and require frequent attention.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Recent technological advances have enabled higher degrees of control over the creation of 3D cell cultures in areas including matrix stiffness and composition, spatial orientation and creation in an automated and high-throughput manner.

“Recent technological advances have enabled higher degrees of control over the creation of 3D cell cultures in areas including matrix stiffness and composition, spatial orientation and creation in an automated and high-throughput manner.”

May combine two claims.

The reported engraftment rate can be variable and heavily influenced by ovarian cancer histotype, treatment history, stage and site of malignancy, with higher engraftment rates observed in non-epithelial histotypes.

“The reported engraftment rate can be variable and heavily influenced by ovarian cancer histotype; treatment history; stage and site of malignancy, with higher engraftment rates observed in non-epithelial histotypes (Wu et al., 2019).”

• cites Wu et al., 2019Not checked yet

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May combine two claims.

While there is still no perfect 3D in vitro model that can replace in vivo preclinical models, methodological advances are moving the field towards more accurate representations of human tumors, including in regards to drug response.

“While there is still no “perfect” 3D in vitro model that can replace in vivo preclinical models, methodological advances are moving the field towards more accurate representations of human tumors, including in regards to drug response.”

• AssumptionRests on an assumption: Two-dimensional growth of cancer cells as monolayers may fail to recapitulate aspects of the derivative cell behavior and morphology.
• AssumptionRests on an assumption: Differential drug responses in 2D versus 3D cultures have been observed in many in vitro models of cancer, including ovarian cancers.
• AssumptionRests on an assumption: There is still no perfect 3D in vitro model that can replace in vivo preclinical models.

May combine two claims.

More recent developments have addressed some concerns about PDX models, with higher rates of successful engraftment and propagation of rarer ovarian cancer histotypes such as low-grade serous ovarian cancer and mucinous ovarian cancer, as well as evaluation of drug responses for homologous recombination deficient mutated ovarian cancers and enabling evaluation of immunotherapies through humanized

“More recent developments have addressed some of these concerns, with higher rates of successful engraftment and propagation of rarer ovarian cancer histotypes such as LGSOC (De Thaye et al., 2020) and MOC (Ricci et al., 2020) as well as evaluation of drug responses for homologous recombination deficient (HRD) mutated ovarian cancers (George et al., 2017) and enabling the evaluation of immunotherap”

• cites De Thaye et al., 2020Not checked yet

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• cites Ricci et al., 2020Not checked yet

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• cites George et al., 2017Not checked yet

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May combine two claims.

Round-bottomed ULA plates allow high consistency between replicates from a cell line or patient sample, as well as facilitating the ability to section and morphologically analyze biologically-relevant structures.

“This method allows high consistency between replicates from a cell line or patient sample, as well as facilitating the ability to section and morphologically analyze biologically-relevant structures.”

May combine two claims.

The natural occurrence of ovarian cancer is low in the aging mouse, with rapid progression times contrasting with the development of human ovarian cancer.

“Further, the natural occurrence of ovarian cancer is low in the aging mouse, with rapid progression times contrasting with the development of human ovarian cancer (Sale and Orsulic, 2006).”

• cites Sale and Orsulic, 2006Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Matrigel has been used for over 40 years as a mimic for the basement membrane and a structural support for many cell types.

“Matrigel, derived from the murine Engelbreth-Holm-Swarm (EHS) sarcoma, has been used for over 40 years as a mimic for the basement membrane and a structural support for many cell types (Orkin et al., 1977).”

• cites Orkin et al., 1977Not checked yet

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May combine two claims.

Some ovarian cancer cell lines grow well in both subcutaneous and intraperitoneal locations, while others show a strong propensity to grow in one location only, suggesting a preference for a particular microenvironment.

“Further, while some cell lines grow well in both SC and IP locations, others show a strong propensity to grow in one location only, suggesting a preference for a particular microenvironment.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The ID8 model has also been used to study metastasis and immune infiltrates at the trocar site.

“This model has also been used to study metastasis and immune infiltrates at the trocar site, where an incision is made into the abdomen for laparoscopic surgery (Wilkinson-Ryan et al., 2019).”

• cites Wilkinson-Ryan et al., 2019Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The most widely used mammalian model is the mouse, sharing 85 percent protein-encoding gene homology with humans.

“The most widely used mammalian model is the mouse (Mus musculus), sharing 85 percent protein-encoding gene homology with humans (Makałowski et al., 1996)”

• cites Makałowski et al., 1996Not checked yet

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May combine two claims.

Limitations of primary tumor tissue implanted heterotypically into immunodeficient mice include the inability to recapitulate immune responses, site-specific tumor microenvironment interactions and that the tumor may not metastasize.

“Limitations of primary tumor tissue implanted heterotypically into immunodeficient mice include the inability to recapitulate immune responses, site-specific tumor microenvironment interactions and lastly, that the tumor may not metastasize (Jin et al., 2010).”

• cites Jin et al., 2010Not checked yet

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May combine two claims.

Cell numbers as low as 10 cells per droplet will form spheroids that are uniform in both volume and circularity, amenable to many downstream analyses including high throughput analysis of drug responses.

“Further, cell numbers as low as 10 cells per droplet will form spheroids that are uniform in both volume and circularity, amenable to many downstream analyses including high throughput analysis of drug responses (Raghavan et al., 2015).”

• cites Raghavan et al., 2015Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

A number of different methodologies and techniques are being used in order to more efficiently create 3D cell culture models of cancer, including ovarian cancers.

“A number of different methodologies and techniques are being used in order to more efficiently create 3D cell culture models of cancer, including ovarian cancers.”

May combine two claims.

Higher RGD concentrations encouraged spheroid cell dispersion and drug sensitivity, whereas hydrogels with lower RGD concentrations had preserved cell aggregations with CSC-like changes and drug resistance.

“An extension of this work by the same authors showed higher RGD (arginine-glycine-aspartic acid) concentrations encouraged spheroid cell dispersion and drug sensitivity, whereas hydrogels with lower RGD concentrations had preserved cell aggregations with CSC-like changes and drug resistance when grown on PEMM hydrogel discs with varying RGD concentrations (Zhou et al., 2021).”

• cites Zhou et al., 2021Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Synthetic ECMs are becoming a more popular in vitro ECM option compared to gold standard EHS-derived ECMs, due to a higher degree of control over properties such as stiffness, pore size and biofunctionalization.

“Synthetic ECMs are becoming a more popular in vitro ECM option compared to gold standard EHS-derived ECMs, due to a higher degree of control over properties such as stiffness, pore size and biofunctionalization.”

May combine two claims.

This study highlighted the need to consider the immunogenic properties of biomaterials to match hydrogel models for their appropriate application, and may have implications on future 3D in vitro immunotherapy models.

“This study highlighted the need to consider the immunogenic properties of biomaterials to match hydrogel models for their appropriate application, and may have implications on future 3D in vitro immunotherapy models.”

May combine two claims.

Proteins are unable to interact with alginate matrix, and as such ECM-cell signaling is lacking in alginate models and is considered a more synthetic ECM that can be biofunctionalized by the addition of peptides.

“However, proteins are unable to interact with the matrix, and as such ECM-cell signaling is lacking in alginate models and is considered a more synthetic ECM that can be biofunctionalized by the addition of peptides (Rowley et al., 1999).”

• cites Rowley et al., 1999 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The use of ovarian dECMs might benefit 3D in vitro ovarian models, due to the preservation of ECM proteins and growth factors found in the native ovary.

“However, the use of ovarian dECMs might benefit 3D in vitro ovarian models, due to the preservation of ECM proteins and growth factors found in the native ovary.”

May combine two claims.

A 4-arm PEG-maleimide based hydrogel was designed to recreate the omentum ECM with GFOGER, PHSRN-RGD, RGD, and DGEA biofunctionalization peptide motifs, adjusting stiffness to a physiological level of ∼2.9 kPa for omental tissue and incorporating MMP-degradable crosslinkers.

“A 4-arm PEG-maleimide based hydrogel was designed to recreate the omentum ECM with GFOGER (collagen-I), PHSRN-RGD (fibronectin), RGD (fibronectin, vitronectin, collagen-VI), and DGEA (collagen-IV) biofunctionalization peptide motifs, adjusting stiffness to a physiological level of ∼2.9 kPa for omental tissue and incorporating MMP-degradable crosslinkers (Brooks et al., 2019).”

• cites Brooks et al., 2019 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Alginate features high biocompatibility, biodegradability, low immunogenicity, and low cost, which have been the drivers behind its use in tissue engineering and drug delivery studies.

“Features such as high biocompatibility, biodegradability, low immunogenicity, and low cost have been the drivers behind its use in tissue engineering and drug delivery studies (Gombotz and Wee, 1998).”

• cites Gombotz and Wee, 1998Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Self-assembling peptide-based hydrogels are increasingly being used as a biomimetic material for 3D in vitro culture for their engineerability, ability to form well-defined nanofibers with natural amino acid constituents and absence of animal-derived contaminants.

“Self-assembling peptide-based hydrogels are increasingly being used as a biomimetic material for 3D in vitro culture for their engineerability, ability to form well-defined nanofibers with natural amino acid constituents and absence of animal-derived contaminants (Yang et al., 2020).”

• cites Yang et al., 2020Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Synthetic alternatives are becoming more prominent but have yet to meet the standards of enabling the propagation of patient-derived spheroids and organoids as well as having mechanical properties to enable bio-printing for highly reproducible and high-throughput ovarian cancer model development.

“Synthetic alternatives are becoming more prominent but have yet to meet the standards of enabling the propagation of patient-derived spheroids and organoids as well as having mechanical properties to enable bio-printing for highly reproducible and high-throughput ovarian cancer model development.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Crosslinking of collagen that increases stromal stiffness has also been implicated in chemoresistance.

“Crosslinking of collagen that increases stromal stiffness has also been implicated in chemoresistance (Sterzyńska et al., 2018).”

• cites Sterzyńska et al., 2018Not checked yet

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May combine two claims.

The reported average modulus value of Matrigel is approximately 450 Pa, which remains below the average stiffness of human or mouse ovary or omentum.

“The reported average modulus value of Matrigel was found to be approximately 450 Pa (Soofi et al., 2009), which remains below the average stiffness of human or mouse ovary or omentum (Alkhouli et al., 2013; Mckenzie et al., 2018; Hopkins et al., 2021).”

• cites Soofi et al., 2009Not checked yet

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• cites Alkhouli et al., 2013Not checked yet

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• cites Mckenzie et al., 2018Not checked yet

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May combine two claims.

PBMCs grown on GelMA hydrogels showed suppressed pro-inflammatory responses to stimulation with LPS, particularly in the presence of TNF, whereby cellular TNF mRNA levels were elevated, but soluble TNF was bound to the hydrogel.

“Interestingly, peripheral blood mononuclear cells or PBMCs grown on GelMA hydrogels showed suppressed pro-inflammatory responses to stimulation with lipopolysaccharide (LPS), particularly in the presence of tumor necrosis factor (TNF), whereby cellular TNF mRNA levels were elevated, but soluble TNF was bound to the hydrogel (Donaldson et al., 2018).”

• cites Donaldson et al., 2018Not checked yet

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May combine two claims.

This hydrogel supported cell growth and viability of SK-OV-3 multicellular spheroids and spheroids from patient-derived ascites, with paclitaxel and doxorubicin treatments mimicking the drug responses seen in patients.

“This hydrogel supported cell growth and viability of SK-OV-3 multicellular spheroids that were pre-made in non-adherent polydimethylsiloxane (PDMS)-coated grids and spheroids from patient-derived ascites, with paclitaxel and doxorubicin treatments mimicking the drug responses seen in patients.”

• cites Brooks et al., 2019 sourceNot checked yet

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Classified as probably not a substantial claim.

Hydrogels based on bioinert polyethylene glycol (PEG) have been widely utilized for in vitro 3D models for their ability to customize biofunctionalization by peptides and hydrogel stiffness control.

“Hydrogels based on bioinert polyethylene glycol (PEG) have been widely utilized for in vitro 3D models for their ability to customize biofunctionalization by peptides and hydrogel stiffness control.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Collagens are the most abundant ECM proteins in the body and are also the most widely used ECM for in vitro cell cultures due to high biocompatibility and commercial availability.

“Collagens are the most abundant ECM proteins in the body and are also the most widely used ECM for in vitro cell cultures due to high biocompatibility and commercial availability.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Visible light promotes higher cell viability and lower free radical damage compared to UV light when using GelMA.

“Visible light, as expected, promotes higher cell viability and lower free radical damage compared to UV light when using GelMA (Noshadi et al., 2017).”

• cites Noshadi et al., 2017Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Excessive macrofibrillar collagen-I produced by resident fibroblasts has been implicated in the promotion of cancer progression, metastatic and chemoresistant tumor microenvironments.

“Excessive macrofibrillar collagen-I produced by resident fibroblasts has been implicated in the promotion of cancer progression, metastatic and chemoresistant tumor microenvironments (Gurler et al., 2015).”

• cites Gurler et al., 2015Not checked yet

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May combine two claims.

Preliminary studies of hydrogels derived from decellularized porcine ovarian ECM highlighted the effect of ECM stiffness on ovarian follicle development, with stiffer matrices reducing oocyte viability and triggering premature follicle release.

“Preliminary studies of hydrogels derived from decellularized porcine ovarian ECM highlighted the effect of ECM stiffness on ovarian follicle development, with stiffer matrices reducing oocyte viability and triggering premature follicle release (Buckenmeyer et al., 2016), though this effect has not been investigated with ovarian cancer cells.”

• cites Buckenmeyer et al., 2016Not checked yet

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May combine two claims.

In the mesothelial models, fewer efficacious drug hits were observed than in traditional 2D models, but similar drug responses were observed in vivo in PDX models.

“Though the mesothelial models had fewer efficacious drug hits than traditional 2D models, similar drug responses were observed in vivo in PDX models (Kenny et al., 2014; Lal-Nag et al., 2017).”

• cites Kenny et al., 2014Not checked yet

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• cites Lal-Nag et al., 2017Not checked yet

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May combine two claims.

GelMA is a semi-synthetic bioengineered, biocompatible material with high batch-to-batch consistency, control of mechanophysical properties, innate RGD responsive peptide motifs and ability to be cleaved by MMPs, having been designed as an alternative to Matrigel.

“GelMA is a semi-synthetic bioengineered, biocompatible material with high batch-to-batch consistency, control of mechanophysical properties, innate RGD responsive peptide motifs and ability to be cleaved by MMPs, having been designed as an alternative to Matrigel (Zhu et al., 2019).”

• cites Zhu et al., 2019Not checked yet

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May combine two claims.

Concerns regarding the use of Matrigel include batch-to-batch variation, potential for xenogeneic contaminants derived from mouse on human cells, inefficient cell retrieval requiring temperature reversal to 4°C, potential DNA/RNA contamination from the matrix, and matrix autofluorescence that reduces signal-to-noise ratio when imaging fluorescently stained cells in situ.

“Aside from commercial availability and high biocompatibility with a wide range of cell types, there continues to be concerns regarding the use of Matrigel in a number of areas, including: batch-to-batch variation, potential for xenogeneic contaminants derived from mouse on human cells, inefficient cell retrieval requiring temperature reversal to 4°C, potential DNA/RNA contamination from the matrix”

• cites Graf and Boppart, 2010Not checked yet

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• cites Hughes et al., 2010Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Tumor-on-a-chip microfluidics systems have been used to model peritoneal metastases as well as vasculature in solid tumors.

“Tumor-on-a-chip microfluidics systems have been used to model peritoneal metastases as well as vasculature in solid tumors.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Synthetic matrices are limited by their biocompatibility but can be biofunctionalized with peptides and full-length ECM proteins.

“In contrast, synthetic matrices are limited by their biocompatibility but can be biofunctionalized with peptides and full-length ECM proteins.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The material properties of Matrigel and other natural matrices are limited in their printability as bioinks due to temperature sensitivities and pre-determined stiffnesses, highlighting the flexibility of synthetic matrices that can be modified to best mimic in vivo conditions.

“The material properties of Matrigel and other natural matrices are limited in their printability as bioinks due to temperature sensitivities and pre-determined stiffnesses, highlighting the flexibility of synthetic matrices that can be modified to best mimic in vivo conditions.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Droplet-based bioprinting systems enable the precise and agile fabrication of microtissue cultures by overlaying drops of biomaterial.

“Droplet-based bioprinting systems enable the precise and agile fabrication of microtissue cultures by overlaying drops of biomaterial.”

May combine two claims.

Analysis of ovarian tumor organoids derived from multiple tumor sites within the same patient showed differential drug sensitivities, emphasizing the need to account for intrapatient tumor heterogeneity.

“The analysis of ovarian tumor organoids derived from multiple tumor sites within the same patient showed differential drug sensitivities, emphasizing the need to account for intrapatient tumor heterogeneity (De Witte et al., 2020).”

• cites De Witte et al., 2020Not checked yet

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May combine two claims.

CRISPR-Cas9 genome editing to introduce common HGSOC gene defects into mouse oviduct and OSE cell organoids showed that both organoid types could become carcinogenic and that drug sensitivities in HGSOC patients may be cell lineage-dependent.

“An extension of this work has similarly used CRISPR-Cas9 genome editing to introduce common HGSOC gene defects into mouse oviduct and OSE cell organoids, showing that both organoid types could become carcinogenic and that drug sensitivities in HGSOC patients may be cell lineage-dependent (Lõhmussaar et al., 2020).”

• cites Lõhmussaar et al., 2020Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Ovarian cancer cell lines were utilized during optimization of bioink biocompatibility, showing high cell viability during and after the extrusion process.

“While this study focused on oocyte maturation ex vivo, ovarian cancer cell lines were utilized during optimization of bioink biocompatibility, showing high cell viability during and after the extrusion process.”

• cites Wu et al., 2021Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Indirect contact co-cultures, such as by the use of transwells or conditioned media, mimic cellular signaling in the absence of physical cellular contact, and enable simple segregation of cell types for ease of downstream analyses of individual cell population behavior.

“Indirect contact co-cultures, such as by the use of transwells or conditioned media, mimic cellular signaling in the absence of physical cellular contact, and enable simple segregation of cell types for ease of downstream analyses of individual cell population behavior.”

May combine two claims.

In comparison to xenograft models, organoid or tumoroid cultures require significantly shorter times for development from small starting samples, have a higher success rate and accurately reproduce the genetic and phenotypic features of the derivative tumor, allowing for personalized medicine strategies.

“In comparison to xenograft models, organoid or tumoroid cultures require significantly shorter times for development from small starting samples, have a higher success rate and accurately reproduce the genetic and phenotypic features of the derivative tumor, allowing for personalized medicine strategies (Hidalgo et al., 2014).”

• cites Hidalgo et al., 2014Not checked yet

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May combine two claims.

Varying success rates have been reported for ovarian cancer organoids/tumoroids, particularly attributed to the heterogeneity of these cancers, and propagation success has been highly dependent on starting sample volume and sample handling.

“While there is growing evidence that ovarian cancer organoids/tumoroids are becoming the new benchmark for pre-clinical models compared to traditional 2D methods, varying success rates have been reported, particularly attributed to the heterogeneity of these cancers, and propagation success has been highly dependent on starting sample volume and sample handling.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The number of published studies utilizing 3D bioprinting for ovarian cancer is limited.

“As a relatively new approach to 3D cell model creation, the number of published studies is limited for ovarian cancer.”

May combine two claims.

The organotypic mesothelial model was more cost and time-efficient with similar results to in vivo models when testing micellar-based nanoparticle therapies to prevent early metastasis.

“This organotypic model was also more cost and time-efficient with similar results to in vivo models, when testing micellar-based nanoparticle therapies to prevent early metastasis (Lu et al., 2019).”

• cites Lu et al., 2019Not checked yet

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May combine two claims.

Wnt pathway induction resulted in tumoroid growth arrest in HGSOC organoids, which was rescued by BMP signaling.

“In contrast to traditional organoid culture methods that utilize Wnt to maintain stem-like properties, Wnt pathway induction resulted in tumoroid growth arrest in HGSOC organoids, however was able to be rescued by BMP signaling (Hoffmann et al., 2020).”

• cites Hoffmann et al., 2020Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Bioreactors have largely been used to study the effects of fluid flow as a physiological mechanical stimulus on cell behavior.

“Bioreactors have largely been used to study the effects of fluid flow as a physiological mechanical stimulus on cell behavior.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Microgravity, as a biomechanical force, has been reported to reduce metastatic markers, change cell metabolism and chemosensitivity in a variety of cancer cell lines, though the in vivo effect is unknown.

“Microgravity, as a biomechanical force, has been reported to reduce metastatic markers, change cell metabolism and chemosensitivity in a variety of cancer cell lines, though the in vivo effect is unknown (Takeda et al., 2009; Vidyasekar et al., 2015).”

• cites Takeda et al., 2009Not checked yet

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• cites Vidyasekar et al., 2015Not checked yet

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May combine two claims.

Low passage primary ovarian and endometrial cancer cell lines propagated as multicellular spheroids in a rotating cell culture system showed similar histological markers to the primary tumor with differentially expressed markers including prohibitin, VDAC1 and annexin 4 identified in 2D versus 3D culture methods.

“Low passage primary ovarian and endometrial cancer cell lines propagated as multicellular spheroids in a rotating cell culture system, showed similar histological markers to the primary tumor with differentially expressed markers including prohibitin, VDAC1 and annexin 4 identified in 2D versus 3D culture methods (Grun et al., 2009).”

• cites Grun et al., 2009Not checked yet

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May combine two claims.

Further work confirmed the production of chondroitin sulphate in the 3D culture similar to that observed in the in vivo tumor; however, this was not observed in 2D culture.

“Further work confirmed the production of chondroitin sulphate in the 3D culture similar to that observed in the in vivo tumor; however, this was not observed in 2D culture (Goodwin et al., 1997; Grun et al., 2009).”

• cites Goodwin et al., 1997Not checked yet

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• cites Grun et al., 2009Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The majority of bioreactor-based models for ovarian cancer have been used for the study of fluid shear stress pressures on cancer invasion and proliferation.

“The majority of bioreactor-based models for ovarian cancer have been used for the study of fluid shear stress pressures on cancer invasion and proliferation.”

May combine two claims.

Three-dimensional co-cultures, particularly when combined with ECM scaffolds, are in vitro biomimetic models that may better represent the in vivo situation and more accurately predict cellular responses in a patient.

“Three-dimensional co-cultures, particularly when combined with ECM scaffolds, are in vitro, biomimetic models that may better represent the in vivo situation and more accurately predict cellular responses in a patient.”

May combine two claims.

Kopper and colleagues performed gene editing in normal non-tumor organoids established from fallopian tube or ovarian epithelium using CRISPR-Cas9 for modelling TP53 mutations, and determined that HRD ovarian cancer organoids with fewer RAD51 loci were more sensitive to the PARPi niraparib, analogous to responses observed in vivo.

“Kopper and colleagues have performed gene editing in normal non-tumor organoids established from fallopian tube or ovarian epithelium using CRISPR-Cas9 gene editing for modelling TP53 mutations, and determined that HRD ovarian cancer organoids with fewer RAD51 loci were more sensitive to the PARPi niraparib, analogous to responses observed in vivo (Kopper et al., 2019).”

• cites Kopper et al., 2019Not checked yet

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May combine two claims.

The organotypic mesothelial model lacks vasculature, immune cells, and cells from adipose tissue.

“While this co-culture model has been quite successful, as a scalable, 3D pre-clinical model of ovarian cancer metastases, it lacks vasculature, as well as immune cells and cells from adipose tissue.”

May combine two claims.

Masiello and colleagues adapted the orbital shaker to rotate at physiologically relevant speeds and utilized typical culture dishes to investigate the effects of rotational speeds, cell density and well size on spheroid formation, resulting in more rounded and consistent spheroid formation.

“Masiello and colleagues adapted the orbital shaker to rotate at physiologically relevant speeds and utilized typical culture dishes to investigate the effects of rotational speeds, cell density and well size on spheroid formation (Masiello et al., 2018). This study resulted in more rounded and consistent spheroid formation, amenable to the analyses of functional endpoints.”

• cites Masiello et al., 2018Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

In the context of ovarian cancers, mechanotransduction and shear stress from ascites fluid build-up and flow in the peritoneum have been shown to drive ovarian cancer metastasis.

“In the context of ovarian cancers, mechanotransduction and shear stress from ascites fluid build-up and flow in the peritoneum have been shown to drive ovarian cancer metastasis.”

May combine two claims.

There is growing evidence that 2D cultures are more divergent and 3D cultures are better models to reproduce and predict patient drug responses.

“There is growing evidence that 2D cultures are more divergent and 3D cultures are better models to reproduce and predict patient drug responses.”

May combine two claims.

The study showed correlation between macrophage recruitment and tumor invasiveness and results were replicated in in vivo PDX models.

“The study showed correlation between macrophage recruitment and tumor invasiveness and results were replicated in in vivo PDX models, with future work looking to identify correlations between macrophage infiltration and chemoresistance.”

• cites Scott et al., 2021Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The field of 3D bioprinting, currently in its infancy, is rapidly emerging as an answer to the manual, low throughput methods of creating 3D cell models, including organoids and tumoroids.

“The field of 3D bioprinting, currently in its infancy, is rapidly emerging as an answer to the manual, low throughput methods of creating 3D cell models, including organoids and tumoroids.”

May combine two claims.

Primary ovarian cancers cells grown as organoids had HRD scores, growth and drug cytotoxicity more strongly correlated with the original tumor compared to monolayer cultures, indicative that 3D tumoroid cultures are better mimics of patient tumor behavior.

“A study by Jabs and colleagues documented that primary ovarian cancers cells grown as organoids had HRD scores, growth and drug cytotoxicity more strongly correlated with the original tumor compared to monolayer cultures, indicative that 3D tumoroid cultures are better mimics of patient tumor behavior (Jabs et al., 2017).”

• cites Jabs et al., 2017Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Tumor-on-a-chip devices utilize microfluidics to simulate effects of vascular flow in solid tumors and more specifically in the context of ovarian cancer, mimicking the hydrodynamics that influence ascitic seeding in the peritoneum and contributing to metastases.

“Tumor-on-a-chip devices utilize microfluidics to simulate effects of vascular flow in solid tumors and more specifically in the context of ovarian cancer, mimicking the hydrodynamics that influence ascitic seeding in the peritoneum and contributing to metastases (Figure 3).”

May combine two claims.

Hill and colleagues employed organoids from HGSOC for DNA repair profiling and were able to predict the therapeutic sensitivity in patients to PARP inhibitors.

“Hill and colleagues employed organoids from HGSOC for DNA repair profiling and were able to predict the therapeutic sensitivity in patients to PARP inhibitors.”

• cites Hill et al., 2018 sourceNot checked yet

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May combine two claims.

Advantages of microfluidic chip systems include the ability to utilize small amounts of starting material, homogenous creation of large numbers of spheroids, portable sizing, and the potential to control drug or chemokine gradients with integration of multiple wells or chips.

“Advantages of microfluidic chip systems include the ability to utilize small amounts of starting material, homogenous creation of large numbers of spheroids, portable sizing, and the potential to control drug or chemokine gradients with integration of multiple wells or chips.”

May combine two claims.

Induction of inflammatory cytokines such as MCP-1 and TNF mirrored the pro-inflammatory vascular microenvironment observed in the vicinity of ovarian tumors in vivo and inferred some regulation of cancer progression.

“Induction of inflammatory cytokines such as MCP-1 and TNF also mirrored the pro-inflammatory vascular microenvironment observed in the vicinity of ovarian tumors in vivo and inferred some regulation of cancer progression.”

May combine two claims.

Perfused spheroids formed larger subcutaneous tumors that were chemoresistant, regulated by the PI3K/AKT signaling pathway, when transplanted into nude mice as xenografts.

“These findings were further validated when transplanted into nude mice as xenografts, with perfused spheroids forming larger subcutaneous tumors that were found to be chemoresistant, regulated by the PI3K/AKT signaling pathway.”

• cites Ip et al., 2016Not checked yet

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May combine two claims.

A direct comparison of spheroid formation and carboplatin sensitivity in four ovarian cancer cell lines in either PDMS-based microfluidic devices with microwells, ULA plates or hanging drop showed microfluidic devices created more homogeneous spheroids with similar carboplatin sensitivities to ULA-plate derived spheroids.

“A direct comparison of spheroid formation and carboplatin sensitivity in four ovarian cancer cell lines in either PDMS-based microfluidic devices with microwells, ULA plates or hanging drop showed microfluidic devices created more homogeneous spheroids with similar carboplatin sensitivities to ULA-plate derived spheroids (Patra et al., 2020).”

• cites Patra et al., 2020Not checked yet

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May combine two claims.

This disruption was partially rescued by addition of atorvastatin, with results reproduced using primary HGSOC cells with prior atorvastatin treatment in vivo.

“This disruption was partially rescued by addition of atorvastatin, a statin drug used for preservation of endothelial junctions, with results reproduced using primary HGSOC cells with prior atorvastatin treatment in vivo.”

• cites Saha et al., 2020 sourceNot checked yet

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May combine two claims.

Numerous studies have shown the utility of ovarian cancer organoids of various histotypes for drug screening, with maintenance of mutational profiles and accurate reproduction of treatment responses when challenged with FDA-approved clinically utilized drugs.

“Further, numerous studies have shown the utility of ovarian cancer organoids of various histotypes for drug screening, with maintenance of mutational profiles and accurate reproduction of treatment responses when challenged with FDA-approved clinically utilized drugs (Kopper et al., 2019; Maenhoudt et al., 2020; Nanki et al., 2020).”

• cites Kopper et al., 2019Not checked yet

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• cites Maenhoudt et al., 2020 sourceNot checked yet

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• cites Nanki et al., 2020Not checked yet

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May combine two claims.

RNA sequencing of these tumoroids identified cell-specific pathways that may contribute to carboplatin sensitivity or resistance, and has potential for use in stratification of patients, to guide treatment strategies before clinical recurrence.

“RNA sequencing of these tumoroids identified cell-specific pathways that may contribute to carboplatin sensitivity or resistance, and has potential for use in stratification of patients, to guide treatment strategies before clinical recurrence (Gorski et al., 2021).”

• cites Gorski et al., 2021Not checked yet

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May combine two claims.

Microfluidic chips have been used to investigate platelet extravasion in the presence of both primary endothelial cell and ovarian cancer cells, whereby platelets were found to induce cancer cell mediated disruption of the endothelial layer.

“Microfluidic chips have also been used to investigate platelet extravasion in the presence of both primary endothelial cell and ovarian cancer cells, whereby platelets were found to induce cancer cell mediated disruption of the endothelial layer (Saha et al., 2020).”

• cites Saha et al., 2020 sourceNot checked yet

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May combine two claims.

The ring-shaped geometry eliminates the need for sample transfer or tumoroid dissociation, and can utilize very small starting cell numbers.

“The ring-shaped geometry is particularly advantageous as it eliminates the need for sample transfer or tumoroid dissociation, and can utilize very small starting cell numbers.”

May combine two claims.

HGSOC tumor organoids from primary and interval debulking surgeries showed histological concordance with the original tumor and reliably predicted carboplatin sensitivity and resistance.

“For the prediction of drug response, HGSOC tumor organoids from primary and interval debulking surgeries showed histological concordance with the original tumor and reliably predicted carboplatin sensitivity and resistance (Gorski et al., 2021).”

• cites Gorski et al., 2021Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Investigation into compressive stress to model external compressive stimuli such as ascites accumulation that increases hydrostatic pressure as a driver of metastasis is a relatively new approach and its effect on treatment is still unknown.

“Investigation into compressive stress to model external compressive stimuli such as ascites accumulation that increases hydrostatic pressure as a driver of metastasis is a relatively new approach and its effect on treatment is still unknown.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Microfluidic devices have great potential as more physiological and reproducible 3D in vitro models of ovarian cancer, but there are still drawbacks, namely in costing.

“While microfluidic devices have great potential as more physiological and reproducible 3D in vitro models of ovarian cancer, there are still a number of drawbacks to this new technology, namely in costing.”

May combine two claims.

Ovarian cancer is an umbrella term for multiple histotypes, with differing sites of origin, different genetic and epigenetic events and survival rates.

“As already discussed, ovarian cancer is in fact an umbrella term for multiple histotypes, with differing sites of origin, different genetic and epigenetic events and survival rates.”

• cites Peres et al., 2018Not checked yet

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