Guest post medicine

Linköping researcher protests bad science of corneal implants

This is a guest post by o Jaywant Phopase, principal research engineer at the Linköping University (LiU) in Sweden. He asks for your advice on the case former LiU professor May Griffith, whom he accuses to have misappropriated his data

Imagine: Your collaborative research work is about to submitted for publication, but you are not convinced of its scientific validity. The lead author tells you: either you accept her interpretation of results and become co-author, or she kicks you off the paper. Her shady claims will pass peer review and be published, the scientific community as well as clinicians and patients will be misled.  You can be part of it, with another paper decorating your CV, or you surrender your data and leave, but this paper is happening.

This is what happened to Jaywant Phopase, principal research engineer at the Linköping University (LiU) in Sweden, who now asks for your advice below. The university is known to readers of my site for the scandal around the fake professor and predatory conference organiser Ashutosh Tiwari. Incidentally, Phopase’s research was originally performed at the same Faculty of Science and Engineering (IFM), where Tiwari found support and protection by the former prefect Ulf Karlsson. Same Karlsson who allegedly used to bully Phopase, exactly because the latter raised a fuss about bad science being published and patients abroad being mistreated.

That science in question was led by former LiU professor May Griffith, then at LiU Faculty of Medicine and Health Sciences (FSM). Griffith’ research project was about artificial corneal implants, made as a composite of a chemical polymer and human collagen, manufactured at LiU and tested for biocompatibility on human subjects in Ukraine and India. For that she was found guilty of research misconduct by “repeated negligence”, in a LiU investigation from 2015 (see LiU press release and the Swedish-language report summary). Here is what was found by the three external investigators:

  • Biocompatibility test operations with biosynthetic corneas have been conducted on blind patients, without adequate prior animal tests. One can only fantasise which benefit exactly the patients whose blindness was not caused by a corneal defect were promised from those corneal implants.
  • Animal studies by the company Adlego Biomedical AB have not sufficiently advanced while human experiments in India and in Ukraine already were taking place: “these tests have not yet reached the level required to form the basis of an application to the regulatory authorities”.
  • Research-grade porcine collagen was occasionally used to manufacture corneal implants for human tests in Ukraine. Not human collagen, and not medicinally approved quality, which brings severe risk of toxin contamination or infection. Investigation found “non-compliance with documentation procedures for the handling of chemicals”,  “partly contradictory and irrelevant information” was filed by Griffith’ team.

LiU then assessed “whether the faculty’s decision will also lead to employment-related consequences for the researcher, such as a warning or a salary deduction”. Whatever they decided, Griffith is not at LiU anymore, but back in her home country Canada, as professor at the University of Montreal.

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However, the results of those human experiments from India and Ukraine were published in a Nature-themed journal on January 31st 2018:

M. Mirazul Islam, Oleksiy Buznyk, Jagadesh C. Reddy, Nataliya Pasyechnikova, Emilio I. Alarcon, Sally Hayes, Philip Lewis, Per Fagerholm, Chaoliang He, Stanislav Iakymenko, Wenguang Liu, Keith M. Meek, Virender S. Sangwan & May Griffith

Biomaterials-enabled cornea regeneration in patients at high risk for rejection of donor tissue transplantation

npj Regenerative Medicine volume 3, Article number: 2 (2018) doi:10.1038/s41536-017-0038-8

The authors pretend that animal studies were performed before tests in patients, and of course all their materials are described as safe and certified: “European Medical Devices Directive MDD 93/42/ECC and its associated ISO standards were followed”. Never mind that the findings of LiU investigation say something different. Also, good for Griffith et al that the journal’s editors or reviewers never bothered to ask for ethical approvals for those clinical tests in Ukraine and India. “Written informed consent” from the patients, whatever that meant, sufficed here fully.

 

It is strange why LiU did not interfere with the journal to clarify the ethical shortcomings of that paper, maybe they might still do it. On the other hand, LiU coordinates a ongoing EU project, funded with €6mn to put those corneal implants into EU-wide clinical use (though Griffith is not part of it):

Advanced Regenerative and REStorative Therapies to combat corneal BLINDNESS

“ARREST BLINDNESS is therefore to develop and validate new regenerative-based therapies addressing a spectrum of blinding disorders of the cornea. These conditions either have no effective current treatments, depend on a scarce supply of donor tissue, or non-standardized methods are hindering validation of promising regenerative treatments. To achieve our objective, we will implant GMP-fabricated collagen-based bioengineered scaffolds to replace or regenerate the corneal stroma in cases of stromal thinning, scarring, dystrophy or trauma; deliver therapeutic epithelial stem and endothelial cells to the cornea to restore its transparency; deliver regenerative factors to promote neural growth and function; and actively maintain corneal immune privilege in high-risk situations by targeted therapeutic approaches to regress blood and lymphatic vessels.”

Now Griffith wants to publish a follow-up study. The corneal implants used in the clinical tests in Ukraine and India were not specially sterilised, though they were manufactured in sterile lab conditions. For a proper, i.e., ethically approved clinical trial one needs to ascertain sterility and the post-sterilisation stability of those collagen-based corneal implants. This is what Griffith announced to have achieved with electron beam irradiation, allegedly “without changing their physical, chemical or functional properties”. Only, regardless what Griffith’s tests in rabbits proved, that was not really the case in Phopase’s own lab analyses. Neither did Griffith ever ran a positive control for sterilisation efficiency by irradiating any actual dirty, bacteria contaminated corneal implants, as Phopase discusses below.

 

 


Appeal to scientific community for support to improve research results and oppose biased science

By Jaywant Phopase

I’m a researcher at Linköping University and would like to discuss some of my results from the manuscript which is supposed to be submitted soon. I have some concerns and doubts about our results and there is a serious disagreement about the conclusions between me and one of the senior authors, namely Professor May Griffith. I tried my best to discuss my views and concerns based on facts and my findings, however it’s not going anywhere. I therefore thought that I should reach out to the scientific community and get some help and expert comments.

The aim of this work was to investigate the effect of electron-beam (e-beam) irradiation on artificial corneal implants, which previously have been implanted into the eyes of blind humans to test biocompatibility. The material these corneal implants are made of, is called RHCIII-MPC: RHC being recombinant human collagen type III, MPC being 2-Methacryloyloxyethyl phosphorylcholine. We fabricated the RHCIII-MPC corneal implants in a clean lab and sealed them into sterile vials. These implants were then sent to Sterigenics, Denmark, and irradiated with three different doses of e-beam (17 kGy, 19kGy and 21 kGy). After e-beam irradiation, the implants were analyzed and compared with the control samples, which were unirradiated implants. The effect of e-beam irradiation on composition, structural changes and degradation rate of implants was evaluated using Fourier transformed infrared spectroscopy (FTIR) and biodegradation study, where irradiated and unirradiated implants were subjected to collagenase degradation. My observations were as follows.

FTIR analysis: The FTIR analysis of e-beam irradiated implants (all the doses, 17, 19 and 21 kGy) showed changes in the composition of implants. The amount of MPC polymer increased with increasing dose of e-beam irradiation. The peak intensity of MPC polymer increased with the increasing dose of e-beam. This also indicated the fact that these implants contained unreacted MPC monomer which got polymerized after e-beam irradiation. This also raised the concern about the use of these implants as they have been implanted into the humans without e-beam irradiation, meaning they likely contained unpolymerized MPC. We also observed the change in amide I and amide II bonds for collagen, indicating the changes in collagen structure. This is also in good agreement with the literature previously reported.

Biodegradation analysis:

The biodegradation study showed that degradation rate of collagen in these implants increased significantly after e-beam irradiation and was much higher than in control unirradiated implants. The degradation rate slowed down after 12 hours because most of the collagen is degraded by that time and what remains is the MPC polymer which does not undergo degradation. The biodegradation study also confirmed the fact that the content of MPC polymer, the second polymer network in these implants, increased considerably after e-beam exposure in all the e-beam doses (17, 19 and 21 kGy). Furthermore, after exposing these implants to collagenase degradation for extended period, we got very stable thin film of MPC polymer from all the e-beam irradiated samples but not from the control samples (those without e-beam irradiation).We also confirmed that these films were nothing but the MPC polymer, by characterizing them using FTIR. These results are in good agreement with FTIR analysis described above. All this means, irradiation damaged the collagen structure and made it susceptible to enzymatic degradation. We also seeded human corneal epithelial cells (HCEC) on these MPC polymer films and found out that the cells were not able to attach or grow. Taken together, this means that irradiated RHCIII-MPC corneal implants are likely to quickly lose their collagen coating due to in vivo biodegradation and fail to be colonised by corneal epithelium when implanted into patients. They will basically lose their biocompatibility. These facts are quite crucial in my opinion and I’m insisting to include them in the manuscript. The senior author does not share the same view in this context and would like to exclude these observations and instead declare that low dose e-beam irradiation (17 kGy) has no significant effect on the RHCIII-MPC corneal implants.

Furthermore, the senior author has also included the following conclusion in our manuscript.

“Low dose e-beam irradiation (17 kGy) is an effective method of sterilization for RHCIII-MPC corneal implants.”

In my opinion this is clearly a misleading. The aim of our study was only to investigate the effect of e-beam irradiation on RHC-III-MPC implants. Therefore, we never validated if e-beam irradiation (any dose) was efficient to sterilize the contaminated/infected RHCIII-MPC corneal implants. It is very important to note that all the implants were fabricated in clean lab and were sealed into sterile vial. All the implants were sterile, before we sent them for e-beam irradiation. Therefore, it is no wonder that these implants were sterile after e-beam irradiation. I never understood, why so much of tax money was wasted to test the sterility of these implants after e-beam irradiation, when we knew that these implants were sterile before we subjected them to e-beam irradiation. We never performed any control study or even a single experiment to check if a 17 kGy dose is enough to kill any contamination present within these implants. I have also discussed this with few biologists as well with the person from Sterigenics, Denmark, who performed e-beam irradiation on our implants. He clearly indicated that the penetration depth of e-beam is limited, and it cannot penetrate thick materials. Therefore, we cannot claim that any of the e-beam doses we have used is enough to sterilize our implants, unless we validate it using infected samples (positive control). Moreover, the sterilization dose can also vary depending on the type of contaminants present in the implants. There are several articles about sterilization studies performed using different techniques, including e-beam irradiation which supports my argument above.

Based on my observations described above, I also have a concern regarding the long term performance and also use of these implants in highly inflamed corneal conditions (eg. chemical burn, HSV infection). The concentration of collagen-digesting enzymes (collagenases) is quite high during inflammation. Therefore, degradation of e-beam irradiated collagen implants will be higher than it was determined in past human experiments with unirradiated RHCIII-MPC corneal implants. The leftover MPC polymer network will then get in contact with the surrounding tissue and cells. As described above, cells were not able to attach to MPC polymer and I wonder what will happen in such scenario. MPC polymer is in fact known for its antifouling properties and is used to coat biosensor devices to avoid the attachment of proteins and cells on the surface.  (http://www.whoi.edu/cms/files/Chae_07_36863.pdf).

I invite all the researchers and clinicians to help me with your critical comments and correct me, in case any of my observations/conclusions are inappropriate. Please do not hesitate to write me in case you need any more information or if you have any questions.

Thank you very much in advance for your support and help.

Jaywant Phopase, PhD, Docent

Principal Research Engineer / Biträdande universitetslektor

Linköping University

Email: jaywant dot phopase AT liu dot se


The above letter does not necessarily represent the official view of LiU.

If you have an advice for Jaywant Phopase, please comment below.

Update 12.03.2018. The article in question has now been published, without Phopase:

Simpson F, Edin J, Islam MM, Buznyk O, Kozak ML, Liszka A, Merrett K, Gustafsson HP, Griffith M.

E-beam sterilization of recombinant human collagen-phosphorylcholine corneal implants for transplantation.

Ann Eye Sci 2018;3:AB085. doi: 10.21037/aes.2018.AB085

Update 13.03.2017. I received from LiU HR director, Pia Rundgren, an email in cc, where it looks like Linköping University blackmails me to remove Phopase’s institutional affiliations which I myself added to his guest post discussing his own work there. There seems to be an implicit threat of disciplinary consequences to Phopase should I not remove those affiliations:

Dear Jaywant,

As you must be well aware of by now, LiU has no intention of interfering with any statements made/information shared by you in your private capacity. And we have no opinion as to the content. But as an employee at LiU you are obligated to, when engaging in social media, at all times make sure that there is no confusion about whether or not your statements in this aspect are made by you as a representative of the University. We simply ask of you to abide to this obligation. How you chose to proceed to abide by this obligation is primarily your own choice.This is an obligation that applies to all employees of LiU. Neither the obligation, nor this communication is of any relevance to Mr Schneider.

Phopase asked me to comply with the order by LiU for his sake (hence the edited version above) and declared:

“Please kindly note that my intentions behind my article is purely scientific. There had been serious disagreement regarding the research results, which I believe are very serious and might be misused for clinical trails by the clinicians. Both the LiU Deans, (Prof. Nilssson and Prof. Södherholm) were involved in this discussions and I have informed both of them about my intentions that I will contact the scientific community to peer review my results and conclusions”.

Update 27.03.2017: Phopase’s institutional affiliation was restored with a disclaimer now,  after LiU’s Chief Legal Adviser Christina Helmér informed me in an “official letter“:

“that the university has no intention of interfering with any statements made by JP, he is merely reminded of the obligation to make sure that there is no confusion about whether or not his statements are made by him acting as a representative of the university or not. JP is then asked to revise his statements in this aspect. There are no measures to prohibit JP from discussing his research. LiU does not request that JP remove his LiU affiliation”

Update 31.10.2018. I decided to publish now the documents I earlier obtained from LiU on the Griffith case. There are original complaints (here and here) , statements on these complaints from the external investigators at Karolinska Institutet (here , here and here) and statement on financial investigation,


 

 

 

 

 

 

 

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19 comments on “Linköping researcher protests bad science of corneal implants

  1. Dear Jaywant,

    I am unable to comment on the scientific details, but I can say this as ethicist: I you feel any sort of doubt regarding the intergrity of this publication, my advice is that you should recluse yourself from the list of authors, and, as a consequence, deny the remaining author team right to use whatever input you have supplied to the collaboration. You should do this openly, and of course notify all co-authors of this decision, and explain your reasons.

    I have notified my bioethics colleague Vardit Ravitsky at the University of Montreal of the situation.

    The troubling fact that LiU does not seem to take action towards the former publication and demand retraction is a separate, albeit troubling, matter. If you want I can assist you finding people at LiU that could help you move that issue forward. You can find my email via my website.

    Liked by 1 person

  2. Definitely do not associate yourself withe the paper. The damage done in the long term is far more than the short term hit of one less paper on your CV.

    You could, of course publish your part of the data in a separate paper, stating they have been used elsewhere, but you have a different interpretation. Data belong to the institution, not the PI, so this may be possible – it is ultimately an employment issue – is your position independent of the PI, so your income does not depend on their grants, but instead you are employed by the University (or course there may be an institutional CoI here, in that PI of the paper is Head of Dept or associated with senior management in some way). If you are not financially dependent on the PI, then of course you can publish your data elsewhere, at the very least as a preprint and there are journals that would certainly consider the preprint for publication, e.g., PeerJ. This route, if feasible, provides you with a solid paper. It also lets the cat out amongst the pigeons.
    However, there is a risk here and it depends on the term of your employment.

    Like

  3. Dear Jaywant
    Are those implants really copolymers or are they just parallel polymerized networks of two polmers that are kind of intertwinted w/o any covalent attachments between the two polymer networks?
    From your descriptions it sounds like the latter, and therefore it is not suprising that a) you do not have 100% conversion of MPC and b) one is falling apart slowly in those degradation tests and the other is not.
    I think it prudent to check that no left-over MPC monomers are present and to find a way to covalently attach the two polymer networks to each other to make true copolymers.

    From an ethical standpoint it is horrible what is taking place in those human experiments, and they are treated merely like guinea pigs, nothing more, nothing less.
    Do not even think to remain as an author, nothing good comes from this.

    Cheers, oliver

    Like

  4. May Griffith was former Prof. in Linkoping University (LiU), School of Medicine ( https://www.youtube.com/watch?v=vX2hxhqbkPk). When I was there as a postdoc, I heard terrible stories about her activities such as fake cornea implantations performed out of Sweden, and couple of surgeries performed in Eastern Europe ended up with dead patients -very similar to Paolo Macchiarini case- but somehow all information was shadowed by the University. Everyone in the department became so silent when I started to ask questions about her and her activities. She was employed around 2009, and her activities and her lab were terminated around summer 2016, her students are suddenly sent to another department or other labs starting from 2014 to 2015 and nobody knew the reason why? Then, she turned back to Canada where she came from (https://research.uottawa.ca/people/griffith-may). I heard that couple of her students complained about her and her activities but it looks like University decided to keep to story secret, decided to terminate the lab activities. This is another aspect of the story!

    Like

  5. and here what I found on pubpeer, there is a clear scientific misconduct in a paper where she is a last Author. https://pubpeer.com/publications/8D89F6FC6E1DECD712917DC9ED5CAC. Things do not smell good up there!

    Like

  6. Klaas van Dijk

    Dear Jaywant,

    I would like to congratulate you with your laudable decision to make this posting and to ask readers for comments and/or feedback about this issue.

    I tend to think that I am already able to read between the lines of your posting that you have already decided by yourself that you don’t want to be engaged (anymore) with this manuscript and/or with researchers which are engaged in scientific misconduct. This posting shows towards my opinion that you have a high level of what’s called ‘moral leadership’ in the new version of the ACRCR (the Australian Code of the Responsible Conduct of Research).

    I am unable to comment on the scientific details as they are way outside my own field of research. I do fully support the view of Dave Fernig that you must not associate yourself with this manuscipt. I advise you to keep a maximum distance from May Griffith et al. I would like to advise you to follow the other items of the advise of Dave Fernig.

    I remember a talk with a PhD student from a non-EU country at RUG (The Netherlands) who told me that one of his fellow-countrymen (a former PhD student at RUG, also one of my acquaintances) had immediately left a post-doc position at a US-based university as soon as he became aware that his supervisor / his group was engaged in activities which were most likely falling within the definition of scientific misconduct (he has now a post-doc position at a well-respected group at a university in another European country).

    I always refer to the submission declaration of the well-respected ‘Journal of Sea Research’ at https://www.elsevier.com/journals/journal-of-sea-research/1385-1101/guide-for-authors when a corresponding author / lead author / guarantor / senior author (etc.) is stating that the manuscript will be submitted without consent of all authors. “Submission of an article implies that (..) its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out”.

    So my advise is that you are firm towards the other authors (and in particular to May Griffith) that they first need your permission before the manuscript can be submitted, and that this permission must be an explicit one. I leave it up to you if this implies that they must thus forcefully remove you as a co-author when they still want to submit this manuscript, or that you decide that you will voluntarily step down as co-author.

    All the best,

    Klaas van Dijk / Groningen / The Netherlands

    Like

  7. Agrippina

    Mirabile lectu. According to the 2018 paper ( https://www.nature.com/articles/s41536-017-0038-8 )
    “In India, clinical testing was performed in accordance with the Declaration of Helsinki, relevant laws of India and after approval by the ethics committee (LEC 01-14-014) of the LV Prasad Eye Institute (LVPEI) and trial registration at Clinical Trial Registry-India (CTRI/2014/10/005114).”

    The status of the referenced trial is “not yet recruiting” and no subjects have been enrolled http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=9854&EncHid=&userName=2014/10/005114

    Just in case (same link, shortened) http://tinyurl.com/ycrg6maq

    Even if the trial was open for recruitment and had recruited subjects, according to Table 1 in the paper and exclusion criteria in the trial registration, subject 1 is excluded due to active infection, and subject 6 is excluded due to glaucoma. Specialists may be able to spot additional exclusions
    https://www.nature.com/articles/s41536-017-0038-8/tables/1

    Also: according to the paper implants for clinical use were made at Karolinska Institute’s Vecura facility. What were the terms of the Material Transfer Agreement with the authors?

    The “Data Availability Statement” is idiotic. Clinical trial protocols are NOT available in the study registration on Clinicaltrials.gov nor through the WHO trial registration platform: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2014/10/005114

    In my opinion this gives the appearance of brazen non-compliance with widely shared ethical principles, guidelines, and perhaps regulations and law for research on human subjects. I would be pleased to correct the foregoing based upon additional verifiable not-insane information.

    Like

  8. Since this study is organized from Sweden, I assume they would also need ethical approval in Sweden. This is required in Norway, and I will be surprised if they have different rules in Sweden.

    Like

  9. Smut Clyde

    Update 12.03.2018. The article in question has now been published, without Phopase:
    E-beam sterilization of recombinant human collagen-phosphorylcholine corneal implants for transplantation.
    Ann Eye Sci 2018;3:AB085. doi: 10.21037/aes.2018.AB085

    As the “AB085” suggests, this was a single-page Abstract — a list of claims without supporting evidence. It looks like this issue of the ‘Annals of Eye Research’ was given over to the Abstracts of “The Vision Health Research Network Annual Research Day, and International Symposium on Retinal and Choroidal Angiogenesis (Montreal)” – there is a Preface, explaining that the Vision Health Research Network has gone into collaboration with the journal and the publisher.
    http://aes.amegroups.com/article/view/4019/html

    Jeffrey Beall did include AME Publishing Company on his list of potentially predatory journals. Confusingly, it also goes by the name of “Pioneer Bioscience Publishing Company”. Before that, though, Beall described AME / PB as “a borderline medical publisher, and there’s not a strong case to be made for adding it to my list”
    https://web.archive.org/web/20160616223722/https://scholarlyoa.com/2016/02/11/japanese-open-access-journal-is-a-joke/#comment-402955

    Like

  10. Pingback: Linköping University and Tiwari’s predatory conferences – For Better Science

  11. Pingback: Trachea transplanters without borders – For Better Science

  12. Deception is very tempting and some people are good at that

    Like

  13. Pingback: Linköping: scamferences no crime as long as LiU trademark protected – For Better Science

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