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TOPIC: Ectopic bone by non-expanded adipose cells

Ectopic bone by non-expanded adipose cells 02 Jun 2014 13:55 #1751

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The discovery of the ROBUST trial (270 patients) back in 2012 was at the time for me an exciting discovery, especially since the IP of Cytori is rather strong in this field.
Link here : Basel- ROBUST clinic

I never really got into looking for scientific publications by the principal investigators of the study, since I always have been focused in respect of bone formation with ADRCs on the work by the Dutch group in Amsterdam around Marco Helder.
The Swiss however are at least "as advanced " as the Dutch and not surprisingly I found the study which probably triggered ROBUST.

The title you find in the thread- whereby "ectopic" is something "grown independently in soft tissue and not as part of the musculoskeletal system". Actually they arrived at similar conclusions as the Helder Group.

Bone issues for the elderly are a big thing and I could imagine that Baxter has been talking to Cytori already, since Baxter Biomaterials are used in the study.

From the Conclusion:

This study reinforces the feasibility of an intraoperative use of autologous SVF cells for bone regeneration. The approach requires only one surgical procedure, similar to autologous bone grafting but clearly with reduced morbidity at the donor site. Moreover, it does not require extensive processing and culture of the isolated cells, thereby also reducing the costs and regulatory burdens otherwise associated with advanced cellular therapies. The use of low doses of rhBMP-2 was essential in the ectopic model to drive osteoblastic differentiation of SVF progenitors, but could be bypassed upon implantation at an orthotopic site, in the context of a bone environment where such physiological amounts of BMPs are likely already present. Recent work on the established interaction between the immune system and osteoprogenitor cell function (Liu et al., 2011) also prompts for further studies in immunocompetent models with a proper onset of inflammatory processes. However, the introduction of alternative in vivo models requires the use of animal as opposed to human adipose-derived cells, which are known to have markedly different biological properties and osteogenic potential (Levi et al., 2011) and thus would limit the potential clinical relevance of the generated findings. In this regard, one of the most compelling challenges in the routine clinical implementation of this approach is related to the large variability in phenotype and bone forming capacity of human adipose-derived cells from different donors (Scherberich et al., 2007). Therefore, one additional effort will have to involve the identification of reliable quality control/potency markers of the implanted cells, in order to ultimately define the number of cells with a specific phenotype which should be introduced per unit of construct volume to ensure reproducible bone formation.

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Board moderator and Site-owner. I still regret the day I started analysing the prospects of MacroPore (now Cytori) back in 2004- a left-over from the tech-bubble at that time from the century change in my portfolio- and became addicted to Cytori´s fat cell technology. :cry:

Ectopic bone by non-expanded adipose cells 02 Jun 2014 14:37 #1752

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Curious if ROBUST has the same issues as getting participants in this study as ATHENA has had...though ATHENA had some of its own study specific issues...how long will it take to get 270 people to agree to the study ?

Fas, just cant remember, but wasnt therealready a history between Baxter and Cytori somewhere way back when ?

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Ectopic bone by non-expanded adipose cells 02 Jun 2014 15:08 #1753

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Very unlikely that they will have recruitment problems-

The Swiss are number one in creating bone fractures due to the winter-sport (skiing etc) also for elderly :grin: :joy: and either you get standard of care- your own iliac crest material or the composite cell graft. Both are not really enjoyable procedures.

No- Cytori had a "run-in" with Medtronic in the past. The only thing in common was the cardiac cell therapies for CHF. Baxter stopped further development.

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Ectopic bone by non-expanded adipose cells 02 Jun 2014 16:38 #1754

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Medtronic...that was it !!! Thanks Fas.

I did remember that Baxter had a cardiac program separate from Cytori that they had stopped.

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Ectopic bone by non-expanded adipose cells 03 Jun 2014 14:59 #1756

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Going over the paper a couple of times (again) and going back to my notes from 2008-2011, it seems that we have a situation AGAIN, where Cytori was dead wrong on the scientific side of things. Basically similar to immonu-modulary virtues of ADRCs which were never recognized (see my HARDCORE article) and culminated into Cytori taken a license on Thomas Ichim´s patent on the related science.

This is pretty much the same on bone generation and differentiation of which Patricia Zuk and Cytori scientists have always claimed that BMP2 and ADRCs together DO NOT influence any improved therapeutic working besides their own single benefit. I do not feel like writing a single article on it ( I should since its important, but do not have the stamina at present)

The conclusion in the paper (see later) have already been proven in practice by the Amsterdam group of Marco Helder in the periondental clinic. ROBUST is going on already for about two years and would have been stopped if the scientific premises were false. They are continuing, which is benificial to Cytori but contrary to the science that Cytori has preached in the past.

That - is simply sad. :puke:

This study validates an intraoperative manufacturing concept for the generation of grafts with osteogenic/ vasculogenic potential derived from human adipose tissue. The formation of bone tissue was shown to require the delivery of a low dose of rhBMP-2, which could not induce ectopic ossification by itself. The reproducibility of bone tissue formation might well be improved by increasing the density of implanted SVF cells, which not only supported but directly contributed to bone tissue formation. The in vitro results suggest that the mode of action of rhBMP-2 did not involve an increase in the percentage of SVF cells recruited to the osteogenic lineage, but rather a stimulation of the osteoblastic differentiation of the committed progenitors.

The dose, which to the best of our knowledge is lower than the minimal one ever reported for stimulation of adipose-derived cells in vivo (Jeon et al., 2008), was not intrinsically associated with osteoinductivity and supported bone formation only by acting in concert with the implanted cells . :happy: Moreover, it cannot be excluded that the combination of implanted human cells and rhBMP-2 could have recruited resident cells from the host which may have directly contributed to bone formation in conjunction with implanted bone-forming cells




Most likely therefore the mechanism is that the growth factor (BMP2) acts to the progenitors (most likely pericytes) as an injury signal and induces the activated progenitor to differentiate into bone.

THIS IS FANTASTIC- the progenitors are NOT plastic adherent so this procedure ONLY works with fresh cells and will not work with cultured stuff. :cool: :nice:
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Ectopic bone by non-expanded adipose cells 03 Jun 2014 15:34 #1757

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All well and good, but until it is marketable...and we all know Cytori is incapable of marketing anything...its just science. :yawn:

Who brings it to market ?

We have already seen EU approvals alone mean nothing in terms of a market. :cry:

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Ectopic bone by non-expanded adipose cells 04 Jun 2014 07:42 #1759

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Fas,

Great find. Great study. The findings in this study definitely provide the basis for the ROBUST trial. I can only assume that the decision to have a trial size of 270 patients, which is very large, is based on a high degree of confidence in the protocol that was based on the study findings.

When you look at how complex it is to make a good animal model/trial that will provide the insights and data to go forward in human trials we get an understanding of the difficulty of what Cytori is undertaking. This is great stuff and it is HUGE that we are not paying for it. The translational stuff/trials is a pipeline that continues to provide data/validation of ADRC therapy and Celution's role in that therapy.

I believe that the 6 month data in Scleroderma/Sclerodactyly should soon be available. If the beneficial effect is maintained then I believe that there will be an announcement of a larger European trial with reimbursement potential. If this occurs the blinkers will be taken off, and the investment community will finally be able to see what we do ............. a treatment platform that covers a range of medical conditions that is UNPRECEDENTED. The translational studies will then become INVALUABLE (adjective : beyond calculable or appraisable value; of inestimable worth; priceless) :woohoo: :joy:

When that happens we will be focusing on other issues eg. How easy is it to make a deal? Do you go with Olympus Terumo for orthopedic indications, or Baxter?? Does one get Japan/Asia and the other USA/Europe?? Maybe Medtronic would like to make amends for its past transgressions ......... who knows? Decisions Decisions.............. :KO:
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Ectopic bone by non-expanded adipose cells 04 Jun 2014 10:08 #1762

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Yes John,

I think we only need some "proof of concept" evidence out there to convince the medical community and patients i.e. papers and study results.

Since we got the approvals -a lot should be there already- unpublished- and waiting for D-Day.

Our day will come. :nice:

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Board moderator and Site-owner. I still regret the day I started analysing the prospects of MacroPore (now Cytori) back in 2004- a left-over from the tech-bubble at that time from the century change in my portfolio- and became addicted to Cytori´s fat cell technology. :cry:
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