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WSCS 2015: Stem Cell Therapies Using Adipose Tissue - From Fat Grafts to 3D Cultures

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WSCS 2015: Stem Cell Therapies Using Adipose Tissue - From Fat Grafts to 3D Cultures

Adipose Tissue Was Considered An Unreliable And Unpredictable Material For Tissue Reconstruction Until Very Recently. With The Development Of Standardized Techniques For Harvesting, Processing And Delivering Fat Grafts Pioneered By Sidney Coleman Md, The Indications And Uses For These Grafts Quickly Spread. Initially Thought Of As STRUCTURAL Grafts, Their Regenerative Impact Was Evident To Practitioners. This Finding Was Buttressed By The Discovery That Adipose Tissue Is An Abundant Source Of Mesenchymal Stem Cells, Capable Of Delivering Therapeutic Doses Of Mscs In A Single Operative Session (ZUK Et Al 2001). Current Advances In Fat Grafting Technology Have Focused On Delivering The Full Regenerative Potential Of Adipose Derived Mscs Within The Constraints Of Fda Regulatory Standards. Fat Grafting Is A Regenerative Technnology Already In Use Clinically For Many Conditions Including Reversal Of Radiation Damage, Degenerative Joint Disease, And Many Other Conditions. We Are Just Beginning To Understand How To Harvest The Full Potential Of Fat Grafting.

Video Transcript

Moderator

Ricardo Luis Rodriguez, Md, Cosmeticsurg


Speakers

Annie Bowles, Tulane University


William W. Cimino, Phd, The Gid Group, Inc.


Camillo Ricordi, Md, University Of Miami Diabetes Research Institute



Welcome to this session, My name is Ricardo Rodriguez and their current president of the felt as theInternational Federation for adipose therapeutics on science we are a society that's purely dedicated to studying adipose cell therapies including everything from fat grafts to SBF we have we just had our annual meeting our next meeting is in San Diego next year.

I left Yeltsin Fliers out here if you're really interested in adipose tissue regenerative therapies this is the place where all the leading scientists in the world meet so their first hour lecture today was supposed to be Brunel from Tulane University however he had this weekend is receiving another major award so he could not make it so he sent and bowls and I have another correction to make Adam Katz who was a person who discovered in mesenchymal stem cells in adipose tissue was scheduled to talk and he also couldn't make it and he was actually gonna be the one talking about 3d cultures so the 3dcultures is not going to be included on this lecture anyway so without further ado and bowls she's a PhD candidate on the Dr. Bruce Parnell at the center of a stem cell research.

Tulane University and she's going to talk to us today about some things we can do with SBC SBF rather I would like to thank all the organizers for this conference and allow me to present on behalf of my PR Dr BruceBunnell unfortunately for him as an able to make a bit fortunate for me I'm able to stand in his place but we'll talk about some of vascular fraction in adipose derived stem cell-based therapy.

I first want to introduce the stromalvascular fraction or SPF initially when white adipose tissue is harvested it undergoes a mile digestion procedure after this digestion procedure though adipose tissue is centrifuged into three layers that are able to be acquired the top lipid layer where is the mature adipocytes and they lipids the middle aqueous layer and the show more vascular fraction pellet at the very bottom which typically is plated in culture expanded to obtain the homogeneous population ofadipose-derived stem cells are ASC's and many clinical applications have been proposed using ASC's in much many results have been evaluating the safety and efficacy and uses of a sec for many clinical indications and knowing.

The advantages of using ASC's known that the ASC's are within the SDF looking at the FB app is one of our focus is in our lab and looking at and evaluating the safety in effect advocacy of this more fresh product the more crude heterogeneous cell population of SPF with flow cliometric analysis we looked at those several sub populations of SPF this in particular is there are isolation and our method of isolation and also filtering obtained these sub populations the majority that being the hippo home at a poetic cells are the cd3 positive cells the AFC's within that population so these two are the large majority that compose the SPF the adipocyte preadipocyte and that the oil sales and smooth muscle cells and to a lesser extent cells that have matured and have our of the eyelid and lymphoid lineages looking at the applications that are currently used SPF is to enhance at graph so fat grafts that had been used for many cosmetic and reconstructive procedures.

where a fat graft is supplemented with freshly isolated SPF and is typically administered straight back to the patientknown as also sell assisted liposuction but using these studies where they had demonstrated safe be an epic AC and perhaps some other mechanisms and indications that these mechanisms wear SPF is more beneficial than juhas ledng a fat graft alone has led us into our investigation currently in the United States their recruitment of clinical trials for multiple sclerosis and osteoarthritis but much evidence for using FBI has come from many veterinary medical applications where many horses and dogs and other animals with bone and soft tissue disorders have been treated with no adverse effects reported and more of my field of study looking at the Murine models of neurodegenerative diseases autoimmune diseases inflammatory diseases all together these studies have given us a good indication.

The SBF administers therapy is safe and ameliorate pathology it anyway to seize their anti-inflammatory and immuno modulatory and perhaps promote tolerance and this is all very important for many neurodegenerative diseases which I will go into so talking about how this translates to human patients multiple sclerosis RRMS patients and patients are about over two million people worldwide making it the leading neurode generative disease affecting young adults typically ages 20 to 45 and it's believed that a genetic factor is incited by an environmental component that instigates an autoimmune reaction against Milan which is an essential component of the central nervous or CNS tissues now this milan is produced by oligodendrocytes and create the sheet that wraps around nerve axons for normal neurotransmission know when it's a reaction happens cells of the periphery of the lymphoid tissues are primed by this an agenda as foreign and then go into the peripheral blood circulate break down the blood brain barrier and infiltrate into the central nervous system issues and hear the South now not only encroach on the CNS tissues but they generate.

These inflammatory demyelinating lessions and depending where these localized patients with MS produce signs and symptoms of disease such as cognitive and motor impairments batiks pasticity and progressive paralysis now most MS patients are first diagnosed with relapsing-remitting disease but since these remains an unmet clinical disorder and many of the current disease-modifying drugs out there are acting systemically targeting only implementation and also have neutralizing antibody such as interferon beta many of these patients in most of these cases develop a more chronic and progressive form of Ms now capitulating these immunological neurological on pathological features amass the best model out there is the murine experimental auto immune encephalomyel it is EAE mouth now this mouse develops I T cell-mediated autoimmune disease by the administration into the subcutaneous planks of the tail the myelin oligodendrocyte glycoprotein which is emulsified with an adjutant and tuberculosis and can confidently with this administration is a ninja parentsand intraperitoneal injection of our protectees toxin on the date of induction and as well its forty-eight hours later now this is the typical lamina pathogenesis and how it is graphed inour forum where we look at the severity of disease which is daily clinical scoring looking at the score of wine.

Which is some gait abnormalities which progresses into a score of 2 which is weakness of the Highlands a score of 3which is partial paralysis of the hind limbs and a score for which is complete paralysis of the hind limbs and as you can see here signs of disease or apparent after four to five days post induction a disease which is on day 0 and looking at this overall progression looking at in there'd is RTE mouse compared to the sham which is in bloom as the disease progresses this is all a result of the breach of the blood brain barrier infiltration of the immune cells into CNS tissues and a widespread inflammation throughout the CNS with inflammatory demyelinating lesions as you can see here the lesions are demarcated by be black arrows going back to what we've known as a utility of ASC's and now that stromal vascular fraction SVF contains those a sec and have similar benefits we would like to look at other properties we know that a sec are able to differentiate into cell lineages like most other mesenchymal stem cells are able to really new and they also produce anti inflammatory and immunological immunomodulatory effects that are therapeutic but more importantly.

I would like to take the kids we like to look at the capacity of SPF in a sec to be able to migrate to these damaged areas on their own provide a minimum and modulatory andanti-inflammatory effects in trophic support there at the sites of damage and see what other mechanisms that they are providing as therapeutic benefit so little about the experimental design here identified again the scoring system that's news for the daily clinical scoring and throughout this 30 day trial all the mice undergo motor function tests which here you can see is atop-down view of our video recording which is five minutes each of each mouth the mouse is then detected by movement using an evasion by notice technologies where a lot of these parameters motor base parameters are able to be generated and analyzed for quantitative comparison throughout the 30 day trial.

Researchers will allow for behavior and motor function testing as well which includes rearing behaviors and grooming at the end of the trial which is data thirty tissues are harvest did our tissues of interest are the lymphoid tissues which are the lymph nodes this plane the blood as well as the scent CNS tissues for this particular study we're looking at the late stage therapy how effective is SPF after preexisting pathology so this translates to also with humans with pre-existing pathology and how separative these cells can be so the groups that we were able to design for as the SPF treated EAE mice that received one million FBF sells these 1,000,000 a sec administered to the AFC treated EAE mice in the vehicle controls and looking at dates when he is when we decided is our late-stage therapy again pre-existing disease with inflammatory demyelinating lesions already occurs at this time.

So we ultimately want you answer the question of what is the effect its efficacy of SPF treatment at late stages these and more importantly what are these mechanisms that are being harnessed by s via and that way we have better indications in better evidence for something that can go translation only looking back again at the daily clinical scoring day twenty is the time of injection of these cells whether it be SPF a sec or vehicle and as you can see here in the green which is the amelioration of observable disease signs from the SPF treatment group A at these in the middle with the blue squares and then the in the red is our vehicle control group looking at the mean score and committed disease course we can see that there are there was are duction of the disease course meaning that there is a male aeration of these signs of disease anywhere from 20 to 30 days.

This was quantified looking at the behaviour protected rears Wallington grooming about all of these behaviors really require a lot of balance coordination and motor function so it's very important to note that our vehicle-treated mice were unable to execute any of these during the twenty to thirty days post induction whereas the AFC and SPF treated mice were able to significantly greater looking at this top-down view again so this is the compiled tracks over five minutes of each of our mice and there's a representative mouse here that is shown for each group looking at day 20 wherein all groups consider about of reduction of motor function is seen as well as you can indicate some cognitive defects most normal mice like to scavenge the area several times and it has a very even spread whereas these mice with disease perhaps forget where they going or they're just not able to go and go into this wide motor function the AFC and SPF mice do represent and/or do show that there is recovery of these motor functions even five days after.

The injection of South this is the gating strategy that's used for the next couple of slides looking at the different how identified the different cell populations in these other tissues that we investigate in order to look at the immune system activities and how are these changed with the administration of South looking at the peripheral blood spleen and lymph nodes these tissues were put into a single cell suspension and staying for an analyzed with loads of Tom and Jerry now looking at their similar trends with all three of these tissues but there were significant alterations in the immune cell populations in the peripheral blood again this is the communication between the peripheral lymphoid tissues and the central nervous system so what's out there what's being migrated can all be inferred from this data looking at the total T cells here which to the sub populations the helper T cells these were significantly greater increase with SPF administration as well as at the Milo population the macrophage population looking at this plan analysis.

These same populations we have the lymphoid cells the T cells and B cells as well as the macro phages were all significantly greater in the SBF treated planes of the EMI a similar trend here in the lymph node issues but most importantly here we are able to detect regulatory T cells so this is something that we are not able to look at will never got results for before but with SPF treatment we see that there is regulatory T cell induction in the lymph nodes and this was significantly greater than the vehicle or a secret so this is where there some kind of distinguished between a sec SPF that we are able to see most of you know regulatory T cells are the good T cells they promote immune tolerance they want to counter the autoimmune effects that are happening in Vivo looking at the central nervous system tissue this is particularly the spinal cord sections of the cervical section cellular infiltration in milan was able to be quantified using stained sections of AT&;T and Lex off a spoon respectively and these were quantitatively compared and I'm looking at a total sales per field for the cells that have infiltrated into CNS tissues.

They are seasoned SPF had a significant reduction compared to vehicle-treated mice whereas the Milan levels which were higher significantly higher in the AFC and SPF treated by so perhaps there are some remyelination or perhaps the SVF ASC's are inducing some kind of precursor oligodendrocyte shoe restored the deficit that have already occurred in the CNS tissues and then analysis of the inflammatory lesions as you can see in the images they are mainly depicted and then they're quantified by the surface area and number of lesions using image scope software and as you can see here there's a significant reduction with cell therapy and the number of lesions and the surface area looking at the gene expression in the spinal cords interleukin 10 which is produced to induce T regulatory cells as well as is produced by T regulatory cells is significantly more I'm sorry not significantly but there is a greater increase with the SPF treatment as well as interleukin 6 was which is one of those pleiotropic cytosine.

Which we believe is beneficial in this mouth and this disease here also similarly with the brain analysis of the gene expressions looking at I'll turn increase in child sex increase with the SPF treatment looking at the serum levels we had analyzed it to look at a particular cytosine and there was a reduction in their planetary ones in an increase in the aisle 10 with in Vitro proliferation assays were able to look at modulation of the immune system where weary stimulate these cells with the MOG an agenda again for the second exposure and as you can see here spf did not have a proliferative response suggesting some very potent immune modulatory effects so ultimately we believe this is a very comprehensive a treatment that would be very efficacious 48 you might as well as these results will translate for the human ms disease we saw improvement with motor function behaviors as well as restoring a lot of the deficit that we're in the central nervous system tissues so we support the use of SPF as a promising therapy for MS patients with preexisting disease and I want to thank my lab as well as.

The Dr Geoff gamble flat who is a close collaborator of oursand thank you thank you the next speaker when introduced is will home question silly intercession Dr Bill C me know dr. CBO has 30 years of experience in research and product development in the medical industry he has three engineering degrees includinga PhD in bio engineering is currently the CEO of the GID Group a leading adipose tissue and science and technology a company I've actually used this device inmy own research I love it and I recommend it to anybody who's doing research as a quick method of getting spf anyway so we'll take it preciate thank you for the invitation I'd like to address really working from adipose tissue I'm gonna start with the anatomy and work all the way to clinical results we've got several clinical outcomes I'd like to share with you but I always start with the anatomy and the magic of adipose and stem cells and stromal vascular fraction and all these words to get used all come from here and I want to make sure there's no confusion basic adipose we have the adipocytes you see the little fibriles this is our extra cellular matrix we've got the vascular structure and attached to all of that mostly to the vascular structurein the extra cellular matrix we have this host of heterogeneous mono nuclear cells called the stromal vascular fraction so fat when we start with a fat graft.

We start over here we have the adipocytes we have the extra cellular matrix we have the vascular structure we have the SPF part of the SPF is what we call the ASC's and in previous talk so here we have SPF is a sub population and I'm speaking specifically of only the mono nuclear aidid non floating cells and from there we have a sub population which is the ASC's which are the bio markers 45negative 34 + 31 negative which would be our progenitor cell fraction and that he is 10 to 15 percent of the stromal vascular fraction by count so we look at Apple's by volume and between these two or three slides everything flows from this is by the way it is eighty-five to 90 percent by volume isadipocyte varies from men to women varies from site to site but largely speaking it's the majority is adipocyte whole fat is about 10 to 15 percent ECM+ vascular structure and less than half a percent that would be the maximum would be all these stromal vascular cells concentrated.

If you take all that and you exercise it you can get somewhere between two and four millions pf cells in the perfect condition that's how many you would be there if you could get every single one of them and all of those sales I said before 10to 15 percent is a secso let's talk about fat versus SP effort is a disease in a sort of a hierarchical understanding that graphs do contain as he has any a season there's a lot of people that say they're using their doing stem cell grafts are fat grafts yes there is SPF in a sec in fact but the concentration is very low by volume consideration is not concentrated at the adipocytes which are the majority of that are not regenerative they're useful for constituting volume or initiating of agreat player but they're not the regenerative cells SPF starts here and retain gets rid of the adipocytes the extra cellular matrix the vascular structure and you end up with a heterogeneous population of ASC's heterogeneous population called the SPF of which 10 to 15 percent is a sec and importantly.

All the adipocytes in RBCs oil droplets and cell fragments are goners's start here and we played them we culture them expand them and you go further and you get to sort of I homo genius ASC progenitor population with no adipocytes or ECM as a picture of a nice cell pellet this is not spun hard for those of you who are used to test you hard spinning this is if you look very careful these pictures are too clear but does the RBCs and some lights hemoglobins at the very bottom if you spend as hard as you could separate out into a white and red layer may be the most important slide in presenting today on the issue of concentration of regenerative cells concentration of regenerative cells is the issue we need to get these cells in a fat graft you've got a relatively low concentration of about 24 million SPF sales program or mill a whole fat of that there's going to be some a sec at the 10 to 15 percent population because you can now take the cells and concentrate them are between 100 and 200 million FCF the F cells are Graham about fifty to a hundred times that a fat ok the SEC follow forum by 10 to 15 percent ten to fifteen hundred times that of fat and then AC's obviously our own 100%roughly speaking concentration of agencies you get about between high and low 60 to 300 million cells in the ground with fluid ok.

So how do you gets pf three major raised one that we know most about is the enzymatic method has been studied the longest it's known most is known about this and the beauty of the enzymatic mast is the collage is highly specific to the collagen structure so it is specific to release these cells and it takes about 60 to a hundred and twenty minutes depending on what method is going on and the vast majority of that time is where the enzyme is working on the extracellular matrix there's a lot of mechanical methods that are being looked at those blenders meshes shakers in centrifuges metal balls these are mechanical impact and disruption of the adipose tissue to attempt to release the stromal vascular fraction and cells that are bonded into the east takes less time with you have the impact of mechanical damage on the tissues explant culture is also used.

We culture whole tissue and is the cells become a pop product they start to migrate off of the extra cellular or vascular structure and into the culture medium this takes three to three to seven days depending on what's going on the key to all of these is really an efficiency how many cells can I get per gram of fat I don't havean infinite source of adipose and how many can I get in semantics is known in it and if I went back through the past 20 years it started at two hundred thousand cells program then it went to four hundred and depending on your process where typically running about a million cells per gram of fat but it can follow that it varies with patient 500,000 2,000,000 cells per gram of fat with high viability of 75 to 80% this viability is my way not compromised so much by the enzyme so leaving exposure to the enzyme the viability is maintained a lot of this liabilities lost in the harvest process and that's what you see here CFU analysis too strong over 5% and as I said before is highly specific the collagenase is highly specific to release of these cells mechanical tends to be less productive with regard to yield I'm looking at 10 to two hundred and fifty thousand.

This is why they reported our experiences towards the lower end but the big concern that we have in this analysis it works both ways and I'm not commenting too much other than the reality is we tend to see very low CFU and performance and we do see liabilities down towards 50% explain culturing obviously you get highly viable cells there replicating should have a major clinical impact we need some way to get from my body fat over to science and research and that process needs to be fast reliable and safe so what we've been going on here working on is a system that is usable a nano wire has quality control system processing time less than an hour and so you can put tissue in a sterile field into the device and when it comes out of the device it is the cellular structure that you're looking for work something like this it's not any different from a lot of other systems other than it's been optimized for simplicity and effectiveness harvest of washing space enzymatic digestion a centrifuge phase extract.

The cell pellet back to the patient very direct in our first major commercial effort we had andit will be a product called the SBF this is the total time frame we got it down to sixty minutes the majority is dissociation in a shaker and removal centrifuging a fifty of the sixty minutes we're currently working at about42 minutes tip to tail so from harvest debris injection of the patient is now42 minutes is what it looks like it's another device when we have a strong vascular fraction extracted in two to three disarranged for an orthopedic injection important piece here this is what the extra cellular matrix in the basket the structure look like we retain it in a mechanical structure and a mash the cells have been released from this and this is what the new looks like after its been largely associated with regard to performance over the years.

We've had several independent groups and studies this is seven hundred thousand nine hundred fifty thousand cells per meal of fat on average that's what ours pf yield is we're currently running right there are 1,000,000 SPF sales per gram of fat liabilities running 75 to 85 percent consistently and reliably this is the age curves what happens to bad as people age same plot both sides linear regression to the downward direction the important point here is the younger patients obviously have a much higher yielding and they're they're wonderful with regard to sales but its 800,000 where's by the time you're over sixty it falls but it only costs about 500,000 cells per gram of fat enzyme concentration is a huge topic with regard to regulate regulatory environments with it I don't want to bore you with all these numbers needless to say collage collagenase can be easily removed from this dissociation with 122 delusions we generally run about five CD use per million cells so twenty million dollars would have between fifty and a hundred CD use in adults and a CD you by bike or just be quantified is a thousand balloons unit.

We're running around point 05 2.1 when she is in a dose which is 99% removed from the initial concentration to dissociated issue clinical applications really the best part we focus on three areas the orthopedic area primarily osteoarthritis but also ligament and tendon repair wound care and then some aesthetic breast reconstruction surgery are good examples of all three the osteoarthritis trials are not pretty to look at because there're no results to look at other thanto tell you that they were small safety trials three-month and one-year follow-up single injection of SPF of two to three mils and the patient was its own control under IRB these are both been published in their respective journals these are available online and in the journals are summarized the first trial here this is pain intensity this is of course compromise pain scale pain interference pain behavior.

All things related to what I follow up with the WOMAC all declined 10 of 10 patients improved but decreased patient and here's the big one seven of 10 went from their initial osteo arthritic pain 20 pain at three months and this was statistically significant the second trial was one year long we had the same these are two different scales this is what's called the warm and very common in office and orthopedic realm that scores visual analogue pain scale oldest the same sort of the same measuring the same thing I'll just talk about this one eight of eight patients decreased in six of eight had a score of less than 10 at one year statistically significant a score of less than 10 is phenomenally low pain compared to initial score.

So the summary of the two trials eighteen years to independent trials 17 of 18patients had decreased pain in three months and 8 of 8 who would we followed out to a year we're still had decreased paying these two trials are now involved in a full FDA IDE level 1 blinded randomized trial peripheral vascular disease these pictures are pretty graphic if this is not your bent we did a temptation trial in Nicaragua where all patients were slated for amputation so these are bad diabetic ulcers this patient has a 57 year old female you can see the condition this is three months post excisional surgery so no cells have been used this is just getting rid of you know getting the wound ready for cellular treatment so this is three months after this and you can see the condition of the woman at that point she was treated with cells under the wound and also down the lower vascular structure of the lower leg.

We were working on the vascular flow in the leg this is four months of this is four months here and this is spontaneous incomplete closure at eight to nine months this woman was gonna have a foot cut off we had no other way to do this we have ten patients in a row like this she the 2nd US is also peripheral vascular disease you can see the condition 75 year old man same conditions he was treated with sales in the excised area and also down the leg the same way this is what it looks like at six months post there and there's complete closure at eight to nine months so we have a series of town and won't go further I'm gonna talk about burns also done in Nicaragua this was a significant burn to the right arm a kitchen wound she had had 10 extra 10 surgeries to release the contractility and the scars after six years she still could not oppose her thumb and fingers these two were locked together and she could not pick up apiece of paper and pencil she could not right and she had consistent pain.

We treated her with a little bit of fat to the back that was enhanced with SPF. We put a half a sec if cell enhanced and lactated ringers and says he's joined the same way we treat the knees and this is her hand at three weeks this picture is important to realize as far as she could open her hand this is what she could do it three weeks and we can begin to pick the skin off the back of her hand being like this where she was scarred down before this is a place for you I don't know how to do this is her how do we make that go touch it yeah I'll run over so what we'll do this she shows you she's a journalist and Central America how she could type shows he was doing for six years she could only do this because this is the only thing that would work.

Then she shows you that you can use the full hand and she types and she more importantly she's pain-free from breast this is on the left side you can see a congenital malformation here this was augmented looks like this that preaching is now three years out with no loss of volume same thing here this is a standard breast augmentation pre-op in this across the top post op and the volume is now over two years and retained so those patients are all not to burn but the breast patients are published in this paper 774 patient series skip the regulatory it's a complex and involved issue the point was to be able to conclude with this to be able to go from an operating room.

All the way through therapy in less than one hour in cellular treatment and with these are three areas we've been working so but that include Thank You Like It truly efficient engineer a lot of material in very little time very well expressed next is Camille Ricordi. He's a Goodman Stacey Joyce Goodman professor of surgery at the University of Miami a distinguished professor of medicine professor of bio medical engineering microbiology immunology and the director of the Diabetes Research Institute and cell transplant program at the University of Miami well forget about all of that what impressed me.

The most of him or his pictures with a rolling stones when he was young that's his there are many people who have lost their former presentation not alter carevaries a little extra I wanted to give a little beginning to show you a different perspective on using a deposition cell therapies which is using at the site of cell transplantation and this is a review article that I mentioned yesterday has summarized the 25 years experience in i lov processing and transplantation for your enjoyment in this is this engineering Opera Minipancreas meaning the current bank rushing to abdominal that we've been working on at the University of Miami in with collaborators are advised to use as a platform technology to include besides insulin producing cells also other cell types that may help inducing tolerance immuno modulation.

I miss arrives as well as conform alcoating encapsulation to introduce a battery technology this is just mentioned because we did the first patient last post and the procedure is practically sitting using a biological scuffle fuller solvable comprised of out of gas plasma from the recipient's blood human recombinant and islands here you see a class that is less than half a millimeter in diameter you mix them with tautologous plasma see them bylaparoscopic surgery in the momentum then draped human recombining on being an additional layer of plasmin eyelets and domain term without any stage and then let them get revascularization by the dalai this has been the first results have been rather impressive this was before I let transplantation on thirty one unit per day off in Syrian huge variability aggressively credibility especially severe hypoglycemia that is the reason for indication of an islet cell transplantation and this is after barely transplanted the three months visit of insulin completely since the second week with a very stable glucose control this is continuous glucose monitoring system.

So it's been very exciting and now we're teaching other centers worldwide about this procedure to try to build up the numbers in the next few months but the other reason you can use factors you heard is that you can use it forRegenerative Medicine application and wound healing this is how I got them barbizon commentary mother came to Miami to the cell transplant center asking for help to characterize this result but other than why they were trying to understand why they were obtaining better results clinical initially was done in plastic surgery application and cosmetic surgery to use more let needles and they practically what they did is to obtain avery fine adipose tissue preparation going through to class the reduction with this system that has been developed than in a kid that is this possible and you have it also here and exhibits time and is comprised by to feel their one little bigger like four millimeters than one millimeter and you practically passed the delight prosperity in a full immersion system will see.

If you're lucky with this movie so you're past the lab prosperity through the first screen first class size reduction in full immersion without any covered dish should I mentioned you actually take the solution inside the container to amounts if I'd are already scheduled be able to wash them out by counter flow while the fact remains in the higher portion then you flip the searing the cylinder and now you have the smaller screen one millimeter on top and you a spiratesailing from this bag and I'm Porsche and how to best the product the adipose tissue reduce class their product which is ready for clinical use for the procedure less like 15 minutes or fewer but Israel is important the fact that you have a disposable doesn't use any environment does not require centrifugal any specialized equipment in the operating room if you look at confocal microscopy of this micronized class the republicans tissue can appreciate.

There is a huge rise in suicides that I'm not a deeper sense that the cells comprising the stromal vascular fraction and various sides and the hillsides and all the self-described before we've been collaborating with blue prepares to chairman of orthopedic UCLA and I'm not careful and Cleveland to try to understand mechanistically while the system work and it seems that they part is that the parasites that aligning all this microvascular structure the terror and reach a final twice as many in the Lite version product compared to like prosperity who fat percentage this may be part and sales because they respond to injury being activated and producing.

Mrs.with regenerative potential so you're not an immuno modulatory another properties regenerative properties of embassies and this is one of this class they're so fly by James if you put them in culture that generates themselves and you can move towards advanced cell therapy with expanded the messages from this class there but is not the primary use right now is used as a minimally manipulated tautologous tissue providing both structural scaffold and activating various sides this is interesting why say activating precise because we've seen in proteomics analysis that there are differences between the cells contain in the light prosperity or what comes out of the Lite version after the class production design study by Bruno pails group that have been just recently resigned today without getting into detail of their analysis.

But if you look at the secretory activity of life in general elections compared to us we have you see that you have many more Americans both for angiogenesis and cytokines and then if you digest Li project with enzymes you lose Soyuz like enzyme digestion reduce the secretory activity of the nitrogen fractions and this is just the beginning of what you have time to understand mechanistically of what could be some reason why this appears to be a better product in the hands of some so this fact that the secrets in between multiple factors growth factors cytosine involving tissue regeneration peres could be important to another factor that we found intriguing is that is that when you look at exorcism and microbiological content of liposome compared to an enzymatic allay process tissue find huge differences like the exam at exactly the same as radical size but if you can compare collagenous treated to Lipper jammed this concentrator intense concentration analyzed by nano particle tracking analysis shows big difference very highly significant so you know.

There have been a lot of studies and hypothesis on how exercise may be critical agency no regeneration and regenerative medicine therapies this is an excellent review if you want to check it out on the current landscape of Ms system itself secret and how this could constitute the basis for maybe preconditioning we were discussing yesterday 23 gallon target maximum a corporation called the trans-pacific factions that could help stem cell therapies as well so clinical experience has been a several thousand cases now as of june 2015 both radiotherapy damage or vocal cords incontinence but I space colorectal burning crosses femoral head necrosis diabetes chronic wounds and other applications this is all publish micro fracture purified Black Pearl Jam in order kinetics surgery procedure overall kinda twenty patients treated with this Olivia you want to check the details of these studies are on Open Access publication this is lame chronic in limbo scheme a study by being torn collaborator also they're interesting for the potential Neon Genesis responsive there little gem treated tissue they show that there has been even in cultured.

In-vitro culture a big effect on she said that on the bottom of the well place and showing their results on my project treated versus are even a combination of cells that were treated with different agents so this is the same showing now arterial genesis in schemic muscle tissues and this is another appt clinical application was recently published on the recovery of functional any contingency after micro fragmented photographs life for James and this at the site of injection system and commentary before and one year

after this is important because apparently when you use single cells or expanded MS is the fact is transient well he received a defect and then a one-year down here and the fact disappear but the muscle freak seems to recover and he received the persistence of their works and incontinence car in addition of the manometry the today show.

I'm now several trials over going on diabetic foot ulcers and reference centers in authoritarian bargain this trials and with very interesting initial results and here is in order kinetics surgery date also published so I let you go exploded details online as well as regeneration in difficult cases of oral surgery applications it seems that there is an increasing storage any potential of lipid German York on comparator little gem exposed to collage nous enzyme are digested fat and this may have relevance to clinical application as I mentioned yesterday the whole system started from this racing horse that was treated couldn't talk anymore was treated for a major contributor problem and this is after the treatment that was too bad this movie's done but this was the biopsy to demonstrate a newly formed a large at the site of injection incorrectly cure this other examples in bone fracture that are delayed unions severe pain in the fracture with no sign of killing nine months.

The fracture and then after the lissome application was very good healing and complete recovery functionally this is a femoral head necrosis cases that are now also undergoing clinical trials were doing light pajamas mix with the hydroxy told a crowd of the calcium hydroxyapatite this is another interesting application specially for me that I have already rated this rolling downhill ski racing when I was younger and was interested to see that 9 45minutes they can do this kind to me if I am preserve ablation injection of liposome transplant and be done in 45 minutes this is another new trial potential application that will be very interesting to follow cannot salinascame in portland is a huge orthopedic practice and we are very excited to seethe initial results in 60 patients treated for me also tried this was confirmed by x-ray and MRI results before and followed then now up to costliposome injection with the improvement of the season terms.

But also some encouraging results as far as MRI before and after like James treatment this is another case twelve months after Labor Day Treatment injection with a reduction of the joint space narrowing that persisted for over one year and this was it this is another MRI before injection and three months after lissome treatment so this is another interesting case 300 this is the beginning of 100 subject IRB approved by this institute that this was the first case of a power from this trial showing as results showed their functional score improvement the pain scale reduction with a twenty years particularly virtually no pain and also their evidence that MRI of increased doubling of the thickness suggesting cartilage reconstitution 01752 1.5 millimeter of cartilage a twenty or so in conclusion it seems to be an effective solution for many clinical application is very easy to apply and has an early anti-inflammatory and pain medication followed by effect on cartilage and bone that cannot be after a minimum of four weeks and continue to improve for many months usually beyond one year.

So this is just the beginning of this experience there are several dozens clinical trial now I'm going worldwide has been approved in EuropeUSA China Australia Middle East and Japan and as a matter of fact a little brother couldn't be sure to present because in Japan training a bunch of selected surgeons thank you for your attention and questions anybody have any questions ok so and with interest the difference between the SEC and how you would expect the pure culture cells to be more potent than work better but instead we're seeing the multitude of different cell seems to work together what do you attribute that they're only about 10% a way that. We I read there were differences between each of us in this is because when I heard we harvest adipose tissue from my there's a considerable amount of hair and such things that we have to filter out but looking at our populations with 10%being a video that the combination of an it is windy and I believe is what makes it so hoping for these neurodegenerative or that happened in the body so they target different area and I didn't get to show the data but we used SPSS down and he's from GFP positive crying and then they were administered date my and we were able to tax and GST the periphery which were in the lane and lymph node from the SPF injection 9 a.m. and then looking at the central nervous system.

These cells were intraperitoneally injected and they found their way and usually they got stands out pathology but I would think of it more like of activity so if they mean systems actively responding and then also in the central nervous system these are key elements that give us insight into what mechanisms that SBS use is that different from a sec yeah I agree with you I think that works in a different way and it contains what we call amplifier cells to the signals and and in many ways I think will prove to be better for certain conditions that is seized bill I so you're very impressive results with healing of diabetic feet.

I was 14 years I was in winter clinic and I always could heal everything but. I could never keep it healed and I think that would diabetics the main problem is that neuropathy which now did you happen to measured sensory function after SPF course I bet you there must be some kind of improvement after we wouldn't we didn't have that study but the patient you're right and I just report that anecdotally there is an important part to what you just described and that is not only did we inject under the wound and we took angiograms and so we took pre-op and post-op and which you can see is under the wound where it was injected you to see it blush you just see that circular structure start to form but we knew that these people were all compromise so in the end agree and we looked at the lower limb and we actually found the steno tic points as we walked down and we injected around these points and then we looked at them post operatively and you can actually see flowing basket the structure.

We have flow Doppler and so to maintain like you said you couldn't keep them closed or keep them healed we directly address the vascular supply and that's what seemed to mean that's as much of well. I cant say what percentage but that's as much of the solution is injecting under the moon itself I was referring more to the neural function yes they get their neuropathic ulcers essentially and but ii do think and I have heard from people who do stem cell therapies anecdotally improvement in sensory function after stem cell injections and I was just wondering if you guys are planning to measure that so we have another these are what I would call at this point case reports so these are people with neuropathic pain and no officer and andwe they were the pain was so bad.

They were considering amputation and they rejected and their pain is greatly and significantly reduced I wouldn't say all the way gone but significantly reduced down the back of the leg and foot so we looked at the vascular structure and we found where was narrowed and where there was you know simpson where that that was not true and so we would put injections of SPF with fluid all the way around so there's like 15 injections going down the back of the cat pictures were trying to lay a write down the arterial feed and then in the foot as well I'm our country University alumni questionnaire and you guessed it be a model I'll 17 now we have and that's one of the mechanism that we're looking into that he found how they were differentially so in our studies we see all 17 governors hi and that I predicted a positive and a question for Camilla if you look at the immunomodulatory differences between post and telegraph line and played Clifford James is one better than the other we did a comparative study be looking through some of these but one of the impressive Brian southerly nope service like that it was clear.

That there is a trial ongoing in sclerodermathat not only improve the aesthetic but also the best club but it disappears and those seen in other studies in alopecia are which is also to me you have growth of hair again so it seems that is definitely an immuno modulatory effect and you can imagine we're looking to buy your habits and at Strategy forum for islet transplantation to see if you can both promote angiogenesis and had some immuno modulatory tracked the intriguing is that depending how you use them and since we found for example when you inject them with riches publishing in clinic but it is correct we make out in 42 patients randomized prospective using MS is expanded from a medical card and it's like if you see this effect on himor not immunity.

Then you see a protective effect on island rejection in other islet transplant Britannique another benefit expand those cells and you see them for example on a scaffold inner-city all but disappear so it seems so that is very important how you use it is not just a cell types and you can have a modification of the phenotype in effect depending how their culture already interested in order preconditioning and how to learn which condition may be more conducive to the immuno modulatory fortunately we're running out of time we just have more time for one more question regarding your needs were your new joint work with these yes how were the keys to the stem cell products delivered to the needs just enter articular injection or either one or both cases and take care of the injection but you have to be kind of recommended they don't do this.

I know that I would want to have it done by an orthopedic surgeon with ultrasound guided to make sure that you know exactly where you go because apparently they way you daily relative silence and especially if you deliver too much of a volume could be leading to side and desirable side so we don't have a table that has all the specific objectives will be fine condition but I'm not actually starting to sound guided supposed to fluoroscopic Lee order guided his team in Gaza which made out okay so we used orthopedic experienced orthopedic injections and if you tap the need and you can show that you can withdraw a little bit of synovial fluid you know your inter cooler and so we would look for that a CCC or two and then the injection was between three and four ccs of lactated ringers with the dose of cells suspended in LR running over so well.

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