News

CE mark approval for Arthrys

Tiss’You has obtained CE mark approval for Arthrys, a new medical device based on peptides derived from hydrolyzed collagen.

Within the mission to always look for new and better solutions to help our body’s natural healing abilities, Tiss’You has developed Arthrys, a ready-to-use injectable solution for the intra-articular treatment of osteoarthritis and for structural strengthening of connective tissues. Its mechanism of function is based on peptides with an average molecular weight of 3KDa. The formulation of this device, enriched with vitamin C and magnesium, directly strengthens the structure of the extra-cellular tissue matrix naturally rich in collagen, decreasing pain and improving joint function.

 

Read the product sheet for more information.

New Lipocell clinical study in orthopedics

We are proud to share a new clinical study on Lipocell, published by Dr. Gianluca Castellarin, orthopaedic surgeon expert in regenerative medicine.

The study shows the long-term benefits of Lipocell infiltration in patients with osteoarthritis. In particular, it shows the results on 92 patients (59 males, 33 females) with average age 52 and osteoarthritis grade II or II on the Outerbridge scale.

About pain symptoms, the patients show a 50% reduction already at the first follow-up at one month and, at one year later, an average value of 1 VAS scale point, which corresponds to a near absence of pain. According to the functionality, measured with the Womac questionnaire, patients recover significantly already at the first visit and maintain positive results for up to one year.

In some selected patients, the study also shows a control MRI scan where it was possible to observe a reduction, or even disappearance, of the peri-lesional subchondral edema and, in one case, also a reduction of the chondral lesion.

Lipocell is a medical device able to purify, directly in the operating room, the patient’s adipose tissue, naturally rich in mesenchymal stem cells. The product thus processed, according to minimal manipulation requirements, is able to release molecules useful for repairing damaged tissue and modulate inflammation, restoring the homeostatic balance of the joints and slowing osteoarthritic progression.

We thank all authors of the work and in particular Dr. Gianluca Castellarin for the care and sharing of the paper, which is available for a consultation below.

 

Castellarin G, Mosca S, Micera G, Moroni A. Intra-articular administration of purified autologous adipose tissue for knee osteoarthritis treatment. Minerva Ortop Traumatol 2020;71:93-7. DOI: 10.23736/S0394-3410.20.03976-4

Stem cells and mesenchymal cells: Let’s make it clear

There is a sentence I often hear when people talk about regenerative medicine: “It’s wrong to talk about stem cells, you have to say mesenchymal cells.” It’s claimed both by doctors and non-experts, but to understand how strange this phrase sounds, you should read the following example.

To celebrate his job promotion, Andrew asked Juliet out for dinner, promising her to pay for it. As the bill comes,  Juliet remembers his promise and asks Andrea: «You have the money, don’t you?». The man, after checking his wallet, replies: «No, I only have cash.»

STEM CELLS

To tell in an article what a stem cell is would not do justice to a biological prodigy that now is the absolute protagonist of biomedical research. Moreover, I would risk boring the reader, or even worse, confusing him: the exact opposite of this piece’s intent. I will only describe two properties for which these cells are so appreciated: self-renewal and differentiation.

Through self-renewal, a cell can clone itself during replication. When a stem cell divides, at least one of the two daughter cells does not undergo any modification and remains identical to the mother cell. This is important for the stem cell pool to remain quantitatively stable over time. With the onset of pathologies and the progress of aging, this ability weakens.

With differentiation, a stem cell can specialize in a tissue-specific function, such as: being a skin cell (keratinocyte), a muscle cell (myocyte), a nervous system cell (neuron). Differentiation is a progressive process that takes place through epigenetic modifications, i.e., changes that silence parts of the DNA that are not useful for those specific functions. In this way, only the valuable genes remain active and what was once a stem cell can now replace damaged cells and contribute to the functioning of a tissue.

Stem cells can be adult, or “less adult” and differentiation potential can be toti-, pluri-, multi-, oligo- or unipotent. The next paragraph will help us to understand these differences.

MESENCHYMAL CELLS

The myth of the stem cell is born through the belief that it can regenerate any tissue. A totipotent stem cell can give rise to everything (even to life). A pluripotent stem cell can give rise to almost everything (it cannot generate an organism from scratch). The latter exists only in the embryo, or it can be obtained through the reprogramming of an adult cell by reversing the process of differentiation. There are ethical issues with embryos, and reprogramming exploits advanced cell manipulation techniques, such as the Yamanaka method (Nobel prize for medicine in 2010 for the famous iPSC – induced Pluripotent Stem Cells) or the somatic cell nuclear transfer (do you remember Dolly The Ship?).

However, if we take a step back, there are also adult stem cells that can be multi-, oligo- or unipotent. Multipotent stem cells cannot differentiate in all tissues as pluripotent ones, but only in those falling under the same embryonic origin. As suggested by the mes- prefix, mesenchymal cells are adult stem cells that can differentiate in all tissues originated from mesoderm (the germ layer that originates the musculoskeletal system, blood cells, and other organs). They were first identified in bone marrow in 1970, then in different tissues and only in 2001 in fat. In regenerative medicine, they are appreciated for the simplicity of the harvest and use. Even if they cannot differentiate in all cell subtypes, they have an excellent stem cell capacity that we have not mentioned so far. In response to the environmental stimuli, they can release molecules able to promote regeneration.

SO?

Not all stem cells are mesenchymal cells, but all mesenchymal cells are stem cells. In scientific literature, the chosen acronym is always MSCs, which stands for Mesenchymal Stem Cells. The doubt, for researchers, is of a different kind. In 2008, a discovery claimed that MSCs derive from pericytes, which are contractile cells that surround capillaries. It is not yet certain whether all MSCs originate from pericytes, but it is sure that not all pericytes become MSCs.

If the last sentence is somehow confusing, that’s because biology is complicated. However, there is one thing that we can be sure about: if you know your meaning, it is not dangerous to talk about stem cells. Indeed, you may risk giving a good impression.

Omar Sabry

Sources:

Pierre Charbord.  Bone marrow mesenchymal stem cells: historical overview and concepts. Hum Gene Ther. 2010 Sep; 21(9): 1045–1056. DOI: 10.1089/hum.2010.115

Patricia A. Zuk. The Adipose-derived Stem Cell: Looking Back and Looking Ahead. Mol Biol Cell. 2010 Jun 1; 21(11): 1783–1787. DOI: 10.1091/mbc.E09-07-0589

Arnold I Caplan. All MSCs Are Pericytes? Cell Stem Cell 2008, 3 (3), 229-30 DOI: 10.1016/j.stem.2008.08.008

Lipocell Publication

Please note our latest publication in the Special Issue entitled “Advances in Regenerative Medicine and Tissue Engineering” by MDPI Processes magazine. In this last article, we characterized Lipocell from the cellular and histological point of view. The following paragraphs are technical hints dedicated to insiders; the general publican can jump to the conclusion of the article.

 

HOW MANY CELLS ARE THERE?

The mechanism of function of Lipocell technology is a dialysis membrane that separates the elements of a solution, in this case, lipoaspirate. The filter has a porosity equal to 50 µm that retains adipose tissue, but permeable to washing solution, blood, and excess oil. The mesenchymal stem cell (MSCs) count was performed by comparing the standard device with smaller filters (15 and 20 µm). Lipocell, on average, has 2-3 times more MSC than untreated fat. At the same time, no differences were found between the different filters, suggesting that a filter with lower porosity is not useful to retain more cells.

 

FROM RED TO YELLOW

Excess of blood and oil, in case of lipofilling (re-integration of adipose tissue into the patient for filling or regenerative purposes), can be a problem. These are waste residues, without recognized biological activity, which can cause inflammatory reactions. The 50 µm Lipocell filter can purify tissue from these elements more effectively and quickly than smaller filters or other methods.

 

A MORE CONSERVATIVE METHOD THAN CENTRIFUGATION

From a regulatory point of view, excessive manipulation of adipose tissue turns the product into an ATMP, which stands for Advanced Therapeutic Medicinal Product. Consequently, it should be subject to strict regulation that is not compatible with routine clinical practice. Cell culture, for example, substantially modifies the cellular product. The same can be said of enzymatic digestion or significant mechanical manipulation which, by altering the structure of the tissue, become more than minimal manipulation. In our article we have characterized the elements of the extracellular matrix through biochemical analysis and performed histologies to compare the Lipocell product with untreated and centrifuged fat. Lipocell maintains a tissue architecture fully comparable to native fat, while the centrifuged one shows a substantial alteration of the structure.

 

THE RINGER’S LACTATE

The procedure with Lipocell also involves the use of a washing solution. Results have shown that washing with Ringer’s Lactate (instead of saline) fully preserves the proliferative potential of MSCs. The mechanism of action behind this novelty requires further investigation. Still, a possible explanation may be that the adipose tissue cells, after liposuction, go into ischemic shock due to lack of oxygen (as they no longer have a vascular supply). In oxygen deficiency, the cells initiate anaerobic respiration, which is a less efficient way to produce energy, but the administration of lactate ion could compensate this reaction by restoring the Krebs cycle and thus improve cell survival.

 

REGENERATIVE MEDICINE FOR ALL

Lipocell is a medical device classified IIa for intra-operative processing of adipose tissue. The mechanism of function is based on a dialysis membrane, which, in combination with a washing step, can separate adipose tissue from waste elements such as excess wash solution, free oil, and blood. The final product is enriched with MSC with great regenerative potential (see our recent article: “Fat is beautiful”), with the advantage of being easily injectable and with a preserved tissue architecture that meets the most stringent regulatory requirements.

Fat is beautiful

If there is something underestimated in our body, that is undoubtedly the fat (medical term: adipose tissue). 

Large hips, swollen belly: people would love to remove fat from their bodies. Yet, for thousands of years, being overweight was a reason for admiration, a sign of prosperity and fertility, but also a charm. Only in the contemporary age, the concept of beauty shifted to the thin, setting it as a model for the most disparate reasons including the appropriate medical notion that correlates obesity to several diseases. 

Why does fat exist? From a biological point of view it is neither to make us beautiful, nor to make us ugly, but to perform some important tasks, such as protecting organs and tissues by acting as a mechanical barrier, preventing the dispersion of heat generated by our body and regulating the energy reserves (glucose and lipids) with accumulation and release when needed. Fat tissue regulates many important physiological functions, such as metabolism, fertility, coagulation, but the most surprising fact is the abundant presence of adult stem cells, which makes fat an attractive cellular source also because of the ease of its collection. The reason why this resource exists is not clear to researchers and, notably, stem cells were discovered in adipose tissue recently, in 2001.

However, already at the beginning of the 20th century, some people sensed that fat could be a special tissue. During the First World War, Dr. Hippolyte Morestin, a plastic surgeon pioneer, tried to perform the first facial reconstructions of wounded soldiers, using autologous human fat. And in even older times, during the American Revolution, pig fat was used to treat war burns. With the evolution of reconstructive surgery, fat has maintained its importance both for aesthetic reasons and for its volumetric capacity, to fill the large voids of tissue loss. The technique is called lipofilling and it consists of the suction of fat (liposuction) from the subcutaneous to re-inject it on the patient himself. Over the years, the procedure has evolved to obtain increasingly refined grafts, purified from residual oil that causes inflammatory reactions and reduced in size for better survival of the implant. It is with this progression that it has been understood that the adipose tissue is mostly a regenerative tool and not only a volumizer. Only later, researchers identified an abundant presence of mesenchymal stem cells in fat, able to differentiate in the cells of connective tissues (bone, cartilage, muscle, etc..), but especially to release molecules useful for tissue repair in case of damage.

Today, fat is back in fashion. At least in medicine. Many medical devices, such as Lipocell, can purify adipose tissue directly in the operating room, making it injectable and useful for the treatment of a wide range of diseases ranging from osteoarthritis to diabetic foot. However, biology is complex, men are mysterious machines and we do not know all the reasons why adipose tissue is so special and useful in medicine. Probably, this does not depend only on the regenerative and anti-inflammatory activity of stem cells. In our laboratory, we are analyzing the extracellular matrix components of adipose tissue and investigating the anti-oxidant power of lipids, which could have a great influence on the mechanisms of tissue regeneration. The goal is to understand what are the differences between individuals and how much diet and habits can affect the therapeutic potential of this tissue.

Anyway, we should not despair for those extra-pounds on the belly, because today we have a (scientific) excuse to say that “fat is beautiful”.

Omar Sabry

 

Sources:

Benmoussa N, Hansen K, Charlier P. Use of Fat Grafts in Facial Reconstruction on the Wounded Soldiers From the First World War (WWI) by Hippolyte Morestin (1869-1919). Ann Plast Surg. 2017 Nov;79(5):420-422. doi: 10.1097/SAP.0000000000001221.

Murray CK, Hinkle MK, Yun HC. History of infections associated with combat-related injuries. J Trauma. 2008 Mar;64(3 Suppl):S221-31. doi: 10.1097/TA.0b013e318163c40b.

Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001 Apr;7(2):211-28. doi: 10.1089/107632701300062859

Monocytes treatment for hip OA – Case Report

The orthopaedic group led by Dr. Vincenzo Madonna at Humanitas Castelli in Bergamo has published a case report using our device Monocytes.

Regenerative medicine is useful for treating damaged tissues through a minimally invasive approach. In this way, it is possible to prevent major surgeries, or speed up recovery after surgery. When we talk about last-stage osteoarthritis, however, it is necessary to sacrifice the joint with a prosthesis and biological therapies are no longer useful. Nevertheless, cartilage often ages on both joint sides and when it’s time for the implantation of a prosthesis (ed. knee or hip, it is the same), regenerative medicine can be useful in the so-called “contralateral” joint, ie in the opposite side.

In this work, the clinical results of this therapeutic strategy emerge. Before treatment, the patient reported disability and lameness caused by the arthritic condition of her right hip, which was a candidate for prosthesis, but also continuous pain and limitation of mobility on the left side. The replaced hip (the right one) achieved the expected good results, but also the other joint treated (the left one) with Monocytes (ed. mononuclear cells from peripheral blood) showed total pain relief and excellent recovery of mobility, with a very high index of satisfaction from the patient.

Monocytes can restore joint homeostasis through the release of growth factors and inflammation mediators. Moreover, macrophages, which derive from the differentiation of monocytes, can recycle the oxidized elements of synovial fluid such as hyaluronic acid and lubricin, improving the metabolic and mechanical balance of the joint.

We thank all the authors of the work and in particular Dr. Francesca De Caro for the care and sharing of the work, which is available for a consultation below.

 

Francesca De Caro, Arcangelo Russo, Gabriele Cortina, Marco Collarile, Vincenzo Condello, Vincenzo Madonna. New Trends in Treatment of Osteoarthritis: “From Cells to Metal”. A Case Report of Simultaneous Different Approach to Bilateral Hip Osteoarthritis. Ann Case Report 2019, 11: 247. DOI: 10.29011/2574-7754/100247

 

Omar Sabry

 

Cartilage regeneration: myth or reality?

Some animals can regenerate entire parts of their body with an inner ability that does not require external intervention. One example is the axolotl, a small salamander that lives in Xochimilco lake, in Mexico, which can regrow limbs, lungs, spinal cord and even parts of the brain if they are damaged, without scars. Also, the common lizards that we are used to finding in our gardens can regenerate their tail, without difficulties (ed. and without stem cells injections). Humans have lost this biological peculiarity during evolution as far as we are not even able to counteract accumulative damage, such as the ones that occur with joints use and injuries. As a result, cartilage is consumed, developing osteoarthritis.

So far, the most common belief is based on the idea that cartilage cannot regenerate and that the recycling of matrix elements, such as collagen, is almost impossible due to the structural complexity of the tissue and the absence of vessels that should carry nourishment and oxygen. However, at Duke University, this issue has been studied and the comparison we made at the beginning was appropriate to discover that even in our cartilage, the most stubborn tissue in terms of regeneration, there is an innate regrow ability – so far unappreciated – regulated by the same mechanisms that allow the salamanders not to worry when they lose a limb around.

The team of researchers analyzed the biological clock of articular collagen, discovering that they can date proteins as “old” or “young” according to their turn-over (ed. the metabolic exchange of substances or cells). If we take the lower limb as an example, this protein age follows a position-dependent gradient: in the hip, we find the “oldest” proteins and in the ankle the “youngest”, while in the knee there’s a good average. So, the hip itself is an older joint in comparison with the ankle and less subject to self-repair mechanisms; that’s a fact that correlates properly with statistics showing that hip osteoarthritis is more frequent than ankle osteoarthritis, and also, as a result of damage, the hip healing rate is slower compared to knee or ankle healing. This “articular age” is not only a consequence of the joints mechanics and the load to which they are subjected, but it also depends on the biological activity of some molecules called microRNA, able to regulate the collagenic turn-over in humans and the regrowth of the limb in salamanders. They are, in fact, the same group of molecules, following a precise distribution gradient, resulting in more activity in the distal part of the limb (in the extremities) and less active in the proximal part (in the center). Consequently, it will be easier for a salamander to regenerate a “paw” than the entire limb and it is easier for a man to heal his ankle than his hip.

The axolotl is an animal model well characterized for regeneration and discovering that joint tissue repair is regulated by the same elements, albeit limited, is a big step forward in the development of new therapeutic approaches. In modern medicine, many surgical techniques and different cell therapies are now used for cartilage reconstruction, but from a theoretical point of view, it is believed that cartilage cannot regenerate. This discovery comes after others that have demonstrated the presence of cell progenitors in mature cartilage and stem cells in neighboring tissues. Therefore, research should not only focus on slowing down the arthritic processes by extinguishing destructive catabolic phenomena, but also on providing anabolic elements to support – that’s something we can say today – the natural regenerative capacity of cartilage.

Omar Sabry

 

Sources:

Ming-Feng Hsueh, Patrik Önnerfjord, Michael P. Bolognesi, Mark E. Easley, Virginia B. Kraus. Analysis of “old” proteins unmasks dynamic gradient of cartilage turnover in human limbs. Science Advances, 2019; 5 (10): eaax3203 DOI: 10.1126/sciadv.aax3203

Alberto Siclari. Il trattamento delle lesioni cartilaginee. Cic, 2019. ISBN: 9788893890243

Tiss’You for cartilage repair

At Ciceron Hotel in Rome, the “International Cartilage Regeneration & Joint Preservation Society (ICRS)” will present its Focus Meeting entitled “One Step Cartilage Repair”. The society has always been a promoter of the themes around cartilage repair, through the divulgation of the latest news from the world of medical research. This year, ICRS offers a complete overview of all possible “one-step” interventions for cartilage defects, from bone marrow stimulation to the latest news regarding orthobiologics and regenerative medicine.

 

Tiss’You joined ICRS bringing a talk on the scientific agenda, through Prof. Riccardo Ferracini (Genoa) and Dr. Ilaria Roato (Turin), entitled: “Regenerative Treatment of Knee Osteoarthritis with Infusion of Low Manipulated Adipose Tissue”. This report will provide some preliminary data of the most recent studies in which the company is involved.
 

28th Isokinetic Medical Group Conference

During the 28th Isokinetic Medical Group Conference, we held a workshop entitled “Regenerative medicine and multimodal approach to prevent early osteoarthritis onset on late-career and former soccer players”. Our speakers Dr. Andrea Bruno1, Dr. Massimo De Donato1, and Dr. Elisabetta Tibalt2 presented different approaches to manage the trauma and the degeneration of cartilage that can occur in professional and amateur athletes investigating how to ameliorate quality life – not only in sports people – but also in the larger population of former players.

Dr. Andrea Bruno spoke about regenerative medicine approaches, which can be a conservative and preventive approach to avoid major surgeries. Regenerative medicine tools are autologous cell and tissue therapies and involve PRP, bone marrow concentrates, adipose tissue derivatives (rich in mesenchymal stem cells), and mononuclear cells. The latter, due to its minimal invasiveness, was taken as an example showing the good clinical outcome in a case-report of a former marathoner suffering of grade II primary osteoarthritis (abstract and case report available in attachment).

Sometimes surgery is necessary, for example in a cartilage defect of traumatic origin. Dr. Massimo De Donato spoke about cartilage defects treatment, showing the rationale and good results of subchondral stimulation such as microfractures – which are iatrogenic fractures in the cartilage to promove its repair – but evidencing also the existing limits. For this reason, he introduced the argument of II-generation microfractures, namely nanofractures, which are more precise and standard, avoiding subchondral compaction and ameliorating cartilage repair with native type-II collagen and glycosaminoglycans (abstract available in attachment).

Treatment is only one step in the path of healing. Dr. Elisabetta Tibalt spoke about an underestimated but fundamental topic: the preliminary education and rehabilitation program that a patient must face before and after a regenerative treatment. Even if little can be found in the scientific literature, there are several good recommendations, i.e. quadriceps strengthening and neuromuscular joint control in case of knee osteoarthritis. The first phase of a biological activity must go along with protection and joint activation programs. After that, a second phase of progressive loading and functional joint restoration must follow. When there is cartilage repair maturation, it’s time for activity restoration.

 

1Arthroscopic and Reconstructive Orthopedic Unit of the Knee, Head of unit: Dr. Enrico Arnaldi, Humanitas Research Hospital, Rozzano, Milan, Italy.

2ESW Therapy & Research Center, Rehabilitation Department, Head of unit: Dr. Stefano Respizzi, Humanitas Research Hospital, Rozzano, Milan, Italy

Tiss’You flies to London for the 28th Isokinetic Medical Group conference

During the last weeend of April, Wembley Stadium in London will host the 28th international Isokinetic conference dedicated to the prevention, diagnosis, treatment and rehabilitation of sports-related injuries. To fuel the collaboration between the famous sports medical group and our company [LINK = https: //www.tissyou.com/tissyou-care-isokinetic-shake-hands/], Tiss’You will be an important sponsor of the event.

During this conference, the football-related medical community aims to interface with global sports to encourage the knowledge share and best practices to improve the health, athletic development and performance of athletes. With the scientific collaboration of ortopeadic surgeons and specialists from Istituto Clinico Humanitas, we will contribute with a workshop dedicated to the prevention and treatment of early osteoarthritis in end-carrer and former athletes; the symposium program and the possibility of booking a place are available below: