Tiss'You Regenerative Company

What are the key changes in the new Medical Devices Regulation?

On May 26, 2021, the new Medical Devices Regulation, commonly abbreviated as MDR, will enter into force in Europe. It replaces the previous MDD (Medical Device Directive), which has been in the field since 1993 with the aim of harmonizing medical device laws in Europe. The MDR brings a significant amount of regulatory changes, with a major impact not only on manufacturers, but also on all stakeholders involved in the device lifecycle.

The new regulation is about four times more extensive than the previous one, in terms of documents and annexes, and the word “safety” appears 290 times compared to 40 in the MDD. All accidents, injuries, and eventual deaths related to the use of a specific device will be entered in a European portal with the task of centralizing and making transparent the information on medical devices. The new rules will require manufacturers to generate clinical data about the safety and performance of their devices, especially in relation to equivalence standards. Individual product traceability will be one of the critical aspects through the implementation of Unique Device Identification (UDI), required on all product labels.

The definition of “medical device” will also be expanded to include all devices previously defined as non-medical or aesthetic that were previously unregulated, e.g., products for disinfection, contact lenses, lasers for hair removal. Non-CE marked products will have to comply immediately with the general safety and performance requirements of MDR, while all devices already CE cleared will have to comply within four years.

The new MDR regulation was supposed to be effective from May 26, 2020, but due to the Covid-19 pandemic and the resulting international economic crisis, it was postponed one year to relieve national health authorities, notified bodies, and medical device manufacturers. A MedTech Summit survey conducted in March 2020 that interviewed companies showed that: 17% of manufacturers consider themselves fully ready to comply with the MDR, 15% say they are “not ready at all,” and 65% say they would have fully exploited the remaining time of the old MDD to be prepared.

The new regulation is an opportunity to improve – versus the past – the transparency of technical information on medical devices, thus ameliorating the quality of processes and products.

Synthetic bone substitutes and collagen membranes in dentistry

Reconstructive bone surgery aims to regenerate the loss or resorption of bone through materials and techniques that allow to mimic and activate specific and fundamental reparative mechanisms such as osteogenesis, osteoinduction, and osteoconduction.

• Osteogenesis: formation of new bone tissue by the direct action of progenitor cells and osteoblasts
• Osteoinduction: regulatory activity of growth factors capable of triggering the differentiation of mesenchymal cells in the osteoblastic lineage and the process of bone regeneration
• Osteoconduction: support provided by a scaffold that allows the deposition of a new osteoid substance

Any regenerative technique must comply with these three elements, together with the vascularization of the treated site and the stability of the graft. When the bone defects are small and the patient is in good health, the bone has an excellent healing capacity, with intrinsic “genesis” and “induction”; it is sufficient that the surgeon fills the void of the loss of substance with grafts or bone substitutes to promote only osteoconduction. This provides the three-dimensional structure to sustain the regeneration process.

Autologous bone is taken from the patient himself and offers many advantages because, in addition to the osteoconductive bone matrix, it can also provide osteogenic and osteoinductive elements thanks to the presence of cells and growth factors. However, the availability of autologous bone in the endo-oral site is limited, while harvesting from other parts of the body (iliac bone) is invasive, risky, and not always possible. In addition to autologous tissue grafting, there are three main categories of bone substitutes: homologous, heterologous, and synthetic.

Homologous bone is from a cadaveric donor. It can be received from tissue banks, but even in this case, various limitations do not always allow its use.

Heterologous bone substitutes are biological grafts derived from animals (usually bovine or equine) that are decellularized and cleared of all antigenic elements. They offer different solutions, in granules or blocks of cortical, or spongy bone, with different resorption and revascularization times. Some heterologous bone substitutes detain a preserved protein/collagen component that can promote rapid osseointegration, as well as indirect osteoinduction.

Synthetic bone substitutes, available in a wide range of different materials, e.g., hydroxyapatites, calcium phosphates and sulfates, have very heterogeneous characteristics usually provide the osteoconductive scaffold for bone neoformation.

SpherHA synthetic bone substitutes

Tiss’You has developed SpherHA, a line of synthetic bone substitutes, composed of bio-mimetic nano-structured hydroxyapatite. Hydroxyapatite is a mineral found in the inorganic component of human bone. Both the composition and crystal structure of SpherHA are extremely similar to the mineral matrix of our bones, with a calcium to phosphate ratio of 1.67: the same as natural bone apatite.

The highly porous and interconnected structure and its composition ensure an excellent osteoconduction and circulation of nutrients, and also a real active stimulus to the formation of new bone tissue, favoring the processes of cell colonization and early vascularization. The nano-structure of SpherHA crystals provides a very high surface area to volume ratio that ensures complete degradation by osteoclastic activity with consequent remodeling into new viable bone tissue. These elements, along with the bio-mimetic properties, make SpherHA an ideal bone substitute for osseointegration and regeneration of bone defects.

SpherHA is available in several formats: porous chips, dense granules, injectable paste, and moudable crunch. In dental surgery, the indication is for filling small and medium periodontal and peri-implant bone defects, for filling post-extraction sockets, and for sinus lift.

Download SpherHA catalog (PDF)

Collagen and GBR (Guided Bone Regeneration)

In reconstructive bone surgery, especially in dentistry, it is important to guide bone growth limited to the damaged area, using barrier membranes to prevent the entry of not-osteogenic elements in the treated site. This procedure, called GBR (Guided Bone Regeneration), avoids the infiltration of fibroblasts from adjacent soft tissues, thus preventing the formation of fibrous tissue at the graft site.

For this purpose, Tiss’You has developed Collygen, an absorbable membrane of equine-derived atelocollagen, easily applicable without the need for fixation, for the protection of bone grafts in regenerative surgery techniques. Collygen, thanks to its collagen texture, actively participates in the healing process of the treated site, in addition to its passive protection activity. Recently, it has been demonstrated that the collagen membranes, which in the past were considered only passive barriers, act instead as a real bioactive compartment, interacting with the cellular components that home to the graft site. The processes thus activated contribute to the formation of bone tissue and its improved remodeling.

Download Collygen catalog (PDF)

Sometimes bone regeneration needs a little push

Regenerative medicine aims to improve or restore the natural healing capacity of our body through external means. It is difficult for some tissues to trigger their reparative mechanisms, hampered by conditions such as the absence of oxygen and nutrients, a chronic inflammatory state, and a tissue matrix complex to remodel. However, bone tissue regeneration is very likely to succeed thanks to the excellent vascularization of the tissue. That’s why, following a fracture, bone stabilization and rest are sufficient for complete healing.

Although bone propensity to heal itself, regeneration is only successful if all the elements – that the experts bring together in the so-called “Diamond Concept” – are present: cells, growth factors, scaffold, stability, and vascularization. The cells are the actors of the formation of new tissue; the growth factors are the signals for good coordination of processes; the scaffold is the support where the tissue matrix grows; mechanical conditions determine stability; vascularization allows the arrival of oxygen and any other missing ingredient. If one or more of these are absent, the bone will not heal, and pathological conditions, such as pseudoarthrosis, will rise.

Pseudoarthrosis is characterized by a fibrous callus, the result of failed healing, and persistent pain that must be treated with surgery to remove sclerotic bone tissue. The site’s cleaning will make a void that must be filled with a bone matrix, which may come from the patient himself, a donation, or synthetic origin. If the patient has risk conditions, it is essential to take advantage of cell therapies and growth factors to boost the regenerative capacity. Finally, the biological implant must have absolute mechanical stability.

Tiss’You offers different solutions for the treatment of pseudoarthrosis (or other bone diseases such as avascular necrosis and bone cysts), starting from procedural kits that exploit mesenchymal cells from adipose tissue (Lipocell) or mononuclear cells from peripheral blood (Monocytes). Recently, we have introduced SpherHA, a synthetic bone substitute based on hydroxyapatite nanocrystals, a calcium phosphate compound remarkably similar to the mineral matrix contained in our bones. SpherHA is available in many formats to meet different orthopedics, neurosurgery, and dentistry needs, such as dense granules, porous chips, injectable paste, and moldable crunch.

Thanks to the high surface/volume ratio, the device is an ideal scaffold for osteointegration; moreover, the highly porous and interconnected structure promotes cell colonization, nutrient circulation, and rapid vascularization. After offering filling and support, SpherHA bone substitutes are completely degraded by osteoclastic activity and physiologically remodeled into new vital bone tissue.

For further details: SpherHA – Product sheet

AMIC technique and collagen

Cartilage tissue has a complex structure and absent vascularization, thus it has a poor regenerative capacity following trauma or consumption. The reparative response occurring with fibrosis condemns the cartilage to osteoarthritic degeneration. For the patient, all this translates into joint pain and limitation or blockage of movement.

In the nineties, a technique was introduced – quickly became popular – for treating cartilage defects of traumatic origin. It was the autologous chondrocyte implantation (ACI), i.e., implantation of autologous chondrocytes, expanded in the laboratory, taken from the patient. This technique was then improved with the use of matrices (getting more performant generation after generation) which were exploited as support for chondrocytes (MACI). The technique, although being brilliant and promising, was too expensive and forced to be performed in two different surgical times (a few weeks apart). These limitations, together with regulatory restrictions introduced in the following years, did not affect its popularity in the scientific literature but made it almost completely abandoned in favor of faster and less invasive solutions.

Matrix-induced autologous chondrogenesis, more commonly known by its acronym AMIC, is a one-step surgical technique for repairing focal defects. It does not require expensive cell culture in the laboratory and can be performed with minimal invasiveness on the patient (in arthroscopy or mini-arthrotomy). It consists of controlled fracturing of the subchondral bone corresponding to the cartilage defect. This causes bleeding and a release of bone marrow cell precursors (e.g., stem cells) capable of enhancing tissue healing processes. After micro-fractures, the defect is covered with a collagen membrane in order to protect the repair site, coagulate bleeding, and provide ideal conduction for tissue remodeling. The collagen membrane is populated by cells arriving from the marrow, or, alternatively, can be enriched with autologous stem cells of another origin (e.g., from adipose tissue) obtained in the same surgery. The technique, in use for many years all over the world, allows a homogeneous repair of the defect and improves chondrogenesis offering satisfactory clinical results.

Tiss’You’s line of biomaterials features CollYgen, a highly pure equine-derived type I atelocollagen membrane. It is available in several formats, one specifically made for the treatment of cartilage defects with a rough side to improve adhesion and provide an optimal three-dimensional environment for repair processes. Collygen is a membrane that is physiologically resorbed in 4-6 weeks, a time in which it is able to protect the implant site and promote the formation of new cartilage tissue.

See CollYgen GCR dedicated brochure for AMIC technique: COLLYGEN GCR BROCHURE

The value of collagen and the innovation of peptides

Carried out by Ferdinand Magellan in 1520, the first circumnavigation of the globe ended with the dramatic loss of almost the entire crew due to scurvy. This disease presents catastrophic symptoms such as small and numerous bleedings caused by the fragility of blood vessels, failure to heal wounds, teeth loss, widespread pain, respiratory failure, and cardiac arrest. The cause was found in the food: vitamin C was not present at all in the supplied carried onboard. This micronutrient, found in citrus fruit, fresh fruit, pepper, tomatoes, potatoes, and broccoli, can only be assimilated through the diet. It is essential for the amino acid proline’s hydroxylation, which is a fundamental process for the synthesis of collagen. Without this reaction the degeneration of collagen triggers scurvy, a disease that did not only affect pirates and explorers in the past but also represents a risk for some populations today.

Collagen is the main protein of all connective tissues. It is an elastic protein with a supporting function, formed by three polypeptide chains wrapped together. This particular structure can create more excellent resistance to tension than a steel wire of equal diameter. The chains are made of a repeated tri-peptide unit, glycine-X-Y, where generally X is a proline (Pro) and Y a hydroxyproline (4-Hyp). Glycine is needed to tighten the collagen chains, while Pro and 4-Hyp are responsible for the chains’ coiling (the importance of vitamin C hides here). Although evolution has developed such sophisticated resistance, collagen is not free from specific degradation processes, such as trauma, oxidative stress, and inflammation. The release of peptides from the collagen chain triggers new collagen synthesis and reshapes the extracellular matrix of connective tissues. Exploiting this mechanism, even the exogenous administration of peptides provides the essential elements for the protein’s reconstitution, activating the biosynthesis processes and negatively regulating the degradation processes. Food supplementation of collagen peptides follows just this philosophy. Still, the effects are minor and require high amounts of peptides for prolonged periods due to their dispersion in all tissues and not only in the target areas.

Recently, we announced the arrival of the Arthrys, a medical device based on a ready-to-use injectable solution of hydrolyzed collagen peptides, further enriched with vitamin C and magnesium to protect peptides from oxidation. Tiss’You has developed Arthrys as a comfortable injection to immediately drive these peptides where needed. This device can be used in any medical practice to treat small and large joints, tendons, muscles, and ligaments. The high concentration of peptides allows strengthening tissues’ collagen structure, stimulating their synthesis and preventing their degradation through a pro-regenerative activity. Besides, treatment with peptides counteracts pain and inflammation and improves joint function.

Arthrys is an easy infiltration that lasts a few seconds and can be performed by your physician. It can be used alone or in combination with other treatments. It is also indicated to improve the surgical course following surgery, reducing post-operative pain, and accelerating functional recovery.

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.

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

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