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ABOUT OSTEOARTHRITIS AND REGENERATIVE MEDICINE

Osteoarthritis (OA) is the commonest form of arthritis. A degenerative and chronic disorder associated with damage to the cartilage and surrounding tissues.

Characterized by damage and loss of cartilage, it causes friction between bones, as a consequence huge pain and disability.

Joints of the knees, hips, back (spine),fingers, thumbs and neck are commonly affected.

  • Analgesics, anti-inflammatories and chondroprotectors are used in an early stages.
  • Cortisone injections, hyaluronic acid and/or PRP (Platelet Rich Plasma) when pain and dysfunction increases. These treatments have dose limitations.
  • End stage prosthetic implants.

There is a gap between drug treatments and the most invasive treatment, the surgery for a prosthetic implant.

Between 60 and 100 new cases are diagnosed every year per 100,000 people. Worldwide, 9,6% of men and 18% of women aged>60 suffer from OA.

Regenerative medicine is the name received by the therapies that are applied to tissue regeneration and organism structure improvement.

The goal of regenerative medicine is to repair damaged tissues by means of cells, proteins and/or biomaterials by addressing directly to the disease root cause, not only to symptoms.

Regenerative therapies based on stem cells have proven to be very promising in the treatment of degenerative diseases related to age. However, more studies are required to widen clinic effectiveness.

Recently, a step forward has been taken in use of immune system modulating elements, like cytokines or exosomes. These elements support existing regenerative strategies. As an example: mesenchyme cells of bone marrow or adipose tissue, and in some cases they can substitute them.

Regenerative therapies will be the next medicine revolution.

Cytokines are proteins released by blood cells and platelets. They are in charge of immunity and of regulating wound healing.

Several cytokine families exist, such as pro-inflamatory cytokines which promote inflammation, anti-inflammatory cytokines which produce the opposite effect and growth factors* which stimulate cartilage growth among many other roles. 

Our body works properly when pro-inflammatory, anti-inflammantory and growth factors are balanced, in other words, when homeostasis exists. Even though inflammation is a necessary process of healing, this state cannot be prolonged for an extended period of time since tissues can be damaged permanently and this would cause cartilage degradation. 

*Growth factors: It is a type of cytokine mainly related to cell multiplication and growth. These cytokines are mainly stored in blood platelets.

 

OA is characterized by an unbalance of cytokines that produce cartilage degradation (pro-inflammatory cytokines) and cytokines that try to heal it (anti-inflammatory and growth factors).

Cartilage degradation is produced by inflammatory activation carried out by some cytokines such as IL-1β, IL-6, IL-2, IL-8 y TNF among others. While healing is carried out by cytokines IGF-1, BMP, PDGF-BB, TGF-β, IL-4, IL-10 y IL-13.

Nowadays, Spanish public health system does not offer an effective treatment for osteoarthritis before requiring a prosthesis. Analgesics (Paracetamol, Acetaminophen,…), NSAIDs (Ibuprofen, Naproxen, Indometacin,…), Opioids (Tramadol,…) are the most commont drugs used for pain reduction. These drugs must be taken under medical prescription and a frequent consumption can damage liver and stomach.

In cases of high pain levels, a glucorticoid intra-articular infiltration could be provided. At some medical centers, hyaluronic acid infiltrations could be carried out. This treatment, though, is more common in private health services.

None of the aforementioned treatments are focused on solving the disease but they are oriented to reduce pain and improving patient’s quality of life prior to the point where the prothesis is the only possible solution.

*Intra-articular infiltration: Is an ambulatory treatment that consist in an injection in the articulation and which does not require anaesthetic.

*Hyaluronic acid: it acts as a lubricant in the articulation which partially reduces pain.

Private health services offer regenerative medicine treatments oriented to slow down and even stop the progression of osteoarthritis before requiring a prosthesis.

As these treatments will give more evidences of their efficacy, it is foreseeable that they will be included into Spanish public health system. 

Regenerative medicine treatments can be divided into two different groups:

  • Mesenchyme stem cells* treatments obtained from bone marrow or adipose tissue. This kind of treatment require surgery and anaesthetic.
 

In some cases, specially when treating with bone marrow samples, a cell culture is carried out in laboratories and it can take several days. In these cases, it is considered as an advanced therapy and an authorisation from sanitary regulators is required to guarantee a correct culture (facilities, process, transport, preservation, etc.) as well as a correct clinical use.

*Meshenchyme stem cells: they are multipotencial cells that can be differenciated (with appropiate signals) into different cell types such as skeletal tissues, cartilage, bones or fat.
  • Treatments with products obtained from venous blood (40-60ml). This kind of treatments are outpatients. For obtaining the product, the medical center must have closed devices or, in case they are opened, it is necessary to have the appropriated equipment in order to avoid possible contaminations. In this category, following treatments can be found.
 
    • Plateled Rich Plasma and/or growth factors*(PRP)
    • Autologous* Condicioned Serum (ACS).
    • Autologous Protein Solution (APS).
    • Autologous Cytokine Rich Serum (ACRS) obtained by QREM®Cytokine system.

PRP, ACS, APS and ACRS are not cell therapies or treatment nor advanced medicine therapies. However, they must be administrated always under medical presctription and guarantee some quality requirements of production.

*Growth factors: It is a type of cytokine mainly related to cell multiplication and growth. These cytokines are mainly stored in blood platelets.

*Autologous: from the patient

PRP is the acronym of Plateled Rich Plasma. PRP is a blood-derived product obtained through blood centrifugation and it contains a high concentration of platelets (between 4 to 6 times normal values). When platelets are activated, they release growth factors that contribute to stimulate cartilage growth.

Platelets can be activated by natural means if they are exposed to coagulation factors from the body, or artificially by adding calcium chloride before injection.

ACS is the acronym of Autologous Conditioned Serum. ACS is a blood-derived product obtained by an incubation process of blood of 6 hours or more at a temperature of 37ºC. With this incubation, anti-inflammantory cytokines from white blood cells are released.

ACS contains mainly anti-inflammatory cells and some growth factors. While anti-inflammatory ctyokines stop OA, growth factors stimulate cartilage regeneration.

APS is the acronym of Autologous Protein Solution. APS contains high concentration of white blood cells and platelets. The process does not include incubation but it requires blood processing with an opened system. Part of white blood cells and platelets are activated during this process releasing anti-inflammatory cytokines and growth factors. The rest can be activated after injection when contacting with coagulation factors produced by the body.

ARCS  is the acronym of Autologous Rich Cytokine Serum. Like ACS, ARCS is a non-cellular product. ARCS directly contains anti-inflammatory cytokines and growth factors with double goal of stopping OA and stimulating cartilage regeneration. The product obtaining process is based on coagulation inducement for activating platelets and stimulating white blood cells. There is no incubation nor manual manipulation. The process is carried out by a Lab-in-a-box* device. Like APC and PRP, ARCS is obtained in doctor’s office in less than one hour.

*Lab-in-a-box: Totally automatic system, closed and sterile which enables to be used as an outpatient treatment with no risk. QREM CYTOKINE system for obteining ARCS is a Lab-in-a-box system.

ARCS can be used for other musculoskeletal diseases different than osteoarthritis, such as tennis elbow and other tendinopathies. 

ARCS should always be used under medical prescription, and this treatment must be prescribed by a doctor. 

ABOUT QREM CYTOKINE TECHNOLOGY

Qrem Cytokine is a novel system for obtaining cytokines which intervene in tissular regeneration. Based on patient’s own blood, Autologous Rich Cytokine Serum (ARCS) is obtained through a patented biological process that emulates an ex vivo tissular damage.

This is a sanitary product class IIa that is currently being commercialized in Spain but it will be soon exported to other countries. This product has the CE marking MED31489 granted by Notified Body KIWA Cermet (nº 0476).

Is a Lab-in-a-Box device, a closed and automatic desktop system, that consists in a device (Q-Device) and a single-use disposable sterile kit (Q-kit). It can be installed in all kind of doctor’s office, no matter how small it is. No specific training or special facilitiy infrastructures are required.

Q-Device: Desktop equipmentQ-Kit: single-use disposable sterile kit

Tecnologia Regenerativa Qrem S.L. is a Barcelona-based company founded in 2016 with medical product installation and fabrication licence number 7096-PS granted by Spanish Agency of Medicines and Medical Devices (AEMPS).

ARCS is an autologous non-cellullar biological product that is obtained from patient’s blood without significant handling process. This is why it is subjected to AEMPS regulation corresponding to these type of products[4].

[4] https://www.aemps.gob.es/medicamentosUsoHumano/medSituacionesEspeciales/docs/PRP-AEMPS-DEF-mayo13.pdf

The main difference is the use of leukocytes during the ARCS obtaining process which allows to obtain anti-inflammatory cytokines.

ARCS does not contain platelets, fibrinogen nor other type of blood cells but it directly contains the anti-inflammatory and anabolic cytokines (also known as growth factors) which intervene in the tissular regeneration process. While PRP contains only the mediator (platelets), ARCS directly contains the active ingredient (cytokines); and, while PRP requires CaClto be added for platelet activation, ARCS is obtained through a fully biological process, without additives.

The successful experience with PRP, mainly in moderate desases and with young patients, has empowered the investigation of new orthobiological therapies such as Qrem Cytokine to improve efficacy and to widen the range of people who can benefit of this kind of therapies.

 

Q-Device carries out a multi-step process which takes about 30 minutes. This process emulates an ex vivo tissular damage that produces the blood cells to be activated and to release the regeneration modulating cytokines which are contained in ARCS.

The Q-Kit is composed by two main containers (F and A) joined by a channel which contains a valve. This valve allows to transfer from F to A at the appropriate moment in the process. Container F is filled by 18ml of peripheral patient’s blood plus 2ml of sodium citrate (anticoagulant). Container A is filled by 20ml of peripheral blood. This filling action is done through luer-lock ports which contain non-return valves to guarantee an hermetic process. Blood and ARCS are air-tightly enclosed inside the Q-kit during the whole process.

First steps are for obtaining a platelet and leukocyte concentrated plasma in F container and a primary serum in A container. This primary serum contains autologous activators such as trombine and calcium as well as anti-inflammatory cytokines and growth factors. Next step is the opening of the intermediate valve which allows the transfer of leukocyte and platelet concentrated plasma to primary serum. This mixture enables the platelets and leukocytes to be activated creating a fibrine matrix. Last steps are oriented to brake this fibrine matrix which releases ARCS.

Aforementioned steps are automatically carried out by Q-Device.

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