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Cartilage transplantation

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Knee cartilage is an important element of supporting-motor apparatus. The most part of loading is put on this zone of leg. Cartilage tissue is what suffers in case of traumas and injuries. The tissue becomes worn, thin, loses elasticity, and a person has different diseases developing.

Cartilage is a thin elastic tissue. Knee joints have two types of cartilage: fibrous (meniscus) and hyaline. Fibrous tissue is very robust and can resist pressure. Hyaline tissue is more elastic and can cover the surface along which the joints move. Unfortunately, hyaline tissue recovers very slowly. New formations are usually fibrous tissues of poor quality.

First and foremost, cartilage tissue has connective function: it serves to lower friction in places where bones are connected. The inner surface of the joint is covered with joint fluid that serves as lubricant. Joint fluid is important for human joints just like machine oil is important for a car.

The second function of this fluid is to provide cartilage tissue with nutrition. Since joint cartilage has almost no blood capillaries, blood hardly flows into them. Therefore, all nutrients get inside with joint fluid.

Normally, the thickness of the hyaline and meniscus cartilage is from 1 to 6 mm. Over time, the cartilage loses its functions. Its thickness can be reduced by a factor of 2. This happens because of a number of reasons:

  • Congenital and acquired joint defects.
  • Age-related decrease in the production of collagen and synovial fluid.
  • Injuries of hyaline cartilage and meniscus as a result of intensive loadsto the joint (most often when doing sports).
  • Overweight.
  • Genetic factors.
  • Chronic diseases (hemochromatosis, arthritis, gout, etc.).
  • Inflammatory processes in the joints (inflammation of the synovial membrane, tendon, etc.).
  • Hormonal imbalance.
  • Low physical activity.
  • Bad habits.

With age and due to various diseases, the degeneration of cartilaginous tissues can cause severe pains and difficulties when performing even the most usual actions (walking, tilting, flexing the join). You can feel soreness even while being at rest.

The main problem when treating damaged cartilage: it does not regenerate without external stimulation. Cells of cartilaginous tissue cannot restorespontaneously, which is why degenerative processes are irreversible. As a result, without a shock absorber, the bones of the joint begin to rub against each other. The joint gets inflamed, the mobility decreases and, finally, you may need a joint replacement. That is how osteoarthritis develops.

The irreversibility of the cartilage deterioration was always considered by patients and doctors all over the world as an immutablelife fact. That is because cartilage degeneration is not only an inflammatory, but also a genetic process. At the moment, the only, very complex, but effective method to restore degenerated joint is transplantation of the cartilaginous tissue, andGerman orthopedists are among the firsts who implemented the technique at the highest professional standard.

The performance of the cartilaginous surfaces of the joints, like any others connective tissues in our body, deteriorates with age. It is the same process that causes wrinkles to the skin. Osteoarthritis is early and quick degeneration of cartilage caused by infection, trauma or structural knee problems. Cartilage transplantation can be successful if doctors have managed to slow down the cartilage degradation and bringit to the age-appropriate level (normal aging process).

There area number of signs that articular cartilagegot thinner:

  • Knee joint blockade with restrictedunbending.
  • Pain with passive movements.
  • Crunching and clicking in the knee while walking.
  • Lameness or inclining to one side.
  • Joint stiffness in the morning.

Cartilage transplantation helps to reduce pain in the knee significantly or even completely, slows further deterioration down and delays in the need for partial or total knee arthroplasty. And what is the most important, the restoration of cartilage helps patients to return to the activities they did in thepast: to work and play sports.

Cartilage transplantation is not possible in all patients. Ideally, these patients are from 15 to 55 years old, but the decision is made individually based on physical strength and overall health. A number of successful cartilage transplantations have been already performed in active people under the age of 65, and now they can again practice their favorite sports, such as skiing.

Indications for cartilage transplantation

  • The area of defective cartilage is 2.5 - 10 cm².
  • Meniscus is intact.
  • Anatomical axes of the joint are not displaced.
  • Ligaments of the knee are not damaged.

Contraindications to the Procedure

The following factors,even more than the age of the patient, can forestall successful transplantation:

  • Excess weight of the patient (overweight is an additional burden on the joints). Solution: preoperative weight control.
  • Offset of the joint axes, for example, x-shaped legs. Solution: The displacement can be corrected by osteotomy along with cartilage transplantation.
  • Simultaneous damage of the cartilage on both joint surfaces both at the top and bottom (usually, as a result of trauma). In this case, joint resurfacing is the bestdecision.
  • Genetically weak cartilaginous tissue. Solution: partial or total joint replacement.
  • Instability of the knee due to damaged ligaments. Solution: The ligaments should be restored, for example, by reconstructing the anterior cruciate ligament.
  • Instability of the knee joint due to a severely damaged meniscus. Solution: preference is given to resurfacing.
  • The area of ​​the defectivecartilage is too large (more than 10 cm2). Solution: The surgeon may recommend resurfacing.
  • Other diseases that hinder a quick recovery. Solution: in this case, a surface replacement can be a more suitable option, because, in this case, it is possible to load the joint the next day after the operation.

Comprehensive analysis of all pros and cons of transplantation is necessary for a good and long-term result. Sometimes even young patients are rejected for cartilage transplantation and partial knee joint replacement may be a better option for them.

It is known that cartilaginous tissuesdo not regenerate, but without suchan absorbinglayer,friction in the damaged joints increases and a person experiences rather intense pain. This is especially true for the most mobile joints deformed as a result of trauma or chronic disease. In a number of cases, with severe deformations, surgeryto replace cartilaginous tissues is strictly recommended.

Arthroscopy (a method used to replace cartilage) is an endoscopic surgery that is performed without opening the joint, so it does not leave large scars on the skin and does not damage underlying tissues. In modern German clinics, this procedure is quick and low traumatic. A patient does not need to stay in a hospital longandreceive alot of medications and therapeutic procedures after the surgery. Artificial joints do not need much time to function normally. Shortly after the surgery, the patient no longer feels any discomfort and can move without limitations, as usually.

In German clinics, two types of implants are used to replace cartilage tissues: made from natural tissues and from artificial materials. In the first case, a piece of cartilage is taken from the patient’s own tissues (from healthy, not degenerated area). This tissue has been growing in the laboratory for some time, until it reaches the size required for transplantation. Another possibility, if the area to be restored is relatively small, is to take the required amount of cartilage.

In other cases, an implant made of artificial materialwith characteristics very close to biological cartilage is used. The process of engrafting is a bit slower than when replacing with natural tissues, but also short enough if the patient takes all prescribed therapeutic procedures and takes care to support the immune system with the healthy lifestyle. Rehabilitation should be carried out under the supervision of the attending physician and in conditions that are comfortable for the patient.

Natural cartilage implantsare mostly recommendedfor younger people, since the ability of their tissues to regenerate is higher than that inelderly patients. In older patients, replacement of cartilaginous tissues with either whole grafts or with implants made of artificial material is mostly indicated.

The issue of using this or another type of implant is solved individually and depends on the patient's condition (concomitant chronic diseases, immune and cardiovascular system disorders, acute infectious diseases, etc.). Statistics of patients who had cartilage repair shows that with a comprehensive approach, the prognosis is almost always favorable.

Biological Restoration of Cartilage with the Patient’s Own Tissues

In 1990, there was a reporton an attempt to restore the cartilage of the knee joint using autotransplants taken from the patients’ rib. Cartilage defects of 3-4 degree were repaired with rib perichondraltissues fixed with fibrin glue.

In arthroscopic examination, after 1 year, it was found that the defect area of the cartilage was filled by 90%, and the patients reported improvement in their condition. When examined after 8 years, it was found that 20% of the transplanted cartilage got an endochondral ossification in 20% of cases, which caused deterioration in 60% of patients. Repairing of the damaged cartilage with the help of the periosteum was first applied in a laboratory trial, and then in a clinic. However, all patients did not have good and excellent results, but only satisfactory and unsatisfactory results. In younger patients with exfoliating osteochondritis in the area of ​​the condyles of the hip, a year after the plasticity of the periosteum, there were good resultsin 80% of the cases. Nevertheless, after 8 years, 75% of the patients had unsatisfactory results, and, in 50% of the patients, progression of deforming arthrosis was observed. In the long term perspective, after arthroscopic examination and biopsy, no formation of hyaline cartilage in the area repaired with the periosteum was found.

Transplantation of Osseous-Cartilaginous Grafts from Areas with Intact Articular Cartilage

According to the method, intact cartilage was taken in the intercondylararea or in the area of the outer condyle of the femur. In arthroscopic examination, after 2 years, it was found that a 15 mm area of the defected cartilage was restored. A histological examination proved splicing of the transplanted cartilage with the cartilage of the knee joint. Several studies reported 80% of positive outcomes. This technique was used in the treatment of defects less than 2 cm2, but its long-term results are unknown.

AutologousChondrocyte Implantation

In 1987, clinical trials to transplant a culture of native chondrocytes to the defected areaof cartilagewere undertaken. The technique of transplantation of autologous chondrocytes, which is called Carticel, was developed by the Genzyme Corporation.

The method is applied only fordegenerative cartilage of the knee joint. Deficiency of articular cartilage can be detected in different clinical situations. It can be diagnosed during primary arthroscopy, which is done to fix a joint injury, or it may be an accidental finding in arthroscopy for meniscus and joint ligament reconstruction.

If a degenerative cartilage defect is found, it is consideredif Carticel is indicated. If it is advisable, first, a biopsy of intact cartilage is performed, usually in the region of the upper medial or lateral condyle of the femur or in the intercondylararea. The cartilage can be taken in two or three spots up to full depth. The total weight of the cartilaginous material is 200-300 mg. The cartilage is placed in a special vessel and planted to grow. The procedure of cartilaginous culturegrowing lasts at least 3 weeks. During this time, the number of auto chondrocytes increases 10-12 times, which is 12 million cells. The volume of the culture for implantation is usually 0.2-0.3 cm3.

For chondrocyte implantation, it is necessary to perform arthrotomy of the knee joint. During arthrotomy, debridement of the degenerative cartilage is performed, up to healthy cartilage. Cicatrices are removed and the subchondral bone is released, which should be intact and bloodless. Through a separate cut,apiece of the periosteum of the tibia is taken from the anterior medial surface of the tibia, a bit larger than the size of the degenerative area of the cartilage. The cartilage defect is covered by the periosteum, which faces the defect with its cambial layer. Periosteum is sewnto the edges of the defect with resorbablethreads. A seam is covered with fibrin glue, which is made from patient's tissues with a small hole leftfor a catheter. A suspension of chondrocytes is drawn into a syringe and inserted into the catheter under the periosteumtothe defective area. The remaining hole is sealed with fibrin glue. The surgical wound is sewn in the traditional way.

The operation can be successful if a number of requirements are met: a cartilage defect is located in the area of the condyles of the femur;it is regional and extends to the entire depth of the cartilaginous layer; the biomechanics of the joint is normal; the joint is stable, not deformed;a range of movements in the joint is not altered; the patella is in the correct position. Contraindications to chondrocyte transplantation are:inflammation in the joint, arthritis, moderate and severe joint degeneration, and deforming arthrosis.

Until recently, the main treatmentsfor knee cartilage defects were joint lavage and articular surfacedebridement. With the implementation ofarthroscopes, the idea of ​​cleaning joints from non-viable fragments of cartilage, intra-articular loose bodies and synovial fluid with dissolved lytic enzymes has become firmly established.

Approximately 2/3 of patients had been having an improvement in their condition for about 3 years after the procedures. In patients with deforming arthrosis, improvement was observed in 52% of cases, but after 3 years this indicator was reduced to 44%. In some studies, positive results were observed in 2/3 of patients 5 years after arthroscopy. It had been proved that the debridement of the joint was superior to lavage in efficiency.

In patients with osteoarthritis, in cases of complete degeneration of joint cartilage, up to the exposure of the subchondral bone, arthroscopic lavage and debridement were ineffective methods of treatment.

It is known that it was suggested to fill the defect with fibrin to repair the cartilage. For this purpose, cartilage abrasion,microdrilling and microfracturing of the subchondral bone were done during arthroscopy. In these cases, joint debridement was performed to clean the articular surface fora better contact of fibrin with the underlying bone. Abrasive arthroplastyinvolved bone treatment with an arthroscopic drill until petechial bleeding from the subchondral layer of the bone occurred. Multiple bone reaming led to emerging of a defect of the bone marrow and forming a fibrous deposit. Similar goals were pursued whenthe bone was processed with a special perforator, and, as a result, the surface of the defect was covered with multiple micro-fractures of the bone.

At the heart of all these techniques, there was the idea to destroy the integrity of the bone so that the elements of the bone marrow could arise from the depth of the spongy layer of bone to the surface of the defect. As a result, with repeated arthroscopy, fibrous tissue or fibrous cartilage was found in the area of the defect.

Unfortunately, the newly formed tissue was inferior to hyaline cartilage in its mechanical properties and could not carry the loads that the knee joint withstands. The attempt to stimulate the growth of cartilaginous tissue led to the fact that the new fibrous cartilage did not have sufficient strength and quickly deteriorated.

A large number of studies showed a worsening of the condition of patients in a short time after such interventions. In patients older than 40 years, pain remained in 66% of cases, and only 12% of patients did not have any complaints. It was reported that 5 years after abrasionarthroplasty, relatively better results were reported in younger patients.

Proper postoperative rehabilitation of patients was of great importance for improving the results of treatment. With repeated arthroscopy, it was found that newly formed cartilage appeared better in a group of patients who were continuously involved into special physical programs to restore knee joint functions if compared with another group of patients who did not exercise on the permanent basis.

First, it should be noted that cartilage tissue is fragile and is easily damaged. In order to restore patient’s ability to have normal life without pain, German specialists use modern methods of restoration of hyaline cartilage of knee joint and prophylactics of pathologies of cartilage tissue.

First, doctors resolve to non-surgical (conservative) treatment methods including medication therapy.

Cartilage protector is a modern method of restoration of cartilage tissue. As a rule, these medications contain glucosamin (it strengthens cartilage tissue and makes it more resistant to mechanic damage) and chondroitin (ensures rigidness of cartilage tissues during stretching and compression). Cartilage protectors can also be used as a preventative measure, not only to treat cartilage pathologies at early stages (when the cartilage is fully destroyed, it cannot be restored).

If you decide to use cartilage protectors, it’s crucial to be patient and follow doctor’s recommendations strictly, because such treatment can be pretty long.

Today, Germany and many other countries develop new methods of surgical restoration of cartilage tissue in knee joint.

Various methods of restoration of cartilage tissue include:

  • Cartilage transplantation. There are two types of transplantation: in the first case, a sample of healthy cartilage is taken from patient’s own body and transplanted on the affected area; in second case, surgeons transplant tissue grown in a laboratory.
  • sanitation of cartilage. This method presupposed endoscopic removal of catrilage damage and polishing of its surface. The method allows activating regeneration profess and ceasing further damage of cartilage.
  • Use of stem cells‘ properties. The surface of cartilage is processes so that microscopic holes would form. Stem cells gather in the holes and form new cartilage then. The main disadvantage of this method is low strength of new tissue, because at early stages it contains a minor amount of cartilage corpuscle.
  • Endoprosthetics is a radical method of treatment of knee joint. In some cases, the worn cartilage can be replaced, but sometimes the entire knee joint should be replaced, including its bone components.

For many years, doctors believed that the process of cartilage tissue destruction can be slowed down, but it cannot be restored. However, innovations of German specialists allow growing cartilage tissue in joints in the affected area: patient’s cells are used for that.

Growing of cartilage in knee joint starts with minimal invasion and endoscopic visualization that helps to evaluate the state of joint surface, the volume of damage, and to take cells from healthy cartilage tissue. After that, the cells are sent to a laboratory where the cartilage tissue is being grown.

The procedure of knee joint cartilage transplantation is made with a minimally invasive method and arthroscopic equipment. A surgeon makes two incisions 1-2 cm each, and injects cells via these cuts using special instruments. Arthroscopy presupposes cutting pathological areas, drilling or polishing to form young cartilage tissue. The joint is cleared to boost regeneration.

When doctors have to deal with deep damage of bones, microfracture method is applied. Special instruments are used to make small holes in the damaged zone. Thanks to this surgical manipulation, new cells get to the surface, which contributes to formation of cartilage. Autotransplantation of cartilage corpuscle is constantly being improved in Germany. Recently, АТХ 3D technology made a lot of fuss: it allows preventing the need to replace joints at early stages. In this case, spheres with special covering of cartilages cells is put in the damaged area that is processed beforehand.

The previous ATX method required some kind of transporting substance for cells not to wash away. For this purpose, doctors had to grow collagen matrix and fix it on cartilage, or they had to use patient’s periosteal coverage.

This way, spheroids provided patients with spare treatment of joint cartilage with minimal surgery risks. In this case, arthroscopic control is combined with microarthrotomy technique.

Three-dimensional transplantation of cartilage cells (autogenous matrix-induced transplantation of cartilage corpuscle) presupposes transplantation of 3D spheres of cartilage cells (spheroids) in the prepared area of defect without putting coverage off.

After that, surgery is performed with microarthrotomy technique under arthroscopic control. This method is minimally invasive, which means it guarantees spare treatment and greatly reduces the risks connected with surgery. Grow power of cartilage tissues around the defect is much higher when compared to patient’s real age.

The first stage of arthroscopic surgery (endoscopy of joint) is taking samples of patient’s cartilage tissues. Cartilage cells are taken from the sampled tissues and taken to state-of-art laboratories to be cultivated in sterile conditions.

Cartilage tissues are taken from a healthy, minimally damaged and minimally loaded joint area. Surgical invasion can be made on outpatient basis: it gets about 30 minutes. At the same time, about 120-150 ml of patient’s blood is taken. The blood is used to obtain serum in a laboratory.

Cartilage cells multiplicate in serum taken from patient’s blood. This method eliminates contact with foreign protein and helps to sustain normal conditions for cells grows at optimal level. Therefore, the risk of cartilage rejection is reduced, because doctors use patient’s own cells.

The process of cell aging takes about 3-4 weeks when small three-dimensional cartilage cell aggregates are formed. When the process of cultivation is finished, biological material is sent to a doctor. Transportation of material should be made within a few hours in certain conditions, in special cooled containers to preserve the quality of cells.

Cartilage tissues (chondrospheres) are used to fill the processed cartilage defect of joint. Cells are fixed to bone tissues, fill up the defect and eliminate it. As soon as cartilage spheroids start contacting with the defect, their connecting molecules (adhesive proteins) maintain relative mechanical instability near bone tissue during 10 minutes. After that, cartilage cells grow into the defect and fill it up.

This operation is made by minimally invasive method with arthroscopic control, and lasts for about 30-60 minutes. At the first stage, damaged cartilage tissue is removed, and patient’s aggregates of cultivated cartilage cells are put in.

The medical benefit of cartilage cell transplantation was being proved during 25 years since introduction of this method.

Patient’s body does not consider the implanted material to be a foreign body, because it has the same features as natural cartilage. Therefore, live cartilage corpuscle can build up new fully functioning cartilage layer. Due to the fact that the cartilage cells cultivated in the form of spheres (so called „spheroids“) are put directly into the damaged joint lacking cartilage tissues, cells continue developing right the place where the cartilage tissue is required. That helps to develop healthy autogenous cartilage tissue that has all protective features the damaged joint lacked.

Non-surgical methods used to fix cartilage in case of joint degeneration can only diminish painful sensations, but are not enough to restore the right joint surface.

Surgical methods, such as drilling, micro-fracture, and brain cell stimulation don’t restore glossy cartilage. In most cases, the above mentioned methods are not enough, because cartilage is replaced by fibrous cartilage that has somewhat different mechanic and elastic peculiarities than joint cartilage.

Hyalograft C is a good alternative to cartilage transplantation: it allows eliminating or reducing pain, improves movement of joint and helps patient to get back to active life and sports.

Basing on clinical examination and additional analyses, a doctor will evaluate cartilage damage and figure out a type of treatment with cultivated cells. Transplantation of autologic joint cartilage consists of two stages:

  1. The first stage is diagnostic arthroscopy during which the doctor defines the size, location and type of damage. He decides whether autological cartilage transplantation is possible in this case, or some other method will work better, for instance, mosaic method. If the doctor decides to perform treatment with autological cartilage transplantation, he takes a small fragment of healthy cartilage. Gathered cartilage cells (cartilage corpuscles) will be multiplied by tissue growing, then transferred to nutritional medium that consists of hyaluronic acid where they’ll continue multiplying. 5-7 weeks after the first arthroscopy, a transplant will be ready for implantation in the damaged area.
  2. After that, the second stage of treatment goes. It can be arthroscopy, or miniarthrotomy. This time, the transplant is put into the damaged area. After the second intervention, a patient needs to go through rehabilitation program that’s crucial for therapeutic success.

Arthroscopy is performed under local or general anesthesia. The operation requires making two small cuts about 5 mm each on the front part of knee: it makes injection of camera and operation instruments possible.

During arthroscopy, doctors gather a bit of glossy joint tissue (about 150-200 mg) from healthy surface to multiply it. The material is the size of a rice grain. After that, biopsy material is transferred to nutritional medium that is also used for transportation back to laboratory.

Tissue bioengineering is a modern innovative technique that allows reconstructing different live tissues, including joint cartilage.

After two weeks of multiplication in liquid nutritive medium, the cells are transported into a construction of hyaluronic acid where they also continue multiplying. In 2-3 weeks, Hyalograft- C sample is ready to be transferred to the damaged area.

Autologic cartilage cells are cultivated together with non-autologic proteins. During the production process, cells are washed, and a little amount of proteins can stay in the diluted material. However, there were no reports of negative outcomes connected with a small amount of these proteins.

Sampled cartilage cells are put into the medium that contains 2 antibiotics: penicillin and streptomycin. If a patient is sensitive to these antibiotics, he should inform the doctor about it. The main benefit of autological cartilage transplantation is that there’s no possibility that the transplant will be rejected by patient’s body, because transplanted cartilage corpuscles are patient’s own cells.´

During the second operation – implantation that is usually performed in 5-7 weeks after biopsy – the medium with cartilage cells (cartilage corpuscles) is taken to the damaged place. It is done by an arthroscopic method, or method of miniarthtopy.

The transplant (diluted cartilage ready for transplantation) is processed so that to obtain the size and the form of the damaged area. Thanks to its adhesiveness, the biopsy material fixes to the damaged place and fills it up. In rare cases, transplant fixation with fibrin glue is required.

The risk of complications is very low, but it may concern vessels, nerves, post-surgery infections, embolia, thrombosis, movement or loss of transplant.

When transplantation is over, the treated joint will be immobilized for 24 hours and fixed with drainage. One day after, a person will be able to make active and passive movements without load on the limb during 6-8 weeks. Additionally, intense physical therapy is used to improve movement of joints and muscles.

Patient will start in a clinic for 2-4 days. Rehabilitation course will be figured out by a physical and performed by a specialist of physical therapy. Detailed treatment plan after transplantation depends on the volume of operation and location of damage.

Full loading of joint is possible in 12 weeks only. During this period, a patient can walk and climb the stairs. In 3-6 weeks a patient can get back to easy exercises and sports – cycling, swimming. Later on, physical exercises can be improved and increased to full load, but they shouldn’t be performed during the first year after operation.

Biological regeneration of joint surface requires intense post-surgery treatment. The results of trials show that full reconstruction is possible after 12-24 months only. According to the results of clinical studies, the efficiency of transplantation in isolated damaged knee joint cartilage is about 80-85%.

Rehabilitation after Cartilage Transplantation

  • Period I (from 1 to 6 weeks):
    • walking on crutches;
    • complete immobility of the knee when walking;
    • sleep in an orthopedic cast to 4 weeks;
    • complete restriction of load on the leg for 2 weeks, stepping on the toe to 4 weeks, starting full stop from 5 weeks;
    • passivemovements in the joint up to 90°.
  • Period II (from 6 to 12 weeks):
    • walking on crutches until 8-9 weeks;
    • the load on the leg is not more than half of the body weight;
    • wearing a knee when needed;
    • passive extension of the joint and flexion up to 125°;
    • stimulation of the muscles of the thigh and lower leg.
  • Period III (from 12 to 26 weeks):
    • walking up to 3 km per day, jogging from the week 20;
    • flexion in the joint to 135°.
  • Period IV (from 26 to 52 weeks):
    • a full range of movements in the knee joint without restrictions;
    • sports: ice skating and roller skating, cycling – from 6 months; aerobics and running – from 8 months;contact sports – from 12 months.
GermanMedicalGroup + 49 (7221) 39-65-785 Flugstrasse 8a 76532 Baden-Baden Germany Knee cartilage is an important element of supporting-motor apparatus. The most part of loading is put on this zone of leg. Knee cartilage is an important element of supporting-motor apparatus. The most part of loading is put on this zone of leg. 2017-11-13 Knee cartilage is an important element of supporting-motor apparatus. The most part of loading is put on this zone of leg.

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