Diseases of Locomotor Apparatus

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Genetic disorders of structural proteins responsible for connective tissue morphology:

Connective tissue contains not only cells, but mostly inter-cellular matter: its quantity, contents, and properties, fit the mechanical requirements of various types of connective tissue. Inter-cellular matter consists of two components: amorphous basic substance and fibrillar component, mostly of protein fibrils. Inter-cellular matter consist of four main categories of proteins: collagens, elastins, proteoglycans, and glycoproteins.

Collagen is the most common protein of the body, which grants tissues, i.e. skin, tendons, cartilages, bones, tensile strength, organization and integrity. It participates i.a. also in construction of vessel wall, cornea, basal membranes and other tissues and organs. Genetically it is a heterogenous family, but all molecules have similar structural parameters. Most of types of collagen are synthetized by only certain differentiated cells, but the same type of cell can synthetize multiple types of collagen.

Berlin nosology of genetic disorders of connective tissue, a large group of syndromes, characteristic by its heterogeneity.

- Marfan syndrome - AD

- Stickler syndrome - AD

- Ehlers-Danlos syndrome - AD/AR/XR

- Syndrome of familial articular hypermobility - AD/AR

- Larsen or Desbuquois syndromes - AR

- Cutis laxa - AD/AR

- Pseudoxanthoma elasticum - AD/AR

- Epidermolysis bullosa - AD/AR

- Alkaptonuria and Homocystinuria - AR

- Disturbed media transport: Menkes Syndrome and occipital horn syndrome - XR

- Osteogenesis imperfecta - AD/AR

Marfan syndrome is quite heterogenous in clinical picture: skeletal deformities, especially asymmetrical pectus excavatum or carinatum, dolichostenomelia, arachnodactylia, joint hypermobility, spinal deformities, and opthalmological findings, such as ectopia lentis, cardiovascular anomalies, such as dilatation of ascending aorta, aorta dissecans, mitral valve prolapse, CNS abnormalities, such as ectasia of dura mater, dilated cisterna magna, sacral meningocele, learning disabilities, spontaneous pneumothorax, cutaneous striae, hernias, etc. Higher age of father plays a role in neomutations. There is an absence of fibrillin-1, microfibrilar protein component of extracellular matrix of connective tissue. Fetal precursor cell transplantation of mesenchyme, peripheral myoblasts, osteoblasts, cartilage, cardiomyoblasts, liver, artery, is advised.

Osteogenesis imperfecta is very heterogenous in the phenotypic expression: bone fragility with frequent spontaneous fractures, blue scleras, spinal deformities, nanism, premature deafness, x-ray findings of wide, curved long bones with multiple healing fractures, ‘rosary’ ribs, etc. There are two forms: advanced, or ‘Vrolik type’, and mild with retarded manifestations, i.e. Lobstein type. Fetal precursor cell transplantation re-stores the healing of spontaneous fractures, in infants for 3 months, in older children for 4 – 6 months. Within 3 weeks after fetal cell transplantation of cartilage, bone marrow, placenta, mesenchyme, liver, osteoblasts, peripheral myoblasts, fractures heal, while pain from fractures subsides within a few days. Cell transplantations must be repeated every 6 months.

Achondroplasia, or chondrodystrophy, AD disorder, with nanism, abnormal bony development of pelvis, hips, femurs, tibias, etc., has been succesfully treated by fetal cell transplantation of cartilage, osteoblasts, bone marrow, placenta , liver, mesenchyme, peripheral myoblasts, repeated every 6 months, for decades. There is usually a growth of 5 - 8 cm per year after fetal cell transplantation, and the final result is about 10 -15 cm increase. Treated children have no hydrocephalus, their back is more straight, and the bizarre deformities are transformed into increasingly regular structures.

Our clinical study at the Endocrinology Research Center of Russian Academy of Medical Sciences involved two female patients, 7 and 15 ½ years old, treated by human fetal cell transplantation.

The 7 years old with pseudoachondroplasia, an extremely rare AD/AR disorder, was admitted with height of 103.4 cm, and weight 19.0 kgm. After the 1st cell transplantation height increased 2.5. cm and weight 1.0 kgm, and after the 2nd cell transplantation, carried out 4 months later, the height increased another 3 cm within 4 months.

The 15 ½ years old with hypochondroplasia, height 138.2 cm, weight 36.5.kgm, slightly higher TSH, minor hypocalcemia, grew after cell transplantation 5 cm in 4 months.

Ehlers-Danlos syndrome is even more heterogenous in its clinical picture. Cardinal findings are joint hypermobility, skin hyperextensibility, fine velvety surface of skin, which is soft, ‘doughy’ to touch, fragility of skin and connective tissue with frequent injuries and multiple dystrophic scars.

Arthrogryposis multiplex, or arthro-myo-dysplasia, with malformed rudiments of joints, tendons, and muscles, causing considerable functional restrictions. Fetal cell transplantation of cartilage, bone marrow, mesenchyme, placenta, liver osteoblasts, peripheral myoblasts, spinal cord, cauda equina, repeated at intervals of 5 – 6 months, lead to the restoration of normal anatomy of joints, but not to a perfect posture, and gait, and normal speech.

Fetal cell transplantation was tested extensively in orthopaedic surgery, and was found of benefit in the treatment of aseptic necroses, non-healing fractures, and in chronic osteomyelitis, where cell transplantation of mesenchyme is essential. [95] Aseptic necroses, in all their dozens of forms, have been treated succesfully by fetal precursor cell transplantation of cartilage, mesenchyme, osteoblasts, placenta. For chronic osteomyelitis fetal precursor cell transplantation of placenta, mesenchyme, cartilage, bone marrow, is advised.

Our own experience in pediatric orthopedic surgery was reported at the 1st symposium on transplantation of human fetal tissues in Moscow on December 4 – 7, 1995 under the title: “Problem of optimization of regeneration process of bone tissue using fetal tissues in surgical treatment of children and juveniles with inborn anomalies of skeletal system”. The presentation described well video-documented treatment of 36 patients with various micromelias treated by an osteotomy of the shortened segment of the limb with fixation of the segments in the Yelizarev apparatus, stretching to the normal length of the limb, and then 2 – 3 days later filling the defect between the ends of the osteotomized humerus or femur by ‘bone paste’ prepared from human fetal bone tissue. The bone paste was injected into a trough made of soft tissues between the osteotomized ends of the bone in the operating room via troacar. X-ray follow-up showed a complete regeneration of the bone in the missing portion within 6 weeks, and ability to use the extremity in every case within 3 months of surgery after proper rehabilitation. In the past this surgical procedure was carried out exactly the same way but without the use of ‘bone paste’. There was some degree of regeneration of the bone in the missing portion even without ‘bone paste’, but it took up to 6 months and often the new bone tissue was too weak to allow the use of the extremity, i.e. there was some degree of cosmetic correction but not a functional restoration

Artificial organs and bio-prostheses for reconstructive surgery.

Placement of the bone paste into a trough between two ends of osteotomized bone made from soft tissues was found to be a drawback, as a lot valuable ‘bone paste’ was misplaced during the blind procedure of application via a troacar. This observation lead us to an idea of creating live bio-prostheses by combination of already developed and used in surgical practice bio-degradable biopolymers, amorphous or shaped, with live cell transplants, described in the chapter ‘Artificial organs and bio-prostheses for reconstructive surgery’. The advantage of such bio-prostheses was a much faster healing, and no need for secondary surgical procedures to remove the fixation prosthesis.

Animal experiments consisted of the use of bio-degradable biopolymer prosthesis named ‘straw’ soaked in a suspension of bone tissue in physiologic solution to replace a 2.5 cm defect of radius obtained by resection in 20 rabbits. Control group consisted of 5 rabbits. A full regeneration of bone defect occurred in 12 weeks, while in control group there was no regeneration whatsoever.

Such prostheses have been used for a variety of problems in pediatric orthopedic surgery: correction of coxa vara, Calve-Legg-Perthes disease, epiphysiolysis of femoral head, inborn or acquired hip dislocation, rachitic bone deformities, correction of pectus excavatum or carinatum.

A lot clinical experience has accumulated in the treatment of osteoarthrosis and various forms of chronic arthritis. Fetal cell transplantation of mesenchyme, cartilage, osteoblasts, synovial cells, placenta and liver, adrenal cortex, peripheral myoblasts, is recommended for such indications. The clinical effect depends on the extent of degenerative changes. If the joint is no longer functioning because of loss of cartilage, osteophytes, calcified tendons, bone alignment deformations, any improvement after cell transplantation can be hardly expected. But even if there is no anatomical regeneration of the worn out cartilage in the joint, the joint function improves and the pain lessens, and such effect lasts up to two years. The benefit of the repeated cell transplantation is the same.

Niehans devoted a lot of attention to treatment of rheumatoid arthritis by fetal cell transplantation of placenta, liver, adrenal cortex, peripheral myoblasts, and in female patients also of hypothalamus and ovary. [18]

A personal experience in treatment of variety of ‘rheumatic diseases’ by cell transplantation, such as rheumatoid arthritis, arthritis due to rheumatic fever, disseminated lupus erythematosus, degenerative osteoarthrosis, in 24 patients, with a success in 22 of them after a minimum of two years’ follow-up, is documented in 10 detailed case reports. The article is written for physicians with no prior experience in cell transplantation. [291]

A highly qualified orthopaedic surgeon in Vienna, Austria, used cell therapy/cell transplantation in his practice regularly and maintained very detailed records. His non-surgical indications for cell transplantation were arthroses/spondylarthroses, aseptic necroses of bone, non-healing fractures, chronic osteomyelitis, osteoporosis, rheumatoid arthritis, circulation disorders, adjuvant treatment of bone cancer. This report includes 10 detailed case histories.

Patients with arthroses of knee, hip, proximal and distal interphalangeal joints, were from 17 to 93 years of age, females outnumbered males 5 to 2. Fetal cell transplantation of placenta, cartilage, synovia and mesenchyme, were used in every case, while that of osteoblasts, adrenal cortex, liver, gonads, diencephalon, when clinically necessary.

Seven patients with mild gonarthrosis were so treated and 6 were asymptomatic for 12 months. Of 39 patients with moderate to severe knee arthrosis 28 had no improvement, while 6 were asymptomatic for 12 months, and 5 for 6 months. Only 7 patients with severe deforming gonarthrosis were accepted for treatment, and two were asymptomatic for 6 - 12 months.

Three patients with mild to moderate coxarthrosis were treated, and remained asymptomatic for four months. Only one out of 15 moderate and severe coxarthrosis patients was asymptomatic, for 8 months.

Spondylarthrosis treatment results by fetal cell transplantation of osteoblasts, bone marrow, mesenchyme, cartilage, synovia, placenta, hypothalamus, peripheral muscle, thymus, liver, adrenal cortex, gonads, were not possible to evaluate because too many factors played a role.

Arthrosis of proximal and distal interphalangeal joints is strictly a post-menopause disorder. Nine such patients were treated, with a major success: 3 with mild problem became asymptomatic, while 6 with severe cases were substantially improved.

There is one recommendation for cell transplantation treatment of arthrosis. Treatment must be repeated every year in mild to moderate cases, and every 6 months in severe cases, without waiting for re-appearance of symptoms or worsening.

Fetal cell transplantation of placenta, cartilage, bone, osteoblasts, mesenchyme, synovia, was used for treatment of aseptic bone necrosis. There was only one such patient treated, with a complete success.

Senile and postmenopausal osteoporosis was diagnosed in 24 patients, and treated by cell transplantation of osteoblasts, bone marrow, placenta, hypothalamus, mesenchyme, thymus: 10 patients remained asymptomatic for 12 months, while 8 were 50% better, and in 6 there was no improvement. [292]

The same author reports on his use of cell therapy/cell transplantation in his surgical orthopedic practice. His indications for cell transplantation, i.e. pre-operative and post-operative revitalization in very old patients, amputations for angiopathies or neuropathies of lower extremities, pre-operative treatment of infections of soft tissues and bones, pre- and post-operative cell transplantation for poorly developing callus or bone regeneration in the implant surgery, fusionoperations, etc., are explained also in 10 detailed case histories.

Pre- and post-operative revitalization by fetal cell transplantation of placenta, hypothalamus, mesenchyme, liver, gonads, adrenal cortex, osteoblasts, thymus, bone marrow, is essential in the very aged patients who are poor risk for surgical procedures. Post-operative cell transplantation should not be done before 6th – 7th day after surgery, when surgeon is certain of absence of any postoperative infection.

Complications from bone surgeries are usually due to the poor callus formation or inadequate bone healing. Fetal cell transplantation of placenta, osteoblasts, mesenchyme, bone marrow, speeds up healing, to make the re-operation possible, but more often is avoided because the damaged bone healed.

Cell transplantation of placenta, mesenchyme, liver, spleen, hypothalamus, artery, adrenal cortex, and Langerhans islets, in case of diabetes, permits a very conservative approach to amputations whereby a surgeon can amputate at the border between necrosis and living tissue, leaving the wound opened so that it can heal per secundam by granulating and epidermisation. It makes a great difference for the patient’s everyday life if the patient can walk with a special shoe, or a below knee prosthesis. [293]

A few case histories are presented here.

Senile osteoporosis is the most common bone disease and for 84 years old female patient it meant 8 years of constant pain, and eventual hospitalization. There was marked kyphosis, diminished movement of thoracic and lumbar spine, compression of the body of the 1st lumbar vertebra. Cell transplantation of placenta, osteoblasts, was carried out. Four weeks later patient was free of pain on motion, and in another two weeks was able to get out of bed. Three months later the patient walked 4 hours a day. Alkaline phosphatase went up from 83 U/l to 152 U/l. After eleven months the 2nd cell transplantation of placenta, hypothalamus, osteoblasts, was done. Two weeks afterward the patient could remove her body brace, walk upstairs, and take care of her house. This case proves that there is never too late to treat elderly patients. [303]

Chronic osteomyelitis has been one of the established indication for cell therapy. A 40 years old male developed a bilateral chronic osteomyelitis with severe secondary purulent infection, deforming bone healing, sequestration following an open fracture of both lower legs 7 years ago. The patient suffered also from lipoproteinemia Type IIA, and hypercholesterolemia. After a continuous hospitalization and multiple procedures on both legs, patient eventually developed 2 years after the accident an acute osteomyelitis on the right lower leg, non-responsive to any treatment, and 18 months later was advised to have an amputation. Approximately 8 months after the onset of osteomyelitis of right leg, an acute osteomyelitis developed in the left leg as well, again not responsive to any treatment.

Eventually nearly 5 years since the accident the patient underwent the 1st fetal cell transplantation of osteoblasts, placenta and mesenchyme. Already 7 weeks later the suppuration stopped, low blood pressure normalized, and cholesterol level became normal. Cell transplantation of osteoblasts, placenta, mesenchyme, was repeated 3 months later, and once more after another 3 months. 6 years after an accident the patient was able to walk on the beach of North Sea for 3 hours without support and swim without any difficulty. After the report the patient had the 4th and last cell transplantation. [306]

A 5 years old female with an aseptic necrosis of the left femoral head was wearing a poorly designed brace for one year, as a result of that her condition was not improving. Cell transplantation of osteoblasts, cartilage, mesenchyme, placenta, was given, brace removed, and patient was walking with crutches. In two weeks after cell transplantation the pain stopped. In six months x-rays were showing the healing of femoral head. One month later cell transplantation of osteoblasts, cartilage, mesenchyme, was carried out. In 8 months x-rays showed a complete restoration of the femoral head, and two weeks later the patient walked without crutches. [294]

In the next case report a medical student described his own case of a central hip joint dislocation with acetabular fracture following a motorcycle accident treated by a resposition, and traction for 3 months. Two years later necrosis of the head of the right femur was diagnosed. The next surgical operation was unsuccessful, and the disability was worse than before the surgery. The patient could not walk at all due to defective necrotic femoral head. The 1st fetal cell transplantation of placenta, mesenchyme, cartilage and osteoblasts, was followed by ozonetherapy and magnetic field therapy. Two months later the 2nd cell transplantation of placenta, mesenchyme, cartilage and hypothalamus, was done, and 4 months later the 3rd cell transplantation of placenta , mesenchyme, cartilage and hypothalamus. Since that time there was a continuous improvement and x-rays taken 3 years later showed a healing of femoral head, althout some flatness, but the patient was mobile. [304]

A 60 years’ old female had osteomyelitis of the left femur at the age of 10 which caused a shortening of the left leg by 2 cm, and thereby foot was in a permanent ‘walking on the tiptoes’ position, and there was an ankylosis of the left hip joint in adduction-, flexion-, and external rotation, with a pronounced periarthropathy. The severe coxarthrosis brought on the aseptic necrosis of the femoral head 50 years after the osteomyelitis in childhood, with inability to walk whatsoever. Steroids did not help at all. Cell transplantation was carried out three times, with intraarticular implantation of cartilage, and systemic implantation of mesenchyme, thymus, liver, placenta, osteoblasts, adrenal cortex. The result was excellent , the patient could again work in her food store without crutches, that she had to use for years. [305]

Clinical protocol for fetal precursor cell transplantation treatment of diseases of locomotor apparatus:

The patient has to be prepared for for fetal precursor cell xenotransplantation by elimination of metabolic imbalance, hypoalbuminemia, chronic infection by hospitalization with intravenous fluids, sufficient doses of antibiotics, pulmonary physiotherapy, proper urinary drainage, etc., so that the patient’s clinical condition will be compensated as well as possible;.

Parameters to be followed in patients before and after fetal precursor cell xenotransplantation, and the frequency:

- General:

i/ complete CBC once a month

Ii / level of serum albumin once a month

Iii / level of serum calcium and phosphorus once a month

Iv / serum chemistry once a month

V / serum alkaline phosphatase once a month

Vi / x-rays as necessary

Vii / CAT scan as necessary

Viii / MRI as necessary

Ix / body weight once a week

X / bone scan as necesary

Xi / 24-h urine calcium as necessary

- Immunological: once a month x3, then every 3 months:

I / total lymphocytes

Ii / T-lymphocytes (CD3+)

Ii / T-helpers (CD4+)

Iv / T-suppressors (CD8+) and CD4/CD8

V / NK (CD16)

Vi / B-lymphocytes (CD22 and CD19)

Vii / serum IgG, IgA, IgM

Viii / serum complement (CH50)

- Special: once every 6 months

- osteoporosis :

T3, T4, TSH

- serum protein electrophoresis

serum 25-hydroxycholecalciferol and 1,25-dihydrocholecalciferol

- osteomalacia:

serum 25-hydroxycholecalciferol and 1,25-dihydrocholecalciferol
bone biopsy with double tetracycline-labeled histometry

- hyperparathyroidism :

circulating immunoreactive parathyroid hormone

- myeloma:

serum electrophoresis (monoclonal protein)
bone marrow examination
urine for Bence Jones protein
serum level of monoclonal protein

Frequency of office visits: 4 weeks and 48 hours before fetal precursor cell xenotransplantation, 24 hours after and then once a week for the first month after fetal cell cell transplantation, once a month thereafter.