I sent a mail including the following content to some sites in the spring of 2014 .
〝Disturbances were caused over the existence of STAP-cell which had been shown by a Japanesr female researcher, however even if the same as dark matter, black body, worm-hole, this is a virtual being at present, it's very significant to continue to study about the cell.
It seems that she caught 'something' to be able to strikingly get near the embryonic limit.
As unexpected wonderful results can be often drawn from such a field, the same as homunculus ( through chemical topo-logical operations ), multiwave oscillator, it's hesitated to give up such quests″
Checking various cases of fracture of bone, osteoporosis is classified into three types ( 1. low osteo-density type 2. osteo-quality deterioration type 3. the mixture of 1 and 2 ) rather than a single disease from viewpoints of osteo-density and osteo-quality.
Especially, the mixture type ( 3 ) has high risk to cause fracture of bone, medical treatments must be performed on it quickly to prevent successive fractures.
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In particular, estimations of inter-molecular cross-links of collagen to regulate osseous quality, markers of oxidative stress and saccharification ( such as pentosidine, homocysteine ) to bring anomaly to collagen can be regarded as surrogate markers to find out osteo-quality deterioration.
It's possible to use combinations of existing medicines against osteoporosis as tailor-made treatments against three types of this disease at present ( in 2013 ).
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Then, it's important to estimate measurement of osteo-density and osteo-quality markers at the same time for tackling this disease according to diverse symptoms.
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By the way, as oxidative stress is a factor to promote deteriorations of not only osteo-quality but also polyethylene as a material for artificial joint,
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when a replacement with an artificial joint was performed on an osteo-quality deterioration typed patient, it's necessary to observe the course after the operation for a long time.
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Osteo-quality is important as a factor to regulate the strength of bone except for osteo-density.
And, osteo-quality is regulated by characters of materials composing a bone and characters of a structure formed on those materials ( fine or microscopic structure ).
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Furthermore, osteo-density depends on the extent of calcification of bone and the fine structure of bone.
These factors are controlled by re-modelings of bone.
Namely, if bone-absorption is promoted, the extent of calcification falls.
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So that, fine structures and osteo-density dependent on the factor also deteriorate.
Inversely, if bone-absorption is suppressed, the extent of calcification and the fine structure are improved.
It's known that collagen occupies 20 % in weight, besides it occupies 50 % ( about half ) in volume of the texture respectively.
It has been found out that the strength of this collagen itself is regulated by a mechanism independent of the re-modeling of bone according to recent studies.
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The formation of bridges ( or cross-links ) to interlock adjacent collagen-molecules is a representative modification process after interpretation of collagen.
Besides, this is a factor to regulate calcification and the strength of collagen-fiber.
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The formation of collagen bridges ( or collagen cross-links ) is complicatedly controlled by functionalities of osteo-blast and conditions around the collagen ( oxidative stress, saccharificational stress and carbonyl stress, etc ).
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As oxidative stress promotes the deterioration of polyethylene for artificial joint, we must take not only local conditions around each artificial joint but also constitutions and diseases ( especially, lifestyle-related diseases ) to increase oxidative stress into consideration.
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Studies on the influences of factors to increase oxidative stress on bones consequently enable us to predict abrasions and loosenings caused after the replacement with artificial joint.
The increases of respective stresses are promoted due to lack of estrogen and aging too.
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Furthermore, the accumulation of advanced glycation end products ( AGEs ) on bone can be induced by promoting these stresses.
We show it in this section that consequently, such processes can lower the strength of bone and increase the risk of fracture of bone.
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A bone composing a wing of a bird has sufficient strength and lightness to fly.
The torus ( cavity ) structure of a bone of a wing of a bird is very similar to torus structures of wings and bridges of a plain.
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If bones and muscles successively work on something, organizations composing those organs adaptively vary depending on applied external forces.
And, they have an inclination to be tougher according to such variations.
Such variations can be regarded as functional adaptations by organizations themselves on self-organizations ( without instructions from the brain ).
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( • ) One of the functional adaptations simulated with cell-automaton
〈 Rules 〉
A weight is applied to a matter of square cells.
And, a stress generated at each cell is transformed into a numerical value,
if a higher stress is generated at the cell, the strength (= Young's modulus) of the cell rises.
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This model is different from usual models of cellular automaton, the temporal state of each cell is determined by one's own stress namely the whole state of cells rather than cells on both sides.
→ interactions between each part and the whole ( local scale and non-local scale )
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In an actual living body, if the stress on a part increases due to an applied weight to the part, a substance to strengthen osseous tissues around the part is released.
It's supposed that aging is one of the main factors to lower such a feed-back function, so that an osteoporosis is caused.
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A bone has a typical porous structure, it contains many cross-links and its density also is high at young generation.
But, because of aging, cross-links are reduced, its density decreases and the strength declines.
As re-modeling contributes to tissue ( organization ) - regeneration, we should pay attention to re-modeling.
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Here, we should notice that a bone of a wing of a bird has cavity structure, but unexpectedly it has high strength too.
Namely, we must take not only structural viewpoints but also material viewpoints into consideration.
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An enzyme to synthesize ATP is roughly divided into two units, one of those two units is composed of a toroidal part of plural trans-membrane polypeptides and an neighboring part to it.
Another of above two units sticks into the saddle part of the torus.
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1. Aging of bone ; changes of osteo-collagens into AGEs
From the viewpoint of material, a bone is likened to a reinforced concrete.
In this case, mineral ingredient corresponds to reinforced concrete, collagen-proteins correspond to reinforcing bars.
※ Collagens contained in bones are mainly classified into I-type.
The quake-resistance (≒ the strength of bone) of a building made of inferior reinforcing bars falls.
※ Recently, it has been found out that some theories for architecture hold even on the strength of bone.
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AGEs as aging cross-links are over-inducted into osteo-collagens due to primary osteoporosis, diabetes, renal failure and aging, etc, consequently the strength of bone lowers.
Oxidative stress and saccharification related to ground substantial protein give considerable influences on over-aging of collagen.
By the way, it's impossible to estimate the risk of fracture of bone only on calcium-based parameters dependent on the promotion of bone-absorption and the drop in osteo-density following it.
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It also is necessary for catching the risk of fracture at high precision to estimate changes of collagen into AGEs.
Plural estimation methods to utilize AGEs ( pentosidine ) in a blood or an urine as 'osteo-quality markers ( osteo-matrix markers )' for estimating material deterioration have been reported domestically and internationally.
Those methods also are effective to estimate the risk of fracture of bone.
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According to longitudinal researches over Nagano cohort, it has been made clear that it's possible to estimate the risk of bone-fracture at high accuracy by combining measurement of osteo-density with data of markers to regulate osteo-qualities (≒ data of osteo-material markers).
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Furthermore, according to these clinical studies, it's possible to explain 93 % of the risk of new fracture of vertebra over the women at postmenopause on four factors ( namely, osteo-density, bone-fractures in the past or at that time, age, osteo-material markers ).
Besides, as high valued osteo-quality markers had relation to 33 % of the risks of fracture, they can be regarded as markers to predict fractures.
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But, even if AGEs-structured bodies such as pyrraline, carboxymethyl arginine were contained at high value, they did not have relation to the risk of fracture so much.
Accordingly, it has been made clear that the increase of oxidative stress gives considerable influences on the deterioration of osteo-quality.
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The strength of collagen is regulated by cross-linked structures inter-locking adjacent molecules.
Then, collagen-molecules secreted from osteo-blasts are regularly ordered.
Next, adjacent collagen-molecules coupling through each cross-link are stabilized.
There are two kinds of cross-links.
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One is called good-natured enzyme-dependent cross-link ( immature or mature cross-link ), this plays role to regularly place molecules and strengthens bone with moderate elasticity.
By the way, immature or mature cross-link is called 'physiological cross-link' .
Such cross-links are orderedly formed through actions of enzymes called lysyl oxidase generated from osteoblasts.
Furthermore, these cross-links give influence on calcification.
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Meanwhile, under an AGEs-cross link ( aging or bad-natured cross link ), collagen-molecules are over-tied at random, the organization itself loses flexibility, elasticity and consequently it becomes easier to be broken.
Pentosidine is a representative cross link of AGEs.
As this matter has a positive correlation with the total quantity of AGEs , it's generically utilized as a surrogate marker to catch the total quantity.
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2. Relations of changes of osteo-collagens into AGEs with microscopic bone-fractures
Saito found out that bone-fracture at micro scale as a main factor to lower the strength of bone is caused by over-formations of AGEs-cross links among collagen-molecules.
To understand inter-relations which hold among such factors to determine osteo-quality, it's convenient to liken bone to reinforced concrete.
As we know, cracks found out on an outer wall made of reinforced concrete are originated in exhaustions of those reinforcing bars due to aging.
In this case, micro-damages correspond to cracks on a reinforced concrete.
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3. Changes of osteo-collagens into AGEs with aging
Saito analyzed influences of aging on formations of collagen-bridges in human bones ( 0 〜 84 in age ).
Especially, proximal humerus, distal radius, ilium, femoral neck, fourth lumbar vertebral body and the middle of tibia are known as parts easy to cause fracture due to osteoporosis.
Collagens were extracted from these respective parts, pentosidines ( AGEs-cross links ) contained in them were quantified and the number of cross links per collagen-molecules was calculated out.
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So that, it's found out that pentosidines increase with aging over all taken parts.
The quantity of pentosidines in not only blood but also urine increases with aging in proportion to such variations.
Besides, the increase of AGEs in bones with aging are found out independently of gender.
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4. Bone-matrix marker ; pentosidine and homocystein
Saito and others performed bone-biopsies ( cortical bone, cancellous bone ) on primary osteoporosis victims who had received femoral neck fractures ( 15 〜 25 cases ) and analyzed extracted collagens.
As the result, it has been made clear that AGEs-cross links namely pentosidines are over-formed even in young osteo-domains in early stages of calcification in cases of fracture.
Many supplementary examinations have made clear that over-formations of AGEs namely pentosidines in osteo-collagen directly cause the fall in strength of bone.
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It's known that pentosidines contained in urine at high value have positive correlation with changes of osteo-collagens into AGEs .
Furthermore, cooperative researches with Shiraki and others have shown that these pentosidines at high value can be regarded as a factor to represent the risk of fracture independently of osteo-density.
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The same investigation as that to know the risk of new generation of vertebral fracture were executed over uncured 432 women at postmenopause.
So that, especially, a group at maximum quartile value of pentosidines contained in urine ( 47.5 pM/mgCr , on compensations with creatinine ) has the risk of fracture independently of osteo-density, existing fractures, age and renal function.
※ maximum quartile value ;
gathered data are divided into four groups in order of size of value, the maximum group of those four groups.
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Furthermore, according to some researches of symptom on contrast, if pentosidines are contained in osteo-collagen of a person at high value, homocysteines contained in blood of the person also are at high value.
Significantly, it has been successively reported that hyperhomocysteinemia is not only a risky factor to cause hardening of the arteries but also the risk of fracture independent of osteo-density in general people.
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Then, to check whether hyper-homocysteinemia excessively induces variations of osteo-collagens into AGEs or not, we made tests on rabbits from which ovaries are eliminated ( but they had same remodeled bones as human bones ).
So that, it has been found out that if hyper-homocysteinemia is caused, pentosidines are excessively generated in osteo-collagen and changes of osteo-collagens into AGEs are promoted.
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Furthermore, it also has been made clear that the strength of bone is weakened without fall in osteo-density due to this process.
Namely, it's probable that homocysteines in blood at high value promote changes of osteo-collagens into AGEs and increase the risk of fracture.
OFELY study showed that the risk of fracture rises in a group containing pentosidines in urine at high value too.
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And, Saito & others found out that the group of the patients who show the brittleness of bone is classified into following three types on osteo-density and osteo-quality according to vertical investigations in age over 502 women at postmenopause ( Nagano-cohort ).
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① Low osteo-density type ;
This type is 3.6 times higher than the cases at YAM > 80 % in risk of fracture.
※ YAM ;
The abbreviation of Young Adult Mean. Namely, a mean of young generations in osteo-density.
② Osseous deterioration type ;
This type is 3.6 times higher than the cases at YAM > 80 % in risk of fracture.
③ ① + ② ;
This type is 7.2 times higher than the cases at YAM > 80 % in risk of fracture.
In this case, the rate among respective types in number in Nagano cohort was as follows.
① : ② : ③ = 5 : 3 : 2
Namely, it was made clear that the appearance of osseous deterioration type is not necessarily rare.
Homocysteines in blood at high value ( > 13 nmol/mL ) and pentosidines in urine at high value ( > 47 pmol/mg creatinine ) are useful as surrogate markers to find out symptoms of such osseous deteriorative osteoporosis.
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It's possible to request measurements of homocysteines in blood and pentosidines in blood or in urine of contractors for inspection.
However, in Japan at present ( 2013 ), we can't apply the health insurance to such measurements on osteoporosis.
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Furthermore, according to vertical studies in age over 251 osteoporotic patients at postmenopause,
it has been made clear that in cases of ③ low osteo-density + osseous deterioration type osteoporosis, even if osteo-densities were raised with bisphosphonate ( a kind of bone-absorption suppressive drug ), the risk of fracture was 'not' reduced.
These facts mean that we must primarily suppress variations of bone collagens into AGEs to sufficiently improve the strength of bone.
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5. Changes of bone-collagens into AGEs with diabetes and fall in renal function
In the case of II-type diabetes, hardening of the arteries often appears as a complication.
According to meta-analyses, it has been made clear that a fracture of bone can be caused even at high osteo-density.
So, it's supposed that fractures are actually originated in osseous deterioration.
And, Saito & others made clear the following mechanism on observations of rats which naturally received diabetes.
Low vitamin B6-state ( a state containing vitamin B6 at low value ) and remarkable durable hyper-glycemia originated in the failure of action of insulin bring over-formations of pentosidines in osteo-collagen,
consequently they cause the fall in the strength of bone without lowering the osteo-density.
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In the case of II-type diabetes, pentosidines contained in blood or urine at high value also can be regarded as a risk of fracture independent of other some factors.
This is a considerable example to show the correlation between the increase of pentosidines in bone-collagen and the fall in the strength of bone.
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Furthermore, Saito & others made clear that renal functional failure not only increases oxidative stress, carbonyl stress but also promotes variations of osteo-collagens into AGEs.
Besides, they drew it from bone biopsies over cases with renal failure that variations of osteo-collagen into AGEs bring falls in functions as osteo-blasts ( namely, fall in function to form bone ).
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6. Limits of models with rodents ( such as rat, mouse ) in estimating changes of bone into AGEs
It's difficult to find out a significant increase of AGEs in an osseous substance of a rodent with short life span on aging and pathological models.
Though AGEs increase under remarkable high blood sugar even in the case of rodent, the increase is very small in comparison with that in a human osseous tissue.
We must execute tests on larger-sized animals with longer life span ( rabbit, dog, monkey, etc ) to obtain more reliable estimations.
Therefore, as human being is same as rodent in formation of enzyme-dependent cross-links, we perform experiments with rodents to estimate such formations.
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Meanwhile, we plan a test on larger-sized animals for measurements of AGEs in osseous tissues, clarification of pathology and estimation of drug effect.
※ And, results drawn from human osseous tissue biopsies are compared with these data.
Furthermore, remodelings (≒ renewal of tissues namely metabolism ) are not carried out in bones of rodent.
Namely, those cases are different from cases of human being, as a single modeling is continued for a life span, it's not proper to analyze aging process of human bone with rodents.
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・ Conclusion
Briefly explaining of osteoporosis, changes of osteo-collagen into AGEs are promoted by some factors ( ・ fall in osteo-density originated in the promotion of bone-remodeling, ・ fall in function of osteo-blast, ・ promoted oxidative stress ),
consequently osseous tissues are remarkably weakened.
Oxidative stress increases at menopause, variations of osseous tissues into AGEs are promoted without hyper-homocysteinemia.
In particular, as the cases at low osteo-density + osseous deterioration have remarkable high risk of fracture, we must estimate markers related to osteo-density and osseous markers at the same time, choose an effective medicine which is suitable to the pathological type.
Furthermore, if the replacement with an artificial joint is performed on an osseous deterioration type osteoporotic case at high oxidative stress, as it's highly probable that a tissue-deterioration originated in the oxidation of polyethylene also is promoted,
we should take the use of medicines or chemicals with anti-oxidative actions into consideration too.
• High-polymer materials which are used as main bio-materials in the field of orthopedics
〈 Preface 〉
As the goal of regenerative medicine is to revive lost living functions, roles of bio-materials to help the purpose are still left.
1. Present conditions of materials to fix bones for treatment for fracture
Artificial materials with high strength are used to restore a fractured part and support the chest in respective fields such as orthopedics, oral surgery and thoracic surgery.
Primarily, plates and screws for joining bones should be used as supplementary tools to cure of fractures, they need to be removed as quickly as possible after recovery to prevent the weakening of bone.
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At present, most of the clinical materials to fix bones are made of metal or ceramic.
But, elastic degrees of these materials are so high that they can deform bones.
And, metallic ions flowing out of those materials can injure the living body.
Accordingly, if those materials are same as bones in elastic degree and they are well resolved-absorbed into the living body, they are convenient to join bones.
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So that, it also will be possible to cancel various bad influences caused by foreign matters which are left in a living body for a long term.
Researches to apply poly-lactic acid as a kind of possible high polymer to be resolved and absorbed into a living body to cure for fracture have a comparatively old history.
Gen and others developed materials made of PLLA ( PoLy-Lactic Acid ) to cure of fracture, those materials have been clinically utilized over the world ( the same as a surgery-assisting robot called da Vinci ).
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Furthermore, the following way to mold was devised to improve its mechanical characters.
Once a tissue is molded with degradable & absorbable high-polymer materials in vivo containing hydroxyapatite such as PLLA, its strength and elastic degree are improved by uni-axially stretching the molded tissue.
Moreover, a poly-lactic acid rod processed with injection molding is uni-axially stretched at high temperature, high magnification ( 7 〜 12 times ), so that the fibrillated tissue gets higher strength and higher elastic degree.
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Besides, Gen and others produced an other material to join bones by uni-axially stretching a fusion-molded body made of PLLA with viscous mean molecular mass of more than two hundred thousands.
But, in cases of above materials to fix bones, as only the initial strength and the hydrolysis-resistance (≒ durability against hydrolysis) are taken into consideration, those materials have been still in-sufficient in elastic degree, durability of strength in living body.
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Especially, in-sufficiencies of following aspects have been pointed out.
・ Degradabilities and absorbabilities in vivo after the fracture is cured.
・ The promotion of degradabilities & absorbabilities in vivo after the degree to keep the initial strength gets 0 .
In general, a cure for fracture is completed for about 6 〜 8 months.
By the way, after the above material to cure of fracture is implanted into a living body, as the molecular mass is reduced, the strength also falls.
Accordingly, such a character is desirable for curing of fracture in some sense.
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But, the initial strength gets 0 and the molecular mass also are reduced from two hundreds thousands to thousands 〜 tens of thousands within about 4 months after the implantation.
Furthermore, particle-like crystals are left in the living body for about 3 〜 5 years.
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Therefore, even if these materials are applied to osteo-tissues, as speeds required to decompose and absorb them are so slow, the cavity of the bone is occupied with fibrous tissues, osseous tissues are not re-organized in a part into which a material to heal fracture is implanted even after 3 〜 5 years pass and the part will be left to be hollow.
Such a situation not only remarkably lowers the dynamical strength to bear a weight but also causes various following complications more seriously.
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2. Present conditions of artificial joint ( 2013 )
Basic conditions necessary to materials for artificial joint are as follows.
① Exellent suitabilities for living body
② Sufficient dynamical strength
③ Excellent abrasion-resistant properties ( durabilities against abrasion )
④ Which are chemically stable without deteriorations of materials
Though artificial joints to satisfy above respective conditions are desired, actual situations have been still insufficient for such requirements.
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Until now, metals have been mainly used as hard materials for artificial joint.
But, recently, ceramics also are partially being used for artificial joint.
Especially, alumina is preferred due to following properties.
・ Exellent suitabilities for living body and mechanical strength
・ This material has better affinity with Ultra High Molecular Weight PolyEthylene ( UHMWPE ) than metals in abrasive character.
But, as this alumina is fragile, zirconium is more expected as a stronger ceramic for artificial joint recently.
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As stated in the above, various shaped artificial joints are clinically applied, they are synthesized by combining hard materials such as metals and ceramics with soft materials such as UHMWPE ( Ultra High Molecular Weight PolyEthylene ).
Then, osteo-cement plays a main role to fix an artificial joint in the bio-osseous tissue.
Osteo-cement is solidified by polymerizing methyl methacrylate in a living body.
Particularly, this osteo-cement has succeeded in strongly joining an artificial joint to a bionic bone.
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However, osseous tissues around the osteo-cement get necrotic due to the heat of about 90 ℃ generated in polymerizing osteo-cement and residual monomers, fibrous tissues are formed instead of osseous tissues.
Therefore, after a long time passes from the implantation, the 'loosening' of the artificial joint is caused as the most serious complication.
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Recently ( 2013 ), it has been found out that not only problems related to osteo-cement but also abrasions of UHMWPE ( Ultra High Molecular Weight PolyEthylene ) give remarkable influences on such the generation of 'loosening' .
There are many clinically applied cases except for representative artificial joints sold at present as shown in the above.
As those models also are constantly varied, those contents also will be further changed after several years.
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More than 30 years have passed since artificial joints were developed and they were clinically applied to patients suffering from arthro-diseases.
For those some decades, many bed-ridden patients could walk again and return to society.
In the sense, artificial joints could considerably contribute to social welfare.
But, after about 10 〜 20 years, after 5 years at the earliest from an operation, the 'loosening' of artificial joint is caused as a complication at high frequency.
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Consequently, as osseous tissues around the artificial joint are damaged, it's needed to execute a surgery again for healing the injury.
Such problems are being reported over the world, they are regarded as serious problems in the field of orthopedics.
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Recently, some causes which bring damages to bone have been made clear.
According to those reports, it has been found out that as UHMWPE used as a material for rubbing parts of artificial joint is low in abrasion-resistance in comparison with cartilage, it's poor in stress-relaxation against impulsive weight.
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