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Биотехнологии и биоматериалы

New osteoinductive bioplastic materials in reconstructial surgery

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Currently there are various bioplastic materials, which have osteoconductive and/or osteoinductive properties. Materials comprising substantially pure hydroxyapatite, such as “Osteogaf”, “Bio-Oss”, “Osteomin”, “Ostim”, mainly show conductive properties, though they can also have light osteoconductive action (12, 13).

Another group of materials is in whole or in part dematerialized bone tissue, as well as combination of these materials with biologically active substances, such as morphogenetic proteins, growth factors etc (7). Most important requirement for bioplastic materials remains their inductive and antigenic specificity. Besides, various surgeries require materials, which have, in addition to above mentioned factors, good plastic and strength properties for required forms and configurations producing and sustaining when filling cavities and bone defects.

All the above considered, Russian company OOO “Connectbiofarm” developed technology of bone collagen and glycosaminoglycans preparation and on their basis made biocomposite materials of “Biomatrix” and “Osteomatrix” lines. Main difference between these groups of materials is that “Biomatrix” comprises bone collagen and bone glycosaminoglycans, and “Osteomatrix” in addition to the same two components of bone tissue comprises natural hydroxyapatite (7) A source of these materials is sponge and cortical bones of different animals and human. Bone collagen derived by this technology doesn’t comprise other proteins, and it allows the materials to be absolutely inert to immune system of the recipient. These materials represent new generation of bioimplants, which have already won recognition both in stomatologic and orthopedic practice (1,2,3,4,6). They were effectively applied in cases of imperfect osteogenesis, hand reconstruction, surgical treatment of periodontics and jawbones defects repair.

These materials are still unique to have collagen and mineral structure of natural bone substantially intact, but at the same time they are completely free of antigenic specificity. Besides, their big advantage is containing bone glycosaminoglycans affinely connected with collagen and hydroxyapatite. Last significantly sets them apart existent analogs and considerably increases their osteogenic properties.

In the set of experiments carried on by OOO “Conectbiofarm” company, in addition to known properties of bone matrix, we succeeded to discover some new mechanisms of action for these biocomposite materials.

Thus, currently for bone and soft tissues growth acceleration the technique of different cells stimulation by platelet-rich plasma is frequently used. This new biotechnology of guided tissue engineering is, in the opinion of some authors, real breakthrough in surgical practice (14, 15, 17). However, preparation of such plasma requires certain equipment, and in some cases specially trained staff (17, 18).

Using “Biomatrix” and “Osteomatrix” materials for this purpose completely solves this problem with minimum costs, because there is no need to isolate platelets from patient’s blood. Thus, we found out that 1 cm3 of “Biomatrix” material is able to fix just about all platelets (90%) in 1 ml of blood, that is 226 – 304 millions of platelets. Platelets fixation by bone collagen derived in our technology carries quickly and is completed in few minutes. In comparison with known techniques, using “Biomatrix” material offers the possibility to considerably improve concentrating of platelets.

At the same time, collagen is precisely that protein which is able to activate Hageman factor (blood-coagulation factor) and complement system. Therefore, bone collagen in the composition of “Biomatrix” and “Osteomatrix” materials can activate main systems of blood plasma proteolysis, responsible for haemodynamic balance control and providing of body regenerative reactions.

Unlike platelet-rich plasma, which doesn’t have osteoconductive action itself, i.e. can’t initialize bone formation without bone cells, “Biomatrix” and “Osteomatrix” materials have this property. Thus, at “Biomatrix” and especially “Osteomatrix” intramuscular implantation ectopic bone tissue formation occurs, which directly proves osteoinductive activity of these materials.

It should be also noted that “Osteomatrix” line materials comprise natural bone hydroxyapatite, which can affinely accumulate on its surface bone morphogenetic proteins synthesized by osteoblasts, and as a result additionally stimulate osteogenesis (“induced osteoinduction”). At the same time there aren’t any objections about possibility of tumors progression as a consequence of recombinant proteins using, because in case of “Biomatrix” and “Osteomatrix” materials applying in zone of implantation there are only proteins synthesized by recipient body besides them (17).

“Biomatrix” and “Osteomatrix” lines materials have one more unique quality – they are able to affinely fix glycosaminoglycans. In vitro we found out that this process, like platelets fixation, occurs in a short period of time, and quantity of fixed glycosaminoglycans is bigger than physiological index. At the present time it is well known that either collagen or hydroxyapatite, using separately, have mainly osteoconductive properties, i.e. can act only as “auxiliary” material for new bone formation. However, these molecules can also have a light osteoinductive effect on osteoblastic cells, due to some of their biological properties. This osteoinductive effect increases at combined application of these two types of molecules (5, 11, 16).

On the other hand, if there are glycosaminoglycans along with collagen and hydroxyapatite in the materials, such complex is structurally closer to natural bone matrix and, therefore, can have its functional characteristics to the fuller extent.

It is known that glycosaminoglycans influence on many connective tissue metabolism indices. They can reduce proteolytic enzymes strength, suppress these enzymes and oxygenous radicals synergic effect on intercellular matrix, block inflammation mediators synthesis due to antigenic determinant masking and chemotaxis cessation, prevent cell apoptosis induced by disturbing factors, as well as reduce lipid synthesis and as a result impede degradation processes. Besides, these compounds take direct part in formation of collagen fibers and intercellular matrix on the whole (8). At an early stage of connective tissue injury they act like initiators of temporal matrix formation and help to suspend rough scar formation, and subsequently provide its substitution by normal appropriate for the certain part connective tissue. Also it has been proved that chondroitin sulphates have a pronounced effect on bone mineralization (10).

In particular set of experiments we educed that when “Osteomatrix” material acts upon human cartilaginous cell culture, induction of their chondrogenic properties occurs. Under the influence of the material chondrocytes formed sandwich-like structures, in which, due to reproduction stimulation, steep increase of cell quantity was observed. In compacted layers of these cells there also was the highest activity of alkaline phosphatase, enzyme responsible for matrix mineralization during ossification.

Further it was found that after implantation of “Biomatrix”, “Allomatrix-implant” or “Osteomatrix” on rabbits, ectopic bone formation occurs with its subsequent colonization by bone marrow. The same materials also were successfully applied as substrates at stem stromal progenitor cells grafting 4.
Therefore, biotechnologically produced “Biomatrix” and “Osteomatrix” materials have unique properties.

They are able to specifically fix platelets and lead to blood clot formation with subsequent platelets activation and growth factors release, specifically fix glycosaminoglycans and stimulate connective tissue cells metabolism, inducing osteogenesis. It is combination of these unique properties, which causes substantial advance of the materials at bone defects restoration.

Besides, experimental and clinical results objectively prove that, basing on contemporary bone engineering foundations, OOO “Conectbiofarm” developed and introduced into native clinical practice bone collagen-, sulfated glycosaminoglycans- and hydroxyapatite-based biocomposite materials (9). Applying of these effective and safety biomaterials of new generation offers great opportunities at solving various problems of bone tissue repair in traumatology and orthopedics, as well as other areas of surgical practice.


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