DE102011109548A1 - Bionic composite materials, where the materials are constructed from resilient connective tissue fibers with genetic methodology and/or organic-technological methods and from biological coupling molecules such as laminin and fibronectin - Google Patents

Abstract

The bionic composite materials, is claimed, where the materials are: constructed, with genetic methodology and/or organic-technological methods, from resilient connective tissue fibers (fibrillin-microfibrils, elastin, oxytalan fibrils and analogous fibrils and fiber structures of a resilient system of an extracellular matrix of connective tissues) and biological coupling molecules such as laminin and fibronectin; and compensated and/or dissipated to conduct electrical loads along the fiber structures and the coupling molecules and/or over the fiber- or fiber structures of the materials. The bionic composite materials, is claimed, where the materials are: constructed, with genetic methodology and/or organic-technological methods, from resilient connective tissue fibers (fibrillin-microfibrils, elastin, oxytalan fibrils and analogous fibrils and fiber structures of a resilient system of an extracellular matrix of connective tissues) and biological coupling molecules such as laminin and fibronectin; and compensated and/or dissipated to conduct electrical loads along the fiber structures and the coupling molecules and/or over the fiber- or fiber structures of the bionic materials. The materials have a biotechnological exploitation of a biodigital bioelectric signal generation and signal transmission along the designated native supramolecular protein structures. The coupling molecules have semiconductive properties, and the bionic material is stored within a resilient fibrillar network by an electrical charge. The materials are obtained form resilient microfibril-fabrics, fibers, complex elastic fibers or other structures from the genetic material of vertebrates, resilient fibrils, fibrillin-rich microfibrils and elastic fibers of the extracellular matrix of body tissues of animal species of other animal classes such as animal species of arthropods, insects and drosophila with inclusion of resilin, fibrillin-rich microfibrils in nano-fibril level and/or polyps and jellyfish with the fibrillin rich microfibrils. The materials have a desired temperature of 37[deg] C and a smaller moisture content. The materials are obtained, with the genetic methodology, from cellular and tissue samples of battle-fresh warm blooded animals for slaughter of agriculture. The complex of resilient fiber structures is obtained from central elastin core and surrounds the resilient microfibrils, where the defined resilient and electrical characteristics are incorporated with the specific coupling molecules. The electrical loads are conducted and/or derived by the bionic material and are capacitively stored in a defined manner. The electric conductivity of the bionic material is larger than an ionic conductivity of the bionic material. Catalyst in an aqueous solution having characteristic properties is obtained by a humid or aqueous environment or an electrolyte solution, where an interstitial tissue is represented by a body tissue. The bionic composite materials are manufactured in connection with collagen or other polymer materials. The biopolymers are changed with technical and biotechnological methods with additional synthetic steps to optimize biophysical, biochemical and material-technical properties and to adapt other concrete applications. The materials are insertable as biogenous nanoelectronic signal lead structure in the conceptual of DNA-computer, and the structures of the resilient fibrillar fibers and microfibrils are used together with other intracellular signal line simulating native, biotechnologically manufactured protein structures with usable organic-electronic properties.

Description

1. Own starting point

The scientific research and biotechnological exploitation of bionic principles of nature has been particularly successful in the field of the extracellular matrix of the connective and supporting tissues of many animal species and of humans (20; 25).

With its macroscopic spongiosa structure (trajectories, lightweight construction), its collagen-fibril-apatite-matrix composition (fiber-composite materials) and its biological training, performance and structural adaptation (Wolff's law), bone provides the classic 'but at least the best-known' model 'for the development of new bionic concepts and technological solutions (20, 8, 17, 19).

At that time the applicant recognized the articular cartilage of large joints (eg bovine, ovine and porcine knee joints) as highly suitable for biophysical measurements and viable modeling of the structure and function of the cartilaginous extracellular matrix (1-4, 9) The bone is traversed by an arc-shaped architecture of collagen fibrils.

The biophysical and physicochemical behavior of cartilage tissue (40; 22; 21; 26; 36). It was and is a bit surprising that a biologically and biophysically essential aspect of cartilage matrix biology, concerning the special electrophysiological collagen fibril signaling function, was not seen until the mid-1980s, despite suggestive experimental data (17) and after the own publication of the new concept in designated journals (2; 1) was also not taken up so far and only occasionally quoted (29).

Unless the description of the invention relates to a derivation from the scientific findings of the experimental work with articular cartilage and derived deductions, the recognized and conceptually described conditions on the intact joint and arthrosis joint as well as the extracellular matrix under these circumstances will be described and discussed again here ,

Characteristic and characteristic of articular cartilage is its homogenous tissue architecture (for the biological target function of the articular cartilage, to minimize the structure-stressing absorption of kinetic energy in the joint level (6):
It is not the forces acting on a dynamically loaded joint or the kinetic energy flowing through them that are decisive; the kinetic energy absorbed in the joint level is stabilized in physiological limits for the joint biology (eg mechanical-electrical coupling), above which causes molecular and histological structural damage, deformation, contusion, rupture (6).

Accordingly, articular cartilage contains no nerves and no blood vessels, no supportive and "lining cells" only cartilage cells (chondrocytes) and extracellular matrix.

• – Knieknorpel der Maus: um 334.000 Chondrozyten/mm³ Knorpelgewebe;
• – Knieknorpel beim Rind: um 20.000 Chondrozyten/mm³,
• – Menschliches Kniegelenk: um 14.000 Chondrozyten/mm³ (26).

For reasons of oxygen and substrate supply, the number of chondrocytes per 1 mm ² cartilage surface in the knee joint of humans and the mouse is practically constant at about 25,000 to 27,000 (26). The thicker the articular cartilage layer of a joint, the more the chondrocyte density per mm ^{3 of} articular cartilage decreases:

• - knee cartilage of the mouse: by 334,000 chondrocytes / mm ³ cartilage tissue;
• - knee cartilage in cattle: by 20,000 chondrocytes / mm ³ ,
• - Human knee joint: around 14,000 chondrocytes / mm ³ (26).

This is a difficult situation for the attending physician (a cartilage cell in the patellar cartilage of the human knee joint is responsible for a very large matrix area).

The situation is very favorable for the matrix biophysicist and matrix physiologist:
Articular cartilage of the bovine or pig's knee contains 1 to 5% by volume of chondrocytes and thus about 95 to 99% by volume of a relatively homogeneously structured extracellular cartilage matrix (about 70% water, about 50% collagen, 25% proteoglycans (swelling molecules) in the dry matter ).

As with no other body tissue, macroscopic biophysical measurements on "battle fish" (undenatured) cartilage tissue, with sufficient knowledge of cartilage matrix architecture and correlation with biochemical, histomorphological, physicochemical, biomechanical, and bioelectrical data of the cartilage samples examined, lead to the derivation of well reproducible results Function and physiology of the cartilage matrix up to the molecular and biopolymer matrix structure possible (1-5, 9-12), can be scientifically proven to the problems of completely different, biotechnological, nanobiological and even nanoelectronic fields of research and work (5) ,

Especially in the last two decades, body tissues with abundant elastic fiber systems (made of elastic microfibrils and elastin) have been extensively studied in their extracellular matrix (24; 47; 54; 55), in particular arterial wall with its cyclic, pulse-synchronous biomechanic-elastic stress; scientific efforts, especially in the search for biological tissue replacement of the vascular wall of large arteries (56, 63).

Biotechnology dealt here with the medical problem of arterial replacement with elastin, and had a longer path to far-reaching mastery of the technical problems (71, 56, 63, 65, 66, 69, 70).

On the one hand, the well-established practical application in the field of arterial replacement materials has also stimulated parallel biotechnological tasks for the use of supramolecular nanofibrils in new materials, composite materials, nanotechnologically structured surfaces (65, 70, 72).

On the other hand, the basic medical research was promoted for the elucidation of the structure and function of the extracellular matrix of elastic tissues, here was also an extensive study of the elastic microfibrils, which in vivo enclose the elastic core of the elastic fibers, here essential biological regulations, such as Fibrillogenesis, mediate (48, 52, 53, 54-56, 76).

Often, when using nanotechnical materials in new materials, composites, and surface protection, it may not be so aware that it was once derived from bionic ideas and concepts from the extracellular matrix of body tissues that such modern, innovative nanotechnology has the same scale dimension with the native fibrillar systems of the extracellular matrix of bone, cartilage and tendon tissue as well as arterial wall:
Collagen fibrils type II of the cartilage matrix have about 50 nm 0 and a period length of 64 and 67 nm; Fibrillin-rich 'microfibrils' of the elastic fibers have about 10-12 nm ⌀ and a periodicity of about 56 nm (23, 26, 24, 48, 55).

A bionic view of biotechnology and nanotechnology on the results and innovative scientific concepts of medical and applied basic research can continue to be useful and profitable.

• – dass sich die biotechnologische Forschung für die medizinische Anwendung mit dem Gewebsersatz aus kollagenen und elastischen Fasersystemen; also vornehmlich mit den biomechanischen Eigenschaften beschäftigt (48; 56; 63; 66), nicht aber eigentlich mit speziell bioelektrischen Phänomenen, zumal der fibrillären biologischen Nanostrukturen, die im Schrifttum beschrieben wurden (17; 28; 29; 37; 1–5), und
• – dass in der Bio- und Nanotechnologie zwar bezüglich der DNA des Zellkerns nanoelektrische und nanoelektronische Fragestellungen innovativ bearbeitet werden (30; 38; 68), dass analoge bionische und biotechnologische Themen bezüglich der Strukturproteine und „Nanofibrilien” der extrazellularen Matrix von Knochen, Knorpel, Sehne, Haut, Lunge, Gefäßwand (kollagene und elastische Fasern) jedoch bislang hier weitgehend ausgespart blieben, zumindest eher nachrangig publiziert werden (65; 66; 48; 73).

From the point of view of a doctor interested in questions of applied connective tissue research, it seems remarkable that

• - that biotechnological research for medical use involves tissue replacement from collagenous and elastic fiber systems; (48; 56; 63; 66), but not with special bioelectric phenomena, especially the fibrillar biological nanostructures described in the literature (17; 28; 29; 37; 1-5), and
• - that in the field of biotechnology and nanotechnology, although nanoelectrical and nanoelectronic issues are dealt with innovatively with regard to nuclear DNA (30; 38; 68), analogous bionic and biotechnological issues concerning the structural proteins and "nanofibrils" of the extracellular matrix of bone, cartilage, Tendon, skin, lungs, vascular wall (collagenous and elastic fibers), however, have so far largely been left out here, at least to be published later (65, 66, 48, 73).

The applicant sees from the point of view of the hierarchical electrophysiological regulation concept for the extracellular matrix of the articular cartilage and the consistent in 1989 integrated biosensor and signaling concept of the native collagen fibrils (2; 9; 1) and from the now so many years of this special one Viewpoint of viewed, apparently biologically analogous in various aspects to be postulated electrophysiological phenomena in the physiology and pathophysiology of the extracellular matrix in particular the so-called elastic mesenchymal and connective tissue of the skin, the lung tissue, the arterial wall, etc.

Athenstaedt u. a. (29) described and experimentally measured the phenomenon of a pyroelectric and piezoelectric sensor structure in human epidermis in 1982 and also for measurements on epidermal structures of other species.

Athenstaedt (28) measured the pyroelectric behavior of dried fribrillar (nanobiological) collagen protein structures of nervous tissue as early as 1970. But only Regling and Rückmann (2-4) came from experiment and biological concept to the consequence that there would be in addition to the biosensor function of native fibrillar collagen (in the cartilage matrix) a nerve-analogous bioelectric signal transmission.

The not yet published, from researched data of the literature on the most different body tissues of humans and in the field of biology since 2000 step by step elaborated expansion and generalization of the biolectric biosensor and signaling concept to the matrix of other tissue and organ systems and - in justified biological concept - also on the other fibrillar matrix structures - the elastic fibers and elastic microfibrils - is the patent idea to be described here and description of the implementation and biotechnological as well as micro- and nanoelectronic use of this own activity on the medical subject.

Thus, this is an extension of the inaugurated electrophysiological biosensor and Signalleit concept of collagen fibrils of body tissues on a new physiological and pathophysiological concept of elastic fibers and elastic 10-12 nanometer thick microfibrils and derived from this development of new biotechnical nanotechnological fields of work, which outlined, presented and discussed in the present description.

Not all considerations, researched data and facts can be explained and explained here.

However, it seems important to note that many years of special attention have been devoted to the fundamental biophysical, bioelectrical, electromechanical, and bioelectronic properties of native biopolymer and protein structures, as well as relativistic physical data and models (28; 29; 37; 39; 31-35; 47 ; 2; 9; 5; 10-11, 13) is understood as the important basis and justification for the elaboration and generalization of the own collagen-biosensor and signal-guidance concept, which is to be presented here in breaks.

For the description to be presented here, this requires that the applicant - also with regard to the perhaps non-medical, biotechnologically or nanoelectronically specialized laser and partner - attempt to present and explain this derivation and justification of the scientific and technological statement in more detail, even for the purpose necessary acceptance of perhaps multiple redundancy - from different perspectives - and extension of the presentation for this goal.

In principle, in this particular biotechnological-electrical / electronic field, new bionic approaches and modeling based on biological model (14) may still be attractive and useful, since nature - from the point of view of the applicant - phylogenetically - has more than 3 billion years - evidently developed and optimized "nanobiological" solutions, which perhaps could not be achieved with comparable synthetic fiber structures and without the close reference to bionic models.

Although nanotechnology has also produced completely new material concepts (eg nano tubes), even for potentially nanoelectronic applications (74, 67). Their biological environmental compatibility provided, however, their technical coupling to biopolymers, z. As in a fictitious DNA computer (30), be technically problematic.

On the other hand, the structural proteins and biopolymeric fibrils of the extracellular matrix of nanoscale body tissues in their genetically determined structure are phylogenetically extremely conservative (ie biologically successful).

The fibrillins of the fibrillin-rich microfibrillin of the vertebrate and human elastic fibers are virtually unchanged from the fibrillin in the blueprint of jellyfish (24).

The collagens of different animal classes show a dependency of their shrinkage temperature on the body temperature of the respective animal species (23).

Elastin is first developed in vertebrates (vertebrates) with its highly developed circulatory system (23, 24). However, the arthropods (eg, insects) have a functionally analogous elastic structural protein Resilin, which allows them the elastic wing beat (23, 24, 75).

For isolated collagen type I fibroses (ie nanofibers of bone and tendon tissue), its piezoelectric activity and pyroelectric polarization have been confirmed in 2009 with modern single-fiber measurement (41), as already shown by the measurements of Fukada (37) on collagen preparation and by Athenstaedt (28) - between 1954 and 1971 - had already been shown experimentally and validly.

For elastic microfibrils, elastin and resilin corresponding basic bioelectric studies are not known here.

In the medical literature, the biological hypothesis of an electrophysiological function of the collagen fibrils of the nerve-less extracellular matrix of the connective and supporting tissues (1-4; 9) published by the applicant was, as stated, not discussed and perceived in detail, even the biophysical undoubted piezoelectricity of the collagen fibrils (37; 28; 41) in their biological significance for the structural and performance adaptation of bones and connective tissues and thus as a substantive aspect in the biological underlay of Wolff's law so far skeptical in the literature skeptical to restrained discussed (27).

On the other hand, physicians interested in holistic medicine have been searching for decades for a regulative 'interface' between the free nerve endings of the soft connective tissue and the Connective tissue cells have long and unsuccessfully searched for "small nerve fibers" in the extracellular matrix (44).

So it was probably a - before the own publications (1-4) - difficult anatomic-physiological task, z. For example, in the really histologically clear, voluminous extracellular matrix of articular cartilage, an anatomical electrical conductor can be found between the vegetative nerve fibers in the medullary space between the subchondral cancellous bone of the bone and the chondrocytes isolated in the articular cartilage (cartilaginous cells).

Since it was about a short distance of millimeter bioelectric signal conduction, a biophysicist or biotechnologist would search for an anatomical "ladder" structure of smaller cross section than the nerve fibers of the ischial nerve and with a small signal amplitude (perhaps the size of a piezo signal (see p 37, 28, 21, 27) .- In the histological field of vision only the collagen fibrils of the cartilaginous matrix, which are known to radiate from the subchondral bone into the articular cartilage (Benninghoff's model, 1925), contacted each chondrocyte membrane 1000 times (45). - but the collagen fibrils were already occupied with their undisputed biomechanical task.

Their own new idea was that here nature may pack not a thin elastic "tether" and an equally-thick, equally-electromechanically active "bioelectric signal conductor" (as the end of the nervous system) side by side, but a useful fibrillar pyroelectric supramolecular protein structure for both Functions (and as a biomechanical biosensor of the matrix and as a fixation structure for enzymes and as a receptor for tissue hormones and others m).

For a new conceptual understanding of the supramolecular fibrillin-rich (nano) microfibrils of the extracellular matrix of the elastic body tissue, the applicant faced the same heuristic challenge.

• – dass in der extrazellulären Knorpelmatrix eine bevorzugte elektrische Leitfähigkeit entlang den nativen Kollagenfibrillen besteht, so dass daraus für die nervlosen extrazellulären Matrix in vivo – neben ihrer tensilen, biomechanischen Funktion – eine nerv-analoge biologische Signalleitfunktion der Kollagenfibrillen in vivo gefolgert und konzipiert werden kann: (a) im Kontext der Matrixbiosensor-zu-Zell-Kommunikation, (b) der Zell-zu-Zelt-Kommunikation sowie (c) einer kollagenfibrillen-vermittelten Informationsübertragung zwischen freien Nervenendigungen und den Zellen des Knorpel-, Knochen- und Bindegewebes) (1–4, 9).

The applicant has - after the literature already described the concept of a Kollagenfibrillenassoziierten, piezo or pyroelectric biosensor (17; 29) - at the time its first time in the literature from its own, with H.-I. Rückmann carried out measurements on fresh-cut cartilage tissue (2-4, 9-12),

• That in the extracellular cartilage matrix there is a preferred electrical conductivity along the native collagen fibrils, so that in addition to their tensile, biomechanical function, a nerve-analogous biological signaling function of the collagen fibrils in vivo can be inferred and conceived in vivo for the nerve-less extracellular matrix: (a) in the context of matrix biosensor-to-cell communication, (b) cell-to-cell communication, and (c) collagen-fibril-mediated information transfer between free nerve terminals and the cartilaginous, bone, and connective tissue cells ( 1-4, 9).

• • Aus kalkulierten Literaturdaten wurde gefunden, dass die Kollagen-Einzelfibrillen der Knorpelmatrix (um 70% Wassergehalt) infolge des stark hygroskopischen Verhaltens der Aggrakane/Proteoglykane (PG) einen Wassergehalt von nur etwa 1% aufweisen (2), bei welchem Kollagen die höchsten piezo-elektrischen Konstanten aufweist (37).
• • Mit dem eigenen Kollagenfibrillen-Konzept hebt sich die konträre Diskussion über die biologische Relevanz piezoelektrischer (17, 28) und strömungselektrischer Phänomene (22, 21, 27) der extrazellulären Matrix im konzipierter hierarchischer elektrophysiologischer Matrixregulation auf (1–4; 9). Da die Ampitude von Piezopotentialen in Knorpel und Knochen etwa 10³ mal kleiner ist als die Amplitude von Strömungspotentialen bei der Belastung von physiologischfeuchtem Knorpel oder Knochen (21), resultierte die auf den ersten Blick schlüssige Folgerung, dass die Piezoelektrizität von Kollagen-fibrillen in vivo als ein nicht relevantes Artefakt anzusehen sei (21; 27). Sind die Piezosignale hingegen Teil eines bioelektrischen Signalsystems entlang den nerv-analogen Kollagenfibrillen der Matrix (1, 9), so ist dann ihre Amplitude von einigen Nanoampere und ihre Relaxation innerhalb 10^–9 bis 10^–7 sec. (21) eben die optimal geeignete Dimension eines bioelektronischen Signals (1–4; 9).
• • Die funktionell-biomechanische Leistungsabstimmung aller Gelenkknorpelareale eines intakten oder arthrotisch vorgeschädigten Kniegelenkes lässt sich, was gleichfalls im medizinischen Schrifttum noch nicht reflektiert wurde, aus strömungselektrisch definierten, für ein jeweiliges Gelenk charakteristischen Korrelationsgeraden beschreiben (1–4, 12, 9).
• • Mit einem neuen Synovia-Regelkonzept (7) führte das eigene hierarchische elektrophysiologische Knorpelmatrixkonzept (1; 9) zu einem neuen Verständnis der Pathogenese und Krankheitsdynamik der Arthrose (6; 7).

The own bioelectric collagen fibril biosensor and signal conduct hypothesis led in the examination by the Inauguratoren (1, 2) to a series in consistent consistent and scientifically relevant biological and medical consequences:

• Calculated literature data have shown that the collagen monofilaments of the cartilage matrix (by 70% water content) have a water content of only about 1% due to the highly hygroscopic behavior of the aggrakane / proteoglycans (PG) (2), in which collagen has the highest piezoelectricity electrical constant (37).
• • The contrarian discussion on the biological relevance of piezoelectric (17, 28) and flow-electrical phenomena (22, 21, 27) of the extracellular matrix in conceptualized hierarchical electrophysiological matrix regulation (see pp. 9) is canceled out with the own collagen fibril concept. Since the amplitude of piezopotentials in cartilage and bone is about 10 ³ times smaller than the amplitude of flow potentials in the loading of physiologically moist cartilage or bone (21), the conclusion that emerged at first glance is that the piezoelectricity of collagen fibrils in vivo was to be regarded as a non-relevant artifact (21; 27). If, on the other hand, the piezoelectric signals are part of a bioelectrical signal system along the nerve-analogous collagen fibrils of the matrix (1, 9), then their amplitude of a few nanoamperes and their relaxation within 10 ^-9 to 10 ^-7 sec. (21) is the optimal one Dimension of a bioelectronic signal (1-4, 9).
• • The functional-biomechanical performance of all joint cartilage areas of an intact or arthrotically damaged knee joint can be described, which has not yet been reflected in medical literature, from a fluidically defined correlation line characteristic of a particular joint (1-4, 12, 9).
• • With a new synovial control concept (7), the own hierarchical electrophysiological cartilage matrix concept (1; 9) led to a new understanding of the pathogenesis and disease dynamics of osteoarthritis (6; 7).

The biotechnological, bioelectronic dimension of the concept was already referred to at the beginning of the 90's: (5) and patent specification DE 43 14 688 A1 (File P 43 14 588.4, filing date: 29.4.93).

The invention now to be described by the applicant, the technological use of electrical and nanoelectric properties of biogenic supramolecular elastic fiber and fibril systems, elastin, fibrillin-rich microfibrils and kompexe elastic nano-fibers of these, concerning physiological quaternary structure, derives from the Previous experimental studies and biophysical measurements on native, fresh-sliced collagen-fibril-containing cartilage tissue and the resulting scientific analysis and further conclusions and nanotechnological statements.

Since both the electrophysiological cartilage matrix concept including the medical implications (1-4; 6-16; 25) (after the end of the university life phase of the applicant 02/1996) and the bioelectronic conclusions (5) of 1993 (at that stage of development nanoelectronic biotechnology) At that time there was little resonance in the literature (now available as review (1) and reprint 2010 (25; 7; 9)), in the following - as already announced and justified - some general remarks on the elastic fibril system, then the derivation, the results and the statement of their own electrophysiological Kollagenfibrillenkonzeptes again outlined in a brief overview and explained with illustration, to then describe content and message of the invention, namely the novel technological and bioelectronic use of said biogenic elastic nanofibrils and elastic fiber structures.

2. Elastic fiber systems of the extracellular matrix of body tissues

The definition, classification and naming of the different biopolymeric fibril and fiber systems of the extracellular matrix, even when limited to vertebrate body tissues (vertebrates), are still significantly divergent (23; 24; 49; 54-55; 61; 62 ) and needs for the description of the invention beforehand a comment.

In the histological-anatomical literature, 3 extra-cellular fiber groups are or have been distinguished for a long time: collagen fibers (from fibril-forming collagen type I, II or III), reticular fibers and elastic fibers. Ushiki (62) points out that reticular fibers are built up from collagen fibrils in order to be able to calculate the collagen fibers.

Ag ⁺ ion stainability characteristic of reticular fibers is due to a reaction of Ag ⁺ with small volume proteoglycans (PG) attached to the collagen fibrils of the reticular fibers; it is not an Ag ⁺ staining of the fibrils themselves (62).

Also, the collagen fibrils of the extracellular matrix of articular cartilage and vertebrate bone tissue are surrounded by small PGs per collagen period (42, discussed at 1, 2, 9).

However, in the bone matrix, the collagen fibrils are additionally occupied segmentally with apatite crystals; and in the cartilage matrix, the collagen fibrils are correspondingly surrounded by large, hygroscopically swollen PG and PG-hyaluronate complexes, so that in both cases the small PGs of the collagen fibrils are "masked" and not argyrophil stainable.

• (a) Kollagenfasern und Kollagenfibrillen verschiedener Fibrillentypen, welche eine typische Periodengliederung von 64 bis 67 nm aufweisen und pro Periodensegment u. a. von sterisch assoziierten Proteoglykanen (PG) umgeben sind (in der Knochenmatrix zusätzlich von segmentalen Apatitkristallen umgeben, in der Knorpelmatrix zusätzlich von voluminösen PG und PG-Hyaluronat-Komplexen) und
• (b) elastischen Fasern und elastische Mikrofibrillen, die aus elastischen Mikrofibrillen und Elastin bestehen und die in unterschiedlicher Quantität die extrazelluläre Matrix vermutlich aller Körpergewebe durchziehen, auch aus methodischen Gründen und bei fehlen-der Fragestellung noch nicht in allen vollständig beschrieben wurden.

Thus, two tensile fiber types of the extracellular matrix of mesenchymal and connective tissues are assumed:

• (a) Collagen fibers and collagen fibrils of different types of fibrils, which have a typical periodic breakdown of 64 to 67 nm and are surrounded per periodic segment, inter alia sterically associated proteoglycans (PG) (in the bone matrix additionally surrounded by segmental apatite crystals, in the cartilage matrix additionally of voluminous PG and PG-hyaluronate complexes) and
• (b) elastic fibers and elastic microfibrils, which consist of elastic microfibrils and elastin and which, in varying quantities, pass through the extracellular matrix, presumably all of the body tissues, have not been fully described in all, also for methodological reasons and in the absence of a problem.

Elastic fibers are distinguished into elastin fibers, elaunin fibers and oxytalan fibers (24, 55; 57; 58; 60; 62). All three contain elastic microfibrils 10-12 nanometers in diameter.

The relative proportion of elastin is large in elastin fibers, smaller in elaunic fibers. Oxytalane fibers consist only of bundles of elastic microfibrils without elastin core (24, 55, 62, 63).

A larger number of known structural proteins mediate the arrangement of fibrillin proteins to the microfibril-associated glycoproteins MAGP-1 and -2 et al., Mediating the steric association between elastin core and surrounding microfibrils of the elastic fibers (Emilin-1 and -2 et al.) Or mediate contacts to other components of the extracellular matrix, to basement membranes, to the cell membrane (55, 63, 24) or even to inorganic surfaces.

Elastic microfibrils belong to the blueprint of the connective tissue matrix of all body tissues (23, 24). In fabrics with cyclic-elastic stress, there are numerous elastin fibers and elaunic fibers made of microfibrils and elastin.

In the meantime, modern histomorphological studies have reliably established that elastic fibers and microfibrils are not found in certain elastically stressed body tissues (arterial wall, lung, skin; 59; 63; tendon, tendon sheath, nerve sheath; 49; 60) 61), instructive example is the articular cartilage (51; 57; 64). The elastic fibrous system is more pronounced in the matrix of the so-called elastic cartilaginous tissue (eg auricle, nasal septum), contains a network of elastic fibers, but is also present in the cartilage of the cartilage (57, 64).

With morphological reports that the detection of elastic fiber structures and microfibrils is difficult even with conventional electron microscopy, requiring technical artifices (61) or specialized methodology (50; 57; 64), a completion of the image is expected here, for example via the topographic distribution of fibrillin-rich microfibrils and oxatalan fibers.

It has been demonstrated that elastic microfibrils attach to the cell membrane via receptor or attachment structures (43; 63); However, as in the case of collagen fibrils, biogeochemical regulation has not been discussed so far, but rather the function of 'cell attachment' and biochemical receptor model-mediated biological regulation of microfibrils (43, 53).

Functionally interesting in terms of elastic properties and energy recovery, but also with respect to a potential nanotechnological use of 10-12 nanometers thick elastic microfibrils is their specific segmental folding of the microfibrillar structure in the non-extended state (48; 54), which in the histological picture is a segmental pearlescent. and functionally permit elastic elongation of the microfibrils (54, 48), possibly even plastic elongation in the area of the folding structure without fibril rupture, with the possibility of biochemical repair (similar to the plastic period elongation of collagen fibrils, Bonart, 1974, ref in 2).

Although elastin is hygroscopic (completely dry of glassy consistency), the numerous apolar amino acids - desmosine and isodesmosine - limit the hygroscopic behavior, and the consistency of elastin is apparently correspondingly less dependent on the PG population of the matrix.

In an interdisciplinary analogy, the biological hypothesis of a bioelectrical signal line along the elastic fibrillin-rich microfibrils seemed plausible in the applicant's perspective; In this case, it seems obvious, if not yet tested, to look for a new, additional, elastic matrix biosensor in the segmental elastic folding structure of the pearlescent microfibrils (54, 48). (Experimental data will only be compiled if such a hypothesis is formulated in advance).

3. Electrophysiological-bioelectronic collagen fibril concept

Because it makes sense for the description and the explanation of the claim for invention to understand, the former own scientific approach to the described hierarchical electrophysiological matrix concept and the bioelectrical biosensor and signal-guiding function of the native collagen fibrils will be explained again (1-4, 9, 6) ; 7) and with some measurement data in the picture.

The applicant dealt from 1981 as a physician and specialist in orthopedics, (Department of Orthopedics Charité), from 1982 in a collaboration with the solid state physicist H.-I. Rückmann (Physics Section of the Humboldt University) u. a. also with a follow-up of some bioelectrical experiments published by R. O. Becker (New York) in 1964 (17).

As early as 1964 Robert O. Becker (17) had formulated the idea of an elementary biosensor of the bone matrix consisting of a collagen period and an attached apatite crystal ( ), but at that time did not recognize the possibility of directional signal propagation of the piezoelectric or rectified bioelectrical signal generated in a collagen-apatite biosensor.

Becker knew that collagen can react piezoelectrically (Fukada and Yasuda, 1957; 37), so that a biphasic piezoelectric signal can be generated from the stretching and relaxation of the helical structures of a collagen period.

This led RO Becker (17, 19) to the conclusion that in the collagen fibrils under physiological strain so obviously a significant information of the functional stress of the respective micro-region of the bone is generated, but on the other hand, such biphasic (+/-) - Piezosignale not directly can lead to an osteocyte (bone cells) stimulating environment change of the claimed bone matrix.

(It should be explained that numerous data show that it can generally be assumed that in a defined range of values an electronegative / mildly basic change in the environment stimulates cell metabolism, an electropositive / slightly acidic change in the environment will have cell metabolism in the sense of a positive feedback compared to the functional stress can influence the bone structure, see also 7).

RO Becker (1964; 17) had the standard work of orthopedic functional adaptation of the bone in mind (20; 8) and looked for an electrophysiological underlay of Wolff's law for a so-called second messenger, by means of which the primary biphasic piezotentials of the claimed collagen Periods transformed into an electronegative environment change of the claimed bone matrix.

This was done with the model of RO Becker (17) inaugurated model of a diode-like pn-junction between collagen period (n-material) and surrounding apatite crystal (p-material) as 'second messenger', so that the biphasic piezo potentials generated during bone stress at the collagen-apatite junctions are converted into monophasic electronegative charge input.

Becker (17) estimated that approximately 10 ⁹ elemental collagen-apatite biosensors are located in the matrix environment of each bone cell, whose rectified biosensor signals can be superimposed to an electronegative change in the environment and thus to a biologically significant signal of functional loading. According to the current state of knowledge, he found an attractive hypothesis for an electrophysiological underlay (17) of Wolff's law (the biomechanical functional adaptation of the bone structure) (20).

RO Becker et al. (17) conceived a technically simple, yet ingenious experiment of recording a voltage-current characteristic of fresh, cuboid bone samples by selecting the electrode position of an applied galvanic μA exposure of the bone sample so that the current flow through the postulated pn (positive-negative) collagen-apatite transitions of the bone matrix occurred ( ).

For this purpose, a cortical bone sample of a long tubular bone (thus dominating longitudinally parallel collagen fibril architecture) and an electrode position on orthogonally adjacent edge surfaces of the bone sample were selected (referred to as collagen interface and flank electrode) (see ).

Indeed, the macroscopic electrical measurement on fresh bone specimens resulted in the expected diode-like UI characteristic, and it appeared to confirm that an electronegative milieu shift in the bone matrix generated from piezoelectricity of the bone provided the sought-after biological signal for structure and training adaptation of the bone.

In Becker's measurement (9; ), only the change in the current direction of the galvanic exposure leads to an approximately 5 to 30-fold change in the electrical conductivity of the fresh bone sample (in non-linear function of voltage U and current I, as in a technical diode).

However, in the sixties there have been fierce physical objections (46) to Becker's solid-state concept of bioelectrical regulation of bone structure (1964), since bones fresh from the bone have a water content of 6%.

However, it was only with the first published by Alice Maroudas 1968 (40; 22) for the first time ion exchange model of the cartilage matrix, which with the later inclusion of dynamic tests on cartilage and bone and computer model calculations, namely at MIT (Grodzinsky, 21) The now undisputed flow model concept, which is well documented in models and data, led to (21; 27; 12; 2; 9; 7).

The piezo potentials of the collagen fibrils are undisputed in amplitude 10 ³ times smaller than the generated during bone stress flow electricity, and the piezo signals relax within only 10 ^-9 to 10 ^-7 sec. (21, 27).

Thus, in the literature, R. O. Becker's postulate of an electronegative change in the environment of the extracellular matrix, which was generated from piezoactivity of the collagen, was refuted and biologically insignificant (27), as was not published by Becker himself.

Regling and Rückmann built from 1982 both a modified flow kinetics Measuring apparatus (modified according to AJ Grodzinsky; ) as well as the technically simple apparatus for recording a voltage-current characteristic of fresh bone samples (modified according to RO Becker; and ) on.

Already substantiated by its own scientific research on bioelectrical regulation mechanisms in the extracellular matrix of cartilaginous tissue and its pathophysiological significance for pathogenesis and disease dynamics of arthrosis (6), RO Becker's measurement approach to slaughtered cortical bone samples with longitudinally parallel collagen fibril orientation (17; ) transferred to an analogue own measurement approach on freshly slaughtered pig bone cartilage samples with longitudinally parallel collagen fibril orientation (2; ).

At the freshly cut rib cartilage at about 60-70% water content, the sole change of the galvanic current direction resulted in a diode-like UI measurement curve analogous to Becker's measurement ( ).

In a strictly formal procedure, Becker's measuring principle was subsequently transferred to shaft-fresh cylindrical cartilage samples from the pig's knee joint ( ).

In articular cartilage, the collagen fibrils are not predominantly longitudinally parallel, as in the corticalis of long bones or as in the cortical region of cartilaginous rib segments. In the articular cartilage, the collagen fibrils (logically derivable also from the bone sections of Julius Wolff) form the so-called Benninghoff arcades, running arcuately with insertion of both ends of the fibril arc in the subchondral bone.

So if one wants to transfer Becker's measuring principle to articular cartilage cylinders, the so-called 'cut surface electrode' at the base of the cartilage disc, the so-called 'flank electrode', now takes place on a surface of the cortical cartilage of cortices Articular cartilage cylinder positioned ( ).

With this measurement arrangement, which was based purely on the theoretical model, a diode-like UI measurement curve was again obtained for articular cartilage (for the first time in the literature) (1-4, 9; ).

These facts are again reported here in this detailed detail, because a quick, rather volatile assignment of the subsequently derived own scientific statement to the fundamentally rejected yes in the literature at that time Becker's piezo and Semikonduktionskonzept not understand the request to be described here If necessary, the lack of reaction of the literature to the publications of 1989 and 2000 (2; 1; 25) contributed to this.

The scientifically decisive idea in the analysis of these own measurement results of diode-like voltage-current curves on fresh, physiologically moist rib and articular cartilage samples was that Becker's measurement already contained information on wet bone samples, which RO Becker did not at that time recognized:
According to physical rules, in Becker's model, the 10 ⁿ billion semiconduc- tive collagen-apatite transitions of the examined bone sample can also be modeled as a summed collagen-apatite diode in the middle of the sample. Then, however, a diode-like measurement curve of the physiologically moist tissue sample can only be obtained via the externally applied Ag / AgCl electrodes if the electrical conductivity along the collagen fibrils is considerably greater than the electrical conductivity through the aqueous and apatite matrix phase ,

However, if a high electrical conductivity along the native collagen fibrils in the examined sample is measured in comparison with the electrical conductivity of the remaining extracellular matrix, then such a phenomenon must also be inferred for the conditions in vivo.

If, then, the collagen fibrils of the cartilage matrix contact chondronectin on the cell membranes and fibrillar structures of the cytoskeleton extend from the attachment structures to the cell nucleus, as is seen in the literature (Kleinman et al., 1979, Akiyama et al., 1981, ref A complete reinterpretation of the classical Becker's measurements of cortical bone and their transfer to the first such examination of rib and articular cartilage was made:
At that time, the newly developed electrophysiological biosensor and signal line concept of collagen fibrils was designed, describing the continuation of the nervous system via nerve-analogous collagen fibrils to the cells of cartilage, bone and other connective tissue (2, 9, 1).

No longer an "analogous bioelectronic" signal from the superposition of billions of semi-conductively rectified charge inputs into a diffuse electronegative environment change in the vicinity of a bone cell (17) was recognized as the significant electrical signal for a biological underlay of Wolff's law.

Rather, a biological hypothesis has now been scientifically formulated that every single, in a claimed, 64 nanometer long Collagen period generated and semi-conductively rectified single signal is transmitted as a "digital bioelectronic" signal to the assigned for this matrix area bone or cartilage cell via collagen fibril.

• – über die Kollagenfibrillen in Knorpel- und Knochengewebe und weiteren Körpergewebe mit Kollagenfibrillen, also über ca. „ein Drittel des Körperproteins”,
• – über die konzeptionelle „Verlängerung des Nervensystems” (einer linear gerichteten Informationsübertragung) im menschlichen und tierischen Organismus von den sog. freien Nervenendigungen des Gefäß-Bindegewebes bis zu jeder Bindegewebszelle;
• – über eine konsequent „digital-bioelektronische Organisation und Signalleitung” in der extrazellulären Bindegewebsmatrix als Basis von deren Morphologie und funktioneller Leistungsanpassung mit letztlich Auswirkungen auch auf das medizinisches Verständnis von Krankheit, Alter und Trainingsanpassung;
• – über mögliche „biotechnologisch-nanotechnologische und ggf. auch nano-elektronische Folgerungen” der wissenschaftlichen Folgerung aus der Neuinterpretation der dargelegten makroskopischen bioelektrischen Messung und aus dann deren über diverse Jahre fortgeführt unternommener Prüfung auf Nutzen und Schlüssigkeit für ein neues pathophysiologisches Bindegewebsverständnis aus biophysikalischer wie aus medizinisch-biologischer Sicht.

At the time, Regling and Rückmann (3; 4; 2; 9; 1) assumed that they were offering a new biological hypothesis supported by numerous own, experimentally collected and interdisciplinary researched data

• Via the collagen fibrils in cartilage and bone tissue and other body tissue with collagen fibrils, ie over approximately "one third of the body protein",
• - on the conceptual "extension of the nervous system" (a linear directional transfer of information) in the human and animal organism of the so-called free nerve endings of the connective tissue connective tissue to each connective tissue cell;
• - through a consistent "digital-bioelectronic organization and signal conduction" in the extracellular connective tissue matrix as the basis of their morphology and functional performance adjustment with ultimate impact also on the medical understanding of disease, age and exercise adaptation;
• - on possible "biotechnological-nanotechnological and possibly also nano-electronic conclusions" of the scientific conclusion from the reinterpretation of the presented macroscopic bioelectric measurement and then their continued over several years undertaken check for utility and conclusiveness for a new pathophysiological connective tissue understanding from biophysical as well medical-biological point of view.

• (a) Seinerzeit konnten manche Nachuntersucher die Becker'schen U-I-Messungen nicht reproduzieren, indem sie über mindestens 24 Stunden alte Knochenproben untersuchten.
• (b) Lange Zeit wurde aus elektronenmikroskopischen Studien der Zellmembran-Kontakt von Kollagenfibrillen als selten oder nicht vorhanden vermutet, indem solche Kontaktareale an den extrem dünnen Gewebsschnitten für konventionelle Elektronenmikroskopie nur mit geringer Wahrscheinlichkeit zur Abbildung kamen. Poole und Flint (1986) untersuchten daraufhin Chondrozyten-Quetschpräparate elektronenoptisch. Jetzt kamen größere Zellmembranareale zur Darstellung, und die Zahl der Kollagenfibrillen-Attachmentpunkte konnte in der Größenordnung von 10³ pro Knorpelzelle abgeschätzt werden (Neuronen des Gehirns werden auf ihrer Zellembran bekanntlich von ca. 10³ Neuriten anderer Nervenzellen kontaktiert) (ref. bei 6; 1).
• (c) Einer ursprünglich von A. Szent-Györgyi (1941) konzipierten festkörperphysikalischen Konzept in der Biochemie stellten sich über Jahrzehnte Widerstände entgegen, weil die damalige experimentelle Methodik 1941 nicht hinreichend artefaktfrei war. Cope und Straub (35) räumten in einer aufwändigen biochemischen Studie zur Aktivierungsenergie der Cytochromeoxidase diese Vorbehalte gegen die im Grundsatz schlüssige biologische Hypothese von großer konzeptioneller Tragweit von Szent-Györgyi aus.

At this point, only once again, even for the non-medical reader, is illustrated by some examples of what actually simple methodological circumstances can sometimes influence or prevent the understanding and acceptance of experimental findings referenced here, so why such a detailed presentation of those considered relevant Issues on the topic took place:

• (a) At the time, some followers could not reproduce the Becker UI measurements by examining bone samples that were at least 24 hours old.
• (b) For a long time, electron microscopy studies suggested that cell membrane contact of collagen fibrils was rare or absent, with such contact areas being extremely unlikely to be imaged on the extremely thin tissue sections for conventional electron microscopy. Poole and Flint (1986) then examined chondrocyte squeeze preparations electron-optically. Larger cell membrane areas were now displayed and the number of collagen fibril attachment points could be estimated in the order of 10 ³ per cartilage cell (neurons of the brain are known to be contacted on their cell membrane by about 10 ³ neurites of other nerve cells) (ref. 1).
• (c) A solid-state physical concept originally conceived by A. Szent-Györgyi (1941) in biochemistry resisted for decades because the experimental methodology of 1941 was not sufficiently free of artifacts. Cope and Straub (35), in an elaborate biochemical study on the activation energy of cytochrome oxidase, dismissed these reservations against the basically conclusive biological hypothesis of great conceptual bearing on Szent-Györgyi.

4. Description of the innovation for the biotechnological use of electrical, mechanical-electrical, micro- and nanoelectronic properties of elastin. elastic microfibrils and elastic fibers as well as Resilin

The invention associated with the application does not relate to the simple presentation of a technology-related experiment as the basis of a proposed invention protection.

It also does not relate to the simple transfer of extensive experimental, and in particular also bioelectric, measurements on fresh tissue samples containing collagen fibrils in a known tissue architecture (with reference to which an application for protection of invention was filed in 1993) .) referred to biogenic supramolecular materials, in particular elastin, fibrillin-rich microfibrils, Resilin and biogenic elastic fibers, which are produced from the genetic information of each eligible animal species biotechnologically.

It is assumed that with the facts described here and below the conception, production and use of biogenic supramolecular structures, as mentioned above, is practically biotechnologically possible or can be achieved in the future according to previously used and patented concepts and procedures hitherto not technologically seen and not addressed, for which also the prerequisites necessary for the technical use of electrical and micro- or nanoelectronic properties of biogenic biopolymers or supramolecular glycoprotein structures from the perspective of the applicant so far not in the here too descriptive way were technologically based.

4.1. Biophysical and relativistic prerequisites

For the biological hypothesis of a biosensor and signaling function of native collagen fibrils (1-4, 9) published at the time, it was initially not necessary to describe the electrophysiological phenomenon of the bioelectric signal conduction of nanoampere pulses along the collagen fibrils in the physical mechanism. Even the detailed mechanisms of biological nerve conduction are not known to be conclusive.

If one wants to use the electrically conductive or electrically signal-conducting structure biotechnologically outside of the natural organism and its tissue structure, the most useful and necessary models for avoiding or at least narrowing down cost-intensive search research are valid and concrete modeling.

Fukada (37) and Athenstaedt (28, 29) have made qualitative and quantitative statements on the piezoelectricity and pyroelectricity of biopolymers and protein structures, which in principle can also be applied to elastic fiber systems.

Cope (31-35) has established solid-state biochemistry as a valid scientific concept in his early work. Not only the idea, but rather a scientific construct of relativistic super-superconducting electrical phenomena in biological structures and biopolymers has been consistently promoted "Room temperature" calculated and measured. By "room temperature" understood F. W. Cope, who, so far known never dealt with collagen or elastin, and the "body temperature" of animal species.

There is a close correlation between the body temperature of animal species and their species-specific collagen (23). The native quaternary structure of structural proteins is dependent on body temperature and other physiological parameters. In an abstract manner, the association-induction hypothesis of Ling et al. a. (39) the dependence of the ordered, native, vital state of the biopolymers and the biological environment on an energetic state realized here.

Regling and Rückmann (9; 10; 1) have concluded that for the native collagen fibrils in addition to the energetic input from piezoelectricity or pyroelectricity, a constant energetic supply (of all native biopolymers) from the energy metabolism of the cells and this in a characteristic high-frequency electrical alternating voltage lying on the fiber network, as also discussed elsewhere for the transmembrane potential of the cells and measured (ref. at 1) is expressed.

It was assumed that the biological signal transmission along the collagen fibrils is a resonance phenomenon of the phylogenetically qualified biological structure and that the estimation of a realistic frequency range of superconducting-analogue signal conduction in biopolymers or postulated so-called Josephsonjunctions in the biological material (34 ) of a cyclotron resonance model (1) was developed according to an idea by H.-I. Rückmann a Schawlow and Devlin (47) experimental setup for the detection of a superconducting jump function on aluminum at very low temperatures, used for a pilot experiment of a resonant circle measurement on fresh pork rib cartilage at 37 ° C (9; 1; 10; 11).

A result graph of such a cartilage tissue oscillation circuit measurement is shown in FIG attached (9; 1).

It is assumed by the applicant that piezo or pyroelectric charge separations can also be induced on dried and thus denatured biopolymers and structural proteins and can thus be measured (28). It is assumed that such concepts have also already been considered or undertaken in nanotechnology.

However, the real conceptual advantage and the innovation to be described is the biotechnological, nanotechnological production and use of supramolecular biopolymer structures, which are capable of a relativistic superconducting switching as electronic code.

It is assumed that a resonant circuit measuring arrangement is modified according to the principle of those according to Schawlow and Devlin (47) ( ) is basically suitable for testing to what extent considered materials with contained elastic microfibrils, elastin or other biogenic Beapolymermaterialien have such a superconducting analog switching in micro regions of the polymer and are suitable for the micro- or nanoelectronic task or after performed technological processing steps still are suitable.

That biopolymers in principle can show superconductivity has recently been reported for DNA-lipid film at very low temperatures (38). To what extent with adequate measuring technology and However, it is not yet possible to detect and maintain sufficient conservation of the physiological quaternary structure and the environmental condition of Josephson junctions of the biopolymer.

4.2. applications

(A)

Nanoelectronics by means of biopolymers is primarily associated with so-called DNA computers, as designed by R. Feynman in 1959 as an idea and tackled by M. Adleman in 1994 in a laboratory concept (30). The conceptual advantage of a fictitious DNA computer is not seen in the aspect of further miniaturization of computers or the increase in signal speed due to 'superconductivity'.

Rather, the expectation here to develop a DNA computer with numerous parallel processors, so a completely new computer concept with the ability to tackle certain problems then for the first time or at least elegantly and efficiently with a computer (30).

As far as information became available, the DNA computer is initially unrealistic in its practical realization, especially because technological access to DNA "computing power" is not yet accessible.

Such access would, in principle, be mediated via the nanoelectronic coupling of a biogenic signal conductor (or via another coupling substrate for the transmission of information).

Since the scientific and technological accessibility of biopolymer signal guiding structures of the cell nucleus as well as of the cytoplasm and the cytoskeleton may be far more complicated than the genetic engineering, preparation and processing of elastic microfibrils and elastic nano-fibers of the extracellular matrix, the latter may be considered a new conceptual and methodological approach Approach, steering the nanoelectronic focus and attention to new biogenic candidates to be eminently interesting.

(B)

It is believed, based on scientific analysis, that fibrillin-rich elastic microfibrils, despite their supramolecular structure, but which are already known and manageable in many details, including genetic data and genetic material, represent the simplest or one of the relatively simplest suitable biopolymer structures, biotechnologically for the use of an electrically-mediated signal transmission, if necessary, according to the mechanism of frequency-modulated signal line via superconducting analog microregions (Josephson junctions) practically realize.

The implementation of the concept requires not only the genetic engineering of all molecular components and the control of their self-aggregation or appropriate biotechnological processes; it also requires the preservation of the microfibrils in a physiological quaternary structure (temperature, humidity, ionic strength, eg Ca ²⁺ ) and the coupling to z. As well as inorganic metal conductors.

Here, the genetic component appears manageable in the prior art.

The intimate coupling of biopolymers to inorganic and metallic surfaces is now in medicine z. B. from the solid accumulation of collagen-containing bone tissue to joint endoprostheses well known, especially in titanium coating appears by means of the numerous coupling molecules of microfibrils to matrix components u. a. (55) not unsolvable. The coupling of collagen and fibrillin-containing microfibrils z. B. to glass is known.

With regard to the conceptual need to preserve or simulate physiological environments for the preservation of the quaternary structure of the elastic microfibrils as a signal conducting structure, it appears to be an advantage that these fibrillin-rich elastic microfibrils consist of 3 archaic conservative fibrillins and a number of species-specific MAGP's (microfibril-associated glycoproteins et al.), so that it can be concluded that among the body tissues of the animal species from the jellyfish to the vertebrates (23; 55; 63) suitable "genetic templates" can be sought for which the biotechnological production or simulation of a milieu condition to maintain the quaternary structure of the elastic, 10-12 nanometer-sized microfibrils including their bioelectronic 'material properties'.

According to this provision, biotechnologically produced elastic microfibrils are suitable for nanoelectronic tasks in which a biogenic Signalleit material is to be used.

This can - given mastery of the technological prerequisites - also be given if the high elasticity and extensibility of microfibrils, so very low brittleness of the signal-conducting nano-material with high tear resistance are relevant for a mission task, so in computers, the vibration load and other mechanical stresses are exposed, z. B. in aerospace.

In addition to the task as a nanoelectronic signal conducting structure, elastic fibrillin-rich microstructures, as described above, also come into consideration as an interface material for the compensation of electric potential gradients, in nanoelectronics, but also in other biotechnological applications.

The technical innovation consists in the fact that said elastic fiber structures are to be used for the utilization of their electrical or bioelectronic conductivity according to a still hypothetical, according to FW Cope relativistic conductivity model of the described supramolecular protein structures, with postulated Josephson junctions in the sense superconducting analogous microregions of the native protein.

It follows from this concept that non-synthetically arbitrarily changed nanofibrils can be used in the sense of the description, but rather protein structures with preserved quaternary structure. This represents a new technological challenge, but it may also open the door to a new branch of biotechnological nanoelectronics.

It is necessary for the realization of an electrically or electronically conductive nanostructure that the genetic set of a selected animal species be used for the genetically produced protein components of the elastic fibers or elastic microfibrils to be produced, and then only for the generation of the supramolecular elastic fiber or fibril Such biotechnological methods are used which preserve the quaternary structure of the protein structure.

Suitable alternating field or magnetic field exposure can simulate the natural environment condition of the structural proteins, if necessary, proportionally.

The elastic fibers / microfibrils can be used in micro- and nanoelectronics with biogenic structures and can be used as an interface material in the nanometer dimension for the compensation of electrical potential gradients, eg. On surfaces or in fiber composite materials

(C)

As discussed in Section 2, when elastin is first formed in vertebrates, elastin always occurs in conjunction with the associated fibrillin-rich microfibrils that contact the cell membrane and cell, and apparently through the integration into the bioelectronic fibrillar signaling system extracellular matrix also determine the sizing of elastic fiber types as elaunic fibers or elastin fibers.

The Applicant believes that biological analysis suggests that elastin may be incorporated into the extracellular matrix biological signaling system only in association with structurally associated, phylogenetically conservative, fibrillin-rich microfibrils.

For the resilience of insects, which is already being worked on from its mechanical elastic properties with regard to biotechnological questions (75), it is likewise assumed that integration into a bioelectric fibrillar signal system of the extracellular matrix takes place via the fibrillin-rich microfibrils.

However, it results from our own biological analysis that elastin and Resilin in the extracellular matrix may be involved in a biological function, as already described above for the elastic microfibrils (in lower animal species), namely for the compensation of electrical potential gradients within the tissue structure , especially the often voluminous extracellular matrix.

As early as the 1960s, R. O. Becker (18) pointed out that measurements using the Hall effect demonstrated that the nerve action, such as the sciatic nerve, is not just an information flow, but also an electrical charge transport. This raises the question of balancing the potential gap in a realistic short time, which apparently can not be expected from the aqueous matrix phase.

As early as 1970, Athenstaedt (28) described - without a biological evaluation - that the permanent longitudinal electrical polarization of the pyroelectric structural proteins of nerves and surrounding collagenous sheath of the nerve sheath was always measured in the opposite direction to the dried preparation. This seems well compatible with electrical charge balancing of the nerve action via the collagenous tissue.

As far as the biomechanical action of the arterial wall with the pulse curve is considered, even without an experiment it is evident that the collagen and elastic fiber system with elastin is here in rapid pulse sequence of the heart action beside the mechanical phenomena of stretching and relaxation as well as elastic "energy recovery" so far evident Little considered to produce electrical charge separations in the fiber systems, which require a rapid electrical charge compensation, by Maxwell's ionic currents hardly reachable.

In this context, the z. B. the extracellular matrix of articular cartilage rather sparse elastic microfibrils and elastic fibers (64; 57) consistent with a previously not discussed in the literature electrical equipotential bonding function in electronic time track.

It is concluded from this:
Since elastin is a biophysically very inert, hydrophobic biopolymer, which can in principle be produced by electrospinning (65), it appears as a technologically perhaps the most controllable biogenic biopolymer in nanotechnological dimension, which is responsible for the task of electrical equipotential bonding on surfaces or may be suitable as a component in a biotechnological composite material, if it is technically possible to produce the elastin structure by preserving or simulating physicochemical and energetic environmental parameters in a physiological quaternary structure.

For the elastic resilin of the insects, which has already been described in detail in the literature (75), but has not been systematically investigated with regard to its bioelectrical material properties, an analogous biotechnological use has to be described, as described above for elastin in a native configuration executed.

5. Summary

For the first time, the applicant described in the literature a nerve-like bioelectric signaling function of the collagen fibrils in the nerve cell-free extracellular matrix of cartilaginous tissue.

R. O. Becker u. a. postulated in 1964 a bioelectric biosensor function collagen / apatite of the extracellular matrix of bone. They postulated a diffuse electronegativity of contaminated areas of the bone matrix, evolving from an overlay of semiconduuctively rectified piezosignals, as a biologically significant signal for a bioelectric underlay of Wolff's law.

His own experimental work and critical analysis in 1989 corrected this concept by inaugurating the interdisciplinary biological hypothesis of a bioelectric signal-guiding function of the collagen fibrils in the nerve-less extracellular matrix of cartilage, bone and other connective tissues of the human and animal organism, so that the electrical biosensor signal of each single collagen period via signal-conducting collagen fibril is directed to the associated cartilage or bone cell for the tissue area. From the 'analogue' bioelectric matrix concept of RO Becker only a 'bio-digital' bioelectric matrix concept with hierarchical electrophysiological regulation levels, in the aqueous matrix phase (electrical flow kinetics etc.) and in the level of signal-conducting collagen fibrils and other structural proteins (solid-state-like effects and biodigital signal processing).

A recent unpublished physiological and pathophysiological generalization and transmission of the biosensor and signaling concept of collagen fibrils has led to a new nanobiological, bioelectronic view of selected supramolecular fibrous protein structures in human and vertebrate body tissues, as well as in an appropriate phylogenetic range of animal species of interest.

The insights and findings gained from this justify a novel biotechnological approach to identifying, primarily fibrillar, native protein structures in terms of their biotechnological production and practical use, primarily exploiting their mechanical-electrical and microelectronic and nanoelectronic properties, which is embodied and discussed in the description of the invention become.

The novel materials to be described or structures conceived for conceptually new application possibilities can also be used as interface material in the nanometer dimension for the compensation of electrical potential gradients, eg. On surfaces or in special fiber composite materials.

Attachment Quoted non-patent literature

• Regling, G .: Conception of a bioelectromagnetic signal system via collagen fibril network; biochemical conclusions and underlying coherent mechanism , I. Solid state effects and hierarchical bioelectrical regulation , II. Electrical aspects, acid and neutral proteases, and the phenomenon of coherence. Electro- and Magnetobiology, 19 (2000), 149-175 ,
• Regling, G., Rückmann, H.-I .: The native collagen fibril - biosensor and signal conductor of the matrix of connective tissues , A new concept for a biological understanding of the regulation of connective tissues. Bioelectrochemistry and Bioenergetics (Elsevier, Lausanne), 22 (1989), 241-254 ,
• Regling, G., Rückmann, H.-I., Buntrock, P .: The supramolecular organization of the cartilage matrix - A model for bioelectrical information transfer between biopolymers in vivo. XIth Jena Symposium on Biophysical Chemistry: Bioelectrochemistry in Biotechnology. Sept. 22-27, 1986 , Erfurt.
• Rückmann, H.-I, Regling, G., Buntrock, P .: The supramolecular organization of the cartilage matrix - A model for bioelectrical information transfer between biopolymers in vivo. Studia biophysica. 119 (1987), 141-145 ,
• Regling, G., Sinh, ND, Rückmann, G .: Nanoelectronic aspects of biochemical regulation in connective tissue matrix. Transactions, XIIIth Annual Meeting, Bioelectrical Repair and Growth Society (BRAGS), Dana Point, Los Angeles, Oct. 10-13, 1993 ,
• Regling, G .: Regulation levels and disease dynamics of the arthrosis joint. Part 1: Arthrosis term and biomechanical functional stress. Part 2: Biomechanical Mechanisms and Synovial Rest pO2. Z. ärztl. Fortbild, 88 (1994), 903-916 (ref. In PubMed) ,
• Regling, G., Jessen, N., Meister, St., Berg, R .: Intra-articular measurement of resting synovial pO2 (oxygen partial pressure of synovial fluid) - a new point of intersection for clinical research in the areas of arthrosis and pain , In: G. Regling (ed.): Wolff's Law and Connective Tissue Regulation, Walter de Gruyter Berlin New York, 1993, 299-320 ; Reprint: G. Regling (ed.): Wolff's Law and Connective Tissue Regulation, Walter de Gruyter, 2010, 299-320 ,
• Regling, G., Pavlov, V .: The Wolff's law and the cancellous bone architecture. Z. Klin. Med. 41 (1986), 473-475 ,
• Regling, G., Rückmann, H.-I .: An integrative concept for an electrophysiological signal system in the connective tissue matrix , The native collagen fibrils as a biosensor and signal-conducting structure between nerve and cell as well as in the intercellular matrix, and a discussion of the underlying mechanism , In: G. Regling (ed.): Wolff's Law and Connective Tissue Regulation, Walter de Gruyter Berlin New York, 1993, 171-192 ; Reprint: G. Regling (ed.), Walter de Gruyter, 2010, 171-192 ,
• Regling, G., Rückmann, H.-I., U. Kappert, T. Volkmann: Electrophysiology of the Connective Tissue Matrix. The biosensor and signal-conditioning function of collagen fibrils. Physical Mechanisms and Consequences for Medicine and Technology , Kleinheubacher Reports, URSI State Committee in the Federal Republic of Germany and the ITG Technical Committees, Volume 36 (1993), 737-746 ,
• Regung, G., Rückmann, H.-I., Sinh, ND, Caps, U., Volkmann, T., Papstein, V .: Mechanisms of the effect of weak electromagnetic alternating field on biological tissue (theory and experiment) , Kleinheubacher Reports, URSI State Committee in the Federal Republic of Germany and the ITG Technical Committees, Volume 37 (1994), 779-786 ,
• Regling, G., Zippel, H., Rückmann, H.-I., et al .: Bioelectrical measurements for an integrative concept of morphogenesis and performance adaptation of mechanically stressed connective tissue. I. Bioelectric deformation potential of articular cartilage in vitro. Z. Klin. Med. 43 (1988), 1771-1777 ,
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QUOTES INCLUDE IN THE DESCRIPTION

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Cited patent literature

• DE 4314688 A1 [0043]

Claims (8)

Bionic materials derived from elastic connective tissue fibers (fibrillin microfibrils, elastin, oxytalan fibrils and analogous fibril and fibrous structures of the elastic extracellular matrix system of connective tissues) and biological coupling molecules (eg laminin) using genetic engineering and / or biotechnological techniques Fibronectin, etc.) having the property of conducting electrical charges along the fiber structures and coupling molecules and balancing and / or dissipating via the fiber or tissue structure of the bionic material. It is u. a. the biotechnological exploitation of a biodigital bioelectronic signal generation and signaling along the designated native supramolecular protein structures. In this case, the coupling molecules can have semiconductive properties and in this way can also proportionally store electrical charge within the elastic fibril network of the bionic material. Materials using genetic engineering techniques as elastic microfibrillar meshes, fibers, complex elastic fibers or other structures of the genetic material of vertebrates, in addition also corresponding elastic fibrils, fibrillin-rich microfibrils and elastic fibers of the extracellular matrix of body tissues of Animal species of other animal classes, by way of example animal species of arthropods (including insects, eg Drosophila and others) with inclusion of resilin and fibrillin-rich microfibrils in the nanofibrillar level as well as by way of example polyps and jellyfish with fibrillin-rich microfibrils, with the advantage that they have or maintain at desired temperatures well below 37 ° C and possibly at lower humidity of the material microfibrils with native helical tertiary structure and thus defined elastic and electrical properties. Materials derived by genetic engineering from cellular and tissue samples of freshly killed warm-blooded animals, e.g. As slaughter animals of agriculture, are obtained and therefore complex elastic fiber structures -. B. from central Elastinscore and surrounding elastic microfibrils - containing the species-specific coupling molecules and thereby defined elastic and electrical properties according to claim 1. Materials according to claims 1 to 3, characterized in that the elastic fibers and fibrils of the material with other materials form an intimate interface compound which is electrically conductive or electrically semi-conductive and conduct electrical charges through the bionic material and also in a defined manner can store proportionally capacitive. Bionic materials having the properties of claim 1 and claims 2, 3 and or 4, whose electrical conductivity along the biopolymeric structures, e.g. B. along fibers of elastic microfibrils or along elastic fibers of elastin / Resilin and surrounding microfibrils and bionic coupling molecules to such considerable extent is greater than ionic conduction and catalysis in aqueous solution, so that they have their described characteristics even in humid or aqueous environment or Get electrolyte solution, as z. B. represents the interstitial tissue fluid of body tissues. Materials according to claims 1 to 5, characterized in that they are used as bionic composite materials, for. As in connection with collagen or other polymer materials, are manufactured and their property described in the claim from the contained elastic fibers, elastin, microfibrils or combinations thereof derive and justify. Materials according to claims 1 to 6, characterized in that the biopolymers contained have been modified by technical or biotechnological methods with additional synthetic steps (up to the complete artificial synthesis of the polymer components of the material according to the bionic model described in the patent) with the aim of biophysical to technically optimize physicochemical and material properties or to optimally adapt them to other concrete applications. Materials of claims 1 to 7, can be used as a biogenic nanoelectronic Signalleitstruktur in the conceptual DNA computer, as far as the said structures of elastic fibrillar fibers and microfibrils are used, also together with other, eg. B. intracellular signal transmission of simulated native biotechnologically produced protein structures with useful bioelectronic properties.

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