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portionately long period, and seems to occur in some sort independently.

These two plans are the ones regularly followed by all those kinds of new-formations which do not directly lead to hyperplasia;1 the normal condition is here in the first instance interrupted by an intermediate state, in which the tissue appears essentially changed, without one's being able straightway to determine whether a growth of a benignant or malignant nature will be developed out of it. This is a stage of seemingly absolute indifference; from the appearance of the individual elements it cannot at all be inferred what their real destiny is; they behave exactly like the so-called formative cells of the embryo, which also at first exactly resemble one another, no matter whether a muscular or nervous element, or anything else, is about to proceed from them. Nevertheless I regard it as very probable that delicate internal differences do really exist, which to a certain extent determine beforehand the subsequent metamorphoses—not merely potential differences in the formative cells, but really material differences, only of so delicate a nature, that we are not as yet able to demonstrate them.

In the development of the embryo a phenomenon has been known for years which positively indicates the existence of such differences in the formative cells, inasmuch as the different segments of the ovum run through their phases of development with different degrees of rapidity, and especially those parts which are destined to form the higher organs, run through their individual stages with much greater celerity than those whose lot it is to form the lower tissues. In the size of the cells also differences seem

1 There are processes which begin with Hyperplasia and end with Heteroplasia, and others again, which begin with Hcteroplasia and end with Hyperplasia. The new formation of vessels, for example, never begins straightway with the formation of vessels, but first of all cells are formed (heteroplasia), and afterwards vessels (hyperplasia) are developed out of these cells.. —From a MS. note by the Author.

EPITHELIOID NEW FORMATION. 405

to exist. In a similar manner we frequently see that in pathological formations also differences occur in reference to the time occupied in their development. Whenever the development of the cells takes place with great rapidity, we may be sure it is a more or less heterologous development. An homologous, hyperplastic formation always presupposes a certain tardiness in the processes which give rise to it; the cells generally remain of a larger size, since the divisions do not usually proceed until very small forms are produced.

Though so extremely simple in nature and in theory, these modes of development are certainly extremely difficult of demonstration in individual places. The parts which apparently ought to be the most conveniently situated for the purpose of investigation, and in which Henle indeed, as long as twenty years ago, all but made the discovery of such a development, are the epithelia. Here, where a development often so abundant takes place upon the surface of a membrane, one would suppose it must be extremely easy to trace its course accurately in the individual cells. Henle, you know, endeavoured to shew that mucus-corpuscles, and indeed many forms which belong to pus, were produced on the surface of mucous membranes along with the epithelium in such a way, that no real difference was to be perceived between the two classes in their earliest stages, and that the mucus-corpuscles must therefore in some sort be looked upon as epithelial cells that had gone astray, as children that had turned out ill, that had been impeded in the progress of their development by some early disturbance, but really were intended to become epithelial cells. Unfortunately the notion was then and long afterwards prevalent, that epithelium like all other tissues was normally developed out of a blastema. It was, you know, imagined that on the surface of every mucous membrane in the first instance there transuded a plastic fluid from the vessels running to the surface, and that the epithelial cells were formed out of it. Schleiden's theory was steadfastly adhered to, that nuclei first form in a fluid, and that membranes do not develop around them until afterwards. At present, however much the different surfaces presented by the skin and the mucous and serous membranes are examined, the conviction is everywhere unmistakeably acquired, that the cellular elements extend down to the very surface of the connective tissue, and that there is nowhere a spot, where free nuclei, blastema or fluid exist, but that on the contrary it is especially the deepest layers which contain the most densely crowded cells. If at the time, when Henle made his investigations, it had been known, that no blastema ever exists in these parts, and that no development de novo ever takes place there, but that the epithelial cells there present must have been developed either from old cells or from the connective tissue underneath them, he too would certainly also have come to the conclusion, that mucus- and puscorpuscles which are not furnished by an ulcerating surface (which would of course be destitute of epithelium), must be derived by direct descent from pre-existing epithelial cells.

So nearly, even at that time, had correct views upon the subject been obtained, but the blastema theory enthralled men's minds, and we all stood under its influence. Besides, it appeared impossible to point out everywhere in the interior of the tissues the requisite antecedent structures. Not until cellular elements had been shown to exist in connective tissue did it become possible to produce a germinal tissue (Keimgewebe) which is present everywhere, and from which in the most various organs similar growths may be developed. Now that we know that connective tissue—or tissues equivalent to it—exists in the brain, the liver, the kidneys, in muscle, cartilage, skin, &C., now there

GROWTH OF BONE. 407

is of course no longer any difficulty in conceiving how the same pathological product may arise in all these apparently so dissimilar structures. No specific blastema of any sort, deposited in all these parts, is at all required, but only the application of a similar stimulus to the connective tissue of the different localities.

Now with regard to the details of this doctrine, allow me in the first place to bring to your notice a concrete example of normal development, which will perhaps be the best calculated to supply you with a picture of the often so complicated processes with which we are here concerned. I choose as my example that organ, in which the process of development is in itself best known, and which at the same time on account of the peculiarity of its structure least admits of misinterpretation, namely the bones. They are too hard and thick for any one to talk about the presence of blastema or exudation in their proper parenchyma. The growth of the bones at the same time affords us direct standards wherewith to compare the different new-formations, which may occur in the bones in morbid conditions, for every one of these new-formations finds a certain prototype in the normal development of bone.

All the larger bones grow, as is well known, in two directions. This is most simply shewn in the long bones, which gradually increase in length and thickness. The growth in length takes place from cartilage, that in thickness from periosteum. But a flat bone also is invested on the one hand with cartilaginous parts or their equivalents (sutures) and on the other with membranes which correspond to periosteum. A growth from cartilage and a growth from periosteum can therefore be distinguished in every bone. This furnishes us with a plan of the development of long bones, which is found even in the writings of Havers, and according to which the new layers of bone incapsulate the old ones, and every more recent layer is not only wider but longer than that next above it in age. Every new layer of osseous substance which is formed out of periosteum is longer (higher) than the one immediately preceding it, inasmuch as new layers of perichondrium are being continually converted into periosteum. At the same time every new layer of osseous substance which grows out of cartilage is broader (thicker) than that which went before it, inasmuch as every new layer of the (growing) cartilage which proceeds to ossification surpasses its predecessor in breadth (thickness). The growth from cartilage, however, can only take place in the direction of the extremities of the bone, inasmuch as the cartilage of its diaphysis is, at a very early period of intra-uterine life, so completely ossified,1 that no cartilage remains excepting at the two ends. Now a tissue once ossified ceases (save under exceptional circumstances) to grow, so that any increase of thickness in the diaphysis must be wholly due to a development out of periosteum, in which growth proceeds much more slowly than in cartilage. This is the reason why the shaft of a long bone is narrower than its extremities.* Whilst in this way parts which were previously either connective tissue or cartilage, are converted into bone, the development of the medullary tissue is going on within the bone. The original bone is extremely dense, a very solid and relatively compact mass. Subsequently the substance of the bone disappears more and more, one part of it after another is dissolved, and the medullary cavity [canal] arises, the size of which is not

1 This complete ossification in long bones is not confined to intra-uterine life, but every new layer of cartilage which grows out of the terminal cartilage up to the age of puberty ossifies (when matters follow a normal course) throughout its whole thickness, so that no cartilage remains at the circumference of the bone.—From a MS. note by the Author.

3 For a diagram of the growth of long bones, see Havers (Osteologia nova, Francof. 1692, Tab. I, fig. 1), and Kolliker (Handbuch d. Gewebelehre, 3rd edit., Leipzig, 1859, p. 259).

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