“Imagination is more important than knowledge. For knowledge is limited to all we now know and understand, while imagination embraces the entire world, and all there ever will be to know and understand.”--Albert Einstein
The tissue repair mechanism regulates thrombin to energize tissue maintenance and tissue repair. It continuously generates small amounts of thrombin in all tissues to energize slow cell turnover and collagen replacement to enable tissue maintenance. It elevates thrombin to energize tissue repair, and restores thrombin to normal levels when the repair process nears completion.
Tissue Maintenance: The selectively permeable vascular endotheliumallows factor VII to slowly and continuously penetrate from blood into extravascular tissues, where it binds totissue factor, which stabilizeslabile factor VII to generate small amounts of thrombin needed for cell turnover and fibroblast collagen production needed to maintain tissues.
Tissue Repair: Trauma disrupts the vascular endothelium and directly exposes tissue factor in extravascular tissues to blood enzymes, thereby triggering an enzymatic interaction of factors VII, VIII, IX and X that rapidly generates thrombin, soluble fibrin and insoluble fibrin. Thrombin activates platelets and binds blood cells into a selectively permeable viscoelastic clot that substitutes for the vascular endothelium.
Like the vascular endothelium, the viscoelastic clot is "selectively permeable." The gigantic size of factor VIII prevents it from penetrating the clot of its own manufacture, which limits clot formation to the immediate vicinity of tissue factor exposure.The clot regulates the penetration of factors VII and X into the damaged tissues beneath its surface, where they interact with tissue factor to generate thrombin that energizes the cell activities that repair tissues. The clot maintains thrombin within a narrow range to optimize tissue repair and prevent excessive thrombin generation that causes malignancy.
Tissue repair thus proceeds in an orderly and predictable sequence:
1. Hemostasis (coagulation and capillary hemostasis) wherein direct exposure of tissue factor in damaged tissues interacts with blood enzymes to rapidly generate insoluble fibrin that forms a viscoelastic clot that halts blood loss, re-isolates damaged tissues from flowing blood, and regulates contact between blood enzymes and damaged tissues to regulate thrombin levels in damaged tissues.
2. Inflammation wherein cells release chemokines, cytokines, bradykinins and prostaglandins that dissolve the basement membrane that holds cells in tight formation to facilitate chemotaxis and soluble fibrin diffusion from blood into damaged tissues, where it forms a molecular matrix that facilitates granulation tissue forrmation. The resulting tissue edema (tumor), exaggerated perfusion (rubor), and nociceptor activation (dolor) causes temporary loss of function (functio laesa) during the healing process.
3. Chemotaxis wherein repair cells move from intact adjacent tissues toward thrombin elevations in damaged tissues to engage in tissue repair.(3)
4. Cell proliferationwherein fibroblast mitosis and collagen generation forms "granulation tissue" that fills empty spaces. Angiogenesis (capillary formation) provides perfusion to healing tissues (rubor). Immune cell proliferation produces antibodies, removes debris, and fights infection. The elevated metabolism of rapidly proliferating cells generates heat (calor) during tissue repair.
5. Remodeling wherein repair cells restore organs and tissues without external influence.(1, 2) Cell-to-cell communications via cellular hormone release and tiny electromagnetic forces enables cell differentiation, specialization, and spontaneous organization that replaces damaged muscle, bone, nerve, and organ tissues.
6. Resolution wherein the gradual restoration of the vascular endothelium reduces thrombin levels to normal, causing clot dissolution and fibroblast apoptosis that shrinks granulation tissues and pulls wound edges together.
1. P. Weiss, A. C. Taylor, Reconstitution of Complete Organs from Single-Cell Suspensions of Chick Embryos in Advanced Stages of Differentiation. Proc Natl Acad Sci U S A 46, 1177-1185 (1960).
2. H. V. Wilson, On the behavior of the dissociated cells in hydroids, alcyonaria, and Asterias. Journal of Experimental Zoology 11, 281-338 (1911).
3. E. E. Peacock, Wound Repair. E. E. Peacock, Ed., (W.B. Saunders Company, ed. Third Edition, 1984), pp. 526.