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Tissue Differentiation and Maintenance: the influence of mechanical stimuli
Nicholas J Giori, MS; Gary S Beaupré, PhD; Dennis R Carter, PhD
Many current problems relating to the repair of skeletal and connective tissues, and to the design and fixation of joint replacement prostheses, are closely related to the responses of regenerating skeletal and connective tissues to mechanical loading. An understanding of the mechanical factors involved in controlling the proliferation and differentiation of cells in skeletal and connective tissue regeneration, and in influencing the maintenance or modulation of mature connective tissues is needed to improve treatment of orthopedic injury and to prevent or reverse some processes of connective tissue degeneration.
Combining concepts developed by F. Pauwels fifty years ago with results of recent in vitro studies regarding mechanical control of various important cellular processes, we hypothesize that loads which cause compressive hydrostatic stress in the tissue will stimulate the net production of cartilaginous matrix constituents, while loads which cause significant distortional (octahedral shear) strain in the tissue stimulate the net production of fibrous matrix constituents. In the case of differentiating pleuripotential tissue, we hypothesize that low distortional strain and low hydrostatic stress permit the direct formation of bone, as in primary fracture healing. These concepts can be graphically represented (Figure 1).
We have conducted computational, in vitro, and in vivo studies to test and refine our mechanically based tissue differentiation concepts.
Figure 1. The tissue differentiation hypothesis.
Mechanical Modulation of Tendon Tissue Composition
Prior in vitro studies have shown that a region of fibrocartilage develops in certain tendons which wrap around bones. This fibrocartilage goes away when the tendon is removed from the channel which guides it over the bone and returns when the tendon is replaced. Using finite element analysis, we mechanically modeled this situation and found that intermittent in vivo loads create a pattern of hydrostatic stress in the tendon tissue which matches the pattern of fibrocartilage development in these tendons (Figure 2). These results supported our mechanically-based tissue differentiation concepts. (J Orthop Res 11:581-591, 1993)
Figure 2a. The rabbit FDL tendon wraps around the talus. Cartilaginous tissue stains darkly (Alcan Blue stain). |
Figure 2b. Finite element analysis of the rabbit FDL tendon. |
In vitro Hydrostatic Compression of Tendon Explants
Based on the results of the prior study, we conducted an in vitro study in which pieces of mature bovine tendon were placed in a medium containing radioactively labeled sulfate. Sulfate is an important building block of proteoglycans, and thus is taken up by tissue synthesizing cartilaginous extracellular matrix. Experimental specimens were intermittently or statically pressurized to 6 MPa while control specimens were unpressurized. After 8 hours of pressurization, there was a statistically significant doubling of sulfate incorporation among pressurized tendon explants compared with controls. This effect was also seen in a parallel set of experiments on cartilage explants. Though additional work must be done to more carefully examine this tissue biochemically, preliminary results support our tissue differentiation concepts. Further in vitro studies such as this one may prove very useful in developing a detailed understanding of mechanical control of tissue modulation.
Mechanical Influences on Tissue Differentiation at Bone-Cement Interfaces
A prior histological analysis of retrieved knees which had undergone cemented Marmor hemiarthroplasty revealed that beneath the central portion of the tibial component a thick, mature layer of fibrocartilage consistently developed, while fibrous tissue separated the bone from cement elsewhere (Figure 3a). Finite element analysis was used to mechanically model this situation, and it was found that the region of fibrocartilage development corresponded to a region in which the differentiating tissue was subjected to intermittent compressive hydrostatic stress of greater than approximately 0.7 MPa (Figure 3b). In almost the entire immature interface, the distortional strain was estimated to be greater than ten percent, suggesting that this level of distortional strain is sufficient to stimulate fibrous extracellular matrix production. (Submitted J Arthroplasty)
Figure 3a. Adopted from Ryd and Linder, J Arthroplasty 4:303-309, 1989. |
Figure 3b. Finite element analysis of the Marmor hemiarthroplasty. |
In vivo Experimental Approach for Relating Tissue Differentiation to Mechanical Loading History
Fifty years ago, researchers conducted a surgical experiment in which a cylindrical plastic implant with cup-shaped ends was placed between the osteotomized bone stumps of a rat fibula. They found that in some cases, they were able to generate within the healing differentiating tissue a structure closely resembling a joint surface.
In this study, we repeated the experiment to verify the results, but modified this experiment such that mechanical control of the differentiating tissue could be more accurately studied. We analyzed retrieved tissue three weeks following surgery, and compared the histologic results with the results of a finite element model of this experiment.
It appears that fibrous tissue develops in regions subjected to intermittent distortional strains greater than approximately 10 percent, and that cartilage and endochondral ossification may only form in regions of lower distortional strain. In addition, inflammation or particulate debris discourage nearby tissue from developing into cartilage and bone.
Republished from the 1994 Rehabilitation R&D Center Progress Report. For
current information about this project, contact
Gary S Beaupré.
