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Biomedical subjects

G Lundborg

Publications and source records attributed to G Lundborg.

At least 181 records · Page 10Linked to original sources

Evidence indicating trophic importance of IGF-I in regenerating peripheral nerves.

The mechanisms influencing regeneration of peripheral nerves are incompletely known, but growth factors are supposed to play a key role. In the present study, we demonstrate, with the aid of immunohistochemical methods, that somatomedin C (Sm-C/insulin-like growth factor I/IGF-I) rapidly increased from low to high concentrations, reaching peak values in 2 weeks, in regenerating sciatic nerves of adult rats. In addition, IGF-I was demonstrated extracellularly, never observed in the control nerves. Reactive Schwann cells appeared to be the major source for IGF-synthesis. Higher concentrations were seen in tubulated nerves as compared to sutured ones. It is proposed that IGF-I exerts important growth supporting effects on regenerating peripheral nerves.

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Mechanical effects of compression of peripheral nerves.

Effects of graded compression on nerve function were analyzed in order to evaluate the relative importance of pressure level and duration of compression for functional deterioration. The pressure was applied by means of a small inflatable cuff. The effects of two pressure levels, i.e., 80 mm Hg applied for 2 hr or 400 mm Hg applied for 15 min, were studied in rabbit tibial nerves. The lower pressure tested, which is known to induce ischemia of the compressed nerve segment, also causes some degree of mechanical deformation of the nerve trunk, which leads to incomplete recovery following pressure release. The duration of compression is of importance for the degree of nerve injury even at the higher pressure level tested.

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Tissue specificity in nerve regeneration.

In 1944 Weiss & Taylor presented experimental evidence against "neurotropism" in nerve regeneration. We used a silicone Y-chamber system to repeat some of those experiments. The proximal stump of transected rat sciatic nerve was introduced into the proximal inlet of the Y. One of the distal outlets was left empty, plugged or occupied by a tendon graft, the other outlet being occupied by a nerve graft. Analysis after 4 and 12 weeks showed in all cases a preferential or exclusive axonal growth towards the nerve piece. The results, indicating the existence of "tissue specificity", are contradictory to the results reported by Weiss & Taylor (30). The findings are discussed with respect to possible influence of humoral, cellular and molecular factors associated with the distal nerve stump as well as the matrix, formed between both nerve segments.

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Intrinsic tendon healing. A new experimental model.

A new experimental model was developed to study intrinsic flexor tendon healing in vivo. Segment of flexor tendons from the synovial sheath region of rabbits' forepaw were cut, resutured and placed in a silicone tube, sealed in both ends with a GORE-TEX pericardial patch (pore-size less than 1 micron), fastened with silicone glue. The chamber was left subcutaneously in the back of rabbits for six weeks. At this time the chamber was filled with clear tissue fluid. Histologically and ultrastructurally the tendon demonstrated fibroplasia with cell proliferation and collagen synthesis in spite of the fact that no extrinsic cells could gain entrance into the chamber--a finding supporting the concept of intrinsic healing.

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Nerve regeneration and pharmacological suppression of the scar reaction at the suture site. An experimental study on the effect of estrogen-progesterone, methylprednisolone-acetate and cis-hydroxyproline in rat sciatic nerve.

Pharmacological suppression of the scar reaction was tested as a possible method for improving axonal regeneration after transection and suture of the sciatic nerve of rats. The animals in the experimental groups were systemically treated post-operatively with estrogen-progesterone, methylprednisolone-acetate (Depomedrone) or cis-hydroxyproline. Only in the cis-hydroxyproline treated animals was there a tendency towards a decrease in fibroblastic activity at the suture site after 4 weeks. However, there was no difference in the growth of axons to the distal nerve segment after pharmacological treatment as compared to non-treated animals, when tested 12 weeks post-operatively. The motor nerve conduction velocity was however significantly greater in both the cis-hydroxyproline and the methylprednisolone-acetate groups as compared with the estrogen-progesterone and the control groups. In conclusion, cis-hydroxyproline and also methylprednisolone-acetate may improve the function of regenerating peripheral nerve, while estrogen-progesterone does not seem to have this effect.

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Competence of nerve tissue as distal insert promoting nerve regeneration in a silicone chamber.

A new peripheral nerve forms across a 10 mm gap within a silicone chamber regeneration model when the distal segment of a transected sciatic nerve, connected to its end organs, is sutured into the distal end of the chamber. We have tested the ability of other tissue inserts to support axonal regeneration in the chamber. When an isolated 2 mm piece of sciatic nerve was sutured into the distal end, fibrin matrix formation, cell immigration and axonal regeneration were identical to those occurring in the control. When the distal nerve insert was replaced with a 2 mm piece of skin or a ligation, a matrix did not form and subsequent cell immigration and axonal regeneration did not occur. When a 2 mm piece of tendon was inserted, a matrix did form at 1 week, but a structure across the gap was observed at later time periods in only 2 out of 7 chambers. The matrix either dissolved before cells could enter the chamber or did not promote cellular immigration and subsequent axonal regeneration. When the distal end was left open, a matrix formed and cells from the reactive tissue outside the chamber entered the matrix and formed a granulation tissue bridge across the gap. This tissue failed to support axonal regeneration; at 3 weeks, axons stopped 1 mm beyond the proximal stump at the interface with the granulation tissue. Thus, matrix formation and a cellular bridge are necessary but not sufficient to ensure regeneration. Successful regeneration across the silicone chamber gap requires humoral and/or cellular contributions available from peripheral nervous tissue and not from the other tested tissues.

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Spatial-temporal progress of peripheral nerve regeneration within a silicone chamber: parameters for a bioassay.

The spatial-temporal progress of peripheral nerve regeneration across a 10-mm gap within a silicone chamber was examined with the light and electron microscope at 2-mm intervals. A coaxial, fibrin matrix was observed at 1 week with a proximal-distal narrowing that extended beyond the midpoint of the chamber. At 2 weeks, Schwann cells, fibroblasts, and endothelial cells had migrated into the matrix from both nerve stumps. There was a delay of 7-14 days after nerve transection and chamber implantation before regenerating axons appeared in the chamber. At 2 weeks, nonmyelinated axons were seen only in the proximal 1-5 mm of the chamber in association with Schwann cells. Axons reached the distal stump by 3 weeks and a proximal-distal gradient of myelination was observed. These observations define the parameters of a morphologic assay for regeneration in this chamber model which can be used to investigate cellular and molecular mechanisms underlying the success of peripheral nerve regeneration.

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Temporal changes of neuronotrophic activities accumulating in vivo within nerve regeneration chambers.

The presence of neuronotrophic factors (NTFs) in noninjured sciatic nerve extract and the course of their accumulation from 3 h to 30 days after nerve transection was examined. Rat sciatic nerves were transected and their proximal and distal stumps sutured into the openings of cylindrical silicone chambers leaving a 10-mm interstump gap. Previous studies had shown that regeneration occurs in chambers containing both stumps but is absent in chambers lacking the distal stump. Chambers became completely filled with fluid 10 to 12 h after implantation. Fluid from chambers without nerve stumps (open-ended) implanted adjacent to nerve-containing chambers had markedly lower trophic activities than those containing one or both stumps. In fluid collected from chambers containing both proximal and distal nerve stumps, the highest titers of NTFs directed to sensory neurons were measured at 3 h posttransection whereas the highest titers of NTFs directed to sympathetic and spinal cord neurons were detected at 1 and 3 days, respectively. Chambers containing only the proximal or only the distal stumps showed similar temporal dynamics for sensory and sympathetic NTFs. Sensory and sympathetic neuronotrophic activity in extracts of proximal and distal stumps followed a similar temporal course to those in chamber fluid. Extracts of nonlesion nerve segments 5 mm from the transection site contained higher sensory and lower sympathetic trophic activity than extracts including the transection site. Spinal cord activity was undetectable in all extracts. Antiserum to nerve growth factor had no effect on fluid or extracts containing high sensory or sympathetic activities. These observations suggested that (i) some NTFs may be present in normal nerves and others may be synthesized or accumulated in response to nerve injury, (ii) sensory, sympathetic, and spinal cord NTFs are separate agents and immunochemically distinct from nerve growth factor, (iii) NTFs predominantly originate from nerve stumps rather than from surrounding fluid, and (iv) proximal and distal nerve stumps accumulate and release NTFs at similar rates.

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Nerve compression injury and increased endoneurial fluid pressure: a "miniature compartment syndrome".

An inflatable miniature cuff was used to apply local compression of 80 mm Hg or 30 mm Hg to a segment of rat sciatic nerve for time periods varying from two to eight hours. The endoneurial fluid pressure was measured by direct micropipette measurement techniques at one or 24 hours after removal of the cuff, and the nerves were subjected to histological analysis. Endoneurial oedema, associated with a four-fold increase in endoneurial fluid pressure, was observed after compression at 80 mm Hg for four hours, and a three-fold increase was found after compression at 30 or 80 mm Hg for eight hours. Such an increase in endoneurial fluid pressure may interfere with intrafascicular capillary flow, and thereby constitute an important pathophysiological mechanism in nerve compression injuries.

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Axonal growth in mesothelial chambers. The role of the distal nerve segment.

An experimental model is presented for studying nerve regeneration over gaps of various lengths between the both ends of a severed nerve. After transferring left and right sciatic nerves of rat to the back, the gap between the two nerve ends could be bridged by a preformed, tube-shaped mesothelial chamber of a desired length. When the gap length was 10 mm or less, a well developed nerve structure was generated in the chamber between the nerve ends, and axons from the left sciatic nerve reinnervated muscles in the right limb via the right sciatic nerve. When the gap length was extended to 15 mm or more no such regeneration occurred. When no distal nerve end was introduced into the chamber, there was a limited growth into this chamber over only 5-6 mm. This "limited growth phenomenon" is discussed with respect to a lack of "trophic" or cellular support from a distal nerve segment. It is also proposed that the termination of growth, seen under these circumstances, may suggest a new principle for avoiding the development of neuromas after nerve transections.

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Experimental tendon grafting within intact tendon sheath.

A chicken toe experimental model was used to study the fate of flexor tendon grafts, introduced into intact tendon sheaths. After perfusion of the limb by India Ink, the vascular pattern of the graft and the synovial sheath could be identified. The grafts showed no or few adhesions to the sheath. With time, there was a conversion from a diffuse superficial vascular pattern towards a concentration of vessels on the dorsal aspect of the graft. In a control group, where the sheath had been resected, adhesions were more apparent, and could be observed still after 16 weeks. These results are in complete agreement with previous experimental findings and further confirm the importance of an intact tube system in the digit.

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Nerve regeneration model and trophic factors in vivo.

The proximal stump of a transected rat sciatic nerve has been observed to regenerate through a cylindrical silicone chamber across a 10 mm gap to the distal stump. The fluid filling such in vivo chambers contains trophic factors that ensure in vitro survival and growth of at least sensory neurons from rodent dorsal root ganglia--as already demonstrated for fluid generated in vitro from Schwann and other cell cultures.

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