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Substance P has a stimulating effect on fibroblast proliferation, collagen organization, and angiogenesis in ruptured and subsequently sutured rat Achilles tendon. This effect is also reflected in the biomechanical properties of the tendon. The aim of this study was to substantiate the effect of exogenous substance P on endogenous substance P, NK-1 receptor, and nerve ingrowth in an in vivo tendon-healing setting. Ninety-six male Sprague-Dawley rats were randomly assigned to one of four groups and injected with saline, substance P (10(-6) micromol/kg BW and 10(-8) micromol/kg BW) associated with neutral endopeptidase inhibitors, or neutral endopeptidase inhibitors alone into the paratendinous region of the ruptured and subsequently sutured Achilles tendons from the second until the sixth day postoperatively. Substance P, NK-1 receptor, and nerve ingrowth (PGP 9.5) were analysed using immunofluorescence at four different time points: one, two, four and six weeks postoperatively. In all groups substance P was predominantly expressed in the extracellular matrix during the first two weeks, corresponding to fibroblast proliferation, and first disappeared from the saline group in the proliferative phase. In contrast, substance P was not expressed in the blood vessel wall during the first two weeks, when angiogenesis was most pronounced. NK-1 receptor was almost always expressed in the blood vessel wall and in the extracellular matrix during this period and disappeared progressively afterwards. No nerve ingrowth was identified. Exogenously administered substance P in sutured rat Achilles tendon rupture does not stimulate sensory nerve ingrowth, but seems to have a booster effect on endogenous substance P for fibroblast proliferation via autocrine/paracrine stimulation.

Background: In the last few years much research has been conducted in methods to promote tendon healing. The aim of this study was to determine if the healing process after operative repair of rat Achilles tendons could be stimulated by the paratendinous injection of a sensory peptide, substance P (SP)., Methods: Ninety-six male Sprague-Dawley rats were randomly allocated to four groups: (I) control buffer injections, (II) injections of SP 10(-6) mol/kg body weight combined with a carrier, (III) injections of SP 10(-8) mol/kg BW with the carrier, and (IV) injections with the carrier only (thiorphan 1 micromol/kg BW and captopril 30 micromol/kg BW, both neutral endopeptidase inhibitors). The influence on tissue repair was determined from the histologic measurement of fibroblast proliferation, angiogenesis, and collagen organization. On days 7, 14, 28 and 42, animals were sacrificed and histologic evaluations were performed on the injured Achilles tendon constructs., Results: The two groups subjected to SP injections showed a significant initial fibroblast proliferation on day 7 (p < 0.05), which rapidly declined by day 14 to the level of cellular proliferation observed with the use of thiorphan and captopril. Capillary proliferation showed a similar evolution, except that in the second week angiogenesis in the treated groups was below the level of the control group. Strikingly, collagen orientation increased faster in the groups injected with SP. This was obvious from the second week already and the difference remained until the completion of the study., Conclusion: This is the first study to demonstrate that paratendinous injections of SP after operative repair of the Achilles tendon in rats appears to provide a boost to the initial stages of healing and significantly accelerate the reparative phase of the healing process.

Retrograde or antidromic stimulation of the nociceptive C fibres is known to lead to the release of sensory neuropeptides Substance P (SP) and Calcitonin Gene-Related Peptide (CGRP) by the peripheral endings of these ultra-thin nerve fibres. These neuropeptides have, among others, a vasodilatory effect, which explains why they play a role in the healing of soft tissues. Burst TENS (Transcutaneous Electric Nerve Stimulation) is known to be most effective in influencing C fibre-evoked activity. This is why burst TENS was used in a randomised study as a stimulus for the healing of the sutured Achilles tendon in 10 patients, versus 10 others who received no stimulus. There was one drop-out in each group, so that 2 x 9 patients remained available for the study. A needle biopsy, performed after six weeks, showed no significant influence of burst TENS on the histological healing stage, as compared with a rat study. However, a semi-quantitative evaluation of the number of fibroblasts showed a significant advantage for the stimulated group: p = 0.007. This means that burst TENS might influence healing of Achilles tendon sutures in man. But above all, it means that a histochemical study of the influence of burst TENS on the release of substance P and CGRP, after suture of the Achilles tendon in man, would be worthwhile.