Abstract
Wound healing is an important aspect of oral and maxillofacial surgery. Positive sensory signs (allodynia, hyperalgesia) and negative sensory signs (hypoesthesia, hypoalgesia) may be encountered. Quantitative sensory testing (QST) has moved from bench to bedside for the detection, therapy selection and monitoring the recovery of individuals with sensory disturbances. Tracking somatosensory changes during normal and abnormal wound healing has not previously been reported. This report presents data obtained by a novel, automated, non-contact psychophysical method for assessment of wound sensitivity after standardized oral mucosal biopsy. By directing graded air puffs towards palatal biopsy wounds, thresholds for sensory detection, pain detection and pain tolerance were repeatedly assessed across 19 days, demonstrating high reliability. Participants recorded daily spontaneous and chewing-evoked maximum pains. Pain detection and tolerance thresholds increased linearly across time. Comparison between air puff evoked pain detection threshold and chewing-evoked pain demonstrated a strong correlation. Thus, for the first time, this study tracked the time course of somatosensory sensitivity of wounds induced by oral biopsies. The psychophysical data on wound healing obtained by this automated, contact-free stimulation method can be utilized as a surrogate marker for clinical pain improvements and standardized assessment of intraoral pain sensitivity, for example in oral mucositis.
A thorough understanding of the wound healing process is critical in oral and maxillofacial surgery for interpreting the relationship between patient discomfort, wound presentation, and underlying biological events. Knowledge has accumulated regarding cellular and molecular mechanisms responsible for epithelial wound healing. Briefly, blood clot formation begins immediately following tissue trauma. At the interface between the clot and surrounding normal tissue, epidermal migration begins within 24 h after injury, yet no tissue cells have invaded the clot before 3 days. After 3 days the clot is enriched by abundant neutrophils secreting growth factors into the wound environment, stimulating further epidermal cell proliferation. Compared to skin wounds, re-epithelialization of oral mucosa occurs more rapidly and with minimal scar formation. This may in part be attributable to earlier resolution of inflammation and differential regulation of various cellular and molecular mechanism in oral mucosal compared to dermal wounds. Despite these advances in the understanding of biological processes involved in acute wound healing, surprisingly little is known about the time course of somatosensory changes and relation to pain evoked by natural function, such as chewing. One possible explanation for the scarce data on extra-oral and intraoral wound sensitivity might be the lack of appropriate stimulus methods because physical contact between the stimulator or stimulus device could impinge natural healing and lead to infection.
The authors recently developed a computer-controlled, multi-valve air puff delivery system for quantitative sensory testing (QST) of open wounds. This novel approach applies a standardized contact-free stimulus to tissue and it is suggested to improve understanding of somatosensory changes in the healing phase. This new knowledge may lead to better pain management and patient care by oral and maxillofacial surgeons caring for mucosal wounds of traumatic, surgical, cancerous or chemoradiation related origin.
Thus, the aims of this study were to examine in an oral mucosal wound healing model: the test–retest reliability of a new air jet tissue stimulation method on palatal wounds; the wound sensitivity in response to standardized 2 s air puff stimuli of quantified flow rates across a 19-day healing period; and to test for correlations between air-puff evoked pain and clinical levels of pain provoked by chewing.
Materials and methods
10 healthy, pain-free individuals (aged 22–39 years; 7 females) were recruited for this study. Subjects received detailed information about the experimental procedure and provided written informed consent. Participants consented not to take any analgesic medication (including over the counter medicine) 3 days prior to or during the study. CHF 500 was offered to each subject for study participation.
Air puff stimulator
A modified portable version of the air puff delivery system previously described was used for stimulation of the oral mucosa ( Fig. 1 a). This system enables application of graded air streams with flow rates starting at 2 l/min (barely noticeable) to 20 l/min which corresponds to an air stream exiting from a triple air syringe commonly used in dental offices. Pilot laboratory observation has shown that on intact oral mucosa, the highest flow rates do not cause any painful sensations.
The application of standardized air puffs first requires fabrication of customized intraoral splints. Alginate impressions were taken of the upper (maxillary) dental arch and palate. The clinician performing the surgery marked the location of the designated palatal biopsy site on the maxillary cast. A second mark was placed equidistant from the midline to serve as control site. A soft dental acrylic splint was fabricated for placement on the maxillary teeth ( Fig. 1 b). Two clear polyurethane tubes (Festo, Dietikon, Switzerland) of 4 mm inner diameter for air stimulation were permanently mounted onto this splint with GC acrylic resin (GC Europe, Heverlee, Belgium). The air tubes served to target the air puffs to the biopsy wound as well as the palatal control site. At the oral end of the tubes, 90° angled nozzles of 2 mm inner diameter were inserted with their palatal openings located 3 mm from the indicated stimulation target centre.
Surgical biopsy
Seated subjects were requested to rinse their mouth with chlorhexidine 0.2% for 60 s. Photographs of the palatal mucosa were taken and subsequently, the stimulation splint was inserted. On one side of the palate (side selection by simple randomization, i.e. tossing a coin) approximately 10 mm from the palatal gingival margin of the second premolar, a mucosal mark at the opening of the stimulation tube was placed indicating the biopsy site. For local anaesthesia, articaine 4% (1 ml) was infiltrated submucosally. After 3 min, a 6 mm punch biopsy of 2–3 mm thickness was obtained.
Psychophysical assessment
The study protocol (with a focus on the subject’s rating procedure) was explained to participants prior to the first examination. Assessment of intraoral somatosensory sensitivity with the air puff stimulator lasted no longer than 30 min and was always performed in the early mornings (8–9 am) of the following days: prior to surgery (baseline at day 1; always a Monday morning) and on subsequent days 2, 4, 5, 8, 10, 12, 15 and 19. Photographs were taken prior to psychophysical testing. Comfortable seating of stimulation tubes was checked and the palatal mucosa dried with cotton gauze before air stimulation.
At baseline (day 1), air-puff stimuli of 2 s duration and randomized interstimulus intervals between 4 and 6 s were applied bilaterally (randomization by Excel 2003, Microsoft Corp., Redmond, USA). The sensory detection threshold (SDT) was defined as the lowest flow rate at which the volunteer sensed an air puff. The SDT was determined, starting at a flow rate of 2 l/min (system inherent lower limit), with subsequent 1 l/min increments. In order to assess the variability between repeated determinations, testing was repeated three times for each site. On postoperative days (days 2–19), photographs of the biopsy wounds were taken and air-puff stimuli applied as described above. SDT, pain detection threshold (PDT; the lowest flow rate that was perceived as just painful) and pain tolerance threshold (PTT; the maximum air flow rate that the subject would tolerate) were determined three times, with 4 min pauses between each series. The average of the three determinations was used for statistical analyses and to provide a coefficient of variation (CV).
Self-reported pain
During the postoperative period (days 2–19), subjects were asked to fill in a pain diary for the three main meals (breakfast, lunch, and dinner), and to indicate spontaneous pain before meals as well as maximum chewing-evoked pain during meals. Subjects were free to select their food. Pain diaries consisted of vertical 0–10 numerical rating scales (NRS) with 0 labelled as ‘no pain’ and 10 as ‘worst imaginable pain’.
Statistical analysis
Means and standard errors (SEM) of the three repeated measurements for SDT, PDT and PTT were computed. The CV was calculated as a measure of intra-subject variability. Threshold data (SDT, PDT, PPT) were analyzed with Repeated Measures Analyses of Variance (RM ANOVA) with Greenhouse–Geisser correction and polynomial within-subject contrasts to check for linear relationships across days. Within-subject contrasts between specific days against subsequent days and against the last measurement day (day 19) were used. Additionally, the paired Wilcoxon signed ranks test together with Bonferroni correction was applied for pain level differences between the time points. Given the small sample size, none of the tests was significant after adjusting for multiple testing. Inter-subject variability for thresholds was analyzed by employing a one-way ANOVA. Spearman correlations between psychophysical and self-reported pain were computed.
Results
All subjects completed the study without adverse events (excessive bleeding, infection). A typical example of the clinical time course is shown in Fig. 2 .
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