Changes in the Thickness and Stiffness of Plantar Soft Tissues in People With Diabetic Peripheral Neuropathy

1484 ORIGINAL ARTICLE Changes in the Thickness and Stiffness of Plantar Soft Tissues in People With Diabetic Peripheral Neuropathy Jia-Hui Sun, MPhil, Benson K. Cheng, PhD, Yong-Ping Zheng, PhD, Yan-Ping Huang, MPhil, Jenny Y. Leung, MBBS, Gladys L. Cheing, PhD ABSTRACT. Sun J-H, Cheng BK, Zheng Y-P, Huang Y-P, Leung JY, Cheing GL. Changes in the thickness and stiffness of plantar soft tissues in people with diabetic peripheral neuropathy. Arch Phys Med Rehabil 2011;92:1484-9. Objective: To compare the thickness and stiffness of plantar soft tissues between people with diabetic peripheral neuropathy (DPN) and healthy subjects. Design: Cross-sectional study. Setting: University research laboratory. Participants: Subjects with DPN (n 70 [35 men, 35 women]; mean age SD, 65.4 8.6y) and healthy control subjects (n 54 [12 men, 42 women]; mean age SD, 57.9 6.1y) were recruited. Interventions: Not applicable. Main Outcome Measures: The thickness and stiffness of the plantar soft tissues were measured by the tissue ultrasound palpation system over the pulp of the big toe (BT), first metatarsal head (MTH), second MTH, and the heel. Results: No significant difference in the thickness of the plantar soft tissues was found in any measurement site between the diabetic group and control group. The plantar soft tissues of the DPN group were significantly stiffer than those of the control group at the BT (85.29kPa vs 50.49kPa), first MTH (96.29kPa vs 62.05kPa), second MTH (84.77kPa vs 52.93kPa), and the heel (65.62kPa vs 44.95kPa) (all P.01). Conclusions: People with DPN tend to have stiffer plantar tissues than do healthy control subjects. The stiffer plantar soft tissues may reduce the cushioning effects of the foot during walking for people with DPN. Key Words: Biomechanics; Diabetes mellitus; Elasticity; Foot; Rehabilitation; Ultrasonography. 2011 by the American Congress of Rehabilitation Medicine LOWER LIMB COMPLICATIONS in people with diabetes are common and can influence the quality of life of these patients and the extent to which they will make use of the health care system. Diabetic peripheral neuropathy (DPN) is one of the most common diabetic complications, occurring in up to 50% of people with diabetes, 1 and it can be an important From the Departments of Rehabilitation Sciences (Sun, Cheng, Cheing) and Health Technology and Informatics (Zheng, Huang), The Hong Kong Polytechnic University, Hong Kong; and Department of Integrated Medical Services, Ruttonjee Hospital, Hong Kong (Leung), China. Supported by a General Research Fund provided by Research Grants Council in Hong Kong (PolyU 5131/06E). No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. Reprint requests to Gladys L. Cheing, PhD, Dept of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China, e-mail: gladys.cheing@inet.polyu.edu.hk. 0003-9993/11/9209-01093$36.00/0 doi:10.1016/j.apmr.2011.03.015 predisposing factor leading to foot ulcers. 2 Foot ulceration is one of the major causes of hospitalization for people with diabetes. Fifty percent of all nontraumatic lower limb amputations were performed because of diabetic complications. 3 Therefore, early identification of people who are at risk for developing foot ulcerations is essential for preventing complications from diabetes. A change in the thickness and stiffness of the plantar soft tissues, together with peripheral neuropathy, 4 high plantar foot pressure, 5 previous foot trauma, or foot deformities, 4 could be a possible risk factor for diabetic foot ulcerations. Recent technical advancements make it possible to quantitatively assess the thickness and stiffness of plantar soft tissues. The thickness of plantar tissues reflects morphologic changes in soft tissues, whereas their stiffness reflects the major mechanical property of soft tissues. The thickness and stiffness of plantar soft tissues of healthy subjects have been investigated in previous studies using ultrasonography. 6,7 Previous work on the diabetic foot has examined the thickness of different tissues such as the plantar fascia 8 or the plantar fat pads. 9 D Ambrogi et al 8 found an increase in both the thickness of the plantar fascia and the vertical forces under the metatarsal head (MTH) in people with diabetes (who may or may not have neuropathy). They demonstrated a positive correlation between the thickness of plantar soft tissues and the vertical forces under the MTH (r.52). As compared with a healthy control group, Bus et al 9 showed that the fat pads in the plantar tissues of DPN subjects with toe deformities were significantly thinner under the MTHs but thicker under the phalanges. They postulated that this alteration in fat pad thickness could be due to the distal movement of fat pads caused by toe deformities. Most of these studies tested on the individual layer of the plantar tissues. However, the total plantar soft tissue thickness is composed of various layers of tissues including the plantar skin, fat pads, fascia, and muscle. This total thickness of plantar soft tissues should be considered as a whole when it serves as the cushion for optimizing loadbearing during ambulation. Very few studies have examined the total thickness of the plantar soft tissues at various sites of the sole in subjects with DPN. It is unclear whether the total thickness of the entire plantar tissue is altered in DPN subjects, or whether such a change only occurs in specific locations of the foot. Stiffness indicates the perceived hardness or elasticity of the material when a compression force is applied. The presence of stiffer structures in a diabetic subject s foot reduces the ability of the foot to disperse forces over a BT DPN MTH SWMF List of Abbreviations big toe diabetic peripheral neuropathy metatarsal head Semmes-Weinstein monofilament

TISSUE PROPERTIES IN DIABETIC PERIPHERAL NEUROPATHY, Sun 1485 greater area to reduce high amounts of pressure. Two previous studies 10,11 demonstrated that the plantar tissues in older diabetic subjects were stiffer than those in a group of healthy young people. However, both studies had a very small sample size, with fewer than 8 subjects in each study, and there was a large age difference between the 2 groups. Because ulcers seem to develop more commonly in the forefoot of older people with DPN, it is possible that an uneven distribution of pressure on the feet is responsible. Therefore, it would be of interest to examine whether the potential change in thickness and stiffness of the total plantar tissues is site specific in the foot. The objectives of this study were (1) to investigate the thickness and stiffness of the plantar soft tissues in a group of subjects with DPN as compared with a healthy control group of similar age; and (2) to compare the thickness and stiffness of the plantar soft tissues at different sites of the plantar foot surface, including the big toe (BT), first MTH, second MTH, and the heel, in subjects with DPN. METHODS Participants In this cross-sectional study, 70 people with type 2 diabetes and DPN (mean age SD, 65.4 8.6y; 35 men, 35 women) were recruited from a local outpatient diabetic clinic. Light touch sensation was evaluated with the use of the Semmes- Weinstein monofilament (SWMF) a to screen people for DPN. 12 Inclusion criteria for the DPN group were the inability to detect light touch sensation with a 4.31/2g SWMF in at least 1 of the following 3 sites: the pulp of the right BT and the plantar surface of the first and fifth MTHs. 13 The 4.31/2g SWMF was selected for identifying people with DPN for 2 reasons. First, according to a previous study, the 4.31/2g SWMF is more sensitive than the 5.07/10g SWMF for diagnosing DPN (sensitivity, 60% vs 30%). 14 Second, the present study aimed at recruiting subjects who had early-stage DPN. Exclusion criteria were (1) age younger than 50 or older than 75 years; (2) a history of cardiovascular or neurologic disorders, or both, probably induced by medical conditions other than diabetes; and (3) marked abnormalities of the ankle and foot, such as bone deformities, ulcerations, or skin problems. Fifty-four healthy volunteers without diabetes mellitus were recruited from 2 local community centers by convenience sampling. The control group comprised 12 men and 42 women, with a mean age SD of 57.9 6.1 years. The inclusion and exclusion criteria for the control subjects were identical to those for the subjects with DPN, except that the controls had completely normal sensation on screening with a 4.31/2g SWMF and a normal 8-hour fasting glucose level. Ethical approval was obtained from a local university and a hospital, and written consent was obtained from each participant. Study Procedures Subjects were requested to rest in a supine position for 10 minutes with their knee fully extended and ankle in an anatomically neutral position. The skin of 4 sites 15 on the plantar tissues of the dominant foot, including the pulp of the BT, the first MTH, the second MTH, and the heel, was marked using a permanent marker for further investigations. These sites were selected because they are usually considered to be high-pressure areas where people with diabetes are prone to developing ulcers. 13,16 Subjects were instructed to relax but to avoid moving their feet during the assessment period. The thickness and stiffness of the plantar soft tissues were measured twice by using the tissue ultrasound palpation system, and the values obtained from the 2 trials were averaged for subsequent analyses. Assessment Tool The thickness (mm) and stiffness (in terms of Young s modulus; kpa) of the plantar soft tissues were measured using a tissue ultrasound palpation system. 17 The system consists of a handheld indentation probe equipped with an ultrasound transducer (diameter, 9mm; frequency, 5MHz), located at the tip of the instrument. A compressive load cell was connected in series with the ultrasound transducer for recording the corresponding force response. The transducer was placed on the skin of the selected site with a gentle force (ranged between 3 10 4 and 5 10 4 kpa). The total thickness of the plantar soft tissues between the bony surface and the skin surface of the measurement site was determined from the flight time of the ultrasound echo signal that reflected from soft tissue bone interface (fig 1). With the indentation probe, the operator applied increasing amounts of loading force to compress the plantar tissue and then reduced the force to decompress the plantar tissue. This was done for 5 cycles in each trial. The rate of indentation was maintained approximately at 1 to 2mm/s, and the depth of indentation was limited to no more than 10% of the initial thickness of the tissue. 10 Both the indentation rate and depth were monitored by real-time visual feedback of the indentation response displayed on a computer monitor. The stiffness of the plantar tissues was then calculated using in-house computer software developed by our research team, which is based on the equation below. This equation is a rigorous mathematical solution to the elasticity problem of indentation of a thin elastic layer bonded to a rigid halfspace 18 : E 1 v2 P 2ak v, a h w where h is the thickness of soft tissues, a the radius of the ultrasound transducer, v the Poisson s ratio of tissues, P the applied force, w the depth of indentation, and k a scaling factor. The Poisson s ratio v was taken to be.45 in this study. This value has been widely adopted for the measurement of limb soft tissues in the literature. 19 The scaling factor k presents a theoretic correction for the thickness of the elastic layer, and it is determined by the aspect ratio a/h and the Poisson s ratio v. The P/w ratio was determined by the linear regression of cyclic load indentation responses. The validity of the load and tissue thickness determined by the tissue ultrasound palpation system has been demonstrated in a previous study, 20 and the Young s moduli and thickness of human soft tissues over radius as measured by the tissue ultrasound palpation system were shown to be repeatable. 17 This system was also demonstrated to have an excellent testretest reliability for measuring human scar thickness (intraclass correlation coefficient,.98; P.01). 21 Statistical Analyses Data were analyzed with SPSS statistical software Version 16 for Windows. b Independent t tests and chi-square tests were used to assess the differences in the subject characteristics between the DPN and healthy groups. To investigate whether there were different variances between the groups on the thickness and stiffness of the plantar soft

1486 TISSUE PROPERTIES IN DIABETIC PERIPHERAL NEUROPATHY, Sun Fig 1. (A) The user interface of the tissue ultrasound palpation system (TUPS) software shows the ultrasound echo train. The first echo is associated with the ultrasound transducer-skin interface while the second one represents the tissue-bone interface. The thickness of the heel pad is presented by the distance between the first and second echoes. (B) A typical ultrasound image shows the cross-section of the heel tissues. The tissue interfaces corresponding to the echoes obtained by TUPS for measuring thickness are indicated. tissues, F tests were computed for equality of variances. The normality of the thickness and stiffness of the DPN and healthy groups was assessed by the Kolmogorov-Smirnov test. A general linear model was used to analyze the differences in thickness and stiffness between the DPN and healthy groups. One-way analysis of variance was performed to examine the differences in thickness and stiffness among the 4 sites only in the DPN subjects. The level of significance was set at.05 for all analyses. RESULTS The baseline characteristics are presented in table 1. The DPN group was significantly older (P.01) than the healthy group. The mean body weight and height of the DPN group were significantly greater (P.01) than those of the healthy Table 1: Baseline Patient Characteristics Characteristics DPN Group (n 70) Control Group (n 54) Sex (M/F)* 35/35 12/42.002 Age (y)* 65.4 8.6 57.9 6.1.001 Body weight (kg)* 65.4 10.9 57.5 9.9.001 Body height (m)* 1.63 0.1 1.58 0.1.007 Body mass index (kg/m 2 ) 24.9 3.3 23.1 3.2.167 Diabetic duration (y) 11.6 8.0 NA NA 8-h fasting glucose (mmol/l)* 8.14 2.77 5.16 0.50.001 Hb A 1c (%) 8.0 1.1 NA NA Light touch sensation Pulp of BT* 4.57 0.58 4.05 0.36.001 2nd MTH* 4.66 0.66 4.18 0.25.001 5th MTH* 4.66 0.55 4.36 0.32.001 NOTE. Values are mean SD or as otherwise indicated. Abbreviations: F, female; Hb A 1c, glycosylated hemoglobin; M, male; NA, not applicable. *P.01. P group. Therefore, sex, age, body weight, and body height were treated as covariates in subsequent analyses. The thickness and stiffness of the plantar soft tissues in both the DPN and healthy groups were shown to be normally distributed (P.054). There was no significant difference in the thickness of the plantar soft tissues in any measurement sites between the diabetic group and control group. On the other hand, the plantar tissues over the BT area in the DPN group were 69% stiffer than those of the control group. Similarly, greater stiffness was found over the first MTH (55%), the second MTH (60%), and the heel (46%) in the DPN group. The between-group difference in stiffness was significant in all 4 measurement sites (all P.01). The findings on the thickness and stiffness of the plantar soft tissues between the 2 groups are shown in table 2. The comparison of variance between the groups by means of the F test showed no significant difference between the 2 tested groups (P.947). Within the DPN group, there were significant differences in the thickness of plantar tissue among the 4 measurement sites (P.001). Plantar tissue was thickest over the heel and thinnest over the BT. However, among the 4 sites, the plantar tissue was stiffest over the first MTH (P.009) and softest over the heel (P.003). DISCUSSION Thickness of Plantar Soft Tissues An increase in plantar pressure in subjects with DPN is a known risk factor in the development of diabetic foot ulcers. 5 Previous studies have shown that the thickness of plantar tissues is the strongest predictor of peak plantar pressure. 22,23 Abouaesha et al 22 demonstrated a strong negative relationship between the thickness of plantar tissues under the MTH and dynamic foot pressure in subjects with DPN. They emphasized the importance of retaining adequate thickness in the plantar tissues that serve as a shock absorber, as this is essential to DPN subjects for performing daily activities.

TISSUE PROPERTIES IN DIABETIC PERIPHERAL NEUROPATHY, Sun 1487 Table 2: Comparison on Model-Estimated Means of Biomechanical Properties of Plantar Soft Tissues Between Groups With Sex, Age, Body Weight, and Body Height as Covariates Biomechanical Properties Sites DPN Group Control Group Mean Difference (95% CI) P Thickness (mm) BT 5.16 0.18 4.76 0.87 0.40 ( 0.07 to 0.98).067 1st MTH 8.25 0.28 7.67 0.35 0.58 ( 0.41 to 1.52).257 2nd MTH 8.88 0.28 8.74 0.36 0.14 ( 1.16 to 0.78).696 Heel 18.25 0.52 18.87 0.65 0.62 ( 2.90 to 0.77).252 Stiffness (kpa) BT* 85.29 5.20 50.49 6.62 34.80 (16.81 to 52.78).001 1st MTH* 96.29 7.36 62.05 9.36 34.24 (8.79 to 59.70).009 2nd MTH* 84.77 4.51 52.93 5.92 31.84 (15.97 to 47.72).001 Heel* 65.62 4.10 44.95 4.20 20.67 (8.28 to 33.03).003 NOTE. Data are model-estimated means SE. Covariates appearing in the model are evaluated at the following values: sex, 1.65; age (y), 61.65; body weight (kg), 61.45; body height (m), 1.61. Abbreviation: CI, confidence interval. *P.01. The present study did not find significant differences in the thickness of the plantar soft tissues over each of the measurement sites between the diabetic group and the control group. Our finding on the thickness of plantar tissue is consistent with that reported by Robertson et al, 24 although their subjects with DPN had more severe sensory loss (SWMF 5.07/10g) and a prior neuropathic plantar ulcer. However, our finding on thickness contradicts those reported in 2 previous studies, 10,25 which showed a decrease in the thickness of plantar tissues over the MTH and heel in the group with diabetes mellitus as compared with a healthy control group. However, there were only 4 subjects with DPN (mean age, 63y) and 4 healthy subjects (mean age, 22y) who participated in one of the studies. 10 In a relatively old study published in 1986, Gooding et al 25 used a 10-MHz ultrasound sonogram to determine the thickness of the plantar soft tissue, and reported that the thickness of the sole for the control group was greater than that of people with diabetes (with or without ulcer). However, the present study used different equipment (handheld indentation probe equipped with an ultrasound transducer) for assessing thickness of the sole. Also, the testing position of subjects was different in the 2 studies; their subjects were tested in a prone position with knees flexed, 25 while we examined our subjects in a supine position with knees extended and ankles kept in an anatomically neutral position. Any change in knee and ankle position may lead to a change in the tightness or thickness of the plantar soft tissues. Stiffness of Plantar Soft Tissues The stiffness of soft tissues reflects its mechanical property. The change in the stiffness of plantar tissues can interfere with their natural function as shock reducers and shock absorbers. Our findings showed that the plantar tissues of the DPN group were significantly stiffer than those of the control group in all measurement sites (all P.01). In particular, the plantar tissues were stiffest over the first MTH and softest over the heel of the DPN group. These results suggest that DPN subjects have a poor ability to dissipate abnormal plantar pressure on the plantar tissue, especially in the forefoot region. During weightbearing activities such as standing, walking, running, and jumping, the role of the plantar tissues is to absorb mechanical loading so that the force can be evenly distributed. An increased stiffness in the forefoot would significantly reduce the ability of the foot to tolerate mechanical stresses while bearing weight, thereby predisposing the subject to developing diabetic foot ulcerations. 26 Callus formation is a good example to illustrate the changes of soft tissues on the plantar aspect of the feet in people with DPN. The external pressure could facilitate tissue hyperplasia 22,23 and the formation of calluses, which serve as cushioning to prevent the skin from breaking down. People with DPN could present changes in the skin of feet such as prolonged dry skin with tears and fissures, which associates with impaired sympathetic regulation of sweat glands and impaired skin blood flow and arteriovenous shunt vessels in the feet. 27 These changes could make calluses so stiff that they lose their cushioning function. In this situation, the pressure was focused on the sites with calluses of the feet. A significant correlation between the calluses formation and high plantar pressure was reported in previous studies. 28,29 Our findings on the stiffness of plantar soft tissues are consistent with those reported by several previous studies, 10,30,31 in which the authors used different equipment for measuring stiffness. Piaggesi et al 30 reported an increase in the hardness of the skin (ie, stiffness) as measured by a durometer for people with DPN. They found a strong correlation between this increase in hardness and the severity of neuropathy. Our findings on stiffness measured by the tissue ultrasound palpation system are consistent with those reported in our previous preliminary study 10 that had a small sample size. Similar findings on stiffness were reported by Klaesner et al, 31 in which the soft tissues were measured by a loading-unloading device with an ultrasound transducer (contact area, 3.96cm 2 ; frequency, 10MHz). However, their subjects (both DPN and control groups) were slightly younger than those who participated in our study, and the subjects in their DPN group all had a history of ulcers on the plantar surface of their feet. It is logical to believe that the stiffness of the plantar soft tissue would increase with a history of ulcers. In contrast, Hsu et al 32 did not find any significant difference in the stiffness of plantar tissues at the heel between the healthy control group and a diabetic group by using a self-developed ultrasound indentor system with an ultrasound transducer (diameter, 9mm). Note that Hsu s 32 diabetic group consisted of a mixture of subjects with DPN (n 8) and without DPN (n 13). However, the subjects who participated in the present study all had DPN. It is expected that DPN may influence the stiffness of plantar soft tissue, and this may explain the different findings reported in the 2 studies. The present study further demonstrated that the plantar tissues over the first MTH were the stiffest among the 4 measurement sites on the foot. Klaesner 31 postulated that an increase in the stiffness of the plantar tissues could be due to an accumulation of cross-links of collagen molecules.

1488 TISSUE PROPERTIES IN DIABETIC PERIPHERAL NEUROPATHY, Sun Thickness and Stiffness of Plantar Tissues at Different Sites in People With DPN Our findings demonstrate that the plantar tissues over the heel were the thickest but softest, which allows the heel to perform a cushioning effect during the heel strike phase. In contrast, the plantar soft tissues over the forefoot tend to be thinner but stiffer, which indicates that the plantar tissues over the forefoot in people with DPN have less ability to disperse the pressure as compared with those over other parts of feet. Our findings may partially explain why ulcers are frequently found over the plantar side of the forefoot. Study Limitations We acknowledge that various potential factors may affect the biomechanical properties of the plantar soft tissue, including sex, body weight, body height, shoe wear, and physical activity. Very few studies have examined whether these factors would influence the total thickness of the plantar soft tissue (from the skin to the bone) in the foot. Based on our earlier study, 33 we found no significant sex difference in the thickness of plantar soft tissues at all 4 measuring sites in the foot. However, we found a significant sex difference in the stiffness of the plantar soft tissue only in the heel region, but not at the BT, first, third, and fifth MTHs. Therefore, we did not treat sex as a covariate. No previous study has examined whether physical activities and footwear influence the biomechanical properties of the plantar soft tissues. Future studies are needed to confirm this. Also, most of our subjects had early-stage DPN; therefore, future studies can also clarify whether the history of diabetes and progression of DPN would further affect the biomechanical properties of the plantar soft tissues. This may help to prevent diabetes-associated foot complications such as diabetic ulcer and amputation. CONCLUSIONS People with DPN demonstrated a significant increase in stiffness in most areas of the foot as compared with a healthy control group of similar age. Among the DPN subjects, the plantar tissues over the forefoot area tended to be thinner and stiffer as compared with other areas of the foot. Because people with DPN tend to have difficulty dissipating pressure over the forefoot area, they are at risk for the development of foot ulcers. Therefore, foot care is very important for this client group. It is recommended that they should consider wearing shoes with a wider head, made with soft material that provides good cushioning. References 1. Sangiorgio L, Iemmolo R, Le Moli R, Grasso G, Lunetta M. Diabetic neuropathy: prevalence, concordance between clinical and electrophysiological testing and impact of risk factors. Panminerva Med 1997;39:1-5. 2. Boulton AJM. 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