The Effect of Exercise, Physical Activity, Stepping Characteristics, and Loading on Diabetic Foot Ulcer Healing: A Systematic Review

Diabetes affects an estimated 37.3 million adults in the United States (11.3% of the US population), and an estimated 96 million adults in the United States have prediabetes.¹ Up to 34% of individuals with diabetes will develop a DFU in their lifetime.² Despite standard care, including local debridement, moist wound dressings, and offloading , 20% of DFUs do not heal within 1 year.³ While efforts to advance standard care with wound healing dressings such as skin substitutes and matrix dressings are ongoing,⁴ understanding of the effect of physical activity and plantar foot loading during the offloading period and after wound closure remains limited. It is clear that plantar offloading strategies are critical for wound closure; however, physical activity and exercise are essential for diabetes management.⁵ A better understanding of physical activity and exercise in the context of DFU wound healing in persons with diabetes could facilitate improved patient education as well as improved DFU healing and diabetes management outcomes.

The American Diabetes Association recommends that adults with diabetes complete at least 150 minutes per week of aerobic exercise (moderate to vigorous intensity), with no more than 2 consecutive days without exercise.^5,6 Furthermore, these adults should also perform resistance exercise on nonconsecutive days (2–3 days per week) along with flexibility and balance training, unless doing so is otherwise contraindicated.^5,6 Aerobic and resistance exercise in persons with diabetes carries the benefits of improved insulin efficiency, improved glycemic control, increased cardiac output, improved immune function, decreased HbA_1C levels, decreased blood pressure, improved muscle mass, increased strength, improved physical function, and improved mental health.⁵ Despite the benefits associated with exercise, the reality of exercise performance in this population is grim (period of 2015-2018). Less than 24% of adults with diagnosed diabetes met the recommendation of at least 150 minutes of physical activity per week.¹ While the benefits of physical activity and regular exercise are clear, it is not known how walking or exercise should be dosed, especially in individuals with a plantar DFU.⁷

Recommendations for physical activity and exercise in persons with DFU must take into account multiple factors. Plantar offloading, defined as periods of decreased or modified weight-bearing or plantar pressure distribution, is standard of care intervention for DFU. However, many of the most accessible forms of physical activity and exercise involve weight-bearing, which creates conflicting goals and expectations for patients with DFU. Plantar offloading is critical for wound closure, and understanding physical activity and exercise in the context of wound healing, including both step activity and traditional exercise, may inform how clinicians prescribe and patients can benefit from exercise without compromising DFU healing during the offloading phase. To date, the literature has not identified or integrated safe limb loading patterns, doses of exercise, or amounts of walking during the DFU healing process. The quantification of exercise or walking along with the pattern of plantar force application are important to better consider their effect on DFU healing and wound closure. A more thorough and complete understanding is required to provide clinicians and patients guidance for accurate and safe exercise prescription to facilitate healing and best prepare the skin for plantar reloading without re-ulceration.

The purpose of this systematic review was to determine whether exercise, physical activity, walking step characteristics, or limb loading affect healing outcomes in persons with DFU and whether the quantity of exercise, stepping activities, or limb loading affect the length of time to wound closure in persons with DFU.

The inclusion and exclusion criteria used to address the research questions, including population of interest, interventions, study type, and outcomes measures, are reported in Table 1. Eligible study designs included from the literature search, regardless of sample size, were randomized controlled trials, controlled trials, meta-analysis studies, and cross-sectional cohort studies. Systematic reviews, other reviews, book chapters, studies without the inclusion of primary data, and case studies were excluded. Studies were not restricted by clinical setting (Table 1).

Literature search strategy

A literature search strategy was identified to address the research questions
(Appendix 1). This research protocol was developed and registered on the PROSPERO website (ID: CRD42021224939) prior to performing the literature search. The following databases were searched according to the preestablished search terms (Appendix 1): MEDLINE, ProQuest, Scopus, CINAHL, Ovid, and the Cochrane Library. The search dates were inclusive from 1960 until present. The searches were conducted in December 2020. Only English-language articles were included. A manual search was also performed using article reference lists.

Literature review and extraction

Covidence systematic review software (Veritas Health Innovation; www.covidence.org) was used for all literature review. Literature search results were imported into the software, and duplicate articles were removed. Article titles and abstracts were independently reviewed by 2 reviewers (L.S., D.M.W.). Inclusion and exclusion criteria were used to determine study eligibility (Table 1). If disagreement occurred between the 2 reviewers, consensus was reached through discussion. If consensus was not attained, the article was rated as “maybe.” Articles rated as “yes” or “maybe” underwent a full article review that was independently
performed by 2 reviewers (D.M.W., P.W.K.). Any disagreement was discussed, and if consensus was not attained, an additional team member (D.R.S.) participated in the process to determine eligibility. Data were extracted from all eligible articles and included DFU closure time, healing rate, type of exercise, daily step count, daily stepping characteristics, and loading. Extracted data were stored electronically. Data were extracted by 1 reviewer (D.M.W.) and checked for accuracy/agreement by a second reviewer (D.R.S.).

Quality appraisal

Risk of bias was performed using an appropriate tool for the type of study assessed. The Physiotherapy Evidence Database (PEDro) was used for randomized controlled trials, A MeaSurement Tool to Assess systematic Reviews (AMSTAR-2) was used for meta-analyses, and Scottish Intercollegiate Guidelines Network (SIGN) checklists were used for other article types.

The literature search identified 3339 articles, and 1628 duplicate articles were removed using the proprietary software. An additional 1690 articles were removed for being irrelevant or otherwise meeting exclusion criteria (Table 1) based on review of the title and abstract. Full-text review was completed on 21 articles, 13 of which were excluded because of the study design (n = 5), the outcomes measures assessed (n = 7), or the patient population (n = 1) (Appendix 2). Eight articles remained to be included and data extracted. A systematic review on a similar topic was published in 2021 and included an article that was not identified in the searches for the present review.⁸ The previously unidentified article was added. A total of 9 articles were included in this review (Figure).

The included studies fell into 2 general groups. One group related to assessments quantifying step activity and loading during healing (eTable 2), and the other related to the addition of NWB exercise during the healing process (Table 3). The search returned only 1 study and its secondary analysis that aimed to quantify plantar pressure or directly assess limb loading.^9,10 Eight of the 9 included studies were randomized controlled trials. Critical assessment of each article revealed moderate to high risk of bias (Table 4). The 2 general groups are reviewed sequentially herein.

Step activity

Subjects. Six studies evaluated step activity and loading and had a combined 285 subjects. Subjects from van Netten et al⁹ were not included in this number to avoid double-counting, because this study was a secondary analysis of an included study.¹⁰ All the studies included patients with plantar DFUs. The DFUs were primarily located on the forefoot; however, 1 study also included subjects with ulcerations on the midfoot as well as those with previous Charcot deformity.¹¹ Two studies did not report the age of participants.^12,13 The remaining studies reported mean or median age ranging from 52 to 64 years. Saltzman et al¹¹ was the only study that did not explicitly include subjects with peripheral neuropathy. All of the included studies excluded patients with certain medical conditions, such as active infection,
malignancy, or active Charcot arthropathy or deformity.^9–14

Offloading devices. All the studies used some form of offloading device. These devices included TCC,^11–13 an RCW rendered nonremovable with the addition of a cohesive bandage (termed iTCC),¹⁴ BTCC (removable),^9,10 RCW,^13,14 half shoe,¹² cast shoe (removable),^9,10 Aircast diabetic walker (Aircast),¹² healing sandal,¹³ and an ankle-high FOS.^9,10 TCC and iTCC were the only nonremovable devices used.

Step activity and loading: relationship to wound closure. Steps were measured with pedometers^12,13 and activity monitors (StepWatch,^9–11 Orthocare Innovations LLC; PAMSys,¹⁴ BioSensics LLC). During the offloading period across these studies, time to closure was inversely related to daily step count. When fewer steps were taken, closure occurred more quickly.^9–14 Similarly, while not statistically different, cumulative stresses were reduced in those who healed versus those who did not heal in the study by van Netten et al.⁹

Specific values for daily step activity varied widely across the studies. Using a pedometer, Armstrong et al¹² reported mean ± standard deviation daily step counts of 600 ± 320 for the TCC group, 768 ± 563 for the RCW group, and 1462 ± 1452 for the half shoe group. Lavery et al¹³ also used a pedometer and reported relatively low mean daily step counts: TCC, 1447 ± 1310; shear walker (RCW), 1404 ± 1234; and healing sandal, 4022 ± 4652. Najafi et al,¹⁴ using an activity monitor, reported the mean daily step counts in the iTCC group of 3912 ± 2525 at baseline and 2994 ± 2551 after 4 weeks. For the RCW group, the mean daily step count was 5273 ± 3337 per day at baseline and 5902 ± 3090 at 4 weeks. In the same study, the pattern of walking was considered such that at 4 weeks, the iTCC group had a shorter so-called longest episode of walking than the RCW group (169 steps ± 78 vs. 382 steps ± 232). Those who healed had a longest walking bout that was more than 40% shorter than the longest walking bout in those who did not heal (190 ± 72 vs. 340 ± 234, respectively).¹⁴ In the van Netten et al⁹ study, which used an activity monitor, daily step activity was 7222 ± 3272 for those who healed versus 9706 ± 6520 for those who did not. While the difference was not significant, a small to moderate effect size was observed (d = 0.48). In a different study, standing—another form of limb loading—may have affected wound healing, with daily standing duration (ie, within a 24-hour period) 50% shorter in those who healed compared with those who did not heal (5.7% ± 4.0 vs. 11.4% ± 3.9; P =.025).¹⁴

Values for peak pressure and cumulative stress were reported in Bus et al¹⁰ and the associated secondary analysis.⁹ Peak pressures at the site of the ulcer varied according to offloading device (BTCC, 81 kPa ±55; cast shoe, 176 kPa ± 80; FOS, 107 kPa ± 52; P =.005) and were significantly lower than the patient’s own shoes (BTCC group, 67% reduction ± 26; cast shoe group, 26% ± 34; FOS group, 47% ± 39; P =.029).¹⁰ Reduction in ulcer area during the initial 4 weeks occurred at rates of 77.9% ± 26.6, 68.3% ± 41.6, and 71.9% ± 28.6 in the BTCC, cast shoe, and FOS groups, respectively; differences between groups were not statistically different.¹⁰

Cumulative plantar stress was reportedly 171 MPa per day ± 161 across the subjects in the secondary analysis.⁹ When those subjects were separated into those who healed (n = 21) and those who did not (n = 10), cumulative plantar pressures were reported as 155 MPa per day ± 131 and 207 MPa per day ± 215, respectively. These pressures were 25% lower in those with healed ulcers.⁹   

Length of follow-up. The studies reported follow-up that ranged from 12 to 20 weeks or until wound closure occurred, whichever came first.^9–14 Follow-up periods beyond wound closure were not included, and no information regarding wound re-ulceration was reported.

Step activity group heterogeneity. Groups were heterogeneous in how step activity was determined and in the offloading devices used for treatment. Additionally, adherence of subjects to the prescribed offloading mechanism was described using self-reporting in only 1 study and in the secondary analysis of the same data.^9,10 Not all studies involved only subjects with peripheral neuropathy, and not all studies reported patient age. This degree of heterogeneity did not allow for a meta-analysis of the data.

Addition of NWB exercise during healing

Subjects. The 3 studies that reported the effect of additional exercise on wound healing in persons with DFU enrolled a total of 145 subjects, with mean ages of 66, 74, and 69 years in the control groups and 61, 62, and 69 years in the exercise groups.^15–17 Only 1 study reported that all subjects had neuropathy.¹⁶ The use of an offloading device was not specified in any of the studies. Standardized wound care was reported in only 1 study and included using saline to clean the wound and gauze dressings.¹⁵ A different study explicitly reported that standardized wound care was not used.¹⁶ The remaining study only described wound care as “normal wound dressing.”¹⁷ In the study that explicitly reported non-standardized wound care, the same provider group treated both the control group and the intervention group to ensure similar wound treatment approaches in each group.¹⁶

Exercise intervention. All 3 studies involving exercise included a 12-week exercise period. In 2 studies, exercises included ROM activities to increase blood flow and joint mobility while maintaining an NWB position.^15,16 Exercises were self-managed, and exercise logs were kept by the patients. In both of these studies, patients were asked to perform exercises twice daily for 12 weeks to match the duration of the follow-up assessments. In the study by Flahr,¹⁶ patients were asked to perform 4 exercises for 10 repetitions each, whereas in the study by Eraydin and Avşar,¹⁵ patients were asked to perform 5 to 10 exercises for 10 to 15 repetitions each. In Nwankwo et al,¹⁷ supervised aerobic exercise was performed 3 times per week using a bicycle ergometer. Initial intensity was based on 60% of maximum HR, and the exercise was progressed to 85% of maximum HR. By the ninth week, patients were exercising for 50 minutes per session (Table 3).

Exercise behavior and the relationship to wound closure. For the self-managed studies, exercise logs were assessed and wound evaluations were performed, with both studies assessing wounds at baseline, 4 weeks, 8 weeks, and 12 weeks.^15,16 In their prospective randomized controlled study, Eraydin and Avşar¹⁵ found significant decreases in ulcer size compared with baseline at all of the subsequent time points (4, 8, and 12 weeks) in the exercise intervention group (P ≤.05). In the control group, only the decrease in ulcer size from baseline to 12 weeks was significant (P =.000). Among the patients who performed exercises, those who exercised more than 30 days healed more quickly than those who exercised 30 days or less. From baseline, for those who exercised 0 to 30 days there was a difference in wound size at 12-week follow-up only (P <.001), whereas those who exercised 31 to 60 days had a difference at 4-, 8-, and 12-week follow-up (P <.001), and those who exercised 61 to 90 days exhibited significant differences at every follow-up measurement (P <.001). The amount of exercise affected the speed of wound closure, with those who exercised at a greater frequency achieving more rapid wound closure.¹⁵ In the study by Flahr,¹⁶ some between-group heterogeneity was present; the exercise group had more comorbidities and the control group was older. Wound size decreased in 9 of the 10 subjects in the exercise group. The remaining participant experienced wound deterioration and received a diagnosis of osteomyelitis 4 weeks into the study. In the control group, wound size increased in 3 of the 8 patients. Approximately the same percentage of patients were reported as healed in both groups (exercise, 30%; control, 33.3%), and the percentage decrease in wound size was not different between groups.

In the supervised study, progressive aerobic exercise was performed using a bicycle ergometer, starting at 60% max HR and progressing to 85% max HR over 12 weeks.¹⁷ Duration of exercise was also progressive up to 50-minute sessions by the ninth week. By 12-week follow-up, 61.29% of participants in the exercise group achieved wound closure, compared with 3.33% in the control group.

Length of follow-up. The maximum follow-up was 12 weeks in all 3 studies.^15-17 None of these studies reported information regarding wound re-ulceration.

NWB exercise group heterogeneity. Patient groups in the NWB exercise studies had widely varying wound sizes at baseline and were managed by different means between the 3 studies.^15-17 The exercise interventions were also variable between the studies. Neuropathic status was not reported in 2 of the studies,^15,17 and such status could have contributed to differences in the reported outcomes. This degree of heterogeneity did not allow for performance of a meta-analysis.

The primary purpose of this study was to determine if exercise, activity, step characteristics, or limb loading affects healing outcomes in persons with DFU. The secondary purpose was to determine if the quantity of exercise, step characteristics, or limb loading affects the timeline for wound closure in persons with DFU. A total of 9 studies were identified, 6 of which assessed daily step activity^9–14 and 3 of which assessed NWB exercise.^15-17 Five of the 6 studies that included step activity assessment and wound closure status were randomized controlled trials that compared the efficacy of different offloading devices.^9,10,12–14 Two of these trials reported daily step counts by device group along with device efficacy for wound healing.^12,13 A third trial reported peak plantar pressure by device group in addition to device efficacy.¹⁰ The 2 remaining randomized controlled trials reported step activity in each device group and compared those activity differences to group healing rates.^9,14 The remaining study that assessed step activity focused on the effect of early weight-bearing activity on healing rates.¹¹ Four of the step activity studies had blinding of assessors.^9,10,13,14 The others lacked any type of blinding, increasing the risk of bias.^11,12 Blinding was not used in any of the studies that assessed the addition of NWB exercise to patients’ care plans.^15,16

The majority of studies that investigated step activity reported that lower step activity was linked to more rapid healing.^12-14 Step counts tended to be lower with nonremovable devices, and improved healing outcomes occurred with the use of nonremovable devices (eg, TCC). This finding is consistent with other studies suggesting better healing outcomes with nonremovable offloading devices than with removable offloading devices.¹⁸ It must be considered that both offloading adherence and step activity or cumulative limb loading may contribute to this finding. Furthermore, the removability of a device can result in effects beyond step activity. Najafi et al¹⁴ reported that time spent standing as well as patterns of walking activity were different between healers and nonhealers, with healers spending less time standing and having shorter longest episodes of walking. If devices are only worn to walk, a patient risks adding detrimental cumulative limb loading from standing, especially if offloading devices are not being used.

In these step activity studies, the subject population is consistent with the age and neuropathic status as those of the subject population in other studies that report healing surrounding DFU and offloading,^19–22 making similar results likely. Within this group of step activity studies, age and neuropathic status are also consistent. Despite these consistencies, there is a large variation in the step activity seen across and within the studies.^9–14 Within the studies, there are large standard deviations of the group metrics, which suggests high variation between subjects. Between the studies, high variation in daily step activity is also observed with some variation possibly resulting from the different devices used to measure activity. The high variation could also be related to the type of offloading device worn by the patient. Variability in mean daily step counts is especially apparent when comparing the Armstrong et al¹² and Bus et al¹⁰ studies. In Armstrong et al,¹² the mean daily step count was 600 ± 320 in the TCC group and 768 ± 563 in the RCW group, whereas in Bus et al¹⁰ the BTCC group (removable device) had a mean daily step count of 8300 ± 3252. The wide variation between studies is consistent with the large variability between subjects. Because of this wide variability, it is difficult to identify a target number of steps that a person with a DFU could safely take while wearing an offloading device. Rather, the total number of steps should be considered along with how those steps are being accumulated and how other limb loading activities (eg, standing) are occurring. The length or intensity of walking bouts may affect healing or recovery.^14,23 Limb loading is dependent in part on how well the offloading device reduces plantar pressure of the foot. Although the search for the present review returned only 1 study and its secondary analysis related to specifically quantifying plantar pressure or direct assessment of limb loading, the findings of the present review suggest that the type of offloading device worn and the amount of loading activity performed are the critical factors in DFU healing. Across the studies, the consistent findings are that reduced limb loading via lower daily step activity, less standing duration, and shorter walking bouts in combination with wearing an offloading device facilitates more rapid wound healing. An additional consideration for effect on healing is adherence. Because these studies do not consistently report adherence, it remains an important factor to consider in future research.

In addition to offloading, exercise that improves blood flow or decreases inflammation to the region of ulceration has been shown to promote healing.^24,25 The 3 NWB exercise studies included in this review varied in quality, and all lacked any type of blinding.^15-17 While the populations included were similar, the wound management strategy was not standardized in 1 study¹⁶ and was poorly described in another.¹⁷ One study reported wound healing occurred at a faster rate with more exercise¹⁵; this result is consistent with non-diabetes- related literature regarding the influence of exercise as a means of promoting more rapid healing.²⁵ The overall results, which are consistent with those reported in Tran and Haley,⁸ demonstrated that exercise has a positive effect on wound healing. ^15-17

Blood flow and the immune response to a wound are critical for wound healing to occur.^26,27 This is the case for all wounds across different disease processes. With diabetes, the effect of blood flow and the immune response could be even greater. Wounds need blood flow to bring appropriate cells to the area to manage the healing process. In persons with diabetes, hyperglycemia also affects the immune system and delays the healing process.²⁶ Exercise is known to mitigate hyperglycemia and promote improved disease management in persons with diabetes.⁵ It is for this reason that exercise could potentially have an even more profound effect on wound healing in this population. Beyond increasing blood flow, ROM exercises may promote improved joint mobility. Stiffness is common in persons with diabetes and may contribute to excessive pressure in certain anatomic areas.²⁸ If ROM exercise can serve to enhance joint mobility, it could mitigate areas of high pressure and further facilitate wound closure and healing. Although the use of exercises such as ankle ROM may be helpful for wound healing, such exercise could pose a particular challenge depending on the offloading mechanism used. For example, in persons wearing a TCC, the ankle is effectively immobilized; thus, ROM exercises would be impossible to perform at the foot and ankle. Similarly, ankle ROM would be necessary to use a bicycle ergometer. Future research investigating alternative exercise for persons using nonremovable offloading devices would be important to determine whether similar exercise at different joints (eg, knee, hip, toe) could further speed the healing process for that group as well.

When offloading and exercise are used together, it is clear that exercise prescription (frequency, intensity, timing, type, volume, and progression) matters.²⁹ The more the foot is offloaded, the faster the healing. Likewise, the more the foot is exercised, the faster the healing. A better understanding of how these 2 divergent mechanisms could complement the healing process is an important area for future research. It is also necessary to understand the healing process after wound closure. Without clear evidence suggesting an appropriate range of loading, clinicians and patients must attempt to delicately balance the 2 goals of protecting the healing DFU to allow closure and prevent re-ulceration while encouraging physical activity for diabetes management and protected wound consolidation. Failure to achieve both goals may put patients at risk for either persistently low activity levels or failure to achieve wound closure or re-ulceration, both of which are significant problems in patients with diabetes. Future studies should attempt to identify an optimal loading zone for exercise while encouraging the maintenance of offloading during the time period prior to wound closure, when offloading is vital for healing, and in the context of acceptable offloading (eg, use of a TCC). Such work should continue after wound closure occurs.

This literature review has limitations. Heterogeneity of studies did not allow for a meta-analysis of studies related to step activity or the addition of NWB exercise during healing. Limited research is available regarding the effects of exercise, activity, step characteristics, and loading on healing outcomes in persons with DFU.

Studies indicate that reduced loading via lower daily step activity, less standing duration, and shorter walking bouts in combination with wearing an offloading device facilitate more rapid wound healing. Exercise seems to facilitate more rapid healing, as well. Further research is necessary to elucidate more prescriptive guidelines for both optimal loading and exercise in persons with DFU.