Longitudinal physiological remoulding of lower limb skin as a cause of diabetic foot ulcer: a histopathological examination

Abstract

Objective: Diabetic foot ulcer (DFU) is recognised as a severe complication in patients with type 2 diabetes. With the increasing incidence of diabetes, it represents a major medical challenge. Several models have been proposed to explain its aetiology; however, they have never been assessed by longitudinal histopathological examination, which this study aims to address. Method: Multiplex-immunofluorescence analysis was carried out with lengthwise serial skin specimens obtained from the medial thigh, lower leg, ankle, dorsum of foot and acrotarsium close to the DFU region of a patient with type 2 diabetes receiving above the knee amputation. Results: Proximal-to-distal gradual loss of peripheral nerve was demonstrated, accompanied by compromised capillaries in the superficial papillary plexus and distended CD31-positive capillaries in the dorsum of foot. Neural fibres and capillaries were also significantly compromised in the sweat gland acinus in the ankle and dorsum of foot. Injuries in the superficial papillary plexus, sweat gland acinus, and sweat gland-associated adipose tissues were accompanied by significant infiltration of macrophages. These results indicated that longitudinal impairment of local blood circulation could be the cause of peripheral neuropathy, which initiated ulcer formation. Resultant chronic inflammation, involving sweat gland-associated adipose tissue, gave rise to impairment of wound healing, and thus DFU formation. Conclusion: Longitudinal histopathological examination demonstrated that impairment of local microvascular circulation (rather than the systemic complication caused by type 2 diabetes) was considered the primary cause of peripheral neuropathy, which initiated ulceration. Together with chronic inflammation in the superficial papillary plexus and sweat gland-associated adipose tissue, it resulted in the development of a DFU. Although this is a study of just one individual's limb, our study provided a unique observation, contributing mechanistic insights into developing novel intervening strategies to prevent and treat DFUs.