Pro-inflammatory cytokines are bioactive molecules that enhance inflammatory responses, playing essential roles in infection control, tissue injury response, and immune activation by facilitating pathogen clearance and initiating repair. The major pro-inflammatory cytokines include tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). In contrast, anti-inflammatory cytokines suppress inflammation, alleviate associated symptoms, and promote tissue repair. Key anti-inflammatory mediators include interleukin-4 (IL-4) and interleukin-10 (IL-10). In DFU wounds, pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β are persistently overexpressed, whereas anti-inflammatory cytokines such as IL-10 and transforming growth factor-β (TGF-β) are relatively deficient [4]. This imbalance maintains the wound in a chronic inflammatory state, thereby delaying tissue repair.

Macrophage phenotype regulation is a complex process influenced by epigenetic modifications, metabolic microenvironment, and interactions with other immune cells. Two principal phenotypes are recognized: the pro-inflammatory M1 type and the anti-inflammatory M2 type. In DFU, excessive activation of M1 macrophages coupled with impaired M2 polarization contributes to chronic inflammation, impaired angiogenesis, and delayed tissue repair [5].

VEGF is a highly specific mitogen for vascular endothelial cells and plays a pivotal role in angiogenesis, inflammation, and neuroprotection. VEGF expression is markedly reduced in DFU tissues compared with non-diabetic wounds, resulting in impaired neovascularization, tissue ischemia, and hypoxia, all of which hinder wound repair [6].

bFGF, a member of the fibroblast growth factor family, exerts multiple biological effects, including promoting cell proliferation, differentiation, angiogenesis, and tissue repair. By binding to fibroblast growth factor receptors (FGFRs), bFGF stimulates endothelial cell proliferation and migration, accelerating neovascularization and alleviating ischemia in DFU lesions [7]. Moreover, bFGF has been shown to upregulate VEGF expression, thereby synergistically enhancing revascularization [8].

EGF, a small polypeptide composed of 53 amino acids, binds to its receptor EGFR to activate downstream signaling pathways that stimulate proliferation and differentiation of keratinocytes and fibroblasts, thereby accelerating wound closure. In DFU tissues, EGF levels are significantly reduced, contributing to delayed wound healing [9].

PDGF is a key peptide growth factor regulating cell proliferation, migration, angiogenesis, and tissue repair. Hyperglycemia in DFU patients suppresses PDGF secretion and signaling, resulting in impaired tissue repair and delayed wound closure [10].

The Wnt/β-catenin pathway is critical for embryonic development, tissue homeostasis, and disease progression [11]. It promotes platelet formation and maturation, thereby enhancing the secretion of PDGF, TGF-β1, and VEGF. In DFU patients, this pathway is downregulated, leading to impaired wound healing [12]. Activation of Wnt/β-catenin signaling has been shown to accelerate DFU wound repair.

The Notch signaling pathway is an evolutionarily highly conserved intercellular communication system involved in the regulation of embryonic development, tissue homeostasis, and injury repair [3]. It also plays a significant role in modulating macrophage function [13]. Studies have shown that this signaling pathway exhibits a spatiotemporally dependent dual regulatory effect during wound healing [14]. Specifically, on one hand, inhibition of Notch signaling has been demonstrated to enhance the repair of diabetic foot ulcers [15]; on the other hand, evidence also suggests that activating Notch signaling after skin injury can accelerate the healing process by promoting angiogenesis and modulating inflammatory responses [16]. This discrepancy indicates that Notch signaling may play distinct roles in physiological and pathological healing processes, and its precise regulation requires consideration of the specific healing stage and cellular microenvironment. Therefore, therapeutic strategies targeting this pathway must fully account for its spatiotemporal specificity, implementing precisely timed or cell type-specific interventions to achieve therapeutic benefits and avoid potential adverse effects.

The TGF-β/Smad pathway regulates cell proliferation, differentiation, apoptosis, migration, and immune modulation. In DFU wounds, activation of this pathway promotes M2 macrophage polarization while reducing M1 macrophage activity [17]. Consequently, stimulation of TGF-β/Smad signaling facilitates wound healing in DFU.

The PI3K/AKT/mTOR cascade is one of the most critical intracellular signaling pathways, governing processes such as cell growth, proliferation, metabolism, survival, and migration. Its activation enhances VEGF expression and promotes angiogenesis [18]. Experimental studies confirm that PI3K/AKT/mTOR activation accelerates DFU wound healing.

The NF-κB pathway is a central transcriptional regulator involved in inflammation, immune responses, cell proliferation, and apoptosis. In DFU, NF-κB is abundantly expressed in perivascular macrophages and drives chronic inflammation [19]. Suppression of NF-κB signaling reduces inflammation within DFU wounds and promotes tissue repair.

In TCM, internal therapy refers to the administration of herbal prescriptions or dietary adjustments aimed at regulating qi and blood, harmonizing yin and yang, and restoring the functional balance of the internal organs. It represents a fundamental approach to the systemic treatment of disease.

3.1.1. Application of Single Herbs

Curcuma longa (turmeric) is a traditional Chinese medicinal herb with functions of invigorating blood circulation, promoting qi flow, unblocking meridians, and alleviating pain. Its primary bioactive component, curcumin, has been extensively studied [21]. In an animal study, Yunjingmo et al. [22] reported that curcumin, the active component of Curcuma longa, promotes wound healing by activating the TGF-β/Smad signaling pathway, thereby suppressing inflammatory responses and inducing angiogenesis.

3.1.2. Application of Classical Formulas

Simiao Yong’an Decoction (composed of Lonicera japonica [honeysuckle], Scrophularia ningpoensis, Angelica sinensis, and licorice) was first proposed by the Qing dynasty physician Bao Xiang’ao. It is a representative prescription for heat-toxin type gangrene and continues to be widely applied in modern clinical practice. Modern pharmacological studies have shown that key components of the formula, such as chlorogenic acid from Lonicera japonica [23], harpagoside from Scrophularia ningpoensis [24], and ferulic acid from Angelica sinensis [25], possess anti-inflammatory, antioxidant, and angiogenesis-promoting activities. Chen Xiao [26] reported that Simiao Yong’an Decoction promotes wound healing by elevating the expression of bFGF, EGF, and VEGF. Yanghe Decoction was first recorded by the Qing dynasty physician Wang Hongxu in Waike Zhengzhi Quansheng Ji (Complete Collection of External Medicine). Its original composition includes Rehmannia glutinosa, deer horn gelatin, cinnamon, ephedra, white mustard seed, prepared ginger charcoal, and licorice. With a therapeutic focus on warming yang, nourishing blood, dispersing cold, and unblocking stagnation, it is primarily used for the treatment of yin gangrene. Huangqi Yanghe Decoction is a clinical modification of Yanghe Decoction, in which Astragalus membranaceus (Huangqi) is added to strengthen qi and tonify the spleen. This modification is particularly indicated for patients with marked qi and blood deficiency or pronounced yang deficiency, enhancing circulation and reinforcing the original warming and tonifying effects. Research indicates that components such as astragaloside IV from Astragalus membranaceus [27] and cinnamaldehyde from cinnamon [28] may exert their effects by modulating immune and inflammatory signaling pathways. In animal studies, Bao Yaling et al. [29] found that Huangqi Yanghe Decoction activates the PI3K/AKT signaling pathway while inhibiting NF-κB activation, thereby reducing inflammation and promoting angiogenesis.

In TCM, external therapy refers to the use of surface stimulation, topical herbal applications, or physical interventions applied to meridians, acupoints, or affected areas. The goal is to regulate qi and blood, harmonize yin and yang, and thereby achieve therapeutic effects.

3.2.1. Topical Herbal Applications

Zizhu Ointment (composed of cinnabar, Lithospermum erythrorhizon [gromwell root], Daemonorops draco [dragon’s blood], donkey-hide gelatin, borneol, and astragalus) possesses the functions of clearing heat and detoxifying, removing necrotic tissue and promoting granulation, as well as tonifying qi and nourishing blood. In an animal study, Han Qiang et al.[30] demonstrated that Zizhu Ointment accelerates DFU wound healing by downregulating inflammatory mediators such as IL-1, IL-6, and TNF-α, and by suppressing NF-κB and PI3K signaling pathways. Xianglei Tangzu Ointment (primarily derived from Plectranthus amboinicus extract and total saponins of Centella asiatica) is a domestically developed, nature-inspired formulation. It promotes DFU wound healing by inhibiting polarization toward the M1 macrophage phenotype and enriching M2 macrophages, thereby shifting the inflammatory microenvironment toward repair [31].

3.2.2. Acupuncture

Acupuncture, an essential component of traditional Chinese therapy, integrates needling and moxibustion techniques to stimulate meridians and acupoints. Its therapeutic effects are achieved by regulating qi and blood, harmonizing yin and yang, thereby treating disease and promoting health. In a clinical study conducted at Shenyang Seventh People’s Hospital, Wang Zengmin and colleagues [32] demonstrated that acupuncture combined with conventional pharmacotherapy enhanced the clinical efficacy in DFU patients. This combined approach improved serum levels of bFGF and VEGF, thereby accelerating wound healing and shortening ulcer closure time.

Standard treatment for DFU includes glycemic control, local debridement, and antibiotic therapy. Glycated hemoglobin (HbA1c) levels should be maintained below 7% [33]. Glycemic control can be achieved through oral hypoglycemic agents or insulin therapy. Local management involves removal of necrotic tissue, purulent exudates, and infectious foci. Based on bacterial culture and drug susceptibility testing, appropriate antibiotics are selected to reduce microbial proliferation.

4.2.1. Endovascular Intervention of Lower Limb Arteries

This technique involves balloon angioplasty or stent implantation of stenotic or occluded arteries under the guidance of X-ray or other imaging modalities, with the goal of restoring blood flow to the affected limb. In a meta-analysis, Yi Tingwan et al. [34] concluded that peripheral endovascular intervention significantly improves the ankle-brachial index in DFU patients, enhances ulcer healing efficiency, shortens healing and hospitalization time, and reduces the risk of amputation.

4.2.2. Free Flap Transplantation for Repair

This technique involves harvesting skin and subcutaneous tissue with an intact vascular system from a donor site in the patient and transplanting it to the defect site. Blood vessels are anastomosed under a microscope to reconstruct circulation, thereby restoring both the function and appearance of the wound. Liu Xin et al. [35] conducted a systematic review of numerous domestic and international clinical cases of DFU treated with this technique, demonstrating that free flap transplantation significantly improves limb salvage rates and five-year survival. However, the procedure is associated with a relatively high incidence of postoperative complications, and perioperative management remains complex and challenging [36]. Therefore, clinicians must carefully weigh the risks and benefits when considering free flap transplantation for DFU repair.

4.2.3. Tibial Transverse Transport (TTT)

This technique originates from the “Law of Tension-Stress” proposed by Russian orthopedic surgeon Ilizarov in the 1950s. By applying controlled mechanical tension to the tibia, TTT improves local microcirculation, thereby enhancing foot perfusion and promoting healing of leg and foot ulcers. In a clinical study, Wei Jihua et al. [37] reported that TTT significantly increased serum VEGF and bFGF levels in DFU patients and activated the Notch signaling pathway. Computed tomography angiography (CTA) of the lower limbs performed eight weeks postoperatively revealed abundant new arterioles in the calf muscles and subcutaneous tissue of the treatment group, whereas no obvious neovascularization was observed in the control group. Ultimately, in the treatment group, nine patients achieved complete ulcer healing, with minimal scar formation and wound appearance resembling normal tissue.

Platelet concentrates (PC) are prepared by centrifugation of whole blood to yield a concentrate rich in platelets. The main components include high concentrations of platelets, leukocytes, fibrin, and multiple growth factors such as PDGF, VEGF, and TGF-β. Depending on preparation methods, PC can be classified as platelet-rich plasma (PRP), platelet-rich fibrin (PRF), and concentrated growth factors (CGF) [38]. The therapeutic effect of PC is mediated through the release of growth factors and other bioactive molecules from platelets, thereby promoting tissue repair and exerting anti-inflammatory effects.

In a clinical study, Chen Xiaoyan [39] demonstrated that PRF therapy in DFU patients enhanced VEGF expression and stimulated angiogenesis. Moreover, PRF modulated macrophage polarization, shifting M1-type macrophages toward the M2 phenotype, thereby augmenting anti-inflammatory activity at the wound site and accelerating healing.

4.4.1. Vacuum Sealing Drainage (VSD)

VSD is a wound management technique that promotes healing by applying continuous negative pressure while sealing the wound surface. The sustained negative pressure removes exudates, necrotic tissue, and bacteria, while simultaneously stimulating granulation tissue formation. In a clinical study, Jiao Jiao [40] reported that VSD increased VEGF levels in DFU wound tissue, thereby accelerating ulcer healing.

4.4.2. Hyperbaric Oxygen Therapy (HBO)

HBO involves placing the patient in a pressurized chamber above one atmosphere and administering high-concentration oxygen. The therapeutic principle is to increase environmental pressure and oxygen intake, thereby raising the level of physically dissolved oxygen in the blood. This process improves tissue oxygenation, promotes repair, and suppresses infection. In a systematic review, Wang Zhi [41] found that HBO facilitated ulcer healing in DFU patients and significantly reduced the incidence of major amputations.