Регенеративная терапия на основе коллагена в критическом ишемическом диабиотическом ульце: доклад по делу о лимб-алкоголе.

Key Clinical Message In chronic ischemic diabetic foot ulcers refractory to conventional care, injectable collagen‐based regenerative therapy can promote granulation, infection control, and reepithelialization, achieving durable limb salvage, particularly when integrated with endovascular revascularization in patients with diffuse peripheral arterial disease.

Key Clinical Message

In chronic ischemic diabetic foot ulcers refractory to conventional care, injectable collagen‐based regenerative therapy can promote granulation, infection control, and reepithelialization, achieving durable limb salvage, particularly when integrated with endovascular revascularization in patients with diffuse peripheral arterial disease.

Introduction

Diabetic foot ulcers (DFUs) complicated by severe ischemia and infection remain a leading cause of morbidity, lower‐limb amputation, and prolonged hospitalization worldwide. Patients with end‐stage renal disease (ESRD) on hemodialysis and diffuse peripheral arterial disease (PAD) are particularly vulnerable to poor wound‐healing outcomes, as conventional therapies frequently fail to achieve closure in this population.

Wound healing is a complex, tightly coordinated process comprising four interdependent phases: hemostasis, inflammation, proliferation, and remodeling that collectively restore tissue integrity after injury [ 1 ]. In chronic diabetic and ischemic ulcers, this physiological cascade becomes impaired by persistent inflammation, excessive protease activity, and poor vascularization, leading to extracellular matrix (ECM) degradation and arrested repair [ 1 ]. Injectable collagen‐based hydrogels have been shown to facilitate angiogenesis and ECM reorganization in wound‐healing models, supporting their role as biologically active scaffolds rather than inert fillers [ 2 ].

Beyond their structural role, collagen‐based biomaterials actively modulate cellular signaling, angiogenesis, and macrophage polarization, thereby enhancing tissue regeneration in chronic ischemic wounds. Injectable collagen formulations have been developed to support fibroblast proliferation, ECM remodeling, and local angiogenic activity. We report a case of a chronic ischemic diabetic foot ulcer that responded dramatically to collagen‐based regenerative therapy after prolonged unsuccessful conventional management, resulting in durable limb salvage on two separate occasions.

Case History/Examination

Patient History

A 58‐year‐old man with long‐standing, poorly controlled type 2 diabetes mellitus, hypertension, dyslipidemia, ischemic heart disease (status post two prior diagnostic coronary angiographies without intervention), and end‐stage renal disease (ESRD) on regular hemodialysis for more than five years presented with a chronic, infected, nonhealing ulcer of the right foot. His vascular history was notable for previously diagnosed bilateral lower‐limb peripheral arterial disease (PAD), with a prior right lower‐limb endovascular angioplasty approximately two years earlier. Additional surgical history included excision of a brain mass in 2010, appendectomy, and right inguinal hernioplasty. He had also experienced severe COVID‐19 pneumonia with residual pulmonary fibrosis. The patient was maintained on long‐term cardiovascular and antiplatelet therapy, including aspirin, bisoprolol, nifedipine, amiodarone, and an oral hypoglycemic agent. The current ulcer had been present for more than one year prior to presentation at our service, having failed multiple prior interventions, including broad‐spectrum antibiotics, repeated surgical debridement, vacuum‐assisted closure (VAC), and advanced topical dressings.

Clinical Findings on Examination

On examination, the initial ulcer was located on the plantar surface (sole) of the right foot and appeared as a deep, irregular, necrotic lesion with slough and foul discharge, accompanied by surrounding erythema and tenderness (Figure  1 ). Peripheral pulses were diminished, and local skin temperature was reduced, consistent with severe ischemia. Plain radiography of the right foot demonstrated bony deformities consistent with diabetic Charcot neuroarthropathy, joint disorganization, subluxation, and bone resorption with periarticular sclerosis predisposing the patient to recurrent ulceration at deformity‐related pressure points (Figure  2 ).

Initial clinical appearance of the plantar ulcer, showing a deep necrotic lesion with central slough, exposed deep tissue, foul discharge, and surrounding erythema.

Plain radiograph of the right foot showing Charcot neuroarthropathy with bone resorption, joint disorganization, and periarticular sclerosis.

Several weeks later, while the plantar ulcer was in partial recovery, two additional ulcers developed simultaneously over the great toe and the posterior heel. The toe lesion was characterized by a shallow ulcerative base with exposed dermis and mild exudation (Figure  3 ), whereas the heel lesion exhibited a deeper necrotic center with undermined edges and signs of pressure‐induced ischemia (Figure  4 ).

Great toe ulcer at presentation: Shallow ulcerative base with exposed dermis and mild exudation.

Posterior heel ulcer at presentation: Deeper necrotic center with undermined edges and evidence of pressure‐induced ischemia.

Timeline

A chronological summary of the patient's clinical course is presented in Table  1 .

TABLE 1 Chronological timeline of clinical events and interventions. Time point Event > 1 year prior Chronic, nonhealing plantar foot ulcer; conventional therapy (broad‐spectrum antibiotics, repeated debridement, vacuum‐assisted closure, advanced dressings) all unsuccessful. Recurrent multidrug‐resistant infections. Baseline (Day 0) Initiation of injectable collagen‐based regenerative therapy for the plantar ulcer. Weeks 1–3 Three sessions of Collagen‐Poly + Collagen‐Matrix (2 mL) to the plantar ulcer. Weeks 4–10 Seven sessions alternating Collagen‐Tissue + Matrix and Collagen‐Tissue + Muscle; progressive granulation and contraction. Weeks 10–12 Development of two additional ulcers over the great toe and posterior heel. Weeks 12–17 Five sessions for the toe and heel ulcers: two Collagen‐Poly + Matrix, two Collagen‐Poly + Muscle, one Collagen‐Poly + Matrix. Month 3 Complete epithelialization of all ulcers; wound cultures negative; resumption of weight‐bearing in protective footwear. ~Month 15 Thermal burn injury (neuropathy‐related) producing a new ischemic ulcer. ~Month 15 CT angiography reveals severe femoral/tibial stenoses with peroneal occlusion → percutaneous angioplasty and stenting. Months 15–17 Collagen‐based regenerative therapy reinitiated for 2 months. Month 17 onward Substantial wound improvement; complete limb preservation maintained.

Chronological timeline of clinical events and interventions.

Differential Diagnosis, Investigations, and Treatment

Differential Diagnosis

Given the patient's long‐standing diabetes, ESRD, and clinical picture, the differential diagnosis included neuropathic (Charcot‐related) ulceration, purely ischemic ulceration from PAD, infected diabetic foot ulcer with possible underlying osteomyelitis, and uremia‐related calciphylaxis. Calciphylaxis was considered less likely in the absence of characteristic painful violaceous skin lesions or vascular calcifications on histology, although diffuse arterial calcification was later confirmed radiologically. The final clinical diagnosis was a chronic, infected, ischemic diabetic foot ulcer with underlying Charcot neuroarthropathy in a patient with diffuse PAD and ESRD on hemodialysis.

Investigations

Plain radiography of the right foot (Figure  2 ) demonstrated changes consistent with Charcot neuroarthropathy. Over the protracted clinical course, repeated wound‐swab cultures grew a sequence of multidrug‐resistant Gram‐negative and Gram‐positive organisms, including
Escherichia coli
(with later isolation of an extended‐spectrum β‐lactamase [ESBL]–producing strain),
Pseudomonas aeruginosa
, Acinetobacter species, Enterococcus species, coagulase‐negative Staphylococcus , methicillin‐resistant
Staphylococcus epidermidis
(MRSE),
Enterobacter cloacae
, and
Proteus mirabilis
(including an ESBL‐producing strain). The patient further developed two distinct episodes of methicillin‐resistant
Staphylococcus aureus
(MRSA) bacteremia, documented on aerobic blood cultures and requiring prolonged courses of intravenous antibiotics. Targeted antimicrobial regimens, tailored to culture‐and‐sensitivity results, comprised repeated courses of intravenous vancomycin, meropenem, ceftazidime, and amikacin, alongside oral agents according to susceptibility profiles. Despite this aggressive antimicrobial therapy, the wound remained necrotic and nonhealing, with extensive slough, foul odor, and surrounding cellulitis.

At the time of recurrence, CT angiography (Figure  5 ) followed by bilateral lower‐limb diagnostic catheter angiography (performed via bilateral 6 Fr antegrade femoral access under Doppler guidance) revealed extensive bilateral disease. Both superficial femoral arteries were heavily calcified but patent. The right popliteal artery demonstrated an upper‐pole atheromatous stenosis of approximately 30% with distal patency; the right anterior tibial artery, tibial trunk, and posterior tibial artery were diseased but patent, with total occlusion of the right peroneal artery. On the left, the popliteal artery was diffusely diseased but patent, the anterior tibial and posterior tibial arteries demonstrated severe atherosclerosis with multiple severe stenoses, the tibial trunk was diseased but patent, and the left peroneal artery was totally occluded. These bilateral findings provided the roadmap for endovascular intervention described in Section  3.3.3 .

CT angiography of the right lower limb prior to catheterization, showing diffuse arterial calcification, severe tibial and peroneal artery stenoses, and markedly reduced distal perfusion.

Severity Assessment at Presentation

Objective measures of wound and ischemia severity at initial presentation are summarized below; values refer to the index (plantar) ulcer at the time of treatment initiation
Diabetic foot ulcer classification: Wagner Grade 3 (deep ulcer extending to bone with surrounding infection); University of Texas classification 3D (Grade 3, with infection and ischemia). Peripheral vascular assessment: Ankle‐Brachial Index (ABI) and Toe‐Brachial Index (TBI) were not reliably measurable because of diffuse, non‐compressible arterial calcification (medial calcific sclerosis). The clinical stage was consistent with Rutherford category 5 (ischemic ulceration with minor tissue loss). Objective documentation of the underlying ischemia is provided by the CT and catheter angiography described above and in Figure  5 . Key laboratory parameters: Documented during the acute infective and peri‐procedural admissions, laboratory testing reflected active infection, chronic anemia, and uncontrolled diabetes on a background of established renal failure: C‐reactive protein markedly elevated (up to 39.1 mg/L; reference 0–5), hemoglobin 9.7–10.4 g/dL, glycated hemoglobin (HbA1c) 7.5%–8.0%, fasting/random blood glucose up to 354 mg/dL, and serum creatinine 6.5–9.3 mg/dL consistent with end‐stage renal disease on hemodialysis. Serum albumin was 4.5 g/dL. Composite limb‐risk classification: Society for Vascular Surgery WIfI (Wound, Ischemia, foot Infection) score W3/I3/fI3, corresponding to clinical stage 4, a very‐high‐risk stratum for major lower‐limb amputation, particularly given the documented MRSA bacteremia and bilateral chronic limb‐threatening ischemia.

Diabetic foot ulcer classification: Wagner Grade 3 (deep ulcer extending to bone with surrounding infection); University of Texas classification 3D (Grade 3, with infection and ischemia).

Peripheral vascular assessment: Ankle‐Brachial Index (ABI) and Toe‐Brachial Index (TBI) were not reliably measurable because of diffuse, non‐compressible arterial calcification (medial calcific sclerosis). The clinical stage was consistent with Rutherford category 5 (ischemic ulceration with minor tissue loss). Objective documentation of the underlying ischemia is provided by the CT and catheter angiography described above and in Figure  5 .

Key laboratory parameters: Documented during the acute infective and peri‐procedural admissions, laboratory testing reflected active infection, chronic anemia, and uncontrolled diabetes on a background of established renal failure: C‐reactive protein markedly elevated (up to 39.1 mg/L; reference 0–5), hemoglobin 9.7–10.4 g/dL, glycated hemoglobin (HbA1c) 7.5%–8.0%, fasting/random blood glucose up to 354 mg/dL, and serum creatinine 6.5–9.3 mg/dL consistent with end‐stage renal disease on hemodialysis. Serum albumin was 4.5 g/dL.

Composite limb‐risk classification: Society for Vascular Surgery WIfI (Wound, Ischemia, foot Infection) score W3/I3/fI3, corresponding to clinical stage 4, a very‐high‐risk stratum for major lower‐limb amputation, particularly given the documented MRSA bacteremia and bilateral chronic limb‐threatening ischemia.

Taken together, these objective parameters confirmed that the patient presented with a chronic, infected, ischemic diabetic foot ulcer at very high risk of major lower‐limb amputation, supporting the use of an adjunctive regenerative approach in addition to standard wound and vascular care.

Treatment

Initial conventional management for more than one year had included:
Broad‐spectrum intravenous and oral antibiotics guided by repeated wound cultures Repeated surgical debridement and vacuum‐assisted closure (VAC) therapy Multiple topical agents, including silver‐impregnated dressings, hydrogels, and antimicrobial gauze.

Broad‐spectrum intravenous and oral antibiotics guided by repeated wound cultures

Repeated surgical debridement and vacuum‐assisted closure (VAC) therapy

Multiple topical agents, including silver‐impregnated dressings, hydrogels, and antimicrobial gauze.

After multidisciplinary review and informed consent, injectable collagen‐based regenerative therapy was initiated as an adjunct to ongoing wound care. The therapy used four injectable Collagen Medical Devices (CMDs) manufactured by Guna S.p.a. (Milan, Italy): MD‐POLY, MD‐MATRIX, MD‐TISSUE, and MD‐MUSCLE. Each is a CE‐marked, sterile, ready‐to‐use medical device based on Type I porcine collagen (approximately 100 μg per 2‐mL vial) combined with auxiliary substances of natural or mineral origin selected to target specific tissue compartments. MD‐POLY provides general regenerative scaffolding, MD‐MATRIX supports extracellular matrix reorganization, MD‐TISSUE targets connective‐tissue repair, and MD‐MUSCLE supports muscle and deeper soft‐tissue regeneration. Products were used singly or in combination according to wound depth and the predominant tissue requiring repair.

Sessions were delivered weekly under sterile conditions by perilesional intradermal and subcutaneous injection using a 27‐gauge needle, distributing approximately 0.2–0.5 mL per injection point at multiple sites circumferentially around the wound margins and into the wound bed where exposed deep tissue was present. The typical total volume administered per session was 4 mL (two 2‐mL vials combined). The treatment protocol below was tailored to each ulcer:

Plantar (Sole) Ulcer Protocol

Three initial sessions of Collagen‐Poly + Collagen‐Matrix (2 mL). Seven subsequent sessions alternating Collagen‐Tissue + Matrix and Collagen‐Tissue + Muscle.

Three initial sessions of Collagen‐Poly + Collagen‐Matrix (2 mL).

Seven subsequent sessions alternating Collagen‐Tissue + Matrix and Collagen‐Tissue + Muscle.

Progressive improvement was observed across treatment, with healthy granulation, reduction in ulcer depth and surface area, and ultimately complete epithelialization (Figure  6A–C ).

Sequential progression of the plantar ulcer during collagen‐based regenerative therapy. (A) Early response showing reduced necrosis with peripheral granulation. (B) Mid‐treatment with markedly contracted wound margins and healthy granulation. (C) Complete reepithelialization with restoration of plantar surface integrity.

Toe and Heel Ulcer Protocol

Two sessions of Collagen‐Poly + Matrix. Two sessions of Collagen‐Poly + Muscle. One final session of Collagen‐Poly + Matrix.

Two sessions of Collagen‐Poly + Matrix.

Two sessions of Collagen‐Poly + Muscle.

One final session of Collagen‐Poly + Matrix.

Both lesions responded with rapid granulation, infection control, and near‐complete closure over the following weeks (Figures  7 and 8 ).

Great toe ulcer following collagen therapy, demonstrating granulation, infection clearance, and near‐complete epithelialization.

Posterior heel ulcer following collagen therapy, with infection resolution and contraction of the wound margins to a small residual epithelial defect.

Endovascular Revascularization (Recurrence)

On recurrence, approximately one year after initial healing, the patient underwent bilateral lower‐limb diagnostic catheter angiography via 6 Fr antegrade femoral access under Doppler guidance, followed by left‐sided endovascular intervention. Three vessels of the left lower limb were treated by percutaneous balloon angioplasty using NanoCross balloons: the left anterior tibial artery (2.5 × 120 mm), the left peroneal artery (3 × 80 mm), and the left posterior tibial artery (2 × 80 mm), each crossed using a 0.014‐in. wire with guiding‐catheter support. No stents were deployed. Angiographic result was excellent, with restoration of flow through the anterior and posterior tibial arteries. The patient tolerated the procedure well, and no access‐site complications were observed. Collagen‐based regenerative therapy was reinitiated thereafter and continued for two further months.

Conclusion and Results (Outcome and Follow‐Up)

Within weeks of initiating collagen‐based regenerative therapy, all ulcers demonstrated healthy granulation tissue, reduction in slough, and progressive contraction. By three months, wound cultures were negative, and complete epithelialization had been achieved, with restoration of structural integrity of the foot. The patient resumed weight‐bearing in protective footwear without ulcer recurrence in the immediate follow‐up period.

Approximately one year later, the patient sustained a new ischemic ulcer following a thermal burn injury related to diabetic peripheral neuropathy, which became infected and was complicated by cellulitis (documented in the hospital record as an infected foot burn with cellulitis in the setting of peripheral vascular disease). After endovascular revascularization, collagen‐based regenerative therapy was reinitiated for two months, resulting in substantial wound improvement and continued limb preservation.

The patient reported significant pain relief, improved quality of life, and avoidance of amputation after prolonged treatment failure. He emphasized the psychological benefit of being able to ambulate and return to his daily activities. No adverse events were attributable to the collagen‐based therapy, and adherence to the planned injection schedule was complete.

Discussion

This case illustrates the potential of collagen‐based regenerative therapy as an effective adjunctive treatment for chronic ischemic diabetic ulcers that are unresponsive to conventional measures. Collagen enhances the natural wound‐healing cascade by supporting fibroblast migration, promoting angiogenesis, and stimulating ECM remodeling.

Injectable collagen formulations function as temporary extracellular scaffolds that facilitate fibroblast migration and proliferation, stimulate synthesis of Type I and III collagen, and promote angiogenesis. By stabilizing the wound environment and supporting cellular repair, injectable collagen transforms a chronic, nonhealing ulcer into an active, regenerative wound capable of proper remodeling [ 1 ].

In addition to its structural and biochemical functions, collagen modulates the immune microenvironment by shifting macrophages from the pro‐inflammatory M1 to the pro‐regenerative M2 phenotype, thereby enhancing angiogenesis, fibroblast proliferation, and matrix synthesis processes typically impaired in chronic ischemic and diabetic wounds [ 3 ]. This regenerative mechanism likely explains the rapid granulation and closure observed in our patient after collagen therapy was introduced.

Recent advances in collagen‐based regenerative materials incorporate platelet‐derived growth factors and bioactive peptides to enhance angiogenic signaling, cellular infiltration, and scaffold vascularization, paving the way for more personalized and effective treatment strategies in complex ischemic wounds [ 4 ]. Several clinical studies have demonstrated that injectable collagen and dermal matrix applications significantly enhance healing rates in DFUs while remaining safe and well tolerated, with low rates of infection or other complications [ 5 ]. The use of dermal matrix as an adjuvant therapy has been shown to accelerate wound closure in difficult‐to‐heal ulcers [ 5 ].

These findings are consistent with previous clinical experience showing that collagen‐based materials can achieve rapid and durable healing outcomes. In one trial of 26 patients with complex leg ulcers treated using a dermal substitute and thin skin graft, complete graft attachment occurred in 88.5% of cases, with the remaining 11.5% achieving more than 70% surface adherence; most ulcers healed completely within four weeks, and no recurrence was reported after three months of follow‐up [ 6 ].

In the present case, collagen injections contributed to infection resolution, improved local vascularization, and complete tissue repair. The recurrence of a new ischemic ulcer one year later, which again responded to collagen therapy after endovascular revascularization, further supports its role as a regenerative and limb‐salvaging intervention in complex diabetic wounds. The clinical success observed here highlights the potential of collagen therapy to bridge the gap between conventional wound care and advanced tissue‐engineering approaches, particularly in patients with limited vascular reconstructive options.

Importantly, this case suggests that the early integration of collagen regenerative therapy with vascular interventions may act synergistically, improving perfusion, reducing the risk of major amputation, and accelerating recovery in patients with combined diabetic and ischemic pathology [ 7 ]. While these results are encouraging, this remains a single‐patient experience; controlled clinical trials are needed to confirm efficacy and define optimal treatment protocols across broader patient populations.

In conclusion, collagen‐based regenerative therapy achieved remarkable tissue repair and durable wound closure in a chronic ischemic diabetic foot ulcer refractory to standard care, and again in a recurrent ischemic ulcer following revascularization. In this patient, it served as an effective limb‐salvaging modality, suggesting a promising role for collagen‐based interventions as complementary therapy in severe ischemic diabetic wounds. Early integration with vascular procedures may further enhance outcomes, although prospective controlled studies are required to validate these observations.

Learning Points

Chronic ischemic diabetic foot ulcers in patients with ESRD and diffuse PAD are frequently refractory to conventional wound care and carry a high risk of major amputation. Injectable collagen‐based regenerative therapy can promote granulation, infection control, and reepithelialization in wounds previously unresponsive to debridement, antibiotics, and VAC therapy. Combining collagen therapy with endovascular revascularization may produce a synergistic effect, supporting limb salvage even in recurrent ischemic ulceration. Multidisciplinary management incorporating vascular intervention, infection control, and regenerative therapy is critical for limb preservation in high‐risk diabetic patients.

Chronic ischemic diabetic foot ulcers in patients with ESRD and diffuse PAD are frequently refractory to conventional wound care and carry a high risk of major amputation.

Injectable collagen‐based regenerative therapy can promote granulation, infection control, and reepithelialization in wounds previously unresponsive to debridement, antibiotics, and VAC therapy.

Combining collagen therapy with endovascular revascularization may produce a synergistic effect, supporting limb salvage even in recurrent ischemic ulceration.

Multidisciplinary management incorporating vascular intervention, infection control, and regenerative therapy is critical for limb preservation in high‐risk diabetic patients.

Author Contributions

Omair Bseiso: methodology, investigation, writing – original draft, writing – review and editing. Ma'moun Qawasmeh: methodology, data curation, investigation, visualization. Zaid Mujahed: methodology, data curation, investigation, visualization. Anas Zahdeh: writing – original draft, writing – review and editing. Orjuwana Abu Zir: writing – original draft, writing – review and editing.

Funding

The authors have nothing to report.

Ethics Statement

This case report did not require formal ethics committee approval, in line with the policies of the contributing institutions for de‐identified single‐patient case reports.

Consent

Written informed consent was obtained from the patient for publication of this case report and all accompanying clinical images. Patient identifiers have been removed from the manuscript and figures in accordance with institutional and journal guidelines.

Conflicts of Interest

The authors declare no conflicts of interest.