Mesenchymal stem cells derivatives as a novel and potential therapeutic approach to treat diabetic foot ulcers.

SUMMARY: Diabetic foot ulcer morbidity and mortality are dramatically increasing worldwide, reinforcing the urgency to propose more effective interventions to treat such a devastating condition. Previously, using a diabetic mouse model, we demonstrated that administration of bone marrow mesenchymal stem cells derivatives is more effective than the use of bone marrow mesenchymal stem cells alone. Here, we used the aforementioned treatments on three patients with grade 2 diabetic foot ulcers and assessed their beneficial effects, relative to the conventional approach. In the present study, two doses of cell derivatives, one dose of mesenchymal stem cells or one dose of vehicle (saline solution with 5% of human albumin), were intradermally injected around wounds. Wound healing process and changes on re-epithelialization were macroscopically evaluated until complete closure of the ulcers. All ulcers were simultaneously treated with conventional treatment (PolyMen® dressing). Patients treated with either cell derivatives or mesenchymal stem cells achieved higher percentages of wound closure in shorter times, relative to the patient treated with the conventional treatment. The cell derivative and mesenchymal stem cells approaches resulted in complete wound closure and enhanced skin regeneration at some point between days 35 and 42, although no differences between these two treatments were observed. Moreover, wounds treated with the conventional treatment healed after 161 days. Intradermal administration of cell derivatives improved wound healing to a similar extent as mesenchymal stem cells. Thus, our results suggest that mesenchymal stem cell derivatives may serve as a novel and potential therapeutic approach to treat diabetic foot ulcers. LEARNING POINTS: In diabetic mouse models, the administration of mesenchymal stem cells derivatives have been demonstrated to be more effective than the use of marrow mesenchymal stem cells alone. Mesenchymal stem cells have been explored as an attractive therapeutic option to treat non-healing ulcers. Mesenchymal stem cells derivatives accelerate the re-epithelialization on diabetic foot ulcers.

Minimally invasive surgery for diabetic plantar foot ulcerations.

Complications of diabetes mellitus constitute the most common indications for hospitalization and non-traumatic amputations in the USA. The most important risk factors for the development of diabetic foot ulcerations include the presence of peripheral neuropathy, vasculopathy, limited joint mobility, and pre-existing foot deformities. In our study, 500 diabetic patients treated for plantar forefoot ulcerations were enrolled in a prospective study from 2000 to 2008 at the Federal University of São Paulo, Brazil. Fifty-two patients in the study met the criteria and underwent surgical treatment consisting of percutaneous Achilles tendon lengthening to treat plantar forefoot ulcerations. The postoperative follow-up demonstrated prevention of recurrent foot ulcerations in 92% of these diabetic patients that maintained an improved foot function. In conclusion, our study supports that identification and treatment of ankle equinus in the diabetic population may potentially lead to decreased patient morbidity, including reduced risk for both reulceration, and potential lower extremity amputation.

Ten years of a multidisciplinary diabetic foot team approach in Sao Paulo, Brazil.

Diabetes mellitus can cause devastating foot problems including loss of protective sensation with subsequent ulcerations and amputations. The natural history and pathophysiology of diabetic foot ulcers is best understood and managed by a multiprofessional team approach. The main factors for prevention and treatment of these devastating diabetic foot conditions are shown, with special attention to education of the patient. This approach decreases the morbidity of the disease, besides its economical and social feasibility.

Análise de fatores associados à ulceração de extremidades em indivíduos diabéticos com neuropatia periférica / Analysis of factors associated with extremity ulceration in diabetic subjects with peripheral neuropathy

A neuropatia periférica é o principal fator de risco para ulceração em pé de indivíduos diabéticos. Este estudo testou a associação de doença arterial periférica (DAP) à ulceração do pé em amostra de pacientes com neuropatia sensório-motora simétrica distal e se marcadores inflamatórios subclínicos também se associariam a esse evento. Foram avaliados 32 indivíduos diabéticos tipo 2 com exame do monofilamento de 10 g alterado, estratificados em 2 grupos segundo a história ou presença de úlcera nas extremidades inferiores. O grupo "com úlcera" (n = 18) incluiu aqueles que apresentavam úlcera ativa ou cicatrizada, ou que tiveram alguma amputação em membro inferior decorrente de complicações da úlcera. Além do exame neurológico e monofilamento, foram submetidos a bioestesiometria, avaliação vascular com Doppler e exames laboratoriais. Os grupos foram semelhantes quanto à distribuição dos sexos, média de idade e tempo de diabetes. O grupo com úlcera apresentou valores médios de altura (1,70 ± 0,06 vs. 1,63 ± 0,11 m; p = 0,044) e limiar de percepção vibratória no maléolo medial (40,9 ± 13,0 vs. 30,6 ± 12,3 V; p = 0,040) mais elevados que o sem a úlcera. Os grupos não diferiram entre si quanto à média dos marcadores inflamatórios. A resposta do reflexo patelar foi também pior no grupo com úlcera (p = 0,047), no qual se observou maior proporção de indivíduos com o índice hálux-braquial alterado (p = 0,030) quando comparado ao sem úlcera. Conclui-se que a DAP está associada à presença de úlcera (atual ou pregressa) em membros inferiores de indivíduos diabéticos neuropatas. A pesquisa de alteração de fluxo de artérias digitais de membro inferior (no hálux) contribuiu para detectar tal associação. Associação de neuropatia ulcerada a marcadores inflamatórios não foi observada, não sendo possível excluí-la devido às limitações do tamanho da amostra. Estudos prospectivos deverão examinar a sensibilidade do índice hálux-braquial...

Peripheral neuropathy is the main risk factor for foot ulceration in diabetic subjects. This study examined the association of peripheral arterial disease (PAD) with foot ulceration in a sample of diabetic subjects with peripheral neuropathy, and also if inflammatory markers would be associated with this event. We evaluated 32 type 2 diabetic individuals with abnormal 10-g monofilament exam, who were stratified in 2 groups according to history or presence of lower extremities ulcer. The group "with ulcer" (n = 18) included the ones that had active or cicatrized ulcer, or some lower-extremity amputation due to ulcer complications. In addition to the neurological examination and monofilament test, they were submitted to biothesiometry, lower extremity vascular assessment with Doppler, and laboratory determinations. No difference between the groups was found concerning sex distribution, mean age, and duration of diabetes diagnosis. The group with ulcer showed higher mean values of height (1.70 ± 0.06 vs. 1.63 ± 0.11 m, p = 0.044), vibration perception threshold measured in medial malleolli (40.9 ± 13.0 vs. 30.6 ± 12.3 V, p = 0.040) than the group without ulcer. The groups did not differ regarding the mean values of the inflammatory markers. Response to patellae reflex was worse in the group with ulcer (p = 0.047), in which a higher proportion of individuals with abnormal toe-brachial index (p = 0.030) was observed as compared to those without ulcer. We concluded that PAD is associated with the presence of ulcer in neuropathic subjects. The assessment of digital arteries flow in lower limbs (in great toe) contributed to detect such association. Association of diabetic foot ulcers and inflammatory markers was not observed, but cannot be excluded due to limitations of sample size. Prospective studies should examine the sensitivity of the toe-brachial index to identify PAD in diabetic individual at risk of ulceration.