Cost-effectiveness of using adjunctive porcine small intestine submucosa tri-layer matrix compared with standard care in managing diabetic foot ulcers in the US.

OBJECTIVE: To estimate the cost-effectiveness of using tri-layer porcine small intestine submucosa (SIS; Oasis Ultra) as an adjunct to standard care compared with standard care alone in managing diabetic foot ulcers (DFUs) in the US, from the perspective of Medicare. METHOD: A Markov model was constructed to simulate the management of diabetic neuropathic lower extremity ulcers over a period of one year in the US. The model was used to estimate the cost-effectiveness of initially using adjunctive SIS compared with standard care alone to treat a DFU in the US at 2016 prices. RESULTS: At 12 months after the start of treatment, the use of adjunctive SIS instead of standard care alone is expected to lead to a 42 % increase in the number of ulcer-free months, 32 % increase in the probability of healing, a 3 % decrease in the probability of developing complicated ulcers and a 1 % decrease in the probability of undergoing an amputation. Health-care resource use is expected to be reduced by 11-14 % among patients who are initially managed with adjunctive SIS compared with those initially managed with standard care alone, with the exception of debridement, which is expected to be reduced by 35 %. Hence, the total health-care cost of starting treatment with adjunctive SIS instead of standard care alone was estimated to reduce payer costs by 1% (i.e. $105 per patient) over 12 months following the start of treatment. CONCLUSION: Within the study's limitations, the use of adjunctive SIS instead of standard care alone improves outcome for less cost and thereby affords a cost-effective use of Medicare-funded resources in the management of neuropathic foot ulcers among adult patients with type 1 or 2 diabetes mellitus in the US.

The microbiome of diabetic foot osteomyelitis.

The purpose of this investigation was to evaluate the diversity of bacteria in diabetic foot osteomyelitis using a 16S rRNA sequencing approach and to compare the results with conventional culture techniques. In this prospective observational study, we obtained 34 bone samples from patients admitted to our hospital with a moderate-severe diabetic foot infection. We analysed the distribution of the 16S rRNA gene sequences in the bone samples, using an Illumina MiSeq Personal Sequencer. We compared the genera that were detected with the cultured pathogens in the bone samples with conventional techniques. In the 23 samples that had positive results with both techniques, Staphylococcus, Corynebacterium, Streptococcus and Propionibacterium spp. were detected in 20, 18, 13 and 11 samples, respectively. Significantly more anaerobes were detected with 16S rRNA sequencing compared to conventional techniques (86.9 % vs. 23.1 %, p = 0.001) and more Gram-positive bacilli were present (78.3 % vs. 3.8 %, p < 0.001). Staphylococcus spp. were identified in all of the sequenced bone samples that were negative with conventional techniques. Mixed genera were present in 83.3 % (5 of 6) of the negative samples. Anaerobic and fastidious organisms may play a more significant role in osteomyelitis than previously reported. Further studies with larger populations are needed in order to fully understand the clinical importance of the microbial diversity of diabetic foot osteomyelitis.

Ability of commercial demineralized freeze-dried bone allograft to induce new bone formation.

Demineralized freeze-dried bone allograft (DFDBA) has been used extensively in periodontal therapy. The rationale for use of DFDBA includes the fact that proteins capable of inducing new bone; i.e., bone morphogenetic proteins, can be isolated from bone grafts. Commercial bone banks have provided DFDBA to the dental practitioner for many years; however, these organizations have not verified the osteoinductive capacity of their DFDBA preparations. The aim of this study was to determine the ability of commercial DFDBA preparations to induce new bone formation. DFDBA with particle sizes ranging from 200 to 500 microns was received from six bone banks using various bone production methods. Different lots of DFDBA from the same tissue bank were sometimes available. A total of 14 lots were examined. The surface area of bone particles in each sample was measured morphometrically and the pH of a solution containing the particles after suspension in distilled water determined. Samples from each DFDBA lot were implanted intramuscularly (10 mg) or subcutaneously (20 mg) into three different animals and tissue biopsies harvested after 4 weeks. One sample from each tissue bank was implanted and harvested after 8 weeks. At harvest, each area where DFDBA had been implanted was excised and examined by light microscopy. The ability of DFDBA to produce new bone was evaluated and the amount of residual bone particles measured. The results show that bone particles from all tissue banks had a variety of shapes and sizes, both before implantation and after 1 or 2 months of implantation. The pH of particle suspensions also varied between batches, as well as between tissue banks. None of the DFDBA induced new bone formation when implanted subcutaneously. Intramuscular implants from three banks induced new bone formation after 1 and 2 months. DFDBA from two banks caused new bone formation only after 2 months. However, DFDBA from one bank did not induce new bone at all. Particle size before implantation correlated with particle size after implantation. However, particle size did not correlate with ability to induce bone. The results show that commercial DFDBA differs in both size and ability to induce new bone formation, but that the two are not related. The study also indicates that wide variation in commercial bone bank preparations of DFDBA exist and that ability to induce new bone formation also varies widely. Furthermore, the results suggest that methods or assays for evaluating the ability of DFDBA to induce new bone should be developed and standardized.

Evaluation of 2 novel approaches for assessing the ability of demineralized freeze-dried bone allograft to induce new bone formation.

BACKGROUND: Because of the wide variation in the ability of human demineralized freeze-dried bone allograft (DFDBA) to reproducibly induce new bone formation, there is a need for a reliable measure of bone induction activity. In this study we examined an immature osteoprogenitor cell line for its potential utility in measuring the activity of DFDBA in vitro. METHODS: We characterized the response of 2T9 cells, an immature osteoprogenitor cell line derived from the calvariae of transgenic mice containing the SV40 T-antigen driven by the mouse bone morphogenetic protein (BMP)-2 promoter, to recombinant human BMP-2 by measuring alkaline phosphatase specific activity, osteocalcin production, and matrix mineralization. Responses were compared to those obtained with 1,25-(OH)2D3. In addition, 2T9 cells were cultured with active or inactive human DFDBA in the presence or absence of BMP-2. We also tested the hypothesis that radio-opacity of tissue following implantation of DFDBA in vivo correlates with the ability of human DFDBA to induce new bone. DFDBA from 9 different donors, stratified by age, were implanted subcutaneously in the thorax of 18 nude (nu/nu) mice. Tissue was harvested at 36 days postoperatively and examined histologically and biochemically for calcium and phosphorus uptake. RESULTS: 2T9 cells exhibited a dose- and time-dependent response to soluble BMP-2. Proliferation was decreased and alkaline phosphatase activity, osteocalcin production, and mineralized nodule formation were increased. The effects were dose- and time-dependent. Peak effects on alkaline phosphatase and osteocalcin were noted on day 8, whereas mineral deposition did not begin to occur until day 12. 1,25-(OH)2D3 did not regulate these effects unless used with BMP-2. When the cells were exposed to active or inactive DFDBA in the presence or absence of BMP-2, no effect on 2T9 cell differentiation was observed. This indicated that DFDBA released no soluble factors with bone inductive ability and that if any active factors were adsorbed to the DFDBA, they were inactivated. When DFDBA was implanted subcutaneously in the thorax of nude mice, there was no histologic evidence of new bone formation. However, there was a donor age-dependent decrease in Ca and P uptake of the implanted tissue, reflecting a donor age-dependent decrease in remineralization of DFDBA. CONCLUSIONS: These data indicate that cell culture assays like the one used in this study may not be appropriate indicators of bone induction ability by DFDBA since soluble factors may not be responsible for bone induction in vivo. Nonetheless, in vitro assays are still needed. While Ca and P uptake by DFDBA-implanted tissue in the present study correlated with the age-dependent decrease in bone induction at intramuscular sites in a previously reported study, these data show that early x-rays may actually detect remineralization and not new bone formation. Thus, assessment of bone induction ability may still depend on histologic analysis of animal models.

The role of revascularization in transmetatarsal amputations.

Data from 37 patients who underwent a transmetatarsal amputation from January 1993 to April 1996 were reviewed. The mean age and diabetes duration of the subjects were 54.9 (+/- 13.2) years and 16.6 (+/- 8.9) years, respectively. The follow-up period averaged 42.1 (+/- 11.2) months. At the time of follow-up, 29 (78.4%) of the 37 patients still had foot salvage, 8 (21.6%) had progressed to below-the-knee amputation, and 15 (40.5%) had undergone lower-extremity revascularization. Twelve (80%) of the 15 revascularized patients preserved their transmetatarsal amputation level at a follow-up of 36.4 months. The authors concluded that at a maximum of 3 years follow-up after initial amputation, transmetatarsal amputation was a successful amputation level.

Differential infectivity and immunopathology in murine experimental infections by two natural clones belonging to the Trypanosoma cruzi I lineage.

Immunopathology of Chagas' disease in Balb/c mice infected with 2 Trypanosoma cruzi clones, belonging to the T. cruzi I lineage and presenting different in vitro virulence (P/209 cl1 > SO34 c14) was compared. In the acute phase, evading mechanisms such as parasite-induced lymphocyte polyclonal activation and T cell immunosuppression were higher in mice infected with the clone giving a higher parasitaemia (P/209 cl1). A similar increase of non-specific isotypes was observed in both infections with IgG2a prevalence. Interestingly, CD8+ cell hypercellularity and lymphocyte immunosuppression were observed during the chronic phase (245 days post-infection) in mice infected by the most virulent clone. In the same way, the parasite-specific antibody response was more intense in P/209 cl1-infected mice over the acute phase. During the chronic phase this response remarkably dropped down in SO34 cl4-infected mice exclusively. Finally, P/209 cl1-infected mice presented a more severe inflammation and tissue damage in heart and quadriceps than SO34 cl4-infected mice. This comparative study showed differences between the two clones: a higher virulence in vivo being clearly associated with a greater ability to induce evasion mechanisms and severe tissue damage.