Autografts have been shown to stimulate osteogenesis, osteoclastogenesis, and angiogenesis, and subsequent rapid graft incorporation. Large structural allografts, however, suffer from limited new bone formation and remodeling, both of which are directly associated with clinical failure due to non-unions, late graft fractures, and infections, making it a priority to improve large structural allograft healing. We have previously shown the osteogenic ability of a polymer-coated allograft that delivers bone morphogenetic protein-2 both in vitro and in vivo through both burst release and sustained release kinetics. In this study, we have demonstrated largely sequential delivery of bone morphogenetic protein-2 and vascular endothelial growth factor from the same coated allograft. Release data showed that loading both growth factors onto a polymeric coating with two different techniques resulted in short-term (95% release within 2 weeks) and long-term (95% release within 5 weeks) delivery kinetics. We have also demonstrated how released VEGF, traditionally associated with angiogenesis, can also provide a stimulus for allograft remodeling via resorption. Bone marrow derived mononuclear cells were co-cultured with VEGF released from the coated allograft and showed a statistically significant (p < 0.05) and dose dependent increase in the number of tartrate-resistant acid phosphatase-positive multinucleated osteoclasts. Functionality of these osteoclasts was assessed quantitatively and qualitatively by evaluating resorption pit area from both osteo-assay plates and harvested bone. Data indicated a statistically significant higher resorption area from the cells exposed to VEGF released from the allografts over controls (p < 0.05). These results indicate that by using different loading protocols temporal control can be achieved when delivering multiple growth factors from a polymer-coated allograft. Further, released VEGF can also stimulate osteoclastogenesis that may enhance allograft incorporation, and thus mitigate long-term clinical complications. © 2017 Orthopedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1086-1095, 2017.
According to 5- and 10-year clinical follow-up studies large-scale bone allografts have a high failure rate, largely due to poor allograft incorporation with adjacent bone and subsequent poor remodeling. The goal of this study was to develop a methodology to deliver growth factors from large-scale bone allografts in a temporally controlled manner. Intact long bone allografts were coated with a micron-scale thick layer of degradable polymer that maintained inherent pore structures and acted as a delivery vehicle for bone morphogenetic protein-2 and vascular endothelial growth factor. VEGF was loaded onto the surface of the polymer to produce rapid release, to encourage initial vascularization at the defect site, while BMP-2 was encapsulated within the polymer layer to promote a more sustained release, to encourage bone formation over time. Release kinetics from factor-loaded polymer-coated allografts show an early burst release of VEGF over the first 7 days followed by a more sustained release of BMP-2 over the second and third week. In vitro cell studies using human mesenchymal stem cells confirm the bioactivity of the released BMP-2. In-vivo results show robust bone formation over the first 8 weeks of healing in femoral segmental defects in rats implanted with BMP-2 loaded polymer-coated allografts. A microscale thin coating of degradable polymer on a large-scale bone allograft provides temporal control over the delivery of growth factor loaded onto one allograft, while maintaining its microscale pore structure. Enhancing the incorporation and subsequent remodeling of allografts would reduce the incidence of allograft failure over time, and potentially speed healing at the earliest stages after implantation.
Large scale cortical allografts suffer from poor incorporation and healing and often end in graft failure 5-10 years after implantation. To reduce these failures we have developed a growth-factor loaded cortical allograft capable of delivering one or two factors with a degree of temporal control and precision that permits the early release of one growth factor followed by the later and more sustained release of the other. We have loaded vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2 (BMP-2), both critical components of bone formation and repair, onto cortical long bone allografts such that the VEGF is released first and followed shortly by BMP-2. Coated and factor-loaded allografts were placed into a critical sized rat femoral segmental defect and allowed to heal for either 4 or 8 weeks. Healing at each time point was compared to allografts loaded with only BMP-2 and allografts containing no growth factors. Results indicate statistically significant increases in new bone formation from 4 to 8 weeks around allografts loaded with both VEGF and BMP-2 over allografts with no growth factor, suggesting that factorloaded polymer-coated allografts delivering multiple factors with temporal precision may provide a new off-the-shelf tool to the orthopedic surgeon for management of large-scale orthopedic bone defects.
Summary Objectives To evaluate the clinical outcomes and costs of managing pneumonia and severe malnutrition in a day clinic (DC) management model (outpatient) vs. hospital care (inpatient). Methods Randomised clinical trial where children aged 2 months to 5 years with pneumonia and severe malnutrition were randomly allocated to DC or inpatient hospital care. We used block randomisation of variable length from 8 to 20 and produced computer‐generated random numbers that were assigned to one of the two interventions. Successful management was defined as resolution of clinical signs of pneumonia and being discharged from the model of care (DC or hospital) without need for referral to a hospital (DC), or referral to another hospital. All the children in both DC and hospital received intramuscular ceftriaxone, daily nutrition support and micronutrients. Results Four hundred and seventy children were randomly assigned to either DC or hospital care. Successful management was achieved for 184 of 235 (78.3%) by DC alone, vs. 201 of 235 (85.5%) by hospital inpatient care [RR (95% CI) = 0.79 (0.65–0.97), P = 0.02]. During 6 months of follow‐up, 30/235 (12.8%) in the DC group and 36/235 (15.3%) required readmission to hospital in the hospital care group [RR (95% CI) = 0.89 (0.67–1.18), P = 0.21]. The average overall healthcare and societal cost was 34% lower in DC (US$ 188 ± 11.7) than in hospital (US$ 285 ± 13.6) (P < 0.001), and costs for households were 33% lower. Conclusions There was a 7% greater probability of successful management of pneumonia and severe malnutrition when inpatient hospital care rather than the outpatient day clinic care was the initial method of care. However, where timely referral mechanisms were in place, 94% of children with pneumonia and severe malnutrition were successfully managed initially in a day clinic, and costs were substantially lower than with hospital admission.
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