| 1. |
- Docherty-Skogh, Ann-Charlott, et al.
(författare)
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Bone morphogenetic protein-2 delivered by hyaluronan-based hydrogel induces massive bone formation and healing of cranial defects in minipigs
- 2010
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Ingår i: Plastic and reconstructive surgery (1963). - 0032-1052 .- 1529-4242. ; 125:5, s. 1383-1392
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Tidskriftsartikel (refereegranskat)abstract
- Background: Reconstruction of large craniofacial bone defects is a challenge using bone transplants or alloplastic materials. The use of bone morphogenetic protein (BMP)-2 together with a suitable carrier is an attractive option that may facilitate new bone formation. The authors have developed a hydrogel that is formed in situ by the cross-linking of multifunctional hyaluronic acid and polyvinyl alcohol derivatives mixed with hydroxyapatite nanoparticles, in the presence of BMP-2. The aim of this study was to evaluate the suitability of the hydrogel as a carrier for BMP-2 in repairing critical size cranial defects in a minipig model. Methods: Cranial defects (2 × 4 cm) were created in 14 minipigs. The experimental groups were as follows: group 1, craniotomy and application of 5 ml of hydrogel with 1.25 mg of BMP-2 (n = 6); group 2, craniotomy and application of 5 ml of hydrogel without BMP-2 (n = 6); and group 3, craniotomy with no further treatment (n = 2). Results: After 3 months, computed tomographic and histologic examinations were performed. There was spontaneous ossification in the untreated group, but the healing was incomplete. The hydrogel alone demonstrated no further effects. The addition of 1.25 mg of BMP-2 to the hydrogel induced a greater than 100 percent increase in bone volume (p = 0.003) and complete healing of the defects. Histologic examination revealed compact lamellar bone in the BMP group without intertrabecular fibrous tissue, as was seen in the other groups. The hydrogel was resorbed completely within 3 months and, importantly, caused no inflammatory reaction. Conclusion: The injectable hydrogel may be favorable as a BMP-2 carrier for bone reconstruction.
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| 2. |
- Docherty Skogh, Ann-Charlott
(författare)
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Craniofacial bone reconstruction with bone morphogenetic protein-2
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bone defects in the craniofacial area are a clinical challenge and can be the result of trauma, tumour resection or congenital malformations. The golden standard for reconstruction is autologous bone grafts, but bone may not always be readily available and donor-site morbidity might follow. Alternatives to autologous tissue are sought in the field of tissue engineering, where a range of biomaterials, bone forming cells and growth factors are combined, searching to engineer the missing tissue. The use of bone morphogenetic proteins (BMPs) together with different carriers has been explored ever since Marshall Urist discovered the BMPs in 1965. In this thesis we use BMP-2, together with different carriers in an attempt to reconstruct cranial defects in different species. In paper Ia we look into ectopic bone induction with BMP-2 and heparin/chitosan in a rat model. The resulting bone induction is compared to BMP-2 and type I collagen, and found to be superior in the BMP-2 and heparin/chitosan group. In the following clinical study, paper Ib, BMP-2, heparin/chitosan and titanium mesh are used for the reconstruction of large cranial defects in humans. The patients demonstrate a postoperative inflammatory reaction and week bone formation, and the results are disappointing and discourage the use of heparin/chitosan in a clinical setting. The healing of cranial defects in minipigs with BMP-2 and hyaluronan-based hydrogel is studied in paper II. The defects treated with BMP-2 and hyaluronan-based hydrogel demonstrate 119 percent ossification, indicating complete healing and bone overgrowth to some extent. Animals treated with hydrogel alone show 58 percent ossification and 53 percent ossification in the control group, showing a significant difference in induced bone volumes between the BMP-treated animals and animals treated with hydrogel alone. Bone healing of cranial defects in rats comparing hyaluronic acid hydrogel and type I collagen is studied in paper III. Immunohistochemistry and histomorphometric analysis show more active bone formation in the BMP-2 and hydrogel group with significant increase in bone formation two to four weeks after surgery compared to BMP-2 and collagen or hydrogel alone. In the last study (paper IV) cranial reconstruction after neurosurgery with BMP-2 and hydrogel is studied. Boreholes are randomized into treatment with BMP-2 and hydrogel, hydrogel alone, autologous bone and Tisseel™ or Spongostan™ (negative control). Bone healing in holes treated with BMP-2 and hydrogel or autologous bone and Tisseel™ is significantly increased compared to negative control. In conclusion tissue engineering of bone with heparin/chitosan and hyaluronan-based hydrogel with BMP-2 show good bone inductive capacity, superior to type I collagen and BMP-2. Hyaluronan-based hydrogel has more attractive qualities regarding the inflammatory response and BMP-2 and hydrogel produce bone comparable to bone autografts.
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| 3. |
- Engstrand, Thomas, et al.
(författare)
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A novel biodegradable delivery system for bone morphogenetic protein-2.
- 2008
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Ingår i: Plastic and reconstructive surgery. - 1529-4242. ; 121:6, s. 1920-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The efficacy of recombinant growth factors in vivo is highly dependent on the delivery vehicle. The authors investigated the osteoinductive effects of recombinant human bone morphogenetic proteins (BMP)-2 implanted together with a complex of heparin and chitosan. METHODS: Sixty rats were used. Three different carriers in gel formulation (type I collagen, heparin/type I collagen, and heparin/chitosan) were mixed with either 0, 10, or 50 microg of BMP-2, making the number of groups nine. The gels were injected into the quadriceps muscles of both legs in 45 rats (n = 10 per group). Freeze-dried formulations of the carriers were also tested with the same amounts of BMP-2 using 15 rats (n = 5 per group). Four weeks after implantation, the quality and amount of newly formed bone were assessed. RESULTS: Chitosan was shown to protect the heparinase-mediated degradation of heparin in vitro. The osteoinductive effects of BMP-2 in combination with heparin/chitosan were superior as compared with BMP-2 implanted together with type I collagen. Interestingly, the heparin/chitosan complex induced a small amount of bone also without BMP-2 added. The heparin/chitosan was completely absorbed after 4 weeks as determined by histologic evaluation, and a normal active bone formation was present. The freeze-dried formulations of the carriers demonstrated similar osteoinductive effects as the gels. CONCLUSIONS: An osteoinductive formula for clinical use is needed for general bone reconstruction. Heparin in complex with chitosan has the ability to stabilize or activate the growth factor in vivo and induce the generation of new bone in good yields.
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| 4. |
- Engstrand, Thomas, et al.
(författare)
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Development of a bioactive implant for repair and potential healing of cranial defects
- 2014
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Ingår i: Journal of Neurosurgery. - 0022-3085 .- 1933-0693. ; 120:1, s. 273-277
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Tidskriftsartikel (refereegranskat)abstract
- The repair of complex craniofacial bone defects is challenging and a successful result is dependent on the size of the defect, quality of the soft tissue covering the defect, and choice of reconstruction method. The objective of this study was to develop a bioactive cranial implant that could provide a permanent reconstructive solution to the patient by stimulating bone healing of the defect. In this paper the authors report on the feasibility and clinical results of using such a newly developed device for the repair of a large traumatic and therapy-resistant cranial bone defect. The patient had undergone numerous attempts at repair, in which established methods had been tried without success. A mosaic-designed device was manufactured and implanted, comprising interconnected ceramic tiles with a defined calcium phosphate composition. The clinical outcome 30 months after surgery revealed a restored cranial vault without postoperative complications. Computed tomography demonstrated signs of bone ingrowth. Examination with combined 18F-fluoride PET and CT provided further evidence of bone healing of the cranial defect.
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| 5. |
- Skogh, Ann-Charlott Docherty, et al.
(författare)
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Variation in Calvarial Bone Healing Capacity : A Clinical Study on the Effects of BMP-2-Hydrogel or Bone Autograft Treatments at Different Cranial Locations
- 2013
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Ingår i: The Journal of craniofacial surgery (Print). - 1049-2275 .- 1536-3732. ; 24:2, s. 339-343
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Tidskriftsartikel (refereegranskat)abstract
- Background: Bone morphogenetic protein-2 (BMP-2) together with a suitable carrier is an attractive option that may be used for craniofacial bone reconstruction. In this prospective randomized study, a hyaluronan-based hydrogel with BMP-2 was used to achieve bone healing in standardized critical-size cranial defects in humans after neurosurgery. Methods: Twelve patients were randomized into the treatment group (N = 6) or control group (N = 6). In the treatment group, holes made during craniotomy were treated with hydrogel with BMP-2, 250 mu g/mL, or hydrogel without BMP-2. In the remaining hole/s in the same patient, Spongostan (Ethicon) alone or Tisseel (Baxter) mixed with autologous bone matrix were used as negative and positive controls, respectively. In the control group, the holes were treated with Spongostan or Tisseel mixed with bone autograft. Bone healing was assessed with CT scans after 3 and 6 months. Bone areas in treated defects were measured and statistical analysis was performed. Results: Independent of location, bone healing in defects treated with Tisseel with autograft, hydrogel alone, or hydrogel with BMP-2 was significantly increased compared to negative control (P < 0.001, P = 0.002, and P = 0.005, respectively). In general, all defects healed significantly better in the frontal bone as compared to parietal-temporal location, except for defects treated with Tisseel and autograft, which healed well independently of location. No local or systemic side effects, including excessive bone overgrowth or inflammatory reaction, were seen in treated patients. Conclusions: Tissue engineering of bone with hyaluronan-based hydrogel shows good healing of cranial defects, comparable with bone autografts. The hydrogel itself may represent a novel alternative to autologous bone transplants in craniofacial bone repair. The study also reveals a general superior healing capacity in the frontal bone as compared to parietal/temporal bones.
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