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In this work a radiopaque premixed calcium phosphate cement (pCPC) has been developed and evaluated in vivo. Radiopacity was obtained by adding 0–40 % zirconia to the cement paste. The effects of zirconia on setting time, strength and radiopacity were evaluated. In the in vivo study a 2 by 3.5 mm cylindrical defect in a rat vertebrae was filled with either the pCPC, PMMA or bone chips. Nano-SPECT CT analysis was used to monitor osteoblast activity during bone regeneration. The study showed that by adding zirconia to the cement the setting time becomes longer and the compressive strength is reduced. All materials evaluated in the in vivo study filled the bone defect and there was a strong osteoblast activity at the injury site. In spite of the osteoblast activity, PMMA blocked bone healing and the bone chips group showed minimal new bone formation. At 12 weeks the pCPC was partially resorbed and replaced by new bone with good bone ingrowth. The radiopaque pCPC may be considered to be used for minimal invasive treatment of vertebral fractures since it has good handling, radiopacity and allows healing of cancellous bone in parallel with the resorption of the cement.

Background and Purpose: Cerebral cavernous malformations (CCM) present as mulberry-like malformations of the microvasculature of the central nervous system. Current medical treatment of CCM lesions is limited to surgical removal of the vascular malformations. It is, therefore, important to identify therapeutic drug treatments for patients with CCM. Propranolol has shown great benefit in the treatment of infantile hemangioma. In addition, patients with CCM who receive propranolol have demonstrated a reduction of their lesions. Our investigation set out to provide preclinical data to support propranolol as a therapeutic treatment. Methods: An inducible endothelial-specific Ccm3 knockout murine model (CCM3 iECKO ) was used, with assessment of lesion quantity and size following oral treatment with propranolol. Scanning and transmission electron microscopy were used to characterize the CCM3 iECKO lesions and the effects of propranolol on the disease. Immunofluorescent imaging was used to investigate pericyte coverage in the propranolol-treated CCM3 iECKO mice. Results: With propranolol treatment, the lesion quantity, size, and volume decreased in both the brain and retina in the CCM3 iECKO model. Novel characteristics of the CCM3 iECKO lesions were discovered using electron microscopy, including plasmalemmal pits and thickening of the endothelial-pericyte basal membrane. These characteristics were absent with propranolol treatment. Pericyte coverage of the CCM3 iECKO lesions increased after propranolol treatment, and vascular leakage was reduced. Conclusions: This study supports the concept that propranolol can be used to reduce and stabilize vascular lesions and can, therefore, be suggested as a pharmaceutical treatment for CCM.

Macrophages play a key role in determining the fate of implanted biomaterials, especially for biomaterials such as calcium phosphates (CaPs) where these cells play a vital role in material resorption and osteogenesis, as shown in different models, including clinical samples. Although substantial consideration is given to the design and validation of different CaPs, relatively little is known about their material–cell interaction. Specifically, the intracellular content of different CaP phases remains to be assessed, even though CaP-filled macrophages have been observed in several studies. In this study, 2D/3D ToF-SIMS imaging and multivariate analysis were directly applied on the histology samples of an explant to reveal the content of macrophages. The cellular content of the macrophages was analyzed to distinguish three CaP phases, monetite, beta-tricalcium phosphate, and pyrophosphate, which are all part of the monetite-based CaP implant composition under study. ToF-SIMS combined with histology revealed that the content of the identified macrophages was most similar to that of the pyrophosphate phase. This study is the first to uncover distinct CaP phases in macrophages from a human multiphasic CaP explant by targeted direct cell content analysis. The uncovering of pyrophosphate as the main phase found inside the macrophages is of great importance to understand the impact of the selected material in the process of biomaterial-instructed osteogenesis.

The restoration of cranio‐maxillofacial deformities often requires complex reconstructive surgery in a challenging anatomical region, with abnormal soft tissue structures and bony deficits. In this proof‐of‐concept, the possibility of vertical bone augmentation was explored by suspending hemispherically shaped titanium‐reinforced porous calcium phosphate (CaP) implants (n = 12) over the frontal bone in a sheep model (n = 6). The animals were euthanized after week 13 and the specimens were subject to micro‐computed tomography (μCT) and comprehensive histological analysis. Histology showed that the space between implant and the recipient bone was filled with a higher percentage of newly formed bone (NFB) versus soft tissue with a median of 53% and 47%, respectively. Similar results were obtained from the μ‐CT analysis, with a median of 56% NFB and 44% soft tissue filling the void. Noteworthy, significantly higher bone‐implant contact was found for the CaP (78%, range 14%–94%) versus the Titanium (29%, range 0%–75%) portion of the implant exposed to the surrounding bone. The histological analysis indicates that the CaP replacement by bone is driven by macrophages over time, emphasized by material‐filled macrophages found in close vicinity to the CaP with only a small number of single osteoclasts found actively remodeling the NFB. This study shows that CaP based implants can be assembled with the help of additive manufacturing to guide vertical bone formation without decortification or administration of growth factors. Furthermore, it highlights the potential disadvantage of a seamless fit between the implant and the recipient's bone.

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