Deformable titanium for acetabular revision surgery: a proof of concept.

Custom-made triflange acetabular implants are increasingly used in complex revision surgery where supporting bone stock is diminished. In most cases these triflange cups induce stress-shielding. A new concept for the triflange is introduced that uses deformable porous titanium to redirect forces from the acetabular rim to the bone stock behind the implant and thereby reduces further stress-shielding. This concept is tested for deformability and primary stability.Three different designs of highly porous titanium cylinders were tested under compression to determine their mechanical properties. The most promising design was used to design five acetabular implants either by incorporating a deformable layer at the back of the implant or by adding a separate generic deformable mesh behind the implant. All implants were inserted into sawbones with acetabular defects followed by a cyclic compression test of 1800N for 1000 cycles.The design with a cell size of 4 mm and 0.2 mm strut thickness performed the best and was applied for the design of the acetabular implants. An immediate primary fixation was realized in all three implants with an incorporated deformable layer. One of the two implants with a separate deformable mesh needed fixation with screws. Cyclic tests revealed an average additional implant subsidence of 0.25 mm that occurred in the first 1000 cycles with minimal further subsidence thereafter.It is possible to realize primary implant fixation and stability in simulated large acetabular revision surgery using a deformable titanium layer behind the cup. Additional research is needed for further implementation of such implants in the clinic.

Additively manufactured space-filling meta-implants.

The unprecedented properties of meta-biomaterials could pave the way for the development of life-lasting orthopedic implants. Here, we used non-auxetic meta-biomaterials to address the shortcomings of the current treatment options in acetabular revision surgery. Due to the severe bone deficiencies and poor bone quality, it can be very challenging to acquire adequate initial implant stability and long-term fixation. More advanced treatments, such as patient-specific implants, do guarantee the initial stability, but are formidably expensive and may eventually fail due to stress shielding. We, therefore, developed meta-implants furnished with a deformable porous outer layer. Upon implantation, this layer plastically deforms into the defects, thereby improving the initial stability and homogeneously stimulating the surrounding bone. We first studied the space-filling behavior of additively manufactured pure titanium lattices, based on six different unit cells, in a compression test complemented with full-field strain measurements. The diamond, body-centered cubic, and rhombic dodecahedron unit cells were eventually selected for the design of the deformable porous outer layer. Each design came in three different relative density profiles, namely maximum (MAX), functionally graded (FG), and minimum (MIN). After their compression in bone-mimicking molds with simulated acetabular defects, the space-filling behavior of the implants was evaluated using load-displacement curves, micro-CT images, and 3D reconstructions. The meta-implants with an FG diamond infill exhibited the most promising space-filling behavior. However, the required push-in forces exceed the impact forces currently applied in surgery. Future research should, therefore, focus on design optimization, to improve the space-filling behavior and to facilitate the implantation process for orthopedic surgeons. STATEMENT OF SIGNIFICANCE: Ideally, orthopedic implants would last for the entire lifetime of the patient. Unfortunately, they rarely do. Critically sized defects are a common sight in the revision of acetabular cups, and rather difficult to treat. The permanent deformation of lattice structures can be used to create shape-morphing implants that would fill up the defect site, and thereby restore the physiological loading conditions. Bending-dominated structures were incorporated in the porous outer layer of the space-filling meta-implants for their considerable lateral expansion in response to axial compression. A functionally graded density offered structural integrity at the joint while enhancing the deformability at the bone-implant interface. With the use of a more ductile metal, CP-Ti, these meta-implants could be deformed without strut failure.

Radiation-induced melanoma-associated leucoderma, systemic antimelanoma immunity and disease-free survival in a patient with advanced-stage melanoma: a case report and immunological analysis.

BACKGROUND: Melanoma is an immunogenic tumour. The development of skin depigmentation or melanoma-associated leucoderma (MAL) has been associated with favourable clinical outcome in patients with metastatic melanoma, especially after immunotherapy. Evidence for clinically meaningful enhancement of melanoma-directed autoimmunity, as indicated by MAL, after radiotherapy without immunotherapy has not yet been published. OBJECTIVES: We investigated whether a patient with stage IV melanoma, who developed leucoderma in the irradiated skin areas following radiotherapy and experienced exceptional disease-free survival of 3 years despite brain metastasis, possessed antimelanoma immunity that could be linked to the favourable disease course. METHODS: A detailed immunological analysis was performed consisting of immunohistochemistry of several melanoma tissues, and analyses of T cells isolated from the blood and MAL skin tissue for melanocyte/melanoma specificity and functionality, as well as the presence of a melanoma-specific antibody response. RESULTS: Immunological analyses showed the presence of CD8+ T cells and antibody responses directed against melanocyte differentiation antigens expressed in the primary tumour, lymph node and brain metastasis, indicating adequate tumour recognition by activated T cells. CONCLUSION: The immune responses found in this patient, probably enhanced by radiotherapy, are thought to have contributed to his favourable clinical course. Radiotherapy may act as local immunotherapy in patients with melanoma by destroying melanocytes, leading to the induction, or enhancement, of already existent antimelanoma immunity. As in patients treated with immunotherapy, this may lead to MAL, also at distant sites from the treated area. This patient is a clear example of the positive prognostic value of MAL, which is possibly induced by radiotherapy, for patients with melanoma.

Activation of the aryl hydrocarbon receptor suppresses sensitization in a mouse peanut allergy model.

Food allergy is an increasing health problem in Western countries. Previously, it has been shown that the intensity of food allergic reactions can be regulated by regulatory T (T(reg)) cells. In addition, it has been shown that activation of the aryl hydrocarbon receptor (AhR) regulates T-cell responses by induction of T(reg) cells. Therefore, we hypothesized that activation of the AhR pathway can suppress development of food allergic responses through the induction of T(reg) cells. This was investigated by using a mouse model for peanut allergy. C3H/HeOuJ mice (AhR(b)(-2)) were sensitized to peanut by administering peanut extract (PE) by gavage in the presence of cholera toxin and were treated with the prototypical AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (0.6, 1.7, 5, and 15 µg/kg body weight) on days 3 and 11 orally. The functional role of CD4(+)CD25(+)Foxp3(+) T(reg) cells was investigated by depleting these cells with anti-CD25 mAb during sensitization to PE. TCDD treatment dose dependently suppressed sensitization to peanut (PE-specific IgE, IgG1, and IgG2a and PE-induced IL-5, IL-10, and IL-13, respectively). The percentage, but not the number, of CD4(+)CD25(+)Foxp3(+) T(reg) cells dose dependently increased by AhR activation in both spleen and mesenteric lymph nodes. Depletion of CD4(+)CD25(+)Foxp3(+) T(reg) cells markedly reversed the suppressive effect of TCDD on PE-specific antibody levels and PE-induced IL-5, IL-10, and IL-13 cytokine production. Present data demonstrate for the first time that activation of the AhR by TCDD suppressed the development of Th2-mediated food allergic responses. A functional shift within the CD4(+) cell population toward CD4(+)CD25(+)Foxp3(+) T(reg) cells appeared to underlie this effect. This suggests that the AhR pathway might provide potential therapeutic targets to treat food allergic diseases.