(W1130-05-27) Engineering and Optimization of 3D Printed Parenteral Implants

Purpose: Orthopedic surgeries often involve the placement of a foreign body, such as a prosthetic joint, joint components, or others to stabilize bone structures or repair fractures. These new devices in the body facilitate post-surgical infections to patients, which implies a high cost for the Health System and hinders the lives of patients. Currently common treatments such as bone cement loaded with antibiotic, is not an effective solution, since it can produce resistance in the patient without eradicating the infection. Surgical location infection (ILQ) represents 30% of all causes of healthcare-related infections, being one of the most feared complications in surgical patients and greatly affecting the countries of America and Europe. In view of the difficulties and risks that arise in infections caused after hip arthroplasty and taking advantage of the high effectiveness of amphotericin B (AmB) as an antifungal, the hypothesis underpinning this work was that the development of a 3D printed implant containing AmB can serve as an innovative approach to prevent infections. Hence, the objective of this work was to optimize the fabrication of AmB-loaded 3D printed implants for their use in ILQs.

Methods: The design of the 3D printed implant was inspired in a spider web morphology taking into account the shape of the acetabular component where the implant would be placed. Geometries were designed by a ACD software and then transferred to a .stl file for printing in a Flashforge Fuse Deposition Modelling 3D printer. Quality by design approach was implemented to optimise the fabrication of AmB-loaded 3D printed implants. The three factors whose effect was investigated were: the percentage of AmB dissolved in the medium prior to drug loading, the dimensions of the implant (in particular, the height) and the amount of ethanol utilised to load the drug within the implant. The amount of drug loaded within the implants and the morphology of the spider web were evaluated as responses. The optimized spider web was evaluated for drug release and toxicity in red blood cells. Morphology was assessed by scanning electron microscopy.

Results: The optimized spiderweb geometry was consisting of a 20 x 9 mm structure with three main branches of 4 x 4 mm with a 1 mm height. The AmB loading process was optimized when using a 75% ethanol content in the solvent mixture to solubilize the drug and an AmB concentration of 5 mg/ml (Fig 1). The total amount of AmB loaded in the web was 0.4% over a 6 h period. AmB was released over a 24 h period exhibiting a biphasic kinetic which is preferable to prevent earlier fungal infection at the prosthesis. Micrographs (FIG 2.C) showed the well-structured implant obtained after 3D printing. However, after the drug loading process in solvents, a deterioration in the structure was visualized leading to a detriment of the geometrical conformation. Lower diffusion kinetics should be employed to prevent damage of the final structure of the spiderweb. Toxicity studies in Red Blood Cells showed a significant protection of the 3D printed spider web in the cells. The sustained release of the drug resulted in a significant reduction of the toxicity compared to the drug dissolved in DMSO. The Hemolysis concentration that produced 50% hemolysis (HC₅₀) was 20µg/ml -fold lower for the AmB-loaded implant compared to the drug. This is beneficial bearing in mind the necessity of a safe as well as efficacious antimicrobial formulation.

Conclusion: A 3D printed parenteral implant was successfully engineered in a spider web morphology well-adapted to the acetabular component of the hip prosthesis. AmB showed a sustained release from the implant which translated into a significant reduction in the toxicity on red blood cells. This implant can be a promising approach in the management of infections associated to hip arthroplasties.

Acknowledgements: In patent process


Figure 1. Quality by design of Amphotericin B loaded 3D printed implants.


Figure 2. a)Top view of the spiderweb design in TinkerCad b)Optimized 3D printed spiderweb c)Unloaded 3D printed spiderweb d)Loaded with AmB 3D printed spiderweb


Figure 3. Hemolytic toxicity 3D printed implant. Key: AmB dissolved in DMSO (black squares); and AmB loaded in the 3D printed implant (red circles).