(T1230-04-22) 3D-Printed Drug-Eluting Scaffolds for Mechanical Support and Regeneration: A Personalized Approach to Implant-associated Surgical Site Rehabilitation

Purpose: Rapid prototyping or additive manufacturing approaches have gained importance in the precise fabrication of complex tissue constructs for tissue regeneration. Thermoplastic polymers are materials of choice due to their ease of fabrication using the Fused Deposition Modeling (FDM) technique for layer upon layer addition. Despite being a manifesting trend in additive manufacturing, FDM usage is often limited by its multiple fabrication steps and high processing temperature. Thermoplastic single-step extrusion, a single-step direct deposition technique, utilizes nozzle-based extrusion of molten feed using pneumatic pressure to fabricate constructs on a printing platform based on CAD (Computer-Aided Design) models.

Implant-associated surgical site rehabilitation always faces the challenge of immune cascade from installed implants and poor regeneration of damaged tissues. The use of metallic plates could mechanically support the healing tissue structure yet finds it difficult to mimic the natural biofunctional properties of the surrounding tissues exactly. Such plates either stay inside the patient's body for a lifetime or need secondary surgery for removal. Biodegradable polymeric-based scaffolds could be the best bet for accurately restoring, maintaining, and improving surgical site rehabilitation within optimal time. Polymeric scaffolds could encompass porous structure to facilitate tissue growth, remain completely biocompatible within predicted resorption time, and remain less invasive towards the surrounding tissues. An ideal scaffold should have adequate macrostructure and open-pore geometry to allow cell growth with predictable surface properties for cell attachment and structural resorption over time. Thermoplastic extrusion could fabricate patient-focused personalized polymeric scaffolds with such properties with options to alter the implant geometry, infill, and drug loading within no time, without tweaking the formulation composition. A biodegradable polymer, polycaprolactone (PCL), was selected due to its thermal stability at higher extrusion temperature and autocatalytic degradation observed over time with cleavage of ester linkages. PCL scaffolds have a relatively longer resorption time once installed inside the body, resulting in the extended release of actives. Ketoprofen, an anti-inflammatory agent, was utilized as a model drug molecule. Our investigation aimed to understand the influence of printing parameters on the nature of drug elution from scaffolds and their physiochemical properties without changing the formulation composition.

Methods: 3D-printed polymeric scaffolds were fabricated by the thermoplastic extrusion approach using a thermoplastic printhead with stainless steel cartridge with a 0.2 mm nozzle. The 3D printer provides versatility to mount a thermoplastic printhead and utilizes temperature and pressure-regulated polymeric feed extrusion to design scaffolds on the preheated platform. PCL (molecular weight, ~80 k) was mixed uniformly with ketoprofen in different ratios and filled the stainless steel cartridges before extrusion. The temperature and pressure was optimized for printing based on the melting temperature of the feed composition. Upon fabrication, the surface morphology and roughness were characterized by Keyence VHX 6000 microscope. The surface wettability was investigated by determining the contact angle by using a static drop technique. Figure 1 shows the pattern of printed batches with variation in the printing parameters. In addition to that, various printing parameters (print speed, temperature, nozzle size) and 3D-modeling parameters (implant geometry, direction of layer addition & slicing) also were investigated for their effect on overall drug elution from the scaffold. Fig 2 shows the characterization of scaffolds, including the eluting implants' solid-state characterization, microscopic morphology, compressive stiffness, and in-vitro release. The in vitro release profile of ketoprofen from implants was investigated in PBS: ethanol (95:5) (pH 7.4) as release media for 2 months.

Results: The printed scaffolds showed the amorphous nature of ketoprofen, confirmed through thermal analysis, and ensured stability for six months after fabrication. The morphological characteristics and printing parameters corroborated the predicted drug release and mechanical strength. The implants with 10% infill showed the quickest release, whereas increased infill density (75%) proportionally sustained the release of drug (55% drug release in 20 days, 10% w/w drug loading). The printing temperature and printing speed significantly affected the overall printing process, the scaffold's structural integrity, and the elution pattern (Figure 3). The nozzle size also significantly contributed to the overall precision of the printing process. The batch-to-batch reproducibility was evident, and uniformity in drug content was quantified. Some limitations observed were occasional weight variation between batches of the same processing parameters and longer melt residence time for the larger batches.

Conclusion: Drug-eluting PCL scaffolds were fabricated by thermoplastic extrusion and characterized for their thermal characteristics, surface properties and in-vitro release profile. The drug loading of the fabricated scaffolds has been found consistent, and the technology appears to be viable for the on-site manufacture of personalized scaffolds intended for implant-associated surgical rehabilitation. Such scaffolds could offer a significant advantage in controllable drug release to support regenerating tissues and prevent the surge of inflammatory mediators. We further aim to investigate the biocompatibility of the scaffolds using in-vitro cell-based models like osteosarcoma, investigating the cell adhesion, proliferation, and viability. Such polymeric scaffolds could offer promising clinical significance in tissue regeneration and mechanical support.


Figure 1. Printing batches of polymeric scaffolds with different printing parameters


Figure 2. The physicochemical characterization of PCL-K scaffolds


Figure 3. The release profile of PCL-K scaffolds with different infill and other printing parameters