Personalized Volumetric Tissue Generation by Enhancing Multiscale Mass Transport through 3D Printed Scaffolds in Perfused Bioreactors

Abstract

Engineered tissues provide an alternative to graft material, circumventing the use of donor tissue such as autografts or allografts and non-physiological synthetic implants. However, their lack of vasculature limits the growth of volumetric tissue more than several millimeters thick which limits their success post-implantation. Perfused bioreactors enhance nutrient mass transport inside lab-grown tissue but remain poorly customizable to support the culture of personalized implants. Here, a multiscale framework of computational fluid dynamics (CFD), additive manufacturing, and a perfusion bioreactor system are presented to engineer personalized volumetric tissue in the laboratory. First, microscale 3D printed scaffold pore geometries are designed and 3D printed to characterize media perfusion through CFD and experimental fluid testing rigs. Then, perfusion bioreactors are custom-designed to combine 3D printed scaffolds with flow-focusing inserts in patient-specific shapes as simulated using macroscale CFD. Finally, these computationally optimized bioreactor-scaffold assemblies are additively manufactured and cultured with pre-osteoblast cells for 7, 20, and 24 days to achieve tissue growth in the shape of human calcaneus bones of 13 mL volume and 1 cm thickness. This framework enables an intelligent model-based design of 3D printed scaffolds and perfusion bioreactors which enhances nutrient transport for long-term volumetric tissue growth in personalized implant shapes. The novel methods described here are readily applicable for use with different cell types, biomaterials, and scaffold microstructures to research therapeutic solutions for a wide range of tissues.

Emerging perspectives on 3D printed bioreactors for clinical translation of engineered and bioprinted tissue constructs

“…On day 24, the development of a human calcaneus bone scaffold with a volume of 13 mL and 1 cm thickness was achieved successfully for heel bone tissue regeneration. 102…”

Achieving Precision Healthcare through Nanomedicine and Enhanced Model Systems

“…Utilizing composite techniques such as 3D printing and perfused bioreactors, Forrestal et al engineered personalized implants capable of long-term tissue growth and enhanced nutrient transport. 82 Kazimierczak et al further compared the effectiveness of rotating and perfusion bioreactors in the production of a living bone construct using human bone marrow-derived mesenchymal stem cells (BMDSCs) (Figure 9). 80 These studies demonstrate that the most efficient outcomes may arise from the combination of different technologies, thus resulting in more complex and robust testing systems, further emphasising cross-disciplinary collaborations to drive the innovation process.…”

“…In the future, a combination of advanced models and techniques is most likely needed. Utilizing composite techniques such as 3D printing and perfused bioreactors, Forrestal et al engineered personalized implants capable of long-term tissue growth and enhanced nutrient transport . Kazimierczak et al further compared the effectiveness of rotating and perfusion bioreactors in the production of a living bone construct using human bone marrow-derived mesenchymal stem cells (BMDSCs) (Figure ).…”

A Preclinical Trial Protocol Using an Ovine Model to Assess Scaffold Implant Biomaterials for Repair of Critical-Sized Mandibular Defects

“…Although autologous bone flaps are effective in restoring bone continuity, long and complex operations are required and are associated with substantial donor site morbidity. For some cases autologous bone is not suitable for replicating the complex 3D geometries, as in the facial region of the skull. − Bone tissue engineering provides a feasible alternative by enabling the design and manufacture of tissue scaffolds, which support tissue regeneration via cell adhesion and nutrient transport. − Unlike free flaps, tissue scaffolds can be additively manufactured so that they are patient specific, enabling the scaffold to match the actual size and shape of the defect. − Scaffold architecture, biomaterials selection, additive manufacturing, implantation, and performance evaluation are crucial steps that need to be carefully planned and implemented to ensure optimal experimental and clinical outcomes. For oral cancer patients, there are additional challenges that are not often encountered in long bone defects, such as oral microflora, postoperative radiotherapy, and cantilever loading.…”