Gerardo Figueroa Romero

Critical size bone defects do not heal without surgical intervention, and the current methods of treatment lack long-term efficacy and patient satisfaction. Our lab has previously demonstrated the use of 3D printed scaffold mimicking biological tissue structure in the regeneration of large critical size bone defects. In this study, we highlight the effect of dynamization and hardware removal in the regeneration of critical size bone defects treated with our instrumentalized 3D printed polymer scaffold. We demonstrate the sensate capabilities of our scaffolds in long-term monitoring of bone healing and bone-implant biomechanics. All scaffold-implanted groups demonstrated rapid bone growth in the defect space. Dynamization resulted in an increased union rate and bone volume. The hardware removal group demonstrated increased bone stiffness compared to the non-dynamized and control groups.

Substantial hurdles in achieving a digitally connected body with seamless, chronic, high-fidelity organ interfaces include challenges of sourcing energy and ensuring reliable connectivity. Operation is currently limited by batteries that occupy large volumes. Wireless, battery-free operation is therefore paramount, requiring a system-level solution that enables seamless connection of wearable and implantable devices. Here, we present a technological framework that enables wireless, battery-free implant operation in freely moving subjects, with streaming of high-fidelity information from low-displacement, battery-free implants with little user interaction. This is accomplished using at-distance wirelessly recharged, wearable biosymbiotic devices for powering and communication with fully implantable NFC-enabled implants. We demonstrate this capability with osseosurface electronics that stream bone health insight. Eleven-month-long large animal studies highlight the ability of implants to relay information on bone health without negative impact on the subjects. Clinical translatability is shown through fracture healing studies that demonstrate biomarkers of bone union.

Background: Delayed bone healing is common in orthopaedic clinical care. Agents that alter cell function to enhance healing would change treatment paradigms. 4-aminopyridine (4-AP) is a U.S. Food and Drug Administration (FDA)-approved drug shown to improve walking in patients with chronic neurological disorders. We recently showed 4-AP’s positive effects in the setting of nerve, wound, and even combined multi-tissue limb injury. Here, we directly investigated the effects of 4-AP on bone fracture healing, where differentiation of mesenchymal stem cells into osteoblasts is crucial. Methods: All animal experiments conformed to the protocols approved by the Institutional Animal Care and Use Committee at the University of Arizona and Pennsylvania State University. Ten-week-old C57BL/6J male mice (22 to 28 g), following midshaft tibial fracture, were assigned to 4-AP (1.6 mg/kg/day, intraperitoneal [IP]) and saline solution (0.1 mL/mouse/day, IP) treatment groups. Tibiae were harvested on day 21 for micro-computed tomography (CT), 3-point bending tests, and histomorphological analyses. 4-AP’s effect on human bone marrow mesenchymal stem cell (hBMSC) and human osteoblast (hOB) cell viability, migration, and proliferation; collagen deposition; matrix mineralization; and bone-forming gene/protein expression analyses was assessed. Results: 4-AP significantly upregulated BMP2 gene and protein expression and gene expression of RUNX2, OSX, BSP, OCN, and OPN in hBMSCs and hOBs. 4-AP significantly enhanced osteoblast migration and proliferation, collagen deposition, and matrix mineralization. Radiographic and micro-CT imaging confirmed 4-AP’s benefit versus saline solution treatment in mouse tibial fracture healing (bone mineral density, 687.12 versus 488.29 mg hydroxyapatite/cm³ [p ≤ 0.0021]; bone volume/tissue volume, 0.87 versus 0.72 [p ≤ 0.05]; trabecular number, 7.50 versus 5.78/mm [p ≤ 0.05]; and trabecular thickness, 0.08 versus 0.06 mm [p ≤ 0.05]). Three-point bending tests demonstrated 4-AP’s improvement of tibial fracture biomechanical properties versus saline solution (stiffness, 27.93 versus 14.30 N/mm; p ≤ 0.05). 4-AP also increased endogenous BMP2 expression and matrix components in healing callus. Conclusions: 4-AP increased the healing rate, biomechanical properties, and endogenous BMP2 expression of tibiae following fracture. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.