Cosurface electrode architectures are able to deliver personalized electric stimuli to target tissues. As such, this technology holds potential for a variety of innovative biomedical devices. However, to date, no detailed analyses have been conducted to evaluate the impact of stimulator architecture and geometry on stimuli features. This work characterizes, for the first time, the electric stimuli delivered to bone cellular tissues during in vitro experiments, when using three capacitive architectures: stripped, interdigitated and circular patterns. Computational models are presented that predict the influence of cell confluence, cosurface architecture, electrodes geometry, gap size between electrodes and power excitation on the stimuli delivered to cellular layers. The results demonstrate that these stimulators are able to deliver osteoconductive stimuli. Significant differences in stimuli distributions were observed for different stimulator designs and different external excitations. The thickness specification was found to be of utmost importance. In vitro experiments using an osteoblastic cell line highlight that cosurface stimulation at a low frequency can enhance osteoconductive responses, with some electrode-specific differences being found. A major feature of this type of work is that it enables future detailed analyses of stimuli distribution throughout more complex biological structures, such as tissues and organs, towards sophisticated biodevice personalization.
Replacement orthopedic surgeries are among the most common surgeries worldwide, but clinically used passive implants cannot prevent failure rates and inherent revision arthroplasties. Optimized non-instrumented implants, resorting to preclinically tested bioactive coatings, improve initial osseointegration but lack long-term personalized actuation on the bone–implant interface. Novel bioelectronic devices comprising biophysical stimulators and sensing systems are thus emerging, aiming for long-term control of peri-implant bone growth through biointerface monitoring. These acting-sensing dual systems require high frequency (HF) operations able to stimulate osteoinduction/osteoconduction, including matrix maturation and mineralization. A sensing-compatible capacitive stimulator of thin interdigitated electrodes and delivering an electrical 60 kHz HF stimulation, 30 min/day, is here shown to promote osteoconduction in pre-osteoblasts and osteoinduction in human adipose-derived mesenchymal stem cells (hASCs). HF stimulation through this capacitive interdigitated system had significant effects on osteoblasts’ collagen-I synthesis, matrix, and mineral deposition. A proteomic analysis of microvesicles released from electrically-stimulated osteoblasts revealed regulation of osteodifferentiation and mineralization-related proteins (e.g. Tgfb3, Ttyh3, Itih1, Aldh1a1). Proteomics data are available via ProteomeXchange with the identifier PXD028551. Further, under HF stimulation, hASCs exhibited higher osteogenic commitment and enhanced hydroxyapatite deposition. These promising osteoinductive/conductive capacitive stimulators will integrate novel bioelectronic implants able to monitor the bone–implant interface and deliver personalized stimulation to peri-implant tissues.
Fabrication of vascularized large-scale constructs for regenerative medicine remains elusive since most strategies rely solely on cell self-organization or overly control cell positioning, failing to address nutrient diffusion limitations. We propose a modular and hierarchical tissue-engineering strategy to produce bonelike tissues carrying signals to promote prevascularization. In these 3D systems, disc-shaped microcarriers featuring nanogrooved topographical cues guide cell behavior by harnessing mechanotransduction mechanisms. A sequential seeding strategy of adipose-derived stromal cells and endothelial cells is implemented within compartmentalized, liquefied-core macrocapsules in a self-organizing and dynamic system. Importantly, our system autonomously promotes osteogenesis and construct’s mineralization while promoting a favorable environment for prevascular-like endothelial organization. Given its modular and self-organizing nature, our strategy may be applied for the fabrication of larger constructs with a highly controlled starting point to be used for local regeneration upon implantation or as drug-screening platforms.
Spinal cord injury (SCI) is a yet untreatable neuropathology that causes severe dysfunction and disability. Cell-based therapies hold neuroregenerative and neuroprotective potential but, although being studied in SCI patients for more than two decades, long-term efficacy and safety remain unproven, and it is still debated which cell types result in higher neurological and functional recovery. In a comprehensive scoping review of 142 reports and registries of SCI cell-based clinical trials, we addressed the current therapeutical trends and critically analyzed the strengths and limitations of the studies. Schwann cells, olfactory ensheathing cells (OECs), macrophages, and various types of stem cells (SCs) have been tested, as well as combinations of these and other cells. A comparative analysis between the reported outcomes of each cell type was performed, according to gold-standard efficacy outcome measures like the ASIA impairment scale (AIS), motor and sensory scores. Most of the trials were in the early phases of clinical development (phase I/II), involved patients with complete chronic injuries of traumatic etiology, and did not display a randomized comparative control arm. Bone marrow SCs and OECs were the mainly used cells, while open surgery and injection were the most common methods, delivering cells into the spinal cord or submeningeal spaces. Transplantation of support cells, such as OECs and Schwann cells, resulted in the highest AIS grade conversion rates (improvements in ∼40% of transplanted patients), which surpasses the spontaneous improvement rate expected for complete chronic SCI patients within one-year post-injury (5-20%). Some stem cells, such as peripheral blood-isolated ones (PB-SCs) and Neural SCs (NSCs) and also present potential for improving patients’ recovery. Complementary treatments, particularly post-transplantation rehabilitation regimes, may highly contribute to neurological and functional recovery. However, unbiased comparisons between the tested therapies are difficult to draw, given the great heterogeneity of the design and outcome measures used in the SCI cell-based clinical trials, and how these are reported. It is therefore crucial to standardize these trials when aiming for clinical evidence-based conclusions of higher value.
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