Cell Transplantation for Repair of the Spinal Cord and Prospects for Generating Region-Specific Exogenic Neuronal Cells.

Spinal cord injury (SCI) is associated with currently irreversible consequences in several functional components of the central nervous system. Despite the severity of injury, there remains no approved treatment to restore function. However, with a growing number of preclinical studies and clinical trials, cell transplantation has gained significant potential as a treatment for SCI. Researchers have identified several cell types as potential candidates for transplantation. To optimize successful functional outcomes after transplantation, one key factor concerns generating neuronal cells with regional and subtype specificity, thus calling on the developmental transcriptome patterning of spinal cord cells. A potential source of spinal cord cells for transplantation is the generation of exogenic neuronal progenitor cells via the emerging technologies of gene editing and blastocyst complementation. This review highlights the use of cell transplantation to treat SCI in the context of relevant developmental gene expression patterns useful for producing regionally specific exogenic spinal cells via in vitro differentiation and blastocyst complementation.

Sagittal balance in sitting and standing positions: A systematic review of radiographic measures.

Background: Sagittal imbalance can be caused by various etiologies and is among the most important indicators of spinal deformity. Sagittal balance can be restored through surgical intervention based on several radiographic measures. The purpose of this study is to review the normal parameters in the sitting position, which are not well understood and could have significant implications for non-ambulatory patients. Methods: A systematic review was performed adhering to PRISMA Guidelines. Using R-software, the weighted means and 95% confidence intervals of the radiographic findings were calculated using a random effect model and significance testing using unpaired t-tests. Results: 10 articles with a total of 1066 subjects reported radiographic measures of subjects with no spinal deformity in the sitting and standing position. In the healthy individual, standing sagittal vertical axis -16.8°was significantly less than sitting 28.4° (p < 0.0001), while standing lumbar lordosis 43.3°is significantly greater than sitting 21.3° (p < 0.0001). Thoracic kyphosis was not significantly different between the two groups (p = 0.368). Standing sacral slope 34.3° was significantly greater than sitting 19.5° (p < 0.0001) and standing pelvic tilt 14.0° was significantly less than sitting 33.9° (p < 0.0001). Conclusions: There are key differences between standing and sitting postures, which could lead to undue stress on surgical implants and poor outcomes, especially for non-ambulatory populations. There is a need for more studies reporting sitting and standing radiographic measures in different postures and spinal conditions.

Electrical stimulation affects the differentiation of transplanted regionally specific human spinal neural progenitor cells (sNPCs) after chronic spinal cord injury.

BACKGROUND: There are currently no effective clinical therapies to ameliorate the loss of function that occurs after spinal cord injury. Electrical stimulation of the rat spinal cord through the rat tail has previously been described by our laboratory. We propose combinatorial treatment with human induced pluripotent stem cell-derived spinal neural progenitor cells (sNPCs) along with tail nerve electrical stimulation (TANES). The purpose of this study was to examine the influence of TANES on the differentiation of sNPCs with the hypothesis that the addition of TANES would affect incorporation of sNPCs into the injured spinal cord, which is our ultimate goal. METHODS: Chronically injured athymic nude rats were allocated to one of three treatment groups: injury only, sNPC only, or sNPC + TANES. Rats were sacrificed at 16 weeks post-transplantation, and tissue was processed and analyzed utilizing standard histological and tissue clearing techniques. Functional testing was performed. All quantitative data were presented as mean ± standard error of the mean. Statistics were conducted using GraphPad Prism. RESULTS: We found that sNPCs were multi-potent and retained the ability to differentiate into mainly neurons or oligodendrocytes after this transplantation paradigm. The addition of TANES resulted in more transplanted cells differentiating into oligodendrocytes compared with no TANES treatment, and more myelin was found. TANES not only promoted significantly higher numbers of sNPCs migrating away from the site of injection but also influenced long-distance axonal/dendritic projections especially in the rostral direction. Further, we observed localization of synaptophysin on SC121-positive cells, suggesting integration with host or surrounding neurons, and this finding was enhanced when TANES was applied. Also, rats that were transplanted with sNPCs in combination with TANES resulted in an increase in serotonergic fibers in the lumbar region. This suggests that TANES contributes to integration of sNPCs, as well as activity-dependent oligodendrocyte and myelin remodeling of the chronically injured spinal cord. CONCLUSIONS: Together, the data suggest that the added electrical stimulation promoted cellular integration and influenced the fate of human induced pluripotent stem cell-derived sNPCs transplanted into the injured spinal cord.

Accelerated differentiation of human induced pluripotent stem cells into regionally specific dorsal and ventral spinal neural progenitor cells for application in spinal cord therapeutics.

Spinal cord injury can attenuate both motor and sensory function with minimal potential for full recovery. Research utilizing human induced pluripotent stem cell (hiPSC) -derived spinal cell types for in vivo remodeling and neuromodulation after spinal cord injury has grown substantially in recent years. However, the majority of protocols for the differentiation of spinal neurons are lengthy, lack the appropriate dorsoventral or rostrocaudal specification, and are not typically replicated in more than one cell line. Furthermore, most researchers currently utilize hiPSC-derived motor neurons for cell transplantation after injury, with very little exploration of spinal sensory neuron transplantation. The lack of studies that utilize sensory populations may be due in part to the relative scarcity of dorsal horn differentiation protocols. Building upon our previously published work that demonstrated the rapid establishment of a primitive ectoderm population from hiPSCs, we describe here the production of a diverse population of both ventral spinal and dorsal horn progenitor cells. Our work creates a novel system allowing dorsal and ventral spinal neurons to be differentiated from the same intermediate ectoderm population, making it possible to construct the dorsal and ventral domains of the spinal cord while decreasing variability. This technology can be used in tandem with biomaterials and pharmacology to improve cell transplantation for spinal cord injury, increasing the potential for neuroregeneration.

Epidural stimulation restores muscle synergies by modulating neural drives in participants with sensorimotor complete spinal cord injuries.

Multiple studies have corroborated the restoration of volitional motor control after motor-complete spinal cord injury (SCI) through the use of epidural spinal cord stimulation (eSCS), but rigorous quantitative descriptions of muscle coordination have been lacking. Six participants with chronic, motor and sensory complete SCI underwent a brain motor control assessment (BMCA) consisting of a set of structured motor tasks with and without eSCS. We investigated how muscle activity complexity and muscle synergies changed with and without stimulation. We performed this analysis to better characterize the impact of stimulation on neuromuscular control. We also recorded data from nine healthy participants as controls. Competition exists between the task origin and neural origin hypotheses underlying muscle synergies. The ability to restore motor control with eSCS in participants with motor and sensory complete SCI allows us to test whether changes in muscle synergies reflect a neural basis in the same task. Muscle activity complexity was computed with Higuchi Fractal Dimensional (HFD) analysis, and muscle synergies were estimated using non-negative matrix factorization (NNMF) in six participants with American Spinal Injury Association (ASIA) Impairment Score (AIS) A. We found that the complexity of muscle activity was immediately reduced by eSCS in the SCI participants. We also found that over the follow-up sessions, the muscle synergy structure of the SCI participants became more defined, and the number of synergies decreased over time, indicating improved coordination between muscle groups. Lastly, we found that the muscle synergies were restored with eSCS, supporting the neural hypothesis of muscle synergies. We conclude that eSCS restores muscle movements and muscle synergies that are distinct from those of healthy, able-bodied controls.

Changes in patterns of traumatic brain injury in the Michigan Trauma Quality Improvement Program database early in the COVID-19 pandemic.

OBJECTIVE: The authors' objective was to investigate the impact of the global COVID-19 pandemic on hospital presentation and process of care for the treatment of traumatic brain injuries (TBIs). Improved understanding of these effects will inform sociopolitical and hospital policies in response to future pandemics. METHODS: The Michigan Trauma Quality Improvement Program (MTQIP) database, which contains data from 36 level I and II trauma centers in Michigan and Minnesota, was queried to identify patients who sustained TBI on the basis of head/neck Abbreviated Injury Scale (AIS) codes during the periods of March 13 through July 2 of 2017-2019 (pre-COVID-19 period) and March 13, 2020, through July 2, 2020 (COVID-19 period). Analyses were performed to detect differences in incidence, patient characteristics, injury severity, and outcomes. RESULTS: There was an 18% decrease in the rate of encounters with TBI in the first 8 weeks (March 13 through May 7), followed by a 16% increase during the last 8 weeks (May 8 through July 2), of our COVID-19 period compared with the pre-COVID-19 period. Cumulatively, there was no difference in the rates of encounters with TBI between the COVID-19 and pre-COVID-19 periods. Severity of TBI, as measured with maximum AIS score for the head/neck region and Glasgow Coma Scale score, was also similar between periods. During the COVID-19 period, a greater proportion of patients with TBI presented more than a day after sustaining their injuries (p = 0.046). COVID-19 was also associated with a doubling in the decubitus ulcer rate from 1.0% to 2.1% (p = 0.002) and change in the distribution of discharge status (p = 0.01). Multivariable analysis showed no differences in odds of death/hospice discharge, intensive care unit stay of at least a day, or need for a ventilator for at least a day between the COVID-19 and pre-COVID-19 periods. CONCLUSIONS: During the early months of the COVID-19 pandemic, the number of patients who presented with TBI was initially lower than in the years 2017-2019 prior to the pandemic. However, there was a subsequent increase in the rate of encounters with TBI, resulting in overall similar rates of TBI between March 13 through July 2 during the COVID-19 period and during the pre-COVID-19 period. The COVID-19 cohort was also associated with negative impacts on time to presentation, rate of decubitus ulcers, and discharge with supervision. Policies in response to future pandemics must consider the resources necessary to care for patients with TBI.

Projected timeline to achieve gender balance within the United States neurosurgical workforce exceeds 150 years: a National Plan and Provider Enumeration System analysis.

OBJECTIVE: Despite incremental progress in the representation and proportion of women in the field of neurosurgery, female neurosurgeons still represent an overwhelming minority of the current US physician workforce. Prior research has predicted the timeline by which the proportion of female neurosurgery residents may reach that of males, but none have used the contemporary data involving the entire US neurosurgical workforce. METHODS: The authors performed a retrospective analysis of the National Plan and Provider Enumeration System (NPPES) registry of all US neurosurgeons to determine changes in the proportions of women in neurosurgery across states, census divisions, and census regions between 2010 and 2020. A univariate linear regression was performed to assess historical growth, and then Holt-Winter forecasting was used to predict in what future year gender parity may be reached in this field. RESULTS: A majority of states, divisions, and regions have increased the proportion of female neurosurgeons from 2010. Given current growth rates, the authors found that female neurosurgeons will not reach the proportion of women in the overall medical workforce until 2177 (95% CI 2169-2186). Furthermore, they found that women in neurosurgery will not match their current proportion of the overall US population until 2267 (95% CI 2256-2279). CONCLUSIONS: Whereas many studies have focused on the overall increase of women in neurosurgery in the last decade, this one is the first to compare this growth in the context of the overall female physician workforce and the female US population. The results suggest a longer timeline for gender parity in neurosurgery than previous studies have suggested and should further catalyze the targeted recruitment of women into the field, an overhaul of current policies in place to support and develop the careers of women in neurosurgery, and increased self-reflection and behavioral change from the entire neurosurgery community.

The Effects of the COVID-19 Pandemic on Penetrating Neurotrauma at a Level 1 Trauma Center.

BACKGROUND/OBJECTIVE: The COVID-19 pandemic has had a profound impact on the global delivery of health care. Recent data suggest a possible impact of the pandemic on patterns of neurotrauma. The aim was to assess the impact of the pandemic on the incidence of neurotrauma, with a focus on cranial gunshot wounds (cGSWs) at a large Midwestern level 1 trauma center. METHODS: We conducted a retrospective review of our trauma registry from March through September 2020 and compared it to the same months in 2019. Odds ratios were utilized to assess for differences in patient demographics, injury characteristics, rates of neurotrauma, and rates of cGSWs. RESULTS: A total of 1188 patients presented with neurotrauma, 558 in 2019 and 630 in 2020. The majority of patients were male (71.33% in 2019; 68.57% in 2020) and Caucasian (78.67% in 2019; 75.4% in 2020). Patients presented with cGSWs more frequently in 2020 (n = 49, 7.78%) than in 2019 (n = 25, 4.48%). The odds of suffering a cGSW in 2020 was 73.6% higher than those in 2019 (95% confidence interval = [1.0871, 2.7722]; P = 0.0209). The etiology of such injury was most commonly assault (n = 16, 21.62% in 2019; n = 34, 45.95% in 2020), followed by self-inflicted injury (n = 4, 5.41% in 2019; 12, 16.22% in 2020). CONCLUSIONS: Despite the government-mandated shutdown, we observed an increase in the number of neurotrauma cases in 2020. There was a significant increase in the incidence cGSWs in 2020, with an increase in assaults and self-inflicted injuries. Further investigation into socioeconomic factors for the observed increase in cGSWs is warranted.

Advances in Epidural Spinal Cord Stimulation to Restore Function after Spinal Cord Injury: History and Systematic Review.

Epidural spinal cord stimulation (eSCS) has been recently recognized as a potential therapy for chronic spinal cord injury (SCI). eSCS has been shown to uncover residual pathways within the damaged spinal cord. The purpose of this review is to summarize the key findings to date regarding the use of eSCS in SCI. Searches were carried out using MEDLINE, EMBASE, and Web of Science database and reference lists of the included articles. A combination of medical subject heading terms and keywords was used to find studies investigating the use of eSCS in SCI patients to facilitate volitional movement and to restore autonomic function. The risk of bias was assessed using Risk Of Bias In Non-Randomized Studies of Interventions tool for nonrandomized studies. We were able to include 40 articles that met our eligibility criteria. The studies included a total of 184 patient experiences with incomplete or complete SCI. The majority of the studies used the Medtronic 16 paddle lead. Around half of the studies reported lead placement between T11- L1. We included studies that assessed motor (n = 28), autonomic (n = 13), and other outcomes (n = 10). The majority of the studies reported improvement in outcomes assessed. The wide range of included outcomes demonstrates the effectiveness of eSCS in treating a diverse SCI population. However, the current studies cannot definitively conclude which patients benefit the most from this intervention. Further study in this area is needed to allow improvement of the eSCS technology and allow it to be more widely available for chronic SCI patients.

Human induced pluripotent stem cells integrate, create synapses and extend long axons after spinal cord injury.

Numerous interventions have been explored in animal models using cells differentiated from human induced pluripotent stem cells (iPSCs) in the context of neural injury with some success. Our work seeks to transplant cells that are generated from hiPSCs into regionally specific spinal neural progenitor cells (sNPCs) utilizing a novel accelerated differentiation protocol designed for clinical translation. We chose a xenotransplantation model because our laboratory is focused on the behaviour of human cells in order to bring this potential therapy to translation. Cells were transplanted into adult immunodeficient rats after moderate contusion spinal cord injury (SCI). Twelve weeks later, cells derived from the transplanted sNPCs survived and differentiated into neurons and glia that filled the lesion cavity and produced a thoracic spinal cord transcriptional program in vivo. Furthermore, neurogenesis and ionic channel expression were promoted within the adjacent host spinal cord tissue. Transplanted cells displayed robust integration properties including synapse formation and myelination by host oligodendrocytes. Axons from transplanted hiPSC sNPC-derived cells extended both rostrally and caudally from the SCI transplant site, rostrally approximately 6 cm into supraspinal structures. Thus, iPSC-derived sNPCs may provide a patient-specific cell source for patients with SCI that could provide a relay system across the site of injury.

A systematic review of telehealth for the delivery of emergent neurosurgical care.

INTRODUCTION: In 2017, the American Association of Neurological Surgeons and Congress of Neurological Surgeons published a statement in support of adopting telemedicine technologies in neurosurgery. The position statement detailed the principles for use and summarised the active efforts at the time to address barriers that limited expansion of use, such as reimbursement, liability, credentialing and patient confidentiality. The primary aim of this systematic literature review was to identify the available published literature on the application of telemedicine to neurosurgical patient care, with a specific focus on neurotrauma and emergent neurological conditions. METHODS: This Level II systematic review of the literature was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 guidelines. Following removal of duplicates, 359 studies were yielded from database query. Following application of inclusion and exclusion criteria, 78 articles were identified for full-text review. RESULTS: Full-text screening yielded a total of 11 studies for the final analysis. The study interventions took place in seven unique countries and included both developed and developing nations. Data captured spanned the years 1997 to 2019. The total cumulative number of patients who received neurosurgical telemedicine consultations captured by this review was 37,224. DISCUSSION: This review of the literature suggests that telemedicine in emergent settings offers safe, feasible, and cost-reducing methods of increasing access to high acuity neurosurgical care and may serve to limit unnecessary inter-facility transfers. As infrastructure and regulatory guidelines continue to evolve, neurosurgical patients, both domestic and abroad, will benefit from improved access to expertise afforded by telemedicine technologies.

PRES secondary to autonomic dysreflexia: A case series and review of the literature.

Context: Autonomic dysreflexia (AD) is a complex syndrome seen in patients with spinal cord injuries (SCI) and can be life-threatening with a significant negative impact on the health of the individual. Posterior reversible encephalopathy syndrome (PRES) is thought to be caused, in part, by rapid elevations in blood pressure; leading to posterior cerebral circulatory edema. This can result in seizures, blindness and can progress to fatal intracranial hemorrhages.Findings: Here we present two cases of patients with SCI who developed PRES from AD. Each patient was correctly diagnosed, leading to appropriate treatment of the factors leading to their AD and subsequent resolution of their PRES symptoms.Conclusions/Clinical Relevance: In SCI patients who present with new seizures, visual deficits, or other neurologic signs, PRES should be considered as a part of the differential diagnosis as a good outcome relies on rapid recognition and treatment of AD.

Regionally Specific Human Pre-Oligodendrocyte Progenitor Cells Produce Both Oligodendrocytes and Neurons after Transplantation in a Chronically Injured Spinal Cord Rat Model after Glial Scar Ablation.

Chronic spinal cord injury (SCI) is a devastating medical condition. In the acute phase after injury, there is cell loss resulting in chronic axonal damage and loss of sensory and motor function including loss of oligodendrocytes that results in demyelination of axons and further dysfunction. In the chronic phase, the inhibitory environment within the lesion including the glial scar can arrest axonal growth and regeneration and can also potentially affect transplanted cells. We hypothesized that glial scar ablation (GSA) along with cell transplantation may be required as a combinatorial therapy to achieve functional recovery, and therefore we proposed to examine the survival and fate of human induced pluripotent stem cell (iPSC) derived pre-oligodendrocyte progenitor cells (pre-OPCs) transplanted in a model of chronic SCI, whether this was affected by GSA, and whether this combination of treatments would result in functional recovery. In this study, chronically injured athymic nude (ATN) rats were allocated to one of three treatment groups: GSA only, pre-OPCs only, or GSA+pre-OPCs. We found that human iPSC derived pre-OPCs were multi-potent and retained the ability to differentiate into mainly oligodendrocytes or neurons when transplanted into the chronically injured spinal cords of rats. Twelve weeks after cell transplantation, we observed that more of the transplanted cells differentiated into oligodendrocytes when the glial scar was ablated compared with no GSA. Further, we also observed that a higher percentage of transplanted cells differentiated into V2a interneurons and motor neurons in the pre-OPCs only group when compared with GSA+pre-OPCs. This suggests that the local environment created by ablation of the glial scar may have a significant effect on the fate of cells transplanted into the injury site.

Examining the Emergency Medical Treatment and Active Labor Act: impact on telemedicine for neurotrauma.

The Emergency Medical Treatment and Active Labor Act (EMTALA) protects patient access to emergency medical treatment regardless of insurance or socioeconomic status. A significant result of the COVID-19 pandemic has been the rapid acceleration in the adoption of telemedicine services across many facets of healthcare. However, very little literature exists regarding the use of telemedicine in the context of EMTALA. This work aimed to evaluate the potential to expand the usage of telemedicine services for neurotrauma to reduce transfer rates, minimize movement of patients across borders, and alleviate the burden on tertiary care hospitals involved in the care of patients with COVID-19 during a global pandemic. In this paper, the authors outline EMTALA provisions, provide examples of EMTALA violations involving neurosurgical care, and propose guidelines for the creation of telemedicine protocols between referring and consulting institutions.

Accelerated differentiation of human pluripotent stem cells into neural lineages via an early intermediate ectoderm population.

Differentiation of human pluripotent stem cells (hPSCs) into ectoderm provides neurons and glia useful for research, disease modeling, drug discovery, and potential cell therapies. In current protocols, hPSCs are traditionally differentiated into an obligate rostro-dorsal ectodermal fate expressing PAX6 after 6 to 12 days in vitro when protected from mesendoderm inducers. This rate-limiting step has performed a long-standing role in hindering the development of rapid differentiation protocols for ectoderm-derived cell types, as any protocol requires 6 to 10 days in vitro to simply initiate. Here, we report efficient differentiation of hPSCs into a naive early ectodermal intermediate within 24 hours using combined inhibition of bone morphogenic protein and fibroblast growth factor signaling. The induced population responds immediately to morphogen gradients to upregulate rostro-caudal neurodevelopmental landmark gene expression in a generally accelerated fashion. This method can serve as a new platform for the development of novel, rapid, and efficient protocols for the manufacture of hPSC-derived neural lineages.

One hundred years of neurosurgery: contributions of American women.

The end of the first 100 years of any endeavor is an appropriate time to look back and peer forward. As neurosurgery celebrates its 1st century as a specialty, the increasing role of women neurosurgeons is a major theme. This article documents the early women pioneers in neurosurgery. The contributions of these trailblazers to the origins, academics, and professional organizations of neurosurgery are highlighted. The formation of Women in Neurosurgery in 1989 is described, as is the important role this organization has played in introducing and promoting talented women in the profession. Contributions of women neurosurgeons to academic medicine and society as a whole are briefly highlighted. Contemporary efforts and initiatives indicate future directions in which women may lead neurosurgery in its 2nd century.

3D Printed Neural Regeneration Devices.

Neural regeneration devices interface with the nervous system and can provide flexibility in material choice, implantation without the need for additional surgeries, and the ability to serve as guides augmented with physical, biological (e.g., cellular), and biochemical functionalities. Given the complexity and challenges associated with neural regeneration, a 3D printing approach to the design and manufacturing of neural devices could provide next-generation opportunities for advanced neural regeneration via the production of anatomically accurate geometries, spatial distributions of cellular components, and incorporation of therapeutic biomolecules. A 3D printing-based approach offers compatibility with 3D scanning, computer modeling, choice of input material, and increasing control over hierarchical integration. Therefore, a 3D printed implantable platform could ultimately be used to prepare novel biomimetic scaffolds and model complex tissue architectures for clinical implants in order to treat neurological diseases and injuries. Further, the flexibility and specificity offered by 3D printed in vitro platforms have the potential to be a significant foundational breakthrough with broad research implications in cell signaling and drug screening for personalized healthcare. This progress report examines recent advances in 3D printing strategies for neural regeneration as well as insight into how these approaches can be improved in future studies.

Strategies for Oligodendrocyte and Myelin Repair in Traumatic CNS Injury.

A major consequence of traumatic brain and spinal cord injury is the loss of the myelin sheath, a cholesterol-rich layer of insulation that wraps around axons of the nervous system. In the central nervous system (CNS), myelin is produced and maintained by oligodendrocytes. Damage to the CNS may result in oligodendrocyte cell death and subsequent loss of myelin, which can have serious consequences for functional recovery. Demyelination impairs neuronal function by decelerating signal transmission along the axon and has been implicated in many neurodegenerative diseases. After a traumatic injury, mechanisms of endogenous remyelination in the CNS are limited and often fail, for reasons that remain poorly understood. One area of research focuses on enhancing this endogenous response. Existing techniques include the use of small molecules, RNA interference (RNAi), and monoclonal antibodies that target specific signaling components of myelination for recovery. Cell-based replacement strategies geared towards replenishing oligodendrocytes and their progenitors have been utilized by several groups in the last decade as well. In this review article, we discuss the effects of traumatic injury on oligodendrocytes in the CNS, the lack of endogenous remyelination, translational studies in rodent models promoting remyelination, and finally human clinical studies on remyelination in the CNS after injury.

Interspecies Organogenesis for Human Transplantation.

Blastocyst complementation combined with gene editing is an emerging approach in the field of regenerative medicine that could potentially solve the worldwide problem of organ shortages for transplantation. In theory, blastocyst complementation can generate fully functional human organs or tissues, grown within genetically engineered livestock animals. Targeted deletion of a specific gene(s) using gene editing to cause deficiencies in organ development can open a niche for human stem cells to occupy, thus generating human tissues. Within this review, we will focus on the pancreas, liver, heart, kidney, lung, and skeletal muscle, as well as cells of the immune and nervous systems. Within each of these organ systems, we identify and discuss (i) the common causes of organ failure; (ii) the current state of regenerative therapies; and (iii) the candidate genes to knockout and enable specific exogenous organ development via the use of blastocyst complementation. We also highlight some of the current barriers limiting the success of blastocyst complementation.