The influence of osteoporosis on mechanical complications in lumbar fusion surgery: a systematic review.

Background: Adults undergoing spine surgery often have underlying osteoporosis, which may be a risk factor for postoperative complications. Although these associations have been described, osteoporosis remains profoundly underdiagnosed and undertreated in the spine surgery population. A thorough, comprehensive systematic review summarizing the relationships between bone mineral density (BMD) and specific complications of lumbar fusion surgery could be a valuable resource for raising awareness and supporting clinical practice changes. Methods: PubMed, Embase, and Web of Science databases were searched for original clinical research articles reporting on BMD, or surrogate measure, as a predictor of complications in adults undergoing elective lumbar fusion for degenerative disease or deformity. Endpoints included cage subsidence, screw loosening, pseudarthrosis, vertebral fracture, junctional complications, and reoperation. Results: A total of 71 studies comprising 12,278 patients were included. Overall, considerable heterogeneity in study populations, methods of bone health assessment, and definition and evaluation of clinical endpoints precluded meta-analysis. Nevertheless, low BMD was associated with higher rates of implant failures like cage subsidence and screw loosening, which were often diagnosed with concomitant pseudarthrosis. Osteoporosis was also a significant risk factor for proximal junctional kyphosis, particularly due to fracture. Many studies found surgical site-specific BMD to best predict focal complications. Functional outcomes were inconsistently addressed. Conclusions: Our findings suggest osteoporosis is a significant risk factor for mechanical complications of lumbar fusion. These results emphasize the importance of preoperative osteoporosis screening, which allows for medical and surgical optimization of high-risk patients. This review also highlights current practical challenges facing bone health evaluation in patients undergoing elective surgery. Future prospective studies using standardized methods are necessary to strengthen existing evidence, identify optimal predictive thresholds, and establish specialty-specific practice guidelines. In the meantime, an awareness of the surgical implications of osteoporosis and utility of preoperative screening can provide for more informed, effective patient care.

Lessons Learned From the First-In-Human Compassionate Use of Connect-EA™ in Ten Patients With Esophageal Atresia.

INTRODUCTION: Delayed primary repair of esophageal atresia in patients with high-risk physiologic and anatomic comorbidities remains a daunting challenge with an increased risk for peri-operative morbidity and mortality via conventional repair. The Connect-EA device facilitates the endoscopic creation of a secure esophageal anastomosis. This follow-up study reports our long-term outcomes with the novel esophageal magnetic compression anastomosis (EMCA) Connect-EA device for EA repair, as well as lessons learned from the ten first-in-human cases. We propose an algorithm to maximize the advantages of the device for EA repair. METHODS: Under compassionate use approval, from June 2019 to December 2022, ten patients with prohibitive surgical or medical risk factors underwent attempted EMCA with this device. All patients underwent prior gastrostomy, tracheoesophageal fistula ligation (if necessary), and demonstrated pouch apposition prior to EMCA. RESULTS: Successful device deployment and EMCA formation were achieved in nine patients (90%). Mean time to anastomosis formation was 8 days (range 5-14) and the device was retrieved endoscopically in five (56%) cases. At median follow-up of 22 months (range 4-45), seven patients (78%) are tolerating oral nutrition. Balloon dilations (median 4, range 1-11) were performed either prophylactically for radiographic asymptomatic anastomotic narrowing (n = 7, 78%) or to treat clinically-significant anastomotic narrowing (n = 2, 22%) with no ongoing dilations at 3-month follow up post-repair. CONCLUSION: EMCA with the Connect-EA device is a safe and feasible minimally-invasive alterative for EA repair in high-risk surgical patients. Promising post-operative outcomes warrant further Phase I investigation. LEVEL OF EVIDENCE: IV, Case series of novel operative technique without comparison group.

Renal Embolization-Induced Uremic Swine Model for Assessment of Next-Generation Implantable Hemodialyzers.

Reliable models of renal failure in large animals are critical to the successful translation of the next generation of renal replacement therapies (RRT) into humans. While models exist for the induction of renal failure, none are optimized for the implantation of devices to the retroperitoneal vasculature. We successfully piloted an embolization-to-implantation protocol enabling the first implant of a silicon nanopore membrane hemodialyzer (SNMHD) in a swine renal failure model. Renal arterial embolization is a non-invasive approach to near-total nephrectomy that preserves retroperitoneal anatomy for device implants. Silicon nanopore membranes (SNM) are efficient blood-compatible membranes that enable novel approaches to RRT. Yucatan minipigs underwent staged bilateral renal arterial embolization to induce renal failure, managed by intermittent hemodialysis. A small-scale arteriovenous SNMHD prototype was implanted into the retroperitoneum. Dialysate catheters were tunneled externally for connection to a dialysate recirculation pump. SNMHD clearance was determined by intermittent sampling of recirculating dialysate. Creatinine and urea clearance through the SNMHD were 76-105 mL/min/m2 and 140-165 mL/min/m2, respectively, without albumin leakage. Normalized creatinine and urea clearance measured in the SNMHD may translate to a fully implantable clinical-scale device. This pilot study establishes a path toward therapeutic testing of the clinical-scale SNMHD and other implantable RRT devices.

Feasibility of an implantable bioreactor for renal cell therapy using silicon nanopore membranes.

The definitive treatment for end-stage renal disease is kidney transplantation, which remains limited by organ availability and post-transplant complications. Alternatively, an implantable bioartificial kidney could address both problems while enhancing the quality and length of patient life. An implantable bioartificial kidney requires a bioreactor containing renal cells to replicate key native cell functions, such as water and solute reabsorption, and metabolic and endocrinologic functions. Here, we report a proof-of-concept implantable bioreactor containing silicon nanopore membranes to offer a level of immunoprotection to human renal epithelial cells. After implantation into pigs without systemic anticoagulation or immunosuppression therapy for 7 days, we show that cells maintain >90% viability and functionality, with normal or elevated transporter gene expression and vitamin D activation. Despite implantation into a xenograft model, we find that cells exhibit minimal damage, and recipient cytokine levels are not suggestive of hyperacute rejection. These initial data confirm the potential feasibility of an implantable bioreactor for renal cell therapy utilizing silicon nanopore membranes.

The Rearing of Maternal-Fetal Surgery: The Maturation of a Field from Conception to Adulthood.

Maternal-fetal surgery is fraught with inherent controversy from within the medical community and general public. Despite these challenges, the field of maternal-fetal surgery evolved into an international enterprise. Carefully nurtured by pioneers with foresight and resilience, the field navigated ethical dilemmas with rigorous scientific methodology, collaboration, transparency, and accordance. These central pillars are consistent throughout the brief but momentous history of maternal-fetal surgery, serving as the catalyst for its success. The maturation of fetal intervention is an exemplar of technological innovation propelling clinical innovation, as well as a celebration of mastering the delicate balance between caution and optimism.

Esophageal Magnetic Compression Anastomosis in Esophageal Atresia Repair: A PRISMA-Compliant Systematic Review and Comparison with a Novel Approach.

The use of magnet compression to endoscopically create an esophageal anastomosis is an intriguing approach to esophageal atresia repair, but published cases with an existing available device have demonstrated mixed success. One major shortcoming has been the formation of subsequent severe, recalcitrant strictures after primary repair. To address the limitations of the existing device, we recently introduced and reported success with specially designed bi-radial magnets that exhibit a novel geometry and unique tissue compression profile. The aim of this study is to compare the outcomes using our novel device (novel group, NG) with those of previous reports which utilized the historical device (historic group, HG) in a PRISMA-compliant systematic review. Seven studies were eligible for further analysis. Additionally, one of our previously unreported cases was included in the analysis. Esophageal pouch approximation prior to primary repair was performed more frequently in the NG than in the HG (100% NG vs. 21% HG; p = 0.003). There was no difference in the overall postoperative appearance of postoperative stricture (95% HG vs. 100% NG; p = 0.64). The number of postoperative dilatations trended lower in the NG (mean 4.25 NG vs. 9.5 HG; p = 0.051). In summary, magnetic compression anastomosis adds a new promising treatment option for patients with complex esophageal atresia. Prior approximation of pouches and a novel magnet design have the potential to lower the rate of stricture formation.

The novel application of an emerging device for salvage of primary repair in high-risk complex esophageal atresia.

INTRODUCTION: Preservation of native esophagus is a tenet of esophageal atresia (EA) repair. However, techniques for delayed primary anastomosis are severely limited for surgically and medically complex patients at high-risk for operative repair. We report our initial experience with the novel application of the Connect-EA, an esophageal magnetic compression anastomosis device, for salvage of primary repair in 2 high-risk complex EA patients. Compassionate use was approved by the FDA and treating institutions. OPERATIVE TECHNIQUE: Two approaches using the Connect-EA are described - a totally endoscopic approach and a novel hybrid operative approach. To our knowledge, this is the first successful use of a hybrid operative approach with an esophageal magnetic compression device. OUTCOMES: Salvage of delayed primary anastomosis was successful in both patients. The totally endoscopic approach significantly reduced operative time and avoided repeat high-risk operation. The hybrid operative approach salvaged delayed primary anastomosis and avoided cervical esophagostomy. CONCLUSION: The Connect-EA is a novel intervention to achieve delayed primary esophageal repair in complex EA patients with high-risk tissue characteristics and multi-system comorbidities that limit operative repair. We propose a clinical algorithm for use of the totally endoscopic approach and hybrid operative approach for use of the Connect-EA in high-risk complex EA patients.

Antimicrobial susceptibility of biliary stents do not predict infectious complications after whipple.

BACKGROUND: Postoperative infectious complications after a pancreaticoduodenectomy remain a significant cause of morbidity. Studies have demonstrated that a preoperative biliary stent increases the risk of postoperative infectious complications. Few studies have investigated the specific preoperative biliary stent bacterial sensitivities to preoperative antibiotics and the effect on infectious complications. The goal of this study was to investigate if the presence of a preoperative biliary stent increases the risk of postoperative infectious complications in patients undergoing a pancreaticoduodenectomy. Additionally, we aimed to investigate biliary stent culture sensitivities to preoperative antibiotics and determine if those sensitivities impacted postoperative infectious complications after a pancreaticoduodenectomy. METHODS: A retrospective chart review of patients who had undergone a pancreaticoduodenectomy at a single institution tertiary care center from 2007 to 2018 was performed. Perioperative variables including microbiology cultures from biliary stents were collected and analyzed. RESULTS: A total of 244 patients underwent a pancreaticoduodenectomy. A preoperative biliary stent was present in 45 (18%) patients. Infectious complications occurred in 25% of those patients with a preoperative biliary stent, and 19% of those without (P = .37). Of those patients with a stent that was cultured intraoperatively, 92% grew bacteria and 61% of those were resistant to the preoperative antibiotics administered. Of the patients with a preoperative biliary stent and bacteria resistant to the preoperative antibiotics, 17% developed a postoperative infectious complication, compared with 20% if the bacteria cultured was susceptible to the preoperative antibiotics (P = .64). CONCLUSION: Infectious complications after pancreaticoduodenectomy are a significant cause of morbidity. Stent bacterial sensitivities to preoperative antibiotics did not reduce the postoperative infectious complications in the preoperative biliary stent group suggesting a multifactorial cause of infections.

Association of obesity with postoperative outcomes after proctectomy.

BACKGROUND: Prior efforts evaluating obesity as a risk factor for postoperative complications following proctectomy have been limited by sample size and uniform outcome classification. METHODS: The ACS NSQIP was queried for patients with non-metastatic rectal adenocarcinoma who underwent elective proctectomy. After stratification by BMI classification, multivariable modeling was used to identify the effect of BMI class on adjusted risk of 30-day outcomes controlling for patient, procedure, and tumor factors. RESULTS: Of 2241 patients identified, 33.4% had a normal BMI, 33.5% were overweight, 21.1% were obese, and 12.0% were morbidly obese. Increased risk of superficial surgical site infection (SSI) was observed in obese (OR 2.42, 95%CI:[1.36-4.29]) and morbidly obese (OR 3.29, 95%CI:[1.77-6.11]) patients when compared to normal BMI. Morbid obesity was associated with increased risk of any complication (OR 1.44, 95%CI:[1.05-1.96]). BMI class was not associated with risk adjusted odds of anastomotic leak. CONCLUSIONS: Morbid obesity is independently associated with an increased composite odds risk of short-term morbidity following elective proctectomy for cancer primarily due to increased risk of superficial SSI.

Simple Lithography-Free Single Cell Micropatterning using Laser-Cut Stencils.

Micropatterning techniques have been widely used in cell biology to study effects of controlling cell shape and size on cell fate determination at single cell resolution. Current state-of-the-art single cell micropatterning techniques involve soft lithography and micro-contact printing, which is a powerful technology, but requires trained engineering skills and certain facility support in microfabrication. These limitations require a more accessible technique. Here, we describe a simple alternative lithography-free method: stencil-based single cell patterning. We provide step-by-step procedures including stencil design, polyacrylamide hydrogel fabrication, stencil-based protein incorporation, and cell plating and culture. This simple method can be used to pattern an array of as many as 2,000 cells. We demonstrate the patterning of cardiomyocytes derived from single human induced pluripotent stem cells (hiPSC) with distinct cell shapes, from a 1:1 square to a 7:1 adult cardiomyocyte-like rectangle. This stencil-based single cell patterning is lithography-free, technically robust, convenient, inexpensive, and most importantly accessible to those with a limited bioengineering background.

A Premature Termination Codon Mutation in MYBPC3 Causes Hypertrophic Cardiomyopathy via Chronic Activation of Nonsense-Mediated Decay.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in myosin-binding protein C3 ( MYBPC3) resulting in a premature termination codon (PTC). The underlying mechanisms of how PTC mutations in MYBPC3 lead to the onset and progression of HCM are poorly understood. This study's aim was to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with MYBPC3 PTC mutations by utilizing human isogenic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). METHODS: Isogenic iPSC lines were generated from HCM patients harboring MYBPC3 PTC mutations (p.R943x; p.R1073P_Fsx4) using genome editing. Comprehensive phenotypic and transcriptome analyses were performed in the iPSC-CMs. RESULTS: We observed aberrant calcium handling properties with prolonged decay kinetics and elevated diastolic calcium levels in the absence of structural abnormalities or contracile dysfunction in HCM iPSC-CMs as compared to isogenic controls. The mRNA expression levels of MYBPC3 were significantly reduced in mutant iPSC-CMs, but the protein levels were comparable among isogenic iPSC-CMs, suggesting that haploinsufficiency of MYBPC3 does not contribute to the pathogenesis of HCM in vitro. Furthermore, truncated MYBPC3 peptides were not detected. At the molecular level, the nonsense-mediated decay pathway was activated, and a set of genes involved in major cardiac signaling pathways was dysregulated in HCM iPSC-CMs, indicating an HCM gene signature in vitro. Specific inhibition of the nonsense-mediated decay pathway in mutant iPSC-CMs resulted in reversal of the molecular phenotype and normalization of calcium-handling abnormalities. CONCLUSIONS: iPSC-CMs carrying MYBPC3 PTC mutations displayed aberrant calcium signaling and molecular dysregulations in the absence of significant haploinsufficiency of MYBPC3 protein. Here we provided the first evidence of the direct connection between the chronically activated nonsense-mediated decay pathway and HCM disease development.

Cardiovascular tissue bioprinting: Physical and chemical processes.

Three-dimensional (3D) cardiac tissue bioprinting occupies a critical crossroads position between the fields of materials engineering, cardiovascular biology, 3D printing, and rational organ replacement design. This complex area of research therefore requires expertise from all those disciplines and it poses some unique considerations that must be accounted for. One of the chief hurdles is that there is a relatively limited systematic organization of the physical and chemical characteristics of bioinks that would make them applicable to cardiac bioprinting. This is of great significance, as heart tissue is functionally complex and the in vivo extracellular niche is under stringent controls with little room for variability before a cardiomyopathy manifests. This review explores the critical parameters that are necessary for biologically relevant bioinks to successfully be leveraged for functional cardiac tissue engineering, which can have applications in in vitro heart tissue models, cardiotoxicity studies, and implantable constructs that can be used to treat a range of cardiomyopathies, or in regenerative medicine.

Concise Review: Mending a Broken Heart: The Evolution of Biological Therapeutics.

Heart failure (HF), a common sequela of cardiovascular diseases, remains a staggering clinical problem, associated with high rates of morbidity and mortality worldwide. Advances in pharmacological, interventional, and operative management have improved patient care, but these interventions are insufficient to halt the progression of HF, particularly the end-stage irreversible loss of functional cardiomyocytes. Innovative therapies that could prevent HF progression and improve the function of the failing heart are urgently needed. Following successful preclinical studies, two main strategies have emerged as potential solutions: cardiac gene therapy and cardiac regeneration through stem and precursor cell transplantation. Many potential gene- and cell-based therapies have entered into clinical studies, intending to ameliorate cardiac dysfunction in patients with advanced HF. In this review, we focus on the recent advances in cell- and gene-based therapies in the context of cardiovascular disease, emphasizing the most advanced therapies. The principles and mechanisms of action of gene and cell therapies for HF are discussed along with the limitations of current approaches. Finally, we highlight the emerging technologies that hold promise to revolutionize the biological therapies for cardiovascular diseases. Stem Cells 2017;35:1131-1140.

Efficient Genome Editing in Induced Pluripotent Stem Cells with Engineered Nucleases In Vitro.

Precision genome engineering is rapidly advancing the application of the induced pluripotent stem cells (iPSCs) technology for in vitro disease modeling of cardiovascular diseases. Targeted genome editing using engineered nucleases is a powerful tool that allows for reverse genetics, genome engineering, and targeted transgene integration experiments to be performed in a precise and predictable manner. However, nuclease-mediated homologous recombination is an inefficient process. Herein, we describe the development of an optimized method combining site-specific nucleases and the piggyBac transposon system for "seamless" genome editing in pluripotent stem cells with high efficiency and fidelity in vitro.

Disruption of cell-cell contact-mediated notch signaling via hydrogel encapsulation reduces mesenchymal stem cell chondrogenic potential: winner of the Society for Biomaterials Student Award in the Undergraduate Category, Charlotte, NC, April 15 to 18, 2015.

Cell-cell contact-mediated Notch signaling is essential for mesenchymal stem cell (MSC) chondrogenesis during development. However, subsequent deactivation of Notch signaling is also required to allow for stem cell chondrogenic progression. Recent literature has shown that Notch signaling can also influence Wnt/ß-catenin signaling, critical for MSC differentiation, through perturbations in cell-cell contacts. Traditionally, abundant cell-cell contacts, consistent with development, are emulated in vitro using pellet cultures for chondrogenesis. However, cells are often encapsulated within biomaterials-based scaffolds, such as hydrogels, to improve therapeutic cell localization in vivo. To explore the role of Notch and Wnt/ß-catenin signaling in the context of hydrogel-encapsulated MSC chondrogenesis, we compared signaling and differentiation capacity of MSCs in both hydrogels and traditional pellet cultures. We demonstrate that encapsulation within poly(ethylene glycol) hydrogels reduces cell-cell contacts, and both Notch (7.5-fold) and Wnt/ß-catenin (84.7-fold) pathway activation. Finally, we demonstrate that following establishment of cell-cell contacts and transient Notch signaling in pellet cultures, followed by Notch signaling deactivation, resulted in a 1.5-fold increase in MSC chondrogenesis. Taken together, these findings support that cellular condensation, and establishment of initial cell-cell contacts is critical for MSC chondrogenesis, and this process is inhibited by hydrogel encapsulation.