Propelling Minimally Invasive Tissue Regeneration With Next-Era Injectable Pre-Formed Scaffolds.

The growing aging population, with its associated chronic diseases, underscores the urgency for effective tissue regeneration strategies. Biomaterials play a pivotal role in the realm of tissue reconstruction and regeneration, with a distinct shift toward minimally invasive (MI) treatments. This transition, fueled by engineered biomaterials, steers away from invasive surgical procedures to embrace approaches offering reduced trauma, accelerated recovery, and cost-effectiveness. In the realm of MI tissue repair and cargo delivery, various techniques are explored. While in situ polymerization is prominent, it is not without its challenges. This narrative review explores diverse biomaterials, fabrication methods, and biofunctionalization for injectable pre-formed scaffolds, focusing on their unique advantages. The injectable pre-formed scaffolds, exhibiting compressibility, controlled injection, and maintained mechanical integrity, emerge as promising alternative solutions to in situ polymerization challenges. The conclusion of this review emphasizes the importance of interdisciplinary design facilitated by synergizing fields of materials science, advanced 3D biomanufacturing, mechanobiological studies, and innovative approaches for effective MI tissue regeneration.

Ventriculoperitoneal Shunt Placement Safety in Idiopathic Normal Pressure Hydrocephalus: Anticoagulated Versus Non-Anticoagulated Patients.

BACKGROUND: Many patients with idiopathic normal pressure hydrocephalus (iNPH) have medical comorbidities requiring anticoagulation that could negatively impact outcomes. This study evaluated the safety of ventriculoperitoneal shunt placement in iNPH patients on systemic anticoagulation versus those not on anticoagulation. METHODS: Patients >60 years of age with iNPH who underwent shunting between 2018 and 2022 were retrospectively reviewed. Baseline demographics, comorbidities (quantified by modified frailty index and Charlson comorbidity index), anticoagulant/antiplatelet agent use (other than aspirin), operative details, and complications were collected. Outcomes of interest were the occurrence of postoperative hemorrhage and overdrainage. RESULTS: A total of 234 patients were included in the study (mean age 75.22 ± 6.04 years; 66.7% male); 36 were on anticoagulation/antiplatelet therapy (excluding aspirin). This included 6 on Warfarin, 19 on direct Xa inhibitors, 10 on Clopidogrel, and 1 on both Clopidogrel and Warfarin. Notably, 70% of patients (164/234) used aspirin alone or combined with anticoagulation or clopidogrel. Baseline modified frailty index was similar between groups, but those on anticoagulant/antiplatelet therapy had a higher mean Charlson comorbidity index (2.67 ± 1.87 vs. 1.75 ± 1.84; P = 0.001). Patients on anticoagulants were more likely to experience tract hemorrhage (11.1 vs. 2.5%; P = 0.03), with no significant difference in the rates of intraventricular hemorrhage or overdrainage-related subdural fluid collection. CONCLUSIONS: Anticoagulant and antiplatelet agents are common in the iNPH population, and patients on these agents experienced higher rates of tract hemorrhage following ventriculoperitoneal shunt placement; however, overall hemorrhagic complication rates were similar.

Injectable bioactive poly(propylene fumarate) and polycaprolactone based click chemistry bone cement for spinal fusion in rabbits.

Degenerative spinal pathology is a widespread medical issue, and spine fusion surgeries are frequently performed. In this study, we fabricated an injectable bioactive click chemistry polymer cement for use in spinal fusion and bone regrowth. Taking advantages of the bioorthogonal click reaction, this cement can be crosslinked by itself eliminating the addition of a toxic initiator or catalyst, nor any external energy sources like UV light or heat. Furthermore, nano-hydroxyapatite (nHA) and microspheres carrying recombinant human bone morphogenetic protein-2 (rhBMP-2) and recombinant human vascular endothelial growth factor (rhVEGF) were used to make the cement bioactive for vascular induction and osteointegration. After implantation into a rabbit posterolateral spinal fusion (PLF) model, the cement showed excellent induction of new bone formation and bridging bone, achieving results comparable to autograft control. This is largely due to the osteogenic properties of nano-hydroxyapatite (nHA) and the released rhBMP-2 and rhVEGF growth factors. Since the availability of autograft sources is limited in clinical settings, this injectable bioactive click chemistry cement may be a promising alternative for spine fusion applications in addressing various spinal conditions.

Decompression Alone Versus Interspinous/Interlaminar Device Placement for Degenerative Lumbar Pathologies: Systematic Review and Meta-Analysis.

INTRODUCTION: Interspinous devices (ISDs) and interlaminar devices (ILDs) are marketed as alternatives to conventional surgery for degenerative lumbar conditions; comparisons with decompression alone are limited. The present study reviews the extant literature comparing the cost and effectiveness of ISDs/ILDs with decompression alone. METHODS: Articles comparing decompression alone with ISD/ILD were identified; outcomes of interest included general and disease-specific patient-reported outcomes, perioperative complications, and total treatment costs. Outcomes were analyzed at <6 weeks, 3 months, 6 months, 1 year, 2 years, and last follow-up. Analyses were performed using random effects modeling. RESULTS: Twenty-nine studies were included in the final analysis. ILD/ISD showed greater leg pain improvement at 3 months (mean difference, -1.43; 95% confidence interval, [-1.78, -1.07]; P < 0.001), 6 months (-0.89; [-1.55, -0.24]; P = 0.008), and 12 months (-0.97; [-1.25, -0.68]; P < 0.001), but not 2 years (P = 0.22) or last follow-up (P = 0.09). Back pain improvement was better after ISD/ILD only at 1 year (-0.87; [-1.62, -0.13]; P = 0.02). Short-Form 36 physical component scores or Zurich Claudication Questionnaire (ZCQ) symptom severity scores did not differ between the groups. ZCQ physical function scores improved more after decompression alone at 6 months (0.35; [0.07, 0.63]; P = 0.01) and 12 months (0.23; [0.00, 0.46]; P = 0.05). Oswestry Disability Index and EuroQoL 5 dimensions scores favored ILD/ISD at all time points except 6 months (P = 0.07). Reoperations (odds ratio, 1.75; [1.23, 2.48]; P = 0.002) and total care costs (standardized mean difference, 1.19; [0.62, 1.77]; P < 0.001) were higher in the ILD/ISD group; complications did not differ significantly between the groups (P = 0.41). CONCLUSIONS: Patient-reported outcomes are similar after decompression alone and ILD/ISD; the observed differences do not reach accepted minimum clinically important difference thresholds. ISD/ILDs have higher associated costs and reoperation rates, suggesting current evidence does not support ILD/ISDs as a cost-effective alternative to decompression alone.

Bioactive Moldable Click Chemistry Polymer Cement with Nano-Hydroxyapatite and Growth Factor-Enhanced Posterolateral Spinal Fusion in a Rabbit Model.

Spinal injuries or diseases necessitate effective fusion solutions, and common clinical approaches involve autografts, allografts, and various bone matrix products, each with limitations. To address these challenges, we developed an innovative moldable click chemistry polymer cement that can be shaped by hand and self-cross-linked in situ for spinal fusion. This self-cross-linking cement, enabled by the bioorthogonal click reaction, excludes the need for toxic initiators or external energy sources. The bioactivity of the cement was promoted by incorporating nanohydroxyapatite and microspheres loaded with recombinant human bone morphogenetic protein-2 and vascular endothelial growth factor, fostering vascular induction and osteointegration. The release kinetics of growth factors, mechanical properties of the cement, and the ability of the scaffold to support in vitro cell proliferation and differentiation were evaluated. In a rabbit posterolateral spinal fusion model, the moldable cement exhibited remarkable induction of bone regeneration and effective bridging of spine vertebral bodies. This bioactive moldable click polymer cement therefore presents a promising biomaterial for spinal fusion augmentation, offering advantages in safety, ease of application, and enhanced bone regrowth.

Elucidating the pathogenesis behind arteriovenous malformations of the central nervous system: a bibliometric analysis.

Arteriovenous malformations (AVMs) are vascular malformations of the central nervous system (CNS) with potential for significant consequences. The exact pathophysiologic mechanism of AVM formation is not fully understood. This study aims to evaluate bibliometric parameters and citations of the literature of AVMs to provide an overview of how the field has evolved. We performed an electronic search on Web of Science to identify the top 100 published and indexed articles with the highest number of citations discussing the pathogenesis of AVMs. This study yielded 1863 articles, of which the top 100 were selected based on the highest total citation count. These articles included 24% basic science, 46% clinical, and 30% review articles. The most-cited article was a clinical article from 2003, and the most recent was published in 2022. The median number of authors was 6, with the highest being 46 for a clinical article. The top 5 journals were identified, with the highest impact factor being 20.1. 13 countries were identified, with the US contributing the most articles (approximately 70%). Regarding genes of investigation, VEGF was one of the early genes investigated, while more interested in RAS/MAPK has been garnered since 2015. There is a growing interest in AVM genomics and pathogenesis research. While progress has been made in understanding clinical aspects and risk factors, the exact pathophysiological mechanisms and genetic basis of AVM formation remain incompletely understood. Further investigation of key genes in AVM pathogenesis can allow identification of potential therapeutic targets.

Biodegradable poly(caprolactone fumarate) 3D printed scaffolds for segmental bone defects within the Masquelet technique.

Segmental bone defects, often clinically treated with nondegradable poly(methylmethacrylate) (PMMA) in multistage surgeries, present a significant clinical challenge. Our study investigated the efficacy of 3D printed biodegradable polycaprolactone fumarate (PCLF)/PCL spacers in a one-stage surgical intervention for these defects, focusing on early bone regeneration influenced by spacer porosities. We compared nonporous PCLF/PCL and PMMA spacers, conventionally molded into cylinders, with porous PCLF/PCL spacers, 3D printed to structurally mimic segmental defects in rat femurs for a 4-week implantation study. Histological analysis, including tissue staining and immunohistochemistry with bone-specific antibodies, was conducted for histomorphometry evaluation. The PCLF/PCL spacers demonstrated compressive properties within 6 ± 0.5 MPa (strength) and 140 ± 15 MPa (modulus). Both porous PCLF/PCL and Nonporous PMMA formed collagen-rich membranes (PCLF/PCL: 92% ± 1.3%, PMMA: 86% ± 1.5%) similar to those induced in the Masquelet technique, indicating PCLF/PCL's potential for one-stage healing. Immunohistochemistry confirmed biomarkers for tissue regeneration, underscoring PCLF/PCL's regenerative capabilities. This research highlights PCLF/PCL scaffolds' ability to induce membrane formation in critical-sized segmental bone defects, supporting their use in one-stage surgery. Both solid and porous PCLF/PCL spacers showed adequate compressive properties, with the porous variants exhibiting BMP-2 expression and woven bone formation, akin to clinical standard PMMA. Notably, the early ossification of the membrane into the pores of porous scaffolds suggests potential for bone interlocking and regeneration, potentially eliminating the need for a second surgery required for PMMA spacers. The biocompatibility and biodegradability of PCLF/PCL make them promising alternatives for treating critical bone defects, especially in vulnerable patient groups.

3D Stem Cell Spheroids with 2D Hetero-Nanostructures for In Vivo Osteogenic and Immunologic Modulated Bone Repair.

3D stem cell spheroids have immense potential for various tissue engineering applications. However, current spheroid fabrication techniques encounter cell viability issues due to limited oxygen access for cells trapped within the core, as well as nonspecific differentiation issues due to the complicated environment following transplantation. In this study, functional 3D spheroids are developed using mesenchymal stem cells with 2D hetero-nanostructures (HNSs) composed of single-stranded DNA (ssDNA) binding carbon nanotubes (sdCNTs) and gelatin-bind black phosphorus nanosheets (gBPNSs). An osteogenic molecule, dexamethasone (DEX), is further loaded to fabricate an sdCNTgBP-DEX HNS. This approach aims to establish a multifunctional cell-inductive 3D spheroid with improved oxygen transportation through hollow nanotubes, stimulated stem cell growth by phosphate ions supplied from BP oxidation, in situ immunoregulation, and osteogenesis induction by DEX molecules after implantation. Initial transplantation of the 3D spheroids in rat calvarial bone defect shows in vivo macrophage shifts to an M2 phenotype, leading to a pro-healing microenvironment for regeneration. Prolonged implantation demonstrates outstanding in vivo neovascularization, osteointegration, and new bone regeneration. Therefore, these engineered 3D spheroids hold great promise for bone repair as they allow for stem cell delivery and provide immunoregulative and osteogenic signals within an all-in-one construct.

The Predictors of Incidental Durotomy in Patients Undergoing Pedicle Subtraction Osteotomy for the Correction of Adult Spinal Deformity.

Background: Pedicle subtraction osteotomy (PSO) is a powerful tool for sagittal plane correction in patients with rigid adult spinal deformity (ASD); however, it is associated with high intraoperative blood loss and the increased risk of durotomy. The objective of the present study was to identify intraoperative techniques and baseline patient factors capable of predicting intraoperative durotomy. Methods: A tri-institutional database was retrospectively queried for all patients who underwent PSO for ASD. Data on baseline comorbidities, surgical history, surgeon characteristics and intraoperative maneuvers were gathered. PSO aggressiveness was defined as conventional (Schwab 3 PSO) or an extended PSO (Schwab type 4). The primary outcome of the study was the occurrence of durotomy intraoperatively. Univariable analyses were performed with Mann-Whitney U tests, Chi-squared analyses, and Fisher's exact tests. Statistical significance was defined by p < 0.05. Results: One hundred and sixteen patients were identified (mean age 61.9 ± 12.6 yr; 44.8% male), of whom 51 (44.0%) experienced intraoperative durotomy. There were no significant differences in baseline comorbidities between those who did and did not experience durotomy, with the exception that baseline weight and body mass index were higher in patients who did not suffer durotomy. Prior surgery (OR 2.73; 95% CI [1.13, 6.58]; p = 0.03) and, more specifically, prior decompression at the PSO level (OR 4.23; 95% CI [1.92, 9.34]; p < 0.001) was predictive of durotomy. A comparison of surgeon training showed no statistically significant difference in durotomy rate between fellowship and non-fellowship trained surgeons, or between orthopedic surgeons and neurosurgeons. The PSO level, PSO aggressiveness, the presence of stenosis at the PSO level, nor the surgical instrument used predicted the odds of durotomy occurrence. Those experiencing durotomy had similar hospitalization durations, rates of reoperation and rates of nonroutine discharge. Conclusions: In this large multisite series, a history of prior decompression at the PSO level was associated with a four-fold increase in intraoperative durotomy risk. Notably the use of extended (versus) standard PSO, surgical technique, nor baseline patient characteristics predicted durotomy. Durotomies occurred in 44% of patients and may prolong operative times. Additional prospective investigations are merited.

Surgical resection of recurrent intramedullary subependymoma of the cervical spinal cord.

Spinal subependymomas (SE) are rare, often indolent benign tumors presenting most frequently as intramedullary tumors in the cervical spine or cervicothoracic junction. When symptomatic, patients often present with years of sensory changes, weakness, paresthesias, or bowel and bladder dysfunction. Preoperatively, SE are difficult to distinguish radiographically from ependymomas or astrocytomas; however, it is important to make the distinction intraoperatively as complete resection can be curative. Here the authors present a rare case of recurrent, symptomatic cervical subependymoma which underwent gross-total resection and discussion of management strategies and outcomes of all SE at their institution.

Visible light-induced 3D bioprinted injectable scaffold for minimally invasive tissue regeneration.

Pre-formed hydrogel scaffolds have emerged as favorable vehicles for tissue regeneration, promoting minimally invasive treatment of native tissue. However, due to the high degree of swelling and inherently poor mechanical properties, development of complex structural hydrogel scaffolds at different dimensional scales has been a continuous challenge. Herein, we take a novel approach at the intersections of engineering design and bio-ink chemistry to develop injectable pre-formed structural hydrogel scaffolds fabricated via visible light (VL) induced digital light processing (DLP). In this study, we first determined the minimum concentration of poly(ethylene glycol) diacrylate (PEGDA) to be added to the gelatin methacrylate (GelMA) bio-ink in order to achieve scalable and high printing-fidelity with desired cell adhesion, viability, spreading, and osteogenic differentiation characteristics. Despite the advantages of hybrid GelMA-PEGDA bio-ink in improving scalability and printing-fidelity, compressibility, shape-recovery, and injectability of the 3D bioprinted scaffolds were compromised. To restore these needed characteristics for minimally invasive tissue regeneration applications, we performed topological optimization to design highly compressible and injectable pre-formed (i.e., 3D bioprinted) microarchitectural scaffolds. The designed injectable pre-formed microarchitectural scaffolds showed a great capacity to retain the viability of the encapsulated cells (>72 % after 10 cycles of injection). Lastly, ex ovo chicken chorioallantoic membrane (CAM) studies revealed that the optimized injectable pre-formed hybrid hydrogel scaffold is biocompatible and supports angiogenic growth.

3D-printed scaffolds with 2D hetero-nanostructures and immunomodulatory cytokines provide pro-healing microenvironment for enhanced bone regeneration.

Three-dimensional (3D) printing technology is driving forward the progresses of various engineering fields, including tissue engineering. However, the pristine 3D-printed scaffolds usually lack robust functions in stimulating desired activity for varied regeneration applications. In this study, we combined the two-dimensional (2D) hetero-nanostructures and immuno-regulative interleukin-4 (IL-4) cytokines for the functionalization of 3D-printed scaffolds to achieve a pro-healing immuno-microenvironment for optimized bone injury repair. The 2D hetero-nanostructure consists of graphene oxide (GO) layers, for improved cell adhesion, and black phosphorous (BP) nanosheets, for the continuous release of phosphate ions to stimulate cell growth and osteogenesis. In addition, the 2D hetero-nanolayers facilitated the adsorption of large content of immuno-regulative IL-4 cytokines, which modulated the polarization of macrophages into M2 phenotype. After in vivo implantation in rat, the immuno-functioned 3D-scaffolds achieved in vivo osteo-immunomodulation by building a pro-healing immunological microenvironment for better angiogenesis and osteogenesis in the defect area and thus facilitated bone regeneration. These results demonstrated that the immuno-functionalization of 3D-scaffolds with 2D hetero-nanostructures with secondary loading of immuno-regulative cytokines is an encouraging strategy for improving bone regeneration.

Biomechanical behavior of PMMA 3D printed biomimetic scaffolds: Effects of physiologically relevant environment.

Functional cellular structures with controllable mechanical and morphological properties are of great interest for applications including tissue engineering, energy storage, and aerospace. Additive manufacturing (AM), also referred to as 3D printing, has enabled the potential for fabrication of functional porous scaffolds (i.e., meta-biomaterials) with controlled geometrical, morphological, and mechanical properties. Understanding the biomechanical behavior of 3D printed porous scaffolds under physiologically relevant loading and environmental conditions is crucial in accurately predicting the in vivo performance. This study was aimed to investigate the environmental dependency of the mechanical responses of 3D printed porous scaffolds of poly(methyl methacrylate) (PMMA) Class IIa biomaterial that was based on triply periodic minimal surfaces - TPMS (i.e., Primitive and Schoen-IWP). The 3D printed scaffolds (n = 5/study group) were tested under compressive loading in both ambient and fluidic (distilled water with pH = 7.4) environments according to ASTM D1621 standards. Outcomes of this study showed that compressive properties of the developed scaffolds are significantly lower in the fluidic condition than the ambient environment for the same topological and morphological group (p≤0.023). Additionally, compressive properties and flexural stiffness of the studied scaffolds were within the range of trabecular bone's properties, for both topological classes. Relationships between predicted mechanical responses and morphological properties (i.e., porosity) were evaluated for each topological class. Quantitative correlation analysis indicated that mechanical behavior of the developed 3D printed scaffolds can be controlled based on both topology and morphology.