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Lysosomes and lysosome related organelles (LROs) are dynamic organelles at the intersection of various pathways involved in maintaining cellular hemostasis and regulating cellular functions. Vesicle trafficking of lysosomes and LROs are critical to maintain their functions. The lysosomal trafficking regulator (LYST) is an elusive protein important for the regulation of membrane dynamics and intracellular trafficking of lysosomes and LROs. Mutations to the LYST gene result in Chédiak-Higashi syndrome, an autosomal recessive immunodeficiency characterized by defective granule exocytosis, cytotoxicity, etc. Despite eight decades passing since its initial discovery, a comprehensive understanding of LYST's function in cellular biology remains unresolved. Accumulating evidence suggests that dysregulation of LYST function also manifests in other disease states. Here, we review the available literature to consolidate available scientific endeavors in relation to LYST and discuss its relevance for immunomodulatory therapies, regenerative medicine and cancer applications.
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Lisosomas , Proteínas de Transporte Vesicular , Humanos , Lisosomas/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Proteínas de Transporte Vesicular/genética , Animales , Síndrome de Chediak-Higashi/genética , Transporte de Proteínas , MutaciónRESUMEN
Advancements in congenital heart surgery have heightened the importance of durable biomaterials for adult survivors. Dystrophic calcification poses a significant risk to the long-term viability of prosthetic biomaterials in these procedures. Herein, we describe the natural history of calcification in the most frequently used vascular conduits, expanded polytetrafluoroethylene grafts. Through a retrospective clinical study and an ovine model, we compare the degree of calcification between tissue-engineered vascular grafts and polytetrafluoroethylene grafts. Results indicate superior durability in tissue-engineered vascular grafts, displaying reduced late-term calcification in both clinical studies (p < 0.001) and animal models (p < 0.0001). Further assessments of graft compliance reveal that tissue-engineered vascular grafts maintain greater compliance (p < 0.0001) and distensibility (p < 0.001) than polytetrafluoroethylene grafts. These properties improve graft hemodynamic performance, as validated through computational fluid dynamics simulations. We demonstrate the promise of tissue engineered vascular grafts, remaining compliant and distensible while resisting long-term calcification, to enhance the long-term success of congenital heart surgeries.
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Prótesis Vascular , Calcinosis , Ovinos , Animales , Estudios Retrospectivos , Calcinosis/cirugía , Materiales Biocompatibles , PolitetrafluoroetilenoRESUMEN
Despite advances in opioid-sparing pain management, postdischarge opioid overprescribing in plastic surgery remains an issue. Procedure-specific prescribing protocols have been implemented successfully in other surgical specialties but not broadly in plastic surgery. This study examined the efficacy of procedure-specific prescribing guidelines for reducing postdischarge opioid overprescribing. Methods: A total of 561 plastic surgery patients were evaluated retrospectively after a prescribing guideline, which recommended postdischarge prescription amounts based on the type of operation, was introduced in July 2020. Prescription and postdischarge opioid consumption amounts before (n = 428) and after (n = 133) guideline implementation were compared. Patient satisfaction and prescription frequency of nonopioid analgesia were also compared. Results: The average number of opioid pills per prescription decreased by 25% from 19.3 (27.4 OME) to 15.0 (22.7 OME; P = 0.001) after guideline implementation, with no corresponding decrease in the average number of postdischarge opioid pills consumed [10.6 (15.1 OME) to 8.2 (12.4 OME); P = 0.147]. Neither patient satisfaction with pain management (9.6-9.6; P > 0.99) nor communication (9.6-9.5; P > 0.99) changed. The rate of opioid-only prescription regimens decreased from 17.9% to 7.6% (P = 0.01), and more patients were prescribed at least two nonopioid analgesics (27.5% to 42.9%; P = 0.003). The rate of scheduled acetaminophen prescription, in particular, increased (54.7% to 71.4%; P = 0.002). Conclusions: A procedure-specific prescribing model is a straight-forward intervention to promote safer opioid-prescribing practices in plastic surgery. Its usage in clinical practice may lead to more appropriate opioid prescribing.
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BACKGROUND: Opioid overprescribing after surgery is common. There is currently no universal predictive tool available to accurately anticipate postdischarge opioid need in a patient-specific manner. This study examined the efficacy of a patient-specific opioid prescribing framework for estimating postdischarge opioid consumption. METHODS: A total of 149 patients were evaluated for a single-center retrospective cohort study of plastic and reconstructive surgery patients. Patients with length of stay of 2 to 8 days and quantifiable inpatient opioid consumption (n = 116) were included. Each patient's daily postoperative inpatient opioid consumption was used to generate a personalized logarithmic regression model to estimate postdischarge opioid need. The validity of the personalized opioid prescription (POP) model was tested through comparison with actual postdischarge opioid consumption reported by patients 4 weeks after surgery. The accuracy of the POP model was compared with two other opioid prescribing models. RESULTS: The POP model had the strongest association (R2 = 0.899; P < 0.0001) between model output and postdischarge opioid consumption when compared to a procedure-based (R2 = 0.226; P = 0.025) or a 24-hour (R2 = 0.152; P = 0.007) model. Accuracy of the POP model was unaffected by age, gender identity, procedure type, or length of stay. Odds of persistent use at 4 weeks increased, with a postdischarge estimated opioid need at a rate of 1.16 per 37.5 oral morphine equivalents (P = 0.010; 95% CI, 1.04 to 1.30). CONCLUSIONS: The POP model accurately estimates postdischarge opioid consumption and risk of developing persistent use in plastic surgery patients. Use of the POP model in clinical practice may lead to more appropriate and personalized opioid prescribing.
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Analgésicos Opioides , Alta del Paciente , Humanos , Masculino , Femenino , Analgésicos Opioides/efectos adversos , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/inducido químicamente , Estudios Retrospectivos , Cuidados Posteriores , Pautas de la Práctica en Medicina , Identidad de Género , Prescripciones de MedicamentosRESUMEN
Capsular contracture as a result of the foreign body response (FBR) is a common issue after implant-based breast reconstruction, affecting up to 20% of patients. New evidence suggests that tamoxifen may mitigate the FBR. C57BL/6 female mice were treated with daily tamoxifen or control injections and implanted with bilateral silicone implants in the submammary glandular plane. Implants were removed en bloc after 2 weeks and the implant capsules were evaluated histologically. Tamoxifen treatment decreased capsule thickness, decreased the number of αSMA+ cells (477 ± 156 cells/mm control vs 295 ± 121 cells/mm tamoxifen, p = 0.005 unpaired t test), and decreased CD31+ cells (173.9 ± 96.1 cells/mm2 control vs 106.3 ± 51.8 cells/mm2 tamoxifen, p = 0.043 unpaired t test). There were similar amounts of pro- and anti-inflammatory macrophages (iNOS 336.1 ± 226.3 cells/mm control vs 290.6 ± 104.2 cells/mm tamoxifen, p > 0.999 Mann-Whitney test and CD163 136.6 ± 76.4 cells/mm control vs 94.1 ± 45.9 cells/mm tamoxifen, p = 0.108 unpaired t test). Tamoxifen treatment in the mouse silicone breast implant model decreased capsule formation through modulation of myofibroblasts, neovascularization, and collagen deposition. Tamoxifen may be useful for reducing or preventing capsule formation in clinical breast implantations.
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Native arteries contain a distinctive intima-media composed of organized elastin and an adventitia containing mature collagen fibrils. In contrast, implanted biodegradable small-diameter vascular grafts do not present spatially regenerated, organized elastin. The elastin-containing structures within the intima-media region encompass the elastic lamellae (EL) and internal elastic lamina (IEL) and are crucial for normal arterial function. Here, the development of a novel electrospun small-diameter vascular graft that facilitates de novo formation of a structurally appropriate elastin-containing intima-media region following implantation is described. The graft comprises a non-porous microstructure characterized by tropoelastin fibers that are embedded in a PGS matrix. After implantation in mouse abdominal aorta, the graft develops distinct cell and extracellular matrix profiles that approximate the native adventitia and intima-media by 8 weeks. Within the newly formed intima-media region there are circumferentially aligned smooth muscle cell layers that alternate with multiple EL similar to that found in the arterial wall. By 8 months, the developed adventitia region contains mature collagen fibrils and the neoartery presents a distinct IEL with thickness comparable to that in mouse abdominal aorta. It is proposed that this new class of material can generate the critically required, organized elastin needed for arterial regeneration.
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Prótesis Vascular , Elastina , Ratones , Animales , Miocitos del Músculo Liso , Arterias , ColágenoRESUMEN
Background: Tissue-engineered vascular grafts (TEVGs) have the potential to advance the surgical management of infants and children requiring congenital heart surgery by creating functional vascular conduits with growth capacity. Methods: Herein, we used an integrative computational-experimental approach to elucidate the natural history of neovessel formation in a large animal preclinical model; combining an in vitro accelerated degradation study with mechanical testing, large animal implantation studies with in vivo imaging and histology, and data-informed computational growth and remodeling models. Results: Our findings demonstrate that the structural integrity of the polymeric scaffold is lost over the first 26 weeks in vivo, while polymeric fragments persist for up to 52 weeks. Our models predict that early neotissue accumulation is driven primarily by inflammatory processes in response to the implanted polymeric scaffold, but that turnover becomes progressively mechano-mediated as the scaffold degrades. Using a lamb model, we confirm that early neotissue formation results primarily from the foreign body reaction induced by the scaffold, resulting in an early period of dynamic remodeling characterized by transient TEVG narrowing. As the scaffold degrades, mechano-mediated neotissue remodeling becomes dominant around 26 weeks. After the scaffold degrades completely, the resulting neovessel undergoes growth and remodeling that mimicks native vessel behavior, including biological growth capacity, further supported by fluid-structure interaction simulations providing detailed hemodynamic and wall stress information. Conclusions: These findings provide insights into TEVG remodeling, and have important implications for clinical use and future development of TEVGs for children with congenital heart disease.
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To date, there has been limited investigation of bioabsorbable atrial septal defect (ASD) or patent foramen ovale (PFO) closure devices using clinically relevant large animal models. The purpose of this study is to explore the function and safety of a bioabsorbable ASD occluder (BAO) system for PFO and/or secundum ASD transcatheter closure. Using a sheep model, the intra-atrial septum was evaluated by intracardiac echo (ICE). If a PFO was not present, atrial communication was created via transseptal puncture. Device implantation across the intra-atrial communication was performed with fluoroscopic and ICE guidance. Our 1st generation device consisted of a main structure of thin Poly(L-lactide-co-epsilon-caprolactone) (PLCL) fibers, and an internal Poly glycolic acid (PGA) fabric. Four procedures validated procedure feasibility. Subsequently, device design was modified for improved transcatheter delivery. The 2nd generation device has a two-layered structure and was implanted in six sheep. Results showed procedural success in 9/10 (90%) animals. With deployment, the 1st generation device did not reform into its original disk shape and did not conform nicely along the atrial septum. The 2nd generation device was implanted in six animals, 3 out of 6 survived out to 1 year. At 1 year post implantation, ICE confirmed no residual shunting. By necropsy, biomaterials had partially degraded, and histology of explanted samples revealed significant device endothelialization and biomaterial replacement with a collagen layer. Our results demonstrate that our modified 2nd generation BAO can be deployed via minimally invasive percutaneous transcatheter techniques. The BAO partially degrades over 1 year and is replaced by host native tissues. Future studies are needed prior to clinical trials.
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Foramen Oval Permeable , Defectos del Tabique Interatrial , Dispositivo Oclusor Septal , Implantes Absorbibles , Animales , Cateterismo Cardíaco/métodos , Estudios de Seguimiento , Foramen Oval Permeable/cirugía , Atrios Cardíacos , Defectos del Tabique Interatrial/diagnóstico por imagen , Defectos del Tabique Interatrial/cirugía , Humanos , Ovinos , Resultado del TratamientoRESUMEN
Congenital heart disease (CHD) represents a large clinical burden, representing the most common cause of birth defect-related death in the newborn. The mainstay of treatment for CHD remains palliative surgery using prosthetic vascular grafts and valves. These devices have limited effectiveness in pediatric patients due to thrombosis, infection, limited endothelialization, and a lack of growth potential. Tissue engineering has shown promise in providing new solutions for pediatric CHD patients through the development of tissue engineered vascular grafts, heart patches, and heart valves. In this review, we examine the current surgical treatments for congenital heart disease and the research being conducted to create tissue engineered products for these patients. While much research remains to be done before tissue engineering becomes a mainstay of clinical treatment for CHD patients, developments have been progressing rapidly towards translation of tissue engineering devices to the clinic.
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Bioprótesis , Cardiopatías Congénitas , Niño , Cardiopatías Congénitas/cirugía , Humanos , Recién Nacido , Ingeniería de TejidosRESUMEN
Non-healing wounds are a major threat to public health throughout the United States. Tissue healing is complex multifactorial process that requires synchronicity of several cell types. Endolysosomal trafficking, which contributes to various cell functions from protein degradation to plasma membrane repair, is an understudied process in the context of wound healing. The lysosomal trafficking regulator protein (LYST) is an essential protein of the endolysosomal system through an indeterminate mechanism. In this study, we examine the impact of impaired LYST function both in vitro with primary LYST mutant fibroblasts as well as in vivo with an excisional wound model. The wound model shows that LYST mutant mice have impaired wound healing in the form of delayed epithelialization and collagen deposition, independent of macrophage infiltration and polarisation. We show that LYST mutation confers a deficit in MCP-1, IGF-1, and IGFBP-2 secretion in beige fibroblasts, which are critical factors in normal wound healing. Identifying the mechanism of LYST function is important for understanding normal wound biology, which may facilitate the development of strategies to address problem wound healing.
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Lisosomas , Cicatrización de Heridas , Animales , Colágeno , Fibroblastos , Ratones , RepitelizaciónRESUMEN
Macrophages are a critical driver of neovessel formation in tissue-engineered vascular grafts (TEVGs), but also contribute to graft stenosis, a leading clinical trial complication. Macrophage depletion via liposomal delivery of clodronate, a first-generation bisphosphonate, mitigates stenosis, but simultaneously leads to a complete lack of tissue development in TEVGs. This result and the associated difficulty of utilizing liposomal delivery means that clodronate may not be an ideal means of preventing graft stenosis. Newer generation bisphosphonates, such as zoledronate, may have differential effects on graft development with more facile drug delivery. We sought to examine the effect of zoledronate on TEVG neotissue formation and its potential application for mitigating TEVG stenosis. Thus, mice implanted with TEVGs received zoledronate or no treatment and were monitored by serial ultrasound for graft dilation and stenosis. After two weeks, TEVGs were explanted for histological examination. The overall graft area and remaining graft material (polyglycolic-acid) were higher in the zoledronate treatment group. These effects were associated with a corresponding decrease in macrophage infiltration. In addition, zoledronate affected the deposition of collagen in TEVGs, specifically, total and mature collagen. These differences may be, in part, explained by a depletion of leukocytes within the bone marrow that subsequently led to a decrease in the number of tissue-infiltrating macrophages. TEVGs from zoledronate-treated mice demonstrated a significantly greater degree of smooth muscle cell presence. There was no statistical difference in graft patency between treatment and control groups. While zoledronate led to a decrease in the number of macrophages in the TEVGs, the severity of stenosis appears to have increased significantly. Zoledronate treatment demonstrates that the process of smooth muscle cell-mediated neointimal hyperplasia may occur separately from a macrophage-mediated mechanism.
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Prótesis Vascular/estadística & datos numéricos , Neointima/terapia , Ingeniería de Tejidos/métodos , Injerto Vascular/métodos , Ácido Zoledrónico/farmacología , Animales , Conservadores de la Densidad Ósea/farmacología , Femenino , Ratones , Ratones Endogámicos C57BL , Neointima/patología , Andamios del Tejido/químicaRESUMEN
In the field of congenital heart surgery, tissue-engineered vascular grafts (TEVGs) are a promising alternative to traditionally used synthetic grafts. Our group has pioneered the use of TEVGs as a conduit between the inferior vena cava and the pulmonary arteries in the Fontan operation. The natural history of graft remodeling and its effect on hemodynamic performance has not been well characterized. In this study, we provide a detailed analysis of the first U.S. clinical trial evaluating TEVGs in the treatment of congenital heart disease. We show two distinct phases of graft remodeling: an early phase distinguished by rapid changes in graft geometry and a second phase of sustained growth and decreased graft stiffness. Using clinically informed and patient-specific computational fluid dynamics (CFD) simulations, we demonstrate how changes to TEVG geometry, thickness, and stiffness affect patient hemodynamics. We show that metrics of patient hemodynamics remain within normal ranges despite clinically observed levels of graft narrowing. These insights strengthen the continued clinical evaluation of this technology while supporting recent indications that reversible graft narrowing can be well tolerated, thus suggesting caution before intervening clinically.
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The vasculature is innervated by a network of peripheral afferents that sense and regulate blood flow. Here, we describe a system of non-peptidergic sensory neurons with cell bodies in the spinal ganglia that regulate vascular tone in the distal arteries. We identify a population of mechanosensitive neurons, marked by tropomyosin receptor kinase C (TrkC) and tyrosine hydroxylase in the dorsal root ganglia, which projects to blood vessels. Local stimulation of TrkC neurons decreases vessel diameter and blood flow, whereas systemic activation increases systolic blood pressure and heart rate variability via the sympathetic nervous system. Ablation of the neurons provokes variability in local blood flow, leading to a reduction in systolic blood pressure, increased heart rate variability, and ultimately lethality within 48 h. Thus, a population of TrkC+ sensory neurons forms part of a sensory-feedback mechanism that maintains cardiovascular homeostasis through the autonomic nervous system.
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Presión Sanguínea/fisiología , Células Receptoras Sensoriales/fisiología , Animales , Conducta Animal , Fluoresceína/metabolismo , Ganglios Espinales/fisiología , Frecuencia Cardíaca/fisiología , Ratones Transgénicos , Receptor trkC/metabolismoRESUMEN
Tissue engineered vascular grafts hold promise for the creation of functional blood vessels from biodegradable scaffolds. Because the precise mechanisms regulating this process are still under investigation, inducible genetic mouse models are an important and widely used research tool. However, here we describe the importance of challenging the baseline assumption that tamoxifen is inert when used as a small molecule inducer in the context of cardiovascular tissue engineering. Employing a standard inferior vena cava vascular interposition graft model in C57BL/6 mice, we discovered differences in the immunologic response between control and tamoxifen-treated animals, including occlusion rate, macrophage infiltration and phenotype, the extent of foreign body giant cell development, and collagen deposition. Further, differences were noted between untreated males and females. Our findings demonstrate that the host-response to materials commonly used in cardiovascular tissue engineering is sex-specific and critically impacted by exposure to tamoxifen, necessitating careful model selection and interpretation of results.
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Tamoxifeno , Ingeniería de Tejidos , Animales , Prótesis Vascular , Células de la Médula Ósea , Femenino , Ratones , Ratones Endogámicos C57BL , Andamios del TejidoRESUMEN
Wall stress is often lower in tissue-engineered constructs than in comparable native tissues due to the use of stiff polymeric materials having thicker walls. In this work, we sought to design a murine arterial graft having a more favorable local mechanical environment for the infiltrating cells; we used electrospinning to enclose a compliant inner core of poly(glycerol sebacate) with a stiffer sheath of poly(caprolactone) to reduce the potential for rupture. Two scaffolds were designed that differed in the thickness of the core as previous computational simulations found that circumferential wall stresses could be increased in the core toward native values by increasing the ratio of the core:sheath. Our modified electrospinning protocols reduced swelling of the core upon implantation and eliminated residual stresses in the sheath, both of which had contributed to the occlusion of implanted grafts during pilot studies. For both designs, a subset of implanted grafts occluded due to thrombosis or ruptured due to suspected point defects in the sheath. However, there were design-based differences in collagen content and mechanical behavior during early remodeling of the patent samples, with the thinner-core scaffolds having more collagen and a stiffer behavior after 12 weeks of implantation than the thicker-core scaffolds. By 24 weeks, the thicker-core scaffolds also became stiff, with similar amounts of collagen but increased smooth muscle cell and elastin content. These data suggest that increasing wall stress toward native values may provide a more favorable environment for normal arterial constituents to form despite the overall stiffness of the construct remaining elevated due to the absolute increase in load-bearing constituents.
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Ingeniería de Tejidos , Andamios del Tejido , Animales , Arterias , Prótesis Vascular , Colágeno , Elastina , Ratones , PoliésteresRESUMEN
BACKGROUND: Small diameter (<6 mm), bioabsorbable, arterial, tissue-engineered vascular grafts (TEVGs) remain limited by thromboembolism. The objective of this study was to test whether heparin-eluting (HE) TEVGs prevent early thrombosis in a large animal model. METHODS: TEVGs were created with an outer poly-ε-caprolactone electrospun nanofiber layer, with a 15-µm average pore size and an inner layer composed of a 50:50 poly(L-lactide-co-ε-caprolactone) copolymer. Adult female sheep (n = 5) underwent bilateral carotid artery interposition grafting, with a control TEVG in 1 carotid artery and an HE TEVG in the contralateral position. Animals were followed for 8 weeks with weekly Duplex ultrasonography to monitor TEVG performance. RESULTS: All sheep survived to the designated endpoint. At 8 weeks all 5 HE TEVGs were patent. Three of 5 control TEVGs had early thrombotic occlusion at <1 week. More than 97% of heparin release occurred within the first 24 hours. Histologic evaluation of the HE TEVG displayed cellularity like a native carotid artery with no evidence of calcification. Significantly fewer platelets adhered to the HE TEVG than to the control TEVG (P < .001). CONCLUSIONS: This study suggests HE TEVGs prevent acute graft thrombosis. We hypothesize that the HE properties of the HE TEVG during vascular endothelialization is useful for maintaining TEVG patency. This technique may aid in the translation of small arterial TEVGs to the clinic.
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Implantación de Prótesis Vascular/métodos , Prótesis Vascular , Arterias Carótidas/cirugía , Heparina/farmacología , Ingeniería de Tejidos/métodos , Andamios del Tejido , Animales , Anticoagulantes/farmacología , Femenino , Modelos Animales , Diseño de Prótesis , OvinosRESUMEN
Tissue engineered vascular grafts (TEVGs) are a promising technology, but are hindered by occlusion. Seeding with bone-marrow derived mononuclear cells (BM-MNCs) mitigates occlusion, yet the precise mechanism remains unclear. Seeded cells disappear quickly and potentially mediate an anti-inflammatory effect through paracrine signaling. Here, a series of reciprocal genetic TEVG implantations plus recombinant protein treatment is reported to investigate what role interleukin-10, an anti-inflammatory cytokine, plays from both host and seeded cells. TEVGs seeded with BM-MNCs from wild-type and IL-10 KO mice, plus unseeded grafts, are implanted into wild-type and IL-10 KO mice. Wild-type mice with unseeded grafts also receive recombinant IL-10. Serial ultrasound evaluates occlusion and TEVGs are harvested at 14 d for immunohistochemical analysis. TEVGs in IL-10 KO mice have significantly higher occlusion incidence compared to wild-type mice attributed to acute (<3 d) thrombosis. Cell seeding rescues TEVGs in IL-10 KO mice comparable to wild-type patency. IL-10 from the host and seeded cells do not significantly influence graft inflammation and macrophage phenotype, yet IL-10 treatment shows interesting biologic effects including decreasing cell proliferation and increasing M2 macrophage polarization. IL-10 from the host is critical for preventing TEVG thrombosis and seeded BM-MNCs exert a significant anti-thrombotic effect in IL-10 KO mice.
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Prótesis Vascular , Trombosis , Animales , Interleucina-10/genética , Ratones , Trombosis/prevención & control , Ingeniería de TejidosRESUMEN
Tissue engineered vascular grafts (TEVGs) using scaffolds fabricated from braided poly(glycolic acid) (PGA) fibers coated with poly(glycerol sebacate) (PGS) are developed. The approach relies on in vivo tissue engineering by which neotissue forms solely within the body after a scaffold has been implanted. Herein, the impact of altering scaffold braid design and scaffold coating on neotissue formation is investigated. Several combinations of braiding parameters are manufactured and evaluated in a Beige mouse model in the infrarenal abdominal aorta. Animals are followed with 4D ultrasound analysis, and 12 week explanted vessels are evaluated for biaxial mechanical properties as well as histological composition. Results show that scaffold parameters (i.e., braiding angle, braiding density, and presence of a PGS coating) have interdependent effects on the resulting graft performance, namely, alteration of these parameters influences levels of inflammation, extracellular matrix production, graft dilation, neovessel distensibility, and overall survival. Coupling carefully designed in vivo experimentation with regression analysis, critical relationships between the scaffold design and the resulting neotissue that enable induction of favorable cellular and extracellular composition in a controlled manner are uncovered. Such an approach provides a potential for fabricating scaffolds with a broad range of features and the potential to manufacture optimized TEVGs.