Minipig Model Research Articles

Minimally invasive balloon-assisted sinus floor elevation vs. conventional transcrestal procedure in terms of new bone formation in a split-mouth Goettingen minipig model

PurposeCurrently, maxillary sinus floor (SF) elevation is based on off-the-shelf allogeneic, xenogeneic or synthetic bone augmentation materials (BAM) that are implanted via an open lateral sinus wall approach (OSFE). However, this invasive method is associated with postoperative complications caused by an inadequate blood supply of the alveolar ridge. Balloon-assisted procedures are minimal invasive alternatives with lower complication rates. The aim was to evaluate local new bone (NB) formation in the SF following the application of a particulate BAM (Easy graft) via two different SF elevation techniques in a split mouth mini-pig sinus augmentation model.Material and methodsSeven adult Goettingen minipigs were used for evaluation of a biphasic ceramic (PLGA/ß-TCP) BAM in the elevated SF region. Treatments were randomized to the contralateral sinus sites and included two procedures: OSFE (control group) versus minimally invasive SF elevation by a balloon-lift-control system (BLC) (treatment group). The animals were euthanized after 28 and 56 days for analysis of new bone (NB) formation.ResultsThe biphasic synthetic BAM implanted via BLC increased more NB formation (5.2 ± 1.9 mm and 4.9 ± 1.6 mm vs. 2.6 ± 0.5 mm) and osseointegration of the particles (18.0 ± 6.0% and 25.1 ± 18.2% vs. 10.1 ± 8.0%, p < 0.05) compared to the control.ConclusionsImplantation of a biphasic synthetic BAM enhanced NB formation in the mini-pig maxillary sinus at both time points and in both groups, although BLC resulted in a slightly better total NB formation compared to the control.Graphical abstract

Molecular characterization and sub-retinal transplantation of hypoimmunogenic human retinal sheets in a minipig model of severe photoreceptor degeneration.

Retinal degenerative diseases affect millions of people worldwide, and legal blindness is generally associated with the loss of cone photoreceptors located in the central region of the retina called the macula. Currently, there is no treatment to replace the macula. Addressing this unmet need, we employed control isogenic and hypoimmunogenic induced pluripotent stem cell lines to generate spontaneously polarized retinal sheets (RSs). RSs were enriched in retinal progenitor and cone precursor cells, which could differentiate into mature S- and M/L-cones in long-term cultures. Single-cell RNA-seq analysis showed that RSs recapitulate the ontogeny of the developing human retina. Isolation of neural rosettes for sub-retinal transplantation effectively eliminated unwanted cells such as RPE cells. In a porcine model of chemically induced retinal degeneration, grafts integrated the host retina and formed a new, yet immature, photoreceptor layer. In one transplanted animal, functional and immunohistochemical assays suggest that grafts exhibited responsiveness to light stimuli and established putative synaptic connections with host bipolar neurons. This study underscores the potential and challenges of RSs for clinical applications.

Hypoxia Preconditioned Serum Hydrogel (HPS-H) Accelerates Dermal Regeneration in a Porcine Wound Model.

Harnessing the body's intrinsic resources for wound healing is becoming a rapidly advancing field in regenerative medicine research. This study investigates the effects of the topical application of a novel porcine Hypoxia Preconditioned Serum Hydrogel (HPS-H) on wound healing using a minipig model over a 21-day period. Porcine HPS exhibited up to 2.8× elevated levels of key angiogenic growth factors (VEGF-A, PDGF-BB, and bFGF) and demonstrated a superior angiogenic effect in a tube formation assay with human umbilical endothelial cells (HUVECs) in comparison to porcine normal serum (NS). Incorporating HPS into a hydrogel carrier matrix (HPS-H) facilitated the sustained release of growth factors for up to 5 days. In the in vivo experiment, wounds treated with HPS-H were compared to those treated with normal serum hydrogel (NS-H), hydrogel only (H), and no treatment (NT). At day 10 post-wounding, the HPS-H group was observed to promote up to 1.7× faster wound closure as a result of accelerated epithelialization and wound contraction. Hyperspectral imaging revealed up to 12.9% higher superficial tissue oxygenation and deep perfusion in HPS-H-treated wounds at day 10. The immunohistochemical staining of wound biopsies detected increased formation of blood vessels (CD31), lymphatic vessels (LYVE-1), and myofibroblasts (alpha-SMA) in the HPS-H group. These findings suggest that the topical application of HPS-H can significantly accelerate dermal wound healing in an autologous porcine model.

Biosafety Evaluation of a Chimeric Adenoviral Vector in Mini-Pigs: Insights into Immune Tolerance and Gene Therapy Potential.

The biosafety of gene therapy products remains a major challenge to their introduction into the clinic. In particular, the problem of immunogenicity of viral vectors is the focus of attention. Large animals such as pigs, whose anatomical and physiological characteristics are similar to those of humans, have an advantage in testing vector systems. We performed a comprehensive in vitro and in vivo study to evaluate the biosafety of a chimeric adenoviral vector carrying a green fluorescent protein gene (Ad5/35F-GFP) in a mini-pig model. Transcriptome and secretome analyses of mini-pig leucocytes transduced with Ad5/35F-GFP revealed changes restraining pro-inflammatory processes and cytokine production. No adverse effects were revealed through the clinical, instrumental, laboratory, and histological examinations conducted within a week after the direct or autologous leucocyte-mediated administration of Ad5/35F-GFP to mini-pigs. The decrease in cytokine levels in the blood of experimental animals is also consistent with the in vitro data and confirms the immune tolerance of mini-pigs to Ad5/35F-GFP. Here, we show the safety of Ad5/35F in a mini-pig model and provide evidence that Ad5/35F is a promising vector for gene therapy. These results advance our understanding of vector-host interactions and offer a solid foundation for the clinical application of this vector.

Osseointegration of Anodized vs. Sandblasted Implant Surfaces in a Guided Bone Regeneration Acute Dehiscence-Type Defect: An InVivo Experimental Mandibular Minipig Model.

This controlled preclinical study analyzed the effect of implant surface characteristics on osseointegration and crestal bone formation in a grafted dehiscence defect minipig model. A standardized 3 mm × 3 mm acute-type buccal dehiscence minipig model grafted with deproteinized bovine bone mineral and covered with a porcine collagen membrane after 2 and 8 weeks of healing was utilized. Crestal bone formation was analyzed histologically and histomorphometrically to compare three implant groups: (1) a novel, commercially available, gradient anodized (NGA) implant, to two custom-made geometric replicas of implant "1," (2) a superhydrophilic micro-rough large-grit sandblasted and acid-etched surface, and (3) a relatively hydrophobic micro-rough large-grit sandblasted and acid-etched surface. At 2 and 8 weeks, there was no difference between the amount and height of newly formed bone (NBH, new bone height; BATA, bone area to total area) for any of the groups (p > 0.05). First bone-to-implant contact (fBIC) and vertical bone creep (VBC) at 2 and 8 weeks were significantly increased for Groups 2 and 3 compared to Group 1 (p < 0.05). At 8 weeks, osseointegration in the dehiscence (dehiscence bone-implant-contact; dBIC) was significantly higher for Groups 2 and 3 compared to Group 1 (p < 0.05). The amount of newly formed bone (BATA) and NBH was not influenced by surface type. However, moderately rough surfaces demonstrated significantly superior levels of osseointegration (dBIC) and coronal bone apposition (fBIC) in the dehiscence defect compared to the NGA surface at 2 and 8 weeks. For this type of study, clinical trial registration is not required. This study was conducted at the Biomedical Department of Lund University (Lund, Sweden) and approved by the local Ethics Committee of the University (M-192-14).

Choline-deficient, high-fat diet-induced MASH in Göttingen Minipigs: characterization and effects of a chow reversal period.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) is increasing, and translational animal models are needed to develop novel treatments for this disease. The physiology and metabolism of pigs have a relatively high resemblance to humans, and the present study aimed to characterize choline-deficient and high-fat diet (CDAHFD)-fed Göttingen Minipigs as a novel animal model of MASLD/MASH. Göttingen Minipigs were fed CDAHFD for up to 5 mo, and the phenotype was investigated by the analysis of plasma parameters and repeated collection of liver biopsies. Furthermore, changes in hepatic gene expression during the experiment were explored by RNA sequencing. For a subset of the minipigs, the diet was changed from CDAHFD back to chow to investigate whether the liver pathology was reversible. Göttingen Minipigs on CDAHFD gained body weight, and plasma levels of cholesterol, AST, ALT, ALP, and GGT were increased. CDAHFD-fed minipigs developed hepatic steatosis, inflammation, and fibrosis, which in 5 of 16 animals progressed to cirrhosis. During an 11-wk chow reversal period, steatosis regressed, while fibrosis persisted. Regarding inflammation, the findings were less clear, depending on the type of readout. MASH Human Proximity Scoring (combined evaluation of transcriptional, phenotypic, and histopathological parameters) showed that CDAHFD-fed Göttingen Minipigs resemble human MASLD/MASH better than most rodent models. In conclusion, CDAHFD-fed minipigs develop a MASH-like phenotype, which, in several aspects, resembles the changes observed in human patients with MASLD/MASH. Furthermore, repeated collection of liver biopsies allows detailed characterization of histopathological changes over time in individual animals.NEW & NOTEWORTHY The physiology and metabolism of pigs have a relatively high resemblance to humans. This study characterizes a new animal model of MASLD/MASH using CDAHFD-fed Göttingen Minipigs. Göttingen Minipigs fed CDAHFD gained weight and developed hepatic steatosis, inflammation, fibrosis, and cirrhosis. After an 11-wk chow-reversal period, hepatic steatosis and some inflammatory parameters reversed. Combined evaluation of phenotypic, transcriptional, and histological parameters revealed the minipig model showed a higher resemblance to human disease than many rodent models.

Postsurgical Carprofen Does Not Substantially Decrease Bacterial Growth in a Minipig Model of Staphylococcus aureus Deep Surgical Wound Infection

The use of analgesia in bacterial challenge models has been met with some controversy in the literature. Several publications suggest that the use of analgesics in infection models can interfere with the host immune response, change microenvironments subsequently altering bacterial pathogenesis, and directly act as an antimicrobial as was reported with opioids such as morphine. Any such interactions would compromise the experimental results, deterring researchers from the use of analgesia. Herein, we address the possible effect of analgesics on bacterial colonization in a Staphylococcus aureus surgical site infection model in Göttingen minipigs. Retrospectively, an expanded analgesia protocol (buprenorphine presurgery and carprofen postsurgery) was compared with a standard analgesia protocol using buprenorphine alone just before surgery. When examined statistically, the expanded analgesia protocol group was noninferior to the standard analgesia protocol group indicating there was no substantial decrease in bacterial burden when an expanded analgesia protocol was administered. Our results highlight the importance of studying the use of analgesia in all animal models of infection to determine if the analgesics will affect experimental outcomes.

Biomimetic microgels for articular cartilage regeneration. A minipig knee model

The aim of this study is to explore, with an in vivo model, the regeneration of articular cartilage that can be obtained with a strategy that combines the stimulation of the subchondral bone with the implantation of a biomimetic microgel at the site of the cartilage defect. The microgel consists of an agglomerate of two types of microspheres: ones rigid, made of a biodegradable polyester, and the other ones composed of a polymeric network of gelatin and hyaluronic acid that encapsulate platelet-rich plasma (PRP) obtained from circulating autologous blood. A defect of 7 mm in diameter and full depth was performed in the in the articular cartilage at the trochlea of the animal knee, using a minipig model. Microdrilling was performed in the underlying bone and the defect was filled with the microgel in which the platelets it contains were previously activated with calcium chloride. The whole defect containing the microgel was covered with a synthetic membrane to avoid the release of microspheres. The results of the in vivo follow-up of the experiment, the histological analysis and the mechanical measurements of the regenerated tissue 9 months after implantation were compared with those of a group of animals in which only microdrilling was performed and the defect was covered with the membrane and with another group in which a clinical use commercial collagen mesh was implanted. The mean value of the elastic modulus of the newly formed tissue was not significantly different from that of the native tissue in the case of microgel implantation while its content of GAGs, was significantly better than in the other groups.

Rheological and Lipid Characterization of Minipig and Human Skin Tissue: A Comparative Study Across Different Locations and Depths.

Understanding the rheology of minipig and human skin is crucial for enhancing drug delivery methods, particularly for injections. Despite many studies on skin's viscoelasticity, especially the subcutaneous layer, comparative analyses across different clinical sites are scarce, as is data on the impact of hydration or lipid levels. This study employs shear rheology and lipid analysis to evaluate viscoelasticity and lipid content across three anatomical locations-breast, belly, and neck and three different depth layers in Yucatan minipigs. It reports on how viscoelastic properties change with frequency, time, and strain, noting strain-stiffening and shear-thinning at high strain amplitudes. Human male and female abdominal tissues are also compared to minipig tissues, highlighting distinct viscoelastic traits and lipid's role in them. The findings suggest the existence of species, anatomical location, tissue depth, and sex-based rheological differences.Furthermore, the use of male minipig models for studying human male subcutaneous tissue is discussed.

Biomechanical validation of a tibial critical-size defect model in minipigs

BackgroundAutologous cancellous bone grafting still represents the gold standard for the therapy of non-healing bone defects. However, donor site morbidity and the restricted availability of autologous bone grafts have initiated scientists to look for promising alternatives to heal even large defects. The present study aimed to evaluate the biomechanical potential and failure properties of a previously developed metaphyseal critical-size defect model of the proximal tibia in minipigs for future comparisons of bone substitute materials. MethodsFresh-frozen minipig tibiae were divided into two groups, with half undergoing the creation of critical-size defects. Specimens were subjected to biomechanical fatigue tests and load-to-failure tests. CT scans post-test verified bone damage. Statistical analysis compared the properties of defected and intact specimens. FindingsIn this model, it was demonstrated that under uniaxial cyclic compression within the loading axis, the intact tibiae specimens (8708 ± 202 N) provided a significant (p = 0.014) higher compressive force to failure than the tibiae with the defect (6566 ± 1653 N). InterpretationThus, the used minipig model is suitable for comparing bone substitute materials regarding their biomechanical forces and bone regeneration capacity.

First hip hemiarthroplasty in a Göttingen Minipig; surgical and post-mortem protocol

BackgroundProsthetic joint infections (PJI) are recalcitrant, hard-to-treat infections and severe complications of joint arthroplasty. Therefore, there is a need to develop new effective treatment strategies, and animal models of high clinical relevance are needed. This study aimed to develop a detailed surgical protocol for hip hemiarthroplasty in Göttingen minipigs and a thorough post-mortem sampling protocol to pave the way for creating a minipig PJI model.MethodsThree adult female Göttingen minipigs underwent surgery with insertion of a hip hemiarthroplasty, using the anterior approach to the hip joint. After surgery the minipigs were followed closely with daily clinical evaluation and gait scoring. Comprehensive post-mortem analyses were performed with evaluation of macroscopic lesions, microbiology, synovial fluid analysis and histology.ResultsThe study resulted in the first Göttingen minipig with hip hemiarthroplasty and identified several points of awareness when inserting a hip prosthesis in minipigs, especially the high risk of joint dislocation. A spontaneous PJI occurred in one of the minipigs, revealing an impaired ability of the immune cells to reach the bacteria at the bone-prosthesis interface.ConclusionThe present study provides a detailed description of surgical technique and post-mortem sampling and validates the suitability of the hip hemiarthroplasty minipig model for future experimental modeling of PJI.

MICROBIOME AND INFLAMMASOME ALTERATIONS FOUND DURING RADIATION DOSE FINDING IN A SINCLAIR MINIPIG MODEL OF GASTROINTESTINAL ACUTE RADIATION SYNDROME.

Both abdominal radiotherapy and a nuclear event can result in gastrointestinal symptoms, including acute radiation syndrome (GI-ARS). GI-ARS is characterized by compromised intestinal barrier integrity increasing the risk for infectious complications. Physiologically relevant animal models are crucial for elucidating host responses and therapeutic targets. We aimed to determine the radiation dose requirements for creating GI-ARS in the Sinclair minipig. Male, sexually mature swine were randomly divided into sham (n = 6) and three lower hemibody radiation dosage groups of 8, 10, and 12 Gy (n = 5/group) delivered using linear accelerator-derived x-rays (1.9 Gy/min). Animals were monitored for GI-ARS symptoms for 14 days with rectal swab and blood collection at days 0-3, 7, 10, and 14 followed by necropsy for western blotting and histology. Dose-dependent increases in weight loss, diarrhea severity, and mortality (log-rank test, P = 0.041) were seen. Villi length was significantly reduced in all irradiated animals compared to controls ( P < 0.001). Serum citrulline decreased and bacterial translocation increased after irradiation compared to controls. Increased NLRP3 levels in post-mortem jejunum were seen ( P = 0.0043) as well as increased IL-1β levels in the 12 Gy group ( P = 0.041). Radiation dose and survival were associated with significant gut microbial community shifts in beta diversity. Moreover, decedents had increased Porphyromonas, Campylobacter, Bacteroides , Parvimonas , and decreased Fusobacterium and decreased Aerococcus, Lactobacillus, Prevotella, and Streptococcus . Our novel Sinclair minipig model showed dose-dependent clinical symptoms of GI-ARS. These findings provide invaluable insights into the intricate interplay between GI-ARS, intestinal inflammation, and gut microbiota alterations offering potential targets for therapeutic and diagnostic interventions after radiation exposure.

Effect of sequential delivery of 1- and 2-MHz bipolar microneedling radiofrequency energy on thermal tissue reactions in a minipig model.

Bipolar microneedling radiofrequency (RF) treatment generates different patterns of thermal reactions, depending on the skin impedance and RF treatment parameters, including the frequency, power, conduction time, settings of sub-pulse packs, and penetrating depth and type of microneedles used. We compared the effect of sequential delivery of 1- and 2-MHz bipolar RF energy to in vivo minipig skin on thermal tissue reaction. RF treatments at frequencies of 1 and 2MHz were sequentially delivered to minipigs' skin in vivo. A histological study was performed to analyze RF-induced skin reactions at 1-h and at 3-, 7-, and 14-days post-treatment. The skin specimens demonstrated that the two different frequencies of RF treatment generated mixed patterns of the peri-electrode coagulative necrosis (PECN) according to the experimental settings and tissue impedance. In the PECN zone, the tissue coagulation induced by the first RF treatment was surrounded by the effect of the later RF treatment at the other RF frequency. In the inter-electrode non-necrotic thermal reaction zone, the effect of the latter RF treatment was widespread and deep through the dermis, which had received RF treatment at the other frequency first. The delivery of pulsed-type RF energy at sub-pulse packs of 6 or 10 provided effective RF delivery over long conduction time without excessive thermal damage of the epidermis. Nonetheless, by sequential delivery of two different RF frequencies, RF-induced tissue reactions were found to be markedly enhanced. The sequential delivery of 1- and 2-MHz RF energy induces novel histological patterns of tissue reactions, which can synergistically enhance the thermostimulatory effects of each RF setting. Moreover, variations in patterns of tissue reactions can be generated by regulating the order of frequencies and the number of sub-pulse packs of RF used.

Alpha-2-Macroglobulin Attenuates Posttraumatic Osteoarthritis Cartilage Damage by Inhibiting Inflammatory Pathways With Modified Intra-articular Drilling in a Yucatan Minipig Model

Background: Posttraumatic osteoarthritis (PTOA) arises secondarily to joint trauma and is driven by catabolic inflammatory pathways. Alpha-2-macroglobulin (α2M) is a naturally occurring proteinase inhibitor found in human serum and synovial fluid that binds proteases as well as proinflammatory cytokines involved in the pathogenesis of PTOA. Purpose: (1) To investigate the therapeutic potential of intra-articular α2M injections during the acute stages of PTOA by inhibiting inflammatory pathways driven by the cytokines expressed by the synovium in a large preclinical Yucatan minipig model and (2) to determine if 3 intra-articular α2M injections have greater chondroprotective effects compared with 1 intra-articular injection. Study Design: Controlled laboratory study. Methods: A total of 48 Yucatan minipigs were randomized into 4 groups (n = 12 each): (1) modified intra-articular drilling (mIAD) and saline (mIAD + saline), (2) mIAD and 1 intra-articular α2M injection (mIAD +α2M-1), (3) mIAD and 3 α2M injections (mIAD +α2M-3), and (4) sham control. Surgical hindlimbs were harvested at 15 weeks after surgery. Cartilage degeneration, synovial changes, inflammatory gene expression, and matrix metalloproteinase levels were evaluated. Gait asymmetry was measured before and after surgery using a pressure-sensing walkway system. Results: Macroscopic lesion areas and microscopic cartilage degeneration scores were lower in the mIAD +α2M-1 and mIAD +α2M-3 groups compared with the mIAD + saline group (P < .05) and similar to those in the sham group (P > .05). Synovial membrane scores of the mIAD +α2M-1 and mIAD +α2M-3 groups were lower than that of the mIAD + saline group (P < .05) and higher than that of the sham group (P < .05). Interleukin-1 beta, nuclear factor kappa B, and tumor necrosis factor alpha mRNA expression in the synovium and matrix metalloproteinase-1 levels in synovial fluid were significantly lower in the mIAD +α2M-1 and mIAD +α2M-3 groups compared with the mIAD + saline group (P < .05). No significant differences were observed between the mIAD +α2M-1 and mIAD +α2M-3 groups for all measured outcomes. There were early changes in gait (P < .05) between preoperative and postoperative time points for the mIAD + saline, mIAD +α2M-1, and mIAD +α2M-3 groups that normalized by 15 weeks. Conclusion: Animals receiving early α2M treatment exhibited less cartilage damage, milder synovitis, and lower inflammation compared with animals with no α2M treatment. These results exemplify the early anti-inflammatory effects of α2M and provide evidence that intra-articular α2M injections may slow the progression of PTOA. Clinical Relevance: In patients presenting with an acute joint injury, an early intervention with α2M may have the potential to reduce cartilage degeneration from catabolic pathways and delay the development of PTOA.

Use of High-Frequency Ultrasound for the Correlation of Epithelial Rete Peg Variation

ObjectiveRete pegs are projections of the oral epithelium into connective tissue. Their dimensions change during pathological conditions and may correlate with wound-healing status. Non-invasive, high-frequency ultrasound (US) may be able to capture these changes and aid in early detection of histopathological changes. The aim of this preclinical study is to correlate US images with histology and quantify epithelial layers at different tooth sites. MethodsSagittal B-mode images of mid-facial and interproximal oral soft tissue sites were recorded in a preclinical minipig model using a linear array in second harmonic mode (12/24 MHz). Histology samples from the same locations were stained (hematoxylin and eosin), digitized and registered with US images. Manual annotations were used to measure distances D1 (thickness of epithelium on histology vs. hyperechoic zone on US) and D2 (sum of epithelial thickness and length of rete pegs on histology vs. sum of hyperechoic and hypoechoic zone on US) to statistically analyze them. ResultsUltrasonic-derived dimensions yielded a mean bias of -0.64 (55% coefficient of variance [COV]: -180 to +180 µm) and -12 µm (39% COV: -260 to +240 µm) for D1 and D2, respectively. Individualized analysis of D1 and D2 by tooth type showed similar tends in the ability to differentiate between epithelium at different tooth locations, on both histology and US. ConclusionAssessing soft tissue dimensions on a sub-millimeter scale using clinical imaging hardware is still a developing area. Future research might open doors for diagnosis of oral pathologies and abnormal wound healing, and may limit false-positive indications for biopsies.

Relationships of Jugular Bulb Parameters with Cerebral Perfusion and Metabolism After Resuscitation from Cardiac Arrest: A Post-Hoc Analysis of Experimental Studies Using a Minipig Model.

Cerebral blood flow (CBF) decreases in the first few hours or days following resuscitation from cardiac arrest, increasing the risk of secondary cerebral injury. Using data from experimental studies performed in minipigs, we investigated the relationships of parameters derived from arterial and jugular bulb blood gas analyses and lactate levels (jugular bulb parameters), which have been used as indicators of cerebral perfusion and metabolism, with CBF and the cerebral lactate to creatine ratio measured with dynamic susceptibility contrast magnetic resonance imaging and proton magnetic resonance spectroscopy, respectively. We retrospectively analyzed 36 sets of the following data obtained during the initial hours following resuscitation from cardiac arrest: percent of measured CBF relative to that at the prearrest baseline (%CBF), cerebral lactate to creatine ratio, and jugular bulb parameters, including jugular bulb oxygen saturation, jugular bulb lactate, arterial-jugular bulb oxygen content difference, cerebral extraction of oxygen, jugular bulb-arterial lactate content difference, lactate oxygen index, estimated respiratory quotient, and arterial-jugular bulb hydrogen ion content difference. Linear mixed-effects models were constructed to examine the effects of each jugular bulb parameter on the %CBF and cerebral lactate to creatine ratio. The arterial-jugular bulb oxygen content difference (P = 0.047) and cerebral extraction of oxygen (P = 0.030) had a significant linear relationship with %CBF, but they explained only 12.0% (95% confidence interval [CI] 0.002-0.371) and 14.2% (95% CI 0.005-0.396) of the total %CBF variance, respectively. The arterial-jugular bulb hydrogen ion content difference had a significant linear relationship with cerebral lactate to creatine ratio (P = 0.037) but explained only 13.8% (95% CI 0.003-0.412) of the total variance in the cerebral lactate to creatine ratio. None of the other jugular bulb parameters were related to the %CBF or cerebral lactate to creatine ratio. In conclusion, none of the jugular bulb parameters appeared to provide sufficient information on cerebral perfusion and metabolism in this setting.

Comparative osseointegration of hydrophobic tissue-level tapered implants-A preclinical invivo study.

To histometrically compare the osseointegration and crestal bone healing of a novel tapered, self-cutting tissue-level test implant with a standard tissue-level control implant in a submerged healing regimen. In a mandibular minipig model, implants were inserted and evaluated histometrically after a healing period of 3, 6, and 12 weeks. The primary outcome was the evaluation of bone-to-implant contact (BIC) and secondary outcomes were primary stability as per insertion torque and first BIC (fBIC). Outcomes for the test and control implants were compared using Wilcoxon signed-rank tests and mixed linear regression models. Insertion torque values were significantly higher for the test (50.0 ± 26.4 Ncm) compared to the control implants (35.2 ± 19.7 Ncm, p = .0071). BIC values of test implants were non-inferior to those of control implants over the investigated study period. After 12 weeks, the corresponding values measured were 81.62 ± 11.12% and 90.41 ± 4.81% (p = .1763) for test and control implants, respectively. Similarly, no statistical difference was found for fBIC values, except for the 12 weeks outcome that showed statistically lower values for the test (-675.58 ± 590.88 μm) compared to control implants (-182.75 ± 197.40 μm, p = .0068). Novel self-cutting tissue-level implants demonstrated noninferior osseointegration and crestal bone height maintenance to the tissue-level implants. Histometric outcomes between both implants demonstrated test implants were statistically noninferior to control implants, despite substantial differences in the bone engagement mechanism and resulting differences in insertion torque and qualitative bone healing patterns.

Surgical Implantation of Single-Staged Tissue-Engineered Urothelial Tubes in a Minipig Model.

Reconstructive surgeries are often challenged by a lack of grafting tissue. In the treatment of urogenital malformations, the conventional solution has been harvesting gastrointestinal tissue for non-orthotopic reconstruction due to its abundance to reestablish normal function in the patient. The clinical outcomes after rearranging native tissues within the body are often associated with significant morbidity; thus, tissue engineering holds specific potential within this field of surgery. Despite substantial advances, tissue-engineered scaffolds have not yet been established as a valid surgical treatment alternative, mainly due to the costly and complex requirements of materials, production, and implantation. In this protocol, we present a simple and accessible collagen-based tubular scaffold embedded with autologous organ-specific tissue particles, designed as a conduit for urinary diversion. The scaffold is constructed during the primary surgical procedure, comprises commonly available surgical materials, and requires conventional surgical skills. Secondly, the protocol describes an animal model designed to evaluate the short-term in vivo outcomes post-implantation, with the possibility of additional variations to the procedure. This publication aims to demonstrate the procedure step-by-step, with special attention to the use of autologous tissue and a tubular form.

Drug Disposition in Neonatal Göttingen Minipigs: Exploring Effects of Perinatal Asphyxia and Therapeutic Hypothermia.

Asphyxiated neonates often undergo therapeutic hypothermia (TH) to reduce morbidity and mortality. Since both perinatal asphyxia (PA) and TH influence physiology, altered pharmacokinetics (PK) and pharmacodynamics (PD) are expected. Given that TH is the standard of care for PA with moderate to severe hypoxic-ischemic encephalopathy, disentangling the effect of PA versus TH on PK/PD is not possible in clinical settings. However, animal models can provide insights into this matter. The (neonatal) Göttingen Minipig, the recommended strain for nonclinical drug development, was selected as translational model. Four drugs-midazolam (MDZ), fentanyl (FNT), phenobarbital (PHB), and topiramate (TPM)-were intravenously administered under four conditions: control (C), therapeutic hypothermia (TH), hypoxia (H), and hypoxia plus TH (H+TH). Each group included six healthy male neonatal Göttingen Minipigs anesthetized for 24 hours. Blood samples were drawn at 0 (predose) and 0.5, 2, 2.5, 3, 4, 4.5, 6, 8, 12, and 24 hours post drug administration. Drug plasma concentrations were determined using validated bioanalytical assays. The PK parameters were estimated through compartmental and noncompartmental PK analysis. The study showed a statistically significant decrease in FNT clearance (CL; 66% decrease), with an approximately threefold longer half-life (t1/2) in the TH group. The H+TH group showed a 17% reduction in FNT CL, with a 62% longer t1/2 compared with the C group; however, it was not statistically significant. Although not statistically significant, trends toward lower CL and longer t1/2 were observed in the TH and H+TH groups for MDZ and PHB. Additionally, TPM demonstrated a 28% decrease in CL in the H group compared with controls. SIGNIFICANCE STATEMENT: The overarching goal of this study using the neonatal Göttingen Minipig model was to disentangle the effects of systemic hypoxia and TH on PK using four model drugs. Such insights can subsequently be used to inform and develop a physiologically based pharmacokinetic model, which is useful for drug exposure prediction in human neonates.

Determinants of Temperature Development during Dental Implant Surgery

Mechanical and thermal trauma during implant surgery may be reasons for initial peri-implant bone loss. Temperature development during drilling and implant insertion were quantified in this series of in vitro and animal experiments. Polyurethane foam material mimicking different classes of alveolar bone was used as a model material for simulating implant surgery. Using thermocouples, temperature development was determined in the model material at depths of 3 mm and 10 mm during site preparation and implant insertion. Additionally, an infrared camera allowed for measuring drill temperatures both in vitro and as part of an animal trial using an intraoral minipig model. Drill diameter and repeated usage of drills did not have a major effect on temperature generation. The addition of a diamond-like carbon coating, bone density, predrilling, and irrigation heavily affected intraosseous temperatures. In vivo, applying regular drill protocols, an intraosseous temperature rise of approximately 3 °K was determined. Implant geometry as well as the amount of undersizing of an osteotomy governed heat generation during implant insertion. Drill protocols and the amount of undersizing of an implant osteotomy constitute parameters by which clinicians can limit trauma during implant surgery.