Biomimetic synthetic versus xenogenic bone grafts in three-wall alveolar defects: a CT and histology study in miniature pigs
Researchers from the Universitat Politècnica de Catalunya (UPC) and Mimetis Biomaterials, together with implantologist Dr. Ignacio Ginebreda (UIC Barcelona), have compared a biomimetic synthetic calcium phosphate graft with a deproteinised bovine xenograft in standardised three-wall alveolar defects, one of the most common situations in implant dentistry. The study was published in Clinical Oral Investigations and conducted at Versa Biomedical’s facilities in Barcelona (then Specipig). It is one of the 15 preclinical dental studies Versa Biomedical has carried out on dental implants and bone graft regeneration biomaterials.
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About the study:
Purpose
When a tooth is lost and an implant is not placed promptly, the alveolar ridge resorbs, often leaving too little bone to anchor an implant. Bone grafting is the standard solution, and its clinical success depends on preserving the grafted volume while the graft is remodelled into new bone. The study set out to compare a biomimetic synthetic graft, processed at low temperature to resemble the mineral phase of bone, with a long-established xenograft, in terms of volume preservation and tissue response.Methods
Eight Specipig miniature pigs each received eight standardised three-wall defects, 12 mm deep and 10 mm wide. The defects were created in both jaws after tooth extraction by removing half of the buccal bone plate. In each animal, three defects were filled with the synthetic graft, three with the xenograft, and two were left empty as negative controls, in a randomised and balanced allocation. All defects were covered with a resorbable collagen membrane. Four animals were evaluated at 6 weeks and four at 12 weeks, giving 12 replicates per material and time point. Grafted volume was measured by spiral CT one day after surgery and at the endpoint, and analysed with a linear mixed-effects model. Tissue response was assessed in undecalcified samples by backscattered scanning electron microscopy and by light microscopy after Masson’s trichrome staining. All surgeries were performed by Dr. Ginebreda.Results
Empty defects showed no bone regeneration, which confirmed that the model was critically sized. Graft type was the most influential factor, and the synthetic graft preserved about 19% more volume than the xenograft. At 6 weeks, the synthetic graft had lost around 11% of its initial volume and the xenograft around 31%. At 12 weeks, the synthetic graft had gained around 6%, while the xenograft remained about 15% below its initial volume. Anterior sites preserved volume better than posterior ones, and volume improved between 6 and 12 weeks. Whether a defect was in the maxilla or the mandible had no significant effect. Histology showed excellent biocompatibility for both materials, with no inflammation or necrosis. New bone grew in direct contact with the granules, and mature bone with Haversian structure was already present at 6 weeks. Concavities in the synthetic granules were associated with osteoclastic resorption, a sign that the material was taking part in normal bone remodelling.Conclusions
Both biomaterials met the requirements for bone grafting: biocompatibility, osseointegration and osteoconduction. The synthetic graft showed better volume preservation, and granule morphology was identified as an important factor in it. The study also shows what a well-designed miniature pig alveolar model can deliver: a critical-size defect, enough statistical power to tell products and anatomical effects apart, and readouts aligned with how clinicians follow grafted sites in their patients.Keywords
Implant dentistry; Bone regeneration; Bone graft; Xenograft; Synthetic graft; Alveolar defect; Miniature pig.
Suprachoroidal delivery of anti-angiogenic peptide microparticles: GLP ocular safety study in minipigs
Researchers from AsclepiX Therapeutics and the Johns Hopkins University School of Medicine have evaluated a new suprachoroidal formulation of AXT107, an anti-angiogenic peptide for retinal and choroidal vascular diseases, designed to deliver sustained activity from a single injection. The 9-month GLP toxicology study in Göttingen minipigs supporting the safety of this approach was conducted at Versa Biomedical’s facilities in Barcelona (then Specipig).
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About the study:
Purpose
Retinal and choroidal vascular diseases, such as neovascular age-related macular degeneration and diabetic macular oedema, are leading causes of vision loss, and current treatments require frequent intravitreal injections. The study set out to assess whether AXT107, reformulated as microparticles and delivered into the suprachoroidal space, could provide sustained anti-angiogenic activity with a favourable ocular safety profile.Methods
Safety and durability were evaluated in a 9-month GLP toxicology study at Versa Biomedical. Thirty-two Göttingen minipigs were randomised into four groups and received a single suprachoroidal injection in both eyes, using microneedles: vehicle, or 0.125, 0.5 or 1.25 mg of AXT107 per eye. Intraocular pressure, ocular health and systemic exposure were monitored throughout the study. At the end of the study, AXT107 levels were measured in the ocular tissues.Results
In previous rats studies, the microparticle formulation reduced neovascular area by approximately 60% compared with vehicle. In minipigs, OCT imaging confirmed successful delivery to the suprachoroidal space. Intraocular pressure rose briefly after injection and had returned to normal by the first follow-up at one week. Mild ocular findings resolved by day 5. No treatment-related adverse findings were observed for the rest of the study. Nine months after a single injection, AXT107 was still present in the choroid/RPE and sclera, and it was not detected in blood at any time point.Conclusions
Suprachoroidal delivery of AXT107 microparticles showed sustained activity, prolonged tissue retention and a favourable ocular safety profile. The highest dose tested, 1.25 mg per eye, was established as the no-observed-adverse-effect level. These results support further clinical development, and the programme has since advanced into clinical evaluation.Keywords
Ophthalmology; Retinal vascular diseases; Suprachoroidal delivery; Microparticles; GLP toxicology; Göttingen minipig.
Specipig miniature pig in metabolic disease insulin independent SC administration PK study
A pharmacokinetic (PK) assessment was performed in a porcine model (Specipig miniature pig), which was expected to greatly predict PK behaviour of a recombinant S100A9 in the reduction of therapeutic insulin needs after subcutaneous injection in humans. This model showed much greater plasma bioavailability of S100A9 compared to the one obtained at the same dose in the mouse model. Download case
Abstract of the publication:
Type 1 diabetes mellitus (T1DM) is characterized by insulin deficiency leading to hyperglycemia and several metabolic defects. Insulin therapy remains the cornerstone of T1DM management, yet it increases the risk of life-threatening hypoglycemia and the development of major comorbidities. Here, we report an insulin signaling–independent pathway able to improve glycemic control in T1DM rodents. Co-treatment with recombinant S100 calcium-binding protein A9 (S100A9) enabled increased adherence to glycemic targets with half as much insulin and without caus- ing hypoglycemia. Mechanistically, we demonstrate that the hyperglycemia-suppressing action of S100A9 is due to a Toll-like receptor 4–dependent increase in glucose uptake in specific skeletal muscles (i.e., soleus and dia- phragm). In addition, we found that T1DM mice have abnormal systemic inflammation, which is resolved by S100A9 therapy alone (or in combination with low insulin), hence uncovering a potent anti-inflammatory action of S100A9 in T1DM. In summary, our findings reveal the S100A9-TLR4 skeletal muscle axis as a promising therapeutic target for improving T1DM treatment.
Establishment of a reproducible and minimally invasive ischemic stroke model in swine
Researchers of the Cellular and Molecular Neurobiology (CMN) Research Group at the Germans Trias i Pujol Institute (IGTP) have developed and established a novel, reproducible and minimally invasive stroke model in the pig through an endovascular approach. The work has been conducted at the Centre for Comparative Medicine and Bioimage (CMCiB), a centre devoted to translational medicine at the very core of the Can Ruti Campus in Badalona together with the IGTP and the Germans Trias i Pujol University Hospital.
“Being able to reproduce the damage in specific brain areas in the model in Specipig’s pig breed and conventional pigs is important to any study that aims to determine the true neuroprotective effect of new molecules to be tested in brains similar to those of humans.”
Teresa Gasull, Senior Research Investigator & Team leader of the CMN group
Abstract of the publication:
The need for advances in the management/treatment options for ischemic stroke patients requires that upcoming preclinical research uses animals with more human-like brain characteristics. The porcine brain is considered appropriate, although the presence of the rete mirabile (RM) prevents direct catheterization of the intracranial arteries to produce focal cerebral ischemia. To develop a reproducible minimally invasive porcine stroke model, a guide catheter and guide wire were introduced through the femoral artery until reaching the left RM. Using the pressure cooker technique, Squid-12 embolization material was deposited to fill, overflow, and occlude the left RM, the left internal carotid artery, and left circle of Willis wing up to the origins of the middle cerebral arteries (MCAs), mimicking the occlusion produced in the filament model in rodents. Longitudinal multimodal cerebral MRI was conducted to assess the brain damage and cerebral blood supply. The technique we describe here occluded up to the origins of the MCAs in 7 of 8 swine, inducing early damage 90 minutes after occlusion that later evolved to a large cerebral infarction and producing no mortality during the intervention. This minimally invasive ischemic stroke model in swine produced reproducible infarcts and shows translational features common to human stroke.Keywords:
Neuroscience; Stroke.
Dental implant research
Specipig has signed an agreement with Zircon Medical, Swiss-based ceramic implant manufacturer made up of a team of seasoned experts in dentistry who are passionate about improving the quality of life of patients worldwide by making Patent™ the standard, healthy and sustainable choice for tooth replacement.
Several studies involving Zircon’s dental implants and Specipig’s miniature pigs have been run at Specipig’s facilities. Resulting in the publication at the International Journal of Implant Dentistry (2022) 8:37.
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Abstract of the publication:
Purpose
To histologically examine early bone formation around transmucosal implants and to evaluate the influence of surface characteristics on early peri-implant bone healing using a miniature pig model. For this, commercially available dental implants with a rough zirconia (YTZP) surface were compared to surface-modified Ti control implants at 4 and 8 weeks after placement.Methods
Immediately following the extraction of six mandibular premolars, 20 two-piece, tissue-level, screwshaped YTZP implants (Patent™ Standard Zirconia Implant ø4.1 × 11 mm) with a modified rough blasted before sintering surface were inserted in four adult miniature pigs. In addition, four titanium (Ti) tissue-level implants ( Straumann® Standard RN ø4.1 × 10 mm Roxolid ®) with a moderate surface ( SLActive®), one per animal, were placed as control implants. A histological analysis was performed on the hard tissues after 4 and 8 weeks of transmucosal healing.Results
The results show a high rate of osseointegration of the test YTZP dental implants at 4 and 8 weeks following insertion. At 4 weeks, a bone-to-implant contact ratio (BIC) of 73.7% (SD ± 16.8) for the test implants (n = 10) and 58.5% for the first control implant was achieved. The second control implant had to be excluded from analysis. At 8 weeks, a BIC of 82.4% (SD ± 16.9) for the test implants (n = 9) and 93.6% (SD ± 9.1) (n = 2) for the control implant was achieved. No statistical difference was observed comparing 4 and 8 weeks YTZP data (p = 0.126).Conclusions
The results indicate a predictable osseointegration of immediate zirconia implants with a modified YTZP implant surface and a high degree of BIC present at 4 weeks following insertion. After 8 weeks of healing both the zirconia implants and the Ti implants show a BIC indicating full osseointegration. Further studies involving a larger sample size with more time points are needed to confirm these results.Keywords
Animal experiment, Miniature pig, Zirconia implant, Osseointegration, Immediate implant, Transmucosal
A swine model of selective geographic atrophy of outer retinal layers mimicking atrophic AMD: A phase I escalating dose of subretinal sodium iodate
Despite recent advances in treatment of the wet form of AMD,1–6 the clinical outcome of AMD often remains blindness. Nowadays, the great challenge to which the ophthalmologic community is committed lies in finding a treatment that may slow the relentless progression of the atrophic form of the disease, together with other approaches that restore or regenerate the involved part of the diseased retinal tissue. Nowadays, the advanced form of dry AMD with geographic atrophy (GA) may be the first cause of legal blindness among elderly patients in the industrialized world, and it represents up to a third of cases of late AMD.7,8 Besides the impact of the disease among individuals, the economic burden of atrophic AMD (drusen, RPE abnormalities, and/or GA) in the United States is enormous: $26,100 million annually in one study9 and approximately 0.22% of its gross domestic product in 2010 in terms of wage loss from untreated disease in another report.10 Download case