BackgroundConventional ketamine hydrochloride solutions are acidic and hyperosmotic, limiting their tolerability for subcutaneous (SC) delivery. BB106 is a novel ketamine formulation using the multitude of sulfobutylether-beta-cyclodextrin (SBECD) anionic substitutions as ionic counterions to achieve a new ketamine-SBECD salt in solution at near-physiologic pH and isotonicity, thereby enabling SC administration. To support its development for pain and neuropsychiatric indications, we conducted nonclinical toxicology studies in rats and minipigs.MethodsA 2-week repeated-dose SC injection study in rats and a 4-week continuous SC infusion study in Göttingen minipigs were performed, each with a 2-week recovery phase. Assessments included clinical observations, body weights, food consumption, ophthalmology, electrocardiography, clinical pathology, toxicokinetics (TK), and histopathology.ResultsBB106 was well-tolerated in both species. No mortality or dose-limiting systemic toxicity occurred. Clinical signs were consistent with ketamine pharmacology (eg, transient ataxia) and resolved after dosing. Local site reactions were minimal, histologically mild, and reversible. No treatment-related lesions were observed in any of the systemic tissues examined (including liver, kidney, bladder, and brain). TK analyses confirmed consistent systemic exposure without accumulation. SBECD itself produced no adverse effects at the exposure levels tested.ConclusionRepeated SC bolus injections in rats and continuous SC infusion in minipigs demonstrated favorable local and systemic safety profiles for BB106. These findings support its feasibility as an alternative to intravenous ketamine for pain and psychiatric disorders. To our knowledge, this is the first toxicology report of SC administration of an SBECD salt formulation and the results support continued consideration as a potential medicine.

BACKGROUND:Transvenous extraction of chronic cardiac implantable electronic device leads is challenged by fibrotic adhesions and procedural risks. Novel technologies aim to improve safety and efficacy. A high-frequency mechanical vibration system aims to disrupt adhesions. OBJECTIVE:This study aimed to evaluate the initial safety, performance, and usability of a novel vibration-assisted lead extraction system in a preclinical Good Laboratory Practice ovine model. METHODS:9 leads implanted for >2 years (range 2.9-5.25 years) were extracted from 6 sheep using the vibration system under fluoroscopy. The internal lumen of the leads was used to deliver a customized locking stylet. The stylet was used to deliver vibration energy to the lead, applied for up to 20 minutes/animal. Assessments included procedural success, lead integrity, intraprocedural monitoring, 3-day clinical follow-up, laboratory tests, necropsy, and histopathology (heart, lungs, central veins). RESULTS:Procedural success (lead removal) was 100% without adjunctive tools: external cutting sheath was not required for adhesion dissection in all of the cases. Lead release occurred within ∼1 minute in 8 of 9 leads. Primary safety endpoints were met: no central vein or myocardial perforation and no pulmonary embolism. No blood pressure drops, significant arrhythmias, or worsening tricuspid regurgitation occurred. 1 lead fracture (1 of 9) resulted in a retained distal screw (<1 cm) associated with mild localized myocardial necrosis. Anchor device malfunctions required intraprocedural replacement in 2 cases. CONCLUSION:Vibration-assisted extraction of chronic cardiac implantable electronic device leads was feasible with a remarkable acute safety profile in this ovine model, meeting primary safety endpoints. The procedure was characterized by notable technical simplicity and rapid lead release via the internal lumen, successfully obviating the requirement for potentially hazardous external cutting sheaths. Lead fracture and anchor malfunctions indicate areas for further technological assessment and clinical trial.

RC-0315 is a chemotherapy-exposed mesenchymal stem cell-derived secretome developed as a potential advanced therapy for idiopathic pulmonary fibrosis (IPF). A Good Laboratory Practice (GLP)-compliant repeated-dose toxicity study was conducted to evaluate the safety of RC-0315 following intratracheal (ITR) instillation in immunocompetent ICR and SCID mice. Animals received two cycles of three repeated ITR instillations of RC-0315 performed within a 7-day period and separated by a two-week interval. Mice were assigned to saline, vehicle, low-dose, or high-dose groups and were monitored for 3 days (main phase) or 13 weeks (recovery phase) post last administration. No test article-related mortality or toxic clinical signs were observed in either strain. Clinical pathology parameters, body weight, food consumption, and ophthalmologic findings remained within normal limits, with no dose-dependent alterations. Histopathological examination revealed no RC-0315-related adverse findings in the lungs or other organs, and no local toxicity was evident at the site of administration. These findings support the favorable safety profile of RC-0315 when administered via the clinically intended route.

The first-line treatment for unresectable HPV-negative squamous cell carcinoma of head and neck (SCCHN) patients involves weekly or triweekly systemic cisplatin chemotherapy concurrently with radiotherapy. Cisplatin induces severe systemic toxicity that prevents a portion of patients from receiving the standard of care while redirecting them to less effective alternatives. This means worsening prognosis and overall survival (OS). A single-dose long-acting cisplatin limits toxicity. This is an injectable, biodegradable polyanhydride derived from sebacic acid (SA) and ricinoleic acid (RA) investigated as a targeted small-volume, high-payload carrier to improve safety and enhance efficacy.

IntroductionIn vitro viability assays are essential in drug discovery, development, and pharmacovigilance. However, traditional methods for evaluating cell viability rely on destructive processes that render cultures non-viable, limiting them to single endpoint measurements and precluding further analyses.MethodsWe present Neural Viability Regression (NViR), a deep learning-based method that enables real-time, non-invasive quantification of culture viability from microscopy images. Although developed and validated on liver spheroids, the framework includes a retrainable pipeline adaptable to other spheroid types. To demonstrate its applicability, we exposed human liver spheroids to 108 FDA-approved drugs and captured microscopy images over time, using NViR’s viability estimates to predict Drug-Induced Liver Injury (DILI).ResultsNViR’s viability assessments accurately predicted whether a drug induces DILI in humans. Its non-invasive nature enabled frequent viability evaluations throughout experiments, capturing subtle temporal changes while preserving the structural integrity of the cultures and substantially reducing both culture and labor costs.DiscussionThe cost-effectiveness and non-destructive characteristics of NViR enable high-frequency, high-throughput viability assessments, positioning it as a tool to enhance liver safety protocols and reduce both the costs and failure rates in drug discovery and development.

PPAR agonists are promising therapeutic agents approved for managing dyslipidemia and insulin resistance, and emerging evidence suggests they may also affect thyroid hormone metabolism by modulating hepatic enzymes and transporters. We aimed to determine whether dual PPAR activation via saroglitazar modulates hepatic enzymes involved in thyroid hormone clearance, thereby bridging metabolic regulation with thyroid function. To investigate this possibility, female rats were dosed orally with saroglitazar (3, 10, or 30 mg/kg/day) for 28 days. Serum T4, T3, and TSH levels were measured using high-sensitivity immunoassays, and hepatic UGT isoforms and thyroid gene expression were assessed by qPCR. Saroglitazar modestly increased T4 and slightly reduced T3, while serum TSH remained stable, suggestive of a well-compensated HPT axis under the study conditions. Mechanistically, saroglitazar markedly induced hepatic UGT1A1 and UGT1A6, key enzymes in T4 glucuronidation and triggered compensatory upregulation of thyroid-specific genes (TSH, TPO, thyroglobulin, and the TSH receptor). Histological analysis revealed no adverse changes in the liver, thyroid, or pituitary glands. Overall, our findings indicate that saroglitazar modulates thyroid hormone homeostasis in rodents primarily via PPAR-mediated peripheral metabolism and intrinsic thyroidal compensation without central HPT disruption; these adaptive changes are rodent-specific due to the lack of thyroxine-binding globulin and unlikely to translate to humans.

The biodegradation of inflated spacers made of PLCL 70:30 (poly(L-lactide-co-epsilon-caprolactone)) is investigated. This spacer is intended to temporarily position the anterior rectal wall away from the prostate during radiotherapy of prostate cancer. When inflated with phosphate buffer solution, this spacer implant creates space in the anterior rectum, thereby reducing radiation-induced damage. The mechanical stability of such inflated biodegradable systems over time is highly compromised, and their stability is uncertain due to continuous hydrolysis of the polymer material and imbalance with the muscular pressure that constantly acts on the inflated implant. Herein, detailed in vitro and in vivo degradation data of the inflated spacer are reported and correlated with its stability under a constant mechanical pressure that impersonates the pressure created by the anterior rectum on the spacers. The mechanical and physicochemical test results have a direct correlation with the degradation profile of the PLCL material. Mechanical testing demonstrates spacer inflation for at least 13 weeks.

OBJECTIVES:Zintrodiazine (ZY-19489) is a novel triaminopyrimidine-class antimalarial with potent activity against Plasmodium falciparum, including resistant strains. To support paediatric development and meet regulatory requirements, we conducted a comprehensive juvenile toxicity study of Zintrodiazine in rats, focusing on growth, neurodevelopment and toxicokinetics. METHODS:Wistar rats were administered vehicle and 30, 45 or 60 mg/kg/day Zintrodiazine orally from postnatal day (PND) 10-45, followed by a 4-week recovery (PND 46-73). Endpoints included clinical observations, neurobehavioural assays (open field, acoustic startle/pre-pulse inhibition and Morris water maze), sexual maturation, bone growth, clinical pathology, organ weights and histopathology. Toxicokinetic profiling at PND 21 and 45 assessed age- and sex-related exposure differences. RESULTS:No treatment-related mortality, clinical signs or developmental impairment were observed. Body weight, food intake, sexual maturation and femur length were unaffected. Neurobehavioural performance remained normal across all assays. Transient, non-dose-dependent changes in liver and renal biomarkers observed at terminal phase resolved at the end of recovery. Minimal, reversible vacuolation consistent with phospholipidosis was observed in the liver, lymphoid, pulmonary and adrenal tissues at ≥30 mg/kg/day, without inflammation or necrosis. Systemic exposure was dose-proportional; females exhibited higher parent compound and metabolite (ZY-20486) levels, while metabolite exposure declined with age, consistent with maturational biotransformation. The no-observed-adverse-effect level was 60 mg/kg/day (Cmax ≤1572 ng/mL; AUClast ≤35 592 h·ng/mL). CONCLUSIONS:Zintrodiazine demonstrated a favourable juvenile safety profile, with no adverse effects on growth, neurodevelopment or sexual maturation at clinically relevant exposures. These findings provide critical regulatory data supporting progression into paediatric clinical trials and highlight Zintrodiazine's potential as a safe and effective antimalarial for children.

Background/NeedUncontained power morcellation during laparoscopic gynecologic surgery risks intra-abdominal dissemination of benign or malignant tissue, a significant safety concern highlighted by FDA warnings. This has created a critical need for robust and reliable tissue containment systems that can be easily integrated into surgical workflows to mitigate this risk.Methodology and device descriptionThe LapBox Power Tissue Containment System is a single-use device featuring a dual-walled inflatable chamber designed to create a secure environment for morcellation. We conducted a Good Laboratory Practice (GLP)-compliant toxicology study in three female domestic pigs to assess its safety under simulated worst-case conditions. The device was inserted laparoscopically, and the internal dual-walled chamber of the device was inflated to a high pressure (∼160 mmHg) to simulate a localized worst-case compressive scenario, while the overall intra-abdominal insufflation was maintained at a standard 15 mmHg. Postoperative monitoring included clinical observation, bloodwork, and, at day 13, necropsy and histopathology.Preliminary ResultsAll procedures were completed without mortality, morbidity, or device-related complications. The LapBox maintained full structural integrity. Postoperative clinical, hematological, and biochemical parameters showed no adverse effects. Gross necropsy and detailed histopathology confirmed the absence of device-related ischemia, necrosis, thrombosis, or foreign-body reaction.Current statusThis preclinical study demonstrates that the LapBox Power system has an excellent safety profile and biocompatibility, even under extreme conditions. The device is ready for the next stage of evaluation. These findings support its translational potential and warrant further investigation in human clinical studies to confirm its safety and efficacy.

Toxicologic pathologists play a crucial role in the evaluation of animal studies for drugs, environmental chemicals, medical devices, and other agents to determine their safety and potential toxic effects. A significant challenge in this domain is the differentiation between incidental or procedural changes and genuine treatment-related effects. Correct identification and interpretation of such findings are essential to ensure that safety assessments are accurate and reliable for subsequent approval for human use. This review presents several cases in which non-test item-related findings were encountered. By examining procedure-related findings and considering spontaneous background pathology, we underscore the need for meticulous pathological evaluation and proper contextual understanding to avoid misinterpretations that could lead to erroneous conclusions about a substance's safety profile. The insights shared in this review aim to enhance the proficiency of toxicologic pathologists in recognizing and managing various interpretative challenges, with the goal of ultimately improving the accuracy of toxicological assessments, thereby contributing to the safe development of new therapeutics and medical devices and sound characterization of potentially hazardous substances in our environment.

Purpose Radiotherapy is standard-of-care for painful bone metastases yet has limitations and associated side effects. Ablation of sensory nerves endings along the periosteum with magnetic resonance imaging guided high intensity focused ultrasound (MRgFUS) proved safe and clinically effective for pain relief in patients with bone metastases, received FDA and CE approval, but has not gained widespread adoption due to significant cost and procedural and logistical complexity. This preclinical study evaluated the safety and feasibility of a fluoroscopy-guided high intensity focused ultrasound platform to ablate a targeted region along the surface of bones.Methods Two healthy adult pigs received 6 kJ to 10 kJ sonications to the femur, ileum, and ribs. Animals were followed-up for 3 months. Longitudinal clinical observation and follow up magnetic resonance imaging (MRI), and computed tomography (CT) scans were performed. After sacrifice, the targeted bone and adjacent tissues were sent for histopathological evaluation to confirm thermal ablation.Results Clinical observations revealed no neurological or musculoskeletal deficits. MRI scans on day 5 demonstrated robust ablation in all targeted sites. At 12 weeks, CT scans and histopathological evaluation showed complete healing of ablated regions.Conclusions Periosteal bone ablation using the Neurolyser XR in a healthy porcine model is feasible with no adverse events, and no radiological or histological evidence of lasting injury or fracture to the targeted bones.

745 Background: In a Phase 2 trial, treatment of non-resectable locally advanced pancreatic cancer (LAPC) patients harboring the KRAS G12D or G12V mutations, with SiG12DLoder combined with chemotherapy resulted in superior median overall survival (OS) of 9.3 months over chemotherapy (not statistically significant) and Objective Response Rate of 55% (35% over the chemotherapy control), when administered once every 3 months (Clinical trial # NCT01676259, ESMO 2023, abstract FPN: 1626). SIL-204 which is a modified version of siRNA siG12D is composed of a 21-base sense and 23-base antisense strands, both chemically modified and linked to a lipid. SIL-204 is encapsulated in biodegradable PLGA microparticles (MP), for direct release and injection into KRAS mutated solid tumors using an endoscopic ultrasound procedure. The strategy of preventing the synthesis of KRAS mutated protein may have an advantage over other approaches targeting KRAS function using small molecules. Methods: Methods are presented in results section. Results: SIL-204 has an increase stability over siG12D.To enhance stability, base modifications and phosphorothiate bonds at cleavage sites were implemented. SIL-204 exhibited a half-life of more than 48 hours in human serum. SIL-204 has robust KRAS silencing . When tested in Hepa1-6 cells transfected with individual human KRAS mutations, SIL-204 effectively silenced the various G12x mutations found in pancreatic cancer (D,V,R,C) at sub-nanomolar concentration (IC50 range=0.19-0.59) as well as G13D (IC50 =0.37). Addition of a hydrophobic tail to a prototype of SIL-204, SIL-101, increased the silencing of KRAS. Using PANC-1 cells (KRAS G12D mutation), lipid conjugation of the siRNA doubled the siRNA’s silencing efficiency in these cells. In addition, release of SIL-204 from the MP was tested in rats and indicates a prolong and sustained release over our intended treatment regimen SIL-204-MP was administered to tumors from human pancreatic tumor cell lines Capan-1 (KRAS G12V mutation and labelled with luciferase) grown in NSG mice and Panc-1 (grown in Athymic Nude mice). Bioluminescence imaging of tumor growth showed that SIL-204-MP significantly reduced Capan-1 tumor growth compared to vehicle controls, p<0.0005. Furthermore, histopathological analyses of tumor center slices from Capan-1 and Panc-1 models showed induction of significant tumor necrosis with SIL-204 compared to vehicle controls. Conclusions: The preclinical results of SIL-204-MP are promising and as the potential to further enhance the anti-tumor effect demonstrated by siG12DLoder in pancreatic patients. SIL-204 is now in toxicology studies as preparation for clinical trials in non-resectable pancreatic cancer.

Sustainable biomaterials are essential for advancing tissue engineering. This study investigates the in vivo biocompatibility and regenerative potential of seaweed cellulose (SC) scaffolds derived from Ulva sp. and Cladophora sp. as connective support matrices. SC scaffolds were fabricated using an optimized decellularization process that preserved their distinct porous (Ulva) and fibrous (Cladophora) architectures. Subcutaneous implantation in Sprague-Dawley rats demonstrated minimal foreign body response and successful integration over an eight-week period. Histological analysis revealed architecture-driven healing dynamics: Ulva sp. scaffolds promoted compartmentalized healing, characterized by distributed vascularized connective tissue, while Cladophora sp. scaffolds supported stratified tissue organization with aligned collagen deposition. Both scaffolds exhibited progressive vascularization and reduced foreign body response, with no adverse inflammatory reactions observed. These findings highlight the potential of SC scaffolds for regenerative applications that require tailored tissue responses, while their renewable, marine- origin underscores their potential as sustainable biomaterials in advanced healthcare solutions.

Background: Venous sinus stenting is a promising treatment for intracranial venous disorders, such as idiopathic intracranial hypertension and pulsatile tinnitus, associated with transverse sinus stenosis. The VIVA Stent System (VSS) is a novel self-expanding braided venous stent designed to navigate tortuous cerebral venous anatomy. This preclinical study assessed the safety, thrombogenicity, and performance of the VSS in a swine model. Methods: Fifteen swine underwent bilateral internal mammary vein stenting with either the VSS (n = 9) or the PRECISE® PRO RX stent (n = 6, reference). Fluoroscopy and thrombogenicity assessments were conducted on the day of stenting, clinical pathology analysis was carried out throughout the in-life phase, and CT Venography was performed before sacrifice. Animals were sacrificed at 30 ± 3 or 180 ± 11 days post-stenting for necropsy and histological evaluation. Results: Fluoroscopic angiography confirmed the successful VSS deployment with complete venous wall apposition and no vessel damage. The VSS achieved the highest scores on a four-point Likert scale for most performance parameters. No thrombus formation was observed on either delivery system. CT Venography confirmed vessel patency, no stent migration, and complete stent integrity. Histopathology showed a mild, expected foreign body reaction at 30 days, which resolved by 180 days, indicating normal healing progression. Both stents showed increased luminal diameter and decreased wall thickness at 180 days, suggesting vessel recovery. No adverse reactions were observed in non-target organs. Conclusions: The VSS exhibited favorable safety, procedural performance, and thromboresistance in a swine model, supporting its potential clinical use for treating transverse sinus stenosis and related conditions.

Managing conflicts of interest (COIs) in scientific decision-making is important for minimizing bias and fostering public trust in science. Proper management of COIs has added significance when scientists are making decisions that impact public policy, such as assessing substances for carcinogenicity. The International Agency for Research on Cancer (IARC) organizes expert working groups to identify putative carcinogens and determine whether or not the hazard is likely to present significant potential harm to humans. While IARC has policies for managing COIs, prior professional experience with the substance being assessed is not defined as a COI. Indeed, IARC working group members are chosen based on subject matter expertise, including prior publication on the substance under review. However, a person's prior experience with a substance poses a significant potential COI by equipping them with strong pre-existing views about the substance's toxicity and carcinogenicity. To minimize the risk of bias in IARC working groups, participants with voting powers should be independent scientific experts with sufficient professional experience to review carcinogenicity data but with no substantial prior experience with the substance under review. A related IARC practice restricting data review by working groups to selected publications is another significant COI. Instead, all accessible data should be available for consideration by working groups in assessing the carcinogenic hazard of substances. Another recommendation to reduce potential bias would be to reinstate the option of "probably not carcinogenic to humans".

The device development process encompasses an intersection of biological, physical, and engineering sciences principles culminating in translation of data from nonclinical animal studies to predict potential tissue responses in human patients. Evaluation of tissue reactions to the implanted device relies heavily on the core discipline of toxicologic pathology. Historically and currently, a disconnect between physical and biological scientists is highlighted by the frequent miscommunications due to differences in scientific language and divergent approaches to animal study design and/or data generation and interpretation. To facilitate communication among biologists, engineers, and materials scientists in the medical device community, this article provides fundamental principles and key resources necessary for rational pathology evaluation of tissue responses to implanted devices from the expert perspective of experienced toxicologic pathologists. The unique contributions of toxicologic pathologists to developing and marketing medical devices will be discussed, emphasizing the role of expert pathologists in balancing scientific issues with respect to evaluating biological responses and regulatory considerations. Additionally, discrepancies will be addressed that may arise if regulatory guidance is applied rigidly rather than adjusted as warranted by the context-specific evidence to best answer particular safety-related questions.

OBJECTIVES:This exploratory study was aimed to evaluate the safety and preliminary efficacy of Epicare, a 1940 nm thulium-doped yttrium aluminum perovskite (Tm:YAP) laser, for fractional skin ablation in a swine model. The goal was to assess collagen remodeling and tissue responses across varied laser settings to optimize skin resurfacing applications. MATERIALS AND METHODS:Two female domestic swine were subjected to controlled fractional laser ablation using Epicare across 52 marked abdominal sites with varying energy settings. Macroscopic examinations of ablated sites were conducted immediately following ablation and at 1, 3, 7, 14, 22, and 29 days postablation. Histopathological evaluation was conducted immediately posttreatment, and at 1, 7, and 29 days postablation. Observed parameters included epidermal regeneration, dermal remodeling, inflammation, and collagen deposition. RESULTS:Macroscopic evaluations revealed a fractional, clear, and immediate impact of ablation, consisting primarily of erythema and edema, which resolved without complications by Day 14. Histopathological analysis indicated focal, cylinder-like structures associated with necrotic epidermis and dermis, which healed progressively (i.e. from day 1), transitioning to complete epidermal regeneration by Day 7 for most energy settings. By Day 29, advanced collagen deposition and no residual inflammation indicated effective dermal remodeling, consistent with rapid healing and minimal adverse reactions. CONCLUSIONS:Epicare demonstrated a favorable safety profile and effective tissue ablation. These findings support the laser's potential for dermatologic applications while emphasizing the need for further investigation to confirm its efficacy and optimal settings in human clinical trials.

Innovation in the medical device industry is challenging due to the increasing physicochemical, structural, and engineering complexity of devices; proliferation of combination products; advent of long-term implants; and variable approaches to assessing tissue reactions. Nonclinical evaluation of biological responses to implanted devices requires careful study design and implementation of pathology practices to obtain the best data for translating device-related tissue reactions ("toxicity") and associated procedure-induced effects to predict possible outcomes in human patients. This paper outlines optimal pathology practices and related regulatory considerations that frame the nonclinical interpretation of biological responses induced by medical devices and combination products. These pathology practices have been developed by expert pathologists with extensive experience in medical device evaluation to address current guidance found in existing ISO Series standards, regulatory documents, and globally accepted "best practice" recommendations for toxicologic pathology assessment of therapeutic entities. Accordingly, the practices in this paper provide an optimized framework for biological evaluation of tissue responses to medical devices and combination products (both degradable and permanent devices) that should improve the relevance and utility of animal safety data provided to health authorities for human risk assessment.

Apoptotic cells possess immunomodulatory effects that can be utilized to treat imbalanced immune conditions. Information on the preclinical safety of such treatment is sparse. In this study, the safety of apoptotic cells (Allocetra-OTS) was assessed in a GLP toxicological study on Sprague Dawley rats. Three doses of Allocetra-OTS or vehicle were administered intravenously (IV) for 3 consecutive days. Animals in the main study were sacrificed on day 4, while animals from the recovery groups were kept for 14 or 28 days. Allocetra-OTS was well tolerated, and no adverse effects were observed in terms of body weight, clinical signs, food consumption, or ophthalmologic observation. Thus, the No Observed Adverse Effect Level (NOAEL) dose was determined as the highest dose administered. An observed elevation in immune cells was suspected to be due to Allocetra-OTS, similarly to other clinical chemistry parameters; however, it was resolved in the recovery phases. Splenomegaly and dose-related extramedullary hematopoiesis (EMH) in the red pulp were observed, with no adverse events, and were considered to be a normal and expected reaction following the IV administration of cell-based therapies. In conclusion, under the conditions of this study, Allocetra-OTS was concluded to be safe, further supporting its potential candidacy for clinical studies.

Biocompatibility is essential for drug delivery systems to ensure safety. Poly(lactic acid) (PLA) and its copolymers with glycolic acid and caprolactone, are known as safe biodegradable implants and carriers of drugs in clinical use. These polymers have been clinically used for the delivery of peptides, such as: LHRH, somatostatin and growth hormone. While the safety of PLA has been confirmed, the biocompatibility of PLA- based stereocomplexes with peptides has not been investigated. Stereocomplex is a complex formed by two molecules with opposite enantiomeric configuration. D-PLA consists of a chiral monomer thus can adopts a three dimensional structure which is a mirror image of a helix structure, therefore, complexes with insulin into a stereocomplex. In previous reports we demonstrated the formation of such stereocomplex. This study presents the safety evolution of a stereocomplex composed of the water soluble diblock copolymer of D-polylactic acid-co-polyetheylene glycol (DPLA-PEG) and Insulin, following subcutaneous administration of 17 mg sterecomoplex/mouse to Akita−/+ins2 mice. The mice were monitored for blood glucose levels and weight along the experiment, while growth necropsy and histopathology examination were done post sacrificing. Results demonstrated normal body weight gain with no pathological finding of an internal organ and no inflammatory signs at the injection site except of minimal macrophages, after 16 weeks following polymer administration. Hence, Stereocomplex of D-PLA-PEG/insulin is considered biocompatible with no adversity.