As a metabolic epidemic affecting hundreds of millions of people worldwide, the pathological impact of diabetes mellitus extends far beyond blood glucose dysregulation itself. Diabetes-induced bone disorders, in particular, have become a focal point of clinical concern. In the diabetic state, patients often suffer from serious issues such as an increased risk of bone fractures, delayed healing, and impaired bone regeneration. These are primarily attributed to hyperglycemia-induced oxidative stress and the accumulation of advanced glycation end products (AGEs), which trap bone metabolism in a state of low turnover and metabolic paralysis. Current anti-resorptive therapies have proven inadequate in addressing this complex metabolic bone disease and struggle to fundamentally reverse the deep-seated damage diabetes inflicts on bone cells.

In-depth research in recent years has revealed that the functional uncoupling of endoplasmic reticulum-mitochondria crosstalk is a core mechanism underlying abnormal bone metabolism in diabetes. The hyperglycemic environment triggers endoplasmic reticulum stress and leads to excessive mitochondrial fission. These two factors act synergistically through a vicious cycle, not only disrupting calcium homeostasis but also inducing a burst of reactive oxygen species (ROS), ultimately resulting in the functional failure of osteoblasts. Therefore, how to precisely intervene in the aberrant organelle communication within the complex diabetic microenvironment, break the interactive cycle between oxidative stress and cellular dysfunction, and develop a minimally invasive therapeutic platform with good clinical applicability has become a key technical challenge for achieving osseointegration of diabetic implants and bone regeneration repair.

To address the above issues, a team consisting of West China Hospital of Stomatology, Sichuan University; the Affiliated Stomatological Hospital of Kunming Medical University; Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; and the Faculty of Dentistry, The University of Hong Kong, conducted systematic research using ZEPTOOLS' ZEM series scanning electron microscope. The team developed an injectable, photocrosslinkable silk fibroin hydrogel loaded with Mdivi-1, providing an innovative strategy for repairing diabetic implant osseointegration by regulating the functional crosstalk between the endoplasmic reticulum and mitochondria.

Title：Modulating ER-mitochondrial crosstalk to revitalize implant osseointegration in diabetes through an injectable hydrogel platform
Journal：Chemical Engineering Journal
URL：https://doi.org/10.1016/j.cej.2026.177208

To meet the requirement for minimally invasive drug delivery in clinical surgery, the research team successfully synthesized and characterized a novel photocrosslinkable silk fibroin hydrogel system loaded with a Drp1 inhibitor. This system uses natural silk fibroin as the matrix, modified with glycidyl methacrylate to impart photocrosslinking ability, and is precisely loaded with 50 micromolar Mdivi-1. Using ZEPTOOLS' ZEM Ultra field emission scanning electron microscope, it was clearly observed that the hydrogel possesses a uniform, interconnected three-dimensional porous network structure, and the introduction of the drug significantly reduces the average pore size, resulting in a denser network. This precise characterization of the microstructure provides key evidence for understanding controlled drug release and cell migration. Rheological tests further confirmed that the material exhibits excellent shear-thinning properties and self-healing ability, allowing smooth extrusion through a fine needle and rapid shape recovery at the implant site, thereby achieving effective integration of physical properties and biological functions.

During the in vivo animal experimental phase, the researchers used a streptozotocin-induced type 2 diabetic rat model to systematically evaluate the effect of this hydrogel on the osseointegration of titanium alloy threaded implants. Experimental results showed that during an observation period of up to eight weeks, the untreated diabetic group exhibited significant bone loss and sparse trabecular structure. In contrast, after treatment with this composite hydrogel, both the bone volume fraction and trabecular number around the implant were robustly restored. Quantitative micro-computed tomography and histological section cross-validation demonstrated that this system increased the bone-implant contact rate under diabetic conditions to exceed the clinical success threshold of 50 percent, effectively alleviating bone healing disorders caused by metabolic dysregulation.

The study further revealed the microscopic pathway of drug action from a cell biology perspective, focusing on its regulatory effect on mitochondrial dynamics in mouse osteoblast precursor cells. Under hyperglycemic stress, Drp1 protein is overexpressed in osteoblasts, leading to pathological fragmented mitochondrial fission, accompanied by a decrease in membrane potential and a surge in reactive oxygen species (ROS) production. Mdivi-1, continuously released from the hydrogel, effectively inhibits the recruitment of Drp1 to the outer mitochondrial membrane, restores the long rod-like branched network morphology of mitochondria, and enhances the activity of the respiratory chain complex. This intervention in mitochondrial quality control not only eliminates excess oxidative damage but also reactivates the energy supply capacity of osteoblasts under metabolic stress.

The paper ultimately constructed a novel therapeutic framework based on the functional crosstalk between the endoplasmic reticulum and mitochondria, elucidating the deep logic for breaking the pathological vicious cycle. In a high-glucose environment, excessive reactive oxygen species (ROS) generated by mitochondrial dysfunction induce severe endoplasmic reticulum stress through physical contact sites, which in turn exacerbates osteoblast apoptosis and inhibits the expression of key osteogenic genes. The study confirmed that by reducing the abnormal physical contact distance between the two organelles, this hydrogel successfully downregulates the phosphorylation levels of endoplasmic reticulum stress marker proteins, thereby correcting the RANKL/OPG ratio imbalance. This finding not only demonstrates the feasibility of intervening in bone metabolism at the level of organelle crosstalk but also provides important theoretical guidance for the future development of mitochondrial-targeted therapeutic drugs for diabetic complications.

The ZEPTOOLS ZEM series scanning electron microscope is a highly integrated, portable, cost-effective, and practical scientific research instrument. It features fast pump-down, high imaging speed, and a variety of signal detector options, making it suitable for morphological observation and compositional analysis, as well as adapting to various in-situ experimental needs. The instrument has low requirements for installation environment—no special floor restrictions—and is easy to operate, allowing even non-professionals to quickly become proficient. It can be widely applied in fields such as new material development, life sciences, failure analysis, and industrial quality inspection, providing a powerful, high-performance, and cost-effective solution for microscopic characterization to a broad range of research institutes and corporate users.