Advanced Bioresponsive Drug Delivery Systems for Diabetic Vascularized Bone Regeneration

Background

The treatment of bone defects in patients with Diabetes Mellitus (DM) remains a significant challenge, as the diabetic microenvironment severely impedes bone regeneration. Various abnormal factors in the diabetic microenvironment, such as hyperglycemia, increased oxidative stress, heightened inflammation, immune imbalance, and vascular system damage, can lead to delayed or even failed bone tissue repair. In recent years, stimuli-responsive biomaterials capable of responding to endogenous biochemical signals have emerged as effective therapeutic tools for treating diabetic bone defects. These materials regulate the microenvironment and enhance osteogenic capacity, coupling angiogenesis and osteogenesis to provide new insights into the treatment of diabetic bone defects.

This paper, co-authored by Xiaojun Zhou, Shuo Chen, Andrij Pich, and Chuanglong He*, was published in ACS Biomaterials Science & Engineering, Volume 11, Issue 182-207, in 2025. The study systematically summarizes the mechanisms of impaired bone healing induced by diabetes and outlines therapeutic strategies, with a focus on the design of bioresponsive drug delivery systems and their applications in promoting vascularized bone regeneration.

Main Content of the Paper

1. Microenvironment Characteristics and Therapeutic Strategies for Diabetic Bone Defects

The microenvironment of diabetic bone defects differs significantly from that of normal bone defects, primarily characterized by hyperglycemia, chronic inflammation, increased oxidative stress, and vascular damage. These pathological features result in delayed or failed bone healing. The paper first systematically describes the microenvironment characteristics of diabetic bone defects and proposes the following therapeutic strategies: - Blood Glucose Control: Regulating hyperglycemia through local insulin delivery systems or enzyme-functionalized scaffolds such as glucose oxidase (GOx). - Immune and Inflammation Regulation: Alleviating inflammation by modulating macrophage polarization (from M1 to M2 phenotype) and delivering anti-inflammatory drugs. - Oxidative Stress Balance: Clearing excess reactive oxygen species (ROS) using antioxidants or inorganic elements (e.g., Ce, Sr, Mg) to restore cellular function. - Vascularization Regulation: Promoting angiogenesis and subsequent bone regeneration by delivering growth factors (e.g., VEGF, PDGF-BB) or metal ions (e.g., Mg²⁺, Sr²⁺).

2. Design of Bioresponsive Drug Delivery Systems

In response to the unique pathological features of the diabetic microenvironment, the paper details the design of various bioresponsive drug delivery systems, including: - Glucose-Responsive Systems: Glucose-sensitive materials based on glucose oxidase (GOx), concanavalin A (Con A), and phenylboronic acid (PBA), which respond to changes in blood glucose levels for controlled drug release. - pH-Responsive Systems: Achieving drug release in acidic microenvironments through pH-sensitive bonds (e.g., imine bonds, amide bonds) or pH-sensitive polymers (e.g., polyacrylic acid, chitosan). - ROS-Responsive Systems: Designing ROS-responsive materials using ROS-sensitive bonds such as thioethers, thioketals, and phenylboronate esters to clear excess ROS and promote bone regeneration. - Enzyme-Responsive Systems: Enzyme-responsive hydrogels based on matrix metalloproteinases (MMPs), which respond to MMP overexpression in the diabetic microenvironment to release drugs.

3. Drug Delivery Strategies for Promoting Vascularization

Bone tissue is highly vascularized, and angiogenesis is tightly coupled with osteogenesis during bone regeneration. The paper summarizes several drug delivery strategies to promote vascularization, including: - Growth Factor Delivery: Delivery of growth factors such as VEGF and PDGF-BB to directly promote angiogenesis and osteogenesis. - Drug Molecule Delivery: Delivery of small-molecule drugs such as deferoxamine (DFO) and metformin, which have antioxidant and pro-angiogenic effects. - Metal Ion Delivery: Delivery of metal ions such as Mg²⁺ and Sr²⁺ to modulate the immune microenvironment and promote angiogenesis. - Extracellular Vesicle (EV) Delivery: EVs, as key mediators of intercellular communication, can regulate immune responses and promote vascularization and bone regeneration.

4. Applications of Bioresponsive Drug Delivery Systems

The paper also discusses the applications of various bioresponsive drug delivery systems in diabetic vascularized bone regeneration, including: - Injectable Colloidal Delivery Systems: ROS-responsive nanoparticles and microgels that enable precise drug release and promote bone regeneration. - Injectable Hydrogel Delivery Systems: Glucose-responsive hydrogels and ROS-responsive hydrogels that respond to endogenous signals in the diabetic microenvironment to release drugs.

Significance and Value of the Paper

This paper systematically summarizes the pathological features of diabetic bone defects and therapeutic strategies, while detailing the design of various bioresponsive drug delivery systems and their applications in promoting vascularized bone regeneration. These studies provide new insights and methods for the treatment of diabetic bone defects, offering significant scientific value and clinical potential.

Highlights

• Innovation: This paper is the first to systematically summarize the microenvironment characteristics of diabetic bone defects and propose therapeutic strategies, along with the design of various bioresponsive drug delivery systems.
• Application Value: These bioresponsive drug delivery systems can precisely respond to endogenous signals in the diabetic microenvironment, enabling controlled drug release and significantly improving the treatment efficacy of diabetic bone defects.
• Future Directions: The paper also points out future research directions, such as developing adaptive, smart drug delivery systems that can simultaneously regulate pathological microenvironments and regenerative signals.

Conclusion

By systematically summarizing the pathological features of diabetic bone defects and therapeutic strategies, and detailing the design and applications of various bioresponsive drug delivery systems, this paper provides new insights and methods for the treatment of diabetic bone defects. These studies not only hold significant scientific value but also offer new tools and strategies for clinical treatment.