Innovative strategies for diabetic peripheral neuropathy: From clinical management to emerging bioengineering solutions

Abstract

Diabetic peripheral neuropathy (DPN) is a common, incurable complication of diabetes that causes sensory loss, pain, and motor problems. Conventional treatments like blood glucose management, pain relief, and neuroprotective drugs have limited success and do not prevent disease progression. Advances in neurobiology, regenerative medicine, and bioengineering have led to novel therapies that target underlying mechanisms and promote regeneration. Monitoring and evaluating the onset and progression of DPN are essential for effective clinical management. Given rapid advances in understanding DPN and developing new treatments, a comprehensive review that covers clinical progress, molecular pathology techniques, and emerging bioengineering strategies is both timely and essential. This review addresses: (1) DPN pathophysiology; (2) drug therapies from clinical trials since 2020; (3) animal models used in DPN research; (4) progress and challenges in biomaterial-based drug delivery systems; (5) developments and limitations of microfluidic platforms for DPN modeling; and (6) bioengineered devices used for DPN diagnosis and monitoring. Integrating clinical insights, molecular techniques, and bioengineering innovations seeks to create a forward-looking framework for next-generation DPN treatment and management.

Keywords: Animal models; Bioengineered devices; Biomaterial-based drug delivery systems; Diabetic peripheral neuropathy; Drug therapies; Microfluidic platforms.

Graphical abstract

Fig. 1

a) Diabetic peripheral neuropathy pathophysiology [14]; b) Major biological pathways of DPN, created by Biorender.

Fig. 2

Framework of translational and preclinical therapeutic development for diabetic neuropathy, created by Biorender.

Fig. 3

(a) The mechanism of VEGF-loaded ROS-responsive nanodots to improve sciatic neuropathy in diabetic peripheral neuropathy [161]. (b) The mode chart of nano-miR-146a-5p transfection and the potential pathway of miR-146a-5p inhibition of the inflammatory response and apoptosis [163]. (c) Transplantation of engineered exosomes derived from bone marrow mesenchymal stromal cells ameliorated diabetic peripheral neuropathy under electrical stimulation [164]. (d) Synthetic scheme for captopril micelle (CAP-M) formation and incorporation into the mixed Pluronics (Pluronic F127/F68) [168].

Fig. 4

a) Transduction and transmission of stimuli by axons in Microfluidic chambers (MFCs) [192]; b) Structural characteristics and ganglion expression of representative ion channels, receptors, and sensory neuron markers in the sensory nerve organotypic model: Structural characteristics and ganglion expression of representative ion channels, receptors, and sensory neuron markers in the sensory nerve organotypic model: After 28 days in culture, the ganglion-like structures in the microfluidic-based organotypic model successfully expressed key ion channels, including voltage-gated sodium and potassium channels that facilitate action potential initiation and propagation. They also showed expression of N-type and T-type calcium channels involved in pain signaling, along with the α2δ subunit (Cacna2d1), a target for gabapentin therapy. Additionally, the model expressed neurotrophin receptors, C-fiber markers such as transient receptor potential (TRP) channels and P2X3 (P2r), and receptors linked to inflammation, such as bradykinin receptor B2 (Bdkrb2) and histamine receptor H1 (Hrh1). mRNA levels of proinflammatory cytokines and chemokines were also observed. [98]; c) Potential cell types for reproducing the interaction between sensory neurons and PNS, ceated by Biorender; d) Basic requirements for DPN in vitro microfluidics model, created by Biorender.

Fig. 5

a) Acute hyperglycemia-induced pathological modeling using innervated epidermal-like layer chips: The study examined high glucose effects on the substantia nigra's survival, apoptosis, and oxidative stress by analyzing caspase-3 markers and ROS levels. Results showed increased ROS causes oxidative stress. While the number of TRPV1+ neurons didn't change, nerve fibers in the epidermis decreased in length and number. Axonal growth and innervation were specifically suppressed. High glucose didn't significantly affect apoptosis, proliferation, or epidermis thickness. [195]; b) Schematic of gaps in DPN microfluidic platforms for therapeutic research, created by Biorender; c) Statistical analysis of research trends on target organs innervated by sensory neurons (SN); d) Statistical analysis of research trends of SN in reproducing the DPN disease microenvironment.

Fig. 6

a) NerveCheck is a portable, inexpensive ($500) quantitative sensory device designed to assess vibration (VPT), cold (CPT), warm (WPT) perception threshold, and heat pain threshold [216]; b) the point-of-care procedure of DPNCheck™ [228]; c) Sudoscan device with hand and foot electrodes [238]; d) The Neurometer® device [241]; e) The Neuropad device [271]; f) The process of coregistration of MRN sequences of a patient with T2D and small fiber neuropathy [294]; g) Next generation of commercialized DPN assessment devices, created by Biorender.

Fig. 7

a) The self-powered smart insole [320]; b) The stretchable microneedle adhesive patch (SNAP) providing excellent skin penetrability and a robust electromechanical skin interface for prolonged and reliable EP monitoring under varying skin conditions [325]; c) The crosslinked-hydrogel MN-based electrodes for biopotential measurements [329]; d) The adhesive electrode on the skin for epidermal biopotential detections such as electrocardiography (ECG), electromyography (EMG), and electroencephalography (EEG) [330]; e) The bioinspired microfluidic sweat sensor system for extended sweat sampling, transport, and multiday sweat analysis [337]; f) The microfluidic sweat analysis patch for continuously monitoring both sweat secretion rate and composition for long-term without external sweat stimulation [338]; g) design considerations for wearable devices in DPN monitoring, created by Biorender.