Introduction

Pain is an increasingly prevalent health problem affecting 1.5 billion people globally, with the number of adults reporting painful health conditions rising from 32.9% in 1998 to 41.0% in 2014 in USA alone [1]. The severity of this condition deleteriously impacts the quality of life or work activities in approximately 7.4% of the population [2]. Pain presents a unique challenge to treatment owing to both the complexity of the nociceptive signal transmission and modulation, and the high variability of pain perception among individuals. Treatment goals include reduced noxious sensation and improved function, and the specific strategy depends both on the severity and the temporal nature of the pain, and the needs of the patient.

For many years, the World Health Organization (WHO) Pain Ladder, which was initially developed for the treatment of cancer pain, was a simple straightforward tool that has been used to guide both cancer and non-cancer pain management, recommending nonsteroidal anti-inflammatory drugs (NSAIDs) for mild cases (step 1: non-opioids), followed by opioids for moderate and severe conditions (steps 2 and 3) [3].

The use of opioids for pain management is not without its drawbacks. Opioids produce a number of adverse effects ranging from the unpleasant, such as nausea, vomiting, and constipation, to life-threatening respiratory depression. Moreover, opioid use runs the risk of physical and psychological dependence. Between 21 and 29% of patients taking opioids for chronic pain misuse their opioids and approximately 10% develop opioid use disorder [4]. Opioid over-prescribing for pain is considered an initial driving factor for the Opioid Epidemic. Although the rate at which opioids are prescribed peaked in 2012, over 142 million opioid prescriptions were dispensed in 2020 [5]. Despite the decline in prescription opioid use, US opioid overdose deaths continue to rise [6].

As the use of prescription opioids decreases, the necessity of identifying novel, non-opioid pain management options grows. For example, even with the use of local anesthetics and analgesics, it is estimated that 39% of patients who undergo surgery do not have adequate postoperative analgesia and experience mild to severe pain [7]. Moreover, when it comes to the treatment of chronic pain, the average patient can expect only about a 30% reduction in their pain score [8].

Recently, the WHO Pain Analgesic Ladder has been revised to help reduce the role of opioids so that the risk of misuse and dependency might be minimized. The new version allows for the inclusion of non-pharmacological treatment strategies and suggests a bidirectional approach for pain, starting at the bottom and scaling up to manage chronic pain, versus starting with the strongest agent (appropriate for the severity) then working down from there. Additionally, a new step 4 outlines invasive or minimally invasive treatments, including sustained analgesia delivery methods, neuromodulation, nerve block, and ablation therapies [3]. Innovation in biomaterials, biomolecular controlled release, and regenerative medicine are providing new clinical alternatives for pain treatment.

Biomaterial and regenerative medicine are rapidly growing research fields, their potential application to pain management is being actively explored, and significant progress has been made in the last decade. Novel regenerative therapies have been developed to repair degenerated tissues that lead to chronic and inflammatory pain in back, joint, and shoulder, with the potential to identify and eliminate the source of pain. Pain management biomaterials are developed to serve as drug carriers that target specific tissues, cell types, and organelles with sustained, localized, and stimuli-responsive release of pain medication, exhibiting improved efficacy and longer-term relief of pain symptoms. Biomaterial scavengers are designed to remove proinflammatory reactive oxygen species that trigger nociceptors and cause pain hypersensitivity, providing a proactive approach for pain management. Below, we explore and discuss the different scenarios that biomaterials and regenerative medicine can be applied to pain management and present recent progress in the use of biomaterials for chronic pain management.

Regenerative Medicine in Pain Management

Regenerative medicine has the potential to manage or cure pain resulting from tissue injury or inflammation without the continuous use of analgesics. Regenerative therapies including biomaterials, engineered tissues, and medical devices have been developed to support, repair, or replace damaged or abnormal tissues, restore their healthy state, and relieve the associated pain. Currently, regenerative therapies can be used to treat back pain arising from degenerative intervertebral disks (IVD) [9], knee pain caused by osteoarthritis and meniscus degeneration, shoulder pain that results from damaged rotator cuff [10], jaw pain from damaged temporomandibular joint (TMJ) [11], tendinitis pain from a tendon injury, and neuropathic pain from irritated, damaged or inflamed nerves [12].

Regenerative Biomaterials

Biomaterials used to promote tissue regeneration include bioactive ceramics; natural polymers such as chitosan, hyaluronic acid, and collagen; and synthetic polymers such as polycaprolactone (PCL) and poly(lactic-co-glycolic acid) (PLGA) [13]. These materials have shown great promise in bone and cartilage repair [14, 15], and in nerve regeneration [16], and provide a microenvironment that augments the regenerative potential of both the transplanted and host cells [17, 18]. Scaffold pore architecture regulates chondrogenesis and endochondral ossification of bone marrow–derived mesenchymal stem cells (BMSCs) and promotes vascularization [19], and alignment of extracellular molecule hydrogels promotes myotube formation of myoblasts [20]. Polycaprolactone (PCL)–based nano-topographic patches with aligned nanoscale matrix (ridges and grooves of ~ 800 nm) with nanosized pores (~ 100 nm), promote the proliferation and osteogenic mineralization in vivo [21].

The use of regenerative biomaterials for pain management has been extensively studied in IVD, which is the leading cause of low back pain, where PCL microfiber scaffolds, collagen peptide (Pro-Hyp-Gly)-presenting hydrogels, and adipose mesenchymal stem cell–derived tissue-engineered constructs have been tested [9, 22, 23]. For joint pain caused by articular cartilage and meniscus degeneration, hyaluronan scaffolds grafted with biomimetic brush-like nanofibrous polymers improved osteoarthritis within 8 weeks in a rat model by forming a lubrication layer on the cartilage surface [66]. Ramírez-García and colleagues developed novel pH-responsive polymeric nanoparticles to precisely deliver FDA-approved NK1R antagonist aprepitant and inhibit endosomal NK1R signaling. Intrathecal injection of these nanoparticles induced a more complete and persistent relief from nociceptive, inflammatory, and neuropathic nociception in preclinical models than that of opioids. In another study, the δ-opioid receptor (DOPr) agonist [D-Ala(2)-D-Leu(5)]enkephalin (DADLE) was encapsulated into mesoporous silica nanoparticle core (lipoMSN), to selectively target DOPr-expressing neurons and activate their endosomal DOPr for relief from inflammatory pain [67]. One intrathecal injection of the lipoMSN provided an analgesic effect lasting for 6 h in a mouse model of inflammatory nociception. These novel nanomaterials that selectively direct drugs to subcellular compartments open the opportunity for develo** much-needed non-opioid therapies for pain.

ROS Scavenging Biomaterials

Reactive oxygen species (ROS) are byproducts of cellular functions such as oxidative phosphorylation. In pathological conditions, excess ROS accumulates and causes inflammation, cell and tissue damage, and pain [68]. It has been shown that pro-inflammatory microglial activation with aberrant ROS generation in the spinal cord plays a critical role in the development of neuropathic pain [69]. To manage neuropathic pain by reducing ROS levels in microglia, Choi and colleagues developed a novel microglia-targeting ROS scavenging nanomaterial by conjugating microglia-specific antibody CD11b to ceria-zirconia nanoparticles [70]. The targeted delivery facilitated the elimination of both pro-inflammatory cytokines and ROS in microglia and ameliorated mechanical allodynia in a spinal nerve transection-induced neuropathic pain mouse model. Other novel ROS scavenging materials have been proposed for various applications, including ceria nanocrystals decorated mesoporous silica nanoparticles [71], movable hemin-loaded mesoporous silica nanoparticles [72], poly(NIPAAm-co-VP-co-MAPLA-co-MATEMPO) hydrogel [73], and enzyme-mimicking ultrasmall Cu5.4O nanoparticles [74]. Table 1 lists current research a clinical application of biomaterials for pain management.

Table 1 Pain management biomaterials
Full size table

Limitations and Future Direction

Currently, the application of regenerative medicine strategy in pain management mainly focuses on IVD degeneration, as it is the leading cause of low back pain. The association of other tissue injury and degenerative diseases with the development of pain symptoms received less attention. In addition, most of the studies investigating regenerative therapies did not report the efficacy of pain relief compared with other, more traditional, pain management strategies, which is needed to fully evaluate the benefit of these therapies. In future studies, establishing experimental standards to evaluate pain relief and conducting controlled experiments to include pharmacotherapy-only groups are needed to develop regenerative medicine alternatives for pain management. New understanding of the pathophysiology of other types of chronic and inflammatory pain will lead to the development of novel therapies to treat those pain generators. Given the intrinsic variability and complex regulatory network in tissue injury and regeneration, identifying the appropriate combination of bioactive molecules, optimal concentrations, and delivery timing represents a significant challenge. More detailed understanding of cell-environment, cell–cell, and intracellular signaling events during tissue injury response and regeneration process is a prerequisite to develop more effective regenerative therapies. This can be achieved by conducting research to find the key molecules to target, leveraging latest innovations in single-cell technologies, multi-omics, and computational analysis methods such as machine learning. In addition, the biocompatibility of regenerative biomaterials used in tissue repair needs to be refined to reduce the foreign body response and adapted for personalized use according to patient-specific factors such as obesity and diabetes [75].

Drug delivery systems encapsulating analgesics significantly enhanced their efficacy and duration of effect. However, these biocompatible and biodegradable polymeric materials are not compatible with current imaging methods to determine biomaterial-drug biodistribution and local drug concentration [77]. Biomaterials designed to incorporate imaging capability will provide prognostic value for these drug delivery platforms and increase the precision of pain medication delivery [76]. Apart from this, considerable effort will be required to advance these compounds to the clinic, including include toxicology, pharmacokinetic, and pharmacodynamic studies in disease-relevant preclinical models. The therapeutic efficacy of these formulations could be improved by encapsulating antagonists of different targets that co-mediate pain transmission and their signaling pathways [77].