Temporomandibular disorders (TMD) are a heterogeneous group of musculoskeletal conditions encompassing pain syndromes, such as myalgia and arthralgia, as well as structural abnormalities like disc displacement and degenerative joint disease (DJD). DJD is characterized by progressive cartilage degeneration, leading to remodeling of the subchondral bone [1]. TMJ pain during mandibular movements correlates with degenerative changes in joint surfaces, including erosion, flattening, osteophyte formation, sclerosis, and subchondral cyst formation, as observed on radiographic imaging. DJD patients who report functional pain tend to exhibit more severe joint destruction [2]. Structural alterations, such as condylar flattening and erosions, are strongly associated with pain frequency and intensity in DJD patients [3,4]. Clinical and radiographic evaluations indicate that approximately 25–55% of TMD patients exhibit degenerative changes [5,6]. DJD is considered a multifactorial disorder, with some cases occurring idiopathically. Current conservative treatments focus on symptom relief and functional recovery, commonly involving nonsteroidal anti-inflammatory drugs (NSAIDs), occlusal splints, and physical therapy [2]. Minimally invasive approaches, including arthrocentesis, arthroscopy, and intra-articular injections (e.g., hyaluronic acid or corticosteroids), may be employed, while surgical interventions, such as arthroplasty, condylectomy, or total joint replacement, are reserved for severe dysfunction and persistent pain [7]. However, due to limited understanding of DJD pathophysiology and the poor healing potential of avascular cartilage tissue, effective regenerative treatments remain unclear [8].

Recently, prolotherapy has emerged as a promising alternative for TMD treatment. Prolotherapy is a non-surgical regenerative therapy designed to promote cellular proliferation and restore the structural integrity of weakened ligaments and tendons [9]. Also known as "regenerative injection therapy," prolotherapy aims to stimulate the growth and proliferation of new connective tissue, strengthening periarticular ligaments, tendons, and supportive structures when applied to the TMJ [10]. Hypertonic dextrose is the most widely used proliferant, though agents such as polidocanol, manganese, zinc, growth hormone, and platelet-rich plasma (PRP) are also being explored [11]. In orthopedics, polydeoxyribonucleotide (PDRN) has been identified as an effective proliferant, but its application in TMD management remains limited.

Prolotherapy may offer a viable option for regenerating TMJ structures in DJD patients, potentially reversing degenerative changes. This study presents a case series of four patients treated with PDRN and dextrose injections at three-week intervals, demonstrating favorable clinical outcomes.

This study was conducted in compliance with the ethical guidelines set by the institutional and national committees responsible for human experimentation, in accordance with the Helsinki Declaration of 1975, revised in 2008, with approval from the Institutional Review Board (IRB) of Seoul National University Bundang Hospital (IRB: B-2503-960-105). Four patients who underwent TMJ prolotherapy between 2024 and 2025 at the Department of Oral and Maxillofacial Surgery were included. Patients presented with TMJ pain and restricted mouth opening, and Cone Beam Computed Tomography (CBCT) findings confirmed DJD-related changes.

The prolotherapy procedure followed an established protocol [10]. Initial pain control was achieved using 1.8 mL of mepivacaine hydrochloride (Scandonest 3%, Septodont) or 2% lidocaine (1:100,000 epinephrine, Huons, Seongnam, Korea) for auriculotemporal nerve block and superior joint space anesthesia [14]. Hypertonic dextrose or PDRN (Placentex® injection; Pharma Research, Gangneung, Korea; PolyNeo®; DongKwang Pharm, Seoul, Korea) was administered based on prior studies [15]. The dextrose injection consisted of 20% dextrose (Daehan Pharm, Korea), 2% lidocaine (Huons, Seoul, Korea), and saline (Daehan Pharm, Seoul, Korea) in a 2:1:1 ratio, producing a 10% dextrose solution [16]. The anatomical injection sites for TMJ prolotherapy and the respective volumes of either dextrose or PDRN administered were as follows: Posterior disc attachment (2 cc), Anterior disc attachment (1 cc), Upper lateral capsular ligament (0.5 cc), Lower lateral capsular ligament (0.5 cc).

For injection into the superior joint space, the procedure was performed with the patient’s mouth in an open position. The needle was inserted at a point located 10 mm anterior and 2 mm inferior to the canthotragal line, and advanced approximately 20 mm in an anterosuperior direction. For targeting the retrodiscal tissue (posterior attachment of the disc), the injection was also performed with the mouth open. The insertion point was set at 6 mm anterior and 2 mm inferior to the canthotragal line, with the needle directed anteriorly to a depth of approximately 20 mm. To target the anterior attachment of the disc, the procedure was performed with the patient’s mouth in a closed position. The needle was inserted 15 mm anterior and 2 mm inferior to the canthotragal line, and advanced approximately 20 mm in an anteroinferior direction toward the presumed insertion of the lateral pterygoid muscle.

For post-procedural pain management, patients receiving PDRN injections were prescribed Clanza 100 mg (Aceclofenac, United Pharm, Seoul, Korea) once daily (qd) for 7 days or Brufen 200 mg (Ibuprofen, Samil Pharm, Korea) for 2 days. Patients receiving dextrose injections were prescribed Tyrenol (Acetaminophen, 500 mg, Johnson & Johnson, Seoul, Korea). No additional interventions were performed during the prolotherapy treatment or follow-up period. Patients using stabilization splint were advised to continue applying it throughout the treatment period. If patients were not using splints before treatment, they were recommended to have one fabricated after their symptoms improved.

The primary objectives in the treatment of DJD are functional restoration and pain relief. Available treatment modalities can be categorized into non-invasive, minimally invasive, and surgical approaches [7]. Intra-articular hyaluronic acid injections have been considered beneficial for TMJ osteoarthritis; however, their superiority over arthrocentesis remains debated [17]. Steroid injections and platelet-rich plasma (PRP) therapy have demonstrated effects comparable to those of arthrocentesis [18]. Arthrocentesis, which removes inflammatory mediators and disrupts adhesions within the joint, is widely utilized, though its efficacy remains controversial. Despite its potential benefits, it primarily targets inflammation reduction rather than cartilage or bone regeneration [19]. To date, no established treatment has been shown to regenerate degenerated cartilage in TMJ DJD [12,18]. In this case series, four patients who underwent prolotherapy combined with conservative treatment exhibited radiographic evidence of joint regeneration in addition to symptomatic relief. Unlike conventional treatments that focus solely on symptom management, prolotherapy appeared to facilitate joint tissue repair. Consistent with prior studies reporting pain reduction in DJD patients exhibiting osteophyte formation and new bone growth [3,4], our findings suggest that prolotherapy-induced joint regeneration contributed to functional recovery without residual pain. Moreover, prolotherapy is theorized to stimulate tissue regeneration by modulating the inflammatory response, aligning with its fundamental regenerative mechanism. The combination of prolotherapy with conservative management and active mandibular mobilization exercises may have played a pivotal role in enhancing therapeutic outcomes.

Patients with chronic pain-related DJD exhibit distinct inflammatory and anti-inflammatory cytokine profiles compared to patients with general TMD. Notably, they show increased levels of inflammatory Monocyte Chemoattractant Protein-1 (MCP-1), decreased levels of anti-inflammatory Omentin-1, and a downregulation of the transcription of Transforming Growth Factor beta 1 (TGF-β1), an essential anti-inflammatory growth factor [13]. Mélou et al. (2023) reported that various inflammatory and catabolic mediators, along with multiple signaling pathways, influence the progression of DJD [7]. Key inflammatory cytokines, such as Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-1 beta (IL-1β), and matrix-degrading enzymes, including Matrix Metalloproteinases (MMP-3, MMP-9, MMP-13) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS-4, ADAMTS-5), play crucial roles in joint degeneration. Additionally, various signaling pathways, such as estrogen, Hypoxia-Inducible Factor (HIF), Extracellular Signal-Regulated Kinase (ERK), Notch, β-catenin, Indian Hedgehog, Fibroblast Growth Factor (FGF), p38 Mitogen-Activated Protein Kinase (p38 MAPK), and PI3K/Akt, have been implicated in DJD pathophysiology [20,21,22]. Prolotherapy, through intra-articular injection of proliferative agents, can stimulate fibroblast proliferation via both inflammatory and non-inflammatory pathways, thereby strengthening weakened or inflamed connective tissues and reducing pain [23]. Fibroblasts facilitate angiogenesis, cellular proliferation, and collagen deposition by activating key growth factors, including platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), and epidermal growth factor (EGF) [24]. This dynamic tissue remodeling process distinguishes prolotherapy from conventional TMD treatment strategies by promoting structural repair and regeneration rather than merely alleviating symptoms.

Despite ongoing research on the mechanism of action of prolotherapy, its precise biological processes remain incompletely understood. The primary hypothesized mechanism is tissue regeneration, with the effects varying based on the specific proliferant injected. Hypertonic dextrose, typically used at concentrations of 10–25%, induces cell wall lysis and fibroblast activation, triggering the release of growth factors such as PDGF, TGF-β, EGF, basic-FGF (bFGF), and insulin-like growth factor (IGF) [16,25]. These growth factors promote fibroblast activation, collagen precursor formation, and tissue remodeling, mimicking the body’s natural healing processes [11]. Additionally, dextrose provides essential nutrients for damaged cells, exerts potential direct effects on peripheral nerves, facilitates fibrous tissue formation, and has been reported to contribute to ligament, tendon, and cartilage regeneration [26]. However, nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided during prolotherapy, as they interfere with the controlled inflammatory response necessary for tissue repair. While hypertonic dextrose is generally considered safe, caution is advised in patients with uncontrolled or severe diabetes. Since dextrose-based prolotherapy relies on an initial inflammatory response to initiate tissue regeneration, its efficacy may be diminished by NSAIDs or corticosteroids, which suppress this inflammatory phase.

In contrast to NSAIDs and corticosteroids, polydeoxyribonucleotide (PDRN) has been shown to exert anti-inflammatory effects without inducing metabolic side effects or triggering inflammation. Due to its ability to stimulate tissue proliferation, PDRN has been increasingly utilized as a therapeutic option for osteoarthritis in major joints [27]. Derived from salmon sperm DNA, PDRN consists of a mixture of deoxyribonucleotide polymers, with chain lengths ranging from 50 to 2000 base pairs [27]. It serves as a source of pyrimidines and purines, stimulating nucleotide synthesis through salvage pathways. PDRN has been found to downregulate pro-inflammatory mediators, including Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6), and High Mobility Group Box 1 (HMGB1), thereby reducing inflammation. Simultaneously, it upregulates Vascular EGF (VEGF), promoting tissue repair and wound healing [28]. Additionally, PDRN has been observed to modulate key inflammatory cytokines, including TNF-α, IL-1, IL-6, HMGB1, and IL-10, suggesting a potential regulatory role in anti-inflammatory processes. Notably, PDRN exerts its regenerative effects through the activation of adenosine A2A receptors (ADORA2A), which have been shown to play a critical role in musculoskeletal tissue regeneration [27]. Given the essential function of adenosine receptors in inflammation suppression [29], PDRN has emerged as a promising therapeutic agent for managing inflammation in DJD [30]. While in vitro studies have demonstrated its chondroprotective effects, and animal models have shown significant arthritis attenuation compared to controls, clinical studies on TMJ applications remain scarce [31,32].

In cases of degenerative changes in the TMJ, conventional treatments primarily aim to reduce excessive joint loading using occlusal stabilization splints and restrict mandibular movements that exacerbate pain [7]. Additionally, in cases of severe acute bone destruction, anterior open bite may develop, necessitating orthognathic correction to restore occlusion in DJD patients [33,34]. However, these approaches do not facilitate direct bone regeneration and fail to address the structural deterioration of the condyle. In this study, we report successful cases in which 2–3 sessions of prolotherapy not only alleviated TMD symptoms but also contributed to condylar regeneration. All patients received two to three sessions of prolotherapy depending on their clinical response. Prolotherapy generally requires multiple injections to achieve a regenerative effect, as a single session may not sufficiently stimulate fibroblast activation and collagen synthesis. Previous studies have reported favorable outcomes with repeated injections, especially in cases involving joint structures with limited vascularity [35]. The decision to discontinue further injections was based on the resolution of clinical symptoms, functional recovery and radiographic evidence of joint stabilization. Conversely, repeated injections were considered in cases where pain persisted, mouth opening remained restricted, or radiographic findings showed ongoing joint degeneration. In some cases, dextrose was used as a single intermediate injection between PDRN treatments. Hypertonic dextrose acts as a strong inflammatory stimulant, initiating tissue regeneration through controlled inflammation, while PDRN exerts anti-inflammatory and proliferative effects to support sustained healing. The alternating use of these agents was based on their complementary mechanisms, with dextrose promoting initial stimulation and PDRN maintaining regenerative momentum. Since there are no standardized protocols or guidelines for TMJ prolotherapy, we utilized a combination of 10% hypertonic dextrose and PDRN, aiming to enhance pain relief, joint function improvement (e.g., increased mouth opening), and structural recovery. This approach was complemented by occlusal splint therapy to mitigate excessive joint loading. Future prospective studies are warranted to determine the optimal injection intervals, the most effective proliferative agents, and the best combination of adjunctive conservative therapies to achieve the most favorable outcomes in DJD patients.

One limitation of this study is the use of both hypertonic dextrose and PDRN in the same anatomical region across different time points, which may limit the ability to evaluate the independent effects of each proliferant. Future studies should consider designing comparative protocols with distinct injection sites or isolated monotherapy groups to better differentiate the therapeutic roles of each agent. Additionally, this study is the lack of direct evaluation of surrounding TMJ ligaments, which play a significant role in joint stability and movement. Future research incorporating imaging-based ligament assessment using magnetic resonance imaging and ultrasonography may provide deeper insight into the biomechanical impact of prolotherapy.

This case series demonstrates the potential of prolotherapy as a regenerative treatment for TMJ DJD. Unlike conventional symptomatic treatments, prolotherapy may promote joint tissue regeneration, particularly with the use of hypertonic dextrose and PDRN. These findings suggest prolotherapy as a promising intervention for TMJ DJD, warranting further studies to evaluate long-term efficacy and clinical stability.