Among the various proliferants, hypertonic dextrose (typically 10%-25%) remains the most established and widely studied agent⁸. Dextrose is inexpensive, readily available, and has an extensive clinical history across multiple joints⁶. It exerts its therapeutic action by inducing mild osmotic stress, which triggers a transient inflammatory cascade characterized by the release of PDGF and TGF-β and subsequent stimulation of fibroblast activity and collagen deposition^8,11,18. In TMJ applications, 10% dextrose is usually prepared by diluting 50% dextrose with anesthetic and saline to achieve a mildly hyperosmolar solution that elicits a targeted regenerative response^19,20. Over several weeks, fibrovascular tissue develops within the ligamentous framework, enhancing capsular stability and reducing aberrant motion.

Although a universally standardized regimen has not yet been established, most studies recommend three to five sessions administered at 4 to 6-week intervals to allow collagen maturation between treatments¹⁴. Clinical protocols generally employ small injection volumes (0.5-2 mL per site) distributed across multiple peri-articular regions^15,17,18. A typical TMJ prolotherapy session with dextrose consists of injections to the posterior disc attachment (around 2 mL), anterior disc attachment (1 mL), and the superior and inferior aspects of the lateral joint capsule (0.5 mL each), performed under temporo-auricular nerve block. These injections target the key ligamentous support areas of the joint. Patients commonly experience mild post-injection pain for 24-48 hours, as the inflammatory phase, followed by progressive pain relief and improved joint stability. For optimal tissue recovery, a 2 to 3-week interval between sessions is generally recommended for the inflammatory reaction to subside and new collagen to mature. In 2024, Park et al.¹⁸ administered four-site 10% dextrose prolotherapy at 2-3 week intervals to 19 patients with chronic TMJ pain unresponsive to conventional treatments. They observed that pain on the numerical rating scale (NRS) gradually improved, and although maximum mouth opening (MMO) slightly decreased after the first prolotherapy session, it gradually increased in subsequent sessions. In 2025, the same group confirmed these findings in a larger cohort of 66 patients, showing sustained improvement in both NRS pain scores and MMO after a single injection, maintained through follow-up¹⁷. Most patients require two to four sessions depending on clinical response, and special caution is warranted in individuals with diabetes mellitus or heightened pain sensitivity^18,21.

PDRN is a mixture of DNA fragments (50-2,000 base pairs) usually derived from salmon sperm, and promotes healing through pharmacologic rather than purely irritant mechanisms²². Its regenerative actions are primarily mediated by the activation of adenosine A²A receptors (ADORA2A), which play a central role in modulating inflammation, angiogenesis, and tissue regeneration²³. Upon receptor activation, PDRN downregulates pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), IL-1β, IL-6, and high mobility group box 1 (HMGB1), while upregulating the anti-inflammatory cytokine IL-10 and vascular endothelial growth factor (VEGF)²⁴. As a result, PDRN injections tend to cause less post-injection flare than dextrose and allow shorter intervals between treatments. In orthopedic applications, PDRN has demonstrated robust regenerative and anti-inflammatory activity in multiple tissues. In vitro studies show that PDRN enhances fibroblast migration and collagen synthesis, while in chondrocyte cultures it exerts chondroprotective effects and preserves extracellular matrix integrity²⁵. Recent TMJ studies demonstrate that PDRN achieves clinical outcomes comparable to dextrose prolotherapy but with improved tolerability and patient compliance^17,26. Because its biological half-life is approximately 3-4 hours, repeated intra-articular administration as frequently as 1-2 times per week, compared to dextrose prolotherapy²⁷. In 2025, Jang et al.²⁶ evaluated 111 patients with TMJ osteoarthritis treated with 1-3 PDRN injections at 2 to 6-week intervals. They observed improvements in both MMO and pain NRS scores, with particularly favorable outcomes in patients with acute TMD (symptom duration ≤3 months), and noted that the clicking sound resolved in some cases. Similarly, Choi et al.¹⁷ found that administering PDRN injections at shorter 2-week intervals (compared to the typical dextrose injection interval) resulted in similar efficacy to dextrose prolotherapy, with both treatments yielding significant improvements in MMO and visual analogue scale (VAS) scores. Notably, among patients who initially presented with joint sounds, a complete resolution of the sounds was observed in most cases, accompanied by significant reductions in jaw displacement (from 69.6% to 13.0%) and deflection (from 52.2% to 8.7%). This suggests that PDRN can achieve comparable clinical efficacy to the well-established dextrose prolotherapy while offering advantages in comfort and treatment frequency.

Platelet-rich plasma (PRP) has been explored as a biologic analog of prolotherapy, leveraging autologous growth factors to enhance angiogenesis and tissue repair, capitalizing on its angiogenic and anti-inflammatory cytokines²⁸. PRP injections—often combined with arthrocentesis—have demonstrated short-term pain reduction and improved mandibular mobility, though variability in preparation methods hinders cross-study comparisons²⁹. However, PRP is costly, operator-dependent (blood processing), and lacks standardized protocols in TMJ prolotherapy; strictly speaking, PRP is often considered separate from classic “prolotherapy”. Other agents, including polidocanol, morrhuate sodium, and phenol–glycerin–glucose (P2G), have historical use in ligament prolotherapy but only limited application in TMJ disorders³⁰.

Injectable platelet-rich fibrin (i-PRF), a second-generation platelet concentrate, has recently gained attention as a promising orthobiologic adjunct for TMJ disorders. In contrast to PRP, i-PRF is produced without anticoagulants using low-speed centrifugation, which yields a three-dimensional fibrin network that entraps platelets and leukocytes and allows a more gradual release of growth factors over time. In a prospective study, intra-articular i-PRF provided greater reductions in pain scores and better recovery of mandibular function than PRP or hyaluronic acid in patients with TMJ internal derangement³¹. Similarly, a randomized clinical trial reported that i-PRF administered after arthrocentesis yielded larger improvements in pain and MMO compared with hyaluronic acid³². In TMJ osteoarthritis, another randomized trial found that i-PRF led to significant decreases in pain and joint crepitation, together with improved mandibular mobility, suggesting a possible benefit for cartilage and subchondral bone support³³.

In summary, hypertonic dextrose remains the most widely used proliferant for TMJ prolotherapy due to its extensive validation and accessibility. PDRN has recently emerged as an effective, well-tolerated alternative supported by early clinical evidence. PRP and other orthobiologic injections represent a parallel avenue of regenerative therapy for TMJ disorders. Ongoing research is likely to clarify which injectate, or perhaps which combination of injectates, yields the best long-term results for different TMD subsets. In 2025, Ku et al.¹⁵ treated TMJ degenerative joint disease (DJD) by alternating PDRN and dextrose injections, and noted not only symptomatic relief (improvements in MMO and NRS) but also radiographic evidence of new bone formation along eroded condylar surfaces after prolotherapy, suggesting potential for structural regeneration in degenerative joints. Thus, there is interest in whether combining agents (such as using dextrose plus PRP, i-PRF, or sequencing PDRN after a round of dextrose) might harness both inflammatory and non-inflammatory pathways for maximal benefit–though no clinical studies have directly tested combined approaches yet. Clinicians should choose the proliferant based on patient-specific factors—pain threshold, metabolic status, cost, and accessibility—while adhering to precise injection techniques and strict asepsis to ensure safety.

Prolotherapy was first introduced in the 1950s as a regenerative treatment for chronic musculoskeletal pain^30,39. In the TMJ region, although the exact mechanism of action remains incompletely defined, several studies have demonstrated significant improvements in both pain and mandibular function following treatment⁴⁰. A 2025 systematic review confirmed that prolotherapy produced greater reductions in reducing pain and greater increases in jaw opening compared with placebo, autologous blood products, or occlusal splint therapy¹¹. The mechanism underlying pain reduction is not yet fully understood. Proposed explanations include controlled immune-mediated amplification of the inflammatory cascade and the potential role of dextrose or PDRN as substrates for cartilage-matrix biosynthesis⁴¹. In addition, prolotherapy may exert neuromodulatory effects on the periarticular neural network of the TMJ⁴². Activation of potassium channels—similar to that observed in glucose-mediated inhibition of orexin/hypocretin neurons—can induce neuronal hyperpolarization and attenuate nociceptive signal transmission, thereby contributing to analgesia^43-46. This reduction in pain facilitates greater mandibular excursion, whereas improved range of motion may further relieve pain through enhanced synovial lubrication and normalization of joint movement⁴⁷. However, excessive mechanical loading or intensive exercise during the acute inflammatory phase may aggravate osteoarthritic degeneration⁴⁸, while controlled, low-intensity activity has been shown to exert anti-inflammatory and chondroprotective effects⁴⁹. Choi et al.¹⁷ revealed a statistically significant correlation between improvements in MMO and pain reduction. They suggested that patients who actively engaged in rehabilitation exercises following prolotherapy tended to achieve better treatment outcomes.

TMJ osteoarthritis represents one of the more challenging indications for prolotherapy. It is characterized by condylar flattening, osteophyte formation, medullary sclerosis, synovitis, cartilage destruction, and subchondral bone remodeling⁵⁶. Osteoarthritis develops through the interplay of mechanical overload and chronic low-grade inflammation, ultimately involving the entire joint complex—including the subchondral bone, articular cartilage, ligaments, capsule, synovial membrane, and peri-articular musculature⁵⁷. Conventional management has largely been supportive, relying on splint therapy and NSAIDs, given the limited intrinsic capacity for cartilage regeneration. In orthopedics, however, prolotherapy for osteoarthritis has been associated with meaningful pain reduction and functional improvement, and may even stimulate chondrogenesis, as evidenced by favorable radiographic and histologic findings⁷. Accordingly, prolotherapy offers a biologically based approach that not only alleviates pain but also possibly slow or reverse degenerative changes by promoting endogenous repair. Regardless of whether dextrose or PDRN, prolotherapy yielded improvements in MMO and VAS in patients with DJD (osteoarthritis or osteoarthrosis), comparable to outcomes observed in TMD patients with primarily soft-tissue involvement^17,18. A recent case series described four patients with radiographically confirmed TMJ-DJD treated with combined dextrose and PDRN prolotherapy¹⁵. All four experienced marked symptomatic relief and mandibular deviation on opening was corrected. Remarkably, follow-up cone-beam computed tomography (CBCT) imaging showed new cortical bone formation and smoother condylar contours in these joints. Similarly, in a cohort of 111 patients with TMJ osteoarthritis, an approximately 50% reduction in joint crepitation was observed with no significant difference between acute and chronic subgroups²⁶. Collectively, these preliminary data suggest that prolotherapy may not only relieve pain but also contribute to structural restoration in degenerative TMJ disease, supporting its potential role as an early-stage or adjunctive therapy.

Beyond osteoarthritis, prolotherapy is also indicated when TMD symptoms arise from ligamentous laxity or subtle soft-tissue derangements that are not amenable to other treatments. Patients with TMJ hypermobility disorders—such as recurrent subluxation or chronic dislocation caused by ligamentous insufficiency—constitute a classic target population^9,10. In these cases, prolotherapy’s collagen-stimulating and ligament-tightening effects restore functional stability and reduce symptomatic clicking. Likewise, by similar rationale, prolotherapy may serve as an adjunct to botulinum-toxin therapy for neuromuscular disorders such as oromandibular dystonia or dyskinesia, helping to reinforce peri-articular soft-tissue tone^58,59.

In summary, the ideal candidates for TMJ prolotherapy are those with chronic, refractory TMD symptoms—pain, limited motion, or instability—related to ligament, tendon, or mild osseous pathology who seek a minimally invasive treatment option. This includes cases of TMJ hypermobility, disc or capsular dysfunction, and mild-to-moderate DJD. Conventional conservative treatments should be continued in parallel, and contributory factors (e.g., parafunctional habits like bruxism) addressed simultaneously. Contraindications are few but include systemic conditions that impair healing (e.g., uncontrolled diabetes, which may complicate dextrose therapy due to hyperglycemic risk) and the use of immunosuppressive or anti-inflammatory agents that might blunt the desired reparative response—although, notably, PDRN appears less affected by NSAIDs. Future controlled studies using MRI or CT could help determine whether prolotherapy can slow disease progression or promote partial regeneration of joint structures, including open bite from degenerative condylar resorption.