Current Clinical Research Directions on Temporomandibular Joint Intra-Articular Injections: A Mapping Review

This mapping review aims to identify and discuss current research directions on intracavitary temporomandibular joints (TMJs) injections. The inclusion criteria allowed studies published in the last full six years, based on patients diagnosed with temporomandibular joint disorders (TMDs), treated by TMJ intra-articular injections. Medical databases covered by the Association for Computing Machinery, Bielefeld Academic Search Engine, PubMed, and Elsevier Scopus engines were searched. The results were visualized with tables, charts, and diagrams. Of the 2712 records identified following the selection process, 152 reports were qualified for review. From January 2017, viscosupplementation with hyaluronic acid (HA) was the best-documented injectable administered into TMJ cavities. However, a significant growing trend was observed in the number of primary studies on centrifuged blood preparations administrations that surpassed the previously leading HA from 2021.


Background
The temporomandibular joints (TMJs) connect the mandible to the temporal bones. These joints are essential to the proper functioning of the stomatognathic system, including opening and closing the mouth, chewing, and speaking [1]. Rotation and slide in TMJs are palpable on both sides in the preauricular area during abduction and adduction of the mandible [2,3]. Each TMJ consists of the mandibular condyle, the articular fossa of the temporal bone, and the cartilage disc that separates the two bones and cushions them during movement [1,4]. The joint is surrounded by a network of muscles, ligaments, and nerves that help stabilize and control its function [1,5].
Temporomandibular disorders (TMDs) are a collective term for a group of conditions manifested by abnormal function of the temporomandibular joints (TMJs) [6,7]. According to the meta-analysis by Valesan et al., the overall prevalence of TMDs in the adult population is approximately 31% [6] The causes of TMDs are seen primarily in malocclusions, morphological abnormalities, and post-traumatic changes within TMJs, and masticatory istration of any substance, was excluded. More invasive intra-articular manipulations, i.e., arthroscopy or open surgery, were disqualified. Due to the inclusion of studies with varying levels of evidence, the criterion of comparison was not applicable. Changes in any TMDs severity index were allowed as an outcome. Single case reports and any series less than 4 cases were rejected. In order to demonstrate the current directions of research, reports published in the last full 6 years, i.e., from 1 January 2017, to final searches conducted on 13 March 2023, were included.

Search Strategy
The search strategy was based on terms identifying TMJ and injections. In its basic form, the query was: "(temporomandibular OR TMJ OR TMJs) AND (injection OR injections OR puncture OR punctures OR administration OR administrations)".

Results
Of the 2712 records identified, 152 reports were ultimately qualified for the mapping review, with 32, 53, 28, and 39 reports in levels of evidence from 1 to 4, respectively (Figures 1-5, Table A2) [18,19,[22][23][24][25]. In the selection process, a total of 1407 duplicates were rejected, mainly due to overlapping search engines. At the screening stage, 1119 entries not related to TMJs injection treatment were excluded; these were present due to the intentionally unrestrictive choice of keywords in the queries. At the very end of the selection, 34 articles (mainly case reports) were rejected in the course of the full-text evaluation in accordance with the adopted inclusion and exclusion criteria.

Results
Of the 2712 records identified, 152 reports were ultimately qualified for the mapping review, with 32, 53, 28, and 39 reports in levels of evidence from 1 to 4, respectively (Figures 1-5, Table A2) [18,19,[22][23][24][25]. In the selection process, a total of 1407 duplicates were rejected, mainly due to overlapping search engines. At the screening stage, 1119 entries not related to TMJs injection treatment were excluded; these were present due to the intentionally unrestrictive choice of keywords in the queries. At the very end of the selection, 34 articles (mainly case reports) were rejected in the course of the full-text evaluation in accordance with the adopted inclusion and exclusion criteria.

Discussion
TMDs that cause articular pain and mandibular mobility limitation are two main sons for delivering intra-articular injections, except for HD and AB administrations w are performed to treat recurrent subluxation of the temporomandibular [22,24,37,40,44,53,55,57,61,65,66,69,72,73,90,94,96,97,110,111,131,149,160,165,168]. rently, there is an intensive search for the gold standard of TMDs treatment, which i ficult due to the variety of etiologies and the specificity of individual dysfunctions main directions of research on the use of intra-articular injections in this indicatio presented below.

Hypertonic Dextrose (HD) Prolotherapy
Unlike viscosupplementation, HD prolotherapy aims to reduce the range of m of the mandible. The administration of HD as an irritant is one of the treatment met for hypermobility in TMJs. So far, the concentration of HD has not been standardized varies from 12.5% to 25%. Only the studies involving the administration of HD int TMJs are included in this review, but the substance is frequently deposited peri-articu in this indication. Of the two substances applied to TMJs (HD and autologous blood) injections are better documented. The 13 primary studies on intra-articular administr of HD have been summarized in 6 rev [22,24,37,53,65,66,72,73,94,96,97,110,111,131,149,160,165].

Discussion
TMDs that cause articular pain and mandibular mobility limitation are two main reasons for delivering intra-articular injections, except for HD and AB administrations which are performed to treat recurrent subluxation of the temporomandibular joint [22,24,37,40,44,53,55,57,61,65,66,69,72,73,90,94,96,97,110,111,131,149,160,165,168]. Currently, there is an intensive search for the gold standard of TMDs treatment, which is difficult due to the variety of etiologies and the specificity of individual dysfunctions. The main directions of research on the use of intra-articular injections in this indication are presented below.

Hypertonic Dextrose (HD) Prolotherapy
Unlike viscosupplementation, HD prolotherapy aims to reduce the range of motion of the mandible. The administration of HD as an irritant is one of the treatment methods for hypermobility in TMJs. So far, the concentration of HD has not been standardized and varies from 12.5% to 25%. Only the studies involving the administration of HD into the TMJs are included in this review, but the substance is frequently deposited peri-articularly in this indication. Of the two substances applied to TMJs (HD and autologous blood), HD injections are better documented. The 13 primary studies on intra-articular administration of HD have been summarized in 6 reviews [22,24,37,53,65,66,72,73,94,96,97,110,111,131,149,160,165].

Blood Preparations Autotransplantation
Blood preparations are a group of substances obtained from autologous peripheral blood including unprocessed blood and blood concentrates. Autologous blood (AB) is the second, next to HD, substance administered into the TMJs for the treatment of hypermobility. Reports since 2017 describing AB therapy are fewer and generally with a lower level of evidence than these regarding HD (four randomized, one non-randomized, and six uncontrolled) [37,40,44,55,57,61,65,66,69,90]. The only included systematic review on AB therapy administrated intra-articularly suggests the need for randomized trials [168].
Blood concentrates are obtained by centrifuging freshly taken venous blood and are delivered immediately after the preparation. Different protocols allow obtaining various concentrates without the red cell fraction. Some of the concentrates can be collected in liquid form and injected into TMDs. In the discussed years, the administration of preparations referred to as plasma rich in growth factors (PRGF), PRP, I-PRF and liquid phase concentrated growth factor (LPCGF) into the TMJs cavities was described. They differ in the centrifugation procedure, and thus in the composition and effectiveness in anti-inflammatory action and stimulation of tissue regeneration. The lack of a standardized centrifugation protocol for platelet-rich concentrates for injection into TMJs clearly illustrates the active development of a therapeutic standard. Of the 152 reports on blood concentrates included, 120 primary studies were published (including 53 randomized trials) as well as 32 systematic reviews. From 2021, primary research on the substances in question has been more numerous than on HA. [18,23,25,36,46,56,60,62,64,67,68,70,74,75,81,84,85,87,95,101,103,104,107,[112][113][114]118,119,122,123,123,128,[133][134][135][136][137][141][142][143]145,147,148,152,158,161,162,167,169,170].

Mesenchymal Stem Cells (MSCSs) Autotransplantation
MSCs, obtained primarily from autogenous fat, are an attractive injectable due to their high potential to stimulate the regeneration of TMJ structures. Only four primary studies using MSCs for intracavitary administration are known, of which three were randomized.

Drugs Administration
Substances used as drugs for other indications, normally with other routes of administration, are included in this group. CSs are definitely the best studied among them. After HA and PRP, CSs were the third most frequently reported injectables group in 2017-2022 (8 systematic reviews, 10 randomized trials, and 8 other trials) [19,25,38,39,41,45,47,47,49,51,54,62,75,86,121,125,127,134,135,137,140,156,164,166,171]. Nevertheless, since 2020, the number of primary studies on intra-articular injection of CSs has clearly decreased. Other papers describe the use of non-steroidal anti-inflammatory drugs (NSAIDs), local anesthetics (LAs), opioids, and polidocanol. These substances have been used exceptionally and so far there is no well-established knowledge about their effectiveness and safety [24,37,38,62,73,77,79,97,101,108,137,150,165].

Other Substances Injections
Unique studies on the administration of botulinum toxin (BTX), chitosan, and ozone gas provide potential directions for the future development of intra-articular injections. At present, however, these methods should be regarded as insufficiently researched [24,42,83,139,159].

Limitations
This systematic map was limited to injections into the temporomandibular joint cavities. Therefore, studies focusing on pericapsular injections, which are used in the treatment of mandibular hypermobility, were omitted. Therefore, this paper covers only a part of the articles on AB and HD injections.
A separate large group of interventions, not included in this review, is stand-alone arthrocentesis. They have been excluded as there was no intention to administer any substance intra-articularly. However, TMJs lavage relieves pain and increases mandibular mobility similarly to injections of, for example, HA or PRP, and future mapping of papers on this topic should be considered.

Conclusions
In the years 2017-2023, hyaluronic acid was the most common topic of scientific publications among injectables administered into temporomandibular joint cavities (26 randomized controlled trials and 30 other clinical studies). In the same period, there was a significant upward trend in the number of published primary studies focused on centrifuged blood preparations used in the treatment of TMDs. As of 2021, blood products administered into TMJs cavities have become a more popular topic for professional medical articles than hyaluronan. Nevertheless, it should be emphasized that this is a group of substances that differ in composition depending on the centrifugation protocol. The therapeutic efficacies of substances evaluated in at least three clinical trials were synthesized in systematic reviews.