Platelet-Rich Plasma in Treatment of Temporomandibular Joint Dysfunctions: Narrative Review.

BACKGROUND: The aims of this narrative review were to examine up-to-date literature in order to evaluate the effectiveness of arthrocentesis or injections with platelet-rich plasma in temporomandibular affections and to compare them to arthrocentesis alone or with hyaluronic acid (HA) or to hyaluronic acid injections. METHODS: The search of international literature was made on the PMC, PubMed and Cochrane databases, including all full-length text of studies on humans focused on osteoarthritis and disc displacements and their treatment with platelet-rich plasma arthrocentesis or injections. All design studies were included in the review and they were examined for three different outcomes: pain, joint sound and mandibular motion. English papers were only selected. RESULTS: Even though the low number of studies in this field, arthrocentesis with platelet-rich plasma and platelet-rich plasma injections in temporomandibular disorders' management were found to be effective in reducing pain and joint sound as well as in improving mandibular motion in a maximum follow-up of 24 months. CONCLUSION: Comparison to arthrocentesis alone or to HA use in arthrocentesis or by injections provided encouraging results in terms of the effectiveness of platelet-rich plasma use.

Biochemistry, Physiology, and Tissue Interactions of Contemporary Biodegradable Injectable Dermal Fillers.

BACKGROUND: Injectable dermal fillers are becoming increasingly popular for soft tissue augmentation and rejuvenation. Most contemporary biodegradable products are derived from hyaluronic acid, calcium hydroxylapatite, or poly-L-lactic acid. Achievement of desired cosmetic outcomes is largely dependent on selection of the optimal injectable product based on the chemical composition, the physiologic interactions with surrounding tissue, product longevity, and a thorough understanding of potential adverse reactions. OBJECTIVE: To review and describe the biochemistry, physiology, and tissue interactions of the most commonly used contemporary biodegradable dermal fillers. METHODS: A thorough review of the literature was performed with additional review of pertinent clinical cases and corresponding histopathology. RESULTS: This article provides a comprehensive review of the biochemistry, physiology, and potential tissue interactions of the most commonly used biodegradable dermal fillers. The underlying biochemical properties of each product and how they contribute to specific physiologic and adverse tissue reactions is described. CONCLUSION: Understanding of the innate differences in the physical properties, and physiologic responses to soft tissue fillers allows clinicians to achieve desired aesthetic outcomes with fewer adverse events.

Biodynamic performance of hyaluronic acid versus synovial fluid of the knee in osteoarthritis.

Hyaluronic acid (HA), a natural biomaterial present in healthy joints but depleted in osteoarthritis (OA), has been employed clinically to provide symptomatic relief of joint pain. Joint movement combined with a reduced joint lubrication in osteoarthritic knees can result in increased wear and tear, chondrocyte apoptosis, and inflammation, leading to cascading cartilage deterioration. Therefore, development of an appropriate cartilage model that can be evaluated for its friction properties with potential lubricants in different conditions is necessary, which can closely resemble a mechanically induced OA cartilage. Additionally, a comparison of different models with and without endogenous lubricating surface zone proteins, such as PRG4 promotes a well-rounded understanding of cartilage lubrication. In this study, we present our findings on the lubricating effects of HA on different articular cartilage model surfaces in comparison to synovial fluid, a physiological lubricating biomaterial. The mechanical testings data demonstrated that HA reduced average static and kinetic friction coefficient values of the cartilage samples by 75% and 70%, respectively. Furthermore, HA mimicked the friction characteristics of freshly harvested natural synovial fluid throughout all tested and modeled OA conditions with no statistically significant difference. These characteristics led us to exclusively identify HA as an effective boundary layer lubricant in the technology that we develop to treat OA (Singh et al., 2014).

More than just a filler - the role of hyaluronan for skin homeostasis.

In recent years, hyaluronan (HA) has become an increasingly attractive substance as a non-immunogenic filler and scaffolding material in cosmetic dermatology. Despite its wide use for skin augmentation and rejuvenation, relatively little is known about the molecular structures and interacting proteins of HA in normal and diseased skin. However, a comprehensive understanding of cutaneous HA homeostasis is required for future the development of HA-based applications for skin regeneration. This review provides an update on HA-based structures, expression, metabolism and its regulation, function and pharmacological targeting of HA in skin.

Hyaluronan, a ready choice to fuel regeneration: a mini-review.

BACKGROUND: Hyaluronan (HA) is present in extracellular spaces and interstitia of many tissue types. As it is capable of binding high amounts of water, HA provides ideal conditions for cell migration and proliferation. Under conditions of cellular crowding, it also permits lineage-specific differentiation and thus promotes many aspects of healing and tissue remodeling. METHODS: The simplicity of its structure makes it amenable to chemical modifications and/or combined formulations with other bioactive substances. Thus a wide variety of clinical applications have been proposed, several of which are currently being implemented in advanced therapies. RESULTS: Known features of HA biology, in particular regarding synthesis and processes related to signaling and control, have been adopted to elaborate specific products in order to support progress in regenerative medicine. Purified HA, HA-based hydrogels or special HA composites have been formulated together with other well-characterized biomaterials and bioactive factors. HA is currently employed in a variety of therapeutic applications both in its pure form and in a biofunctionalized form. CONCLUSIONS: HA plays an essential role in regenerative processes. Owing to the growing scientific knowledge in this field, medicinal products based on HA have been devised and are being routinely applied in ophthalmology or in trauma and transplantation surgery. Further areas of application are contemplated, such as the use of HA composite scaffold material in tissue engineering, or refined HA hydrogels enabling controlled release of medication.

In vivo angiogenesis effect of porous collagen scaffold with hyaluronic acid oligosaccharides.

BACKGROUND: Tissue engineering is a promising solution for tissue defect repair. A key problem, however, is how to keep the engineered tissue alive after implantation. The ideal scaffold for tissue engineering would be biocompatible and biodegradable and, more importantly, would exhibit good interaction with endothelial cells to promote angiogenesis. MATERIALS AND METHODS: Three different scaffolds were synthesized: collagen/hyaluronic acid (HA) (MW 6.5K), collagen/HA (MW 220K), and collagen only. The synthesized collagen/HA scaffold was analyzed for water content, pore size, and HA content. An animal model for in vivo tissue construct angiogenesis was developed using the inferior epigastric skin flap of mice and perfusion of quantum dots; the average fluorescence intensity per unit area was calculated and correlated with vessel density from histologic examination. RESULTS: The pore size is not statistically different among the three groups and the HA content is not statistically different between the two collagen/HA groups. The fluorescence intensity of the collagen/HA (MW 6.5K) group is increased at day 14, 21, and 28, and is significantly higher than in the other groups. Similar results were also obtained from histologic immunohistochemistry studies. CD31-stained vessels were found co-localized with QD fluorescence and these newly formed vessels were identified at day 14 in the collagen/HA (MW 6.5K) group and increased significantly at day 21 and 28. CONCLUSION: This study showed that collagen scaffolds with short-chain HA (MW 6.5K) revascularize faster than those with long-chain HA (MW 220K) and collagen only. The results of the new animal model for studying scaffold angiogenesis are compatible with the conventional methods of immunostaining and histological examination.

Rheological properties of hyaluronic acid and its effects on salivary enzymes and candida.

OBJECTIVE: To investigate the viscosity and wettability of hyaluronic acid (HA), its effects on lysozyme and peroxidase activities, and its candidacidal activity. MATERIALS AND METHODS: Human whole saliva, HA, hen egg-white lysozyme (HEWL), and bovine lactoperoxidase (bLPO) were used. Viscosity was measured with a cone-and-plate digital viscometer, while wettability was determined by measuring the contact angle. Lysozyme activity was determined by the turbidimetric method. Peroxidase activity was determined with NbsSCN assay. Candidacidal activity was determined by comparing colony forming units. RESULTS: The viscosity of HA solutions was proportional to its concentration, with 0.05 mg ml(-1) of HA in distilled water or 0.5 mg ml(-1) in simulated salivary buffer displaying similar viscosity values to stimulated whole saliva. The contact angle of HA solutions showed no significant differences according to the tested materials and tested HA concentrations. Contact angles of HA solutions on acrylic resin were higher than those of human saliva. HA did not affect lysozyme or peroxidase activities of whole saliva as well as HEWL or bLPO activities. HA also showed no candidacidal activity. CONCLUSIONS: The viscoelastic properties of HA compared with human saliva were objectively confirmed, indicating a vital role for HA in the development of effective salivary substitutes.

Hyaluronan in human tumors: pathobiological and prognostic messages from cell-associated and stromal hyaluronan.

Cancers are supported by a distinct type of connective tissue stroma, crucial for tumor survival and advancement. Hyaluronan is a major matrix molecule in the stroma of many common tumors, and involved in their growth and spreading. Here we focus in recent data on stromal hyaluronan in human tumors, and that on the surface of the malignant cells. Hyaluronan accumulation is most conspicuous in malignancies that develop in cells and tissues normally devoid of hyaluronan, such as single layered epithelia and their hyaluronan-poor connective tissue stroma. The magnitude of the hyaluronan accumulation in the malignant epithelium itself (e.g. colon and gastric cancers) or tumor stroma (breast, ovarian, prostate cancers) strongly correlates with an unfavorable prognosis of the patient, i.e. advancement of the malignancy. A completely different pattern arises from stratified epithelia that normally produce hyaluronan and are surrounded by a hyaluronan-rich stroma. The cell surface of the latter group of tumors (e.g. squamous cell carcinomas of skin, mouth, larynx and esophagus, and skin melanoma) show abundant hyaluronan which tends to get reduced and patchy in the most advanced stages of the tumors, suggesting enhanced turnover. While the assays of human tumors represent snapshots of currently unknown processes and kinetics of hyaluronan metabolism, it is obvious that hyaluronan accumulation at some stage is an inherent feature in most of the common epithelial malignant tumors. The possible contributions of inflammatory cells, stem cells, mutated stromal cells, or otherwise deranged growth factor exchange between stromal and cancer cells are discussed as possible explanations to hyaluronan abundance in the tumors. The importance of hyaluronan in human tumor progression will be further clarified when drugs become available to modify hyaluronan metabolism.

Soft tissue fillers in the nose.

Using soft tissue fillers to correct postrhinoplasty deformities in the nose is appealing. Fillers are minimally invasive and can potentially help patients who are concerned with the financial expense, anesthetic risk, or downtime generally associated with a surgical intervention. A variety of filler materials are currently available and have been used for facial soft tissue augmentation. Of these, hyaluronic acid (HA) derivatives, calcium hydroxylapatite gel (CaHA), and silicone have most frequently been used for treating nasal deformities. While effective, silicone is known to cause severe granulomatous reactions in some patients and should be avoided. HA and CaHA are likely safer, but still may occasionally lead to complications such as infection, thinning of the skin envelope, and necrosis. Nasal injection technique must include sub-SMAS placement to eliminate visible or palpable nodularity. Restricting the use of fillers to the nasal dorsum and sidewalls minimizes complications because more adverse events occur after injections to the nasal tip and alae. We believe that HA and CaHA are acceptable for the treatment of postrhinoplasty deformities in carefully selected patients; however, patients who are treated must be followed closely for complications. The use of any soft tissue filler in the nose should always be approached with great caution and with a thorough consideration of a patient's individual circumstances.

Requirement of Hyaluronan Synthase-2 in Craniofacial and Palate Development.

Cleft palate is a common major birth defect resulting from disruption of palatal shelf growth, elevation, or fusion during fetal palatogenesis. Whereas the molecular mechanism controlling palatal shelf elevation is not well understood, a prevailing hypothesis is that region-specific accumulation of hyaluronan, a predominant extracellular glycosaminoglycan in developing palatal mesenchyme, plays a major role in palatal shelf elevation. However, direct genetic evidence for a requirement of hyaluronan in palate development is still lacking. In this study, we show that Has2, 1 of 3 hyaluronan synthases in mammals, plays a major role in hyaluronan synthesis in the neural crest-derived craniofacial mesenchyme during palatogenesis in mice. We analyzed developmental defects caused by tissue-specific inactivation of Has2 throughout the cranial neural crest lineage or specifically in developing palatal or mandibular mesenchyme, respectively, using Wnt1-Cre, Osr2-Cre, and Hand2-Cre transgenic mice. Inactivation of Has2 either throughout the neural crest lineage or specifically in the developing palatal mesenchyme caused reduced palatal shelf size and increased palatal mesenchyme cell density prior to the time of normal palatal shelf elevation. Whereas both Has2f/f;Wnt1-Cre and Has2f/f;Osr2-Cre mutant mice exhibit cleft palate at complete penetrance, the Has2f/f; Wnt1-Cre fetuses showed dramatically reduced mandible size and complete failure of palatal shelf elevation, whereas Has2f/f;Osr2-Cre fetuses had normal mandibles and delayed palatal shelf elevation. All Has2f/f;Hand2-Cre pups showed reduced mandible size and about 50% of them had cleft palate with disruption of palatal shelf elevation. Results from explant culture assays indicate that disruption of palatal shelf elevation in Has2f/f;Hand2-Cre mutant fetuses resulted from physical obstruction by the malformed mandible and tongue. Together, these data indicate that hyaluronan plays a crucial intrinsic role in palatal shelf expansion and timely reorientation to the horizontal position above the tongue as well as an important role in mandibular morphogenesis that secondarily affects palatal shelf elevation.

Hyaluronic acid and periodontitis.

Hyaluronic acid (HA; synonyms--Hyaluronan, Hyaluronate) is a glycosaminoglycan found in the connective tissue of vertebrates. It is the most abundant glycosaminoglycan of higher molecular weight in the extracellular matrix of soft periodontal tissues. The use of HA in the treatment of inflammatory process is established in medical areas such as orthopedics, dermatology and ophthalmology. In the field of dentistry, it has shown anti-inflammatory and anti-bacterial effects in gingivitis and periodontitis therapy. Due to its tissue healing properties, it could be used as an adjunct to mechanical therapy in the treatment of periodontitis.

Induction of MMP-3 by hyaluronan oligosaccharides in temporomandibular joint chondrocytes.

Low-molecular-weight hyaluronan (LMW-HA) is often increased in osteoarthritic joints; however, its biological function in cartilage has not been clarified. We hypothesize that LMW-HA causes the catabolic activation of chondrocytes through its interaction with CD44. Cartilage explants and chondrocytes, derived from bovine temporomandibular joints (TMJ), were examined for matrix loss and the expression of matrix metalloproteinase-3 (MMP-3) following treatment with hyaluronan oligosaccharides (HA(oligos)). Hyaluronan and CD44 were uniformly distributed throughout the fibrous and cartilaginous zones of the TMJ condyle. Treatment of cartilage explants with HA(oligos) resulted in cartilage matrix loss with increased secreted caseinolytic activity. HA(oligos) treatment of TMJ chondrocytes resulted in enhanced MMP-3 expression, whereas wash-out of the HA(oligos) in the middle of the experimental period reduced this induction. These results suggest that HA(oligos) activate chondrocytes, resulting in a substantial enhancement of proteinase expression, and the removal of HA(oligos) by wash-out reverses this catabolic activation.

Supramolecular synergy in the boundary lubrication of synovial joints.

Hyaluronan, lubricin and phospholipids, molecules ubiquitous in synovial joints, such as hips and knees, have separately been invoked as the lubricants responsible for the remarkable lubrication of articular cartilage; but alone, these molecules cannot explain the extremely low friction at the high pressures of such joints. We find that surface-anchored hyaluronan molecules complex synergistically with phosphatidylcholine lipids present in joints to form a boundary lubricating layer, which, with coefficient of friction µ≈0.001 at pressures to over 100 atm, has a frictional behaviour resembling that of articular cartilage in the major joints. Our findings point to a scenario where each of the molecules has a different role but must act together with the others: hyaluronan, anchored at the outer surface of articular cartilage by lubricin molecules, complexes with joint phosphatidylcholines to provide the extreme lubrication of synovial joints via the hydration-lubrication mechanism.

Adhesive force: the underlying cause of the disc anchorage to the fossa and/or eminence in the temporomandibular joint--a new concept.

The commonly held cause for using the closed lock technique is the prevention of disc sliding by using the non-reducible disc. The purpose of this study was to re-evaluate the pathogenesis of sudden and persistent severely limited mouth opening associated with a total lack of disc sliding in view of the fact that it is promptly released by lavage of the upper compartment of the temporomandibular joint (TMJ). The proposed pathogenesis is based upon earlier clinical and laboratory findings of the first author coupled with pertinent information culled from the literature. It is suggested that sliding of the disc in the TMJ is enabled due to the presence of phospholipids protected by hyaluronic acid (HA) that constitute an efficient lubrication system. Joint overloading may be associated with uncontrolled production of reactive oxygen species (ROS) that causes degradation of the HA, followed by the exposure of the phospholipids to lysis by phospholipase A2 (PLA2). The denuded, smooth and elastic articular surfaces that possess high surface energy become strongly adherent when placed in direct physical contact with each other. The presence of an extremely thin film of fluid (sub-boundary lubrication) between the mating surfaces may cause even higher adhesion. These adhesive forces are probably responsible for the flexible disc anchorage to the fossa and/or eminence. They also explain the immediate release of the disc and rehabilitation of its sliding following arthrocentesis. Since it is uncommon for two opposing surfaces to be stripped bare and to become adherent, the likelihood of anchored disc phenomenon (ADP) occurring and recurring is very low.

Hyaluronan and its potential role in periodontal healing.

Hyaluronan is a natural tissue component, which plays a vital role in the functioning of extracellular matrices, including those of the periodontium. This molecule is also important in relation to the mechanisms associated with inflammation and wound healing. The application of exogenous hyaluronan and hyaluronan-based biomaterials has been successful in manipulating and accelerating the wound healing process in a number of medical disciplines, as evident in ophthalmology, dermatology and rheumatology. It is conceivable that hyaluronan administration to periodontal sites could achieve comparable beneficial effects in periodontal healing and surgery, hence aiding treatment of periodontal disease.

Hyaluronan in the healthy and malignant hematopoietic microenvironment.

The fate of both endogenous and transplanted stem cells is dependent on the functional status of the regulatory local microenvironment, which is compromised by disease and therapeutic intervention. The glycosaminoglycan hyaluronan (HA) is a critical component of the hematopoietic microenvironment. We summarize recent advances in our understanding of the role of HA in regulating mesenchymal stem cells, osteoblasts, fibroblasts, macrophages, and endothelium in bone marrow (BM) and their crosstalk within the hematopoietic microenvironment. HA not only determines the volume, hydration, and microfluidics of the BM interstitial space, but also, via interactions with specific receptors, regulates multiple cell functions including differentiation, migration, and production of regulatory factors. The effects of HA are dependent on the polymer size and are influenced by the formation of complexes with other molecules. In healthy BM, HA synthases and hyaluronidases form a molecular network that maintains extracellular HA levels within a discrete physiological window, but HA homeostasis is often perturbed in pathological conditions, including hematological malignancies. Recent studies have suggested that HA synthases may have functions beyond HA production and contribute to the intracellular regulatory machinery. We discuss a possible role for HA synthases, intracellular and extracellular HA in the malignant BM microenvironment, and resistance to therapy.

Hyaluronic acid lipoate: synthesis and physicochemical properties.

The synthesis and physicochemical characterisation of mixed lipoic and formic esters of hyaluronan (Lipohyal) are presented in this paper. The synthesis was conducted by activating lipoic acid with 1,1'-carbonyldiimidazole to obtain lipoyl imidazolide, which reacted with hyaluronan (HA) in formamide under basic conditions. This procedure allows researchers to modulate easily the degree of substitution over a range of 0.05-1.8. Radical scavenger properties were analysed by UV-vis spectroscopy, where improved performance was demonstrated for Lipohyal with respect to the HA row material and lipoic acid. The chemical modification also causes HA to show an improved resistance to hyaluronidase digestion. These findings show that Lipohyal is a highly interesting derivative for applications in the tricological and dermo-cosmetic field and as an anti-aging ingredient. Moreover, Lipohyal can be easily crosslinked by UV irradiation, resulting in an innovative hydrogel with distinctive viscoelastic properties that is suitable as both a dermal-filler and as an intra-articular medical device.

Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinomas (PDAs) are characterized by a robust fibroinflammatory response. We show here that this desmoplastic reaction generates inordinately high interstitial fluid pressures (IFPs), exceeding those previously measured or theorized for solid tumors, and induces vascular collapse, while presenting substantial barriers to perfusion, diffusion, and convection of small molecule therapeutics. We identify hyaluronan, or hyaluronic acid (HA), as the primary matrix determinant of these barriers and show that systemic administration of an enzymatic agent can ablate stromal HA from autochthonous murine PDA, normalize IFP, and re-expand the microvasculature. In combination with the standard chemotherapeutic, gemcitabine, the treatment permanently remodels the tumor microenvironment and consistently achieves objective tumor responses, resulting in a near doubling of overall survival.