Effect of platelet-rich plasma in Achilles tendon allograft in rabbits.

BACKGROUND: Achilles tendon is composed of dense connective tissue and is one of the largest tendons in the body. In veterinary medicine, acute ruptures are associated with impact injury or sharp trauma. Healing of the ruptured tendon is challenging because of poor blood and nerve supply as well as the residual cell population. Platelet-rich plasma (PRP) contains numerous bioactive agents and growth factors and has been utilized to promote healing in bone, soft tissue, and tendons. OBJECTIVE: The purpose of this study was to evaluate the healing effect of PRP injected into the surrounding fascia of the Achilles tendon after allograft in rabbits. METHODS: Donor rabbits (n = 8) were anesthetized and 16 lateral gastrocnemius tendons were fully transected bilaterally. Transected tendons were decellularized and stored at -80°C prior to allograft. The allograft was placed on the partially transected medial gastrocnemius tendon in the left hindlimb of 16 rabbits. The allograft PRP group (n = 8) had 0.3 mL of PRP administered in the tendon and the allograft control group (n = 8) did not receive any treatment. After 8 weeks, rabbits were euthanatized and allograft tendons were transected for macroscopic, biomechanical, and histological assessment. RESULTS: The allograft PRP group exhibited superior macroscopic assessment scores, greater tensile strength, and a histologically enhanced healing process compared to those in the allograft control group. CONCLUSIONS: Our results suggest administration of PRP on an allograft tendon has a positive effect on the healing process in a ruptured Achilles tendon.

Diagnosis and management of Achilles tendon ailments: the Scottish mist.

The diagnosis and management of Achilles tendon ailments continue to be widely discussed by the scientific community. Also, the nomenclature used to describe the tendinopathic lesion in patients changed over the last decades together with the evolution in the knowledge of the physiopathology of Achilles tendinopathy, and unfortunately, through ignorance and possibly laziness, confusion still abounds. To emerge from these foggy paths, some clarifications are still necessary. The present Editorial tries to clarify some of these issues.

Early delivery of human umbilical cord mesenchymal stem cells improves healing in a rat model of Achilles tendinopathy.

Objective: This study aimed to explore the efficacy and optimal delivery time of human umbilical cord mesenchymal stem cells (hUC-MSCs) in treating collagenase-induced Achilles tendinopathy. Methods: Achilles tendinopathy in rats at early or advanced stages was induced by injecting collagenase I into bilateral Achilles tendons. A total of 28 injured rats were injected with a hUC-MSC solution or normal saline into bilateral tendons twice and sampled after 4 weeks for histological staining, gene expression analysis, transmission electron microscope assay and biomechanical testing analysis. Results: The results revealed better histological performance and a larger collagen fiber diameter in the MSC group. mRNA expression of TNF-α, IL-1ß and MMP-3 was lower after MSC transplantation. Early MSC delivery promoted collagen I and TIMP-3 synthesis, and strengthened tendon toughness. Conclusion: hUC-MSCs demonstrated a therapeutic effect in treating collagenase-induced Achilles tendinopathy, particularly in the early stage of tendinopathy.

Evaluation of Anti-Nociceptive, Anti-Inflammatory, and Anti-Fibrotic effects of noscapine against a rat model of Achilles tendinopathy.

During tendinopathy, prolonged inflammation results in fibrosis and the adherence of tendons to the adjacent tissues, causing discomfort and movement disorders. As a natural compound, noscapine has several anti-inflammatory and anti-fibrotic properties. Therefore, we aimed to investigate the effects of noscapine against a rat model of tendinopathy. We created a surgical rat model of Achilles tendon damage to emulate tendinopathy. Briefly, an incision was made on the Achilles tendon, and it was then sutured using an absorbable surgical thread. Immediately, the injured area was topically treated with the vehicle, noscapine (0.2, 0.6, and 1.8 mg/kg), or dexamethasone (0.1 mg/kg) as a positive control. During the 19-day follow-up period, animals were assessed for weight, behavior, pain, and motor coordination testing. On day 20th, the rats were sacrificed, and the tendon tissue was isolated for macroscopic scoring, microscopic (H&E, Masson's trichrome, Ki67, p53) analyses, and cytokine secretion levels. The levels of macroscopic parameters, including thermal hyperalgesia, mechanical and cold allodynia, deterioration of motor coordination, tendon adhesion score, and microscopic indices, namely histological adhesion, vascular prominence and angiogenesis, and Ki67 and p53 levels, as well as fibrotic and inflammatory biomarkers (IL-6, TNF-α, TGF-ß, VEGF) were significantly increased in the vehicle group compared to the sham group (P < 0.05-0.001 for all cases). In contrast, the administration of noscapine (0.2, 0.6, and 1.8 mg/kg) attenuated the pain, fibrosis, and inflammatory indices in a dose-dependent manner compared to the vehicle group (P < 0.05-0.001). Histological research indicated that noscapine 0.6 and 1.8 mg/kg had the most remarkable healing effects. Interestingly, two higher doses of noscapine had impacts similar to those of the positive control group in both clinical and paraclinical assessments. Taken together, our findings suggested that noscapine could be a promising medicine for treating tendinopathies.

The Transplantation of 3-Dimensional Spheroids of Adipose-Derived Stem Cells Promotes Achilles Tendon Healing in Rabbits by Enhancing the Proliferation of Tenocytes and Suppressing M1 Macrophages.

BACKGROUND: Tendons have limited regenerative potential, so healing of ruptured tendon tissue requires a prolonged period, and the prognosis is suboptimal. Although stem cell transplantation-based approaches show promise for accelerating tendon repair, the resultant therapeutic efficacy remains unsatisfactory. HYPOTHESIS: The transplantation of stem cells preassembled as 3-dimensional spheroids achieves a superior therapeutic outcome compared with the transplantation of single-cell suspensions. STUDY DESIGN: Controlled laboratory study. METHODS: Adipose-derived stem cells (ADSCs) were assembled as spheroids using a methylcellulose hydrogel system. The secretome of ADSC suspensions or spheroids was collected and utilized to treat tenocytes and macrophages to evaluate their therapeutic potential and investigate the mechanisms underlying their effects. RNA sequencing was performed to investigate the global difference in gene expression between ADSC suspensions and spheroids in an in vitro inflammatory microenvironment. For the in vivo experiment, rabbits that underwent Achilles tendon transection, followed by stump suturing, were randomly assigned to 1 of 3 groups: intratendinous injection of saline, rabbit ADSCs as conventional single-cell suspensions, or preassembled ADSC spheroids. The tendons were harvested for biomechanical testing and histological analysis at 4 weeks postoperatively. RESULTS: Our in vitro results demonstrated that the secretome of ADSCs assembled as spheroids exhibited enhanced modulatory activity in (1) tenocyte proliferation (P = .015) and migration (P = .001) by activating extracellular signal-regulated kinase (ERK) signaling and (2) the suppression of the secretion of interleukin-6 (P = .005) and interleukin-1α (P = .042) by M1 macrophages via the COX-2/PGE2/EP4 signaling axis. Gene expression profiling of cells exposed to an inflammatory milieu revealed significantly enriched terms that were associated with the immune response, cytokines, and tissue remodeling in preassembled ADSC spheroids. Ex vivo fluorescence imaging revealed that the engraftment efficiency of ADSCs in the form of spheroids was higher than that of ADSCs in single-cell suspensions (P = .003). Furthermore, the transplantation of ADSC spheroids showed superior therapeutic effects in promoting the healing of sutured stumps, as evidenced by improvements in the tensile strength (P = .019) and fiber alignment (P < .001) of the repaired tendons. CONCLUSION: The assembly of ADSCs as spheroids significantly advanced their potential to harness tenocytes and macrophages. As a proof of concept, this study clearly demonstrates the effectiveness of using ADSC spheroids to promote tendon regeneration. CLINICAL RELEVANCE: The present study lays a foundation for future clinical applications of stem cell spheroid-based therapy for the management of tendon injuries.

Anti-inflammatory effects of sericin and swimming exercise in treating experimental Achilles tendinopathy in rat.

The aim of this study was to assess the effectiveness of combining sericin with swimming exercise as a treatment for type-I collagenase-induced Achilles tendinopathy (AT) in rats, with a focus on inflammatory cytokines. An experimental AT model was established using type-I collagenase in male Sprague-Dawley rats, categorized into five groups: Group 1 (Control + Saline), Group 2 (AT), Group 3 (AT + exercise), Group 4 (AT + sericin), and Group 5 (AT + sericin + exercise). Intratendinous sericin administration (0.8 g/kg/mL) took place from days 3 to 6, coupled with 30 min daily swimming exercise sessions (5 days/week, 4 weeks). Serum samples were analyzed using ELISA for tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), interleukin-10 (IL-10), and total antioxidant-oxidant status (TAS-TOS), alongside histopathological and immunohistochemical assessments of Achilles tendon samples. Elevated TNF-α and IL-1ß and decreased IL-10 levels were evident in Group 2; Of these, TNF-α and IL-1ß were effectively reduced and IL-10 increased across all treatment groups, particularly groups 4 and 5. Serum TAS was notably lower in Group 2 and significantly increased in Group 5 compared to Group 2. Histopathologically, Group 2 displayed severe degeneration, irregular fibers, and round cell nuclei, while Group 5 exhibited decreased degeneration and spindle-shaped fibers. The Bonar score increased in Group 2 and decreased in groups 4 and 5. Collagen type-I alpha-1 (Col1A1) expression was notably lower in Group 2 (P = 0.001) and significantly increased in groups 4 and 5 compared to Group 2 (P = 0.011 and 0.028, respectively). This study underscores the potential of sericin and swimming exercises in mitigating inflammation and oxidative stress linked to AT pathogenesis, presenting a promising combined therapeutic strategy.

Histopathological and histomorphometric investigation of the effects of different irrigation solutions on Achilles tendon healing in rats.

OBJECTIVES: This study aimed to examine the effect of irrigation fluids containing povidone-iodine (PVP-I), rifampicin (RF), and chlorhexidine gluconate (CHG) used during surgery on healing on a rat Achilles tendon model. MATERIALS AND METHODS: Twenty-eight male Sprague-Dawley rats (range, 300 to 400 g) were used in the experiment carried out between November 2022 and December 2022. The rats were divided into PVP-I, RF, CHG, and control groups, with seven rats in each group. Following the tenotomy and repair of the right Achilles tendon, the surgical site was irrigated using PVP-I, RF, CHG, or normal saline (the control group) for 2 min. All rats were sacrificed on the 21st postoperative day. The samples were evaluated histomorphometrically using the scoring system modified by Svensson, Soslowsky, and Cook and histopathologically using the Bonar and Movin classifications. RESULTS: The RF group gave better results in all three scoring systems compared to the control, PVP-I, and CHG groups (p=0.008, p=0.002, and p=0.006, respectively). Cellularity, rounding, and tenocyte morphology showed a significant difference in favor of the RF group (p=0.004). While the distribution of ground substance glycosaminoglycans showed a significant difference in favor of the RF group, there was no significant difference among the other groups (p=0.22). CONCLUSION: Irrigation solutions containing PVP-I, RF, or CHG show no negative effect on Achilles tendon healing. Moreover, the findings suggest that RF irrigation can accelerate the healing process.

An immunohistochemical and biomechanical evaluation of the effect of fat graft on tendon healing.

AIM: To investigate the efficacy of fat grafting in primary tendon healing through immunohistochemical and biomechanical examinations. MATERIAL AND METHOD: The study material comprised a total of 10 male Sprague-Dawley rats, each approximately 10 weeks old. All 10 rats were operated on bilaterally. The right Achilles tendon in all the animals was defined as the study group. The tendon was cut and then repaired, and then fat graft was applied to the repair area. The left Achilles tendon of all the rats constituted the control group. The tendon was cut and repaired with no further application. After 4 weeks, the rats were euthanised and samples were taken from the tendons for immunohistochemical and biomechanical examinations. RESULTS: In the biomechanical evaluations, no statistically significant difference was determined between the groups in respect of peak load and stiffness values (p: .068, p: .089, respectively). In the histopathological evaluation, the tenocyte value of the study group was superior to that of the control group (p: .04). No statistically significant differences were determined between the groups in respect of the other histopathological parameters. In the immunohistochemical evaluations, the type I collagen and TGF values of the study group were found to be higher than those of the control group (p: .011, p: .012, respectively). CONCLUSION: Compared to stem cell applications, the use of fat grafting is clinically easy to apply, has low costs, and has been shown to contribute to tendon healing at an immunohistochemical level with increased collagen and TGF beta values.

Novel CO2-encapsulated Pluronic F127 hydrogel for the treatment of Achilles tendon injury.

Nonsurgical treatment and surgical repairment of injured Achilles tendons seldom restore the wounded tendon to its original elasticity and stiffness. Therefore, we hypothesized that the surgically repaired Achilles tendon can achieve satisfactory regeneration by applying multi-drug encapsulated hydrogels. In this study, a novel bupivacaine-eluting carbon dioxide-encapsulated Pluronic F127 hydrogel (BC-hydrogel) was developed for the treatment of Achilles tendon injuries. The rheological properties of BC-hydrogel were measured. A high-performance liquid chromatography assay was used to assess the release characteristics of bupivacaine in both in vitro and in vivo settings. Furthermore, the effectiveness of BC-hydrogel in treating torn tendons was examined in a rat model, and histological analyses were conducted. Evidently, the degradable hydrogels continuously eluted bupivacaine for more than 14 days. The animal study results revealed that the BC-hydrogel improved the post-surgery mobility of the animals compared with pristine hydrogels. Histological assay results demonstrated a significant reaction to high vascular endothelial growth factor in the surrounding tissues and expression of collagen I within the repaired tendon. This demonstrates the potential of this novel BC-hydrogel as an effective treatment method for Achilles tendon injuries.

Murine Hind Limb Explant Model for Studying the Mechanobiology of Achilles Tendon Impingement.

Tendon impingement upon bone generates a multiaxial mechanical strain environment with markedly elevated transverse compressive strain, which elicits a localized fibrocartilage phenotype characterized by accumulation of glycosaminoglycan (GAG)-rich matrix and remodeling of the collagen network. While fibrocartilage is a normal feature in impinged regions of healthy tendons, excess GAG deposition and disorganization of the collagen network are hallmark features of tendinopathy. Accordingly, impingement is clinically recognized as an important extrinsic factor in the initiation and progression of tendinopathy. Nevertheless, the mechanobiology underlying tendon impingement remains understudied. Prior efforts to elucidate the cellular response to tendon impingement have applied uniaxial compression to cells and excised tendon explants in vitro. However, isolated cells lack a three-dimensional extracellular environment crucial to mechanoresponse, and both in vitro and excised explant studies fail to recapitulate the multiaxial strain environment generated by tendon impingement in vivo, which depends on anatomical features of the impinged region. Moreover, in vivo models of tendon impingement lack control over the mechanical strain environment. To overcome these limitations, we present a novel murine hind limb explant model suitable for studying the mechanobiology of Achilles tendon impingement. This model maintains the Achilles tendon in situ to preserve local anatomy and reproduces the multiaxial strain environment generated by impingement of the Achilles tendon insertion upon the calcaneus during passively applied ankle dorsiflexion while retaining cells within their native environment. We describe a tissue culture protocol integral to this model and present data establishing sustained explant viability over 7 days. The representative results demonstrate enhanced histological GAG staining and decreased collagen fiber alignment secondary to impingement, suggesting elevated fibrocartilage formation. This model can easily be adapted to investigate different mechanical loading regimens and allows for the manipulation of molecular pathways of interest to identify mechanisms mediating phenotypic change in the Achilles tendon in response to impingement.

The Healing Effect of Biodegradable Scaffolds Treated with Bone-Marrow Obtained Mesenchymal Stem Cells on Major Tendon Damage in the Dog as a Model.

The present study aimed to evaluate the implantation of decellularized small intestinal submucosa- extracellular matrix )SIS-ECM( seeded with bone marrow mesenchymal stem cells (BM-MSCs) to repair full-thickness Achilles tendon defect. For this purpose, 20 healthy adult stray dogs aged 8-12 months old (15±3 kg of weight) were enrolled in this study under an aseptic environment and general anesthesia. A 1.5 cm-long segment-based resection was performed in the mid-substance of the Achilles tendon in the control group (n=10) that did not receive treatment. While, in the experimental group (n=10), regarding the defect of the tendon, the stumps were bridged with decellularized SIS seeded with BM-MSCs (5×106) cells implanted. Afterward, the stumps of the tendon were sutured using the modified Kessler technique (4-0) polypropylene thread. The biomechanical observations of the tendon defect showed an increase in the tensile strength in the experimental group, compared to the control animals. It should be mentioned that this difference was significant (P≤0.05). Histopathological observations of biopsies harvested after the 4th, 8th, and 12th weeks revealed that the implanted graft had seeded with MSCs enhanced high-quality cellular infiltration and the host tissue healing was improved. Similar to the normal tendon, a dense organized collagenous tissue with high cellularity and vascularity was observed due to the presence of the remodeled ECM. However, the arrangement of collagen-fiber-derived connective tissue appeared to be more dominant than that in the experimental group, with less adhesion in the 12th week post-treatment. These findings suggest that the BM-MSCs inoculated with SIS can be employed to repair a damaged Achilles tendon due to the fact that this combination enhances the regeneration of the affected tendon.

Investigation of the effects of umbilical cord-derived mesenchymal stem cells and curcumin on Achilles tendon healing - can they act synergistically?

BACKGROUND: It is known that curcumin and umbilical cord-derived mesenchymal stem cells (UC-MSCs) positively affect experi-mental tendon injury healing. This study investigated individual effects and potential synergistic effects of using curcumin and UC-MSCs alone and together. METHODS: Eighty female Wistar albino rats were randomly divided into five groups: Control, curcumin, sesame oil, MSCs, and Curcumin+MSCs groups. In all rats, punch tendon defect was created in both right and left Achilles tendons. While no additional treatment was applied to the control group, curcumin, sesame oil used as a solvent for curcumin, MSCs, and MSCs and curcumin com-bination were applied locally to the injury site, respectively, in the other groups. Curcumin was solved in sesame oil before application. In each group, half of the animals were euthanized in the post-operative 2nd week while the other half were euthanized in the post-operative 4th week. The right Achilles was used for biomechanical testing, while the left Achilles was used for histological evaluation and immunohistochemical analysis of type I, Type III collagen, and tenomodulin. RESULTS: Histologically, significant improvement was observed in the curcumin, MSCs, and Curcumin+ MSCs groups compared to the control Group in the 2nd week. In the 2nd and 4th weeks, Type III collagen was significantly increased in the curcumin group com-pared to the control group. In week 4, tenomodulin increased significantly in the curcumin and MSCs groups compared to the control group. Tendon tensile strength increased significantly in MSCs and Curcumin+MSCs groups compared to the control group in the 4th week. No superiority was observed between the treatment groups regarding their positive effects on recovery. CONCLUSION: Locally used curcumin and UC-MSCs showed positive effects that were not superior to each other in the healing of injury caused by a punch in the Achilles tendons of rats. However, synergistic effects on healing were not observed when they were applied together.

Inhibition of IKKß via a DNA-Based In Situ Delivery System Improves Achilles Tendinopathy Healing in a Rat Model.

BACKGROUND: The inhibition of IKKß by the inhibitor 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-3-pyridine carbonitrile (ACHP) is a promising strategy for the treatment of Achilles tendinopathy. However, the poor water solubility of ACHP severely hinders its in vivo application. Moreover, the effective local delivery of ACHP to the tendon and its therapeutic effects have not been reported. PURPOSE: To investigate the therapeutic effects of IKKß inhibition via injection of ACHP incorporated into a DNA supramolecular hydrogel in a collagenase-induced tendinopathy rat model. STUDY DESIGN: Controlled laboratory study. METHODS: Dendritic DNA, a Y-shaped monomer, and a crosslinking monomer were mixed with ACHP and self-assembled into an ACHP-DNA supramolecular hydrogel (ACHP-Gel). The effects of ACHP-Gel in tendon stem/progenitor cells were investigated via RNA sequencing and validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR). A total of 120 collagenase-induced rats were randomly assigned to 5 groups: blank, phosphate-buffered saline (PBS), DNA-Gel, ACHP, and ACHP-Gel. Healing outcomes were evaluated using biomechanic and histologic evaluations at 4 and 8 weeks. RESULTS: ACHP-Gel enhanced the solubility of ACHP and sustained its release for ≥21 days in vivo, which significantly increased the retention time of ACHP and markedly reduced the frequency of administration. RNA sequencing and qRT-PCR showed that ACHP effectively downregulated genes related to inflammation and extracellular matrix remodeling and upregulated genes related to tenogenic differentiation. The cross-sectional area (P = .024), load to failure (P = .002), stiffness (P = .039), and elastic modulus (P = .048) significantly differed between the ACHP-Gel and PBS groups at 8 weeks. The ACHP-Gel group had better histologic scores than the ACHP group at 4 (P = .042) and 8 weeks (P = .009). Type I collagen expression (COL-I; P = .034) and the COL-I/collagen type III ratio (P = .015) increased while interleukin 6 expression decreased (P < .001) in the ACHP-Gel group compared with the ACHP group at 8 weeks. CONCLUSION: DNA supramolecular hydrogel significantly enhanced the aqueous solubility of ACHP and increased its release-retention time. Injection frequency was markedly reduced. ACHP-Gel suppressed inflammation in Achilles tendinopathy and promoted tendon healing in a rat model. CLINICAL RELEVANCE: ACHP-Gel injection is a promising strategy for the treatment of Achilles tendinopathy in clinical practice.

Percutaneous ultrasonic debridement of equine tendinopathy and desmopathy: A report of 10 cases.

Background: Tendinopathy and desmopathy are significant causes of morbidity in horses. Aim: To evaluate the use of percutaneous ultrasonic debridement (PUD) as a treatment for chronic tendinopathy and desmopathy in the horse. Methods: Eight adult horses with 10 affected limbs presented for lameness, ranging from 60-700 days postinjury. Diagnostic ultrasound identified the following: suspensory branch desmitis (n = 1), suspensory body desmitis (n = 2), Achilles tendinopathy (n = 1), desmitis of the accessory ligament of the deep digital flexor (DDF) tendon (n = 1), DDF tendinopathy (n = 2), and superficial digital flexor tendinopathy (n = 3). All horses had demonstrated lameness ranging from grade 1 to 4 [American Association of Equine Practitioners (AAEP) scale], with a mean pretreatment grade of 2.7. All horses underwent PUD using the Tenex Health TX® System. Results: Follow-up results were available from 6 to 41 months (mean, 23.2 months). Follow-up ultrasound imaging demonstrated improvement in fiber alignment and architectural change in all cases. All horses had a reduction in lameness from the treated tendon or ligament (AAEP grade 0-1; mean AAEP grade, 0.2) following a single treatment; lameness completely resolved in 8 of 10 treated limbs. No adverse events occurred in any case. No horses in this study developed a recurrence of their original lesion. Conclusion: Horses in this study demonstrated improvement following the PUD procedure. The procedure was well-tolerated and safe. Removal of tendinopathic scar tissue with PUD resulted in a return to function and without recurrence of the original lesion in all horses.

Ultrasonographic Finding of Contralateral Achilles Tendon in Patients With Acute Achilles Tendon Rupture: A Prospective Observational Study.

OBJECTIVE: Although the incidence of contralateral Achilles tendon in patients with Achilles tendon rupture is higher than in the general population, there are no studies evaluating the status of the contralateral Achilles tendon. The aim of this study was to investigate the status of the contralateral Achilles tendon in patients with acute Achilles tendon rupture. DESIGN: Prospective observational cohort study. SETTING: University hospital foot and ankle clinic. PARTICIPANTS: Seventy-five patients with acute Achilles tendon rupture who met the inclusion criteria. INTERVENTION: Ultrasonography performed by an orthopedic surgeon who had 8 years of experience in musculoskeletal ultrasonography. MAIN OUTCOME MEASURES: Ultrasonographic abnormalities of the contralateral Achilles tendon at the time of diagnosis of acute Achilles tendon rupture. Abnormalities were categorized as intratendinous lesions, peritendinous lesions, changes in retrocalcaneal bursa, and Achilles tendon thickening. RESULTS: The maximal Achilles tendon thickness had a mean of 4.8 ± 1.0 mm. Nine patients (12%) showed ultrasonographic abnormalities on the contralateral Achilles tendon, and the presence of exertional pain was the sole associating variable with ultrasonographic abnormalities. CONCLUSION: The prevalence of ultrasonographic abnormalities in the contralateral Achilles tendon shown in this study was not higher than that reported in healthy or asymptomatic Achilles tendon. Therefore, routine evaluation of the contralateral Achilles tendon is unnecessary at the time of acute Achilles tendon rupture.

The use of platelet-rich plasma in pathologies of the foot and ankle: A comprehensive review of the recent literature.

Platelet-rich plasma (PRP) is an autologous serum containing higher concentrations of platelets and growth factors above normal blood. The process of obtaining PRP involves the extraction of blood from the patient which is then centrifuged to obtain a concentrated suspension of platelets. PRP continues to evolve as a potential treatment modality with many applications in orthopaedic surgery. The therapeutic components of PRP possess numerous theoretical regenerative properties. The present manuscript outlines how PRP is prepared, noting the tremendous variability between preparation protocols. Given the growing body of evidence examining the use of PRP in pathologies of the foot and ankle, we assess its efficacy as it relates to our field. Specifically, we evaluate the literature in the past five years regarding the role of PRP in treating plantar fasciitis, Achilles tendinopathy, insertional Achilles tendinitis, Achilles tendon ruptures, osteochondral lesions of the talus, hallux rigidus, and ankle osteoarthritis.

Verteporfin attenuates trauma-induced heterotopic ossification of Achilles tendon by inhibiting osteogenesis and angiogenesis involving YAP/ß-catenin signaling.

Heterotopic ossification occurs as a pathological ossification condition characterized by ectopic bone formation within soft tissues following trauma. Vascularization has long been established to fuel skeletal ossification during tissue development and regeneration. However, the feasibility of vascularization as a target of heterotopic ossification prevention remained to be further clarified. Here, we aimed to identify whether verteporfin as a widely used FDA-approved anti-vascularization drug could effectively inhibit trauma-induced heterotopic ossification formation. In the current study, we found that verteporfin not only dose dependently inhibited the angiogenic activity of human umbilical vein endothelial cells (HUVECs) but also the osteogenic differentiation of tendon stem cells (TDSCs). Moreover, YAP/ß-catenin signaling axis was downregulated by the verteporfin. Application of lithium chloride, an agonist of ß-catenin, recovered TDSCs osteogenesis and HUVECs angiogenesis that was inhibited by verteporfin. In vivo, verteporfin attenuated heterotopic ossification formation by decelerating osteogenesis and the vessels densely associated with osteoprogenitors formation, which could also be readily reversed by lithium chloride, as revealed by histological analysis and Micro-CT scan in a murine burn/tenotomy model. Collectively, this study confirmed the therapeutic effect of verteporfin on angiogenesis and osteogenesis in trauma-induced heterotopic ossification. Our study sheds light on the anti-vascularization strategy with verteporfin as a candidate treatment for heterotopic ossification prevention.

Mineral tessellation in mouse enthesis fibrocartilage, Achilles tendon, and Hyp calcifying enthesopathy: A shared 3D mineralization pattern.

The hallmark of enthesis architecture is the 3D compositional and structural gradient encompassing four tissue zones - tendon/ligament, uncalcified fibrocartilage, calcified fibrocartilage and bone. This functional gradient accommodates the large stiffness differential between calcified bone and uncalcified tendon/ligament. Here we analyze in 3D the organization of the mouse Achilles enthesis and mineralizing Achilles tendon in comparison to lamellar bone. We use correlative, multiscale high-resolution volume imaging methods including µCT with submicrometer resolution and FIB-SEM tomography (both with deep learning-based image segmentation), and TEM and SEM imaging, to describe ultrastructural features of physiologic, age-related and aberrant mineral patterning. We applied these approaches to murine wildtype (WT) Achilles enthesis tissues to describe in normal calcifying fibrocartilage a crossfibrillar mineral tessellation pattern similar to that observed in lamellar bone, but with greater variance in mineral tesselle morphology and size. We also examined Achilles enthesis structure in Hyp mice, a murine model for the inherited osteomalacic disease X-linked hypophosphatemia (XLH) with calcifying enthesopathy. In Achilles enthesis fibrocartilage of Hyp mice, we show defective crossfibrillar mineral tessellation similar to that which occurs in Hyp lamellar bone. At the cellular level in fibrocartilage, unlike in bone where enlarged osteocyte mineral lacunae are found as peri-osteocytic lesions, mineral lacunar volumes for fibrochondrocytes did not differ between WT and Hyp mice. While both WT and Hyp aged mice demonstrate Achilles tendon midsubstance ectopic mineralization, a consistently defective mineralization pattern was observed in Hyp mice. Strong immunostaining for osteopontin was observed at all mineralization sites examined in both WT and Hyp mice. Taken together, this new 3D ultrastructural information describes details of common mineralization trajectories for enthesis, tendon and bone, which in Hyp/XLH are defective.

Irreversible Electroporation Improves Tendon Healing in a Rat Model of Collagenase-Induced Achilles Tendinopathy.

BACKGROUND: Treatment of painful chronic tendinopathy is challenging, and there is an urgent need to develop new regenerative methods. Irreversible electroporation (IRE) can lead to localized cell ablation by electrical pulses and induce new cell and tissue growth. Previously, the authors' group reported that electroporation-ablated tendons fully regenerated. PURPOSE: To assess the efficiency of IRE in improving tendon healing using a collagenase-induced Achilles tendinopathy rat model. STUDY DESIGN: Controlled laboratory study. METHODS: After screening for the IRE ablation parameters, a collagenase-induced Achilles tendinopathy rat model was used to assess the efficacy of IRE in improving tendon healing via biomechanical, behavioral, histological, and immunofluorescence assessments. RESULTS: The experiments showed that the parameter of 875 V/cm 180 pulses could ablate most tenocytes, and apoptosis was the main type of death in vitro. In vivo, IRE promoted the healing process of chronic tendinopathy in the Achilles tendon of rats, based on biomechanical, behavioral, and histological assessments. Finally, immunofluorescence results revealed that IRE improved blood supply in the early stages of tendon repair and could potentially reduce neuropathic pain. CONCLUSION: IRE enhanced tendon tissue healing in a rat model of collagenase-induced Achilles tendinopathy. CLINICAL RELEVANCE: IRE may as a potential alternative treatment for tendinopathy in clinical usage.

Overload in a Rat In Vivo Model of Synergist Ablation Induces Tendon Multiscale Structural and Functional Degeneration.

Tendon degeneration is typically described as an overuse injury with little distinction made between magnitude of load (overload) and number of cycles (overuse). Further, in vivo, animal models of tendon degeneration are mostly overuse models, where tendon damage is caused by a high number of load cycles. As a result, there is a lack of knowledge of how isolated overload leads to degeneration in tendons. A surgical model of synergist ablation (SynAb) overloads the target tendon, plantaris, by ablating its synergist tendon, Achilles. The objective of this study was to evaluate the structural and functional changes that occur following overload of plantaris tendon in a rat SynAb model. Tendon cross-sectional area (CSA) and shape changes were evaluated by longitudinal MR imaging up to 8 weeks postsurgery. Tissue-scale structural changes were evaluated by semiquantified histology and second harmonic generation microscopy. Fibril level changes were evaluated with serial block face scanning electron microscopy (SBF-SEM). Functional changes were evaluated using tension tests at the tissue and microscale using a custom testing system allowing both video and microscopy imaging. At 8 weeks, overloaded plantaris tendons exhibited degenerative changes including increases in CSA, cell density, collagen damage area fraction (DAF), and fibril diameter, and decreases in collagen alignment, modulus, and yield stress. To interpret the differences between overload and overuse in tendon, we introduce a new framework for tendon remodeling and degeneration that differentiates between the inputs of overload and overuse. In summary, isolated overload induces multiscale degenerative structural and functional changes in plantaris tendon.