• 3D printing
• Anterior cruciate ligament
• Biomechanics
• Hydroxyapatite
• PLLA
• Tendon-bone healing

• anterior cruciate ligament
• biomechanical
• collagen sponges
• tendon-bone healing

• Biceps tenodesis
• Biceps tenotomy
• Biceps-labral complex
• Long head of the biceps tendon
• Shoulder pathology
• Superior labrum anterior to posterior lesions

• anterior cruciate ligament
• biological augmentation
• reconstruction
• results

• Anterior Cruciate Ligament/drug effects
• Anterior Cruciate Ligament/physiopathology
• Anterior Cruciate Ligament/surgery
• Anterior Cruciate Ligament/transplantation
• Anterior Cruciate Ligament Injuries/drug therapy
• Anterior Cruciate Ligament Injuries/physiopathology
• Anterior Cruciate Ligament Injuries/surgery
• Anterior Cruciate Ligament Reconstruction/methods
• Bone Substitutes/therapeutic use
• Genetic Therapy/trends
• Humans
• Hyperbaric Oxygenation/methods
• Intercellular Signaling Peptides and Proteins/therapeutic use
• Mesenchymal Stem Cell Transplantation
• Transplantation, Autologous

Bone formation plays an important role in early tendon–bone healing after anterior cruciate ligament reconstruction (ACLR). Dedifferentiated osteogenic bone marrow mesenchymal stem cells (De-BMSCs) have enhanced osteogenic potential. This study aimed to investigate the effect of De-BMSCs transplantation on the promotion of bone formation at the tendon–bone interface after ACLR and to further explore the molecular mechanism of the enhanced osteogenic potential of De-BMSCs.

BMSCs from the femurs and tibias of New Zealand white rabbits were subjected to osteogenic induction and then cultured in medium without osteogenic factors; the obtained cell population was termed De-BMSCs. De-BMSCs were induced to undergo osteo-, chondro- and adipo-differentiation in vitro to examine the characteristics of primitive stem cells. An ACLR model with a semitendinosus tendon was established in rabbits, and the animals were divided into a control group, BMSCs group, and De-BMSCs group. At 12 weeks after surgery, the rabbits in each group were sacrificed to evaluate tendon–bone healing by histologic staining, micro-computed tomography (micro-CT) examination, and biomechanical testing. During osteogenic differentiation of De-BMSCs, an siRNA targeting nuclear factor of activated T-cells 1 (NFATc1) was used to verify the molecular mechanism of the enhanced osteogenic potential of De-BMSCs.

De-BMSCs exhibited some properties similar to BMSCs, including multiple differentiation potential and cell surface markers. Bone formation at the tendon–bone interface in the De-BMSCs group was significantly increased, and biomechanical strength was significantly improved. During the osteogenic differentiation of De-BMSCs, the expression of Nanog and NFATc1 was synergistically increased, which promoted the interaction of NFATc1 and Osterix, resulting in increased expression of osteoblast marker genes such as COL1A, OCN, and OPN.

De-BMSCs transplantation could promote bone formation at the tendon–bone interface after ACLR and improve the biomechanical strength of the reconstruction. The Nanog/NFATc1/Osterix signaling pathway mediated the enhanced osteogenic differentiation efficiency of De-BMSCs.

The online version contains supplementary material available at 10.1186/s13287-021-02643-9.

• Anterior cruciate ligament
• BMSCs
• Dedifferentiation
• Osteogenic differentiation
• Tendon–bone healing

• Rotator cuff repair
• biomaterial
• interfacial tissue engineering
• stem cells

The study investigated whether allogeneic human umbilical cord blood-derived MSCs (hUCB-MSCs) could be safely used without treatment-related adverse events, reducing tunnel enlargement, and improve clinical results in human anterior cruciate ligament (ACL) reconstruction.

Thirty patients were enrolled consecutively. They were divided into three groups by randomization. In the negative control group, ACL reconstruction surgery without additional treatment was performed. In the experimental group, a hUCB-MSC and hyaluronic acid mixture was applied to the tendon-bone interface of the femoral tunnels during ACL reconstruction surgery. In the positive control group, only hyaluronic acid was applied. Finally, 27 patients were analyzed after the exclusion of three patients. The incidence of treatment-related adverse events, clinical outcomes, including second-look arthroscopic findings, and the amount of tunnel enlargement, were evaluated.

There were no treatment-related adverse events in the treatment groups. Tunnel enlargement in the experimental group (579.74 ± 389.85 mm³) was not significantly different from those in the negative (641.97 ± 455.84 mm³) and positive control (421.96 ± 274.83 mm³) groups (p = 0.6468). There were no significant differences between the groups in clinical outcomes such as KT-2000 measurement (p = 0.793), pivot shift test (p = 0.9245), International Knee Documentation Committee subjective score (p = 0.9195), Tegner activity level (p = 0.9927), and second-look arthroscopic findings (synovial coverage of the graft, p = 0.7984; condition of the graft, p = 0.8402).

Allogeneic hUCB-MSCs were used safely for ACL reconstruction without treatment-related adverse event in a 2-year follow-up. However, our study did not suggest any evidence to show clinical advantage such as the prevention of tunnel enlargement postoperatively and a decrease in knee laxity or improvement of clinical outcomes.

CRIS, Registration Number: KCT0000917. Registered on 12 November 2013; https://cris.nih.go.kr/cris/index.jsp

• Anterior cruciate ligament
• Healing
• Human umbilical cord blood-derived mesenchymal stem cell
• Randomized control trial
• Stem cell
• Tendon graft healing

Graft regeneration after anterior cruciate ligament (ACL) reconstruction surgery is a complex three-stage process, which usually takes a long duration and often results in fibrous scar tissue formation that exerts a detrimental impact on the patients' prognosis. Hence, as a regeneration technique, stem cell transplantation has attracted increasing attention. Several different stem cell types have been utilized in animal experiments, and almost all of these have shown good capacity in improving tendon-bone regeneration. Various differentiation inducers have been widely applied together with stem cells to enhance specific lineage differentiation, such as recombinant gene transfection, growth factors, and biomaterials. Among the various different types of stem cells, bone marrow-derived mesenchymal stem cells (BMSCs) have been investigated the most, while ligament stem progenitor cells (LDSCs) have demonstrated the best potential in generating tendon/ligament lineage cells. In the clinic, 4 relevant completed trials have been reported, but only one trial with BMSCs showed improved outcomes, while 5 relevant trials are still in progress. This review describes the process of ACL graft regeneration after implantation and summarizes the current application of stem cells from bench to bedside, as well as discusses future perspectives in this field.

• Anterior cruciate ligament
• Bone
• Rotator cuff
• Stem cell
• Tendon

Fibrocartilage transition zone (FC) is difficult to regenerate after surgical re-attachment of tendon to bone. Here, we investigated whether type II collagen-sponges (CII-sponges) facilitated tendon stem/progenitor cells (TSPCs) to adopt chondrogenic phenotypes and further observed if this material could increase the FC areas in bone-tendon junction (BTJ) injury model.

CII-sponges were made as we previously described. The appearance and pore structure of CII-sponges were photographed by camera and microscopies. The viability, proliferation, and differentiation of TSPCs were examined by LIVE/DEAD assay, alamarBlue, and PKH67 in vitro tracking. Subsequently, TSPCs were seeded in CII-sponges, Matrigel or monolayer, and induced under chondrogenic medium for 7 or 14 days before being harvested for qPCR or being transplanted into nude mice to examine the chondrogenesis of TSPCs. Lastly, partial patellectomy (PP) was applied to establish the BTJ injury model. CII-sponges were interposed between the patellar fragment and tendon, and histological examination was used to assess the FC regeneration at BTJ after surgery at 8 weeks.

CII-sponges were like sponges with interconnected pores. TSPCs could adhere, proliferate, and differentiate in this CII-sponge up to 14 days at least. Both qPCR and immunostaining data showed that compared with TSPCs cultured in monolayer or Matrigel, cells in CII-sponges group adopted more chondrogenic phenotypes with an overall increase of chondrocyte-related genes and proteins. Furthermore, in PP injured model, much more new formed cartilage-like tissues could be observed in CII-sponges group, evidenced by a large amount of positive proteoglycan expression and typical oval or round chondrocytes in this area.

Our study showed that CII-sponges facilitated the TSPCs to differentiate toward chondrocytes and increased the area of FCs, which suggests that CII-sponges are meaningful for the reconstruction of FC at bone tendon junction. However, the link between the two phenomena requires further research and validation.

• bone tendon junction
• chondrogenesis
• fibrocartilage transition zones
• tendon stem and progenitor cells
• type II collagen sponges

• anterior cruciate ligament
• knee

Anterior cruciate ligament (ACL) reconstruction was realized using a combination of bone mesenchymal stem cells (BMSCs) and silk–collagen scaffold, and an in vivo evaluation of this combination was performed. By combining type I collagen and degummed silk fibroin mesh, silk–collagen scaffolds were prepared to simulate ligament components. BMSCs isolated from bone marrow of rabbits were cultured for a homogenous population and seeded on the silk–collagen scaffold. In the scaffold and BMSC (S/C) group, scaffolds were seeded with BMSCs for 72 h and then rolled and used to replace the ACL in 20 rabbits. In the scaffold (S) group, scaffolds immersed only in culture medium for 72 h were used for ACL reconstruction. Specimens were collected at 4 and 16 weeks postoperatively to assess ligament regeneration and bone integration. HE and immunohistochemical staining (IHC) were performed to assess ligament regeneration in the knee cavity. To assess bone integration at the graft–bone interface, HE, Russell–Movat staining, micro-CT, and biomechanical tests were performed. After 4 weeks, vigorous cell proliferation was observed in the core part of the scaffold in the S/C group, and a quantity of fibroblast-like cells and extracellular matrix (ECM) was observed in the center part of the graft at 16 weeks after surgery. At 4 and 16 weeks postoperatively, the tenascin-C expression in the S/C group was considerably higher than that in the S group (4 w, p < 0.01; 16 w, p < 0.01). Furthermore, bone integration was better in the S/C group than in the S group, with histological observation of trabecular bone growth into the graft and more mineralized tissue formation detected by micro-CT (4 w, bone volume fraction (BV/TV), p = 0.0169, bone mineral density (BMD), p = 0.0001; 16 w, BV/TV, p = 0.1233, BMD, p = 0.0494). These results indicate that BMSCs promote ligament regeneration in the knee cavity and bone integration at the graft–bone interface. Silk–collagen scaffolds and BMSCs will likely be combined for clinical practice in the future.

• exosomes
• extracellular vesicles
• mesenchymal stem cells
• microvesicles
• regenerative medicine
• secretome
• veterinary

• Animals
• Cryopreservation
• Disease Models, Animal
• Mesenchymal Stem Cells/cytology
• Musculoskeletal Diseases/therapy
• Musculoskeletal Diseases/veterinary
• Regenerative Medicine
• Veterinary Medicine

• Autologous stem cells
• Biologic augmentation
• PRP
• UCL

Tendon-bone interface healing and ligamentization of the graft in anterior cruciate ligament (ACL) reconstruction with autografts are important factors affecting treatment outcome. This study aimed to investigate the effectiveness of a cylindrical titanium-web (TW) in tendon-bone interface healing and graft maturation in ACL reconstruction.

Fourteen mature female CLAWN miniature swine underwent bilateral ACL reconstructions with patellar tendon (PT) autografts. In one limb, the TW/tendon complex was placed into the proximal side of the tibial tunnel. Only the graft was transplanted into the tunnel in the control limb. The proximal side of the graft was sutured into the stump of the native ACL and the distal end was stapled to the tibia. The animals were euthanized at 4 and 15 weeks postoperatively, for histological and biochemical analyses.

Microscopic images in TW limbs showed that ingrowth of tendon-like tissue and mineralized bone tissue into the TW connected the bone and the tendon directly. In contrast, fibrous tissue intervened between the bone and tendon in the control limbs. The total amount of collagen cross-links (which defines the strength of collagen fibers) and the maturation of collagen cross-links in TW tendons were significantly higher (p < 0.05) than those of control limbs. There was no significant difference in the ratio of dihydroxy-lysinonorleucine to hydroxy-lysinonorleucine (an indicator of tissue specific collagen maturation) between TW tendons and that of the native PT.

TW promoted the maturation and formation of collagen cross-links in the grafted tendon while maintaining the cross-links pattern of native tendon collagen, and enabled direct binding of tendon to bone.

• ACL reconstruction
• Collagen maturation
• Enthesis
• Ligamentization
• Miniature swine
• Tendon-bone interface
• Titanium-web

A poly (l-lactic) acid bioengineered anterior cruciate ligament (ACL) matrix has previously demonstrated the ability to support tissue regeneration in a rabbit ACL reconstruction model. The matrix was designed for optimal bone and ligament regeneration by developing a matrix with differential pore sizes in its bone and ligament compartments. Building upon past success, we designed a new bioengineered ACL matrix that is easier to install and can be used with endobutton fixation during ACL reconstruction. To achieve this, a new braiding procedure was developed to allow the matrix to be folded in half, making two-limbs, while maintaining its bone and ligament compartments. The osteointegration of the matrix with and without bone morphogenetic protein 2 (BMP-2) supplementation was evaluated in a rabbit ACL reconstruction model. Two doses of BMP-2 were evaluated, 1 and 10 μg, and delivered by saline injection into the bone tunnel at the end of surgery. A fibrous matrix-to-bone interface with occasional Sharpey’s fibers was the primary mode of osteointegration observed. The matrix was also found to support a fibrocartilage matrix-to-bone interface. In some cases, the presence of chondrocyte-like cells was observed at the aperture of the bone tunnel and the center of the matrix within the bone tunnel. Treatment with BMP-2 was associated with a trend towards smaller bone tunnel cross-sectional areas, and 1 μg of BMP-2 was found to significantly enhance osteoid seam width in comparison with no BMP-2 or 10 μg of BMP-2 treatment. Regenerated tissue was well organized within the bioengineered ACL matrix and aligned with the poly (l-lactic) acid fibers. Disorganized tissue was found between the two-limbs of the bioengineered ACL matrix and hypothesized to be due to a lack of structural scaffolding. This study suggests that the bioengineered ACL matrix can undergo similar modes of osteointegration as current autografts and allografts, and that BMP-2 treatment may enhance osteoblastic activity within the bone tunnels.

• Animals
• Anterior Cruciate Ligament/diagnostic imaging
• Anterior Cruciate Ligament/surgery
• Anterior Cruciate Ligament Injuries/surgery
• Anterior Cruciate Ligament Reconstruction/instrumentation
• Anterior Cruciate Ligament Reconstruction/methods
• Bone Morphogenetic Protein 2/administration & dosage
• Disease Models, Animal
• Feasibility Studies
• Humans
• Materials Testing
• Microscopy, Electron, Scanning
• Osseointegration/drug effects
• Polyesters/chemistry
• Rabbits
• Recombinant Proteins/administration & dosage
• Tibia/diagnostic imaging
• Tibia/physiology
• Tibia/surgery
• Tissue Engineering
• Tissue Scaffolds/chemistry
• X-Ray Microtomography

• DP1 AR068147 NIAMS NIH HHS
• R01 AR063698 NIAMS NIH HHS
• National Institute of Arthritis and Musculoskeletal and Skin Diseases

• Anterior Cruciate Ligament
• Anterior Cruciate Ligament Reconstruction
• Orthopedics
• Osseointegration

• Biologics
• Ligament reconstruction
• Ligament repair
• Orthopedics
• Stem cells
• Stromal cells

• ACL reconstruction
• ACL regeneration
• cell sheet
• knitted silk-collagen sponge scaffold
• ligament stem/progenitor cells
• osteoarthritis prevention

Treatment of anterior cruciate ligament injuries commonly involves the use of polyethylene terephthalate (PET) artificial ligaments for reconstruction. However, the currently available methods require long fixation periods, thereby necessitating the development of alternative methods to accelerate the healing process between tendons and bones. Thus, we developed and evaluated a novel technique that utilizes silicate-substituted strontium (SrSiP).

PET films, nano-coated with SrSiP, were prepared. Bone marrow mesenchymal cells (BMSCs) from femurs of male rats were cultured and seeded at a density of 1.0 × 10⁴/cm² onto the SrSiP-coated and non-coated PET film, and subsequently placed in an osteogenic medium. The osteocalcin concentration secreted into the medium was compared in each case. Next, PET artificial ligament, nano-coated with SrSiP, were prepared. BMSCs were seeded at a density of 4.5 × 10⁵/cm² onto the SrSiP-coated, and non-coated artificial ligament, and then placed in osteogenic medium. The osteocalcin and calcium concentrations in the culture medium were measured on the 8th, 10th, 12th, and 14th day of culture. Furthermore, mRNA expression of osteocalcin, alkaline phosphatase (ALP), bone morphogenetic protein-2 (BMP2), and runt-related transcription factor 2 (Runx2) was evaluated by qPCR. We transplanted the SrSiP-coated and non-coated artificial ligament to the tibiae of mature New Zealand white rabbits. Two months later, we sacrificed them and histologically evaluated them.

The secretory osteocalcin concentration in the medium on the film was significantly higher for the SrSiP group than for the non-coated group. Secretory osteocalcin concentration in the medium on the artificial ligament was also significantly higher in the SrSiP group than in the non-coated group on the 14th day. Calcium concentration on the artificial ligament was significantly lower in the SrSiP group than in the non-coated group on the 8th, 10th, 12th, and 14th day. In qPCR as well, OC, ALP, BMP2, and Runx2 mRNA expression were significantly higher in the SrSiP group than in the non-coated group. Newly formed bone was histologically found around the artificial ligament in the SrSiP group.

Our findings demonstrate that artificial ligaments using SrSiP display high osteogenic potential and thus may be efficiently used in future clinical applications.

• Anterior cruciate ligament injuries
• Nano coating
• Osteogenesis
• PET artificial ligament
• Silicate-substituted strontium

The study investigated the effect of mesenchymal stem cells (MSCs) or fibrin glue on tunnel widening after anterior cruciate ligament (ACL) reconstruction compared with biologic free control without any biologic agents in the rabbit model.

ACL reconstructions were performed in 18 New Zealand white rabbits. All animals were divided into 3 groups according to the following reconstruction conditions and euthanized 12 weeks postoperatively for radiologic and histologic analyses. Thirty-two knees (control group=10; fibrin group=11; MSCs group=11) were finally evaluated. On micro-CT scan, mean femoral tunnel widening on oblique-sagittal image was 0.7±0.4 mm in the control group, 0.22±0.1 mm in the fibrin group and 0.25±0.1 mm in the MSCs group (p=0.001). Fibrin group and MSCs group showed significant differences compared with control group (p=0.002, 0.002). Mean tibial tunnel widening on oblique-sagittal image was 0.76±0.5 mm, 0.27±0.1 mm and 0.29±0.2 mm in the control, fibrin and MSCs group. Fibrin and MSCs group showed significant differences compared with control group (p=0.017, 0.014). Hounsfield Units (HU) were not significantly different between 3 groups (p>0.05). Histological analysis revealed that the architecture of graft in the MSCs group featured hypercellularity and compact collagen deposit.

ACL reconstruction using MSCs seemed decrease tunnel widening in rabbit model. Further study with large animals is required to confirm efficacy on decreasing tunnel widening.

• Anterior cruciate ligament
• Mesenchymal stem cell
• Rabbit model
• Tunnel widening

This article provides a detailed narrative review on the history and current concepts surrounding ligamentous repair techniques in athletic patients. In particular, we will focus on the anterior cruciate ligament (ACL) as a case study in ligament injury and ligamentous repair techniques. PubMed (MEDLINE), EMBASE and Cochrane Library databases for papers relating to primary anterior cruciate ligament reconstruction were searched by all participating authors. All relevant historical papers were included for analysis. Additional searches of the same databases were made for papers relating to biological enhancement of ligament healing.

The poor capacity of the ACL to heal is one of the main reasons why the current gold standard surgical treatment for an ACL injury in an athletic patient is ACL reconstruction with autograft from either the hamstrings or patella tendon. It is hypothesised that by preserving and repairing native tissues and negating the need for autograft that primary ACL repair may represent a key step change in the treatment of ACL injuries.

The history of primary ACL repair will be discussed and the circumstances that led to the near-abandonment of primary ACL repair techniques will be reviewed.

There has been a recent resurgence in interest with regards to primary ACL repair. Improvements in imaging now allow for identification of tear location, with femoral-sided injuries, being more suitable for repair. We will discuss in details strategies for improving the mechanical and biological environment in order to allow primary healing to occur.

In particular, we will explain mechanical supplementation such as Internal Brace Ligament Augmentation and Dynamic Intraligamentary Stabilisation techniques. These are novel techniques that aim to protect the primary repair by providing a stabilising construct that connects the femur and the tibia, thus bridging the repair.

In addition, biological supplementation is being investigated as an adjunct and we will review the current literature with regards to bio-enhancement in the form platelet rich plasma, bio-scaffolds and stem cells. On the basis of current evidence, there appears to be a role for bio-enhancement, however, this is not yet translated into clinical practice.

Several promising avenues of further research now exist in the form of mechanical and biological augmentation techniques. Further work is clearly needed but there is renewed interest and focus for primary ACL repair that may yet prove the new frontier in ligament repair.

• Anterior
• Athletes
• Cruciate
• Ligament
• Primary
• Reconstruction
• Repair

• Animals
• Bone Screws
• Cortical Bone
• Models, Animal
• Rabbits
• Tenodesis/methods
• Time Factors
• Upper Extremity
• Wound Healing
• X-Ray Microtomography

• T32 AR007281 NIAMS NIH HHS

• anterior cruciate ligament
• biomechanical
• deproteinized bovine bone
• grade score
• osteoprotegerin
• sharpey fibers

Bone marrow mesenchymal stem cells (BM-MSCs) are multipotent adult stem cells and have become an important source of cells for engineering tissue repair and cell therapy. Vascular endothelial growth factor (VEGF) promotes angiogenesis and contributes fibrous integration between tendon and bone during the early postoperative stage. Both MSCs and VEGF can stimulate cell proliferation, differentiation, and matrix deposition by enhancing angiogenesis and osteogenesis of the graft in the tunnel.

Injection of intratunnel BM-MSCs and VEGF enhances the early healing process of a tendon graft.

Controlled laboratory study.

In this controlled animal laboratory study, each of 4 groups of rabbits underwent unilateral anterior cruciate ligament (ACL) reconstruction with use of the ipsilateral semitendinosus tendon. The rabbits received intratunnel injection of BM-MSCs and VEGF with a fibrin glue seal covering the distal tunnel at the articular site. Evaluation using magnetic resonance imaging (MRI), collagen type III expression, and biomechanical analyses were performed at 3- and 6-week intervals.

All parameters using MRI, collagen type III expression, and biomechanical analysis of pullout strength of the graft showed that application of intratunnel BM-MSCs and VEGF enhanced tendon-to-bone healing after ACL reconstruction.

Intratunnel injections of BM-MSCs and VEGF after ACL reconstruction enhanced graft tunnel healing. Overall, the femoral tunnel that received BM-MSCs and VEGF had better advanced healing with increased collagen type III fibers and better outcomes on MRI and biomechanical analysis. MRI is the most reliable tool for clinical use in evaluating stages of ACL healing after reconstruction, since biopsy is an invasive procedure.

• anterior cruciate ligament
• bone marrow mesenchymal stem cell
• graft tunnel healing
• vascular endothelial growth factor

• anterior cruciate ligament reconstruction
• biological enhancement
• graft-tunnel healing
• physical stimulation

• BMSC
• fibroblast
• fibrocartilage
• interface
• osteoblast
• tri-culture

• biological augmentation
• biomaterials
• growth factors
• rotator cuff repair
• stem cell therapies

Successful rotator cuff repair requires biological anchoring of the repaired tendon to the bone. However, the histological structure of the repaired tendon-bone interface differs from that of a normal tendon insertion. We analysed differences between the normal tendon insertion and the repaired tendon-bone interface after surgery in the mechanical properties, histomorphometric analysis, and 3-dimensional ultrastructure of the cells using a rat rotator cuff repair model. Twenty-four adult Sprague-Dawley (SD) rats underwent complete cuff tear and subsequent repair of the supraspinatus tendon. The repaired tendon-bone interface was evaluated at 4, 8, and 12 weeks after surgery. At each time point, shoulders underwent micro-computed tomography scanning and biomechanical testing (N = 6), conventional histology and histomorphometric analysis (N = 6), and ultrastructural analysis with focused ion beam/scanning electron microscope (FIB/SEM) tomography (N = 4). We demonstrated that the cellular distribution between the repaired tendon and bone at 12 weeks after surgery bore similarities to the normal tendon insertion. However, the ultrastructure of the cells at any time point had a different morphology than those of the normal tendon insertion. These morphological differences affect the healing process, partly contributing to re-tearing at the repair site. These results may facilitate future studies of the regeneration of a normal tendon insertion.

Many strategies, including various growth factors and gene transfer, have been used to augment healing after anterior cruciate ligament (ACL) reconstruction. The biological environment regulated by the growth factors during the stage of tendon-bone healing was considered important in controlling the integrating process. The purpose of this study was to evaluate the effects of bone marrow-derived mesenchymal stem cells (BMSCs) genetically modified with bone morphogenetic protein 2 (BMP2) and basic fibroblast growth factor (bFGF) on healing after ACL reconstruction. BMSCs were infected with an adenoviral vector encoding BMP2 (AdBMP2) or bFGF (AdbFGF). Then, the infected BMSCs were surgically implanted into the tendon-bone interface. At 12 weeks postoperatively, the formation of abundant cartilage-like cells, smaller tibial bone tunnel and significantly higher ultimate load and stiffness levels, through histological analysis, micro-computed tomography and biomechanical testing, were observed. In addition, the AdBMP2-plus-AdbFGF group had the smallest bone tunnel and the best mechanical properties among all the groups. The addition of BMP2 or bFGF by gene transfer resulted in better cellularity, new bone formation and higher mechanical property, which contributed to the healing process after ACL reconstruction. Furthermore, the co-application of these two genes was more powerful and efficient than either single gene therapy.

• Anterior cruciate ligament
• Sadat-Habdan mesenchymal stimulating peptide
• healing growth factor

• Bridging patch
• Rotator cuff repair
• Tendon-to-bone healing

• Allografts
• Animals
• Biomechanical Phenomena
• Dogs
• Fibrocartilage/transplantation
• In Vitro Techniques
• Models, Animal
• Orthopedic Procedures/methods
• Patella/transplantation
• Patellar Ligament/transplantation
• Rotator Cuff/surgery
• Rotator Cuff Injuries
• Sutures
• Tensile Strength

• R01 AR057745 NIAMS NIH HHS
• AR57745 NIAMS NIH HHS

The major concern of using a large animal model to study rotator cuff repair is the high rate of repair retears. The purpose of this study was to test a non-weight-bearing (NWB) canine model for rotator cuff repair research.

First, in the in vitro study, 18 shoulders were randomized to 3 groups. 1) Full-width transections repaired with modified Mason-Allen sutures using 3-0 polyglactin suture, 2) Group 1 repaired using number 2 (#2) polyester braid and long-chain polyethylene suture, and 3) Partial-width transections leaving the superior 2 mm infraspinatus tendon intact without repair. In the in vivo study of 6 dogs, the infraspinatus tendon was partially transected as the same as the in vitro group 3. A radial neurectomy was performed to prevent weight bearing. The operated limb was slung in a custom-made jacket for 6 weeks.

In the in vitro study, mean ultimate tensile load and stiffness in Group 2 were significantly higher than Group 1 and 3 (p<0.05). In the in vivo study, gross inspection and histology showed that the preserved superior 2-mm portion of the infraspinatus tendon remained intact with normal structure.

Based on the biomechanical and histological findings, this canine NWB model may be an appropriate and useful model for studies of rotator cuff repair.

• Animals
• Arthroplasty/methods
• Biomechanical Phenomena
• Disease Models, Animal
• Dogs
• Humans
• Radial Nerve/surgery
• Rotator Cuff/innervation
• Rotator Cuff/surgery
• Shoulder Dislocation/surgery
• Stress, Mechanical
• Suture Techniques
• Sutures
• Tendons/innervation
• Tendons/surgery
• Tensile Strength
• Weight-Bearing
• Wound Healing/physiology

• R01 AR057745 NIAMS NIH HHS
• AR57745 NIAMS NIH HHS

• Biologic
• Enthesis
• Rotator cuff
• Stem cells

• Animals
• Anterior Cruciate Ligament/surgery
• Anterior Cruciate Ligament Reconstruction/methods
• Autografts
• Collagen
• Disease Models, Animal
• Male
• Rabbits
• Silk
• Time Factors
• Tissue Scaffolds
• Treatment Outcome
• Wound Healing
• X-Ray Microtomography

• collagen
• complex tissue engineering
• mesenchymal stem cell
• microencapsulation
• spinal motion segment

Purpose. In this study, the early and midterm clinical and radiological results of the anterior cruciate ligament (ACL) reconstruction surgery with or without the use of platelet rich plasma (PRP) focusing on the tunnel-widening phenomenon are evaluated. Methods. This is a double blind, prospective randomized study. 51 patients have completed the assigned protocol. Recruited individuals were divided into two groups: a group with and a group without the use of PRPs. Patients were assessed on the basis of MRI scans, which were performed early postoperatively and repeated at least one-year postoperatively. The diameter was measured at the entrance, at the bottom, and at the mid distance of the femoral tunnel. Results. Our study confirmed the existence of tunnel widening as a phenomenon. The morphology of the dilated tunnels was conical in both groups. There was a statistical significant difference in the mid distance of the tunnels between the two groups. This finding may support the role of a biologic response secondary to mechanical triggers. Conclusions. The use of RPRs in ACL reconstruction surgery remains a safe option that could potentially eliminate the biologic triggers of tunnel enlargement. The role of mechanical factors, however, remains important.

The objective of this study was to investigate whether intermittent administration of parathyroid hormone [1–34] (PTH[1–34]) promotes tendon-bone healing after anterior cruciate ligament (ACL) reconstruction in vivo. A rat model of ACL reconstruction with autograft was established at the left hind leg. Every day, injections of 60 μg PTH[1–34]/kg subcutaneously were given to the PTH group rats (n = 10) for four weeks, and the controls (n = 10) received saline. The tendon-bone healing process was evaluated by micro-CT, biomechanical test, histological and immunohistochemical analyses. The effects of PTH[1–34] on serum chemistry, bone microarchitecture and expression of the PTH receptor (PTH1R) and osteocalcin were determined. Administration of PTH[1–34] significantly increased serum levels of calcium, alkaline phosphatase (AP), osteocalcin and tartrate-resistant acid phosphatase (TRAP). The expression of PTH1R on both osteocytes and chondrocyte-like cells at the tendon-bone interface was increased in the PTH group. PTH[1–34] also enhanced the thickness and microarchitecture of trabecular bone according to the micro-CT analysis. The results imply that systematically intermittent administration of PTH[1–34] promotes tendon-bone healing at an early stage via up-regulated PTH1R. This method may enable a new strategy for the promotion of tendon-bone healing after ACL reconstruction.

• Adipose-derived stem-cell
• Cell therapy
• Celula troncal derivada de lipoaspirado
• Experimental
• Manguito rotador
• Repair
• Reparación
• Supraspinatus
• Terapia celular

This study sought to determine if direct application of the lentiviral (LV)-cyclooxygenase 2 (COX2) vector to the tendon-bone interface would promote osteointegration of the tendon graft in a rat model of biceps tenodesis. The LV-COX2 gene transfer strategy was chosen for investigation because a similar COX2 gene transfer strategy promoted bony bridging of the fracture gap during bone repair, which involves similar histologic transitions that occur in osteointegration. Briefly, a 1.14-mm diameter tunnel was drilled in the mid-groove of the humerus of adult Fischer 344 rats. The LV-COX2 or βgal control vector was applied directly into the bone tunnel and onto the end of the tendon graft, which was then pulled into the bone tunnel. A poly-L-lactide pin was press-fitted into the tunnel as interference fixation. Animals were sacrificed at 3, 5, or 8 weeks for histology analysis of osteointegration. The LV-COX2 gene transfer strategy enhanced neo-chondrogenesis at the tendon-bone interface but with only marginal effect on de novo bone formation. The tendon-bone interface of the LV-COX2-treated tenodesis showed the well-defined tendon-to-fibrocartilage-to-bone histologic transitions that are indicative of osteointegration of the tendon graft. The LV-COX2 in vivo gene transfer strategy also significantly enhanced angiogenesis at the tendon-bone interface. To determine if the increased osteointegration was translated into an improved pull-out mechanical strength property, the pull-out tensile strength of the LV-COX2-treated tendon grafts was determined with a pull-out mechanical testing assay. The LV-COX2 strategy yielded a significant improvement in the return of the pull-out strength of the tendon graft after 8 weeks. In conclusion, the COX2-based in vivo gene transfer strategy enhanced angiogenesis, osteointegration and improved return of the pull-out strength of the tendon graft. Thus, this strategy has great potential to be developed into an effective therapy to promote tendon-to-bone healing after tenodesis or related surgeries.

• Animals
• Bone and Bones/metabolism
• Bone and Bones/physiology
• Bone and Bones/surgery
• Chondrogenesis
• Cyclooxygenase 2/genetics
• Gene Transfer Techniques
• Lentivirus/genetics
• Osseointegration
• Osteogenesis
• Rats
• Tendons/surgery
• Tendons/transplantation
• Tenodesis/methods
• Tensile Strength
• Upper Extremity/surgery
• Wound Healing

Tendon–bone junctions (TBJs) are frequently injured, especially in athletic settings. Healing of TBJ injuries is slow and is often repaired with scar tissue formation that compromises normal function. This study explored the feasibility of using kartogenin (KGN), a biocompound, to enhance the healing of injured TBJs. We first determined the effects of KGN on the proliferation and chondrogenic differentiation of rabbit bone marrow stromal cells (BMSCs) and patellar tendon stem/progenitor cells (PTSCs) in vitro. KGN enhanced cell proliferation in both cell types in a concentration-dependent manner and induced chondrogenic differentiation of stem cells, as demonstrated by high expression levels of chondrogenic markers aggrecan, collagen II and Sox-9. Besides, KGN induced the formation of cartilage-like tissues in cell cultures, as observed through the staining of abundant proteoglycans, collagen II and osteocalcin. When injected into intact rat patellar tendons in vivo, KGN induced cartilage-like tissue formation in the injected area. Similarly, when KGN was injected into experimentally injured rat Achilles TBJs, wound healing in the TBJs was enhanced, as evidenced by the formation of extensive cartilage-like tissues. These results suggest that KGN may be used as an effective cell-free clinical therapy to enhance the healing of injured TBJs.

• enthesis
• extracorporeal shockwave
• fibrocartilage
• tendon bone insertion
• vickers hardness

Porous biphasic calcium phosphate (BCP) ceramics exhibit good biocompatibility and bone conduction but are not inherently osteoinductive. To overcome this disadvantage, we coated conventional porous BCP ceramics with nano-hydroxyapatite (nHA). nHA was chosen as a coating material due to its high osteoinductive potential.

We used a hydrothermal deposition method to coat conventional porous BCP ceramics with nHA and assessed the effects of the coating on the physical and mechanical properties of the underlying BCP. Next, its effects on mesenchymal stem cell (MSC) attachment, proliferation, viability, and osteogenic differentiation were investigated.

nHA formed a deposited layer on the BCP surface, and synthesized nHA had a rod-like shape with lengths ranging from ~50–200 nm and diameters from ~15–30 mm. The nHA coating did not significantly affect the density, porosity, flexural strength, or compressive strength of the underlying BCP (P > 0.1). Scanning electron microscopy showed MSC attachment to the scaffolds, with a healthy morphology and anchorage to nHA crystals via cytoplasmic processes. The densities of MSCs attached on BCP and nHA-coated BCP scaffolds were 62 ± 26 cells/mm² and 63 ± 27 cells/mm² (P > 0.1), respectively, after 1 day and 415 ± 62 cells/mm² and 541 ± 35 cells/mm² (P < 0.05) respectively, after 14 days. According to an MTT assay, MSC viability was higher on nHA-coated BCP scaffolds than on BCP scaffolds (P < 0.05). In addition, MSCs on nHA-coated BCP scaffolds produced more alkaline phosphatase, collagen type I, and osteocalcin than MSCs on BCP scaffolds (P < 0.05).

Our results demonstrate that BCP scaffolds coated with nHA were more conducive for MSC adhesion, proliferation, and osteogenic differentiation than conventional, uncoated BCP scaffolds, indicating that nHA coating can enhance the osteoinductive potential of BCP ceramics, making this material more suitable for applications in bone tissue engineering.