• Augmentation
• Healing
• Injection
• Mesenchymal stem cells
• Repair
• Rotator cuff
• Tear

• adipocyte-derived stem cells
• biological scaffolds
• biological therapy
• bone marrow-derived stem cells
• platelet-rich plasma
• rotator cuff repair
• stem cells

• Tendon repair
• preclinical status
• recent advances
• therapeutic approaches

• Tendon Injuries/therapy
• Tendon Injuries/physiopathology
• Humans
• Wound Healing/physiology
• Animals
• Tissue Engineering/methods
• Genetic Therapy/methods
• Platelet-Rich Plasma
• Tendons
• Stem Cell Transplantation/methods
• Intercellular Signaling Peptides and Proteins/therapeutic use
• Intercellular Signaling Peptides and Proteins/metabolism

• Cell therapy
• Growth medium
• Immunomodulation
• Inflammatory priming
• Mesenchymal stem/stromal cells
• Osteoarthritis
• Oxytocin priming
• Regenerative medicine

• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/drug effects
• Humans
• Culture Media/chemistry
• Culture Media/pharmacology
• Immunomodulation/drug effects
• Inflammation
• Cells, Cultured
• Cell Proliferation/drug effects
• Adipose Tissue/cytology
• Adipose Tissue/metabolism
• Cell Differentiation/drug effects
• Osteoarthritis/metabolism
• Osteoarthritis/immunology
• Macrophages/metabolism
• Macrophages/immunology
• Macrophages/drug effects
• Female
• Male

• R21 AR080388 NIAMS NIH HHS
• 5R21AR080388-02 NIH HHS
• National Institutes of Health

• cell-based therapy
• mesenchymal stem cell/marrow stromal cell
• orthopedics
• stem cell differentiation
• stem cells
• tendon
• tenogenic differentiation
• tissue engineering

• Animals
• Rabbits
• Growth Differentiation Factor 5/pharmacology
• Growth Differentiation Factor 5/metabolism
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Wound Healing/drug effects
• Tendons/pathology
• Mesenchymal Stem Cell Transplantation/methods
• Cell Differentiation/drug effects
• Tendon Injuries/therapy
• Tendon Injuries/pathology
• Male
• Tenocytes/metabolism
• Tenocytes/cytology

• bone marrow
• mesenchymal stem cells
• orthopedics
• regenerative medicine

• nanotechnology
• seed cell
• tendon injury
• tendon-derived stem cell
• tissue engineer

• stem cells
• health care

• Humans
• Tendinopathy/therapy
• Tendinopathy/pathology
• Achilles Tendon/pathology
• Male
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cell Transplantation/adverse effects
• Middle Aged
• Female
• Adult
• Transplantation, Autologous
• Mesenchymal Stem Cells/cytology
• Treatment Outcome

• NCT02064062 The UK Stem Cell Foundation

• health care
• stem-cell therapies

• Humans
• Adrenal Cortex Hormones/adverse effects
• Arthroscopy
• Injections
• Range of Motion, Articular
• Rotator Cuff
• Rotator Cuff Injuries/diagnostic imaging
• Rotator Cuff Injuries/drug therapy
• Shoulder
• Treatment Outcome

• regeneration medicine
• sports injury
• sports medicine
• stem cells

• Stem Cell Transplantation
• Sports Medicine
• Wound Healing

• Clinical application
• Mesenchymal stem cells
• Regenerative medicine
• Rotator cuff
• Stem cell therapy
• Tendinopathy

• FE002 primary progenitor tenocytes
• allogeneic cell therapy
• clinical protocols
• hand surgery
• ligamentoplasty
• proof-of-concept
• regenerative medicine
• standardized transplants
• tissue engineering
• translational development

• LADE 20-472 SPEI

• bone marrow aspirate
• clinical trial
• rotator cuff

• Cell therapy
• Regenerative medicine
• Safety
• Stem cells
• Tendinopathy
• Tendons

To report the clinical outcomes after biologically augmented rotator cuff repair (RCR) with a fibrin scaffold derived from autologous whole blood and supplemented with concentrated bone marrow aspirate (cBMA) harvested at the proximal humerus.

Patients who underwent arthroscopic RCR with biologic augmentation using a fibrin clot scaffold (“Mega- Clot”) containing progenitor cells and growth factors from proximal humerus BMA and autologous whole blood between April 2015 and January 2018 were prospectively followed. Only high-risk patients in primary and revision cases that possessed relevant comorbidities or physically demanding occupation were included. Minimum follow-up for inclusion was 1 year. The visual analog score for pain (VAS), American Shoulder and Elbow Surgeons (ASES), Simple Shoulder Test (SST), Single Assessment Numerical Evaluation (SANE), and Constant-Murley scores were collected preoperatively and at final follow-up. In vitro analyses of the cBMA and fibrin clot using nucleated cell count, colony forming units, and live/dead assays were used to quantify the substrates.

Thirteen patients (56.9 ± 7.7 years) were included. The mean follow-up was 26.9 ± 17.7 months (n = 13). There were significant improvements in all outcome scores from the preoperative to the postoperative state: VAS (5.6 ± 2.5 to 3.1 ± 3.2; P < .001), ASES (42.0 ± 17.1 to 65.5 ± 30.6; P < .001), SST (3.2 ± 2.8 to 6.5 ± 4.7; P = .002), SANE (11.5 ± 15.6 to 50.3 ± 36.5; P < .001), and Constant-Murley (38.9 ± 17.5 to 58.1 ± 26.3; P < .001). Six patients (46%) had retears on postoperative MRI, despite all having improvements in pain and function except one. All failures were chronic rotator cuff tears, and all were revision cases except one (1.6 ± 0.5 previous RCRs). The representative sample of harvested cBMA showed an average of 28.5 ± 9.1 × 10⁶ nucleated cells per mL.

Arthroscopic rotator cuff repairs that are biologically augmented with a fibrin scaffold containing growth factors and autologous progenitor cells derived from autologous whole blood and humeral cBMA can improve clinical outcomes in primary, as well as revision cases in high-risk patients. However, the incidence of retears remains a concern in this population, demanding further improvements in biologic augmentation.

IV, therapeutic case series.

• Biological treatment
• Cartilage lesion
• Cell therapy
• Shoulder
• Tendon injury

• Aged
• Aged, 80 and over
• Arthroscopy/methods
• Bone Marrow
• Female
• Humans
• Humerus
• Male
• Middle Aged
• Rotator Cuff/surgery
• Rotator Cuff Injuries/surgery
• Shoulder

• arthroscopy
• augmentation
• biologic
• bursa
• shaver

• cell therapies
• hyaluronic acid
• hydrogels
• progenitor cells
• regenerative medicine
• stabilization
• tendinopathies
• viscoelasticity

• LADE 20-411 Service of Promotion of the Economy and Innovation of the Canton of Vaud (SPEI)

To clinically evaluate patients who underwent a biologic augmentation technique in revision arthroscopic rotator cuff repair using an autologous fibrin scaffold and concentrated stem cells isolated from bone marrow aspirate (BMA) obtained from the proximal humerus.

This is a retrospective review of prospectively collected data from patients who underwent biologic augmentation of revision arthroscopic rotator cuff repair using an autologous fibrin scaffold and BMA obtained from the proximal humerus between 2014 and 2015. Minimum follow-up was 12 months. Outcome measures were collected preoperatively and postoperatively including range of motion as well as American Shoulder and Elbow Surgeons Shoulder Form, Simple Shoulder Test, single assessment numeric evaluation, and visual analog score. In addition, BMA samples of each patient were assessed for the number of nucleated cells and colony-forming units. Regression analysis was performed to investigate whether the number of nucleated cells and colony-forming units had an influence on outcome and failure.

Ten patients who underwent biologic augmentation of revision arthroscopic rotator cuff repair using an autologous fibrin scaffold and concentrated BMA obtained from the proximal humerus between 2014 and 2015 were included. The mean follow-up time was 30.7 (range: 12-49) months. Four patients were revised at final follow-up. Postoperative clinical scores improved significantly: American Shoulder and Elbow Surgeons (28.1 ± 5.4 to 60.9 ± 9.0; P < .01), single assessment numeric evaluation (6.6 ± 2.3 to 65.1 ± 10.9; P < .01), visual analog scale (7.2 ± 0.9 to 3.1 ± 0.9; P < .01), and Simple Shoulder Test (1.6 ± 0.5 to 10.3 ± 5.7; P < .01). Postoperative range of motion increased significantly with regard to flexion (97.0 ± 13.6 to 151.0 ± 12.2; P < .01) and abduction (88.0 ± 14.0 to 134.0 ± 15.1; P = .038) but not with external rotation (38.0 ± 5.7 to 50.5 ± 6.5; P = .16). Less pain was correlated to an increased number of nucleated cells (P = .026); however, there was no correlation between failure rate and number of nucleated cells (P = .430).

Patients who underwent biologic augmentation of revision arthroscopic rotator cuff repair using an autologous fibrin scaffold and concentrated BMA demonstrated a significant improvement in shoulder function along with reduction of pain. However, the overall revision rate for this procedure was 40%.

Level IV, therapeutic case series.

This article focused on the application scenarios of three-dimensional (3D) bioprinting and gene-editing technology in various medical fields, including gene therapy, tissue engineering, tumor microenvironment simulation, tumor model construction, cancer regulation and expression, osteogenesis, and skin and vascular regeneration, and summarizing its development prospects and shortcomings.

3D bioprinting is a process based on additive manufacturing that uses biological materials as the microenvironment living cells. The scaffolds and carriers manufactured by 3D bioprinting technology provide a safe, efficient, and economical platform for genes, cells, and biomolecules. Gene modification refers to replacing, splicing, silencing, editing, controlling or inactivating genes and delivering new genes. The combination of this technology that changes cell function or cell fate or corrects endogenous mutations and 3D bioprinting technology has been widely used in various medical field.

We conducted a literature search for papers published up to March 2021 on the gene modification combined with 3D bioprinting in various medical fields via PubMed, Web of Science, China National Knowledge Infrastructure (CNKI). The following medical subject heading terms were included for a MEDLINE search: “3D printing/gene editing”, “3D printing/genetic modification”, “3D printing/seed cell”, “bioprinting/gene editing”, “bioprinting/genetic modification”, “bioprinting/seed cell”, “scaffold/gene editing”, “scaffold/genetic modification”, “scaffold/seed cell”, “gene/scaffold”, “gene/bioprinting”, “gene/3D printing”. Quantitative and qualitative data was extracted through interpretation of each article.

We have reviewed the application scenarios of 3D bioprinting and gene-editing technology in various medical fields, it provides an efficient and accurate delivery system for personalized tumor therapy, enhancing the targeting effect while maintaining the integrity of the fabricated structure. It exhibits significant application potential in developing tumor drugs. In addition, scaffolds obtained via 3D bioprinting provide gene therapy applications for skin and bone healing and repair and inducing stem cell differentiation. It also considers the future development direction in this field, such as the emergence and development of gene printing, 4D printing. The combination of nanotechnology and gene printing may provide a new way for future disease research and treatment.

• Three-dimensional bioprinting (3D bioprinting)
• genetic modification
• scaffold

• adipose-derived stem cell
• clinical trials
• musculoskeletal disorders

• Adipose Tissue/cytology
• Animals
• Cell Differentiation
• Cell- and Tissue-Based Therapy/methods
• Clinical Trials as Topic/methods
• Clinical Trials as Topic/statistics & numerical data
• Humans
• Mesenchymal Stem Cells/cytology
• Musculoskeletal Diseases/pathology
• Musculoskeletal Diseases/physiopathology
• Musculoskeletal Diseases/therapy
• Regenerative Medicine/methods
• Stem Cell Transplantation/methods

• HI18C0661 Ministry of Health & Welfare, Republic of Korea

To evaluate the efficacy and safety of mesenchymal stem cells (MSCs) therapy in patients with tendon disorders enrolled in prospective clinical studies.

We systematically searched prospective clinical studies that investigated the effects of MSC administration on human tendon disorders with at least a 6-month follow-up period in the PubMed-MEDLINE, EMBASE, and Cochrane Library databases. The primary outcome of interest was the change in pain on motion related to tendon disorders. Meta-regression analyses were performed to assess the relationship between MSC dose and pooled effect sizes in each cell dose.

Four prospective clinical trials that investigated the effect of MSCs on tendon disorders were retrieved. MSCs showed a significant pooled effect size (overall Hedges’ g pooled standardized mean difference=1.868; 95% confidence interval, 1.274–2.462; p<0.001). The treatment with MSCs improved all the aspects analyzed, namely pain, functional scores, radiological parameters (magnetic resonance image or ultrasonography), and arthroscopic findings. In the meta-regression analysis, a significant cell dose-dependent response in pain relief (Q=9.06, p=0.029) was observed.

Our meta-analysis revealed that MSC therapy may improve pain, function, radiological, and arthroscopic parameters in patients with tendon disorders. A strong need for large-scale randomized controlled trials has emerged to confirm the long-term functional improvement and adverse effects of MSC therapies in tendon disorders.

• Mesenchymal stem cells
• Meta-analysis
• Rotator cuff
• Tendinopathy
• Tennis elbow

• Biological augmentation
• Biomaterials
• Corticosteroids
• Growth factors
• Rotator cuff repair
• Rotator cuff tear
• Scaffolds
• Stem cell therapies

Current clinical treatment options for symptomatic, partial-thickness rotator cuff tear (sPTRCT) offer only limited potential for true tissue healing and improvement of clinical results. In animal models, injections of adult stem cells isolated from adipose tissue into tendon injuries evidenced histological regeneration of tendon tissue. However, it is unclear whether such beneficial effects could also be observed in a human tendon treated with fresh, uncultured, autologous, adipose derived regenerative cells (UA-ADRCs). A specific challenge in this regard is that UA-ADRCs cannot be labeled and, thus, not unequivocally identified in the host tissue. Therefore, histological regeneration of injured human tendons after injection of UA-ADRCs must be assessed using comprehensive, immunohistochemical and microscopic analysis of biopsies taken from the treated tendon a few weeks after injection of UA-ADRCs.

A 66-year-old patient suffered from sPTRCT affecting the right supraspinatus and infraspinatus tendon, caused by a bicycle accident. On day 18 post injury [day 16 post magnetic resonance imaging (MRI) examination] approximately 100 g of abdominal adipose tissue was harvested by liposuction, from which approximately 75 × 10⁶ UA-ADRCs were isolated within 2 h. Then, UA-ADRCs were injected (controlled by biplanar X-ray imaging) adjacent to the injured supraspinatus tendon immediately after isolation. Despite fast clinical recovery, a follow-up MRI examination 2.5 mo post treatment indicated the need for open revision of the injured infraspinatus tendon, which had not been treated with UA-ADRCs. During this operation, a biopsy was taken from the supraspinatus tendon at the position of the injury. A comprehensive, immunohistochemical and microscopic analysis of the biopsy (comprising 13 antibodies) was indicative of newly formed tendon tissue.

Injection of UA-ADRCs can result in regeneration of injured human tendons by formation of new tendon tissue.

• Stem cells
• Partial-thickness rotator cuff tear
• Tendon regeneration
• Adipose derived regenerative cells
• Cell-based therapy at point of care
• Case report

• Cell-based therapies
• epicondylitis
• msc
• rotator cuff pathology
• sports injuries
• tenocytes

• cell banking
• chorioallantoic membrane model
• fetal progenitor cell therapy
• pilot safety study
• preclinical animal model
• regenerative medicine
• tendinopathies
• tendon cell therapy
• toxicity evaluation
• transplantation program

• N°833594 - PHAS H2020 Marie Skłodowska-Curie Actions

• Adrenal Cortex Hormones
• Bone Marrow Cells
• Hip Joint
• Tendinopathy

• Alginate
• Bone morphogenetic proteins
• Chitin
• Growth factors
• Rotator cuff
• Scaffold
• Tissue engineering

• Bone mesenchymal stem cells
• Exosome
• Rotator cuff
• Shoulder
• Tendinosis

To evaluate the clinical outcomes of patients who underwent arthroscopic rotator cuff repair augmented using subacromial bursa, concentrated bone marrow aspirate (cBMA), and platelet-rich plasma.

Sixteen patients were included in the study who underwent arthroscopic rotator cuff repair augmented using subacromial bursa, cBMA, and platelet-rich plasma from January 2018 to July 2018 and had a minimum 1-year follow-up. American Shoulder and Elbow Surgeons (ASES), Simple Shoulder Test, Constant-Murley, and Single Assessment Numerical Evaluation (SANE) scores were collected preoperatively and at terminal follow-up. To determine the clinical relevance of ASES scores, the minimal clinically important difference, substantial clinical benefit, and the patient acceptable symptomatic state thresholds were used. In vitro cellular proliferation of subacromial bursa (nucleated cells/gram) and cBMA (nucleated cells and colony-forming units/cc) samples was evaluated and correlated to clinical outcomes scores.

Mean follow-up was 12.6 ± 1.8 months (range 12-19 months). Patients achieved significant improvement in ASES (45.8±22.5_pre vs 88.5 ± 14.6_post, Δ44.7 ± 20.7; P = .001), Simple Shoulder Test (4.3 ± 3.2_pre vs 10.4 ± 1.6_post, Δ5.7 ± 3.9, P = .002), Constant-Murley (44.3 ± 18.2_pre vs 83.6 ± 17.5_post, Δ37.2 ± 21.8; P = .001), SANE (13.3 ± 10.7_pre vs 86.3 ± 17.5_post, Δ71.9 ± 22.9; P = .001), and pain scores (5.0±2.8_pre vs 1.1 ± 1.6_post, Δ3.5±2.5, P = .001) at final follow-up. With regards to ASES score, 93.8% of patients achieved the minimal clinically important difference, 93.8% the substantial clinical benefit, and 62.5% reached or exceeded the patient acceptable symptomatic state criteria. There was a significant positive correlation of nucleated cell count of cBMA with postoperative SANE score (r = 0.707; P = .015) and delta in ASES score (r = 0.727; P = .011). All other correlations were found to be nonsignificant (P > .05, respectively).

Patients undergoing arthroscopic rotator cuff repair augmented using the Mega-Clot with bursa technique achieved significant improvement in functional outcomes at a minimum 1-year follow-up, with 93.8% of patients reaching substantial clinical benefit.

Level IV, therapeutic case series.

To evaluate the time required for colonies to develop from concentrated bone marrow aspirate (cBMA) and subacromial bursal tissue samples.

Samples of cBMA and subacromial bursa tissue were harvested from patients undergoing rotator cuff repair surgery between November 2014 and December 2019. Samples were analyzed for time to form colonies and number of colonies formed. The impact of age, sex, and cellularity (cBMA only) was analyzed. Samples were cultured and evaluated daily for colony formation in accordance with the guidelines of the International Society for Cellular Therapy. Demographic factors were analyzed for impact on time to form colonies and number of colonies formed.

Samples of cBMA were obtained from 92 patients. Subacromial bursa tissue was obtained from 54 patients. For cBMA, older age was associated with more days to form colonies (P = .003), but sex (P = .955) and cellularity (P = .623) were not. For bursa, increased age was associated with longer time to form colonies (P = .002) but not sex (P = .804). Conclusions: Increased age (in cBMA and subacromial bursa tissue) and lower initial cellularity (in cBMA) are associated with longer time to form colonies in culture.

Although connective tissue progenitor cells are widely used in orthopaedic practice, there are few metrics to determine their efficacy. Time to form colonies may serve as an important measurement for determining connective tissue progenitor cell viability for augmentation of rotator cuff repair. Subacromial bursa tissue may represent a viable alternative to cBMA for augmentation of rotator cuff repair, capable of forming colonies expediently in vivo.

• Biologics
• hip abductor
• patches
• tendinopathy
• tendon repair