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Nonoperative Applications of Placental Tissue Matrix in Orthopaedic Sports Injuries: A Review of Literature
Abstract
Objective:
Recently, various amniotic tissue and placental-based tissue matrix (PTM) products have become increasingly available as a nonoperative treatment for tendinopathies and orthopaedic sports injuries. The aim of this review was to evaluate: (1) safety and efficacy of nonoperative use of PTM products, in acute and chronic tendon injuries and (2) the commercially available tissue options to better understand their differences.
Data sources:
A comprehensive literature search was performed. Inclusion criteria were studies reporting on: (1) nonoperative uses of PTM therapy in sports injuries; and (2) clinical outcomes; in (3) human subjects. We excluded: (1) animal studies; (2) basic science studies; (3) non-English language literature; (4) review articles; and (5) duplicate studies. In addition, to determine the various product formulations, their tissue contents, and indications for use, we searched publicly available website content, marketing literature, and Food and Drug Administration (FDA) registration documents.
Main results:
Current evidence investigated various PTM products for the treatment of various tendon injuries with demonstrated efficacy mainly in the short term with follow-up ranging between 6 weeks and 3 months. In addition, across all studies, no specific adverse events were reported. Substantial differences exist among the currently available products due to variations in their tissue source, formulations, processing methods, method of sterilization, preservation, and storage, indications for use, and FDA regulation.
Conclusions:
Placental- and amniotic membrane-derived tissues seem to be safe for the nonoperative treatment of tendinopathies. However, several factors may affect the efficacy and safety profile of these products, and the orthopaedic surgeons should be aware of the differences.
... Research into amniotic-derived products for tissue regeneration within orthopedics has grown in recent years, including for the treatment of plantar fasciitis, ligament and tendon healing, spinal pathology, cartilage restoration, and osteoarthritis. As of 2018, there were eight commercially available amniotic membrane products that have been studied for treatment of musculoskeletal conditions (Table 1) [8]. This chapter will explore the role of amniotic products in orthopedics from the function of the amniotic membrane in vivo through current clinical studies using this orthobiologic treatment. ...
Purpose of review:
Orthobiologics, including amniotic products, have been gaining interest in the past decade for the treatment of various orthopedic conditions including osteoarthritis. However, the use of biologics is varied and is currently available with minimal oversight or regulation. This review will assess the current state of research that utilizes amniotic products both in vitro and in vivo.
Recent findings:
Amniotic tissue derivatives have been shown to have positive effects in animal models for a variety of conditions. Clinical trials are limited with mixed outcomes, yet some recent studies suggest the rationale for continued investigation. While amniotic products appear promising in numerous animal studies, human clinical trials are still lacking. Future studies are needed to assess whether amniotic products have a role in the treatment of osteoarthritis and other orthopedic pathologies.
There are a wide variety of extracellular matrices that can be used for regenerative purposes. Placental tissue-based matrices are quickly becoming an attractive option given the availability of the tissue source and the wide variety of bioactive molecules knows to exist in unprocessed placental tissues. As fresh placental tissues are seldom an option at the point of care, we examined both the composition and bioactivity of a commercially packaged flowable placental connective tissue matrix (FPTM) (BioECM®, Skye Biologics, Inc.) that was preserved by the proprietary HydraTek® process. The FPTM contained significant amounts of collagen and various growth factors such as bFGF, EGF, PDGF, KGF, and PIGF. In addition, it contained high levels of tissue inhibitors of metalloproteinases (TIMP-1 and 2) and molecules known to modulate the immune response including TGF-β and IL-4. In terms of its bioactivity, the FPTM displayed the ability (1) to suppress INF-γ secretion in activated T-cells nearly fourfold over control media, (2) to inhibit methicillin resistant Staphylococcus aureus (MRSA) and Staphylococcus saprophyticus proliferation, (3) to increase the migration of adipose-derived stem cells (ASCs) nearly threefold over control media and (4) to adhere to ASCs in culture. When ASCs were exposed to FPTM in culture, the cells maintained healthy morphology and showed no significant changes in the expression of five genes involved in tissue growth and repair as compared to culture in standard growth media. © 2018 The Authors Journal of Biomedical Materials Research Part B: Applied Biomaterials Published by Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018.
The clinical application of the fetal membranes dates back to nearly a century. Their use has ranged from superficial skin dressings to surgical wound closure. The applications of the fetal membranes are constantly evolving, and key to this is the uncovering of multiple populations of stem and stem-like cells, each with unique properties that can be exploited for regenerative medicine. In addition to pro-angiogenic and immunomodulatory properties of the stem and stem-like cells arising from the fetal membranes, the dehydrated and/or decellularized forms of the fetal membranes have been used to support the growth and function of other cells and tissues, including adipose-derived mesenchymal stem cells. This concise review explores the biological origin of the fetal membranes, a history of their use in medicine, and recent developments in the use of fetal membranes and their derived stem and stem-like cells in regenerative medicine. Stem Cells Translational Medicine 2017;6:1767–1776
Tendinopathy is a common clinical problem and has a significant disease burden attached, not only in terms of health care costs, but also for patients directly in terms of time off work and impact upon quality of life. Controversy surrounds the pathogenesis of tendinopathy, however the recent systematic analysis of the evidence has demonstrated that many of the claims of an absence of inflammation in tendinopathy were more based around belief than robust scientific data. This review is a summary of the emerging research in this topical area, with a particular focus on the role of neuronal regulation and inflammation in tendinopathy.
Amniotic fluid represents rich sources of stem cells that can be used in treatments for a wide range of diseases. Amniotic fluid- stem cells have properties intermediate between embryonic and adult mesenchymal stem cells which make them particularly attractive for cellular regeneration and tissue engineering. Furthermore, scientists are interested in these cells because they come from the amniotic fluid that is routinely discarded after birth. In this review we give a brief introduction of amniotic fluid followed by a description of the cells present within this fluid and aim to summarize the all existing isolation methods, culturing, characterization and application of these cells. Finally, we elaborate on the differentiation and potential for these cells to promote regeneration of various tissue defects, including fetal tissue, the nervous system, heart, lungs, kidneys, bones, and cartilage in the form of table.
. Allogeneic amniotic tissue and fluid may be used to treat chronic plantar fasciosis and Achilles tendinosis. This innovative approach involves delivering a unique allograft of live human cells in a nonimmunogenic structural tissue matrix to treat chronic tendon injury. These tissues convey very positive regenerative attributes; procurement is performed with maternal consent during elective caesarian birth.
Materials and Methods
. In the present investigation all patients were unresponsive to multiple standard therapies for a minimum of 6 months and were treated with one implantation of PalinGen SportFLOW around the plantar fascia and/or around the Achilles paratenon. The patients were given a standard protocol for postimplant active rehabilitation.
Results
. The analogue pretreatment pain score (VAS) of 8. By the fourth week after treatment, all patients had significantly reduced self-reported pain. Twelve weeks following the procedure the average pain level had reduced to only 2. No adverse reactions were reported in any of the patients.
Conclusion
. All patients in this study experienced heel or Achilles pain, unresponsive to standard therapy protocols. After treatment all patients noted significant pain reduction, indicating that granulized amniotic membrane and amniotic fluid can be successfully used to treat both chronic plantar fasciosis and Achilles tendinosis.
Unlabelled:
The cartilage regeneration potential of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) with a hyaluronic acid (HA) hydrogel composite has shown remarkable results in rat and rabbit models. The purpose of the present study was to confirm the consistent regenerative potential in a pig model using three different cell lines. A full-thickness chondral injury was intentionally created in the trochlear groove of each knee in 6 minipigs. Three weeks later, an osteochondral defect, 5 mm wide by 10 mm deep, was created, followed by an 8-mm-wide and 5-mm-deep reaming. A mixture (1.5 ml) of hUCB-MSCs (0.5×10(7) cells per milliliter) and 4% HA hydrogel composite was then transplanted into the defect on the right knee. Each cell line was used in two minipigs. The osteochondral defect created in the same manner on the left knee was untreated to act as the control. At 12 weeks postoperatively, the pigs were sacrificed, and the degree of subsequent cartilage regeneration was evaluated by gross and histological analysis. The transplanted knee resulted in superior and more complete hyaline cartilage regeneration compared with the control knee. The cellular characteristics (e.g., cellular proliferation and chondrogenic differentiation capacity) of the hUCB-MSCs influenced the degree of cartilage regeneration potential. This evidence of consistent cartilage regeneration using composites of hUCB-MSCs and HA hydrogel in a large animal model could be a stepping stone to a human clinical trial in the future.
Significance:
To date, several studies have investigated the chondrogenic potential of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs); however, the preclinical studies are still limited in numbers with various results. In parallel, in the past several years, the cartilage regeneration potential of hUCB-MSCs with a hyaluronic acid (HA) hydrogel composite have been investigated and remarkable results in rat and rabbit models have been attained. (These experimental results are currently in preparation for publication.) Before applying the cartilage regeneration technique in a human clinical trial, it seemed necessary to confirm the consistent result in a larger animal model. At 12 weeks postoperatively, the minipigs were sacrificed, and the degree of subsequent cartilage regeneration was evaluated by gross and histological analysis. The transplanted knee resulted in superior and more complete hyaline cartilage regeneration compared with the control knee. This evidence of consistent cartilage regeneration with composites of hUCB-MSCs and HA hydrogel in a large animal model could be a stepping stone to a human clinical trial in the future.
Damaged connective tissue commonly leads to lower extremity injuries. These injuries can result in inflammation, reduced mobility, and chronic pain. Conservative treatment may include orthotics, offloading the injury, physical therapy, and/or NSAIDs. If conservative treatment fails, surgical intervention may be required. Even after successful surgery, these procedures often result in reduced joint mobility and tendon or ligament strength.
A novel flowable tissue matrix allograft, derived from human placental connective tissue, has recently been made available for minimally invasive treatment of damaged or inadequate tissue (PX50®, Human Regenerative Technologies LLC, Redondo Beach, CA).
Based on the universal role of connective tissue in the body, and its reported antimicrobial, anti-adhesive, and anti-inflammatory properties, we assessed the effects of using this placental tissue matrix in the treatment of a series of lower extremity injuries.
In this pilot study, 9 of 10 patients reported pain levels of 2 or less by week four using the VAS pain scale. This short-term pilot study effectively shows that injectable, flowable amniotic allografts can be used for orthopedic sports injuries of the lower extremities.
Significance: Chronic diabetic foot ulcers (DFUs) remain a challenge for physicians to treat. High mortality rates for DFU patients have pointed to the low effectiveness of standard care and lack of quality wound care products. The composition (collagen-rich tissue matrix and endogenous growth factors and cells) and functional properties (anti-inflammatory, anti-bacterial, and angiogenic) of placental membranes are uniquely suited to address the needs of chronic wounds. This led to the commercialization of placental membranes, which are now widely available to physicians as a new advanced wound treatment option.
Recent Advances: Progress in tissue processing and preservation methods has facilitated the development of placental products for wounds. Currently, a variety of commercial placental products are available to physicians for the treatment of chronic DFUs and other wounds. This review summarizes the key factors that negatively impact DFU healing (including social factors, such as smoking, vascular deficiencies, hyperglycemia, and other metabolic abnormalities), describes the structure and biology of placental membranes, and overviews commercially available placental products for wounds and data from the most recent DFU clinical trials utilizing commercial placental membranes.
Critical Issues: Although the effects of diabetes on wound healing are complex and not fully understood, some of the key factors and pathways that interfere with healing have been identified. However, a multidisciplinary approach for the assessment of patients with chronic DFUs and guidelines for selection of appropriate treatment modalities remain to be implemented.
Future Directions: The biological properties of placental membranes show benefits for the treatment of chronic DFUs, but scientific and clinical data for commercially available placental products are limited. Therefore, we need (1) more randomized, controlled clinical trials for commercial placental products; (2) studies that help to understand the timing of placental products' application and criteria for patient selection; and (3) studies comparing the functional properties of different commercially available placental products.
Background:
Treatment options for plantar fasciitis have resulted in varied patient outcomes. The aim of this study was to compare a novel treatment, cryopreserved human amniotic membrane (c-hAM), to a traditional treatment, corticosteroid. Our hypothesis was that c-hAM would be safe and comparable to corticosteroids for plantar fasciitis in regard to patient outcomes.
Methods:
A randomized, controlled, double-blind, single-center pilot study was completed. Patients were randomized into one of 2 treatment groups: c-hAM or corticosteroid. Patients received an injection at their initial baseline visit with an option for a second injection at their first 6-week follow-up. Total follow-up was obtained for 12 weeks after the most recent injection. The primary outcome measurement was the Foot Health Status Questionnaire (FHSQ). The secondary outcome measurements were the Visual Analog Scale (VAS) and verbally reported percentage improvement. Data were analyzed between groups for the 2 different cohorts (1 injection versus 2 injections). Twenty-three patients had complete follow-up. Fourteen were randomized to receive corticosteroid and 9 were randomized to receive c-hAM.
Results:
Three patients in each group received second injections. With the numbers available, the majority of outcome measurements showed no statistical difference between groups. The corticosteroid did, however, have greater FHSQ shoe fit improvement (P = .0244) at 6 weeks, FHSQ general health improvement (P = .0132) at 6 weeks, and verbally reported improvement (P = .041) at 12 weeks in the one-injection cohort. Cryopreserved hAM had greater FHSQ foot pain improvement (P = .0113) at 18 weeks in the 2-injection cohort.
Conclusion:
Cryopreserved hAM injection may be safe and comparable to corticosteroid injection for treatment of plantar fasciitis. This is a pilot study and requires further investigation.
Level of evidence:
Level I, prospective randomized trial.
Specialized treatment of plantar fasciitis that can reduce inflammation and promote healing may be a possible alternative prior to surgical intervention. We report the results of a randomized clinical trial examining the efficacy of micronized dehydrated human amniotic/chorionic membrane (mDHACM) injection as a treatment for chronic refractory plantar fasciitis.
An institutional review board-approved, prospective, randomized, single-center clinical trial was performed. Forty-five patients were randomized to receive injection of 2 cc 0.5% Marcaine plain, then either 1.25 cc saline (controls), 0.5 cc mDHACM, or 1.25 cc mDHACM. Follow-up visits occurred over 8 weeks to measure function, pain, and functional health and well-being.
Significant improvement in plantar fasciitis symptoms was observed in patients receiving 0.5 cc or 1.25 cc mDHACM versus controls within 1 week of treatment and throughout the study period. At 1 week, American Orthopaedic Foot and Ankle Society (AOFAS) Hindfoot scores increased by a mean of 2.2 ± 17.4 points for controls versus 38.7 ± 11.4 points for those receiving 0.5 cc mDHACM (P < .001) and 33.7 ± 14.0 points for those receiving 1.25 cc mDHACM (P < .001). By week 8 AOFAS Hindfoot scores increased by a mean of 12.9 ± 16.9 points for controls versus 51.6 ± 10.1 and 53.3 ± 9.4 for those receiving 0.5 cc and 1.25 cc mDHACM, respectively (both P < .001). No significant difference in treatment response was observed in patients receiving 0.5 cc versus 1.25 cc mDHACM.
In patients with refractory plantar fasciitis, mDHACM is a viable treatment option. Larger studies are needed to confirm our findings.
Level I, prospective randomized study.
Mesenchymal stem cells (MSCs) are promising candidates for cell therapy and tissue engineering. Increasing evidence suggests that MSCs isolated from fetal tissues are more plastic and grow faster than adult MSCs. In this study, we characterized human mesenchymal progenitor cells from chorionic villi (CV) and amniotic fluid (AF) isolated during the first and second trimesters, respectively, and compared them with adult bone marrow-derived MSCs (BM). We evaluated 10 CV, 10 AF, and 6 BM samples expanded until the MSCs reached senescence. We used discarded cells from prenatal analyses for all the experiments. To evaluate the replicative stability of these cells, we studied the telomerase activity, hTERT gene transcription, and telomere length in these cells. Spontaneous chromosomal alterations were excluded by cytogenetic analysis. We studied the expression of c-myc and p53, tumor-associated genes, at different passage in culture and the capacity of these cells to grow in an anchorage-independent manner by using soft agar assay. We isolated homogeneous populations of spindle-shaped CV, AF, and BM cells expressing mesenchymal immunophenotypic markers throughout the period of expansion. CV cells achieved 14 ± 0.9 logs of expansion in 118 days and AF cells achieved 21 ± 0.9 logs in 118 days, while BM cells achieved 11 × 0.4 logs in 84 days. Despite their high proliferation capacity, fetal MSCs showed no telomerase activity, no hTERT and c-myc transcriptions, and maintained long, stable telomeres. A constant expression level of p53 and a normal karyotype were preserved throughout long-term expansion, suggesting the safety of fetal MSCs. In conclusion, our results indicate that fetal MSCs could be an alternative, more accessible resource for cell therapy and regenerative medicine.
This study was done to evaluate the stemness of human mesenchymal stem cells (hMSCs) derived from placenta according to the development stage and to compare the results to those from adult bone marrow (BM). Based on the source of hMSCs, three groups were defined: group I included term placentas, group II included first-trimester placentas, and group III included adult BM samples. The stemness was evaluated by the proliferation capacity, immunophenotypic expression, mesoderm differentiation, expression of pluripotency markers including telomerase activity. The cumulative population doubling, indicating the proliferation capacity, was significantly higher in group II (P<0.001, 31.7±5.8 vs. 15.7±6.2 with group I, 9.2±4.9 with group III). The pattern of immunophenotypic expression and mesoderm differentiation into adipocytes and osteocytes were similar in all three groups. The expression of pluripotency markers including ALP, SSEA-4, TRA-1-60, TRA-1-81, Oct-4, and telomerase were strongly positive in group II, but very faint positive in the other groups. In conclusions, hMSCs from placentas have different characteristics according to their developmental stage and express mesenchymal stemness potentials similar to those from adult human BMs.
Bone marrow is the traditional source of human multipotent mesenchymal stem cells (MSCs), but placenta appears to be an alternative and more readily available source. This study comprehensively compared human placenta-derived MSC (hpMSC) and human bone marrow-derived MSC (hbmMSC) in terms of cell characteristics, optimal growth conditions and in vivo safety specifically to determine if hpMSC could represent a source of human MSC for clinical trial. MSC were isolated from human placenta (hpMSC) and human bone marrow (hbmMSC) and expanded ex vivo using good manufacturing practice-compliant reagents. hpMSC and hbmMSC showed similar proliferation characteristics in different basal culture media types, fetal calf serum (FCS) concentrations, FCS heat-inactivation experiments, flask types and media replacement responsiveness. However, hpMSC and hbmMSC differed with respect to their proliferation capabilities at different seeding densities, with hbmMSC proliferating more slowly than hpMSC in every experiment. hpMSC had greater long-term growth ability than hbmMSC. MSC from both sources exhibited similar light microscopy morphology, size, cell surface phenotype, and mesodermal differentiation ability with the exception that hpMSC consistently appeared less able to differentiate to the adipogenic lineage. A comparison of both hbmMSC and hpMSC from early and medium passage cultures using single-nucleotide polymorphism (SNP) GeneChip analysis confirmed GTG-banding data that no copy number changes had been acquired during sequential passaging. In three of three informative cases (in which the gender of the delivered baby was male), hpMSC were of maternal origin. Neither hpMSC nor hbmMSC caused any acute toxicity in normal mice when injected intravenously at the same, or higher, doses than those currently used in clinical trials of hbmMSC. This study suggests that human placenta is an acceptable alternative source for human MSC and their use is currently being evaluated in clinical trials.
Human placenta-derived mononuclear cells (MNC) were isolated by a Percoll density gradient and cultured in mesenchymal stem cell (MSC) maintenance medium. The homogenous layer of adherent cells exhibited a typical fibroblast-like morphology, a large expansive potential, and cell cycle characteristics including a subset of quiescent cells. In vitro differentiation assays showed the tripotential differentiation capacity of these cells toward adipogenic, osteogenic and chondrogenic lineages. Flow cytometry analyses and immunocytochemistry stain showed that placental MSC was a homogeneous cell population devoid of hematopoietic cells, which uniformly expressed CD29, CD44, CD73, CD105, CD166, laminin, fibronectin and vimentin while being negative for expression of CD31, CD34, CD45 and alpha-smooth muscle actin. Most importantly, immuno-phenotypic analyses demonstrated that these cells expressed class I major histocompatibility complex (MHC-I), but they did not express MHC-II molecules. Additionally these cells could suppress umbilical cord blood (UCB) lymphocytes proliferation induced by cellular or nonspecific mitogenic stimuli. This strongly implies that they may have potential application in allograft transplantation. Since placenta and UCB are homogeneous, the MSC derived from human placenta can be transplanted combined with hematopoietic stem cells (HSC) from UCB to reduce the potential graft-versus-host disease (GVHD) in recipients.
The development of tendinitis and tendinopathy is often multifactorial and the result of both intrinsic and extrinsic factors. Intrinsic factors include anatomic factors, age-related factors, and systemic factors, whereas extrinsic factors include mechanical overload and improper form and equipment. Although tendinitis and tendinopathy are often incorrectly used interchangeably, they are in 2 distinct pathologies. Due to their chronicity and high prevalence in tendons about the ankle, including the Achilles tendon, the posterior tibialis tendon, and the peroneal tendons, tendinitis and tendinopathies cause significant morbidity and are important pathologies for physicians to recognize.
Tissue engineering and regenerative medicine (TERM) is a field that applies biology and engineering principles to “restore, maintain or repair a tissue after injury”. Besides the potential to treat various diseases, these endeavours increase our understanding of fundamental cell biology. Although TERM has progressed rapidly, engineering a whole organ is still beyond our skills, primarily due to the complexity of tissues. Material science and current manufacturing methods are not capable of mimicking this complexity. Therefore, many researchers explore the use of naturally derived materials that maintain important biochemical, structural and mechanical properties of tissues. Consequently, employing non-cellular components of tissues, particularly the extracellular matrix, has emerged as an alternative to synthetic materials. Because of their complexity, decellularized tissues are not as well defined as synthetic materials but they provide cells with a microenvironment that resembles their natural niche.
Decellularized tissues are produced from a variety of sources, among which the fetal membranes are excellent candidates since their supply is virtually unlimited, they are readily accessible with minimum ethical concerns and are often discarded as a biological waste. In this review, we will discuss various applications of decellularized fetal membranes as substrates for the expansion of stem cells, their use as two and three-dimensional scaffolds for tissue regeneration, and their use as cell delivery systems. We conclude that fetal membranes have great potential for use in TERM.
Background:
Degenerative joint and tendon injuries remain difficult to treat, with few effective conservative treatment options available. Regenerative approaches aim to promote the inherent healing capacity of injured tissues. Micronized dehydrated human amnion/chorion membrane (dHACM) injection is an emerging regenerative option with promising preclinical results.
Objective:
To test the clinical effectiveness of dHACM injection in patients with chronic tendinopathy and arthropathy.
Design:
Case series.
Setting:
Academic medical center outpatient sports medicine clinic.
Patients:
A total of 40 patients with chronic tendinosis or arthropathy who received dHACM over a period of 9 months.
Methods:
A structured interview was administered to patients by telephone to supplement the clinical information available in the medical chart. All patients received an ultrasound-guided injection of dHACM.
Main outcome measures:
The primary outcome was change in pain level, and the secondary outcome was change in activities of daily living (ADLs) and sports/recreation function. More than 30% improvement in average pain and function was considered a successful outcome.
Results:
Patient pain and function were measured at 1, 2, and 3 months after the procedure. Patient-reported average pain scores decreased from a baseline value of 6.4 (95% confidence interval [CI] = 5.7-7.0) to 2.7 (95% CI = 2.1-3.3; P < .001) at 1 month, 1.7 (95% CI = 1.1-2.2; P < .001) at 2 months, and 1.4 (95% CI = 0.9-1.9; P < .001) at 3 months. The percentage of patients achieving clinical success, defined as 30% or greater improvement in pain levels, was 68% at 1 month, 82% at 2 months, and 91% at 3 months. Patient-reported functional impairment in ADLs decreased from 6.8 (95% CI = 6.0-7.5) to 2.0 (95% CI = 1.4-2.7) (P < .001); impairment in sports/recreation decreased from 8.5 (95% CI = 7.9-9.1) to 3.2 (95% CI = 2.6-3.9) (P < .001). Frequency of pain medication use decreased from 29 of 40 patients (72.5%) before the procedure to 9 of 40 patients (22.5%) at final follow up (P < .001). Localized pain at the injection site was common, but no other adverse events or side effects were reported.
Conclusion:
In the setting of tendinosis or arthropathy, dHACM injection was clinically effective in reducing pain and improving function in a majority of adults.
Level of evidence:
IV.
Mesenchymal stem cells (MSCs) represent an ideal source of autologous cell-based therapy for chronic wounds. Functional characteristics of MSCs may benefit wound healing by exerting their multi-regenerative potential. However, cell ageing resulting from chronic degenerative diseases or donor age could cause inevitable effects on the regenerative abilities of MSCs. A variety of studies have shown the relationship between MSC ageing and age-related dysfunction, but few associate these age-related impacts on MSCs with their ability of repairing chronic wounds, which are common in the elderly population. Here, we discuss the age-associated changes of MSCs and describe the potential impacts on MSC-based therapy for chronic wounds. Furthermore, critical evaluation of the current literatures is necessary for understanding the underlying mechanisms of MSC ageing and raising the corresponding concerns on considering their possible use for chronic wound repair.
The primary aim of this study was to compare preoperative assessments with postoperative outcomes from patients undergoing foot and ankle revisions and/or complex reconstructions with tendon and/or nerve involvement using cryopreserved human amniotic membrane and umbilical cord (cHAM/UC). We hypothesized complex foot and ankle surgery using amniotic membrane would be an effective treatment leading to reduced pain and improved functional outcomes. Fourteen patients (6 male and 8 female) underwent open foot and ankle surgery during the study period. All 14 patients included in this cohort reported improvement, namely, lessened pain intensity both on the American Orthopedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale and the pain numeric rating scale (NRS), as well as improved functional status. The mean AOFAS score improved from 50 (range, 17-79) preoperatively to 85 (range, 67-100) postoperatively. The mean NRS score also improved from 8 (range, 4-10) preoperatively to 2 (range, 0-6) postoperatively with a mean percent change in pain NRS of 78% (range 17-100%). Both outcome-scoring systems showed statistically significant differences (p < .0001) when we compared the preoperative and postoperative results. All patients included in the cohort showed improvement in both outcome measures. Further study of long-term endpoints is warranted.
Objective:
The anti-inflammatory and anti-catabolic effects of neonatal Mesenchymal Stromal Cell (MSC) were investigated in a xenogeneic model of mild osteoarthritis (OA). The paracrine properties of MSC on synoviocytes were further investigated in vitro.
Study design:
OA was induced by medial meniscal release (MMR) in 30 rabbit knees. A single early (day 3) or delayed (day 15) intra-articular (IA) injection of MSC isolated from equine Umbilical Cord Wharton's jelly (UC-MSC) was performed. Rabbits were euthanized on days 15 or 56. OA grading was performed and gene expression of inflammatory cytokines and metalloproteinases was measured in synovial tissue. Paracrine effects of UC-MSC were investigated using UC-conditioned vs control medium on rabbit primary synoviocytes stimulated with interleukin 1 beta in vitro.
Results:
No adverse local or systemic responses were observed clinically after xenogeneic UC-MSC injection. At study end point, cartilage fibrillation was lower in early treatment than in delayed treatment group. Cellular infiltrate was observed in the synovium of both UC-MSC groups. OA synovium exhibited a reduced expression of metalloproteinases-1, -3, -13 in the early cell-treated group at d56. In vitro, UC-conditioned medium exerted anti-inflammatory and anti-catabolic effects on synoviocytes exposed to pro-inflammatory stimulus.
Conclusions:
Early IA injection of equine UC-MSC was effective in preventing OA signs in rabbit knees following MMR. UC-MSC target the synovium and modulate the gene expression pattern of synoviocytes to promote an anti-catabolic environment. This confirms the synovium is a major target and mediator of MSC therapy, modulating the expression of matrix-degrading enzymes.
There are limited treatment options for tissue restoration and the prevention of degenerative changes in the knee. Stem cells have been a focus of intense preclinical research into tissue regeneration but limited clinical investigation. In a randomized, double-blind, controlled study, the safety of the intra-articular injection of human mesenchymal stem cells into the knee, the ability of mesenchymal stem cells to promote meniscus regeneration following partial meniscectomy, and the effects of mesenchymal stem cells on osteoarthritic changes in the knee were investigated.
A total of fifty-five patients at seven institutions underwent a partial medial meniscectomy. A single superolateral knee injection was given within seven to ten days after the meniscectomy. Patients were randomized to one of three treatment groups: Group A, in which patients received an injection of 50 × 106 allogeneic mesenchymal stem cells; Group B, 150 × 106 allogeneic mesenchymal stem cells; and the control group, a sodium hyaluronate (hyaluronic acid/hyaluronan) vehicle control. Patients were followed to evaluate safety, meniscus regeneration, the overall condition of the knee joint, and clinical outcomes at intervals through two years. Evaluations included sequential magnetic resonance imaging (MRI).
No ectopic tissue formation or clinically important safety issues were identified. There was significantly increased meniscal volume (defined a priori as a 15% threshold) determined by quantitative MRI in 24% of patients in Group A and 6% in Group B at twelve months post meniscectomy (p = 0.022). No patients in the control group met the 15% threshold for increased meniscal volume. Patients with osteoarthritic changes who received mesenchymal stem cells experienced a significant reduction in pain compared with those who received the control, on the basis of visual analog scale assessments.
There was evidence of meniscus regeneration and improvement in knee pain following treatment with allogeneic human mesenchymal stem cells. These results support the study of human mesenchymal stem cells for the apparent knee-tissue regeneration and protective effects.
Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PEER REVIEW This article was reviewed by the Editor-in-Chief and one Deputy Editor, and it underwent blinded review by two or more outside experts. It was also reviewed by an expert in methodology and statistics. The Deputy Editor reviewed each revision of the article, and it underwent a final review by the Editor-in-Chief prior to publication. Final corrections and clarifications occurred during one or more exchanges between the author(s) and copyeditors.
Background:
Several studies have shown that the application of amniotic membrane as a biological dressing in the management of burns is accompanied by rapid re-epithelialisation and healing as it diminishes the oozing of plasma, bacterial count and fluid, protein and heat loss. This study evaluates the effect of amniotic membrane on graft take in split-thickness skin graft of extremity burns.
Methods:
From October 2008 to January 2010, in a prospective clinical trial, 54 patients (108 limbs) with second and third degree burns, covering 4-15% of total body surface area (TBSA), were included in this study. All patients needed split-thickness skin grafts for burn-wound coverage. Selected patients had symmetric burns on two (upper or lower) extremities. Then in every patient, the extremities were randomly divided into two groups: in one limb, the skin graft was traditionally fixed with skin staples (control group) and in the other limb the skin graft was covered with an amniotic membrane (amnion group). Therefore, in every patient the graft was covered with an amniotic membrane in one extremity and fixed with skin staples in the other extremity. Finally, the duration and success rate of complete graft take was compared between the two groups.
Results:
The study group was composed of 108 limbs in 54 patients (27 males and 27 females) with a mean age of 23.54±4.9 years and burn 9.03±2.69% TBSA. The mechanism of burn was flame (63%), scald (18.5%) and flash (18.5%). The rate of complete graft take was 96.76% and 88.79% in the amnion group and in the control group, respectively. The mean duration of graft take was 6.98±1.35 days in the amnion group and 13.9±1.66 days in the control group. This difference was statistically significant (P<0.001).
Conclusions:
Our results show that although the amniotic membrane has no negative impact on graft take, it significantly reduces the duration of complete graft take, which is very important for both the patient and the health-care system.
Placenta mesenchymal stem cells (PMSCs) have the characteristic features of stem cells including renewability in vitro, surface expression, differentiation potency and ability to adhere to the culture surface. PMSCs expressed genes are normally found in the embryonic tissues before the onset of gastrulation, indicating multipotency. However, the stemness can depend on the stages of the placenta from which the cells were isolated. PMSCs were isolated from two different stages of placenta for comparison, that is the first and third trimesters. Both sets had very similar patterns of surface expression as CD44, CD73, CD90 and CD105, and of self renewability in vitro. Expressions of pluripotency-coupled genes were also confirmed in both sets of cells; however, there was a significant difference in the expression levels: fPMSC (mesenchymal stem cells isolated from the first trimester human placenta) being 2-11-fold higher than tPMSC (mesenchymal stem cells isolated from the third trimester human placenta). Possibly due to the difference in the expression levels of the pluripotency-related genes, induction of genes specific to the ectodermal tissues were more prominent in fPMSC than tPMSC after induced differentiation.
In vitro expanded and frosted ovine amniotic epithelial cells (oAECs) were evaluated for their phenotype, stemness and attitude to differentiate into tenocytes. Fifteen horses with acute tendon lesions were treated with one intralesional injection of oAECs. Tendon recovery under controlled training was monitored. In vitro expanded oAECs showed a constant proliferative ability, a conserved phenotype and stable expression profile of stemness markers. Differentiation into tenocytes was also regularly documented. US controls showed the infilling of the defect and early good alignment of the fibers and 12 horses resumed their previous activity. Histological and immunohistochemical examinations in an explanted tendon demonstrated the low immunogenicity of oAECs that were able to survive in the healing site. In addition, oAECs supported the regenerative process producing ovine collagen type I amongst the equine collagen fibers. Considering our results, oAECs can be proposed as a new approach for the treatment of spontaneous equine tendon injuries.
We have investigated foetal mesenchymal stem cells (MSCs) obtained from first-trimester chorionic villi (CV) and second-trimester amniotic fluid (AF), comparing them to adult bone marrow-derived MSCs.
We report on cell population growth in human allogeneic serum (HS) and platelet lysate (PL), immunophenotype, cytokine expression profile and immunoregulatory activity, of these foetal MSCs on stimulated peripheral blood mononuclear and lymphocyte subpopulations.
Chorionic villi cells grow rapidly in HS, with 20 populations doublings (PDs) after 59 days (six passages), and also in animal serum, with 27 PDs after 65 days (seven passages). PL allowed for expansion in 60% of the samples tested, although it was lower than in HS. HS supported an average of 40 PDs of expansion in 20% of AF cells after 90 days, whereas animal serum supported 28.5 PDs in 66 days. CV and AF cells inhibited proliferation of stimulated T lymphocytes, suppressing population growth of both CD4+ and CD8+ T subpopulations and sometimes also, CD19+ cells.
Our results indicate that CV would be an optimal source of MSCs with high expansion potential in a HS propagation system and immunoregulatory capacity of T and B lymphocytes. More than 90% of CV samples achieved large-scale expansion in HS, which is encouraging for potential clinical applications of these cells.
Mesenchymal stromal cells (MSC) have recently been identified as a therapeutic option in several clinical conditions. Whereas bone marrow (BM) is considered the main source of MSC (BM-MSC), the invasive technique required for collection and the decline in allogeneic donations call for alternative sources. Human umbilical cord (UC) represents an easily available source of MSC (UC-MSC).
Sections of full-term UC were transferred to cell culture flasks and cultured in 5% human platelet lysate (PL)-enriched medium. Neither enzymatic digestion nor blood vessel removal was performed. After 2 weeks, the adherent cells were harvested (P1), replated at low density and expanded for two consecutive rounds (P2 and P3).
We isolated and expanded MSC from 9/9 UC. UC-MSC expanded with a mean fold increase (FI) of 42 735 ± 16 195 from P1 to P3 in a mean of 29 ± 2 days. By processing the entire cord unit, we theoretically could have reached a median of 9.5 × 10(10) cells (ranging from 1.0 × 10(10) to 29.0 × 10(10)). UC-MSC expressed standard surface markers; they contained more colony-forming unit (CFU)-fibroblast (F) and seemed less committed towards osteogenic, chondrogenic and adipogenic lineages than BM-MSC. They showed immunosuppressive properties both in vitro and in an in vivo chronic Graft versus Host disease (cGvHD) mouse model. Both array-Comparative Genomic Hybridization (CGH) analysis and karyotyping revealed no chromosome alterations at the end of the expansion. Animal studies revealed no tumorigenicity in vivo.
UC constitute a convenient and very rich source of MSC for the production of third-party 'clinical doses' of cells under good manufacturing practice (GMP) conditions.
To determine the effects of human amniotic fluid and membrane in the treatment of Achilles tendon ruptures, 72 tendons of 36 Wistar rats were injected with betamethasone sodium phosphate.
By the end of fourth week, both tendons were tenotomized and repaired, then the samples were divided into three groups. The first group was left untreated after suturing. Human amniotic fluid was injected to the second and amniotic fluid and membrane were both administered to the third group. Twenty-four tendons were scored at the end of the first week, and 24 at the end of the second week histopathologically, and 24 biomechanically at the end of the third week.
There was a significant statistical difference only between the histopathological results of Groups 2 and 3 at the first week.
Human amniotic membrane and fluid do not add anything to the healing process of Achilles tendon ruptures in the early phase.
This study describes the epidemiology of a range of adult musculoskeletal soft tissue injuries. Our institution is the only hospital treating adults with musculoskeletal trauma in a well-defined catchment population of about 535,000. Demographic details over 5 years were recorded prospectively. Eighteen injury types were studied including anterior cruciate ligament (ACL) rupture, acromioclavicular joint (ACJ) injury, Achilles, patellar and quadriceps tendon ruptures, hand tendon injuries and mallet finger. 2794 patients presented with ligamentous or tedinous injuries over 5 years. 74.2% of patients were male, giving an incidence of 166.6/100,000 per year for males and 52.1/100,000 per year for females. The mean age was 36.3 years: 33.1 in males, 43.6 in females. 1040 (37.2%) were knee injuries: 75.6% were male with mean age 32.9, compared with 35.3 in females. 947 cases were hand tendon injuries (33.9%): 72.1% were male, with mean age 34.5 compared with 42.0 in females. Meniscal injury of the knee was the commonest injury with an incidence of 23.8/100,000 per year. Other common injuries were hand extensor tendons (18/100,000 per year), ACJ injury (14.5/100,000 per year), Achilles tendon rupture (11.3/100,000 per year), mallet finger (9.9/100,000 per year) and ACL rupture (8.1/100,000 per year). Achilles, patellar and quadriceps tendon rupture and mallet finger were injuries of middle age; rotator cuff tears and biceps tendon rupture were commoner in the elderly but all other injuries predominated in young patients. All injuries were commoner in males. Most soft tissue injuries follow distribution curves previously described for fracture epidemiology but three new distribution curves are presented for the injuries which predominate in middle age.
During the last few decades, the role of sports and physical activity has become more and more important in all modern communities. Conditioning sports are generally considered positive by many governments because of their beneficial effect on human well-being. The risk of injury is increased, for both acute traumas and overuse injuries, and prevention has also become more important in sports. Epidemiologic studies are important when planning prevention programs for sports injuries. Because of individual sport cultures and different sport habits in different countries, national epidemiologic studies are of importance in each individual country.
Overuse injuries are common in recreational and competitive sports as well as in day-to-day activities. The musculotendinous unit comprises the tissue most frequently involved: structural damage to the tendon occurs from repetitive strain and loading, from either endurance or skill activities that require technique and power. The potential for injury is enhanced by a great variety of predisposing intrinsic or extrinsic factors. Tendinous tissue will become fatigued as its basal reparative ability is overwhelmed by repetitive dysfunctional and microtraumatic processes. Tendinitis is the earliest recognisable manifestation of overuse injury: as damage progresses, partial tears and complete ruptures may ensue.
The diagnosis of overuse injury rests with identification not only of the affected tendinous unit, but also of the underlying predisposing condition or conditions. Treatment can then proceed with elimination or correction, if possible, of these conditions, together with control of inflammation and programmes of modalities designed to restore the structural and functional integrity of the tendon.
Knowledge of overuse problems has grown exponentially in the past 3 decades, as evidenced by the outpouring of scientific and medical literature. Sophisticated analytical techniques, supplementing a sound history and physical examination, have greatly facilitated the diagnosis of overuse problems and allowed the application of scientific therapeutic principles. As the number of participants in recreational activities continues to grow, the application of these techniques in ever more innovative ways holds the greatest promise for the prevention of overuse tendon injuries.
There is increasing evidence that synovial fluid plays a major role in the nutrition and healing of tendons, thus it is important to restore the synovial medium after flexor tendon repair. Techniques for primary repair of flexor tendons, which is the therapy of choice in the majority of cases, are detailed.