MEDICAL POLICY
POLICY
RELATED POLICIES
POLICY GUIDELINES
CODING
DESCRIPTION
SCOPE
BENEFIT APPLICATION
RATIONALE
REFERENCES
APPENDIX
HISTORY
Orthopedic Applications of Stem-Cell Therapy (Including
Allograft and Bone Substitute Products Used with
Autologous Bone Marrow)
Number
8.01.52
Effective Date
April 1, 2016
Revision Date(s) 06/09/17; 03/08/16; 09/01/15; 06/09/15; 06/19/14; 08/20/13;
06/10/13; 04/26/13; 10/09/12; 08/20/12; 08/15/12; 07/20/12;
08/09/11
Replaces
N/A
Policy
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Mesenchymal stem cell therapy is considered investigational for all orthopedic applications, including use in
repair or regeneration of musculoskeletal tissue.
Allograft bone products containing viable stem cells, including but not limited to demineralized bone matrix (DBM)
with stem cells, are considered investigational for all orthopedic applications.
Allograft or synthetic bone graft substitutes that must be combined with autologous blood or bone marrow are
considered investigational for all orthopedic applications.
Related Policies
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2.01.16
Recombinant and Autologous Platelet-Derived Growth Factors as a Primary Treatment of Wound
Healing and Other Miscellaneous Conditions
2.01.98
Orthopedic Applications of Platelet-Rich Plasma
7.01.149
Amniotic Membrane and Amniotic Fluid Injections
Policy Guidelines
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Note: This policy does not address unprocessed allograft bone.
Coding
CPT
20999
Unlisted procedure, musculoskeletal system, general
38206
38230
38241
Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; autologous
Bone marrow harvesting for transplantation; allogeneic
Hematopoietic progenitor cell (HPC); autologous transplantation
Description
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Mesenchymal stem cells (MSCs) have the capability to differentiate into a variety of tissue types, including various
musculoskeletal tissues. Potential uses of MSCs for orthopedic applications include treatment of damaged bone,
cartilage, ligaments, tendons and intervertebral discs.
The evidence for stem cell therapy in individuals who have various orthopedic conditions (cartilage defects,
meniscectomy, spinal fusion procedures, osteonecrosis) includes small randomized controlled trials and
nonrandomized comparative trials. Relevant outcomes are symptoms, morbid events, functional outcomes,
quality of life, and treatment-related morbidity. Use of MSCs for orthopedic conditions is an active area of
research. Despite continued research into the methods of harvesting and delivering treatment, there are
uncertainties regarding the optimal source of cells and the delivery method. Studies have included MSCs from
bone marrow, adipose tissue, peripheral blood, and synovial tissue. The largest body of evidence is on use of
autologous MSCs, either concentrated or expanded in culture, for cartilage repair. This evidence includes small
randomized and nonrandomized comparative trials with insufficient data to evaluate health outcomes. In addition,
expanded MSCs for orthopedic applications are not U.S. Food and Drug Administration (FDA)‒approved
(concentrated autologous MSCs do not require FDA approval). Overall, there is a lack of evidence that clinical
outcomes are improved. The evidence is insufficient to determine the effects of the technology on health
outcomes.
Background
MSCs are multipotent cells (also called stromal multipotent cells) that possess the ability to differentiate into
various tissues including organs, trabecular bone, tendon, articular cartilage, ligaments, muscle, and fat. MSCs
are associated with the blood vessels within bone marrow, synovium, fat, and muscle, where they can be
mobilized for endogenous repair as occurs with healing of bone fractures. Bone-marrow aspirate is considered to
be the most accessible source and, thus, the most common place to isolate MSCs for treatment of
musculoskeletal disease. However, harvesting MSCs from bone marrow requires an additional procedure that
may result in donor-site morbidity. In addition, the number of MSCs in bone marrow is low, and the number and
differentiation capacity of bone marrow‒derived MSCs decreases with age, limiting their efficiency when isolated
from older patients.
Tissues such as muscle, cartilage, tendon, ligaments, and vertebral discs show limited capacity for endogenous
repair. Therefore, tissue engineering techniques are being developed to improve the efficiency of repair or
regeneration of damaged musculoskeletal tissues. Tissue engineering focuses on the integration of biomaterials
with MSCs and/or bioactive molecules such as growth factors. In vivo, the fate of stem cells is regulated by
signals in the local 3-dimensional microenvironment from the extracellular matrix and neighboring cells. It is
believed that the success of tissue engineering with MSCs will also require an appropriate 3-dimensional scaffold
or matrix, culture conditions for tissue-specific induction, and implantation techniques that provide appropriate
biomechanical forces and mechanical stimulation. The ability to induce cell division and differentiation without
adverse effects, such as the formation of neoplasms, remains a significant concern. Given that each tissue type
requires different culture conditions, induction factors (signaling proteins, cytokines, growth factors), and
implantation techniques, each preparation must be individually examined.
FDA has stated:
“A major challenge posed by SC [stemcell] therapy is the need to ensure their efficacy and safety. Cells
manufactured in large quantities outside their natural environment in the human body can become
ineffective or dangerous and produce significant adverse effects, such as tumors, severe immune
reactions, or growth of unwanted tissue.”(1)
Regulatory Statkus
Concentrated autologous MSCs do not require approval by FDA.
DBM, which is processed allograft bone, is considered minimally processed tissue and does not require FDA
approval. At least 4 commercially available DBM products are reported to contain viable stem cells:
 Allostem® (AlloSource): partially demineralized allograft bone seeded with adipose-derived MSCs
 Map3™ (rti surgical) contains cortical cancellous bone chips, DBM, and multipotent adult progenitor cells
 Osteocel Plus® (NuVasive): DBM combined with viable MSCs that have been isolated from allogeneic
bone marrow
 Trinity Evolution Matrix™ (Orthofix) DBM combined with viable MSCs that have been isolated from
allogeneic bone marrow
Whether these products can be considered minimally manipulated tissue is debated. A product would not meet
the criteria for FDA regulation part 1271.10 if it is dependent upon the metabolic activity of living cells for its
primary function. Otherwise, a product would be considered a biologic product and would need to demonstrate
safety and efficacy for the product’s intended use with an investigational new drug and Biologics License
Application (BLA).
Other products contain DBM and are designed to be mixed with bone marrow aspirate. Some of the products that
are currently available are:
 Fusion Flex™ (Wright Medical): a dehydrated moldable DBM scaffold that will absorb autologous bone
marrow aspirate.
 Ignite® (Wright Medical): an injectable graft with DBM that can be combined with autologous bone
marrow aspirate.
Other commercially available products are intended to be mixed with bone marrow aspirate and have received
510(k) clearance, such as:
 CopiOs sponge or paste (Zimmer): synthetic bone graft material consisting of mineralized, lyophilized
collagen.
 Collage™ Putty (Orthofix): Composed of type-1 bovine collagen and beta tricalcium phosphate.
 Vitoss® (Stryker, developed by Orthovita): composed of beta tricalcium phosphate.
 nanOss® Bioactive (rti surgical, developed by Pioneer Surgical): nanostructured hydroxyapatite and an
open structured engineered collagen carrier.
FDA product code: MQV
No products using engineered or expanded MSCs have been approved by FDA for orthopedic applications.
In 2008, FDA determined that the mesenchymal stem cells sold by Regenerative Sciences for use in the
Regenexx™ procedure would be considered drugs or biological products and thus require submission of a New
Drug Application (NDA) or Biologic License Application (BLA) to FDA. (2) In 2014, a federal appellate court
upheld FDA’s power to regulate adult stem cells as drugs and biologics and ruled that the Regenexx cell product
fell within FDA’s authority to regulate human cells, tissues, and cellular and tissue-based products (HCT/Ps). (3)
To date, no NDA or BLA has been approved by FDA for this product. As of 2015, the expanded stemcell
procedure is only offered in the Cayman Islands. Regenexx™ network facilities in the United States provide
same-day stemcell and blood platelet procedures, which do not require FDA approval (available at
http://www.regenexx.com/common-questions/regenexx-fda. (Last accessed March 2016.)
Scope
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Medical policies are systematically developed guidelines that serve as a resource for Company staff when
determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject
to the limits and conditions of the member benefit plan. Members and their providers should consult the member
benefit booklet or contact a customer service representative to determine whether there are any benefit limitations
applicable to this service or supply. This medical policy does not apply to Medicare Advantage.
Benefit Application
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The Regenexx™ procedure is currently performed in one location (Regenerative Sciences, Centeno Schultz
Clinic, Bloomfield, Colorado).
Rationale
Populations
Individuals:
 With cartilage defects
Interventions
Interventions of interest
are:
 Stem cell therapy
Comparators
Comparators of interest are:
 Conservative management
 Microfracture
 Autologous chondrocyte
implantation
Individuals:
 With meniscectomy
Interventions of interest
are:
 Stem cell therapy
Comparators of interest are:
 Conservative management
Individuals:
 With spinal fusion
procedures
Interventions of interest
are:
 Stem cell therapy
Comparators of interest are:
 Iliac crest bone graft
Individuals:
 With osteonecrosis
Interventions of interest
are:
 Stem cell therapy
Comparators of interest are:
 Core decompression
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Outcomes
Relevant outcomes include:
 Symptoms
 Morbid events
 Functional outcomes
 Quality of life
 Treatment-related morbidity
Relevant outcomes include:
 Symptoms
 Morbid events
 Functional outcomes
 Quality of life
 Treatment-related morbidity
Relevant outcomes include:
 Symptoms
 Morbid events
 Functional outcomes
 Quality of life
 Treatment-related morbidity
Relevant outcomes include:
 Symptoms
 Morbid events
 Functional outcomes
 Quality of life
 Treatment-related morbidity
This policy was created in 2010 and updated periodically using the MEDLINE database. The most recent
literature update was performed through November 17, 2015.
At the time this policy was created, the literature consisted almost entirely of review articles describing the
potential of stem-cell therapy for orthopedic applications in humans, along with basic science experiments on
sources of mesenchymal stem cells (MSCs), regulation of cell growth and differentiation, and development of
scaffolds. (4) Authors of these reviews indicated that the technology was in an early stage of development. In
literature searches of the MEDLINE database, use of cultured MSCs in humans was identified in only a few
centers in the United States, Europe, and Asia. Since the policy was created, the evidence base has been
steadily increasing, although there is a lack of high-quality randomized controlled trials (RCTs), and nearly all of
the studies to date have been performed outside of the U.S.
Cartilage Defects
The source of MSCs may have an impact on outcomes, but this is not well understood, and the available literature
uses multiple different sources of MSCs. Because of the uncertainty over whether these products are equivalent,
the evidence will be grouped by source of MSC.
One systematic review was published in 2013 that included multiple sources of MSC. In 2013, Filardo et al.
conducted a systematic review of mesenchymal stem cells for the treatment of cartilage lesions. (5) They
identified 72 preclinical papers and 18 clinical reports. Of the 18 clinical reports, none were randomized, 5 were
comparative, 6 were case series, and 7 were case reports. The source of MSCs was adipose tissue in 2 clinical
studies, bone marrow concentrate in 5, and in 11 studies, the source was bone marrow-derived. Many of these
trials had been performed by the same research group in Asia. Following is a summary of the key literature to
date, focusing on comparative studies.
MSCs Expanded from Bone Marrow
Autologous Bone Marrow
In December 2013 (after the systematic review by Filardo et al. was published), Wong et al. reported an RCT of
cultured MSCs in 56 patients with osteoarthritis who underwent medial opening-wedge high tibial osteotomy and
microfracture of a cartilage lesion. (6) Bone marrow was harvested at the time of microfracture and the MSCs
were isolated and cultured. After three weeks, the cells were assessed for viability and delivered to the clinic,
where patients received an intra-articular injection of MSCs suspended in hyaluronic acid (HA), or for controls,
intra-articular injection of HA alone. The primary outcome was the International Knee Documentation Committee
(IKDC) score at six months, one year, and two years. Secondary outcomes were the Tegner and Lysholm scores
through two years and the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scoring
system by magnetic resonance imaging (MRI) at one year. All patients completed the two year follow-up. After
adjusting for age, baseline scores, and time of evaluation, the group treated with MSCs showed significantly
better scores on the IKDC (mean difference, 7.65 on 0-100 scale; p=0.001), Lysholm (mean difference, 7.61 on 0100 scale; p=0.02), and Tegner (mean difference, 0.64 on a 0 to 10 scale; p=0.02). Blinded analysis of MRI
results found higher MOCART scores in the MSC group. The group treated with MSCs had a higher proportion of
patients who had complete cartilage coverage of their lesions (32% vs. 0%), greater than 50% cartilage cover
(36% vs. 14%) and complete integration of the regenerated cartilage (61% vs. 14%). This study is ongoing and
recruiting additional patients.
Wakitani et al. first reported use of expanded MSCs for repair of cartilage defects in 2002. (7) Cells from bone
marrow aspirate of 12 patients with osteoarthritic knees were culture expanded, embedded in collagen gel,
transplanted into the articular cartilage defect, and covered with autologous periosteum at the time of high tibial
osteotomy. Clinical improvement was not found to be different between the experimental group and a group of 12
control patients who underwent high tibial osteotomy alone. Wakitani et al. have since published several cases of
patients treated for isolated cartilage defects, with clinical improvement reported at up to 27 months. (8) However,
most of the defects appear to have been filled with fibrocartilage. A 2011 report from Wakitani et al. was a followup safety study of 31 of the 41 patients (3 patients had died, 5 had undergone total knee arthroplasty) who had
received MSCs for articular cartilage repair in their clinics between 1998 and 2008. (8) At a mean of 75 months
(range, 5-137) since the index procedure, no tumors or infections were identified. Function was not reported.
Another study from Asia evaluated the efficacy of bone marrow-derived MSCs compared with autologous
chondrocyte implantation (ACI) in 36 matched patient pairs. (10) Thirty-six consecutive patients with at least 1
symptomatic chondral lesion on the femoral condyle, trochlea, or patella were matched with 36 cases of ACI
performed earlier, based on lesion sites and 10-year age intervals. Autologous MSCs were cultured from 30 mL of
bone marrow from the iliac crest, tested to confirm that the cultured cells were MSCs, and implanted beneath a
periosteal patch. Concomitant procedures included patella realignment, high -tibial osteotomy, partial
meniscectomy, and anterior cruciate ligament reconstruction. Clinical outcomes, measured pre-operatively and at
3, 6, 12, 18, and 24 months after operation using the International Cartilage Repair Society Cartilage Injury
Evaluation Package, showed improvement in patients’ scores over the 2-year follow-up in both groups, with no
significant difference between groups for any of the outcome measures except for Physical Role Functioning on
the 36-Item Short-Form Health Survey, which showed a greater improvement over time in the MSC group.
A 2010 publication from Centeno et al. of Regenerative Sciences describes the use of percutaneously injected
culture-expanded MSCs from the iliac spine in 226 patients. (11) Following harvesting, cells were cultured with
autologous platelet lysate and re-injected under fluoroscopic guidance into peripheral joints (n=213) or
intervertebral discs (n=13). Follow-up for adverse events at a mean of 10.6 months showed 10 cases of probable
procedure-related complications (injections or stem-cell related), all of which were considered to be self-limited or
treated with simple therapeutic measures. Serial MRIs from a subset of patients showed no evidence of tumor
formation at a median follow-up of 15 months. The efficacy of these procedures was not reported. This procedure
is no longer offered in the United States.
Allogeneic Bone Marrow
In 2015, Vega et al reported a small phase 1/2 RCT of 30 patients with osteoarthritis unresponsive to
conventional treatments.(12) The MSC-treated group received intra-articular injection of expanded allogeneic
bone marrow MSCs from healthy donors and the control group received an intra-articular injection of HA. Followup using standard outcome measures was performed at 3, 6, and 12 months after injection. In the MSC-treated
group, pain scores (VAS and Western Ontario and McMasters Universities Arthritis Index [WOMAC]) decreased
significantly between baseline and the 12-month follow-up, whereas pain scores in the control group did not
improve significantly. A significant improvement in cartilage in the MSC group was supported by T2 MRI. Not
reported was whether the patients or assessors were blinded to treatment in this trial. Additional study in a larger
number of patients in a phase 3 trial with blinding of patients and assessors is needed.
MSCs Concentrated from Bone Marrow
In 2009, Giannini et al reported a 1-step procedure for transplanting bone marrow‒derived cells for type II (>1.5
2
cm , <5 mm deep) osteochondral lesions of the talus in 48 patients.(13) A total of 60-mL bone marrow aspirate
was collected from the iliac crest. The bone marrow‒derived cells were concentrated and implanted with a
scaffold (collagen powder or HA membrane) and platelet gel. In a 2010 publication, Giannini et al reported results
of a retrospective analysis based on the evolution of the investigator’s technique at the time of treatment.
Outcomes following arthroscopic application of the MSC concentrate (n=25) were similar to open (n=10) or
arthroscopic (n=46) ACI.(14) ACI with a biodegradable scaffold is not commercially available in the United States
(see evidence review 7.01.48).
Centeno et al reported a multicenter registry of patients treated with autologous stem cells, bone marrow
concentrate, and platelet-rich plasma.(15) This report focused on 102 patients (115 shoulders) diagnosed with
either osteoarthritis of the shoulder or rotator cuff tears. Patients were treated with a protocol that included a
hypertonic dextrose solution (prolotherapy) injection to create an inflammatory response several days prior to the
bone marrow concentrate injection. The bone marrow concentrate injection included platelet-rich plasma and
platelet lysate. Both Disabilities of the Arm, Shoulder, and Hand scores and numeric pain scale (NPS) scores
decreased by about 50%, although the absolute decrease in the NPS score was a very modest 0.9. Interpretation
of these results is limited by the lack of a placebo control and blinding, subjective outcome measures, and the
multiple treatments used, although it is acknowledged that neither prolotherapy nor PRP appear to have efficacy
on their own. Additional study with randomized and placebo-controlled trials is needed to evaluate this treatment
protocol. (see Related Policies).
Adipose-Derived MSCs
The literature on adipose-derived MSCs for articular cartilage repair comes from 2 different research groups in
Korea. One of the groups appears to have been providing this treatment as an option for patients for a number of
years. They compare outcomes of this new add-on treatment with those of patients who only received other
cartilage repair procedures.
In 2014, Koh et al. reported results of an RCT that evaluated cartilage healing after high tibial osteotomy (HTO) in
52 patients with osteoarthritis of the medial compartment. (16) Patients were randomly assigned via sealed
envelopes to HTO with application of platelet-rich plasma (PRP) or HTO with application of PRP plus MSCs. (Use
of PRP is considered investigational, see Related Policies for further information.) MSCs from adipose tissue
were obtained through liposuction from the buttocks. The tissue was centrifuged and the stromal vascular fraction
mixed with PRP for injection. A total of 44 patients completed second look arthroscopy and 1- and 2-year clinical
follow-up. The primary outcomes were the Knee Injury and Osteoarthritis Outcome Score (KOOS; 5 subscales
with 0-100 scale), the Lysholm score (0-100 scale), and a VAS pain scale (0-100 scale). There were statistically
significant differences for PRP only versus PRP+MSC on 2/5 KOOS subscales; pain (74±5.7 vs. 81.2±6.9,
p<0.001) and symptoms (75.4±8.5 vs. 82.8±7.2, p=0.006). There were also statistically significant differences on
the final pain score for the PRP only versus PRP+MSC groups (16.2±4.6 vs. 10.2±5.7, p<0.001), but the final
Lysholm score was not significantly different between the PRP only and PRP+MSC groups (80.6±13.5 vs.
84.7±16.2, all respectively, p=0.36). Articular cartilage healing was rated as improved with MSCs following video
review of second-look arthroscopy; blinding of this measure is unclear. There are a number of limitations of this
study, including the small sample size, short duration of follow-up, and significant improvements on only some of
the outcomes. All of the significant differences in outcomes were modest in magnitude, and as a result, there is
uncertainty regarding the clinical significance of the findings.
A 2013 publication from this group reported a retrospective comparison of outcomes from 35 patients (37 ankles),
who were older than 50 years of age, had focal osteochondral lesions of the talus, and were treated with
microfracture alone between May 2008 and September 2010. (17) The comparison group was 30 patients (31
ankles) who received MSC injection along with marrow stimulation between October 2010 and December 2011.
MSCs were harvested from the fat pad of the buttock of the patients 1 day before surgery, concentrated, and
injected after the arthroscopic procedure. With an average 22 month follow-up (range, 12-44 months), patients
treated with MSCs showed greater improvements in VAS score, American Orthopaedic Foot and Ankle Society
Ankle‒Hindfoot Scale, Tegner Activity Scale, and the Roles and Maudsley score. A 2014 retrospective review
from this group reported clinical outcomes and MRI results from 49 patients who had undergone marrow
stimulation with or without MSCs at their institution. (18) The use of MSCs in addition to microfracture was
determined by patient choice, and there was an overlap of 26 patients between this report and their 2013
previously discussed publication.(17) This analysis also found modest but statistically significant improvements in
clinical outcomes for the MSC group compared with microfracture alone. Blinded ratings with the Magnetic
Resonance Observation of Cartilage Repair Tissue (MOCART) scale resulted in a score of 49.4 for the
conventional group and 62.1 for the MSC group (p=0.037).
Koh et al. also reported a retrospective analysis of the injection of adipose-derived MSCs from the infrapatellar fat
pad and PRP into arthroscopically-débrided knees of 25 patients with osteoarthritis of the knee. (19) Results were
compared with a randomly selected group of patients who had previously undergone arthroscopic débridement
and PRP injections without stem cells. Although there was a trend for greater improvement in the MSC group, at
final follow-up, there was no significant difference between the MSC and control groups in clinical outcomes
(Lysholm, Tegner, VAS).
Another group reported a Phase I/II trial of intra-articular injection of adipose-derived MSCs for the treatment of
osteoarthritis of the knee. (20) Phase I was a dose escalation study in 9 patients, and Phase II assessed efficacy
of the highest dose in 9 patients. The study of 18 patients was approved by the Korean Food and Drug
Administration. Procedures included liposuction, arthroscopy of the knee 1 week later with MSC injection through
the portal, MRI at 3 and 6 months, and second-look arthroscopy with punch biopsy at 6 months. Intent-to-treat
analysis showed a 39% improvement in Western Ontario and McMaster Universities Arthritis Index at 6 months
after injection and a 45% improvement in VAS. Arthroscopy showed a decrease in size of the cartilage defect and
an increase in the volume of cartilage. Histology showed thick, hyaline-like cartilage regeneration. Additional
study is needed with a larger sample size, sham-treated controls, and longer follow-up.
MSCs from Peripheral Blood
A 2013 report from Asia described a small RCT with autologous peripheral blood MSCs for focal articular cartilage
lesions. (21) Fifty patients with grade 3 and 4 lesions of the knee joint underwent arthroscopic subchondral drilling
followed by 5 weekly injections of HA. Half of the patients were randomly allocated to receive injections of
peripheral blood stem cells or no further treatment. There were baseline differences in age between the groups,
with a mean age of 38 years for the treatment group compared with 42 for the control group. The peripheral blood
stem cells were harvested after stimulation with recombinant human granulocyte colony-stimulating factor, divided
in vials, and cryopreserved. At 6 months after surgery, HA and MSCs were re-administered over 3 weekly
injections. At 18 months after surgery, second look arthroscopy on 16 patients in each group showed significantly
higher histologic scores (about 10%) for the MSC group (1,066 vs. 957 by independent observers) while blinded
evaluation of MRI showed a higher morphologic score (9.9 vs. 8.5). There was no difference in IKDC scores
between the two groups at 24 months after surgery. It is uncertain how differences in patient age at baseline may
have affected the response to subchondral drilling.
MSCs from Synovial Tissue
Akgun et al. reported a small (N=14), though without major bias, investigator-blinded RCT that compared matrixinduced autologous MSCs from synovial tissue versus matrix-induced autologous chondrocyte implantation
(MACI). (22) Both chondrocytes from cartilage and MSCs from synovia were harvested in an arthroscopic
procedure, expanded in culture, and then cultured on a collagen membrane for 2 days. Implantation was
performed with the construct trimmed to the size and shape of the defect and placed with the cells facing the
subchondral bone. Rehabilitation was the same for the 2 groups, with continuous passive motion for at least 1
hour daily and nonweight bearing for the first 6 weeks. The 2 groups were similar at baseline, and all patients
completed the evaluations through 24 months. Outcomes on the KOOS subscales and Tegner activity score were
statistically better in the MSC group, although it is not clear if the difference observed would be considered
clinically significant, with differences of around 6 on the 100-point KOOS subscales and 0.6 on the 10-point
Tegner. The results of this small pilot study do suggest that cartilage repair with matrix-induced MSCs from
synovial tissue may result in outcomes that are at least as good as MACI, warranting additional study in a larger
sample. It should also be noted that neither of these procedures is approved for use in the United States.
Section Summary
The evidence base on MSCs for cartilage repair is increasing, although nearly all studies to date have been
performed in Asia with a variety of methods of MSC preparation. Four randomized studies reported an
improvement in histological and morphologic outcomes. Three of these studies also reported an improvement in
functional outcomes. The method of preparation used in one positive study was to obtain MSCs from bone
marrow at the time of microfracture, culture (expand) over a period of 3 weeks, and inject in the knee in a carrier
of HA. Another randomized trial, using MSCs from peripheral blood, found improvement in histologic and
morphologic outcomes, but not functional outcomes, following stimulation with recombinant human granulocyte
colony-stimulating factor. A third small RCT found that MSCs from synovial tissue and cultured on collagen
resulted in outcomes that were at least as good as those following MACI.
The literature on adipose-derived MSCs includes a Phase I/II study with cultured MSCs and an RCT from a
separate group in Asia that has been using uncultured MSCs as an adjunctive procedure in clinical practice.
Comparisons between patients who have and have not received uncultured adipose-derived MSCs shows
modest improvement in health outcomes that are of uncertain clinical significance. Potential for bias from nonblinded use of a novel procedure on subjective outcome measures is also a limitation of these studies. The phase
I/II study of cultured MSCs from adipose tissue shows promising results for this technology. Additional study in a
larger sample of patients with longer follow-up is needed to evaluate the long-term efficacy and safety of the
procedure. U.S. Food and Drug Administration (FDA) approval for this method has also not been obtained.
Meniscectomy
In 2014, Vangsness et al. reported an industry-sponsored Phase I/II randomized, double-blind, multicenter study
(NCT00225095, NCT00702741) of cultured allogeneic MSCs (Chondrogen™, Osiris Therapeutics) injected into
the knee after partial meniscectomy. (23) The 55 patients in this U.S. study were randomized to intra-articular
injection of either 50x106 allogeneic MSCs, 150x106 allogeneic MSCs in HA, or HA vehicle control at seven to
ten days after meniscectomy. The cultured MSCs were derived from bone-marrow aspirates from unrelated
donors. At two year follow-up, 3 patients in the low-dose MSC group had significantly increased meniscal volume
measured by MRI (with an a priori determined threshold of at least 15%) compared with none in the control group
and none in the high-dose MSC group. There was no significant difference between the groups in the Lysholm
Knee Scale. On subgroup analysis, patients with osteoarthritis who received MSCs had a significantly greater
reduction in pain at two years compared with patients who received HA alone. This appears to be a post hoc
analysis and should be considered preliminary. No serious adverse events were thought to be related to the
investigational treatment.
Spinal Fusion
There is limited evidence on the use of allografts with stem cells for fusion of the extremities or spine or for the
treatment of nonunion, although several large observational studies are ongoing (see Table 1). In 2014, Eastlack
et al. reported outcomes from a series of 182 patients who were treated with anterior cervical discectomy and
fusion using Osteocel Plus in a PEEK cage and anterior plating. (24) At 24 months, 74% of patients (180/249
levels treated) were available for follow-up. These patients had significant improvements in clinical outcomes;
87% of levels achieved solid bridging and 92% of levels had range of motion less than 3º. With 26% loss to followup at 24 months and lack of a standard of care control group, interpretation of these results is limited.
Osteonecrosis
Two randomized comparative trials from Asia have been identified that evaluated the use of MSCs for
osteonecrosis of the femoral head.
MSCs Expanded from Bone Marrow
In 2012, Zhao et al. reported a randomized trial that included 100 patients (104 hips) with early stage femoral
head osteonecrosis treated with core decompression and expanded bone marrow MSCs versus core
decompression alone. (25) At 60 months after surgery, 2 of the 53 hips (3.7%) treated with MSCs progressed and
underwent vascularized bone grafting, compared with 10 of 44 hips (23%) in the decompression group who
progressed and underwent either vascularized bone grafting (n=5) or total hip replacement (n=5). The MSC group
also had improved Harris Hip Scores compared with the control group on independent evaluation (data presented
graphically). The volume of the lesion was also reduced by treatment with MSCs.
MSCs Concentrated from Bone Marrow
Another small trial randomized 40 patients (51 hips) with early stage femoral head osteonecrosis to core
decompression plus concentrated bone marrow MSCs or core decompression alone. (26) Blinding of
assessments in this small trial was not described. Harris Hip Score was significantly improved in the MSC group
(scores of 83.65 and 82.42) compared with core decompression (scores of 76.68 and 77.39). Kaplan-Meier
analysis showed improved hip survival in the MSC group (mean, 51.9 weeks) compared with the core
decompression group (mean, 46.7 weeks). There were no significant differences between the groups in the
radiographic assessment or MRI results.
Section Summary
Two small studies from Asia have compared core decompression alone versus core decompression with MSCs in
patients with osteonecrosis of the femoral head. Both studies reported improvement in the Harris Hip Score in
patients treated with MSCs, although it was not reported whether the patients or investigators were blinded to the
treatment group. Hip survival was significantly improved following treatment with either expanded or concentrated
MSCs. The effect appears to be larger with expanded MSCs compared with concentrated MSCs. Additional
studies with a larger number of patients are needed to permit greater certainty regarding the effect of this
treatment on health outcomes.
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 1. A 2014 review on FDA
3
regulations of adult stem cell therapies for sports medicine identified over 45 ongoing clinical trials on this topic.
Many are observational studies with commercially available products (Cartistem®, AlloStem®, Trinity Evolution™,
Osteocel® Plus).
Table 1. Summary of Key Trials
NCT No.
Ongoing
a
NCT01413061
NCT00885729
Unpublished
a
NCT00951938
NCT0094853
a
NCT00948831
a
NCT00988338
a
NCT00965380
a
NCT01626677/
a
NCT01041001
Trial Name
Planned
Enrollment
Completion
Date
Study of Subtalar Arthrodesis Using AlloStem® Versus Autologous Bone
Graft
Mesenchymal Stem Cells in a Clinical Trial to Heal Articular Cartilage
Defects
140
Feb 2017
50
Jul 2018
A Radiographic and Clinical Study Evaluating a Novel Allogeneic,
Cancellous, Bone Matrix Containing Viable Stem Cells (Trinity
Evolution™ Viable Cryopreserved Cellular Bone Matrix) in Patients
Undergoing Anterior Cervical Discectomy and Fusion
200
Aug 2012
Osteocel® Plus in eXtreme Lateral Interbody Fusion (XLIF®):
Evaluation of Radiographic and Patient Outcomes
Osteocel® Plus in Anterior Lumbar Interbody Fusion (ALIF):
Evaluation of Radiographic and Patient Outcomes
A Radiographic and Clinical Study Evaluating a Novel Allogeneic,
Cancellous, Bone Matrix Containing Viable Stem Cells (Trinity
Evolution™ Matrix) in Subjects Undergoing Foot and Ankle
Fusion
104
Oct 2012
51
Oct 2012
106
Jan 2013
A Radiographic and Clinical Study Evaluating a Novel Allogeneic,
Cancellous, Bone Matrix Containing Viable Stem Cells (Trinity
Evolution™ Viable Cryopreserved Cellular Bone Matrix) in Posterior
Lumbar or Transforaminal Lumbar Interbody Fusion (PLIF or TLIF)
Randomized, Open-Label, Multi-Center and Phase 3 Clinical Trial to
Compare the Efficacy and Safety of Cartistem® and Microfracture in
Patients With Knee Articular Cartilage Injury or Defect/ Long Term
200
Jun 2014
104
May 2015
Follow-Up Study of CARTISTEM® Versus Microfracture
NCT: national clinical trial.
a
Denotes industry-sponsored or cosponsored trial.
Summary of Evidence
The evidence for stem cell therapy in individuals who have various orthopedic conditions (cartilage defects,
meniscectomy, spinal fusion procedures, osteonecrosis) includes small randomized controlled trials and
nonrandomized comparative trials. Relevant outcomes are symptoms, morbid events, functional outcomes,
quality of life, and treatment-related morbidity. Use of mesenchymal stem cells (MSCs) for orthopedic conditions
is an active area of research. Despite continued research into the methods of harvesting and delivering treatment,
there are uncertainties regarding the optimal source of cells and the delivery method. Studies have included
MSCs from bone marrow, adipose tissue, peripheral blood, and synovial tissue. The largest body of evidence is
on use of autologous MSCs, either concentrated or expanded in culture, for cartilage repair. This evidence
includes small randomized and nonrandomized comparative trials with insufficient data to evaluate health
outcomes. In addition, expanded MSCs for orthopedic applications are not U.S. Food and Drug Administration
(FDA)‒approved (concentrated autologous MSCs do not require FDA approval). Overall, there is a lack of
evidence that clinical outcomes are improved. The evidence is insufficient to determine the effects of the
technology on health outcomes.
Practice Guidelines and Position Statements
The American Association of Orthopaedic Surgeons states that stem-cell procedures in orthopedics are still at an
experimental stage; most musculoskeletal treatments using stem cells are performed at research centers as part
of controlled, clinical trials, and results of studies in animal models provide proof-of-concept that in the future,
similar methods could be used to treat osteoarthritis, nonunion of fractures, and bone defects in humans.(27)
In 2006, the Mesenchymal and Tissue Stem-Cell Committee of the International Society for Cellular Therapy
proposed a minimal set of criteria to standardize the characterization of multipotent mesenchymal stem cells. (28)
The proposed criteria for human MSCs included plastic-adherence when maintained in standard culture
conditions; a phenotype of expression of CD105, CD73, and CD90 with a lack surface expression of CD45,
CD34, CD14 or CD11b, CD79 alpha or CD19, and HLA-DR surface molecules; and the capability of differentiating
into osteoblasts, adipocytes, and chondrocytes using standard in vitro tissue culture-differentiating conditions.
U.S. Preventive Services Task Force Recommendations
Not applicable.
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the
discretion of local Medicare carriers.
References
[TOP]
1. U.S. Food and Drug Administration. Assuring safety and efficacy of stem-cell based products.
http://www.fda.gov/BiologicsBloodVaccines/ScienceResearch/BiologicsResearchAreas/ucm127182.htm.
Accessed March 2016.
2. U.S. Food and Drug Administration. Untitled letter. Guidance, compliance, and regulatory information
(Biologics) 2008;
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ComplianceActi
vities/Enforcement/UntitledLetters/ucm091991.htm. Accessed March 2016.
3. Chirba MA, Sweetapple B, Hannon CP, et al. FDA regulation of adult stem cell therapies as used in
sports medicine. J Knee Surg. Feb 2015;28(1):55-62. PMID 25603042
4. Deans TL, Elisseeff JH. Stem cells in musculoskeletal engineered tissue. Curr Opin Biotechnol. Oct
2009;20(5):537-544. PMID 19879127
5. Filardo G, Madry H, Jelic M, et al. Mesenchymal stem cells for the treatment of cartilage lesions: from
preclinical findings to clinical application in orthopaedics. Knee Surg Sports Traumatol Arthrosc. Aug
2013;21(8):1717-1729. PMID 23306713
6. Wong KL, Lee KB, Tai BC, et al. Injectable cultured bone marrow-derived mesenchymal stem cells in
varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized
controlled clinical trial with 2 years' follow-up. Arthroscopy. Dec 2013;29(12):2020-2028. PMID 24286801
7. Wakitani S, Imoto K, Yamamoto T, et al. Human autologous culture expanded bone marrow
mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis
Cartilage. Mar 2002;10(3):199-206. PMID 11869080
8. Wakitani S, Nawata M, Tensho K, et al. Repair of articular cartilage defects in the patello-femoral joint
with autologous bone marrow mesenchymal cell transplantation: three case reports involving nine
defects in five knees. J Tissue Eng Regen Med. Jan-Feb 2007;1(1):74-79. PMID 18038395
9. Wakitani S, Okabe T, Horibe S, et al. Safety of autologous bone marrow-derived mesenchymal stem cell
transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months.
J Tissue Eng Regen Med. Feb 2011;5(2):146-150. PMID 20603892
10. Nejadnik H, Hui JH, Feng Choong EP, et al. Autologous bone marrow-derived mesenchymal stem cells
versus autologous chondrocyte implantation: an observational cohort study. Am J Sports Med. Jun
2010;38(6):1110-1116. PMID 20392971
11. Centeno CJ, Schultz JR, Cheever M, et al. Safety and complications reporting on the re-implantation of
culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell
Res Ther. Dec 2 2010;5(1):81-93. PMID 19951252
12. Vega A, Martin-Ferrero MA, Del Canto F, et al. Treatment of knee osteoarthritis with allogeneic bone
marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. Aug 2015;99(8):16811690. PMID 25822648
13. Giannini S, Buda R, Vannini F, et al. One-step bone marrow-derived cell transplantation in talar
osteochondral lesions. Clin Orthop Relat Res. Dec 2009;467(12):3307-3320. PMID 19449082
14. Giannini S, Buda R, Cavallo M, et al. Cartilage repair evolution in post-traumatic osteochondral lesions of
the talus: from open field autologous chondrocyte to bone-marrow-derived cells transplantation. Injury.
Nov 2010;41(11):1196-1203. PMID 20934692
15. Centeno CJ, Al-Sayegh H, Bashir J, et al. A prospective multi-site registry study of a specific protocol of
autologous bone marrow concentrate for the treatment of shoulder rotator cuff tears and osteoarthritis. J
Pain Res. 2015;8:269-276. PMID 26089699
16. Koh YG, Kwon OR, Kim YS, et al. Comparative outcomes of open-wedge high tibial osteotomy with
platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: a prospective study.
Arthroscopy. Nov 2014;30(11):1453-1460. PMID 25108907
17. Kim YS, Park EH, Kim YC, et al. Clinical outcomes of mesenchymal stem cell injection with arthroscopic
treatment in older patients with osteochondral lesions of the talus. Am J Sports Med. May
2013;41(5):1090-1099. PMID 23460335
18. Kim YS, Lee HJ, Choi YJ, et al. Does an injection of a stromal vascular fraction containing adiposederived mesenchymal stem cells influence the outcomes of marrow stimulation in osteochondral lesions
of the talus? A clinical and magnetic resonance imaging study. Am J Sports Med. Oct 2014;42(10):24242434. PMID 25106781
19. Koh YG, Choi YJ. Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis.
Knee. Dec 2012;19(6):902-907. PMID 22583627
20. Jo CH, Lee YG, Shin WH, et al. Intra-articular injection of mesenchymal stem cells for the treatment of
osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells. May 2014;32(5):1254-1266. PMID
24449146
21. Saw KY, Anz A, Siew-Yoke Jee C, et al. Articular cartilage regeneration with autologous peripheral blood
stem cells versus hyaluronic acid: a randomized controlled trial. Arthroscopy. Apr 2013;29(4):684-694.
PMID 23380230
22. Akgun I, Unlu MC, Erdal OA, et al. Matrix-induced autologous mesenchymal stem cell implantation
versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the
knee: a 2-year randomized study. Arch Orthop Trauma Surg. Feb 2015;135(2):251-263. PMID 25548122
23. Vangsness CT, Jr., Farr J, 2nd, Boyd J, et al. Adult human mesenchymal stem cells delivered via intraarticular injection to the knee following partial medial meniscectomy: a randomized, double-blind,
controlled study. J Bone Joint Surg Am. Jan 15 2014;96(2):90-98. PMID 24430407
24. Eastlack RK, Garfin SR, Brown CR, et al. Osteocel plus cellular allograft in anterior cervical discectomy
and fusion: evaluation of clinical and radiographic outcomes from a prospective multicenter study. Spine
(Phila Pa 1976). Oct 15 2014;39(22):E1331-1337. PMID 25188591
25. Zhao D, Cui D, Wang B, et al. Treatment of early stage osteonecrosis of the femoral head with
autologous implantation of bone marrow-derived and cultured mesenchymal stem cells. Bone. Jan
2012;50(1):325-330. PMID 22094904
26. Sen RK, Tripathy SK, Aggarwal S, et al. Early results of core decompression and autologous bone
marrow mononuclear cells instillation in femoral head osteonecrosis: a randomized control study. J
Arthroplasty. May 2012;27(5):679-686. PMID 22000577
27. American Academy of Orthopaedic Surgeons. Stem cells and orthopaedics. Your Orthopaedic
Connection 2007; http://orthoinfo.aaos.org/topic.cfm?topic=A00501. Accessed March 2016.
28. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal
cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-317.
PMID 16923606
29. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal
cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-317.
PMID 16923606
Appendix
[TOP]
N/A
History
[TOP]
Date
08/09/11
07/20/12
08/15/12
08/20/12
10/09/12
04/26/13
06/10/13
08/20/13
06/19/14
06/09/15
09/01/15
04/01/16
06/09/17
Reason
New policy; add to Therapy section.Policy created with literature review through January 2011;
considered investigational. ICD-10 codes included in policy.
Replace policy. Policy updated with literature review through February 2012; reference 6 added
and references reordered; policy statement unchanged.
Update Related Policies: remove 7.01.48, it was archived.
Update Related Policies – add 2.02.18.
Update Coding Section – ICD-10 codes are now effective 10/01/2014.
Clarification only. Statement within the Benefit Application section stating, “Therefore, requests may
be made for an out-of-network facility” was removed, as this conflicts with the FDA statements in
the rest of the policy. No other changes.
Replace policy. New policy statement added that allograft bone containing viable stem cells is
considered investigational. New policy guideline added that policy does not address unprocessed
allograft bone. Regulatory status section updated regarding allograft bone. Rationale updated
based on a literature review through March 2013. References 4, and 11-15 added; others
renumbered or removed. Policy statement changed as noted.
Update Related Policies. Change title to 2.02.18.
Annual Review. Policy updated with literature review through March 3, 2014; references 5, 13, and
17 added; policy statements unchanged. ICD-10 codes removed in line with code mapping project
and implementation delay.
Annual Review. Policy updated with literature review through February 26, 2015; references 3, 14,
16, 18, 20, and 22 added; investigational statement added on bone graft substitutes that must be
used with autologous blood or bone marrow aspirate; title changed to “Orthopedic applications of
stem cell therapy (including allograft and bone substitute products used with autologous bone
marrow)”. Related policies removed: 2.02.18, 7.01.15 and 8.01.55. CPT code 20999 added to
policy.
Update Related Policies. Add 2.01.98 and 7.01.149.
Annual Review, approved March 8, 2016. Policy updated with literature review through November
17, 2015; references 12 and 15 added. Policy statements unchanged. Title changed to “Orthopedic
Applications of Stem Cell Therapy (Including Allografts and Bone Substitutes Used With
Autologous Bone Marrow)”.
Coding update; updated description for CPT codes 38230 and 38241.
Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts
policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical
technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in
their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific
medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
©2016 Premera All Rights Reserved.
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본 통지서에는 중요한 정보가 들어 있습니다. 즉 이 통지서는 귀하의 신청에
관하여 그리고 Premera Blue Cross 를 통한 커버리지에 관한 정보를
포함하고 있을 수 있습니다. 본 통지서에는 핵심이 되는 날짜들이 있을 수
있습니다. 귀하는 귀하의 건강 커버리지를 계속 유지하거나 비용을 절감하기
위해서 일정한 마감일까지 조치를 취해야 할 필요가 있을 수 있습니다.
귀하는 이러한 정보와 도움을 귀하의 언어로 비용 부담없이 얻을 수 있는
권리가 있습니다. 800-722-1471 (TTY: 800-842-5357) 로 전화하십시오.
Pусский (Russian):
Настоящее уведомление содержит важную информацию. Это
уведомление может содержать важную информацию о вашем
заявлении или страховом покрытии через Premera Blue Cross. В
настоящем уведомлении могут быть указаны ключевые даты. Вам,
возможно, потребуется принять меры к определенным предельным
срокам для сохранения страхового покрытия или помощи с расходами.
Вы имеете право на бесплатное получение этой информации и
помощь на вашем языке. Звоните по телефону 800-722-1471
(TTY: 800-842-5357).
ລາວ (Lao):
ແຈ້ ງການນ້ີ ມີຂ້ໍ ມູ ນສໍາຄັ ນ. ແຈ້ ງການນ້ີ ອາດຈະມີຂ້ໍ ມູ ນສໍາຄັ ນກ່ ຽວກັ ບຄໍາຮ້ ອງສະ
ໝັ ກ ຫື ຼ ຄວາມຄຸ້ ມຄອງປະກັ ນໄພຂອງທ່ ານຜ່ ານ Premera Blue Cross. ອາດຈະມີ
ວັ ນທີສໍາຄັ ນໃນແຈ້ ງການນີ້. ທ່ ານອາດຈະຈໍາເປັນຕ້ ອງດໍາເນີນການຕາມກໍານົ ດ
ເວລາສະເພາະເພື່ອຮັ ກສາຄວາມຄຸ້ ມຄອງປະກັ ນສຸ ຂະພາບ ຫື ຼ ຄວາມຊ່ ວຍເຫື ຼ ອເລື່ອງ
ຄ່ າໃຊ້ ຈ່ າຍຂອງທ່ ານໄວ້ . ທ່ ານມີສິດໄດ້ ຮັ ບຂ້ໍ ມູ ນນ້ີ ແລະ ຄວາມຊ່ ວຍເຫື ຼ ອເປັນພາສາ
ຂອງທ່ ານໂດຍບໍ່ເສຍຄ່ າ. ໃຫ້ ໂທຫາ 800-722-1471 (TTY: 800-842-5357).
ភាសាែខម រ (Khmer):
េសចកត ីជូនដំណឹងេនះមានព័ត៌មានយា៉ងសំខាន់។ េសចកត ីជូនដំណឹងេនះរបែហល
ជាមានព័ត៌មានយា៉ងសំខាន់អំពីទរមង់ែបបបទ ឬការរា៉ប់រងរបស់អនកតាមរយៈ
Premera Blue Cross ។ របែហលជាមាន កាលបរ ិេចឆ ទសំខាន់េនៅកនុងេសចកត ីជូន
ដំណឹងេនះ។ អន ករបែហលជារតូវការបេញច ញសមតថ ភាព ដល់កំណត់ៃថង ជាក់ចបាស់
នានា េដើមបីនឹងរកសាទុកការធានារា៉ប់រងសុខភាពរបស់អនក ឬរបាក់ជំនួយេចញៃថល ។
អន កមានសិទធិទទួ លព័ត៌មានេនះ និងជំនួយេនៅកនុងភាសារបស់អនកេដាយមិនអស
លុយេឡើយ។ សូ មទូ រស័ពទ 800-722-1471 (TTY: 800-842-5357)។
ਪੰ ਜਾਬੀ (Punjabi):
ਇਸ ਨੋਿਟਸ ਿਵਚ ਖਾਸ ਜਾਣਕਾਰੀ ਹੈ. ਇਸ ਨੋਿਟਸ ਿਵਚ Premera Blue Cross ਵਲ ਤੁਹਾਡੀ
ਕਵਰੇਜ ਅਤੇ ਅਰਜੀ ਬਾਰੇ ਮਹੱ ਤਵਪੂਰਨ ਜਾਣਕਾਰੀ ਹੋ ਸਕਦੀ ਹੈ . ਇਸ ਨੋਿਜਸ ਜਵਚ ਖਾਸ ਤਾਰੀਖਾ
ਹੋ ਸਕਦੀਆਂ ਹਨ. ਜੇਕਰ ਤੁਸੀ ਜਸਹਤ ਕਵਰੇਜ ਿਰੱ ਖਣੀ ਹੋਵੇ ਜਾ ਓਸ ਦੀ ਲਾਗਤ ਜਿਵੱ ਚ ਮਦਦ ਦੇ
ਇਛੁੱ ਕ ਹੋ ਤਾਂ ਤੁਹਾਨੂੰ ਅੰ ਤਮ ਤਾਰੀਖ਼ ਤ ਪਿਹਲਾਂ ਕੁੱ ਝ ਖਾਸ ਕਦਮ ਚੁੱ ਕਣ ਦੀ ਲੋ ੜ ਹੋ ਸਕਦੀ ਹੈ ,ਤੁਹਾਨੂੰ
ਮੁਫ਼ਤ ਿਵੱ ਚ ਤੇ ਆਪਣੀ ਭਾਸ਼ਾ ਿਵੱ ਚ ਜਾਣਕਾਰੀ ਅਤੇ ਮਦਦ ਪ੍ਰਾਪਤ ਕਰਨ ਦਾ ਅਿਧਕਾਰ ਹੈ ,ਕਾਲ
800-722-1471 (TTY: 800-842-5357).
‫( فارسی‬Farsi):
‫اين اعالميه ممکن است حاوی اطالعات مھم درباره فرم‬. ‫اين اعالميه حاوی اطالعات مھم ميباشد‬
‫ به تاريخ ھای مھم در‬.‫ باشد‬Premera Blue Cross ‫تقاضا و يا پوشش بيمه ای شما از طريق‬
‫شما ممکن است برای حقظ پوشش بيمه تان يا کمک در پرداخت ھزينه‬. ‫اين اعالميه توجه نماييد‬
‫شما حق‬. ‫ به تاريخ ھای مشخصی برای انجام کارھای خاصی احتياج داشته باشيد‬،‫ھای درمانی تان‬
‫ برای کسب‬.‫اين را داريد که اين اطالعات و کمک را به زبان خود به طور رايگان دريافت نماييد‬
‫( تماس‬800-842-5357 ‫ تماس باشماره‬TTY ‫ )کاربران‬800-722-1471 ‫اطالعات با شماره‬
.‫برقرار نماييد‬
Polskie (Polish):
To ogłoszenie może zawierać ważne informacje. To ogłoszenie może
zawierać ważne informacje odnośnie Państwa wniosku lub zakresu
świadczeń poprzez Premera Blue Cross. Prosimy zwrócic uwagę na
kluczowe daty, które mogą być zawarte w tym ogłoszeniu aby nie
przekroczyć terminów w przypadku utrzymania polisy ubezpieczeniowej lub
pomocy związanej z kosztami. Macie Państwo prawo do bezpłatnej
informacji we własnym języku. Zadzwońcie pod 800-722-1471
(TTY: 800-842-5357).
Português (Portuguese):
Este aviso contém informações importantes. Este aviso poderá conter
informações importantes a respeito de sua aplicação ou cobertura por meio
do Premera Blue Cross. Poderão existir datas importantes neste aviso.
Talvez seja necessário que você tome providências dentro de
determinados prazos para manter sua cobertura de saúde ou ajuda de
custos. Você tem o direito de obter esta informação e ajuda em seu idioma
e sem custos. Ligue para 800-722-1471 (TTY: 800-842-5357).
Fa’asamoa (Samoan):
Atonu ua iai i lenei fa’asilasilaga ni fa’amatalaga e sili ona taua e tatau
ona e malamalama i ai. O lenei fa’asilasilaga o se fesoasoani e fa’amatala
atili i ai i le tulaga o le polokalame, Premera Blue Cross, ua e tau fia maua
atu i ai. Fa’amolemole, ia e iloilo fa’alelei i aso fa’apitoa olo’o iai i lenei
fa’asilasilaga taua. Masalo o le’a iai ni feau e tatau ona e faia ao le’i aulia le
aso ua ta’ua i lenei fa’asilasilaga ina ia e iai pea ma maua fesoasoani mai ai
i le polokalame a le Malo olo’o e iai i ai. Olo’o iai iate oe le aia tatau e maua
atu i lenei fa’asilasilaga ma lenei fa’matalaga i legagana e te malamalama i
ai aunoa ma se togiga tupe. Vili atu i le telefoni 800-722-1471
(TTY: 800-842-5357).
Español (Spanish):
Este Aviso contiene información importante. Es posible que este aviso
contenga información importante acerca de su solicitud o cobertura a
través de Premera Blue Cross. Es posible que haya fechas clave en este
aviso. Es posible que deba tomar alguna medida antes de determinadas
fechas para mantener su cobertura médica o ayuda con los costos. Usted
tiene derecho a recibir esta información y ayuda en su idioma sin costo
alguno. Llame al 800-722-1471 (TTY: 800-842-5357).
Tagalog (Tagalog):
Ang Paunawa na ito ay naglalaman ng mahalagang impormasyon. Ang
paunawa na ito ay maaaring naglalaman ng mahalagang impormasyon
tungkol sa iyong aplikasyon o pagsakop sa pamamagitan ng Premera Blue
Cross. Maaaring may mga mahalagang petsa dito sa paunawa. Maaring
mangailangan ka na magsagawa ng hakbang sa ilang mga itinakdang
panahon upang mapanatili ang iyong pagsakop sa kalusugan o tulong na
walang gastos. May karapatan ka na makakuha ng ganitong impormasyon
at tulong sa iyong wika ng walang gastos. Tumawag sa 800-722-1471
(TTY: 800-842-5357).
ไทย (Thai):
ประกาศนี ้มีข้อมูลสําคัญ ประกาศนี ้อาจมีข้อมูลที่สําคัญเกี่ยวกับการการสมัครหรื อขอบเขตประกัน
สุขภาพของคุณผ่าน Premera Blue Cross และอาจมีกําหนดการในประกาศนี ้ คุณอาจจะต้ อง
ดําเนินการภายในกําหนดระยะเวลาที่แน่นอนเพื่อจะรักษาการประกันสุขภาพของคุณหรื อการช่วยเหลือที่
มีค่าใช้ จ่าย คุณมีสิทธิที่จะได้ รับข้ อมูลและความช่วยเหลือนี ้ในภาษาของคุณโดยไม่มีค่าใช้ จ่าย โทร
800-722-1471 (TTY: 800-842-5357)
Український (Ukrainian):
Це повідомлення містить важливу інформацію. Це повідомлення
може містити важливу інформацію про Ваше звернення щодо
страхувального покриття через Premera Blue Cross. Зверніть увагу на
ключові дати, які можуть бути вказані у цьому повідомленні. Існує
імовірність того, що Вам треба буде здійснити певні кроки у конкретні
кінцеві строки для того, щоб зберегти Ваше медичне страхування або
отримати фінансову допомогу. У Вас є право на отримання цієї
інформації та допомоги безкоштовно на Вашій рідній мові. Дзвоніть за
номером телефону 800-722-1471 (TTY: 800-842-5357).
Tiếng Việt (Vietnamese):
Thông báo này cung cấp thông tin quan trọng. Thông báo này có thông
tin quan trọng về đơn xin tham gia hoặc hợp đồng bảo hiểm của quý vị qua
chương trình Premera Blue Cross. Xin xem ngày quan trọng trong thông
báo này. Quý vị có thể phải thực hiện theo thông báo đúng trong thời hạn
để duy trì bảo hiểm sức khỏe hoặc được trợ giúp thêm về chi phí. Quý vị có
quyền được biết thông tin này và được trợ giúp bằng ngôn ngữ của mình
miễn phí. Xin gọi số 800-722-1471 (TTY: 800-842-5357).