A Double-blind, Randomized Study Comparing Steroid Injection and BioDRestore for Patients With Knee Osteoarthritis
Phase: NA
Conditions: Knee Osteoarthritis
Sponsor: The Hawkins Foundation

A DOUBLE-BLIND, RANDOMIZED STUDY COMPARING STEROID INJECTION AND 
BIODRESTORETM FOR PATIENTS WITH KNEE OSTEOARTHRITIS
Protocol Summary
Title of Study:
A Double-blind, Randomized Study Comparing Steroid Injection and 
BioDRestore for Patients with Knee Osteoarthritis
Study Type:
Postmarket Interventional
Primary Investigator:
Paul Siffri, MD
Primary Endpoint:
Visual Analog Pain Score (VAS), VR-12, Lysholm, SANE and Knee Injury and 
Osteoarthritis Outcome Score (KOOS) at the 6-week, 3-month, 6-month, and 12-
month post-injection time periods between the two groups.
Secondary Endpoints: Inflammatory markers at 6 months post-injection.
Design:
Prospective, randomized, two-arm, double-blind study
Length of Study:
12M follow-up
Sample Size:
84 subjects
Schedule of Events
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Randomization
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Patient Outcomes (VAS, KOOS, 
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Knee aspiration
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X-ray
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Adverse Event Assessment
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1.
Background 
Osteoarthritis (OA), specifically involving the knee, is one of the most common causes of human disease1 
and can lead to significant pain and functional decline2.  A potential element of OA includes degenerative 
tears of the knee meniscus and/or chondropathy, both of which involve destabilization from mechanical 
or biological issues3. 
Cortisone injections are commonly used to temporarily relieve inflammation and pain associated with 
osteoarthritis.  The response or effect of the injection can vary, depending on the stage of OA. 4  Advanced 
OA where little cartilage remains may not provide enough joint space for the injection to be effective. 
Cortisone  injections  can  also  potentially  cause  an  adverse  reaction  in  certain  patient  populations, 
particularly patients with diabetes who may experience a significant increase in blood sugar after a 
cortisone injection.5  
Alternatives to cortisone injections include viscosupplementation, platelet-rich plasma (PRP) injections 
and stem-cell therapy.  One form of therapy that has shown promising results with little reported on in 
literature is amniotic tissue matrices, to include BioDRestoreTM Elemental Tissue Matrix.  BioDRestore is 
a ”morselized, flowable tissue allograft derived from amniotic tissues.  Amniotic tissues have been shown 
to support soft tissue repair, reduce inflammation and minimize scar tissue formation”. 6,7 
This study will compare corticosteroid injection to BioDRestore injection in patients with significant 
(Kellgren-Lawrence grade 3-4) knee osteoarthritis.  Our hypothesis is that BioDRestore will result in 
better outcomes than corticosteroid when injected intra-articularly in patients with knee OA.
2.
Study Endpoints
Primary Endpoint

Visual Analog Score (VAS), VR-12, Lysholm, SANE and Knee Injury and Osteoarthritis 
Outcome Score (KOOS) at the 6-week, 3-month, 6-month, and 12-month post-injection time 
periods.
Secondary Endpoints

Inflammatory markers at 6-months post-injection.
3.
Subject Recruitment and Screening
Screening
Patients who present with osteoarthritis of the knee and are recommended for a knee 
injection will be screened for inclusion into the study. Following discussion of the 
study between the patient and the treating physician, the patient will be given the 
opportunity to move forward with the informed consent process. 
    Enrollment
The subject will be considered enrolled once voluntary informed consent has been 
given, and the form has been signed and dated by all required parties.  
    Randomization
Subjects will be randomized to a treatment arm (corticosteroid or BioDRestore injection) 
using a 1:1 ratio. Once study eligibility has been confirmed, the study coordinator or 
designee will randomize the subject to a treatment arm.  The treatment for each subject 
will be assigned through the study database.  
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Blinding
Study subjects and investigators will be blinded to the treatment assignment for the 
duration of the study to reduce the risk of bias.  The research coordinator will provide the 
randomization to the investigator’s medical assistant (MA) prior to treatment in order for 
the MA to assist with preparation of the injection.
3.1. Inclusion Criteria
Subjects must meet all of the following characteristics for inclusion in the study.
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Male or female, aged 18 to 80 years.
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Willing and able to give voluntary informed consent to participate in this investigation. 
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Patient presents with knee osteoarthritis and Kellgren Lawrence grade 3-4 (OA 
diagnosed and confirmed by treating physician using standing x-ray).
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Candidate for intra-articular knee injection.
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BMI < 40
3.2. Exclusion Criteria
Subjects with any of the following characteristics must be excluded from participation in the 
study:
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Patients who have received intra-articular injection(s) in the last 3 months.
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Patients who have undergone arthroscopic surgery on the study knee in the past year.
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Patients who have undergone arthroplasty on the study knee.
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Ligament instability
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Diabetes (Type 1 or II)
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Inflammatory arthropathies.
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Fibromyalgia or chronic fatigue syndrome.
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Female patient who is pregnant or nursing.
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Chronic use of narcotics.
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Any other reason (in the judgment of the investigator).
3.3. Withdrawal of Subjects from Study
  
Voluntary Withdrawal by Subject
Study participation is voluntary and subjects may withdraw at any point during the study. 
If a subject withdraws from the study, the investigator will make all reasonable efforts to 
determine the reason for the subject’s withdrawal and will document the reason on the 
applicable form and in the patient’s medical record. After a subject withdraws from the 
study, no effort will be made to replace or follow the subject.  However, the subject will 
still be offered clinical management of their knee condition.
   Withdrawal by Investigator
The investigator may withdraw subjects from the study for many reasons, including but 
not limited to the following:
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Occurrence of a serious adverse event
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Investigator’s discretion to withdraw subject for safety reasons
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Subject noncompliance with visits and/or assessments

Subject is lost to follow-up (as defined below)
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    Lost to Follow-Up
Subjects will be defined as lost to follow-up when the following procedures have been 
documented in the subject’s source documentation:
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At least 2 phone calls made on separate dates to the subject are not returned
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A letter is sent to the subject’s last known address and the subject does not reply after 
30 days.
4.
Informed Consent
Investigators are responsible for obtaining and documenting the voluntary informed consent of the 
study subjects prior to conducting any study-related assessments per 21 CFR Part 50.  Prior to 
beginning the trial the investigator must obtain written and dated approval of the informed consent 
form.  Subjects will receive a copy of the initial signed and dated informed consent form prior to the 
subjects’ participation in the trial and any revised informed consent forms during the duration of the trial.
The subject must sign and date the consent form in the presence of the investigator, who must sign 
and date the consent form in the presence of the subject. The communications with the subject 
regarding informed consent process (initial and subsequent) should be documented in the medical record.
5.
Study Procedures
Study Assessments
Visit 1- Baseline Assessment
The following information will be collected at the time of enrollment:

Informed Consent
 
 

Medical History & Demographics
 
 
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Patient Outcomes
 
 :  Subject to complete VAS, VR-12, KOOS, Lysholm and SANE prior to 
injection. 
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Range of Motion Assessment: Measurement taken using goniometer.
 
 
Visit 2- Randomization & Procedure
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Inclusion/Exclusion review
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Randomization
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Procedure:  
 
 For patients with current knee effusion, the investigator will drain the effusion 
prior to the injection. For subjects that do not exhibit any signs of knee effusion, the 
investigator will proceed with the injection. Study subjects will be randomized to receive a 
cortisone or BioDRestore injection.  Subjects will be blinded to the assignment.  Prior to 
the injection, the area will be prepared with sterile solution and numbing agent.  Next, an 
injection of one of the following treatments, dependent on randomization, will be injected 
into the articular space of the knee:
-2 cc of 40 mg/ml Kenalog with 3 cc of saline
-2 cc BioDRestore  with 3 cc of saline 
Knee arthrocentesis (for procedure, see below under “Follow-up Visits”): The study doctor 
will attempt to perform a knee aspiration to provide a delta value for the assay.
Follow-Up Visits (6WK, 3M, 6M, 12M)
The following information will be collected at each follow-up visit:
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Patient Outcomes
 
 :  Subject to complete VAS, VR-12, KOOS, Lysholm, and SANE scales
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6-month only, subject will return to the clinic for the following
 
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Range of motion assessment
Knee arthrocentesis (aspiration): The area will first be prepared with sterile 
solution  and  numbing  agent.  Using  a 10-mL  syringe,  obtain  at  least 
0.25mL of synovial fluid via a parapatellar approach. A knee aspiration 
attempt will be made on all subjects that produced an adequate sample at 
baseline prior  to  the  injection.  Upon  completion,  the  syringe  will  be 
labeled and transported to the Clemson Bioengineering Laboratory of 
Orthopaedic Tissue Regeneration & Orthobiologics lab for analysis. 

Aspirate analysis:  Enzyme linked immunosorbent assay (ELISA) will be 
performed on synovial fluid aspirated from the knees of study patients at 6 
months post-injection to determine if there are quantitative differences in 
soluble mediators and products of osteoarthritis.  Briefly, synovial fluid 
samples will be evaluated in duplicate for inflammatory (interleukin-1 beta; 
IL-1β  and  tumor  necrosis  factor-alpha;  TNF-α),  anti-inflammatory 
(interleukin-1  receptor  agonist;  IL-1RA  and  interleukin-10;  IL-10),  pain 
(prostaglandin-E2;  PGE2)  and  soluble  signals  which  indicate  cartilage 
damage (S100A8 and S100A9 proteins, respectively).  
Briefly,  frozen  (-80oC)  samples  will  be  thawed  and  analyzed  using  a 
bicinchoninic  acid  assay  (BCA)  to  normalize  for  total  protein  content. 
Samples will be diluted accordingly using calibrator diluent supplied with 
ELISA kits.  ELISA will be performed according to manufacturer’s protocols 
and well plates will be analyzed optically on a µ-Quant microplate reader. 
Concentrations will be determined using a standard curved developed from 
known concentrations of supplied analyte.  Experimental sample analyte 
concentrations  (ng/ml)  will  be  plotted  on  histograms  and  group  mean 
concentrations ± standard deviation will be calculated for each experimental 
group.    
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12-month only, subject will return to the clinic for the following
 
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o
Range of motion assessment
o
Radiographs of affected knee
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Allowed Concomitant Medications and Prohibited Treatments
o
Concomitant Medications:  Patients are allowed acetaminophen and/or ibuprofen 
for the first 6 months following treatment.  
o
Prohibited Treatments: Oral steroids, steroid injections and Viscosupplementation 
are not permitted for the first 6 months of the study in the treated knee.
6.
Risk Analysis
Potential Risks
Mild pain and discomfort at the injection site are normal and expected reactions.  While 
rare, complications may occur due to either the cortisone injection or study injection. 
These include the following:

Infection

Post-injection flare
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Localized subcutaneous or cutaneous atrophy
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Skin discoloration
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Stiffness
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Potential Benefits
Participation in this study may offer no benefit to subjects. However, it is possible that 
the use of BioDRestore will result in better outcomes than corticosteroid when injected 
intra-articularly in patients with knee OA.
Study subjects will receive a $50 stipend for each study visit for a total of $300 if all 
visits are completed.
7.
Adverse Events
Definitions
An  adverse  event  is  defined  as  any  untoward  medical  occurrence  in  a  clinical 
investigation in which a subject is administered a study device and which does not 
necessarily have a causal relationship with the device.  An adverse event can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding or an 
abnormal radiographic finding), symptom, or disease temporally associated with the use 
of study device, whether or not related to the study device.  The following are specific 
definitions of adverse events:
Adverse Event (AE) — any untoward medical occurrence in a subject, regardless if there 
is a relationship between the AE and the device. 
Adverse Reaction (AR) - The FDA requires, per 21CFR 1271.350(a), the reporting of certain 
adverse reactions related to implantation, transplantation, infusion or transfer of an HCT/P.  For 
tissue products, an Adverse Reaction is any unintended response, including a communicable 
disease, in the recipient of a human tissue or cell product implantation or transplantation.  An 
Adverse Reaction is considered serious (SAR) if it meets the criteria of a Serious Adverse Event 
(see below).
Serious Adverse Event (SAE)  an adverse event that:
leads to a death
leads to a serious deterioration in the health of a subject that results in a life-
threatening illness or injury
results in a permanent impairment of a body structure or a body function
requires in-subject hospitalization or prolongation of existing hospitalization
results in medical or surgical intervention to prevent permanent impairment to 
body structure or a body function
results in congenital anomaly/birth defect
Treatment for Adverse Events
In the event of an adverse event, the investigator and/or other professional personnel in 
attendance will provide whatever appropriate medical treatment is indicated for the 
problem. 
Documentation of Adverse Events
All adverse events will be documented in the source documentation.   Beginning after the 
study  procedure  has  taken  place,  all  AE’s,  including  those  measured,  observed  or 
volunteered, will be recorded on the applicable case report form.  The investigator will 
review all documentation (e.g., hospital progress notes, laboratory, or diagnostic reports) 
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relative  to the  event  being reported. The investigator  will then  record  all  relevant 
information regarding an AE onto the study CRF. 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and not the individual signs and symptoms.
When reporting an AE, the investigator will evaluate the event for duration, intensity, 
relationship and outcome.
Examples of an AE:
Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency or intensity of the condition.
Significant or unexpected worsening or exacerbation of the condition/indication 
under study.
A new condition detected or diagnosed after study device administration even 
though it may have been present prior to the start of the study.
Pre- or post-procedure events that occur as a result of protocol-mandated 
procedures (e.g., invasive protocol-defined procedures, modification of a 
subject’s previous treatment regimen).
An AE Does NOT Include:
Medical or surgical procedures. The medical condition that leads to the 
procedure is the AE.
Hospital admissions where an untoward medical occurrence did not occur.
Day to day fluctuations of pre-existing disease or conditions present or detected 
at the start of the study that do not worsen.
The condition/indication being studied or expected progression, signs, or 
symptoms of the condition/indication being studied unless more severe than 
expected for the subject’s condition.
Post-operative findings of swelling or pain within two (2) weeks of the initial 
procedure, unless deemed by the physician as of greater severity than expected.
Follow-Up of Adverse Events
After the initial AE report, the investigator is required to proactively follow each subject 
until the event resolves. All AEs documented at a previous visit that are designated as 
ongoing will be reviewed at subsequent visits/contacts.
Adverse events will be followed until resolution, until no further changes in the event are 
expected (i.e. the point at which a subject experiencing a critical adverse event is treated 
successfully and stabilized even though he/she may continue to experience lingering 
sequelae that may never resolve), until the subject is lost to follow-up, or until it is agreed 
that further follow-up of the event is not warranted (e.g. non-serious, study therapy 
unrelated, mild or moderate adverse events ongoing at the subject’s final study visit). 
8.
Reporting of Adverse Events
Investigator Adverse Event Reports
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Investigators are responsible for reviewing all SAEs and determining the relationship to 
the treatment and documenting on the appropriate CRF.  All SAEs must be reported by 
the investigator to the IRB as soon as possible, but no later than ten (10) working days 
after learning of the event.  The investigator must submit a detailed report that will 
identify the description of symptoms, classification of the event, date of onset, severity, 
treatment, and outcome.  Supporting medical records may be obtained as an adjunct to an 
adverse event report and placed in the subject’s study file.
All  AEs  will  be  categorized  as  mild,  moderate  or  severe  based  on  the  following 
definitions:
Mild:  The subject is aware of the sign or symptom, but finds it easily tolerated.  The 
event is of little concern to the subject and/or little clinical significance.  The event is not 
expected to have any effect on the subject’s overall health or wellbeing.
Moderate:  The subject has discomfort enough to cause interference with or change in 
usual activities.  The event is of some concern to the subject’s health or wellbeing and 
may require medical intervention and/or close follow-up.
Severe:  The adverse event interferes considerably with the subject’s usual activities.  The 
event is of definite concern to the subject and/or poses substantial risk to the subject’s 
health or wellbeing.  The event is likely to require medical intervention and/or close 
follow-up and may be incapacitating or life threatening.  Hospitalization and treatment 
may be required.  
Should an AR or SAE occur, an investigator must submit to DermaSciences and to the reviewing IRB a 
report of the event as soon as possible, but in no event later than 48 hours after the investigator first learns  
of the AR or SAE.
Reported ARs and Serious Adverse Events will be reviewed and investigated per Standard Operating 
Procedures.  Upon a receipt and evaluation of an AR or SAE, Derma Sciences will report the results of 
such evaluation to FDA and to all reviewing IRBs and participating investigators within 10 working days 
after receipt of first notice of the AR or SAE.  Thereafter, the Sponsor will submit such additional reports 
concerning the effect per FDA and/or IRB requests.
9.
Source Documentation
Investigators are responsible for obtaining and maintaining complete subject health information in the 
medical record for each subject and each assessment in the protocol (source documents). Source 
documents include all information in original records and certified copies of original records of clinic 
findings, observations or other activities in the study necessary for the reconstruction and evaluation 
of the trial.  Source data are contained in source documents (e.g., hospital records, clinic and office 
charts,  memoranda,  dispensing  records,  subject  questionnaires,  clinic  evaluation  transcriptions, 
operative notes, x-rays, radiology reports, blood collection and shipment records, research subject 
files, etc.) 
10. Disclosure of Data and Data Security
Data Security and Confidentiality
The clinical data obtained in this study will be kept private.  In any sort of published 
report, there will be no identifying information. Records for this study may be reviewed 
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by the IRB and/or other government agencies may inspect and photocopy all medical 
records applicable to involvement in this study.
Participating subjects will be asked to sign a consent form that includes an authorization 
to  use  and/or  disclose  personal  health  information.   Subjects  are  free  to  refuse 
authorization to transfer personal information.  If the subject chooses not to agree to this 
authorization, the subject is not eligible to participate in the study.  Personal information 
(including sensitive personal health information, such as medical history) if relevant to 
the study will be reviewed, collected in a computer database, stored in electronic or 
manual  files,  audited,  and  /  or  otherwise  processed  by  the  investigator,  regulatory 
agencies, and other persons and/or agencies as required by law or allowed by applicable 
regulations.
11. Statistical Procedures
      11.1 
Sample Size Estimate
To determine sample size, we powered the study (a-priori) for the primary outcome measures of VAS, 
VR-12, KOOS, Lysholm, and SANE scales at baseline, 6-week, 3-month, 6-month, and 12-month post-
injection time periods.  Assuming normal distributions among the 2 independent groups’ 5 time-points for 
2 groups and five outcome measures, and assuming an effect size of 0.20 (small) based on between group 
differences  we  constructed  a  sample  size  estimation  using  a  Multivariate  Analysis  of  Variance 
(MANOVA). Measuring global effects, with an expected 80% power, and a standard error of probability 
of 0.05, we estimate the need for a minimum sample size of 70 for statistical significance (~35 per group). 
To account for a 20% drop-out rate, a sample size of 84 subjects will be recruited.  We will employ 
intention to treat and a chains equation, multiple imputation method in which we will assign predictor, 
structural and impute variables. Further, we will not oversample characteristics within each group for 
drop-outs. 
11.2
Data Analyses
Descriptive statistics will be used to describe both groups at baseline. Appropriate tests of differences will 
be used to compare baseline differences in descriptive statistics, pain, range of motion, etc., between the 
two groups (e.g., t-tests and chi-square). Adverse events, including severity of these events will be 
captured and compared between the two groups. A Multivariate Analysis of Variance (MANOVA) will 
be used to measure differences between the targeted outcome measure at each of the given timepoints 
(baseline,  6-week,  3-month,  6-month,  and  12-months  post-injection  time  periods).  A  MANOVA 
investigates the effects of a categorical predictive variable (groups) on 2 or more continuous outcomes, 
which are correlated and represented by a vector of dependent variables.  For all analyses, a p value of 
<0.05 will be considered statistically significant.
 
12. Bibliography
1.
Divine J, Zazulak B, Hewett TE. Viscosupplementation for knee osteoarthritis. Clin Orthop Rel 
Res. 2006; 455:113-122.
2.
Dawson J, Linsell L, Zondervan K, et al. Epidemiology of hop and knee pain and its impact on 
overall health status in older adults. Rheumatology. 2004; 43:497-504.
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403

3.
Laupattarakasem W, Laopaiboon M, Laupattarakasem P, Sumananont C. Arthroscopic 
debridement for knee osteoarthritis (Review). Cochrane Collaboration. Issue 4, 2009.
4.
Younes M, et al.  Systemic effects of epidural and intra-articular glucocorticoid injections in 
diabetic and non-diabetic patients. Joint Bone Spine. 2007, 74(5): 472-6.
5.
Moon HJ, et al.  Changes in blood glucose and cortisol levels after epidural or shoulder intra-
articular glucocorticoid injections in diabetic or nondiabetic patients. Am J Phys Med Rehabil. 
2014, 93(5): 372-8.
6.
Gruss J, et al.  Human amniotic membrane: a versatile wound dressing.  CMA Journal. 1978; 
118:1237-1246.
7.
Niknejad H, et al.  Properties of amniotic membrane for potential use in Tissue Engineering.  
European Cells and Materials. 2008; 15:88-89.
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