Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT02770209 |
| Other study ID # |
PLAGH_002 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
May 11, 2016 |
| Last updated |
May 11, 2016 |
| Start date |
February 2012 |
| Est. completion date |
June 2016 |
Study information
| Verified date |
May 2016 |
| Source |
Chinese PLA General Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
China: Ministry of Health |
| Study type |
Interventional
|
Clinical Trial Summary
This study is aimed at evaluating the feasibility and effectiveness of a completely natural
tissue engineered cartilage, composed of a self-made tissue engineered oriented scaffold and
autologous chondrocytes, for repairing articular cartilage damage following injury. And it
is also aimed at investigating the safety of tissue engineered cartilage transplantation.
Description:
Injured articular cartilage has limited capacity for self repair. Without timely, early and
effective treatment, damage to the articular cartilage progressively worsens, resulting in
joint swelling, pain and dysfunction. The patient ultimately develops osteoarthritis and
will be required to undergo artificial joint replacement. Clinical therapy for cartilage
damage includes microfracture surgery and autologous osteochondral transplantation. However,
the microfracture technique is limited to small-scale damage, and autologous osteochondral
transplantation is hindered by limited supply. With advances in material science, cell
biology, biomechanics and bioreactor technology, the new generation of biomimetic tissue
engineered osteochondral composites display great potential for the repair of cartilage
damage.
Currently, in cartilage tissue engineering, seed cells are derived from autologous or
allogeneic chondrocytes, mesenchymal stem cells, embryonic stem cells or pluripotent stem
cells. Increasing evidence indicates that bone marrow mesenchymal stem cells can be induced
to differentiate into chondrocytes, and these cells have been successfully used in the
treatment of large-size bone defects, cartilage lesions and spinal cord injury. The quality
and quantity of bone mesenchymal stem cells gradually decrease with age, especially in
patients with degenerative diseases. Adipose stem cells and umbilical cord mesenchymal stem
cells are abundant and have similar characteristics to bone mesenchymal stem cells, and both
of these cell types can be induced to differentiate into chondrocytes. Adipose stem cells
and umbilical cord mesenchymal stem cells have been used to repair cartilage defects, but
the findings are still preliminary, and these cells cannot be harvested or cultured in large
quantities. Furthermore, the use of embryonic stem cells is complicated by ethical
considerations. As a consequence, autologous chondrocytes are optimal seed cells for
cartilage tissue engineering.
The transplantation of autologous chondrocytes in combination with tissue engineered
cartilage scaffolds to repair cartilage damage requires researchers to focus on two major
issues, namely, (i) the in vitro amplification of chondrocytes and (ii) the preparation of
biocompatible chondrocyte scaffolds. The preparation of chondrocyte scaffolds requires
advanced technique, and currently, only the Institute of Orthopedics at the Chinese PLA
General Hospital has the capacity to produce acellular cartilage; there is no other source
of tissue engineered cartilage scaffolds in China.
A proprietary allogeneic acellular cartilage-oriented scaffold was successfully created by
the Cartilage Tissue Engineering Research Group, Institute of Orthopedics, Chinese PLA
General Hospital (with intellectual property rights). The innovative scaffold simulates the
composition and spatial structural characteristics of normal cartilage. The preparation
methods are as follows: articular cartilage is pulverized to obtain natural cartilage
extracellular matrix, which is identical in biochemical composition to extracellular matrix
of natural articular cartilage. Then, a porous sponge-like scaffold is prepared using the
freeze-drying technique. In vitro experiments and large-animal articular cartilage injury
repair experiments have produced good results. Using this material, our research group
prepared biomimetic cartilage tissue engineered scaffolds, which mimic the structural
characteristics of natural articular cartilage extracellular matrix. This allogeneic
acellular cartilage scaffold has the following characteristics: (1) it is derived from
allogeneic cartilage, and the extracellular matrix remains intact after allografting,
helping to maintain the numerous components of normal cartilage, particularly type II
collagen and proteoglycans, resulting in enhanced repair. Cartilage scaffolds used outside
of China are mainly composed of types I and III collagen or hyaluronic acid, and vary
greatly from natural cartilage components. The original cartilage structure is difficult to
reproduce with these types of scaffolds, and fibrous cartilage may affect treatment outcome.
(2) The biomimetic scaffold has a similar three-dimensional structure to that of normal
articular cartilage, which is the oriented scaffold structure. The scaffold imitates the
orientation of normal cartilage cells, which are arranged perpendicular to the surface, and
provides a paratactic columnar structure that contributes to the columnar arrangement of
cells. This structure in combination with type II collagen and proteoglycans derived from
normal articular cartilage results in a scaffold structure that is extremely close to that
of normal joint cartilage. Consequently, the repaired cartilage will have normal structure
and function. (3) The oriented scaffold has a good biomechanical property. Its compressive
stress is better than the non-oriented scaffold in wet and dry conditions. (4) The oriented
scaffold has good biocompatibility. Preliminary experiments have investigated the immune
responses of the oriented scaffold of heterogeneous (porcine) and conspecific (rabbit)
acellular cartilage. After the oriented scaffold was implanted into the rabbit, its immune
responses were observed from the aspects of cellular immunity and humoral immunity. Results
suggested that its immunogenicity was low. Thus, it is verified that the oriented scaffold
of acellular cartilage has good biocompatibility.
Adverse Events
1. Security Standard operating procedures for adverse events and severe adverse events
will be developed to ensure that any adverse reactions during the experiment will be
treated quickly to protect the participants.
2. Definitions 2.1 Adverse events Adverse medical events may occur after cartilage
transplantation or microfracture surgery, but they do not necessarily have a causal
relationship with treatment.
Common adverse reactions after cartilage transplantation include fever, joint pain,
swelling and effusion. Common adverse reactions after microfracture surgery include
fever, joint pain, joint swelling and effusion.
2.2 The severity of adverse events Adverse events will be classified into three levels:
general adverse events, vital adverse events and severe adverse events.
2.3 Relationship with tissue engineered cartilage The correlation between adverse
events and tissue-engineered cartilage will be categorized into "definitely related",
"probably related", "possibly unrelated", "irrelevant" or "undetermined".
2.4 Severe adverse events All events occurring during the trial requiring
hospitalization or prolonged hospitalization, or resulting in disability, or affecting
the ability to work, or with a risk of death or life-threatening events will be
recorded.
3. Adverse event recording All adverse events during the experiment will be collected
until the end of the study.
4. Recording and reporting All adverse events will be recorded by physicians, including
description of adverse events, occurrence time, end time, severity, frequency, and
treatment record.
Once a severe adverse event occurs, physicians will not only give necessary treatment,
but also truthfully report to the local Food and Drug Administration Bureau and the
National Food and Drug Administration Bureau within 24 hours, as well as promptly
report to the Ethics Committee. The data, treatment and follow-up results will be noted
in the report.
5. Follow-up observation of non-severe and severe adverse events If a patient suffers a
non-severe adverse event, the course and outcome will be closely monitored. The course
of severe adverse events will be recorded in follow-up reports or summary reports.
Patients will also be monitored, and observations will be recorded for a period of 30
days after a seizure.
Statistical Analysis
1. Study hypotheses All hypotheses will be evaluated with two-tailed tests. A value of P <
0.05 will be considered statistically significant. Baseline data comparability will be
assessed. Two-tailed statistical analysis will be performed with α = 5%.
2. Number of cases A total of 100 patients will be involved in this study and divided into
two groups, with 50 cases in each group.
3. Experimental analysis Experimental data will be analyzed using statistical software,
SPSS 22.0. Measurement data will be expressed as the mean ± SD, median, maximum,
minimum and quartiles; count data will be presented as a percentage (%). Count data
between groups will be compared using chi-square test or Fisher exact test. Measurement
data between groups will be compared using t-test. Nonparametric variables between
groups will be compared using rank sum test.
4. Statistical analysis Statistical analysis will be performed by professional
statisticians who will not be involved in the study. All data will be input and
reviewed, and a statistical analysis report will be prepared.
Administration
1. Preservation of articular cartilage Cartilage tissue will be preserved and transported
in a 50 mL centrifuge tube containing 8 mL of tissue preservation solution, placed on a
test tube rack on top of an ice pack, at 4 °C under sterile conditions. Cartilage
tissue will be transferred to the Institute of Orthopedics at the Chinese PLA General
Hospital within 12 hours.
2. Chondrocyte culture and preservation Autologous chondrocytes will be cultured and
amplified in strict accordance with the standards and requirements of the National
Institutes for Food and Drug Control. All images and data will be recorded. Cartilage
seed cells will be frozen in liquid nitrogen.
3. Data quality assurance (1) Researchers will fill in a case report form (CRF)
accurately. (2) Inspectors will regularly verify that all data recorded are correct and
complete, and that they are consistent with original records, and will be quickly
transferred to the data administrator. (3) The data administrator will further examine
CRF tables and return the form to the researchers. (4) Two data clerks will input
duplicate data into a computer database. (5) The two separate sets of data will be
compared by computer software, and modified according to the CRF. (6) Quality control:
5% of all case data will be randomly selected for manual checking. If the data error is
greater than 0.15%, all the data in the database will be manually checked.
