Pain Clinical Trial
Official title:
Enriched Autologous Fat Grafting for Treating Pain at Amputation Sites
The objective of this pilot study is to assess the efficacy of minimally invasive autologous
fat transfers at the amputation sites and the modulation of pain at the respective sites. Our
investigators hypothesize that autologous fat grafting can provide a minimally invasive
therapy to effectively mitigate pain syndromes at amputation sites, by introducing volume
stable subcutaneous tissue over bony prominences and peripheral nerve trunks, thereby
avoiding major surgical revisions and preserving limb length. The investigators further
hypothesize that enriching the fat graft with autologous adipose stromal cells, a
regenerative medicine approach, will lead to improved retention of the fat graft over time
and result in a more favorable outcome.
The Investigators will evaluate:
1. Treatment of painful amputation sites in 5 patients with fat grafting, intended to
provide additional subcutaneous tissue padding over bony structures and nerve trunks.
Limb anatomy and healing of the graft over time, along with stability/persistence of the
new tissue, will be assessed by high resolution CT scanning with 3D reconstruction.
Patients will be followed for 24 months after treatment to define long term outcomes.
Patients will be enrolled who have pain at an amputation site that limits function
and/or interferes with the ability to use a prosthesis.
2. Biologic properties of the cells within the fat graft and correlate with clinical
outcomes. This will include adipose stem cell yield per volume of fat tissue, cell
proliferation, capacity for adipogenic differentiation, lipolysis, and cell
sub-population analysis by multiparameter flow cytometry. Results of these assays will
be correlated with graft volume retention to search for predictors of good clinical
outcome that are related to variation on adipose biology between subjects.
3. Quality of life measurements in patients before and after autologous fat grafting using
validated psychosocial measures. This will include SF 36, the Beck inventory, and
instruments designed for assessing limb function.
Traumatic amputations are prevalent and pose many challenges for our wounded warriors. A
recent publication reported that during the current conflicts, over 950 military personnel
have sustained combat-related amputations, with 15% of them occurring more than 12 weeks
after initial injury (1). Updated statistics place this number of amputees at over 1050
(personal communication, COL Paul Pasquina, Chief of the Integrated Department of
Orthopaedics and Rehabilitation, Walter Reed National Military Medical Center-WRNMMC). The
ability of a wounded warrior to gain optimal function after an amputation most often depends
on his or her ability to successfully fit and adapt to a prosthesis. Once out of the acute
phase, many patients with amputations suffer from pain when wearing a prosthesis, either from
thin soft tissue cover over bony structures or peripheral nerves not well padded with soft
tissue. Extrinsic residual limb pain is usually mechanical in origin related to the
prosthetic socket or other prosthetic components. It is often the result of a mismatch
between residual limb tissue tolerance and the prosthetic loads on the soft tissues. This
sensitivity is often accentuated by superficial nerve trunks or neuromas at severed nerves
that are exposed to excessive external mechanical loading (2). Poor socket interface,
secondary skin breakdown, and/or pain may severely limit function.
This presents a very difficult clinical problem and historically, when possible, the clinical
procedure would be to involve the surgical revision of the amputation site with associated
shortening of the bone, lengthy scars, and prolonged healing. If a below the knee amputation
has to be converted to an above knee level, then there are serious functional implications.
For local tissues at the amputation site that are of poor quality (e.g. scarred or covered
with a skin graft), a distant muscle flap may be required (3,4). These flaps may require
transfer to the amputation site using microvascular anastomosis of the blood vessels. The
procedure is highly invasive and can add the morbidity of decreased function, deformity, and
risk of wound healing problems at the muscle donor site. Failure rates in lower limb flaps
can be as high as 18.5% (5, 6). Flap ulceration rates tend to be higher in these
weight-bearing flaps, both skin and muscle free flaps frequently need secondary debulking
procedures to improve function, and painful neuromas are not uncommon (6,7).
A clinical solution that allows for the minimally invasive generation of new soft tissue
padding at an amputation site without the need for further limb shortening, lengthy scars, a
prolonged recovery, and significant donor site morbidity would have the potential to
significantly help our wounded warriors and change clinical practice.
Autologous fat grafting as a potential solution. Grafting of autologous fat tissue is a
minimally invasive surgical technique that starts with the harvest of fat tissue from the
abdomen or thighs using liposuction through incisions less than 5mm in length. The
lipoaspirate is then processed to concentrate the adipose fraction and reinjected into the
donor site. This surgical procedure involves the immediate transplantation of a patient's own
tissue in a single operative procedure. It has the advantages of:
- Minimal access incisions
- Ability to transfer significant amounts of tissue (hundreds of grams of tissue)
- Can be used in setting of previous surgical procedures and presence of hardware
- Usually performed as outpatient procedure
- Minimal donor site morbidity at graft harvest site
- Low risk compared with more invasive surgical procedures
- Can be repeated multiple times, if necessary, even using the same donor sites
The transfer of autologous tissues is not a new concept but just another method as we have
seen with many types of flaps using various combinations of muscle, fat and skin have been
well documented. Tissue flaps come from many different locations, and are used in many
different ways to accomplish the desired results. Flaps have their own blood supply, they are
more resilient than skin grafts, and usually produce much better results from a cosmetic
standpoint because they can provide a better match for skin tone and texture. Skin flaps are
also a better choice when tissue "bulk" is needed to fill contour defects. The obvious
advantage is to use autologus tissue versus xenografts and allografts; each having known
risks of rejection and adverse events.
The literature has unequivocally demonstrated that clinical fat grafting in buttocks (a
similar weight-bearing anatomic region) can be performed safely and effectively with
retention rates approximating 75% up to 2 years and beyond (23-25). In an OVID database
search of fat grafting articles, over 9000 articles have referenced the use of fat grafts in
a wide arena of clinical situations. Specifically to this application over 100 references
were relevant to this proposal and provided below.(26-132)
The investigators propose a clinical trial to assess the efficacy of minimally invasive
autologous fat transfer for addressing pain and poor prosthetic fit at amputation sites. This
surgical procedure involves the immediate transplantation of a subject's own tissue and does
not require FDA oversight. Importantly, we will use our knowledge and expertise working with
adipose stromal cells to compare a regenerative medicine cell therapy modification of the fat
grafting procedure with more traditional fat graft preparations.
The biggest problem associated with fat grafting is unpredictable rates of fat graft
resorption. This is likely related to the ability of the regenerating adipose tissue to
rapidly develop a new blood supply. In this study, we will test a regenerative medicine
approach of enriching the adipose graft with autologous adipose stem cells (stromal cell
enriched adipose grafting). This may serve to improve graft retention over time and
potentially improve functional outcomes.
A modified preparation of the fat graft involves concentrating the endogenous stromal cells
in the graft material in an effort to increase graft retention over time. The aspirated fat
material used for fat grafting consists of mature adipocytes, a small amount of fibrous
tissue, and immature adipose stromal cells (ASCs). These adipose stromal cells are a mixed
population of non-lipid laden cells that serve to turn over mature adipocytes and vascular
elements. "Preadipocytes," as well as endothelial precursor cells and multilineage progenitor
cells, are found. Of note, ASCs have been shown to stimulate angiogenesis when stressed under
hypoxic conditions and these cells may be instrumental in healing and volume retention of fat
grafts. Yoshimura, et. al. (133) found that fat aspirated with a liposuction cannula (i.e.
the method of fat harvest for fat grafting) is deficient in ASCs compared to whole fat. This
is due to the fact that a major portion of ASCs are located around larger blood vessels that
are left intact in the donor site after liposuction with a blunt cannula. The relative lack
of ASCs in lipoaspirate may explain problems with fat graft reabsorption over time. Enriching
lipoaspirate with ASCs should increase angiogenesis and, therefore, fat graft retention. This
cell therapy approach takes advantage of the innate ability of ASC's to both secrete
angiogenic factors and also differentiate into mature adipocytes. The improved blood vessel
ingrowth can result in improved graft volume retention and superior reconstructive outcomes.
Our group at the University of Pittsburgh has developed clinically useful and scalable GMP
methods for ASC extraction under an NIH funded program, led by Dr. Rubin (Co-Director of the
Adipose Stem Cell Center) in collaboration with Dr. Albert Donnenberg, director of the
clinical laboratories for cell processing. We are currently starting a fully funded project
with the Armed Forces of Regenerative Medicine (AFIRM). We are utilizing our extraction
techniques to perform ASC enriched fat grafting for facial trauma reconstruction and this has
received IRB approval at our institution. This process is regulated under human cells,
tissues and cellular and tissue-based products (HCT/P) guidelines under section 361 of the
CFR (21CFR1271.10). HCT/P therapies are exempt from the requirement for the submission of an
Investigational New Drug (IND) application.
For this project proposal, we have expanded the team to encompass expertise in reconstructive
fat grafting, lower extremity reconstruction, physical medicine and rehabilitation,
prosthetic design, nutritional support, and evaluation of psychosocial outcomes. Given the
initial success with autologous fat grafting for facial reconstruction after trauma (analysis
ongoing), even without enrichment of the graft with adipose stromal cells, we believe this
therapy can be effectively applied for the treatment of limb pain. This procedure can be
performed on an outpatient basis with no significant incisions on the limb, only small port
sites measuring less than 5 mm. It is noted that this is a completely new, experimental
application of a conventional treatment.
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