Enriched Autologous Fat Grafting for Treating Pain at Amputation Sites (AMP-5)
|First Received Date ICMJE||March 21, 2012|
|Last Updated Date||January 23, 2014|
|Start Date ICMJE||July 2012|
|Estimated Primary Completion Date||March 2016 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Treatment of Painful Amputation Sites [ Time Frame: 26 months ] [ Designated as safety issue: No ]
1) Treat painful amputation sites in 5 patients with fat grafting, 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.
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT01645722 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Enriched Autologous Fat Grafting for Treating Pain at Amputation Sites|
|Official Title ICMJE||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:
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:
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.
|Study Type ICMJE||Interventional|
|Study Phase||Not Provided|
|Study Design ICMJE||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Intervention ICMJE||Procedure: Procedure/Surgery: Enriched Fat grafting
Fat grafting is a minimally invasive clinical procedure that has been widely used by plastic surgeons within reconstructive surgery for many years. Fat tissue to be used for grafting is harvested (usually from abdomen or thighs) in the operating room. The fat tissue is then sterilely centrifuged and allowed to decant before separating the fluid and oil layers from the fat tissue fraction. The aspirated fat is then injected into the amputation stump.In this study, we will concentrate the adipose stromal cells (ASCs) in the fat graft material to assess whether this modification will increase fat graft retention over time. The volume retention in areas treated with ASC concentrated fat grafts will be compared with regions treated with standard fat grafts in the same patient.
|Study Arm (s)||Procedure/Surgery: Enriched Fat grafting
Enriched Fat grafting
Intervention: Procedure: Procedure/Surgery: Enriched Fat grafting
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE||5|
|Completion Date||Not Provided|
|Estimated Primary Completion Date||March 2016 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||18 Years and older|
|Accepts Healthy Volunteers||Yes|
|Location Countries ICMJE||United States|
|NCT Number ICMJE||NCT01645722|
|Other Study ID Numbers ICMJE||PRO11090215|
|Has Data Monitoring Committee||Yes|
|Responsible Party||J. Peter Rubin, MD, University of Pittsburgh|
|Study Sponsor ICMJE||University of Pittsburgh|
|Collaborators ICMJE||Department of Defense|
|Information Provided By||University of Pittsburgh|
|Verification Date||January 2014|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP