The use of blood-derived growth factors, including recombinant platelet-derived growth factors (PDGFs) and platelet-rich plasma (PRP), has been suggested as a treatment for wounds or other miscellaneous non-orthopedic conditions, including but not limited to, diabetic ulcers, pressure ulcers, venous stasis ulcers, and surgical and traumatic wounds.
For individuals who have diabetic lower-extremity ulcers who receive recombinant platelet-derived growth factors (PDGFs), the evidence includes randomized controlled trials (RCTs) and systematic reviews. Relevant outcomes are symptoms, change in disease status, morbid events, quality of life (QOL), and treatment-related morbidity. Results have shown improved rates of healing with use of recombinant PDGF for diabetic neuropathic ulcers and pressure ulcers. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who have pressure ulcers who receive recombinant PDGF, the evidence includes a single RCT. Relevant outcomes are symptoms, change in disease status, morbid events, QOL, and treatment-related morbidity. Results have shown improved rates of healing with use of recombinant PDGF for pressure ulcers. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who have venous stasis leg ulcers or acute surgical or traumatic wounds who receive recombinant PDGF, the evidence includes small RCTs. Relevant outcomes are symptoms, change in disease status, morbid events, QOL, and treatment-related morbidity. The level of evidence does not permit conclusions whether recombinant PDGF is effective in treating other wound types, including chronic venous ulcers or acute traumatic wounds. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who have chronic wounds who receive platelet-rich plasma (PRP), the evidence includes meta-analyses of a number of small controlled trials. Relevant outcomes are symptoms, change in disease status, morbid events, QOL, and treatment-related morbidity. In meta-analyses of individuals with lower extremity diabetic ulcers, PRP demonstrated an improvement over the control groups in complete wound closure, recurrence rate, and healing time, but moderate to high risk of bias and imprecision preclude drawing conclusions on other important outcomes such as recurrence, infection, amputation, and quality of life. In individuals with venous ulcers, PRP did not demonstrate an improvement over the control groups in complete wound closure, recurrence, wound infection or quality of life, although imprecision likely precluded identifying differences on these outcomes. In individuals with pressure ulcers, although PRP reduced wound size, other important outcomes such as complete wound closure were not measured. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who have acute surgical or traumatic wounds who receive PRP, the evidence includes systematic reviews and a number of small controlled trials. Relevant outcomes are symptoms, change in disease status, morbid events, QOL, and treatment-related morbidity. Current results of trials using PRP are mixed and the studies are limited in both size and quality. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.
Recombinant platelet-derived growth factor (ie, becaplermin) may be considered medically necessary when used as an adjunct to standard wound management for the following indications (for further information on selection criteria, see Policy Guidelines next):
Neuropathic diabetic ulcers extending into the subcutaneous tissue
Pressure ulcers extending into the subcutaneous tissue.
Other applications of recombinant platelet-derived growth factor (ie, becaplermin) are considered investigational, including, but not limited to, ischemic ulcers, venous stasis ulcers, and ulcers not extending through the dermis into the subcutaneous tissue.
Use of platelet-rich plasma (ie, autologous blood-derived preparations) is considered investigational for the treatment of acute or chronic wounds, including surgical wounds and nonhealing ulcers.
| CPT | 0232T | Injection(s), platelet rich plasma, any site, including image guidance, harvesting and preparation when performed |
| HCPCS | G0460 | Autologous platelet rich plasma for non-diabetic chronic wounds/ulcers, including phlebotomy, centrifugation, and all other preparatory procedures, administration and dressings, per treatment |
| G0465 | Autologous platelet rich plasma (prp) for diabetic chronic wounds/ulcers, using an fda-cleared device (includes administration, dressings, phlebotomy, centrifugation, and all other preparatory procedures, per treatment) | |
| P9020 | Platelet rich plasma, each unit | |
| S0157 | Becaplermin gel 0.01%, 0.5 gm | |
| S9055 | Procuren or other growth factor preparation to promote wound healing |
| ICD-10-CM | E11.40 | Type 2 diabetes mellitus with diabetic neuropathy, unspecified |
| E11.41 | Type 2 diabetes mellitus with diabetic mononeuropathy | |
| E11.42 | Type 2 diabetes mellitus with diabetic polyneuropathy | |
| E11.43 | Type 2 diabetes mellitus with diabetic autonomic (poly)neuropathy | |
| E11.49 | Diabetes with other diabetic neurological complication | |
| L89.000-L89.96 | Pressure ulcer code range | |
| L97.121-L97.929 | Pressure ulcer lower limbs and foot code range | |
| L98.411-L98.499 | Non pressure chronic ulcer of skin and other sites | |
| L98.A111-L98.A399 | Non-pressure chronic ulcer range |
Appropriate candidates for becaplermin gel for treatment of neuropathic ulcers should meet ALL of the following criteria:
Adequate tissue oxygenation, as measured by a transcutaneous partial pressure of oxygen of 30 mm Hg or greater on the foot dorsum or at the margin of the ulcer
Full-thickness ulcer (ie, stage III or IV), extending through dermis into subcutaneous tissues
Participation in a wound management program, which includes sharp debridement, pressure relief (ie, non-weight bearing), and infection control.
Appropriate candidates for becaplermin gel for the treatment of pressure ulcers should meet ALL of the following criteria:
Full-thickness ulcer (ie, stage III or IV), extending through dermis into subcutaneous tissues
Ulcer in an anatomic location that can be offloaded for the duration of treatment
Albumin concentration >2.5 dL
Total lymphocyte count >1000/μL
Normal values of vitamins A and C.
Individuals are typically treated once daily for up to 20 weeks or until completely healed. Application of the gel may be performed by the individual in the home.
Becaplermin is available in 2-, 7.5-, and 15-g tubes and is applied in a thin continuous layer, about 1/16 of an inch thick (ie, 1.6 mm or the thickness of a dime). The amount of the gel used will depend on the size of the ulcer, measured in square centimeters. However, an average-sized ulcer, measuring 3 cm2, treated for an average length of time of 85 days, will require a little more than one 15-g tube. If the ulcer is treated for the maximum length of time of 140 days, 1.75 of the 15-g tubes would be required.
A variety of growth factors have been found to play a role in wound healing, including platelet-derived growth factor (PDGF), epidermal growth factor, fibroblast growth factors, transforming growth factors, and insulin-like growth factors. Autologous platelets are a rich source of PDGF, transforming growth factors (that function as a mitogen for fibroblasts, smooth muscle cells, and osteoblasts), and vascular endothelial growth factors. Recombinant PDGF also has been extensively investigated for clinical use in wound healing.
Autologous platelet concentrate suspended in plasma, also known as platelet-rich plasma (PRP), can be prepared from samples of centrifuged autologous blood. Exposure to a solution of thrombin and calcium chloride degranulates platelets (releasing various growth factors) and results in the polymerization of fibrin from fibrinogen, creating a platelet gel. The platelet gel can then be applied to wounds or may be used as an adjunct to surgery to promote hemostasis and accelerate healing. In the operating room setting, PRP has been investigated as an adjunct to a variety of periodontal, reconstructive, and orthopedic procedures. For example, bone morphogenetic proteins are a transforming growth factor, and thus PRP has been used in conjunction with bone-replacement grafting (using either autologous grafts or bovine-derived xenograft) in periodontal and maxillofacial surgeries.
PRP is distinguished from fibrin glues or sealants, which have been used for many years as a surgical adjunct to promote local hemostasis at incision sites. Fibrin glue is created from platelet-poor plasma and consists primarily of fibrinogen. Commercial fibrin glues are created from pooled homologous human donors; Tisseel® (Baxter International) and Hemaseel® (Haemacure Corp.) are examples of commercially available fibrin sealants. Autologous fibrin sealants can also be created from platelet-poor plasma. This evidence review does not address the use of fibrin sealants.
This review addresses the use of recombinant PDGF products and PRP for non-orthopedic indications, which include a number of wound closure-related indications.
For this review, the primary endpoints of interest for the study of wound closure are as follows, consistent with guidance from the U.S. Food and Drug Administration (FDA) for the industry in developing products for the treatment of chronic cutaneous ulcer and burn wounds1,:
Incidence of complete wound closure;
Time to complete wound closure (reflecting accelerated wound closure);
Incidence of complete wound closure following surgical wound closure;
Pain control.
In 1997, becaplermin gel (Regranex®; Smith & Nephew), a recombinant PDGF product, was approved by the FDA for the following labeled indication:
“Regranex Gel is indicated for the treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or beyond and have an adequate blood supply. When used as an adjunct to, and not a substitute for, good ulcer care practices including initial sharp debridement, pressure relief and infection control, Regranex Gel increases the complete healing of diabetic ulcers.
The efficacy of Regranex Gel for the treatment of diabetic neuropathic ulcers that do not extend through the dermis into subcutaneous tissue or ischemic diabetic ulcers … has not been evaluated…Regranex is not intended to be used in wounds that close by primary intention.”
In 2008, the manufacturer added the following black box warning to the labeling for Regranex®: “An increased rate of mortality secondary to malignancy was observed in patients treated with 3 or more tubes of Regranex Gel in a postmarketing retrospective cohort study. Regranex Gel should only be used when the benefits can be expected to outweigh the risks. Regranex Gel should be used with caution in patients with known malignancy.”
In 2018, the “Boxed Warning” and “Warnings and Precautions” were changed to remove “increased rate of cancer mortality” and “cancer mortality,” respectively.
The FDA regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation, Title 21, parts 1270 and 1271. Blood products such as PRP are included in these regulations.
Under these regulations, certain products including blood products such as PRP are exempt and therefore, do not follow the traditional FDA regulatory pathway. To date, the FDA has not attempted to regulate activated PRP.2,
Numerous PRP preparation systems have been cleared for marketing by the FDA through the 510(k) process. These devices are intended to concentrate patient plasma at the point of care during bone grafting procedures. The use of different devices and procedures can lead to variable concentrations of active platelets and associated proteins, increasing variability between studies of clinical efficacy.
