XVII. Wound and Fracture Healing

 

A. Pressure Sores

 

[340] COMPARISON OF SEMI-SYNTHETIC AND AUTOLOGOUS CONNECTIVE TISSUE GRAFTS: A PILOT STUDY

Eric E. Sabelman, PhD; William C. Lineaweaver, MD; Kenneth C.W. Hui, MD; Paula Koran, BS; Nicole Diep, BS
Rehabilitation R&D Center, VA Palo Alto Health Care System, Palo Alto, CA 94304; Dept. of Functional Restoration, Stanford University Medical School, Stanford CA 94305; email: sabelman@roses.stanford.edu

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Pilot Project #B1839PA); Plastic Surgery Education Foundation

PURPOSE--Severe ulcerating pressure sores are now treated by reconstructive surgery, using a musculocutaneous flap rotated from an adjacent unaffected site. If this fails and the ulcer recurs, as is frequently the case when the causative compression of soft tissue against a bony prominence cannot be avoided, there may be no remaining donor site for a flap or graft.

METHODOLOGY--A tissue-engineered graft for repair of the deep or recurring ulcer is constructed of natural and synthetic biomaterials inoculated with autologous connective tissue and fat cells, which are nourished either from an external fluid loop through artificial capillaries, or by a microsurgically relocated arteriovenous loop. The synthetic capillary network is a branching mesh of permeable tubes, connected either to vessels at a distance from the injury, or to a supply of culture medium. The latter takes the place of the blood supply until replaced by it; it also provides a means for infusing high-dose antibiotics to combat infection and for raising hydrostatic pressure to resist compression.

PROGRESS--A 1-year pilot project has been completed, in which composite collagen/hyaluronic acid grafts were tested for cell compatibility in vitro. These composite materials were tested for creep compliance and tensile relaxation properties. A subproject now underway involves testing capability of these grafts to resist bacterial and fungal infections common in pressure sores. A second pilot project to perform microsurgical revascularization of semiartificial grafts in rats has begun. This phase includes an effort to develop a better small animal model for pressure sores by impeding revascularization from the periphery of an excision wound.

RESULTS--The matrix that best mimics mechanical and geometric properties of intact tissue is an interdigitated composite of collagen and hyaluronic acid, with the collagen cross-linked using ultraviolet light to avoid toxic chemicals. Three trials of implantation of 2 cm square grafts were made in abdominal pouches in rats; results showed good revascularization from a saphenous vein graft placed between two layers of collagen/hyaluronate matrix. There was some compression in thickness but no migration from the implant site.

FUTURE PLANS--A larger scale animal implantation experiment will show that restoration of tissue volume and vascular supply can be reliably replicated; this will be followed by a proposal for a limited clinical trial. Because the costs and level of surgical skill are anticipated to be lower than reconstructive microsurgery, we expect this type of graft to occupy a place in the therapeutic armamentarium midway between surgery and conservative debridement followed by semiocclusive dressings.

RECENT PUBLICATIONS FROM THIS RESEARCH

 

[341] MEASUREMENT OF PLANTAR FOOT SOFT TISSUE PROPERTIES OF PATIENTS WITH DIABETIC NEUROPATHY FOR PREDICTION OF PLANTAR FOOT PRESSURES AND ASSESSMENT OF PLANTAR ULCERATION RISK

Sheldon R. Simon, MD; Necip Berme, PhD; Felicia Sawyer, MS
The Division of Orthopaedics and the Department of Mechanical Engineering, The Ohio State University, Columbus, OH 43210; email: simon.1@osu.edu; berme.1@osu.edu; sawyer.8@osu.edu

Sponsor: National Institute on Disability and Rehabilitation Research, Washington, DC 20202

PURPOSE--For people who suffer from diabetes, especially those complicated by neuropathy, foot problems can be a common phenomenon. One of the more common is plantar ulceration, which can range from small superficial ulcers to deep penetrating ulcers with bony involvement. Shoe orthotics have been shown to be effective in the reduction of pressures. Currently, a new type of orthotic is being tried which involves a plastic insole filled with silicone gel, but little is known of its effectiveness. This study seeks to determine the efficacy of silicone gel shoe insoles as a therapeutic treatment in reducing plantar pressure and examine if factors such as walking rates and volume of silicone gel has an effect on the pressure-relieving abilities of the insoles.

METHODOLOGY--Fifteen healthy, voluntary consenting, adults participated in this study. None have had any substantial lower limb orthopedic problems or surgeries or sustained any lower limb injuries within the last 6 months. Foot pressure data was collected using the PEDAR System (Novel, Inc., Minneapolis, MN and Munich, Germany), an in-shoe pressure measurement device. Three silicone gel insole conditions were tested: low, medium (or normal), and high volume.

  Each subject first walked approximately 20 feet at his/her own comfortable walking pace in order to determine normal walking velocity, the average of four trials. Slow and fast velocities were then calculated from this average.

  After those velocities were calculated, the subject put on knee-hi stockings and shoes with only the PEDAR inserts in them and walked back and forth approximately 20 feet at the different velocities. Two walking trials were recorded for each velocity. Then one pair of the silicone gel insoles was inserted at random into his/her shoes, and two walking trials at each velocity were then performed over again by the subject. The entire process was repeated until all insoles were tested.

PROGRESS--For each representative step, pressure gradients were computed at each pressure sensor across the metatarsal and heel regions. Except those along the edges, each sensor is adjacent to eight other sensors, thus a total of eight gradient calculations were performed. From these calculations, the one with the largest gradient was used as the pressure gradient for that sensor. This method of computing pressure gradients was used on every pressure sensor except those along the edges which were not used. Pressure gradients were computed as a function of percentage of stance phase. Finally, the peak pressure gradient within each region was then selected as a function of percentage of stance phase.

RESULTS--The results of this investigation show that the silicone gel shoe insoles were effective in reducing plantar pressures under the heel region. However, under the forefoot region, the insoles were not as effective. The difference in the outcome for each region appears to be a function of the dynamic movement of the foot, the timing of the different phases during stance, and the viscosity of the fluid.

RECENT PUBLICATIONS FROM THIS RESEARCH

 

[342] THE USE OF GROWTH FACTORS IN PRESSURE ULCER HEALING: CLINICAL TRIALS

Dale S. Feldman, PhD
University of Alabama at Birmingham, Department of Biomedical Engineering, Birmingham, AL 35294; email: dfeldman@eng.uab.edu

Sponsor: National Institute on Disability and Rehabilitation Research, U.S. Department of Education, Washington, DC 20202-2646

PURPOSE--Optimizing active treatment protocols for pressure ulcers requires speeding up the rate of regenerative healing in order to reduce both the likelihood and impact of other secondary complications. This project was designed to examine the use of fibrin matrices that serve as a drug delivery system for an angiogenic factor (FGF-1) as well as a regenerative scaffold.

METHODOLOGY--1) Development of biodegradable fibrin matrix for delivery of acidic fibroblast growth factor (FGF-I). 2) Development of a porous fibrin matrix. 3) Clinical evaluation of the pressure ulcer healing efficacy of the fibrin matrix with FGF-1.

  Phases 1 and 2 are complete and phase 3 is currently underway. Clinical trials will be conducted with two treatment groups of 10 patients each. Group 1 will receive standard clinical treatment (saline soaked dressings) and Group 2 will receive a biodegradable fibrin matrix with FGF-1 applied to the surface of the wound.

PROGRESS--Progress during the first years has included: the determination of the optimal FGF-l loading of the fibrin matrix (8 g/ml), the in vivo release kinetics, the appropriate delivery techniques clinically, and testing of this system in several animal skin models. It was found that the fibrin and the FGF-1 act synergistically to enhance the healing response. The FGF-1 apparently needs a matrix for the cells and blood vessels to grow into, and the fibrin matrix does not stimulate the angiogenic and healing response as well without FGF-1 incorporation.

  For the porous system, which was made by adding polyethylene glycol (PEG) beads (100-200 µm) into the fibrinogen during the formation of the fibrin matrix, further optimization is needed prior to clinical testing. The current system did not give a better response in open wounds, and, in a related study with meshed skin grafts, the porous system was less effective than the nonporous both due to its lower adhesive strength and the residence time of the PEG.

  In preparation for clinical studies, effort has concentrated on development of the clinical protocol, development of clinical assessment tools, and obtaining FDA approval. For the assessment techniques, three aspects of pressure ulcer healing will be assessed: healing rate, tissue health, and overall clinical impression. For healing rate, the epithelialization rate, contraction rate, and tissue fill rate independent of wound size will be assessed. For tissue health, a scanning laser doppler will be used to assess the blood flow of the entire wound.

  The clinical study is currently waiting on an IND for FGF-1. Based on requirements outlined by the FDA, the protocol has been modified and the project is on hold until certain GMP requirements are met.

FUTURE PLANS--The initial focus is on meeting the FDA requirements and beginning the clinical study. Additionally, efforts will continue to further optimize the porous fibrin matrix.

RECENT PUBLICATIONS FROM THIS RESEARCH

 

[343] MICROPROCESSOR-BASED WHEELCHAIR PRESSURE RELIEF TRAINER AND MONITOR

Robert Price, MSME; Steven Steins, MD; David White, PhD; Denis Anson, MS
University of Washington, Department of Rehabilitation Medicine, Seattle, WA 98195-6490; email: pricer@u.washington.edu

Sponsor: University of Washington, Seattle, WA 98195

PURPOSE--An electronic device is being developed to prompt, monitor, and record wheelchair pressure releases to train and/or observe pressure release behavior. The ultimate goal is to reduce the incidence and magnitude of skin problems associated with inadequate pressure release behavior in wheelchair users.

METHODOLOGY--The device consists of a pressure sensor, a microprocessor, an audio beeper, and batteries. The pressure sensor system consists of a capacitive sensor and an oscillator circuit. The ~12×12×0.2 in sensor pad (38.5×38.5×0.5 cm) is connected to the ~4×6×2.5 in microprocessor and power unit (10.16×15.24×6.35 cm) with a thin cable. The sensor consists of two conductive sheets separated by a dielectric. This simple, cheap, and readily available sensor is placed under the wheelchair seat and changes its capacitance in response to the user's presence. The capacitor is part of a simple oscillator whose output frequency depends on capacitance; effectively forming a nonlinear pressure-to-frequency transducer. Unlike a simple switch, this allows for an adjustable pressure threshold due to a continuous change of frequency with pressure. The oscillator output is fed to the microprocessor's digital input bus. As the sensor is readily short circuited by conductive liquids, it doubles as a urine sensor.

  The microprocessor samples the oscillator's output and decides whether a pressure release has been accomplished. The threshold pressure level is automatically determined when the device is turned on. The microprocessor can provide an audible indication of successful pressure releases as feedback to the user. The microprocessor can record the time and date of the pressure release for later inspection by downloading the stored data to a PC.

  Audible beeps (or other cues) can be provided as reminders to the user that a pressure relief is needed. A voice chip has also been incorporated in one prototype device to provide verbal instructions. Pressure relief reminders can be disabled to provide a "monitor only" capability. Thus, the user's consistency in performing pressure reliefs without prompting can be determined.

  The device has sufficient memory to store about 250 time-stamped events, and is expandable. Battery power is conserved by having the microprocessor idle if the user is off of their cushion for over 30 s. The device checks for the user to return periodically, at which time, normal operation resumes, with idle time recorded in memory. Under typical use conditions, the system will run for about 1 week.

PROGRESS--Refinements to the prototype are planned to extend its capabilities. More durable sensor pad designs are being investigated. The ability to detect squirming, as a pressure release strategy, will be investigated. A urine sensing capability will be investigated; this will be beneficial since the presence of urine accelerates skin breakdown. To adapt the device to a wider spectrum of sensory/cognitive disabilities, other prompting methods will be investigated. Possibilities include voice reminders using a voice chip (prototype already developed), visual cues (flashing LEDs), and vibratory cues. Finally, we plan to extend the duration of time that the monitor will sample behavior by investigating other power sources, such as a rechargeable battery pack.

 

B. Fracture Healing

 

[344] NEW METHODS TO TREAT IMPAIRED FRACTURE HEALING USING GROWTH FACTORS

Dennis A. Chakkalakal, PhD; Michael H. McGuire, MD; Kevin L. Garvin, MD
VA Medical Center, Omaha, NE 68105; Creighton University Medical Center, Omaha, NE 68178; University of Nebraska Medical Center, Omaha, NE 68198

Sponsor: Department of Veterans Affairs, VA Rehabilitation Research and Development Service, Washington, DC 20420
(Project #A833-RA)

PURPOSE--The goal of the proposed research is to develop new, more effective methods to treat fractures that do not respond to normal fracture treatment with the best available methods. The specific objectives are to determine whether exogenous growth factors can restore normal healing in a delayed healing model and whether time-dependent changes in selected osteogenic indices, associated with this restoration, are correlated with changes in the amounts of selected growth factors.

METHODOLOGY--We use surgically created skeletal defects in rat fibula grafted with a DBM cylinder (DBM=acid-demineralized bone matrix) made from femora of allogeneic animals, as experimental models for fracture healing. A 2 mm defect represents a normal healing fracture and a 4 mm defect is the model for a delayed healing fracture in this project. The DBM-grafted skeletal defect provides a well-defined "fracture site" for evaluating the effectiveness of therapeutic agents proposed for stimulation of fracture healing. The growth factors are applied immediately after the skeletal defects are created. The methodology includes measurement of a) bending rigidity of the fibula and mineral content of the repair tissue, b) DNA synthesis, alkaline phosphatase activity, collagen types I, II and X and osteocalcin, and c) growth factors TGFb, PDGF, IGF-I, and IGF-II.

PROGRESS--Sequential stages of repair in 2 mm and 4 mm defects grafted with 5 mm and 7 mm DBM cylinders were investigated during 8 weeks post-surgery. Osteoconductive and osteoinductive contributions of the DBM cylinder were examined by studying groups of animals with DBM grafts pretreated to selectively remove osteoinductive factors. Various osteoinductive substances were applied in the 4 mm defect to evaluate their usefulness as carriers for growth factors. TGFb and PDGF were applied to the DBM cylinder in separate groups of rats at the time of grafting the 4 mm defect to determine if it would stimulate bone repair at 7 weeks. TGFb 1 and BMP2 were applied in combination with microcrystalline hydroxyapatite (MHA) in the defect and the results evaluated at 7 weeks.

RESULTS--Repair sequence in the 2 mm defect is similar to the sequential stages of normal human fracture healing up to union with woven and lamellar bone. In the 4 mm defect model the repair tissue is dominated by fibrous tissue and the rigidity of the fibula is 45 percent less than in the 2 mm defect model at 7 weeks post-surgery. Application of 1 to 100 ng of TGFb 1 or PDGF to the graft did not stimulate bone repair in the 4 mm defect. Application of 500 ng of BMP2 (+MHA) in the defect increased the rigidity of the fibula at 7 weeks significantly compared to the untreated control (p<5×10-4) and the MHA-treated control (p<7×10-5).

IMPLICATIONS--The results of this project may lead to new treatments for difficult fracture healing problems without surgery. Growth factors that are found to be effective in this study could be injected into the fracture site.

 

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Last revised Wed 05/26/1999