[247] COMPARISON OF SEMI-SYNTHETIC AND ANTOLOGOUS CONNECTION TISSUE GRAFTS: A PILOT STUDY
Eric E. Sabelman, PhD; William C. Lineaweaver, MD;
Kenneth C.W. Hui, MD; Feng Zhang, MD; Min Hu, MD, PhD
Rehabilitation R&D Center (640/153), VA Palo Alto Health
Care System, Palo Alto, CA 94304; Department 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; Plastic Surgery Education Foundation, Arlington
Heights, IL 60005
(Pilot Project #1839-AP)
PURPOSE--Chronic pressure sores are now treated by reconstructive surgery, using a musculocutaneous flap. If this fails and the ulcer recurs, as is frequently the case when 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 seeded with autologous connective tissue and fat cells, 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; the network also provides a means for infusing antibiotics to combat infection. The matrix that best mimics mechanical and geometric properties of intact tissue is an interdigitated composite of collagen and hyaluronic acid (HyA), with the collagen cross-linked using ultraviolet light to avoid toxic chemicals.
PROGRESS--A 1-year pilot project demonstrated cell compatibility of collagen/HyA grafts in vitro. A subproject now underway involves testing the capability of these grafts to resist bacterial and fungal infections common in pressure sores. A second pilot project to perform microsurgical revascularization of semi-artificial grafts in rats includes an effort to develop a better small animal model for pressure sores.
Three physical forms of semi-synthetic graft have been created: 1) homogeneous dispersions of random-geometry HyA particles less than 100 µm in diameter, 2) continuous-strand HyA mats or felts, and 3) loosely packed HyA beads 0.5-1.0 mm in diameter. These are processed into porous discs 35-60 mm in diameter and 2-5 mm thick. Methods for controlling swelling and solubility of the HyA component have been adapted from the literature; Dr. Hu has invented a new approach that also enhanced cell adhesion to HyA. Samples of a modified Type I collagen have been provided (Nova-Gen Inc., Fremont, CA), in addition to purchased bovine collagen and in-house prepared rat-tail collagen.
Preliminary implantations in rats were completed, using a subcutaneous abdominal site. Inflammation was minimal, with rapid capillary outgrowth from the arteriovenous loop within 2 wks and preservation of the HyA component for 8 wks. As predicted from in vitro experiments, migrating cells enveloped individual HyA beads or strands, and did not form a fibrous capsule around the entire implant. The abdominal site did not provide a wound margin suitable for testing integration. Alternate sites that would better emulate the clinical pressure sore include latissimus dorsi and rectus abdominus muscle excision wounds, with the latter requiring less extensive mobilization of the saphenous vein to create the arteriovenous loop.
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.
[248] USE OF TRETINOIN TO PREVENT PRESSURE ULCERS IN SPINAL CORD INJURY PATIENTS
Janusz Markowski, MD; Gladys P. Rodriguez, PhD
Spinal Cord Injury Service (128), VA Houston Medical
Center, 2002 Holcombe Blvd., Houston, TX 77030 and Baylor
College of Medicine, Houston, TX 77030
Sponsor: Department of Veterans Affairs, VA
Rehabilitation Research and Development Service, Washington,
DC 20420
(Project #B688-2RA)
PURPOSE--In this study, we seek to determine, through amino acid assays and collagen typing determinations on biopsies taken before and after treatment, whether skin collagen structure has been sufficiently improved by tretinoin cream to expect that the risk of developing pressure ulcers has been diminished in the treated area. Also, we want to determine whether the efficacy of the treatment depends on time since injury or age of the patient by using statistical regression analysis on the data from the amino acid and collagen typing determinations.
This is a controlled, prospective, randomized study. The protocol has been approved by the Institutional Review Board for Human Subjects.
METHODOLOGY--After obtaining informed consent, a 4-mm punch biopsy will be obtained from the sacral area. The biopsy will be assayed for content of the four amino acids characteristic of collagen (hydroxyproline, proline, hydroxylysine, and lysine), and the ratio of collagen Type I to collagen Type III will be determined. The amino acids will be assayed by HPLC chromatography. The collagen typing will be done using gel electrophoresis.
The patient population will consist of 40 male, traumatic spinal cord injury (SCI) patients between 20 and 55 years of age who have had at least one pressure ulcer previously. Additional inclusion criteria: physiologically complete, non-progressive SCI and normal liver function. Exclusion criteria: any metabolic disease affecting protein metabolism, presence of other neurological disorder besides SCI, or cauda equina injuries.
Twenty of the patients will be provided with the tretinoin cream and will be shown how to apply to the skin area at risk. They will apply the cream daily for 1 yr. The other 20 will be given a placebo cream. The patients and the investigators will be blinded to the treatment. The main outcome measure is an improved skin collagen biosynthesis as determined by increased amino acid content and increased content of collagen Type I. Subjects will be recruited from patients at the VA Medical Center in Houston or attending the Spinal Cord Injury Clinic.
PROGRESS--Assays of 10 of the biopsies have been completed. No preliminary analysis of the results can be done since the researchers are blinded to which subjects received the retinol and which received the placebo.
IMPLICATIONS--If this study demonstrates that our hypothesis is correct, that applying tretinoin cream to the skin will improve collagen biosynthesis and thus improve skin tensile strength, then we shall have added a useful therapy to the armamentarium against decubitis ulcers. A stronger skin will be better able to resist mechanical insults such as excessive pressure and shear. This will significantly impact on the cost of treating SCI patients by reducing the number of hospitalizations due to pressure ulcers. Pressure ulcers are a very costly sequelae of SCI. Reducing their incidence will improve the quality of life of the patients, might make it possible for more of them to be active participants in community life, and perhaps even economically self-sufficient.
[249] PREVENTION OF RECURRENT PRESSURE ULCERS AFTER MYOCUTANEOUS FLAP
Sally A. Holmes, MD; Janusz Markowski, MD; Susan L.
Garber, OTR., MS; Jeffrey D. Friedman, MD; Diana H. Rintala,
PhD; Gladys P. Rodriguez, PhD
Spinal Cord Injury Service (128), Houston Veterans
Affairs Medical Center, Houston, TX 77030; Department of
Physical Medicine and Rehabilitation, Baylor College of
Medicine, Houston, TX 77030; email:
holmes.s@houston.va.gov
Sponsor: Department of Veterans Affairs, VA
Rehabilitation Research and Development Service, Washington,
DC 20420
(Project #B2082-2RA)
PURPOSE--The objective of this study is to evaluate the efficacy of individualized education and structured follow-up to reduce the recurrence of surgically repaired pressure ulcers in persons with spinal cord injury (SCI). Additionally, the study will determine whether monitoring levels of urinary collagen metabolites will assist in early ulcer detection. The primary goal of this study is to establish an intervention that will reduce the recurrence of pressure ulcers after surgical repair in persons with SCI. Long-term goals include decreasing the number of hospitalizations, lengths of hospital stay, and medical costs as well as increasing quality of life for persons with SCI.
METHODOLOGY--Subjects with SCI who have undergone surgical repair of one or more pressure ulcers in the pelvic region are recruited and randomized to one of three groups. Four instruments are administered to each subject at the beginning and end of the study: 1) Pressure Ulcer Knowledge Test; 2) Health Beliefs Questionnaire; 3) Modified Major Life Events Questionnaire; and 4) Locus of Control Scale. All subjects are followed for 2 yrs or until they develop a recurrent pressure ulcer. In addition to standard education, Group 1 (intervention group) participants receive 4 hrs of one-on-one education based on the Agency for Health Care Policy and Research (AHCPR) pressure ulcer guidelines. This educational program covers etiology and risk factors for development of pressure ulcers, principles of wound healing and nutritional support, an individualized program of skin care, selection of support surfaces and equipment, as well as mechanisms for accurate documentation and monitoring of education and treatment interventions. Group 1 participants are called monthly for 2 yrs after discharge regarding skin status, pressure ulcer knowledge, and ulcer prevention behaviors practiced; they also send a urine sample monthly for collagen analysis. Group 2 participants receive standard education and follow-up, receiving monthly phone calls only to remind them to send urine samples for collagen analysis. Group 3 participants receive standard education and follow-up.
PROGRESS--Thirty-two subjects have been enrolled in the study (Group 1=16, Group 2=9, and Group 3=7).
PRELIMINARY RESULTS--Seven (22 percent) have been discontinued because of recurrent pressure ulcers, three from Group 2 (33 percent) and four from Group 3 (57 percent). Preliminary results indicate no recurrence in the intervention group (Group 1). Average scores on the Pressure Ulcer Knowledge Test administered prior to discharge are higher for the intervention group than for other groups (80 percent versus 62 percent). Mean concentration of urinary collagen metabolite glucosyl-galactosyl hydroxylysine, which reflects skin breakdown, is lower for Group 1 than Group 2 (17.5 versus 35.7). The ratio of glucosyl-galactosyl hydroxylysine to galactosyl hydroxylysine is within the normal range for Groups 1 and 2 (1.0 and 1.3 respectively); they are not significantly different but the difference is in the expected direction. In subjects who developed recurrent pressure ulcers, glucosyl-galactosyl hydroxylysine increased steadily, surpassing normal long before appearance of the ulcer.
[250] USE OF GROWTH FACTORS IN PRESSURE ULCER HEALING: CLINICAL TRIALS
D.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, US 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 both as a drug delivery system for an angiogenic factor (FGF-1) and as a regenerative scaffold.
METHODOLOGY--We did the work in three phases: 1) development of a biodegradable fibrin matrix for delivery of fgf-1. 2) development of a porous fibrin matrix for delivery of fgf-1. 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 under way.
The clinical trials are being conducted with 3 groups of 10 patients each. Group 1 (controls) receives the standard clinical treatment of saline soaked dressings; Groups 2 and 3 are evaluated in a randomized double blind fashion. The Group 2 patients receive weekly application of fibrin with FGF-1; those of Group 3 receive weekly application of a placebo. Patients in Groups 2 and 3 are assessed at each weekly home visit and each monthly clinic visit, while group 1 is assessed monthly at each clinic visit.
PRELIMINARY RESULTS--Progress has included: determination of the optimal FGF-l loading of the fibrin matrix (8 µg/ml), the in vivo release kinetics, the appropriate clinical delivery techniques, 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 to protect it and to provide a scaffold for 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 still needed prior to clinical usage. The developed system did not give a significant enough improvement over the nonporous system to warrant adding another investigational component to the treatment evaluated during the clinical study.
In preparation for clinical studies, effort has been concentrated on development of the clinical protocols, development of clinical assessment tools, and obtaining an IND for the FGF-1. For the assessment techniques, three aspects of healing are assessed: healing rate, tissue health, and overall clinical impression. For the healing rate, the rates of epithelialization, contraction, and tissue fill--all independent of wound size--are determined. For tissue health, a scanning laser doppler is used to assess blood perfusion and the angiogenic response of the wound at various stages during healing. The study has been modified based on FDA requirements as well as the recent approval of a commercially available fibrin glue (Tissel). The use of Tissel reduces the number of clinic visits required for the spinal cord injured patients enrolled in the study, since an autologous collection procedure is no longer required. At this time, almost one third of the clinical study subjects have been enrolled.
FUTURE PLANS--The main goal is to finish the clinical phase of the study and compile the results. Additionally efforts are continuing in studies to further optimize the porous fibrin matrix, develop other adhesive scaffolds such as PEG cross-linked albumin, and improve the clinical assessment tools.
[251] PROBLEM-SOLVING SKILLS TRAINING IN THE TREATMENT OF PRESSURE ULCERS
Timothy R. Elliott, PhD
University of Alabama at Birmingham, Spain
Rehabilitation Center, Birmingham, AL 35233; email:
elliott@sun.rehabm.uab.edu
Sponsor: National Institute on Disability and Rehabilitation Research, U.S. Department of Education, Washington, DC 20202-2646
PURPOSE--Pressure ulcers are a largely preventable secondary complication following spinal cord injury (SCI). Prevention requires appropriate behavior on the part of the individual and/or caregiver, namely the use the appropriate seating, proper transfer techniques, frequent pressure relief maneuvers, and the like. Despite extensive education of persons with SCI, all treatment centers see some of these individuals return with pressure ulcers requiring surgery or prolonged bedrest in the hospital. Unique behavioral interventions that have promise for improving behavioral compliance, and therefore the prevention of repeat ulcers, are badly needed. Prior work has demonstrated that problem-solving skills can be learned, retained, and applied in everyday situations. The focus of this project is to evaluate the efficacy of problem-solving skills training for the prevention of skin rebreakdown in persons with SCI hospitalized following pressure ulcer surgery or on prolonged bedrest for pressure ulcer healing.
The objective of this study is to test the effectiveness of a problem-solving skills training intervention for pressure ulcer prevention on the following criteria: the degree of self-perceived responsibility for health care and maintenance, the degree of psychosocial impairment secondary to disability, the general problem-solving skills, the demonstrated ability to solve problems specific to skin care and maintenance, the demonstrated compliance with pressure relief maneuvers, and the prevalence of skin rebreakdown following discharge. We also seek to develop and disseminate materials documenting the effectiveness of this intervention and methods for implementation in other agencies by a variety of professionals.
METHODOLOGY--Participants in this study were randomly assigned to one of two groups: a problem-solving skills training group (training) or no treatment (control). Randomization was stratified by neurologic level of injury (paraplegia/tetraplegia) to ensure comparability of the two groups. After randomization, those assigned to the training group who consented to participate were administered an initial battery of measures prior to intervention. They completed the initial battery again after intervention to assess possible changes. Those assigned to the control group were given the pretest battery prior to intervention and then administered the posttest battery 2 wk later. Both groups were further evaluated 6 wk postdischarge and during their next annual follow-up visit.
PRELIMINARY RESULTS--Some 13 training and 28 control subjects have completed the initial battery. Of those, 11 training and 22 controls completed the 10-day followup; 6 training and 12 controls completed the 6-wk follow-up; and 3 training and 8 controls the 1-yr follow-up. Two subjects refused to participate; three training subjects are to be reimbursed. We had originally anticipated enrollment of 34 participants in each group by this time, but encountered considerable difficulty with recruitment and retention of participants: changes in hospital and department practice limited the number of patients available for the study. After the surgical intervention for pressure sores, patients now receive post-operative care in another hospital unit instead of the Spain Rehabilitation Center. Some patients transfer to an interim healthcare facility, and many are indigent and unable to procure reliable transportation back to the outpatient follow-up appointments.
To improve recruitment and participation we made arrangements with plastic surgery to meet with patients admitted for skin flap repair and see them following surgery in other hospital units. We have not recruited patients at the Spain Rehabilitation Center during the past year. Second, a $150 stipend was paid to all participants who agreed to be in the study.
FUTURE PLANS--Data collection is complete, training and control participants are being processed. Staff is involved in analyzing data from intial battery to understand the psychological characteristics of the subjects. Comparisons will also be made between members of the two groups.
[252] IMPROVING TISSUE VIABILITY OF PARALYZED MUSCLE USING NEUROMUSCULAR ELECTRICAL STIMULATION
Ronald J. Triolo, PhD; Kath Bogie, D Phil; John A. Chae,
MD
Cleveland FES Center, Case Western Reserve University,
Cleveland OH 44106; Department of Rehabilitation Medicine,
Metro Health Medical Center, Cleveland OH 44109; email:
rxt24@po.cwru.edu
Sponsor: Spinal Cord Research Foundation/Paralyzed Veterans of America (SCRF Grant #1695); Department of Veterans Affairs Center of Excellence in FES, Cleveland VA Medical Center, Cleveland OH 44106-1702
PURPOSE--Pressure sores are a major secondary complication of spinal cord injury (SCI). They are expensive to treat and often require long periods of bedrest or surgery for successful healing. The purpose of this study is to investigate new techniques for addressing the underlying causes of pressure sores. Neuromuscular electrical stimulation (NMES) can change the characteristics of paralyzed muscles to improve their long-term response to loading, especially while seated in a wheelchair. The objectives of this study are two-fold. First, to determine the effects of exercise with NMES on the tissue viability of the skin and underlying muscle most susceptible to pressure sores. This should alter the intrinsic properties of the tissue that contribute to the cause of decubitus ulcers. Second, to determine the efficacy of using NMES to alter the pressure distribution under the buttocks dynamically while sitting. This will address a primary extrinsic factor in pressure sore formation.
METHODOLOGY--Five individuals with histories of chronic and recurrent pressure sores will be enrolled. Subjects must be pressure sore-free at the time of participation. NMES will be applied bilaterally to the gluteal muscles. Chronically indwelling intramuscular electrodes with percutaneous leads developed at Case Western Reserve University and the Cleveland VA Medical Center will be used with an externally programmable stimulator. Following implantation, a baseline period without stimulation will yield control data for comparison to the post-treatment phases. Subjects will undergo an intensive exercise program with NMES while progressive changes in muscle bulk and blood flow are monitored using computerized tomography (CT) scans and transcutaneous oxygen measurement. Changes in weight distribution both over the long term (due to alterations in the intrinsic muscle properties) and over the short term (due to active muscle contractions) will be assessed using interface pressure measurements. After reconditioning with NMES, seated pressure distributions will be recorded during slowly varying weight shifts produced by stimulated contraction of the gluteal muscles. The location and magnitude of high pressure regions will be monitored to determine the effectiveness of dynamic posture shifting. Finally, NMES will be withdrawn so that progressive changes after long-term use of NMES can be monitored.
PROGRESS--Two individuals with histories of pressure sores are participating in this project. After completing the exercise portion of the protocol, one subject exhibited a 50 percent increase in gluteal thickness as shown by CT scan.
IMPLICATIONS--Dynamic stimulation for weight shifting while sitting is effective in modulating pressures at the seating surface. Both factors may have contributed to no incidence of tissue breakdown or prolonged redness since the first subject joined the study in September 1997. The second subject received indwelling intramuscular electrodes with percutaneous leads in August 1998 and is currently in the exercise phase of the protocol. Additional testing has been completed on a number of regular NMES users. Data from these volunteers indicate that measurement techniques are repeatable and assessment methods are reliable. Individuals with histories of NMES use exhibit healthier skin and muscle than their counterparts with pressure sores as measured by transcutaneous oxygen values. Preliminary data also indicate that seated pressure distribution can be modified by exercise and hypertrophy of the gluteal muscles with NMES, as well as by alternating contractions of the muscles for active weight shifting.
FUTURE PLANS--Recruiting for additional volunteers in this study is ongoing. This investigation should provide preliminary data on the therapeutic use of NMES for improving the properties of paralyzed muscle so that the incidence of pressure sores in people with SCI can be reduced. A larger scale clinical trial will be designed based on the results of this pilot study.
[253] A COMPUTERIZED TECHNIQUE FOR THE ASSESSMENT OF ALTERNATING PRESSURE RELIEF INDEX
Shyam V.S. Rithalia, PhD
Department of Rehabilitation, University of Salford,
Salford M5 4WT, UK; email:
S.Rithalia@rehab.salford.ac.uk
Sponsor: Huntleigh Healthcare plc, Luton, UK; University College Salford, Salford M5 4WT, UK
PURPOSE--Decubitus ulcers result in unnecessary expenditure and misery to the patient. An important aspect in their prevention and treatment is the use of appropriate support surfaces with the object of reducing pressure on the body surface. There is a great deal of interest in finding ways of assessing the possible efficacy of alternating pressure air mattresses (APAMs) and cushions (APACs). The purpose of this project was to develop equipment and software to provide an effective and efficient technique for the assessment of performance criteria of alternating pressure or dynamic support surfaces.
METHODOLOGY--The action of a dynamic support surface is time varying; therefore, it is important that any pressure relieving 'performance' indicator take this factor into account. A computerized system has been developed that continuously measures the air pressure (AP), interface pressure (IP), and pressure/time-cycle characteristics of APAMs and APACs, providing a mouse and keyboard-based graphically oriented interface. The parameter of interest is pressure relief (PR) defined as a percentage of the cycle. This allows like-for-like comparisons to be made, choosing any arbitrary common multiple of the cycle times, such as, 1 hr requires six 10-min or five 12-min cycles. The pressure relief index (PRI) at any given IP threshold is defined as: the length of time (minutes) IP remains below the chosen threshold in 1 hr, divided by 60.
PROGRESS--Since early 1994, we have evaluated six APAMs and five APACs. This has given us a better understanding of their advantages and limitations. From the experience gained, we have also implemented several changes to the original computer program, test procedures, and pressure threshold values. In the case of APAMs for PRI calculations as a percentage of the cycle, the IP thresholds are set at 30, 20, and 10 mmHg; and for APACs the thresholds are 60, 45, and 30 mmHg.
RESULTS--Measurements of IP and pressure/time-cycle indicated significant differences (p<0.001) between products, showing some devices were only capable of momentarily relieving pressure. Results also indicated that PR was sensitive to the design of the support system, principally air pressure, cycle time, and inflation sequence. The APAMs included in the investigation were capable of providing very low or near-zero interface pressures at the sacrum only. However, the corresponding PRI values were better in the case of a mattress that reacted to changes in posture and weight of a subject.
FUTURE PLANS--Performance measurements such as PRI can be extremely useful in looking at differences between APAMs and APACs, but only to indicate relative merit with respect to pressure relief. Ultimate performance is only measurable via controlled clinical trial and assessment of the many other important parameters such as comfort, ease of use, cost, maintenance, and long-term reliability. We are continuing the investigation to assess the relationship between PRI, skin tissue perfusion, and clinical outcome. Through such exercises, the true validity of the performance measurement tools will become evident.
[254] CHARACTERISTICS OF INTRA-TISSUE STRESS AND STRAIN: A STUDY USING A HEEL-CUSHION FINITE ELEMENT MODEL
Michael W. Chang, MD, PhD; Wen-Shiang Chen, MD
Department of Rehabilitation Medicine, School of
Medicine, and the Department of Bioengineering, University
of Washington, Seattle, Washington 98195; email:
mwc@u.washington.edu
Sponsor: University of Washington, Seattle, Washington 98195
PURPOSE--Pressure sores are thought to be caused by excessive intra-tissue compressive or shear stress, which cannot be measured clinically. Such sores are common clinical problems among debilitated patients and for those with insensate skin, and once developed, their management is very costly and labor-intensive. Prevention is therefore essential, especially in the managed-care era when the health care dollar is tightly regulated. An optimal cushion design is perhaps the most effective means of prevention. However, since many factors govern the effectiveness of the cushion for pressure relief, designing an adequate cushion has been a process of trial-and-error and its outcome often unpredictable. We developed a computer model simulating a static heel-cushion contact using finite element (FE) analysis. With the model, we plan to study intra-tissue stress and strain that may be used to optimize cushion design to prevent pressure sores.
METHODOLOGY--A mathematical model was developed using FE analysis software, MARC/MENTAT (MARC Analysis Research Corporation, Palo Alto, CA). T1-weighted MR images of a supine unloaded heel were taken in discrete axial slices by placing a surface coil directly beneath the heel. The cross-sectional images were then manually digitized using NIH Image software. Four-node quadrilateral elements using Herrmann formulation were employed with a fifth pressure node at the center to discrete the two-dimensional (2-D) axial images. The calcaneous bone was modeled as a near-rigid, linear, isotropic material (95 elements, Young's modulus (E)=1,700 kPa, Poisson's ratio (p)=0.1). The skin and subcutaneous tissue were modeled both as a linear isotropic (102 elements, E=64.8 kPa, p=0.49) and as a nonlinear material using either Mooney-Rivlin or Ogden models. A rigid flat surface (100 elements, E=10,000 kPa, p=0.1), or a firm foam cushion (linear isotropic, E=100 kPa, p=0.1) was used as contact surface. The static loading condition was estimated to represent the total gravitational load of the bare foot in a supine position, and applied to the finite element model in small increments.
PRELIMINARY RESULTS--Success was so far achieved with full load using the 2-D nonlinear models. Verifying nonlinear soft tissue models using tissue strain data from the MRI yields satisfactory results, while linear isotropic model will not converge after large loading and soft tissue deformity. Locations of maximum tissue stress were sensitive to soft tissue and cushion material properties. Soft tissue with the linear isotropic model with both rigid and relative softer surface created the maximum compressive stresses near the contact surface. On the other hand, soft tissue using both models created the maximum compressive stress inside the soft tissue near the bone/soft tissue interface. Presence of foam cushion helped to reduce maximum internal tissue stresses in all models.
IMPLICATIONS--Characteristics of the intra-tissue stress and strain can be studied using FE modeling. Soft tissue models used for simulation are sensitive to internal tissue stress and strain distributions. Measurements of in-vivo tissue properties are essential in developing an accurate soft tissue model.
FUTURE PLANS--We plan to extend the model into 3-D, which represents more realistic condition than that of 2-D. Methods of verifying the results using the 3-D soft-tissue contour shape, obtained using MRI, will be developed. An optimization scheme will be developed to design the cushion to minimize the intra-tissue stress. We continue to explore better soft-tissue models, which can represent both static and dynamic contact.
[255] A NEW BIOELECTRIC METHOD FOR EARLY DIAGNOSIS OF DELAYED FRACTURE HEALING
Dennis A. Chakkalakal, PhD; Michael H. McGuire,
MD
VA Medical Center, Omaha, NE 68105; Division of
Orthopaedic Surgery, Creighton University School of
Medicine, Omaha, NE 68131; email:
dchakkal@creighton.edu
Sponsor: Department of Veterans Affairs, VA
Rehabilitation Research and Development Service, Washington,
DC 20420
(Project #A623-2RA) and Health
Future Foundation, Creighton University, Omaha, NE
68178
PURPOSE--Develop a procedure of skin-surface measurements of endogenous electricity for early identification of delayed healing fractures.
METHODOLOGY--This project is designed to test the hypothesis that temporal patterns of voltages measured on the skin surface in the vicinity of bone fractures provide distinct bioelectric signatures for normally healing (NH) and delayed healing (DH) fractures. The voltages are measured using miniature EKG-type Ag/AgCl electrodes within 2 days of the initial treatment and repeated weekly for 8 wks and then at 12, 16, and 24 weeks. The instrumentation and procedure are as described previously for a canine study that is the experimental basis for this project. Patients with long bone fractures treated at the Creighton University Medical Center (CUMC) and Omaha VAMC who give informed consent are included in the study. Their charts are checked at 4 mo after the initial treatment to determine whether the fracture has healed, according to the attending physician. If not, the chart will be followed further to determine the healing time (T). The skin-surface voltage pattern obtained for each patient during fracture healing is parameterized in terms of temporal rate of change positive and negative peaks, and the time(s) of polarity reversal. The relationship between each of these variables and T will be analyzed to develop indices that represent NH and DH electrical signatures.
PROGRESS--To date, 35 patients have been enrolled in the study, all at CUMC (26 males, 9 females, age 10 to 91). Fractures include those of 17 femora, 9 tibiae, 3 tibiae/fibulae, 4 humeri, 1 radius, and 1 ulna. Initial data analysis is being done to establish universal characteristics of NH fractures, if any, regardless of age, gender, type of bone, and type of fracture treatment. We have had two patients who developed clinical nonunions that healed after a second surgical treatment. These patients had much higher positive voltages and different temporal patterns than those observed in the NH patients.
[256] STIMULATION OF BONE HEALING USING BONE-MATRIX-RELATED BIOMATERIALS
Dennis A. Chakkalakal, PhD; Michael H. McGuire, MD;
Kevin L. Garvin, MD
VA Medical Center, Omaha, NE 68105; Division of
Orthopaedic Surgery, Orthopaedic Surgery and Rehabilitation,
University of Nebraska Medical Center, Omaha, NE 68198;
email: dchakkal@creighton.edu
Sponsor: Department of Veterans Affairs, VA
Rehabilitation Research and Development Service, Washington,
DC 20420
(Project #2022-2RA)
PURPOSE--In this study, we seek to evaluate the efficacy of selected biomaterials that are structurally related to bone matrix or one of its macromolecular components, with or without an autologous bone marrow graft, for achieving a complete repair of large bone defects and delayed unions.
METHODOLOGY--The experimental model for bone repair in this research is a segmental defect in the rat fibula, grafted with a demineralized-bone-matrix (DBM) cylinder. The DBM cylinder, prepared in advance from the femur or tibia of allogeneic animals, is slightly longer than the defect and is fitted over the cut ends of the fibula. In this model, a 2-mm defect grafted with a 5-mm DBM cylinder demonstrates the sequential stages of normal human fracture healing. To represent delayed healing or nonhealing human fractures in this model, we use a DBM cylinder from which osteoinductive proteins have been extracted with guanidine HCl, denoted as gDBM. A 4-mm defect grafted with an 8-mm gDBM cylinder has been shown to represent delayed healing. A 6-mm defect grafted with a 10-mm gDBM cylinder represents clinical situations encountered in surgical treatments of nonunions, pseudarthroses, and bone defects resulting from tumor excision.
Two biomaterials are being evaluated for their ability to stimulate bone repair, namely, microcrystalline hydroxyapatite (MHA) and chitosan. The microcrystals of MHA are comparable in size to the amorphous fraction of the hydroxyapatite in bone. Chitosan, derived from chitin by partial deacetylation, is structurally related to glycosaminoglycans in the mineral-bound proteoglycans in bone. The effectiveness of MHA and chitosan, alone and in combination with autologous bone marrow, to overcome deficiencies in bone repair in the above models is investigated. The outcome of treatment is determined at 7 wks postsurgery by measuring bending rigidity of the fibula and bone mineral content of the repair tissue.
To understand the cellular mechanisms involved in the healing process in the presence of these biomaterials, the following markers of osteogenesis are measured at different time points during healing: DNA synthesis, DNA content, bone-liver-kidney type alkaline phosphatase activity (ALP) and osteocalcin at 4 days; ALP, osteocalcin and collagen types I, II, and X at 2 and 5 wks, rigidity and bone mineral content at 3 and 5 wks.
PROGRESS--A manuscript dealing with the normal human bone healing features of the 2-mm defect model is in revision; others dealing with osteoinductive and osteoconductive processes in the above model, representation of impaired human fracture healing in the gDBM-grafted models, the characteristic temporal patterns of cellular osteogenic markers in the normal and delayed healing models, and the stimulation of bone repair using various biomaterials are being finalized. Experiments in which MHA or chitosan is used in combination with autologous bone marrow to stimulate bone repair are in progress.
RESULTS--When the osteoinductive proteins in the DBM graft were removed by guanidine HCl extraction, the rigidity of the fibula decreased by 70 percent. Treatment with MHA or chitosan resulted in modest stimulation of bone repair. Preliminary results indicate that the osteoconductive properties of these biomaterials are fully utilized only when the osteogenic cell pool in the repair site is enriched by autologous bone marrow graft.
[257] IN VIVO STUDY OF THE INCORPORATION OF IN VITRO SYNTHESIZED BONE
Jonathan Garino, MD; Paul Ducheyne, PhD; Treena
Livingston, MSE
Orthopaedic Surgery, Hospital of the University of
Pennsylvania; Departments of Bioengineering and Orthopaedic
Surgery Research, University of Pennsylvania, Philadelphia,
PA 19104; email: jgarino@mail.med.upenn.edu
Sponsor: Department of Veterans Affairs, VA
Rehabilitation Research and Development Service, Washington,
DC 20420
(Project #A2141-RA)
PURPOSE--Due to the profound limitations associated with autogenous and allogenous grafts in bone reconstruction, alternative materials and approaches are being sought. We have developed a porous, bioactive scaffold that stimulates the expression of the osteoblastic phenotype and the production of bone-like matrix in vitro. In this study, we investigate the incorporation of that scaffold in a long bone defect in the rat.
METHODOLOGY--Porous, surface-modified, bioactive
ceramics (pSMC) were prepared from bioactive glass granules,
having a composition of 45 percent SiO2, 24.5 percent
Na2O, 24.5 percent CaO, and 6 percent
P2O5 (in nominal
weight percentages). Porosity and pore size range were 39
percent and 152-390 µm, respectively. The ceramic was
then surface modified in a 2-step procedure to promote
cellular attachment, growth, and formation of a bone-like
matrix. Rat bone marrow stromal cells were isolated and
seeded onto pSMC at a density of
A large, oblong unicortical window defect, measuring 1 mm width × 4.5 mm length, was created bilaterally in the anterolateral, femoral diaphysis of 96 adult, male syngeneic Fisher 344 rats (350-400 g). By a press-fit technique, defects were treated randomly with pSMC, primary, hybrid, or left untreated (specimens called sham) to compare healing rates at 2, 4, and 12 wks. The operated femora were dissected for mechanical (8 femora/group/time point) or histological analyses (8 femora/group/time point). Eight additional animals were used per time point as controls (8 intact femora and 8 femora with defect created at time of sacrifice) for mechanical testing.
Each femur was displaced in torsion at 15°/min until failure. Ultimate torque (N-m) and stiffness (N-m/°) were recorded. All data was analyzed by one-way and two-way ANOVA to test statistical significance (p<0.05) between treatments and time points. Multiple comparisons were performed using single-df orthogonal contrasts (SYSTAT, Systat, Inc., Evanston, IL).
RESULTS--The ultimate torque and stiffness were affected by treatment and by time (p<0.01). By 2 wks, defects treated with the hybrid material had the highest stiffness (0.042±0.009 N-m/°) and no significant difference from intact bone (0.045±0.004 N-m/°). All other groups, including sham control (exhibiting normal repair), were significantly lower than intact bone. Between 2 and 4 wks, there were significant increases in stiffness for primary and sham only, resulting in no significant difference among these groups with intact bone by 4 wks. Stiffness of the pSMC did not increase significantly between 2 and 4 wks. All groups had comparable torque values at 2 wks and were significantly lower than intact bone. Between 2 and 4 wks, there were significant increases in torque for all groups except for pSMC. Torque for hybrid, primary, and sham were comparable to intact bone and pSMC was still significantly lower than intact bone by 4 wks. By 12 wks, all treatments had stiffness and torque comparable to intact bone.
FUTURE PLANS--The next stage of the project is to complete all histological and histomorphometrical analyses, including temporal changes in bony ingrowth and degradation of synthetic material. Our current data indicate the treatment of defects with either tissue-engineered construct aided in the rate of return of mechanical properties. A correlation between histomorphometrical data and mechanical properties will be performed. This will allow us to prove that the material can function not only as a mechanical filler but also that it induces bone formation and ultimately is replaced by and functions as normal bone tissue.
[258] A PROSPECTIVE STUDY OF RISK FACTORS FOR DIABETIC FOOT ULCER
Edward J. Boyko, MD; Jessie H. Ahroni, PhD,
ARNP
Seattle VA Medical Center (111M), Seattle, WA 98108;
Department of Medicine University of Washington, Seattle, WA
98195; email: eboyko@u.washington.edu;
ahroni.jessie@seattle.va.gov
Sponsor: Department of Veterans Affairs, VA
Rehabilitation Research and Development Service, Washington,
DC 20420
(Project #A318-5RA)
PURPOSE--We are conducting prospective research designed to identify risk factors for foot complications associated with diabetes. We are examining the independent contributions of foot deformity, macrovascular and microvascular disease, peripheral neuropathy, and behavioral factors on the risk of developing diabetic foot complications.
METHODOLOGY--Eligible subjects are enrolled in an internal medicine clinic, and meet the criteria for diabetes mellitus by physician diagnosis or treatment with hypoglycemic medication or insulin. Subjects who participate are assessed for the presence of suspected risk factors grouped into four categories: circulation, neuropathy, foot deformity, and self-care behaviors. Circulation factors include lower extremity Doppler blood pressures, toe blood pressures, transcutaneous oximetry, laser Doppler flowmetry, arterial pulse palpation, venous filling time, and capillary refill time. Neuropathy measures include monofilament testing, bioesthesiometry, deep tendon reflexes, intrinsic muscle atrophy, and cardiovascular reflexes reflecting autonomic neuropathy. Foot deformity measures include clinical examinations, posture and gait assessments, joint ankle measurements, and Harris mat and F-Scan testing for abnormal pressure points. Behavioral factors assessed include type of foot wear, diabetes history and control, foot self-care practices, and visual acuity. All subjects receive yearly repeat examinations and a mailed questionnaire on a quarterly basis asking them to report the occurrence of foot problems. We compare rates of outcome occurrence (incidence) by exposures of interest to determine which particular factors are related to risk of diabetic foot ulceration and amputation.
PROGRESS--To date, we have enrolled 1,032 diabetic subjects from the VA Puget Sound Health Care System, Seattle Division, general internal medicine outpatient clinic.
PRELIMINARY RESULTS--Multivariate logistic regression modeling of prevalent neuropathy controlling for sex and race revealed independent and significant associations with age, duration of diabetes, glycohemoglobin level, height, history of lower-extremity ulceration, callus, and edema, and an independent and inverse correlation with ankle-arm index. We found the F-scan insole system to be generally reliable for measurements of high pressure and peak pressure when studying elderly patients wearing their own shoes. We reported that sensory neuropathy, absent Achilles tendon reflexes, and low dorsal foot transcutaneous oximetry independently relate to risk of foot ulceration. We found associations between transcutaneous oximetry and age, ankle blood pressure, and body weight. We reported that foot warming leads to a decline in transcutaneous oximetry and are demonstrating that this is not due to a decrease in blood flow as measured by laser Doppler flowmetry.
We have shown that diabetic subjects who ulcerate have an increased risk of mortality, independent of age, diabetes type, duration, treatment, glycosylated hemoglobin level, history of lower extremity amputation, or cumulative pack years smoked. We have documented the prevalence of radiographic foot abnormalities in patients with diabetes and have shown that clinicians need not elicit many historical and exam findings from diabetic patients suspected of having severe peripheral vascular disease, since the probability of this disorder may be obtained from age, history of peripheral vascular disease, peripheral pulse palpation, and venous filling time.
FUTURE PLANS/IMPLICATIONS--We shall continue this prospective cohort study of persons with diabetes, being followed prospectively for development of a full-thickness cutaneous foot ulcer. Extended follow-up will allow us to identify risk factors for diabetic foot ulceration. The findings to date related to risk factors for foot ulceration should be viewed as preliminary. It appears that plantar pressure, sensory and autonomic neuropathy, and skin oxygenation will be important in the pathogenesis of diabetic foot ulceration. Final analysis will provide additional information concerning risk factors for diabetic foot ulcer and potential means for prevention.
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