VII. Wound and Fracture Healing

Journal of Rehabilitation Research and Development

Rehabilitation R & D Progress Reports 1986

VII . Wound and Fracture Healing

Electrical Stimulation for Augmentation of Wound Healing

Scott R. Crowgey, M.D., and Steven M. Sharpe Veterans Administration Research and Development, Decatur, GA 30033 Sponsor: VA Rehabilitation Research and Development Service

Purpose—This project will attempt to identify ing that could be influenced by electrical stimu- aspects of the wound healing process that may lation. Efforts will then be directed toward de- be augmented by the exogenous influence of veloping mathematical models of the possible electromagnetic fields. A theoretical analysis of electrical interaction of electromagnetic fields the possible effects of electromagnetic fields on with cells and cell structures to determine how wound healing will include analyses of the these interactions could be optimized to im- interaction of electromagnetic fields with cellu- prove wound healing. It is anticipated that the lar structures and of the deposition of heat in literature will not contain all the information damaged tissue via exogenously applied energy necessary to develop these models . Any gaps in fields. This analysis will then be used as a basis necessary information and data will be filled, if for developing a plan for future investigations practical, using tissue phantom modeling mate- into the potential application of electrical stim- rials, blood, and possibly even primitive tissue ulation for the augmentation of wound healing. culture exposed to a variety of known electro- The initial research will involve a review of magnetic environments, using easily construct- the literature to identify aspects of wound healed exposure chambers.

Development of a Mathematical Model of Fracture Healing in Long Bones

Purpose—When a long bone is fractured, its heals in the presence of different stress states mechanical properties change significantly as and how the mechanical properties change ac- the bone heals. However there is very little cordingly will offer insights into the fracture quantitative information on how mechanical healing process for both normal and pathologi- stresses influence the healing process and on cal healing situations. A better understanding how the mechanical properties of the fracture of fracture biomechanics will provide guidelines site change as the bone regenerates back to its in the design of treatment modalities for frac- original shape and structure. tures and fracture nonunions. Much attention has been given to the de- To date, there have been numerous histo- velopment of fixation devices for fractured long logical and morphological studies on the heal- bones, and many different mathematical ing process of fractured bones. The healing models have been used to evaluate the stress process has been categorized into four basic states and deformations caused by the applica- phases: 1) initial reformation of the vascular tion of these devices. The mechanical properties system with formation of soft callus tissue ; 2) assumed at the fracture site influence the reformation of cartilaginous callus ; 3) formation sults of these analyses. The development of a of bone tissue; and 4) remodeling of bone tissue. mathematical model to quantify how a bone These sequential phases stabilize and progres- 228 229

Rehabilitation R&D Progress Reports 1986 sively stiffen and strengthen the healing bone. femur. The appropriate loading and boundary Some data are available on the mechanical conditions are obtained from previous studies properties of the tissues involved, but no using: 1) load-sensing implants and prostheses; models exist that can describe or predict this 2) in vitro experiments; and 3) static and dy- healing process. Our hypothesis is that the namic mathematical models of lower limb transition from the initial phases of fractured forces. An iterative mathematical procedure bone to its original structure, in particular that triggers the transformation of cartilage from the cartilaginous stage to the formation of into bone will be used. This procedure will bone tissue, is influenced by the local state of permit the temporal and geometric pattern of stress and strain within the tissues participat- healing to be both predicted and followed. ing in the healing process . As healing proceeds, In this study two- and three-dimensional the material and structural properties of the nonlinear finite element models of an idealized fracture are changed, resulting in a progressive fractured bone are being developed. Initial frac- increase in the structural integrity of the bone. ture callus geometry was determined from previous studies. Preliminary studies suggest that Progress—The finite element method is being the local strain energy density is a likely candi- used to create a mathematical model of a frac- date for the controlling mechanism that trig- tured long bone. The idealized bone is based gers the transformation from cartilage into upon the midshaft geometry of the human bone.

Bioelectricity in Fracture Healing

John F. Connolly, M .D.; Dennis A. Chakkalakal, Ph.D.; Louis Lippiello, Ph.D. Veterans Administration Medical Center, Omaha, NE 68105, and the University of Nebraska Medical Center, Omaha 68131 Sponsor: VA Rehabilitation Research and Development Service Purpose—To investigate the role of bioelectri- in humans for diagnosis of problem fractures, city in fracture healing, two research projects for choice of the optimum method of treatment, are under way: "Electrical Osteogenesis: Mech- and for prognosis of all fractures. anisms and Causes of Failure," and "Scientific We used both internally fixed and external- Basis for a New Protocol in External Fixation ly fixed long-bone fracture models (radius and of Fractures." The basic knowledge of bioelec- tibia) in dogs that heal normally and those that tricity's role derived from these studies will be are delayed to carry out our studies according used to identify electrical signals that will be to the following two themes: most effective in promoting healing in fractures A) Characterize these long-bone fracture that are difficult to heal . In patients with an os- models through biomechanical, physico-chemi- teoporotic condition, external fixation is pre- cal, vascular, histomorphometric, and biochemi- ferred over internal fixation. However, external cal measurements so that we can understand fixation has a tendency to delay fracture heal- details of the differences between a normally ing. Therefore, we are attempting to identify healing fracture and a delayed-healing one. electrical signals that may be applied to pre- B) Investigate roles of electrical activity vent such a delay. that occur in living systems naturally following injury and of externally applied electricity in Progress—We are developing objective methods altering the various features of these fractures for measuring the rate of return of mechanical revealed from the above study. rigidity, bone blood flow, and skin-surface electrical activity toward normal in fracture heal- Preliminary Results—From the studies under ing in dogs so that these can eventually be used theme A, we obtained the following results: 1) a 230

Wound and Fracture Healing method for determining an index of rigidity of microamperes) applied during the first week the fractured bone; 2) a method for measuring after fracture seem to stimulate cell prolifera- the return of the venous flow in bone toward tive activity that leads to a significant accelera- normal; 3) a predictable relationship between tion of bone formation at the fracture site at 7 the patterns (with respect to time) of the rees- weeks after injury; two different cell popula- tablishment of blood flow and mechanical prop- tions or two different mechanisms may be in- erties; and 4) the relationships between biome- volved in this response. 4) Comparison of five chanical and biochemical features and also be- different electrical signals similar to those used tween biomechanical features and calcification clinically in fracture healing, as applied in long in fractures. bones in dogs, demonstrate widely different fea- From the second set of studies, theme B, tures (amplitude, frequency, etc .), even though the results were as follows: 1) There are two they have comparable clinical efficiency. naturally occurring "batteries" in dogs—one as- Our studies under theme B also suggest sociated with the epidermis of skin and the that none of these signals may be the most ef- other with the endosteum of bone—that become fective one for fracture healing . We expect that activated in response to an injury involving the knowledge about the influence of specific both bone and the surrounding tissues. 2) Skin- electrical parameters on the various features of surface measurements of electrical voltage and fracture healing gained from our studies will be current reveal different patterns associated a useful contribution to the development of with normal and delayed-healing fractures more reliable procedures for electrical therapy within the first 3 to 4 weeks after the injury . 3) and prognosis in fracture healing. Two different DC signals (1 microampere and 7

Stimulation of Repair of Cortical Bone Transplants by Implantation of Piezoelectric Materials: A Development Study G. V. B. Cochran, M.D., M.Sc.D. Orthopaedic Engineering and Research Center, Helen Hayes Hospital, W . Haverstraw, NY 10993, and Surgical Research Service, Castle Point Veterans Administration Medical Center, New York 12511 Sponsor: VA Rehabilitation Research and Development Service ; New York State Department of Health

Purpose—Stimulation of bone healing by mi- plant that not only will stabilize bone but also croampere electric currents now is a recognized will act as a self-generating electrical stimula- form of clinical treatment . For this purpose, tion device that requires no separate power various devices are available that aim to im- source. prove the healing of bone in problem cases, particularly for individuals with delayed nonunion. Progress—To date we have designed and tested Typically, the stimulatory current is provided several versions of the "piezo plate." Initial by a battery-powered device that delivers cur- tests showed that piezoelectric materials placed rent to bone via electrodes or by an external on the plate (so as to be in direct contact with electromagnetic device that induces currents in bone) were not effective, probably because bone. Our purpose is to develop a novel ap- charge density over the surface was too low. proach to electrical stimulation of bone healing Accordingly, we developed a device in which that employs microampere currents generated the piezoelectric material is sealed within the during physiological loading by a piezoelectric plate and all the charge developed is collected material that is incorporated as part of an in- and delivered to bone via electrodes. During the ternal fixation plate . Because piezoelectric ma- past year we concentrated on electronic and terials produce an electrical charge under me- mechanical design considerations necessary to chanical loading, we are thus developing an im- create a version that could be used for trials in 231

Rehabilitation R&D Progress Reports 1986 large animals as a precursor to fabricating an showed that an implanted plate can be activat- initial model for clinical use. ed by external, low-power ultrasound to gener- ate currents in an optimal stimulatory range. Preliminary Results—Our animal tests so far These developments hold promise for reducing have concentrated on the electrical output of the incidence of nonunion in problem fractures prototype plates under functional conditions. and may have potential for enhancing fixation These tests demonstrated that even on intact of joint replacement prostheses. bone (such as in a late stage of fracture healing), the deformation produced by limited Future Plans—The next phase of our study, weightbearing is adequate to produce electric "Testing of Design Parameters for a Prototype currents in the range known to stimulate osteo- Piezoelectric Internal Fixation Plate," has been genesis, after necessary rectification and proc- approved and involves testing the effects of the essing by miniature circuitry . Furthermore, we plate on bone healing in sheep.

Stress Analysis of Internal Fracture Fixation of Long Bones

Gary Beaupre, Ph.D., and Dennis Carter, Ph.D. Rehabilitation Research and Development Center, Veterans Administration Medical Center, Palo Alto, CA 94304 Sponsor: VA Rehabilitation Research and Development Service Purpose—Internal fixation of fractured long ing using realistic mathematical models. All bones using metal plates is a standard proce- studies to date have assumed that no motion or dure for treating fractures that would be unsta- slip occurs between the plate and the bone. ble if treated conservatively (e .g., splinted or However, numerous in vitro tests have shown caused). A possible complication resulting from that slipping between plate and bone occurs to internal fixation is refracture of the bone after a significant degree. By utilizing a nonlinear, the plate is removed. Some clinical studies have mathematical model that permits slipping be- shown refracture rates to be as high as 20 to 25 tween plate and bone, we will be able to deter- percent. mine accurately the extent to which stress Internal fixation is used on the long bones shielding is responsible for bone refracture. of both the lower (femur and tibia) and upper We hypothesize that refracture after plate (humerus, ulna, and radius) extremities . Al- removal is caused by a combination of vascular though exact figures for the number of frac- damage and mechanical stress shielding. The tures treated with internal fixation are not importance of stress shielding has been overem- known, the popularity of this treatment mode phasized in all previous mathematical models is steadily increasing, particularly for treating because earlier studies have not incorporated forearm fractures where full range-of-motion in realistic interface conditions. By including real- pronation and supination may be jeopardized istic interface conditions, we may arrive at a with conservative treatment. significantly different assessment of the Refracture rates for the radius and ulna of amount of stress shielding. This in turn may 10 to 20 percent can be directly interpreted in have significant impact on future plate design terms of longer healing times with an associat- and on current plate application techniques. ed loss of human productivity and increased medical costs for reoperations and prolonged Progress—Using a nonlinear finite element physician treatment. model, we are capable of simulating slipping Although both vascular damage and me- motion between the internal fixation plate and chanical stress shielding have been implicated the fractured bone . Coulomb-friction contact as contributing factors leading to refracture, no elements are used to model the interface be- studies have assessed mechanical stress shield- tween the plate and bone and between the un- 232

Wound and Fracture Healing derside of the screw heads and the plate . Screw ed to how tightly the screws are applied. Loose tightness, friction coefficients, plate material, screws produce minimal stress shielding; tight- and plate-bone conformity will be studied para- er screws produce more stress shielding. Esti- metrically. mates of screw tightness at plate explantation An idealized plated bone model has been combined with the results of the present study developed and analyzed for five possible in vivo suggest that previous predictions of stress loading conditions. The degree of mechanical shielding may be grossly in error. stress shielding is shown to be intimately relat-

Quantifying Fracture Healing by Impulse Transfer Functions

R. E. Jones, M .D.; M. G. Strauss, Ph.D.; R. W. Bucholz, M.D.; K. L. Lawrence, Ph.D. Veterans Administration Medical Center, Dallas, TX 75216 ; University of Texas at Arlington, Arlington, TX 76019; University of Texas Health Science Center at Dallas, Dallas TX 75235 Sponsor: VA Rehabilitation and Research Development Service Purpose—The need for a technique to quantify of the union, a dog model was established, and fracture healing and the role it would play in experiments were performed . Twenty-one male redefining clinical union, identifying delayed mongrel dogs underwent unilateral radial os- unions, and optimizing rehabilitation programs teotomies. The forelimb was placed in a padded for accelerated fracture healing is well recog- plastic spoon splint for 6 weeks postsurgery. nized in the orthopaedic community . Currently, Starting at 2 weeks postsurgery and at weekly only two tests to assess fracture healing are intervals, each dog was placed in an elevated available—the roentgenogram and manual ma- total body harness so that its limbs would hang nipulation. Both are qualitative. Over the past clear of any surface; resonance testing was then 4 years, we have sought to develop a technique performed on the radii of the unconscious dog. to quantify fracture healing in long bones via The impact transfer functions of both radii natural frequency analysis. were obtained by impacting an instrumented hammer at the proximal lateral radius while Progress—The natural frequencies of a struc- an accelerometer was held against the anterola- ture are the frequencies at which the structure teral radius. Similar to the human study, the will vibrate with large amplitudes compared to transfer function was obtained using a Fourier other frequencies. Previous research has shown transform. After the designated healing time how the natural frequencies of the in vitro tibia for a dog had been reached, the dog was euth- change as the depth of a cross-sectional cut in- anized, and both forelimbs were promptly re- creases. The effects of the fracture location, moved. A 10-cm section from each radius was callus size, and calcification process on the nat- removed. The fracture site was at the mid- ural frequencies in vivo, and the relation of length. Each section was subjected to torsional callus strength are being studied. failure. In the clinic, 26 patients with tibia fractures were followed. For the 24 normally heal- Preliminary Results—The results of the tor- ing patients, a correlation of R = 0.74 existed sional tests from 20 dogs showed an increase in between the days postinjury and the normal- torsional strength with increased time until ap- ized natural frequency . Two patients developed proximately 100 days postosteotomy, at which delayed unions and demonstrated different time the torsional strength of the callus was healing curves compared to the normally heal- twice the torsional strength of the intact ing patients. radius. With the data from only 4 dogs ana- In order to establish the correlation be- lyzed, a trend appeared. As time progressed, tween the natural frequencies and the strength the fracture radius natural frequency squared 233

Rehabilitation R&D Progress Reports 1986 divided by the normal radius natural frequency nique and to identify abnormal deviations from squared, also increased . The linear regression the normal healing pattern sooner than present lines for the torsional strength versus time and techniques allow. Clinical union may be quanti- that of the natural frequency versus time are tatively assessed in vivo. This method could very similar in slope. This implies that it would also be used to determine what affects the rate be possible to follow the course of healing in of healing and to tailor an optimal rehabilita- long bone fractures noninvasively by this tech- tion scheme to accelerate fracture healing.

Altered Collagen and Wound Metabolism in Non-Healing Diabetic Ulcers

Roger E. Pecoraro, M .D.; John Olerud, M .D.; Mary Ann Riederer-Henderson, Ph.D.; Ernest Burgess, M.D.; Frederick A. Matsen III, M.D.; Craig Wyss, Ph .D. Seattle Veterans Administration Medical Center, Seattle, WA 98108 Sponsor: VA Rehabilitation Research and Development Service Purpose—This project was designed to test the for subsequent measurement of the extent of hypothesis that potentially correctable metabol- glycosylation of collagen . Nutritional status is ic abnormalities may interact with ischemia, being evaluated by a laboratory panel of nutri- neuropathy, and infection to obstruct healing of tional indicators. Vascular status of diabetic diabetic ulcers. Subjects include diabetic and and nondiabetic amputation subjects is being nondiabetic patients admitted to the Seattle documented by standardized measurements of VAMC Amputation Service who may require limb transcutaneous oxygen tension (TcPO2) lower extremity amputation as a result of dia- and segmental doppler blood pressures. betes and/or vascular disease. We will test To date, we have studied 79 diabetic indi- whether recent poor glycemic control, abnormal viduals who have been candidates for or who ascorbic acid metabolism, altered zinc availabil- have actually received limb amputations. A ity to injured tissue, and increased nonenzyma- total of 49 nondiabetic amputees, all with pe- tic glycosylation of dermal collagen are associ- ripheral vascular disease, were enrolled . In ad- ated with and potentially responsible for failure dition, many of the biochemical and vascular of wound healing that leads to amputation in measurements were standardized in 10 healthy diabetic individuals. nonsmoking elderly males without diabetes or The objective of these cumulative investiga- vascular impairment. Vascular and plasma tions is to identify metabolic abnormalities that metabolic measurements have been made in are potentially correctable and that may con- 150 control diabetic individuals admitted to the tribute to limb loss and wound failure in dia- same hospital but who have not had amputa- betic individuals. tions or lower extremity ulcers. Progress—Glycemic control in diabetic patients Preliminary Results—Both diabetic and non- is being documented by measurements of fast- diabetic amputation patients have shown signif- ing plasma glucose and glycosylated hemoglo- icant deficiencies in plasma zinc and ascorbic bin. Ascorbic acid levels are determined in sam- acid levels. Preliminary analysis of tissue ex- ples of plasma from all patients and in leuko- tracts suggests that ascorbic acid is concentrat- cytes and dermal tissue from selected patients, ed in dermal tissues at sites of cutaneous ulcer- measured by high-performance liquid chroma- ation. Further studies are in progress to deter- tography. Zinc levels are being measured in mine if tissue concentrations of ascorbate and samples of plasma, leukocyte, and wound tissue zinc in these patients are suboptimal for ade- by atomic absorption spectrophotometry. Colla- quate wound healing. Experimental iatrogenic gen fractions are extracted from skin and microwounds have been inflicted on the limbs wound tissue specimens from amputated limbs of a volunteer subgroup of patients 7 days

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before amputation; histologic evaluations of patients with diabetes, unlike nondiabetics re- those tissues, in progress, will provide a semi- quiring amputation resulting from advanced quantitative independent index of cutaneous peripheral arterial disease, often fail to heal wound healing to correlate with the metabolic limb ulcers despite adequate cutaneous oxygen parameters. diffusion. We confirmed the observation that many

Morphological and Clinical Studies of Microwounds in Ischemic Human Tissue

John Olerud, M .D. School of Medicine, University of Washington, Seattle, WA 98195 Sponsor: VA Rehabilitation Research and Development Service

Purpose—The purpose of this project is to Wounds from 18 diabetics, 13 patients with study in a systematic fashion morphological PVD, and 11 normal subjects were fully proc- and clinical features of small standardized essed and evaluated. The results were entered wounds created on the lower extremities of on a computer database, and preliminary data normal elderly subjects and patients with analysis was done . Additionally, we developed a severe peripheral vascular disease (PVD) neces- timetable of immunohistochemical events of sitating amputation. healing in elderly normal subjects using 10 antibodies relevant to the repair process (filag- Progress—We developed a standard human grin, keratin, Ulex europeus I, laminen, type IV wound model for evaluating 12 morphological collagen, type I collagen, type III collagen, vi- events of repair. The events include presence of mentin, thrombospondin, and factor VIII). This scab, epidermal migration, epidermal closure, wound model and timetable will be used for epidermal hyperplasia, amount of stratum cor- comparative studies of normal subjects and pa- neum, stratum granulosum, fibrin neutrophiles, tients with PVD and DM. monocytes, fibroblasts, collagen, and capillaries .

Transcutaneous Oxygen Tension as Predictor of Wound Healing

Frederick A. Matsen III, M.D.; Ernest M. Burgess, M.D.; Craig R. Wyss, Ph.D.; Richard M. Harrington, M.S. Limb Viability Laboratory, University of Washington, Department of Orthopaedics, Seattle, WA 98195 Sponsor: VA Rehabilitation Research and Development Service

Purpose—Transcutaneous oxygen tension is amputation surgery. the surface oxygen tension measured with a small heated sensor sealed to the surface of the Preliminary Results—Both TcPO2 and ABP skin. Cutaneous heating induces local hyperae- were measured before and after 53 vascular mia in the skin under the sensor and allows procedures performed to relieve limb-threaten- measurement of the potential for oxygen deliv- ing ischemia. In the patients without diabetes, ery in relation to metabolic needs . The oxygen those with post-surgical ABP greater than 75 that diffuses through to the surface of the skin Hg or TcPO2 greater than 20 mmHg is that delivered in excess of local metabolic showed resolution of the clinical symptoms needs. This year our group published reports on within 60 days after surgery . All patients fall- the relation between transcutaneous oxygen ing below these levels underwent subsequent tension measurements (TcPO2), ankle systolic limb amputation. blood pressure measurements (ABP), and the Diabetic patients had different results, clinical outcome of both vascular surgery and with many having high ABP in conjunction 235

Rehabilitation R&D Progress Reports 1986 with low TcPO2 . This was attributed to a high cantly increasing risk of amputation failure as incidence of calcific medial stenosis leading to presurgical TcPO2 values decrease . Thirty per- elevated ABP measurements. The clinical out- cent of surgeries on limbs with measurements come of vascular surgery on diabetic patients in the range 11 to 20 mmHg failed; more than was uncorrelated with the postsurgical ABP 60 percent failed on limbs with measurements and poorly correlated with postsurgical TcPO2 . less than 10 mmHg. For above-the-knee ampu- Those with postsurgical TcPO2 below 20 mmHg tations, presurgical TcPO2 had no predictive all had unfavorable outcomes, but many with value in the surgical outcome. higher values also sustained slow healing of Presurgical ABP appeared to have predic- ulcers, persistence of rest pain, and/or limb am- tive value only for patients without diabetes. putation. Among diabetic patients, calcific medial steno- In the study of 284 amputation surgeries, sis appears to interfere with ABP measure- TcPO2 and ABP were measured within the 2 ments. Even among nondiabetic patients, there weeks before surgery . The amputations were were a large number (greater than 50 percent) performed at levels selected by clinical criteria with undetectable pulses but sufficient limb only. The surgery was classified a success if the blood supply to heal an amputation. amputation wound eventually closed and We conclude that presurgical TcPO2 meas- healed, even if it required a long period and/or urements are useful as an addition to or re- local debridement. For both diabetic and non- placement for ABP in evaluating the outcome diabetic patients undergoing either foot or of vascular and amputation surgery. below-the-knee amputation, there is a signifi-

Enhancement of Ulcerated Tissue Healing by Electrical Stimulation

L. Vodovnik, D.Sc.; A. Stefanovska, Dipl .Eng.; R. Turk, M.D.; H. Benko, P.T.; M. Malezic, Dipl .Eng.; V. Kosorok, M.D. Electrical Engineering, E . Kardelj University ; University Rehabilitation Institute ; Jozef Stefan Institute, 61000 Ljubljana, Yugoslavia Sponsor: National Institute for Handicapped Research, Washington, DC; Slovene Research Community, Ljubljana, Yugoslavia Progress—Pulsed or DC electrical currents daily for 20 minutes. Once weekly the volume have been successfully applied in healing indo- of the wound was measured by approximate lent wounds. In our preliminary experiments, measurements of surface and depth, the wound dual-channel stimulation was applied to spinal- was photographed, and wound tissue samples cord-injured patients with decubitus ulcers, to from the center, the periphery, and from even- postamputation wounds, and to ulcus cruris. tual pockets were taken for bacterial tests. After encouraging results on 30 patients, a The size of all wounds decreased after stim- study was started on 10 spinal-cord-injured pa- ulation. The initial healing rate (cm 3/day) de- tients with decubitus ulcers, which had devel- pends on the initial wound volume (cm 3). The oped over a period of several months. Stimula- healing rate per 1 cm 3 initial wound volume tion was started 1 week after admission to the ranged between 0.01 and 0.02 per day. Thus, an Rehabilitation Institute . Two channels of bipha- initial wound of 200 cm3 started to heal with a sic stimulation with tetanizing currents were rate of about 2 to 4 cm 3/day, the rate decreas- applied through four electrodes across the ing exponentially with time . The time constant wound. The stimulation parameters were a fre- of healing is thus between 50 and 100 days. quency of 40 Hz and a pulse width of 250 micro- Bacterial tests had previously produced no con- seconds. The amplitude (up to 50 mA) was ad- sistent relation between the healing process justed to achieve minimal muscle contraction and changes in the types of bacteria. when feasible. Stimulation was applied twice 236 Wound and Fracture Healing

Acceleration of Fracture Healing Electrica Fields Carl T. Brighton University of Pennsylvania, Philadelphia, PA 19104 Sponsor: National Institutes of Health Purpose—The object of the proposed research teogenesis and bone healing will be evaluated is to continue investigating the effects of ap- by incorporation of tritiated thymidine, Ca45, plied electrical fields on the acceleration of and 35SO4 as well as by maximum resistance fracture healing in laboratory animals. The to bending as determined by an Instron Testing proposed research was designed : 1) to deter- Machine. Stress-generated potentials will be mine the optimum parameters of applied (exog- measured in fracture calluses . Origin of stress- enous) electricity for accelerating fracture heal- generated potentials will be evaluated by altering; 2) to determine the role of stress-generated ing collagen in tendon biochemically . The (endogenous) electricity in fracture healing ; and mechanism of action of electrically induced os- 3) to determine the mechanism of electrically teogenesis will be sought by determining: 1) induced osteogenesis at the cell level. PO2 and pH changes in the vicinity of a cath- Methods to be used include the comparison ode; 2) changes in surface of cell membrane ; 3) of the osteogenic response of in vitro fetal rat mitochondria release of calcium; 4) cellular pro- tibia and in vivo healing rabbit fibula to con- liferation and migration; and 5) collagen and stant DC, various pulsed unidirectional electric proteoglycan biosynthesis and processing. fields, and various electromagnetic fields . Os-

Biomechanics of Metastatic Defects in Bone Wilson C. Hayes Beth Israel Hospital, Boston, MA 02215 Sponsor: National Institutes of Health Purpose—Advances in the palliative treatment In Task I, we will conduct retrospective radio- of patients with established metastatic malig- graphic reviews of patients exhibiting metastat- nancies have not only prolonged patient surviv- ic lesions in those regions and will determine al but have also increased the incidence of bony the most frequent sites and approximate shapes metastases and subsequent pathological frac- of the lesions. As part of this task, we will also tures. Thus, prevention and effective treatment develop improved diagnostic imaging proce- of fractures associated with metastatic defects dures for the description of lesion geometries. in bone have become increasingly important as- In Task II, we will determine in vitro the pects of the care of cancer patients . Unfortu- strength reductions associated with simulated nately, there are currently available only the defects in long bones, the proximal femur, and crudest of clinical guidelines for assessing the the spine. In Task III, we will use finite ele- increased fracture risk associated with meta- ment modeling of defects in these regions to static lesions in bone . Therefore, the appropri- provide a theoretical framework for interpret- ate time for prophylactic stabilization of im- ing the experimental results and assessing the pending fractures is not known . This investiga- sensitivity of the fracture risk predictors to in- tion will be directed in the long term to the de- dividual patient variations . In Task IV, we will velopment of comprehensive biomechanical combine these findings by developing structural guidelines for the orthopaedic assessment and predictors of fracture risk for individual pa- treatment of metastatic defects in long bones, tients with particular lesions. Biomechanical the proximal femur, and the spine. guidelines appropriate for each skeletal region A four-phase staged approach will be used . will be developed and tested retrospectively in

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clinical populations. These guidelines should orthopaedic care of patients with metastatic de- represent a significant improvement in the fects in bone.

Management of Burn Injuries

J. H. Evans, Ph.D.; J. M. Courtney, Ph .D.; J. D. S. Gaylor, Ph.D. Bioengineering Unit, Regional Burns Unit, and Plastic and Oral Surgery Unit, University of Strathclyde, G4 ONS Glasgow, Scotland Sponsor: Dow Corning Corporation Purpose—Work continues on providing a materials and hydro-gels. Consideration is broad-based better understanding of the burn being given to mechanical strength and con- wound and hypertrophic scar and on improving formability, mass and energy flux, bacterial the management of burned patients. Currently, control, and drug release. Electromagnetic en- research is directed to assessing burn depth, de- hancement of the rate of expansion of epitheli- termining mass and energy loss from the burn um is being studied in vitro to provide a clini- wound, developing synthetic dressings, in vitro cally acceptable source of autologous skin for expansion of autologous epithelium, and the the management of the severely and extensive- treatment of hypertrophic scars with silicone ly burned patient. gel and pressure garments. Preliminary Results—A substantial trial has Progress—A thermographic technique, employ- demonstrated that a silicone gel dressing can ing a low-cost and convenient pyroelectric Vidi- make a significant contribution to the rate of con camera, is based on previous work using an resolution of hypertrophic scars. On many sites, animal model along with a mechanically particularly the face and hands, it is more man- scanned detector. ageable and better tolerated than is therapy Laboratory and clinical investigations are based on pressure. No significant complications being conducted on novel burn dressings and on have been observed in a trial of 150 patients. candidate materials including silicone-based

Quantitative Evaluation of Nerve Repair Vincent R. Lentz, M.D.; Joseph Rosen, M .D.; John Wikswo, Ph.D.; Kenneth Cummins, Ph .D.; Gordon Abraham, M.S. Rehabilitation Research and Development Center, Veterans Administration Medical Center, Palo Alto, CA 94304 Sponsor: VA Rehabilitation Research and Development Service Purpose—The treatment of peripheral nerve in regeneration sufficient for full functional re- injuries rarely results in recovery of function covery. A number of adjuncts to traditional adequately approaching that before the injury. repair methods offer the promise of increased In dealing with these injuries, the physician or directed regeneration, but the effectiveness faces two major problems . First, the lack of ob- of these new approaches needs to be assessed jective methods for assessing the extent of pe- objectively. ripheral nerve injury or the extent of regenera- The development of a simple method for tion in previously injured nerve compels physi- evaluating the extent of a nerve injury will cians to rely on subjective criteria in making help the physician make objective decisions re- clinical decisions regarding the management of garding the timing and type of care of the in- these injuries. Second, present methods of pe- jured nerve. The use of the appropriate modali- ripheral nerve repair, even those employing ty for the treatment of nerve injuries will en- modern microsurgical techniques, rarely result hance and speed the regenerative process and 238

Wound and Fracture Healing will lead to fuller recovery of function. tribution of added conduction delays. This ap- Purely mechanical (suture) methods of proach requires considerably less computation reapproximating peripheral nerves result in than DCV analysis. We are also investigating very limited functional axonal regeneration. It the possibility of using magnetic recording and/ is thought that this is due primarily to scar for- or stimulating techniques for intraoperative mation at the repair site, which prevents proxi- evaluation of exposed nerve bundles. By em- mal axons from crossing the repair site and es- ploying magnetic coupling for recording, the tablishing functional connections. We have practical problems of mechanical nerve been studying sutureless repair methods that damage, stimulus artifact, and operating-room use biodegradable wraps that provide total cir- ground loops will be minimized . The resulting cumferential alignment of the nerve, block scar signals, which reflect longitudinal current in invasion at the repair site, and improve the mi- the axons, can be analyzed by any of our meth- lieux for axonal regeneration. The preliminary ods of nerve evaluation . Initial experiments on results of our early investigation indicate that magnetic measurement of action currents from none of the purely mechanical alignment tech- rat sciatic nerve, performed in cooperation with niques hold any significant advantages to re- John Wikswo, Ph.D., of Vanderbilt University, generation. Regeneration is being assessed have been quite promising. Innovations by Dr. using electrophysiological methods that esti- Wikswo permit measurements at room temper- mate the number and velocity distribution ature using inexpensive equipment. (DCV) of axons both proximal and distal to the repair site. The analysis methods presently Preliminary Results—During this project we used require involved mathematical computa- have compared the use of a biocompatible, bio- tion and must be performed off line. Such eval- degradable "pseudoperineurial barrier" to uation methods are currently inappropriate for standard microsutures in several primate nerve clinical use by physicians. repair and nerve graft models. In spite of in- This project is based on two fundamental traoperative technical problems with the first- hypotheses. First, we feel that nerve function generation pseudoperineurial barrier, the ini- following injury, or axon regeneration following tial results from postoperative electrophysiolo- repair, can be reliably, quickly, and safely eval- gic assessments of the number of axons having uated by electrophysiological methods that esti- regenerated across the repair site indicate that mate the number and health of the axons cross- the barrier does as well as or better than stand- ing a focal lesion or repair site . For this tool to ard suture repair methods. be generally applicable, it must be appropriate There is mounting evidence that an auto- for both noninvasive and invasive (intraopera- immune reaction follows destruction of the per- tive) studies. Second, to enhance nerve regen- ineurial blood-nerve barrier during nerve eration, in any significant and reliable fashion, injury. We have studied the effects of an im- modern mechanical repair methods will have to munosuppressive agent, Cyclosporin-A, in de- be coupled with other modalities that intrinsi- creasing the initial inflammatory response asso- cally influence the rate and/or direction of ciated with nerve injury in a rat model . Prelim- axonal regeneration (tropic factors), that im- inary histologic results indicate a significant prove the axonal environment at the repair site diminution of inflammatory cells about the (pseudoperineurial barriers), or that decrease repair site. Early electrophysiological studies the effect of scar formation. indicate some enhancement of regeneration . In contrast, studies of the effects of the ability of Progress—We are currently developing a electromagnetic fields to enhance regeneration simple technique for characterizing nerve func- have not produced significant results. tion and regeneration at the repair site. This Encouraging results have been obtained method estimates the number of axons that using simulated data to test the model for char- cross a focal lesion (or repair site) and their dis- acterizing focal conduction delays that occur at 239

Rehabilitation R&D Progress Reports 1986 the site of nerve injury or repair . The programs data from primates and rats. These data indi- will soon be adapted to run on portable evoked cate that the neuromagnetically derived wave- potential equipment, and human intraoperative forms can be processed exactly like the elec- assessments of nerve injuries will soon follow. tronically recorded counterparts . The develop. Several modifications in the neuromagnetic ment of an openable clip-on toroid will permit system have allowed the acquisition of reliable human studies to begin soon.

Nerve Coupler—Sutureless Peripheral Nerve Repair at the Fascicular Level

Joseph Rosen, M.D. Rehabilitation Research and Development Center, Veterans Administration Medical Center, Palo Alto, CA 94304 Sponsor: VA Rehabilitation Research and Development Service Purpose—Current methods of peripheral nerve vides the nerve into two distinct cellular envi- repair often result in unsatisfactory restoraton ronments. The intrafascicular Schwann cells, of function of nerves . Factors at the repair site axons, and endoneurial fibroblasts compose the that can contribute to these poor results in- nerve's regenerating unit. The cellular compo- clude: 1) poor alignment of the repair site by nents of the extrafascicular environment are suture methods; 2) ingrowth of surrounding responsible for the fibrous reaction to injury. scar tissue that blocks the repair site; and 3) In a number of previous papers, the inves- outgrowth of nerve tissue from the repair site tigator has developed and described tubes that into surrounding tissue with consequent neur- reconstruct the perineurium . This sutureless oma formation. method of nerve repair (fascicular tubulization) The importance of our study lies in its po- allows the nerve to reestablish the perineurium tential for improving the current state of pe- naturally. Histology and electrophysiology have ripheral nerve repair. Peripheral nerve damage shown collagen tubes to be an effective repair associated with trauma to bones, tendons, and method in rat monofascicular and cat multifas- other structures occurs in approximately 30 cicular models. Bioresorbable polyglycolic acid percent of extremity trauma. Nerve injuries (PGA) tubes were shown to be successful in the prevent successful rehabilitation more than any rat monofascicular model by qualitative and other form of trauma. Motor dysfunction, loss quantitative histology. No prior methods of of tactile discrimination, sympathetic dystro- nerve repair have used this fascicular tubuliza- phy, and postregenerative pain can greatly tion technique. impair self-care and other tasks of daily life, The results of peripheral nerve repair may leading to long-term disability. Improved nerve be improved by developing a better method to repair would theoretically improve veterans' approximate the transected ends of a nerve. quality of life following nerve repair. The development of a device that couples the Present methods of peripheral nerve repair ends of the nerve together without sutures by suture are based on an anatomical approach might improve on the poor results of suture that attempts to reestablish continuity of the repair. The "nerve coupler" will precisely ap- multiple layers of nervous tissue . In suture proximate the ends of a transected nerve fasci- repair, either the epineurial or perineurial cle. This will improve the alignment at the layers of connective tissue are reconnected by repair site. The device will also act as a barrier sutures to promote healing of the nerve . In to the ingrowth of scar tissue from outside the suture repair, the discrete tissue layers are ob- perineurium. It will serve to block the out- literated by scar tissue at the repair site . An al- growth of intrafascicular nerve tissue into the ternative to this anatomical approach is a cellu- extrafascicular space. lar approach involving the construction of an artificial perineurium. The perineurial layer di- Progress—The first objective of this pilot study 240

Wound and Fracture Healing was to determine a satisfactory design and ma- logical evaluation showed excellent alignment terial for the nerve coupler. Prototype plexig- and minimal cellular reaction at the coupler lass couplers and bioresorbable polyglycolic acid repair site. Studies of 1, 2, and 3 months' dura- (PGA) couplers were studied in the monofasci- tion using PGA couplers again showed simple cular rat peroneal nerve . These 1- to 3-month application of the coupler and excellent gross short-term studies were designed to determine alignment at the sutureless repair site . Micro- how effectively the coupler maintained the in- scopic evaluations of 1- to 3-month animals re- tegrity at the repair site during regeneration. vealed fair to excellent organization at the cou- These studies also compared coupler repair pler repair site and minimal to moderate reac- with controlled perineurial suture repairs. tion to coupler material. Gross and microscopic reactions to coupler materials were evaluated . Repair site organization Future Plans—Our next goal is to obtain was assessed by histology . The results of this VAMC RAG funding to continue our studies of pilot study will be used to modify the design of the nerve coupler in the rat peroneal nerve . We the nerve coupler. would like to perform long-term studies to evaluate repairs using quantitative histology Preliminary Results—Trials of plexiglass cou- and electrophysiology . We would also like to plers in two animals demonstrated simple ap- evaluate new designs and new materials for the plication of the coupler and excellent nerve coupler in future studies. alignment on gross visual examination . Histo-

Evaluation of Tubular Internal Fixation Plate for Fracture Management

Savio L-Y. Woo; Richard Coutts, M.D.; David Amiel, Dip .Ing.; Steven Garfin, M.D.; Wayne Akeson, M .D. Veterans Administration Medical Center, La Jolla, CA 92103 and University of California, San Diego, CA 92103 Sponsor: VA Rehabilitation Research and Development Service Purpose—The overall objective of this project is prove to be advantageous to the recovery of full to determine whether significant advantages structural properties of the underlying bone fol- can be obtained from internal fixation of dia- lowing plate removal. physeal fractures using plates with improved design. Specifically, our goal is to test the Progress—At present, the evaluation of the newly developed design criteria. That is, moder- bone lying beneath both the traditional solid ate bending and torsional plate rigidities are stainless steel (control) and the new tubular needed for early immobilization to achieve frac- (experimental) plates is being performed using ture healing without bone shortening and/or X-ray, geometric measurements, histomorpho- angulation, and low plate axial rigidity is desir- metric measurements, and biochemical tech- able to minimize stress (strain) shielding of the niques. Specifically, a comparison is being made underlying bone during the postunion remodel- between the actual physical properties of bone ing process. A new plate with a tubular cross- and the structural and mechanical properties section is made of stainless steel filled with pol- obtained by biomechanical bending and by yethylene. This plate has the aforementioned axial and torsional testing. desired rigidity characteristics and will be used in a canine unilateral midshaft femoral osteoto- Preliminary Results—Histomorphometric data my mode. A traditional solid stainless steel have shown that on the average, bone porosity plate of identical external geometry will be is higher for the control solid stainless steel used in a separate series of animals with simi- plate, whereas there is an increase in new bone lar osteotomy. In addition, it is also our goal to growth and less porosity for bone lying beneath test whether such a low axial rigidity plate can the experimental hollow plate . This informa-

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tion correlates well with the bioengineering more insight into the problem of localized os- tests performed. With further comparison and teopenia that occurs with the use of internal study of these test results, we hope to provide fixation plate systems.

Biomechanical Considerations of Metal and Composite Materials for Bone Fracture Fixation Plates Savio L-Y. Woo ; Wayne H. Akeson; Richard D . Coutts University of California, San Diego and San Diego Veterans Administration Medical Center, La Jolla, CA 92103 Sponsor: VA Rehabilitation Research and Development Service Progress—This study, together with others, re- fixation of fractured bone for formation of per- futes the necessity of extremely high plate iosteal callus and for union) together with the bending and torsional rigidities (absolute immo- low plate axial rigidity (to allow the healed bilization of the fractured bone ends) for union. bone to share a larger portion of the physiologi- Plates with significantly less rigidities, and ap- cal stresses to reduce the instances of stress- plied without "compression", were able to protection osteopenia)—may be an ideal com- achieve equivalent and better bone healing promise between investigators who advocate with the aid of callus formation. The results of rigid internal fixation systems and those who this series of experiments confirm that osteonal advocate flexible ones . A tubular cross-sectional bone union is slow and mechanically inferior to stainless steel plate may be an optimal design callus union. for such a less rigid fixation plate system. The design criteria developed by our labo- Other materials and designs following these ratory—that is, moderate bending and torsional guidelines also should be pursued. rigidities (to provide adequate but not "rigid"