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Norbert P Haas

Publications and source records attributed to Norbert P Haas.

36 records · Page 2Linked to original sources
PubMed2004

The influence of locally applied platelet-derived growth factor-BB on free tendon graft remodeling after anterior cruciate ligament reconstruction.

BACKGROUND: Ligaments and tendons do not gain mechanical properties of the native tissue after injury or grafting. PURPOSE: To determine the influence of platelet-derived growth factor on tendon graft remodeling. STUDY DESIGN: Laboratory animal study. METHODS: Forty-eight sheep underwent anterior cruciate ligament reconstruction and were sacrificed after 3, 6, 12, and 24 weeks. In 6 animals at each time point, platelet-derived growth factor was locally delivered via coated sutures. After mechanical testing, tissue samples were taken for histologic, immunohistochemical, and electron microscopy evaluations. RESULTS: With platelet-derived growth factor treatment, cross-sectional area was significantly lower at 3 and 12 weeks. Load to failure was significantly higher at 6 weeks. Tensile stress was significantly higher at 3 and 12 weeks. Crimp length was significantly higher at 3 and 6 weeks. Vascular density was significantly higher at 6 weeks. Electron microscopy showed a significantly higher collagen fibril amount at 12 weeks. Differences in these parameters at other time points were not significant. CONCLUSIONS: There were alterations in several but not all time points. The local application of platelet-derived growth factor alters the tissue's mechanical properties during free tendon graft remodeling after anterior cruciate ligament reconstruction. Growth factors present a promising tool toward the complete mechanical restitution of a healing ligament substitute.

Animals↗
PubMed2003

Does partial weight bearing unload a healing bone in external ring fixation?

BACKGROUND: Partial weight bearing is thought to unload and protect the healing bone. Until now, there has been no objective method of assessing the amount of weight placed on the healing zone by the patient. The goal of this study was to determine the effects of partial weight bearing on the loading of the healing bone in tibial osteotomies. MATERIALS AND METHODS: Six patients with complex tibial osteotomies, stabilized with Ilizarov ring fixator constructs, took part in this study. Three-dimensional interfragmentary movements were measured with reflective markers that were attached to the Schanz screws of the fixator. Patients were asked to rest, to co-contract the musculi gastrocnemii, to stand up, to walk slowly and to load partially the affected limb with 20 kg of weight. RESULTS: Compared with co-contraction, ground reaction forces of partial weight bearing, standing up and walking were significantly increased (P<0.05). The interfragmentary movements during partial weight bearing were, however, comparable in partial weight bearing, standing up and walking (P>>0.05). CONCLUSIONS: Partial weight bearing did not unload the defect zone. No direct relationship between interfragmentary movement magnitudes and ground reaction forces was identified. Therefore, the concept of partial weight bearing cannot reliably reduce loading of a healing zone. It may, however, help to prevent patients from undergoing critical situations, such as stumbling, by increasing their general awareness.

Adult↗
PubMed2003

The initial phase of fracture healing is specifically sensitive to mechanical conditions.

Interfragmentary movements affect the quality and quantity of callus formation. The mounting plane of monolateral external fixators may give direction to those movements. Therefore, the aim of this study was to determine the influence of the fixator mounting plane on the process of fracture healing. Identically configured fixators were mounted either medially or anteromedially on the tibiae of sheep. Interfragmentary movements and ground reaction forces were evaluated in vivo during a nine week period. Histomorphological and biomechanical parameters described the bone healing processes. Changing only the mounting plane led to a modification of interfragmentary movements in the initial healing phase. The difference in interfragmentary movements between the groups was only significant during the first post-operative period. However, these initial differences in mechanical conditions influenced callus tissue formation significantly. The group with the anteromedially mounted fixator, initially showing significantly more interfragmentary movements, ended up with a significantly smaller callus diameter and a significantly higher callus stiffness as a result of advanced fracture healing. This demonstrates that the initial phase of healing is sensitive to mechanical conditions and influences the course of healing. Therefore, initial mechanical stability of an osteosynthesis should be considered an important factor in clinical fracture treatment.

Animals↗
PubMed2003

Synergistic effect of IGF-I and TGF-beta1 on fracture healing in rats: single versus combined application of IGF-I and TGF-beta1.

During the last few decades, knowledge about growth factors and their function has increased. However, little is known about the interaction of these factors during bone growth and fracture healing. In vitro studies have shown a higher rate of cell proliferation and cell metabolism after the use of IGF-I and TGF-beta1 in combination, as compared to the single use of these factors. The purpose of this study was to investigate a possible synergistic effect of these growth factors in vivo, using a fracture model. A midshaft fracture of rat tibia (n = 84) was intramedullary stabilized with poly(D,L-lactide)-coated or uncoated titanium K-wires. The growth factors IGF-I and TGF-beta1, singly or in combination, were incorporated in the coating and continuously released during fracture healing. 28 days after fracture, we performed mechanical tests and histomorphological analyses. We found a greater stimulating effect of IGF-I on fracture healing than of TGF-beta1. The combined application of both growth factors resulted in a significantly higher maximum load and torsional stiffness than the use of only one of them. The histomorphometric analyses showed an increase in remodeling of the fracture callus in this group with less cartilaginous and more mineralized tissue than in the other groups. Both growth factors seem to have a synergistic effect on fracture healing in this model.

Animals↗
PubMed2003

Endoligamentous revascularization of an anterior cruciate ligament graft.

After replacement of the anterior cruciate ligament with a free tendon graft, the substitute initially is avascular and without a synovial surface. To ensure long-term survival, the graft must become revascularized. Despite numerous studies on the topic, there still is discussion regarding revascularization. The goal of the current study was to investigate the endoligamentous microcapillary revascularization of the free tendon graft after anterior cruciate ligament replacement with time. Thirty-six mature sheep had an anterior cruciate ligament reconstruction with an ipsilateral flexor tendon split graft. Midsubstance tissue samples were immunostained for von Willebrand factor (Factor VIII) at 6, 9, 12, 24, 52, and 104 weeks to detect the endothelial cells of capillaries. Cross sections of vessels were determined in three zones (subsynovial, intermediate, and center of the graft) and were evaluated by means of histomorphometry using a digital imaging analysis system. The observations showed that capillary vessels, which originate from the synovial envelope, invaded the avascular graft tissue from the surface toward the center zone. The highest level of vascular density was found after 6 weeks, reaching the vascular status of the native anterior cruciate ligament after 24 weeks. These findings are in contrast to the findings of previous studies in animals. The current study showed, for the first time, the kinetics of an endoligamentous revascularization of a free tendon graft at the capillary level. In the current model, the process of revascularization terminated earlier than previously described.

Animals↗
PubMed2003

Where should implants be anchored in the humeral head?

To determine histomorphometric and bone strength distribution of the proximal humerus, analyses were done on 24 freshly harvested human cadaveric humeri. Median ages of 46 and 69 years were recorded respectively for the male group (n = 11; minimum, 34 years; maximum, 76 years) and the female group (n = 13; minimum, 46 years; maximum, 90 years). The humeral head was sliced into four equal horizontal levels (Levels 1-4). Five regions of interest were defined in each cutting plane: anterior, posterior, lateral, medial, and central. Histomorphometric analyses evaluated structural parameters (tissue volume to bone volume ratio, trabecular thickness), connectivity (number of nodes, node to node length), and trabecular orientation (mean bone length). The peak values of histomorphometric parameters and bone strength were identified for the cranial section and decreased caudally. The medial and dorsal aspects of the proximal humeral head were found to be the areas of highest bone strength. The trabecular network formed a pattern that connected the center of the gleaned cavity. The structural and connectivity parameters, bone strength, and trabecular orientation showed region- and level-related characteristics. Knowledge of distribution, microstructure, and quality of bone in the humeral head allows the remaining bone stock to be used effectively, even in elderly patients, with a minimally invasive approach and maximum mechanical stability.

Age Factors↗
PubMed2003

Immediate microcirculatory derangements in skeletal muscle and periosteum after closed tibial fracture.

BACKGROUND: Severe musculoskeletal soft tissue injury sustained after a closed fracture to the extremities significantly influences bone healing and determines the patient's prognosis. The present study was aimed at quantitatively assessing immediate microcirculatory changes in skeletal muscle and periosteum after standardized closed fracture. METHODS: Standardized closed fracture of the left tibia in isoflurane-anesthetized Sprague-Dawley rats (n = 14) was induced using a modified weight-drop technique. The left extensor digitorum longus (EDL) muscle (n = 7) and tibial periosteum (n = 7) were surgically exposed for in vivo fluorescence microscopy 15 minutes after fracture. Nonfractured rats (n = 14) served as controls. EDL muscle edema was determined by the ratio of wet to dry weight (EDL water content). RESULTS: Closed tibial fracture resulted in a significant reduction of functional capillary density, red blood cell velocity, and volumetric blood flow in both EDL muscle and periosteum. Microvascular diameter, leukocyte adherence, and macromolecular leakage were markedly increased, indicating trauma-induced inflammation and endothelial disintegration. EDL muscle edema was found increased significantly after fracture. CONCLUSION: This model permits for the first time direct in vivo visualization and quantification of fracture-induced microhemodynamic changes and cellular interactions within the surrounding soft tissue. It demonstrates that even simple fractures lead to profound microcirculatory disturbances in skeletal muscle and periosteum, and also at sites remote from the diaphyseal fracture site. It provides a useful approach for the development of therapeutic strategies to counteract fracture-induced microvascular dysfunction.

Animals↗
PubMed2003

Biomechanical comparison of expandable cages for vertebral body replacement in the cervical spine.

OBJECT: Recently, expandable cages for vertebral body replacement in the cervical spine have been developed. The purpose of this study was to compare the biomechanical properties of expandable cages with those of a tricortical iliac crest graft and a nonexpandable cage. METHODS: Forty human cervical spines (C3-5) were tested in flexion, extension, axial rotation, and lateral bending. First all motion segments were evaluated intact. After corpectomy of C4 the spines were divided into five groups of eight and the following stabilization techniques were used: 1) autologous iliac crest bone graft; 2) mesh titanium cage; 3) anterior distraction device; 4) Synex-C titanium; and 5) Synex-C PEEK. Additionally, anterior plating and anterior plating plus posterior screw/rod fixation were applied. Stiffness, range of motion, and neutral and elastic zones were determined. In comparison with the intact motion segment all implants significantly increased stiffness in flexion and bending, but decreased stiffness in extension. There were no biomechanical differences between the nonexpandable and expandable cages. Furthermore, there were no biomechanical differences between the tricortical iliac crest graft and the cages, except for Synex-C in rotation. Additional anterior plating significantly increased biomechanical stiffness in all test modes; particularly in rotation mode, combined anterior-posterior stabilization increased stiffness by up to 102% compared with anterior plating alone. CONCLUSIONS: In comparison to a tricortical iliac crest bone graft and a nonexpandable cage, expandable cages have no biomechanical advantages. Due to the low extension and rotational stiffness, none of the implants can be recommended as a stand-alone device. Additional anterior plating increased biomechanical stability adequately. Therefore, additional posterior stabilization should only be considered in cases of severe rotational instability of the cervical spine.

Adult↗
PubMed2002

Mechanical conditions in the internal stabilization of proximal tibial defects.

OBJECTIVES: The goal was to design a method which would permit an assessment of the suitability of a newly developed implant under physiological-like loading conditions. Information obtained from such an analysis is expected to delineate more clearly the indications for a new device prior to clinical utilization. DESIGN: In vitro mechanical stiffness testing and finite element analysis. METHODS: From in vitro testing of proximal tibiae with defects, the stiffness of an internal stabilization system was determined. Using a finite element model, the loading of both the implant and bone was analyzed including all muscle forces. The variation in implant loading and interfragmentary strain for different defect locations was also investigated. RESULTS: Conventional stiffness testing demonstrated the comparability of the experimental findings with the finite element predictions. Under physiological-like loading the implant experienced high bending and von Mises stresses if defects in the region of the shaft were stabilized. A short working length increased implant loading up to the yield strength of the material. CONCLUSIONS: The finite element analysis illustrated the appropriateness of this new device for proximal defects of the tibia, but the implant should be used with hesitation in fractures or defects extending into the diaphyseal region of the bone. RELEVANCE: This new analytical approach helped to identify clinical indications for the implant in which its mechanical attributes would prove advantageous.

Biomechanical Phenomena↗
PubMed2002

Alpha-smooth muscle actin is expressed by fibroblastic cells of the ovine anterior cruciate ligament and its free tendon graft during remodeling.

Contractile fibroblastic cells expressing the alpha-smooth muscle actin isoform, so-called myofibroblasts, have been identified to play a possible role during the healing of the medial collateral ligament by means of restoring the tissues in situ strain via extracellular matrix contraction. Recently, these cells have also been identified to be a normal part of the human anterior cruciate ligament. It has been hypothesized that myofibroblasts play a role in the wrinkling of the extracellular matrix. The goal of the present study was to identify myofibroblasts in the intact ovine anterior cruciate ligament and a free autologous tendon graft during remodeling after anterior cruciate ligament reconstruction. In 36 mature merino sheep the anterior cruciate ligament was replaced with an ipsilateral Achilles tendon split graft. Midsubstance tissue samples were immunostained for alpha-smooth muscle actin at 6, 9, 12, 24, 52, and 104 weeks. Myofibroblasts were identified in the intact ovine anterior cruciate ligament as well as in the Achilles tendon graft prior to implantation. During remodeling the first myofibroblasts were found at six weeks within newly formed fiber bundles. At 24, 52, and 104 weeks myofibroblast distribution and cell density were similar to those of the intact ovine anterior cruciate ligament. These findings indicate that alpha-smooth muscle actin containing fibroblastic cells are a regular part of the intact as well as the remodeled anterior cruciate ligament. There is evidence that myofibroblasts may be involved in maintaining tissue homeostasis in the mature ligament e.g., by means of crimp formation. The presence of these cells during the early remodeling may further indicate that alpha-smooth muscle actin containing fibroblastic cells are involved in the earliest stages of fiber bundle formation. The role and function of this special cell type for the anterior cruciate ligament needs to be further clarified.

Achilles Tendon↗
PubMed2002

Coincidence of recurrent arthritis and Behçet's disease following anterior cruciate ligament reconstruction.

Chronic recurrent inflammation with joint effusion following anterior cruciate ligament (ACL) reconstruction is common. We report an unusual case of a patient also suffering from undiagnosed Behçet's disease. The patient had chronic recurrent joint effusions of the knee 7 years after traumatic rupture of the ACL and autologous tendon reconstruction using a hamstring tendon autograft. Arthroscopic treatment of the notch impingement and therapy of the accompanying rheumatic disease relieved the patient of his ailment. On the one hand, this case report shows the necessity of including chronic rheumatoid joint disease in the differential diagnosis of a persistent impairment of joint homeostasis following ACL reconstruction, and on the other hand it shows the coincidence of Behçet's disease and recurrent joint inflammation in a patient following ACL surgery.

Adult↗
PubMed2002

Systemic application of growth hormone for enhancement of secondary and intramembranous fracture healing.

Hormones are known to influence bone metabolism and cellular mechanisms of fracture healing. Recent technologies in molecular biology offer recombinant production of hormones, which makes them applicable for pharmacological use. To investigate the effect of systemic growth hormone (GH) application experiments were performed in micropig animal models. Systemic daily subcutaneous injection of species-specific recombinant GH was investigated in Yucatan micropigs to evaluate the effect on secondary fracture healing in a standardized gap model (1 cm) and on intramembranous bone formation in distraction osteogenesis (DO). Quantitative computed tomography (qCT), biomechanical testing, measurement of systemic insulin-like growth factor 1 (IGF-1) levels as well as histomorphometric analyses were performed to investigate differences in regenerate formation. Systemic GH administration significantly increased the torsional stability of the regenerate in comparison to the contralateral side in both experiments. qCT showed accelerated fracture bridging in the GH-treated animals in bone defect healing, while in DO histomorphometry elicited larger callus areas in the case of GH application. Systemic IGF-1 levels were significantly increased in both GH-treated groups. These experiments show that the systemic administration of recombinant GH accelerates fracture healing in standardized animal models. Clinical studies have now been initiated in order to prove the safety and the effectiveness of this therapeutical option.

Animals↗
PubMed2002

Atlantoaxial instability in Dyggve-Melchior-Clausen syndrome. Case report and review of the literature.

Dyggve-Melchior-Clausen (DMC) syndrome is a very rare disease. Only 58 cases have been reported in the literature. The syndrome is probably an autosomal recessive inherited disorder, one that is characterized by mental retardation, the short-spine type of dwarfism, and skeletal abnormalities, especially of the spine, hands, and pelvis. Atlantoaxial instability-induced spinal cord compression is a serious and preventable complication. The purpose of this report is to describe the first case of DMC syndrome in which anterior transarticular atlantoaxial screw fixation was used to treat atlantoaxial instability. The authors report on a 17-year-old man with DMC syndrome and concomitant severe atlantoaxial instability. Computerized tomography scanning and magnetic resonance angiography demonstrated an irregular course of the vertebral artery (VA) at C-2, which made a posterior fixation procedure impossible. Additionally, transoral fusion was impossible because the patient was unable to open his mouth sufficiently. Therefore, the patient underwent anterior transarticular screw fixation. Follow-up examination 36 weeks after surgery showed solid fusion without implant failure. In conclusion, treatment of atlantoaxial instability in DMC syndrome must be considered. Specific care must be taken to determine the course of the VA. If posterior and transoral fusion are impossible, anterior transarticular atlantoaxial screw fixation might be the only alternative.

Adolescent↗
PubMed2002

Biomechanical comparison of four anterior atlantoaxial plate systems.

OBJECT: The optimum fixation method to achieve atlantoaxial fusion after resection of the odontoid process remains a matter of discussion. Anterior atlantoaxial plate fixation has been described by Harms as a fixation procedure to be performed after transoral odontoid resection. In recent biomechanical and clinical studies investigators have shown that this procedure is a good alternative to established posterior atlantoaxial fixation techniques, but they have also indicated the biomechanical disadvantages of the Harms plate design. Therefore, three new anterior atlantoaxial plate designs were developed. The purpose of this study was to compare these three newly designed plate systems biomechanically with that used in Harms anterior atlantoaxial plate fixation. METHODS: Twenty-four human craniocervical cadaveric specimens were tested in flexion, extension, axial rotation, and lateral bending in a nonconstrained testing apparatus by using a nondestructive stiffness method. Three-dimensional displacement of C 1-2 was measured with an optical measurement system. Six different groups were examined: 1) control (24 specimens); 2) unstable (after odontoidectomy and dissection of the atlantoaxial ligaments; 24 specimens); 3) Harms (anterior atlantoaxial plate fixation according to Harms; six specimens); 4) subarticular atlantoaxial plate (SAAP; six specimens); 5) transpedicular atlantoaxial plate (TAAP; six specimens); and 6) subarticular atlantoaxial locking plate (SAALP; six specimens). Stiffness, range of motion, and neutral and elastic zones were determined. Compared with the Harms plate, stiffness was significantly higher when methods for placing the SAAP, TAAP, and SAALP devices were used (p < 0.05). Angular displacement of SAALPs was less than that demonstrated in any other group (p < 0.05). Stiffness values in any direction were significantly greater for the SAALP-fixed specimens than for the TAAP, SAAP, Harms, control, or unstable specimens (p < 0.05). CONCLUSIONS: Experimentally, the SAAP, TAAP, and Harms plate achieved less stable fixation than the SAALP. Therefore, if transoral odontoid resection is performed, SAALP-fixed spines will provide significantly improved stability compared with previous fixation devices and methods. This may be a necessary prerequisite for a fast and uneventful osseous fusion even without additional posterior stabilization.

Aged↗
PubMed2002

Influence of cage design on interbody fusion in a sheep cervical spine model.

OBJECT: The purpose of this study was to compare the characteristics of interbody fusion achieved using an autologous tricortical iliac crest bone graft with those of a cylinder- and a box-design cage in a sheep cervical spine model. This study was designed to determine whether there are differences between three interbody fusion procedures in: 1) ability to preserve postoperative distraction; 2) biomechanical stability; and 3) histological characteristics of intervertebral bone matrix formation. METHODS: Twenty-four sheep underwent C3-4 discectomy and fusion in which the following were used: Group 1, autologous tricortical iliac crest bone graft (eight sheep); Group 2, titanium cylinder-design cage filled with autologous iliac crest bone graft (eight sheep); and Group 3, titanium box-design cage filled with autologous iliac crest graft (eight sheep). Radiography was performed pre- and postoperatively and after 1, 2, 4, 8, and 12 weeks. At the same time points, disc space height, intervertebral angle, and lordosis angle were measured. After 12 weeks, the sheep were killed, and fusion sites were evaluated by obtaining functional radiographs in flexion and extension. Quantitative computerized tomography scans were acquired to assess bone mineral density, bone mineral content, and bone callus volume. Biomechanical testing was performed in flexion, extension, axial rotation, and lateral bending. Stiffness, range of motion, neutral zone, and elastic zone were determined. Histomorphological and histomorphometric analyses were performed, and polychrome sequential labeling was used to determine the time frame of new bone formation. Over a 12-week period significantly higher values for disc space height and intervertebral angle were shown in cage-treated sheep than in those that received bone graft. Functional radiographic assessment revealed significantly lower residual flexion-extension movement in sheep with the cylinder cage-fixed spines than in those that received bone graft group. The cylinder-design cages showed significantly higher values for bone mineral content, bone callus content, and stiffness in axial rotation and lateral bending than the other cages or grafts. Histomorphometric evaluation and polychrome sequential labeling showed a more progressed bone matrix formation in the cylindrical cage group than in both other groups. CONCLUSIONS: Compared with the tricortical bone graft, both cages showed significantly better distractive properties. The cylindrical cage demonstrated a significantly higher biomechanical stiffness and an accelerated interbody fusion compared with the box-design cage and the tricortical bone graft. The differences in bone matrix formation within both cages were the result of the significantly lower stress shielding on the bone graft by the cylinder-design cage.

Animals↗
PubMed2002

Bone morphogenetic protein-2 application by a poly(D,L-lactide)-coated interbody cage: in vivo results of a new carrier for growth factors.

OBJECT: Growth factors such as bone morphogenetic protein-2 (BMP-2) have been proven to promote spine fusion and to overcome the disadvantages of an autologous bone graft. The optimum method to deliver such growth factors remains a matter of discussion. The purpose of this study was to determine the safety and efficacy of a new poly(D,L-lactide) (PDLLA) carrier system for BMP-2 and to compare this carrier system with a collagen sponge carrier in a sheep cervical spine interbody fusion model. METHODS: Thirty-two sheep underwent C3-4 discectomy and fusion: Group 1, titanium cage (eight animals); Group 2, titanium cage coated with a PDLLA carrier (eight animals); Group 3, titanium cage coated with a PDLLA carrier including BMP-2 (150 microg) (eight animals); and Group 4, titanium cage combined with a collagen sponge carrier including BMP-2 (150 microg) (eight animals). Blood samples, body weight, and temperature were assessed. Radiographs were obtained pre- and postoperatively and after 1, 2, 4, 8, and 12 weeks. At the same time points, disc space height, intervertebral angle, and lordosis angle were measured. After the sheep were killed 12 weeks postoperatively, flexion-extension radiography was performed to evaluate fusion sites. Quantitative computerized tomography scans were obtained to assess bone mineral density (BMD), bone mineral content (BMC), and bone callus volume (BCV). Biomechanical testing was performed in flexion, extension, axial rotation, and lateral bending. Stiffness, range of motion, neutral, and elastic zone were determined. Histomorphological and -morphometrical analyses were performed, and polychrome sequential labeling was used to determine the timeframe of new bone formation. There were no differences among the groups concerning blood counts, body weight, and temperature. Compared with the noncoated cages, all PDLLA-coated cages showed significantly higher values for BMD of the callus, as well as slightly higher values for BMC, BCV, and the bone volume/total volume ratio. In comparison with the cage-alone group, the BMP-2 groups showed significantly higher values for BMD and biomechanical stiffness. Histomorphological, -morphometrical, and polychrome sequential labeling analyses demonstrated greater progression of callus formation in the BMP-2 groups than in any other group. Compared with BMP-2 delivered using a collagen sponge carrier, BMP-2 application with a PDLLA carrier resulted in a higher BCV and a greater progression of interbody callus formation in the histomorphometrical analysis. CONCLUSIONS: The use of cervical spine interbody fusion cages coated with PDLLA as a delivery system for growth factors was effective. In this 12-week follow-up study, the PDLLA coating showed no adverse effects. The slight but not significant positive effect of the PDLLA carrier on interbody fusion might be a result of the degradation process of the biodegradable carrier. Compared with collagen sponge delivery of BMP-2, the PDLLA-coated interbody cages significantly increased the results of interbody bone matrix formation. In this new combination (implant + PDLLA + growth factor) the cage represents a "real fusion" cage, because it not only serves as a mechanical device for spinal fixation but also as a local drug delivery system.

Animals↗