bone fracture 후 regeneration and remodeling을 위한 최적의 자극은?

[문형철]

골절 후 재활은 인체 기능회복(최화 움직임회복)에 중요한 초점

골절환자 치료의 세가지 핵심

1. fracture된 bone의 재생촉진자 극을 찾아 가장 빠른 bone healing 유도.

2. bone healing 방해요소 제거

3. 골절치유를 위해 시행한 gibs로 발생한 joint stiffness의 정상화

healing process를 촉진할 것인가?

normal healing을 기다릴 것인가?

delayed healing으로 방치할 것인가?

참고) 새로운 뼈 형성을 위한 자극

- 최소필수긴장(minimal essential strain, MES)이라는 용어는 새로운 뼈 형성을 시작하는데 필요한 최소자극을 의미한다. 주의할 것은 노인과 비활동적인 사람들에게 빠른 걷기가 MES를 초과할지도 모르지만 젊은 사람들에게는 MES를 초과하기 위해서는 스프린팅, 점핑, 고 저항운동 활동이 필요할 수 있다는 것이다. 

- 뼈세포는 주기적으로 주어지는 힘이 MES를 초과하지 않도록 각부위의 뼈 양을 조절한다. 이러한 뼈양의 조절은 골절을 예방하기 위한 뼈의 안전한계를 설정한다. MES는 뼈를 골절시킬 수 있는 힘의 약 1/10의 긴장수준으로 알려져 있다.

- 침대안정동안의 척추에 있어서 뼈 무기질양의 보존은 하루에 3시간의 서있기로 충분하다. 

새로운 뼈 형성을 자극하기 위한 중요 트레이닝 개념

- 수많은 연구들이 뼈 무기질 밀도와 부착된 근육양과 힘 사이의 상관관계를 보여주고 있다. 최근의 연구들에서 신체활동은 골밀도보다는 골량, 부위, 폭에 영향을 미치는 것으로 나타났다. 근비대와 근력증강을 자극하는 활동은 뼈의 성장과 관련된 결합조직을 자극하는 것으로 보인다.

1) 부하의 특수성

- 힘들이 새롭고 생소한 것이라면 긴장받는 뼈의 성장을 자극하게 된다. 달리기는 대퇴뼈의 무기질 밀도를 증가시키는 자극은 되지만 손목의 부하를 주기위한 운동은 아니다. 

- 부하의 특수성 개념은 근력 및 컨디셔닝 전문가가 골다공증에 의해 일반적으로 영향을 받는 골격 부위의 골량을 증가시키기 위하여 운동을 처방할때 특히 중요하다. 

2) 운동선택

- 골형성을 자극하기 위한 운동은 많은 근육을 사용하며, 척주와 엉덩이 뼈를 통하여 힘벡터를 조절하며, 더 많은 절대부하가 사용되는 운동들을 중심으로 선택되어야 한다. 

3) 점진적 과부하

- 점진적 과부하는 근력증가를 위한 트레이닝 뿐아니라 골량증가를 위한 트레이닝에도 적용된다. 피로골절이 되지 않을 정도의 점진적 과부하가 필요하다.

4) 트레이닝 다양성

- 새로운 뼈 형성자극을 위한 프로그램을 디자인 할때 고려해야할 다른 사항은 운동선택의 다양함이다. 운동의 다양함을 이용하여 힘벡터의 분산을 변화시키는 것은 주어진 뼈 부위내의 새로운 뼈 형성을 위한 독특한 자극을 제공한다. 

5) 기계적 부하의 필수 요소들

# 부하의 정도(강도)

# 부하의 비율(스피드)

# 힘의 방향

# 부하의 양(반복회수)

6) 저항운동을 통한 기계적 부하

- 고 저항운동에 대한 뼈 반응의 정도는 여전히 분명치 않다.

7) 유산소운동을 통한 기계적 부하

- 뼈성장을 자극하는 유산소 운동은 노젓기, 계단 올라가기, 달리기, 등짐지고 달리기와 같은 강한 신체활동들이다. 새로운 뼈 형성을 위한 유산소운동은 일반적으로 경험하는 일상 활동보다 더욱 강한 유산소운동이어야 한다.

8) 운동선수를 위한 기계적 부하 

뼈 성장을 자극하기 위한 운동처방 지침

변수          권장법

양                10번 반복에 3-6세트

부하             1-10RM

휴식             1-4분

변화            주기화계획

운동선택      스쿼트, 클린스, 데드리프트, 벤치프레스, 쇼울저 프레스

9) 훈련되지 않거나, 노령화된 사람들을 위한 기계적 부하

- 과거 환자 병력, 신체검사, 그리고 관절안정, 유연성, 근력의 분석을 통하여 운동처방이 실시되어야 한다. 안전하고 효율적으로 선택된 운동을 통해서.

뼈 형성자극

1) 골격의 특정부위에 직접 부하를 주는 운동을 이용하라.

2) 구조적 운동 즉 한번에 많은 근군이 관련되며, 척주와 엉덩이 뼈를 통하여 힘 벡터를 전달하며, 더욱 큰 절대부하가 트레이닝에서 사용되게 하는 운동을 이용하라.

3) 점진적으로 근 골격계를 과부하시키며 조직이 자극에 적응됨에 따라 부하를 점진적으로 증가시켜라.

4) 운동선택을 다양화시켜, 새로운 뼈 형성을 위하여 독특한 자극을 계속적으로 주는 힘 벡터의 분포를 변화시켜라.

정리.

1. small strain and high frequency로 반복적인 부하를 주거나 overloading through elevated exercise regime은 bone hypertrophy를 유도한다고 보고되고 있음

- intermittent compressive or shear stress는 endochondral ossification을 촉진

- tensile stress는 intramembranous ossification을 촉진

- constant compressive는 endochondral ossification을 억제하여 cartilage 생성을 촉진

- high shear stress는 fibrous tissue formation을 촉진.

2.  bone formation process은 fracture type, gap condition, fixation rigidity, loading and biologic environment에 달려있음

- fracture type, gap condition, fixation rigidity는 거의 바꿀 수 없는 것

- loading and biologic environment는 바꿀 수 있는 것.

3. Regardless of the fracture healing pathway, mechanical intervention might be the only means to assure bone remodeling after successful callus formation and maturation in order to restore the bone to its original structure and strength. 

- 뼈의 original structure 와 강도를 회복하기 위해서 성공적인 callus formation and maturation 후에  fracture healing pathway와 무관하게 mechanical intervention은 bone remodeling을 확실하게 하는 유일한 방법임. 

골절에 대한 자료.docx

BIOPHYSICAL STIMULATION OF BONE FRACTURE REPAIR, regenerati.pdf

이 논문은 fracture bone의 최적의 재생자극은 무엇인가에 대한 논문

Abstract

Biophysical stimulation to enhance bone fracture repair and bone regenerate maturation to restore its structural strength must rely on both the biological and biomechanical principle according to the local tissue environment and the type of mechanical stress to be born by the skeletal joint system. This paper reviews the possible interactions between biophysical stimuli and cellular responses in healing bone fractures and proceeds to speculate the prospects and limitations of different experimental models in eval‎uating and optimising such non-invasive interventions. 

- bone fracture의 회복, 재생에 관한 최적의 자극

It is important to realize that bone fracture repair has several pathways with various combinations of bone formation mechanisms, but there may only be one bone remodeling principle regulated by the hypothesis proposed by Wolff. There are different mechanical and biophysical stimuli that could provide effective augmentation of fracture healing and bone regenerate maturation. 

- bone fracture repair는 다양한 bone formation mechanism과 함께 몇개의 pathway가 있음.

The key requirements of establishing these positive interactions are to define the precise cellular response to the stimulation signal in an in vitro environment and to use well-established animal models to quantify and optimise the therapeutic regimen in a time-dependent manner.  This can only be achieved through research collaboration among different disciplines using scientific methodologies. In addition, the specific forms of biophysical stimulation and its dose effect and application timing must be carefully determined and validated. 

- 정확한 검증이 되어야

Technological advances in achieving focalized stimulus delivery with adjustable signal type and intensity, in the ability to monitor healing callus mechanical property non-invasively, and in the establishment of a robust knowledgebase to develop effective and reliable treatment protocols are the essential pre-requisites to make biophysical stimulation acceptable in the main arena of health care. Finally, it is important to bear in mind that successful fracture repair or bone regeneration through callus distraction without adequate remodeling process through physiological loading would seriously undermine the value of biophysical stimulation in meeting the  biomechanical demand of a long bone.

Introduction

It is well known that a bone fracture will repair and remodel depending on the ensuing loading conditions (Wolff,

1986; O’Sullivan et al., 1989; Meadows et al., 1990; Aro and Chao, 1991; Cowin, 1993). Both cortical and cancellous bone morphology have been related to the structural stress pattern based on theoretical analysis (Hart et al.,

1984; Rubin and Lanyon, 1984, 1987; Carter, 1987; Hart, 1990). It is very likely that during bone repair and regeneration,the type of stress applied may dictate its material and structural quality. 

In musculoskeletal system, the biomechanical environment plays a key role in repairing, maintaining, and remodeling of bone in meet its functional demands. Based on this fundamental concept, many connective tissue remodeling rules have been proposed to explain the repair process and their biological responses (Chow et al., 1987). When the normal healing and remodeling environment is absent or compromised, reliable and effective biological or biophysical stimulation may

be indicated. Unfortunately, many of the basic biological and biomechanical interactions affecting different connective tissue response are poorly understood. Without this knowledge, it would be difficult to identify the specific cell mediating mechanisms that regulate the normal or delayed repair after bone fracture. Such biologic and biomechanical interactions can help us to identify abnormal repair processes and uncover the enhancing factors for the purpose of augmenting bone fracture healing or bone regenerate maturation.

- 근골격계 시스템에서 biomechanical enviroment는 그들의 기능적 요구에 부응하기 위해 뼈의 remodeling, repairing에 중요한 역할, 하지만 뼈의 repairing에 관한 많은 요소들의 연관성에 대한 연구가 부족

Therefore, it has been the goal of many investigators to search for the relationship between biophysical factors and cellular responses under normal and deficient bone fracture healing conditions. To establish the interdependence

of biophysical stimulation and bone repair and remodeling at the material and structural level, experiments must be carefully designed and performed using appropriate animal models to investigate these cellular and tissue

responses under different forms of biophysical stimulation.

- 이 연구에서는 정상 뼈와 골절 회복상태에서 biophysical factor와 cellular response의 연관성에 대한 연구

When necessary, in vitro cell and tissue culture studies under well-controlled biophysical stimuli must be conducted

in order to isolate other confounding factors at the systemic level. Without knowing the normal histomorphometric and cellular responses associated with different bone fracture healing processes in quantitative terms, it would be nearly impossible to investigate potential stimuli to establish their efficacy in enhancing such a complex biological process.

In any form of fracture fixation, bone fragments under load will experience certain amount of relative motion, which, by unknown mechanisms, determines the morphologic features of fracture repair. Perren (1979) proposed a brilliant hypothesis, the “Interfragmentary Strain Theory”, which related the tissue response to the local mechanical environment. The interfragmentary strain was defined as the ratio of the relative displacement of fracture ends versus the initial gap width (Fig. 1).

* Interfragmentary strain theory

A.      골절부 gap에 존재하는 pluripotential cells이 골절부 gap의 변형에 관여한다

B.       조직이 긴장을 견디는 정도에 따라 callus 형성 진행이 좌우

①        Granulation tissue can withstand 100% strain

②        Fibrocartilage- 10%

③        Bone or osteoblast- 2%

C.      Callus가 커지면서, 안정성이 커지고 적게 변형된 세포가 살아남는다

D.      연골내 뼈 형성은 callus 안쪽에서 바깥쪽으로 진행된다

Although such a concept was an oversimplification of the biomechanical response of the opposing bone and gap tissue, the underlying phenomenon had successfully demonstrated the governing principle of mechanical intervention of tissue formation and transformation. The fracture gap tissue and the existing bone cortex remodeling appeared to follow this rule to prepare for solid bone union. 

- 이 개념이 과도하게 단순화되어 있지만 fracture gap tissue와 bone cortex remodeling은 이 개념을 따름. 

However, the time-related changes in the external callus versus its local deformation under assumed loading conditions did not seem to fit the interfragmentary strain theory (Augat et al., 1998). The original interfragmentary strain theory considered only longitudinal strain along the axial direction (Perren, 1979). Analytical three-dimensional analysis (Cheal et al., 1991) revealed a complex gap deformation and multidirectional principal strains not even considering the extramedullary and intramedullary callus. There may also be additional regulating mechanisms for tissue differentiation during initial fracture healing (Carter et al., 1988). Therefore, the interfragmentary theory had its limitations although it was intended to conceptualize the mechanism involved in achieving “contact healing” or “gap healing” without periosteal callus. 

- 부하가 주어지는 상태에서는  external callus와 그것의 local deformation에 있어서 시간의 변화에 따라 interfragmentary strain theory를 따르지 않음

- 그래서 interfragmentary theory는 한계를 지님. periosteal callus없이 gap healing 또는 contact healing을 달성하는데 관여하는 개념으로는 한계를 지님.

A more general concept would be necessary to deal with the biomechanical effects on fracture repair under a new classification system (Aro and Chao, 1993) based on histological appearance of the healing tissue around the fracture site under different fixation methods. This knowledge can guide us to explore additional biophysical stimuli to modulate bone union pathways. 

- 그래서 새로운 개념이 필요함.

The main objective of this review paper was to discuss the logic, the past research, future prospects, and the potential pitfalls associated with the development of more appropriate models to clarify the relationship between biological relations

and bone fracture healing enhancement using different biophysical stimulation modalities. It is hoped that the knowledge

to be gained could also be expanded to the field of limb lengthening through callus distraction and bone quality maintenance under osteoporosis.

- 이 논문에서는 이러한 문제를 탐구

Physical Modulation of Bone Fracture Healing and Remodeling

It has long been known that mechanical stimulation can induce fracture healing or alter its biological pathway (Rand

et al, 1981; Brighton, 1984; Wu et al., 1984; Aro and Chao,1991; Claes et al, 1997). Repetitive loading under small strain and high frequency or overloading through elevated exercise regime has been demonstrated to cause bone hypertrophy

(Goodship and Kenwright, 1985; Rubin et al.,2001). 

- mechanical stimulation은 fracture healing을 유도

-  small strain and high frequency로 반복적인 부하를 주거나 overloading through elevated exercise regime은 bone hypertrophy를 유도한다고 보고되고 있음. 

The added bone formation is also related to the direction and magnitude of overloading which will affect the internal state of stress of the repairing tissue. However, the regulating cellular mediators responsible for such a phenomenon

remain unknown (Fig. 2). 

- bone formation을 촉진하는 인자로 overloading의 방향과 크기가 중요한데, 이는 조직회복의 internal state of stress에 영향을 줄 수 있음. 

If the underlying effect at the cell membrane or cytoplasmic level could be directly linked to the biophysical stimulant, effective and reliable method to maintain or enhance bone regeneration may be established for the treatment of difficult fractures in patients with deficient osteogenic potential due to either local or systemic abnormalities.

When the mechanisms for tissue formation at the cellular level are understood and well defined, physiological conditions or pharmacological agents may be developed to accomplish the same callus formation and bone regeneration effects without the mechanical interventions which are often difficult to administrate under adverse conditions. 

However, the potential mechanoreceptors on the cell membrane sensitive to stress/strain induced by electromechanical or stream potential signals have yet to be identified. Such a discovery, if successfully accomplished, can significantly help to unravel the mystery of regulating pathway for connective tissue remodeling and disuse atrophy, which has only been theorized without validation. Before this is accomplished, the clinicians treating bone fractures must understand that

there are different biological, physiological, and mechanical factors which can have either positive or negative effects on

fracture repair at the tissue level. It is equally important to recognize the possibility that mechanical loading may be the

only irreplaceable element in governing bone remodeling following successful initiation of the fracture repair process.

수술이야기는 생략

Effects of physical loading on fracture healing pathways

To better describe the effects of mechanical and biological influences on bone fracture repair and remodeling, a revised classification of bone union mechanisms (Chao and Aro, 1989) was proposed to replace the oversimplified primary and secondary bone healing types. The new classification was derived from the histological eval‎uation on the absence or presence of secondary osteons across the fracture gap. Periosteal callus could co-exist with osteon migration when the mechanical environment at the fracture site was appropriate. During fracture repair, there were four basic new bone formation processes: 

다른 논문 그림

1) osteochondral ossification, 

2) intramembranous ossification, 

3) oppositional new bone formation, and 

4) osteonal migration(creeping substitution). 

Bone regenerate through callus distraction is a combination of these basic bone formation processes. The type of bone formation processes and their occurrence would vary according to many factors related to fracture type, gap condition, fixation rigidity, loading and biologic environment. 

- callus distraction을 통한 bone regeneration이 bone formation과정의 조합.

- bone formation process은 fracture type, gap condition, fixation rigidity, loading and biologic environment에 달려있음.

Regardless of the fracture healing pathway, mechanical intervention might be the only means to assure bone remodeling after successful callus formation and maturation in order to restore the bone to its original structure and strength. 

- 뼈의 original structure 와 강도를 회복하기 위해서 성공적인 callus formation and maturation 후에  fracture healing pathway와 무관하게 mechanical intervention은 bone remodeling을 확실하게 하는 유일한 방법임. 

It was proposed that the same bone augmentation effect could also regulate bone remodeling by establishing the optimal strain threshold (Fig.4) as well as loading frequency but such a contention remained to be validated especially in the light of the recent interest of low bone strain as an anabolic stimulus for bone quality maintenance (Rubin et al., 2001).

- 아래 그림과 같이 bone augmentation effect는 적절한 strain threshold와 loading frequency가 주어짐에 의해서 bone remodeling이 조절될 수 있음. 

Basic Forms of Biophysical Stimuli on Bone Fracture Healing

As early as 1955, Yasuda had already discovered the Electric Callus phenomena and postulated that “dynamic energy exerted upon bones is transformed into callus formation”(Yasuda, 1955). Now after nearly a half century, the ability to manipulate bone and other connective tissue using external energy is still doubted by some in spite of years of basic research and clinical investigations. 

- 동적인 에너지가 뼈에 주는 영향은 가골형성임. 

Instruments delivering low intensity pulsed ultrasound (LIPU)(Heckman et al., 1994; Yang et al., 1996; Bolander, 1998),

pulsed electromagnetic fields (PEMF) (Bassett, 1961; Sharrard, 1990; Eyres et al., 1996; Ryaby, 1998), low power

direct current (DC) (Brighton et al., 1981; Brighton and Hunt, 1986), extracorporeal shock wave stimulation (ECSW) (Schaden et al., 2001; Wang et al., 2001), and the low intensity high frequency vibration (LIHFV) (Rubin et al., 2002; Srinivasan et al., 2002; Tanaka et al., 2003) are being promoted by the medical instrument industry with mixed responses in the orthopaedic community. 

- fracture healing을 촉진하기 위한 장비

- low intensity pulsed ultrasound (LIPU)(Heckman et al., 1994; Yang et al., 1996; Bolander, 1998),

- pulsed electromagnetic fields (PEMF) (Bassett, 1961; Sharrard, 1990; Eyres et al., 1996; Ryaby, 1998), 

- low power direct current (DC) (Brighton et al., 1981; Brighton and Hunt, 1986), 

- extracorporeal shock wave stimulation (ECSW) (Schaden et al., 2001; Wang et al., 2001), and the 

- low intensity high frequency vibration (LIHFV) (Rubin et al., 2002; 

These are the basic forms of biophysical stimuli but it is still controversial controversial whether these modalities produce different cellular responses or they all follow a similar osteogenic pathway. The importance of utilizing well-established in vitro tissue culture models must be emphasized to supplement the cellular study results for biophysical stimuli signal and dose effect optimisation.

Biological response

Cultured cell and tissue subjected to different physical and electrical signals of varying intensity in an in vitro setting have been studied using the molecular biology and histomorphological analyses. Single cell under carefully controlled stimulation environment using specially designed equipment was conducted to investigate the basic mechanism of cellular response under stimulation (Bolander, 1998). Biochemical pathways activated in signal transduction under various types of electrical stimulation have also been investigated on bone cells (Brighton et al., 2001). Various animal models from rats, rabbits, canines, sheep, to horses simulating fresh fracture, delayed union, limb lengthening, etc. were studied to eval‎uate the energy sources and their dose effects on tissue response judging from the radiographic, histomorphological, and biomechanical results.

- 골절된 bone cell이 healing 되기 위한 최적의 자극을 찾는 노력에 관한 이야기

The low intensity pulsed ultrasound was found to enhance fracture healing by stimulating earlier synthesis of

extracellular matrix protein, the aggregan in cartilage, possibly altering chondrocyte maturation through endochondral

bone formation pathway (Yang et al., 1996). 

Pulsed electromagnetic fields stimulation was found to induce osteogenesis through upregulating BMP-2 and BMP-4 in osteoblasts (Bodamyali et al., 1998). 

The application of direct current reduced local tissue oxygen concentration which could transform polymorphic cells to bone (Brighton and Hunt, 1986). Such mechanism also applied to mesenchymal cells associated with bone fracture hematoma.

It has been postulated that the extracorporeal shock waves caused microtrauma or microfracture and induce

neovasculization through hematoma formation, which would increase osteoblast or fibroblast activity (Wang et

al., 2001). 

Unfortunately, biological studies at cellular level cannot provide reliable information on the therapeutic effect of biophysical stimulation on tissue response at the system level.

Experimental results in animal models

In animal experiments, positive effects on bone fracture healing enhancement were found consistently in different

models and under a variety of biophysical stimuli. The type of tissue formation in the bone healing process

was found to follow closely the cellular mechanism associated with the specific form of energy. In a well-controlled

canine unilateral delayed union model, pulsed electromagnetic fields (PEMF) stimulation for one hour per day

for a total of eight weeks significantly increased weightbearing on the affected limb with higher mechanical strength

of the healing osteotomy due to increased periosteal new bone formation (Fig. 5). 

Another striking finding in this study was the effect of pulsed electromagnetic fields on the reduction of cortical porosity in the bone adjacent to the osteotomy when compared to the non-treated group (Fig6) (Inoue et al., 2002). However, in a rabbit tibial lengthening model, neither LIPU nor PEMF using the current signal type and dose had demonstrated any significant enhancement effect on bone regenerate maturation (Tis et al., 2002; Taylor et al., 2003).

Clinical use of biophysical stimulation

There are numerous clinical reports to support effectiveness of biophysical stimulation on fresh fracture, delayed union, and bone lengthening. Several prospective, randomized clinical studies have shown the efficacy of low intensity pulsed ultrasound (LIPU) in stimulating bone formation after fracture (Heckman et al., 1994¸ Kristiansen et al., 1997), non-union (Xavier and Duarte, 1983), and bone lengthening (Sato et al., 1999). 

Pulsed electromagnetic fields (PEMF) stimulation has been in clinical use for nearly 30 years on patients with delayed fracture healing and nonunion and demonstrated its effect in a multitude of clinical case reports (Bassett, 1989; Eyres et al., 1996; Ryaby,1998). Double-blinded studies confirmed the clinical effectiveness of pulsed electromagnetic fields stimulation on osteotomy healing (Borsalino et al., 1988; Mammi et al.,1993) and delayed union fractures (Sharrard, 1990). 

Brighton et al. (1981) conducted multi-center study of the nonunion and reported an 84% clinical healing rate of nonunion

with direct current treatment. 

Recently, Schaden et al. (2001) reported 76% of non-union or delayed union patients treated with one time extracorporeal shock wave therapy resulted in bony consolidation with a simultaneous decrease in symptoms.

All these results would strongly support the efficacy of biophysical stimulation as a therapeutic modality in bone fracture repair and bone regenerate augmentation. However, current commercial devices need to utilize the available bioengineering technology to optimize instrument design and treatment protocol development to build biophysical stimulation on firmer foundation. Insufficient effort has devoted to quantify the dose effect by considering timerelated tissue change as a factor to adjust the stimulation signal intensity in the treatment protocol. Additional research is required to specify field intensity and signal scattering as a function of local tissue attenuation and application variation. 

The basic science knowledge related to connective tissue modulation through external energy stimulation must be transformed into the technology of implementation, which could then be brought to the clinical arena as a system under physician’s supervision to provide reliable and cost-effective enhancement on tissue repair, regeneration, remodeling, and maintenance when indicated. A grand vision of Non-invasive Tissue Engineering using biophysical stimulation needs to be shared by the investigators and clinicians as the ultimate goal of such therapeutic modality.

Future Effort Required in Biophysical Stimulation

In vitro cell and tissue culture studies are needed to explore the existence of a cellular response to biophysical stimulants. Under such an experimental setup, the basic biological mechanism responsible for the stimulation effect as well as the potential pitfalls of such intervention could be established. However, the conditions provided for a single cell or a cell population in a culture dish could not reproduce the actual environment in living tissues subject to physical loading. The same limitation may also exist in isolated tissue experiments in a bioreactor. Therefore, useful feasibility studies prior to clinical trial must rely upon well-designed animal experiments using models from which the signal/dose effect on tissue augmentation in response to a biophysical stimulation could be firmly established and quantified.

animal modle 생략

Mechanical manipulation in bone regenerate

Connective tissue manipulation is an important orthopedic procedure in treating limb length discrepancy and angular malformation. Such operative intervention has also been used in the treatment of fracture non-unions (Ilizarov,

1989; Delloye et al., 1990; Marsh et al., 1992). The most commonly applied technique involves callus distraction.

To effectively achieve such mechanical manipulation, a waiting period after bone osteotomy is mandatory. The

length of this crucial time period varies and there is no objective guideline to estimate it in each case using available

information related to tissue compliance and cellular response (Yasui et al., 1993).

In addition, the rate of distraction remains controversial. It would be desirable if the rate of bone distraction could be determined using a noninvasive method of assessing bone regenerate’s biomechanical strength thereby implement the optimal remodeling conditions for bone (Windhager et al., 1995; Kassis et al., 1996).

Research pertaining to the interaction of biomechanical forces and cellular responses will help to establish these essential guidelines. Such experimental studies can also provide useful information on applying proper compressive loading to enhance the consolidation of the distracted tissues. Similar investigations are expected to produce valuable information concerning the distractibility of vessels and nerves in the same operation. It has been proposed that the type of stress applied to immature or undifferentiated tissue, can dictate its regeneration fate (Carter et al., 1988) (Fig. 7).

- intermittent compressive or shear stress는 endochondral ossification을 촉진

- tensile stress는 intramembranous ossification을 촉진

- constant compressive는 endochondral ossification을 억제하여 cartilage 생성을 촉진

- high shear stress는 fibrous tissue formation을 촉진.

If these connective tissue manipulation mechanisms are well established, they can be utilized through appropriate biophysical stimulation to form the required knowledgebase for the ultimate goal of Non-invasive Tissue Engineering.

이후 생략...

Figure 8. (a) Cortical defect repair model and the histomorphometric analysis location along and adjacent to the defect. (b) The microvascular network obtained using the plastic-investment technique (A: The longitudinal crosssection; and B: The transverse cross-section. Areas “1” and “2” were used for vascular density and orientation analysis) and the contact microradiograph (C: The transverse cross-section at the defect mid-section. Areas “3” and “4” were used to study trabecular bone density and architecture using Fourier Transform technique) of the bone at the defect 4 weeks after surgery. (c) The recovery of structural strength under torsion of the tibia containing the cortical defect as a function of healing time.

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