TISSUE REPAIR, WOUND HEALING AND FIBROSIS

WOUND HEALING
TISSUE INJURY
SURGEON

Wound healing is fundamental homeostatic process in response to injury The Understanding is fundamental for practice of surgery Has a closed relationship since a beginning of surgery

Tissue Renewal & Repair

Ability to replace injured or dead cells Ability to repair tissues after inflammation
Regeneration Restitution of lost tissue

injury
Healing Restore original structure but involves colagen deposition and scar formation

REGENERATION
GROWTH OF CELL TISSUE TO REPLACES LOST STRUCTURE HEMATOPOIETIC SYSTEM, THE EPITHELIA OF THE SKIN AND GI TRACT RARELY IN MAMMALS ORGANS AND COMPLEX TISSUES REQUIRES AN INTACT CONNECTIVE TISSUE

HEALING
IS USUALLY TISSUE RESPONSE
1. TO WOUND HEALING 2. TO INFLAMMATORY PROCESS 3. TO CELL NECROSIS IN ORGANS INCAPABLE OF REGENERATION

SCAR FORMATION OCCURS IF ECM FRAMEWORK DAMAGED CHRONIC : FIBROSIS

Tissue Response To Injury

NORMAL CELL PROLIFERATION & TISSUE GROWTH

NORMAL CELL PROLIFERATION & TISSUE GROWTH The size of cell population is determined by:
1. Cell proliferation 2. Differentiation 3. Death by Apoptosis

CELL PROLIFERATION
PHYSIOLOGIC
Ex: Proliferation of endometrial cell during menstruation

PATHOLOGIC
Pathologic condition : injury, cell death or mechanical alteration Excessive physiologic stimuli: nodular prostatic hyperplasia resulting from dihydrotestosterone stimulation

TISSUE PROLIFERATIVE ACTIVITY

DIVIDED INTO 3 GROUPS 1. CONTINUOUSLY DIVIDING TISSUES (LABILE TISSUES), ex: surface epithelia, lining mucosa, columnar epithelium GI tract, etc 2. QUIESCENT TISSUE (STABLE), ex: the parenchymal cell of kidney, liver, pacreas, etc 3. NON DIVIDING TISSUES, ex: neurons, skeletal, cardiac muscle

STEM CELL
Most exciting topic in modern day Regenerative Medicine Hope may one day be used to repair in human tissues such as Heart, Brain, and Skeletal muscle

GROWTH FACTOR
Stimulating Cell Proliferation Also have effects on
Cell locomotion Contractility Differentiation Angiogenesis

EGF, TGF-, HGF, VEGF, PDGF, FGF, TGF , Cytokines

SIGNALING MECHANISM IN CELL GROWTH

AUTOCRINE SIGNALING PARACRINE SIGNALING ENDOCRINE SIGNALING

 AUTOCRINE SIGNALING
LIVER REGENERATION PROLIFERATION OF ANTIGENSTIMULATED LYMPHOCYTE THE GROWTH OF SOME TUMORS

 PARACRINE SIGNALING
CONNECTIVE TISSUE REPAIR OF WOUND HEALING

 ENDOCRINE SIGNALING
HORMONE SECRETION INTO BLOOD BY ENDOCRINE GLAND CARRIED BY THE BLOOD ACT ON DISTANT TARGET CELL

RECEPTORS & SIGNAL TRANSDUCTION PATHWAY

Extracellular matrix

 Mechanical support for cell anchorage Control of cell growth Maintenance of cell differentiation Scaffolding for tissue renewal Establishment of tissue microenvironments Storage and presentation of regulatory

molecules

 Collagen Elastin Proteoglycans and Hyaluronana Adhesive glycoproteins and integrins Fibronectin Laminin Integrins

Influence of ECM & GFs

Tissue remodeling

Luka mengalami penyembuhan normal melalui tiga fase yang saling melengkapi

INJURY
Platelet Kolagen dan ECM

DAERAH LUKA PELEPASAN FAKTOR PEMBEKUAN Fungsi Fibrin CASCADE :

SINYAL KIMIA CITOKIN (GROWTH FACTORS) PDGF
Kemotaksis dan stimulasi

TGF-
Sekresi Sitokin, Peningkatan kemotaksis, Modulasi Kolagen Ekspresi Kolagenase

Penyembuhan Dengan Intensi Pertama

Penyembuhan insisi bedah yang bersih, tidak terinfeksi yang diperkirakan karena jahitan operasi

Insisi hanya menyebabkan gangguan kelangsungan membrane basal epitel dan kematian epitel yang relative sedikit dan sel jaringan penyambung.

Akibatnya, regenerasi epitel lebih menonjol dibandingkan fibrosis.

Ruang insisi yang sempit dengan cepat akan terisi fibrin-bekuan darah; dehidrasi permukaan yang menghasilkan luka scab untuk menutupi dan melindungi daerah perbaikan dan penyembuhan luka.

Dalam 24 jam, tampak netrofil pada bagian tepi insisi, bermigrasi ke arah bekuan fibrin Hari ketiga, netrofil secara luas digantikan oleh makrofag, dan jaringan granulasi dengan cepat memasuki celah insisi. Saat ini serat kolagen tampak pada tepi insisi Selama minggu kedua, akumulasi kolagen proliferasi fibroblast berlanjut. Infiltrasi leukosit, edema dan peningkatan vaskularisasi menjadi sangat berkurang Pada akhir bulan pertama, bekas luka terdiri dari jaringan penyambung seluler yang sama sekali tanpa sel inflamasi dan ditutupi oleh epidermis normal. Kulit tubuh yang rusak pada garis insisi hilang secara permanen.

Kehilangan sel atau jaringan lebih luas infark, peradangan ulserasi, pembentukan abses, atau luka yang besar Penyembuhan sekunder : Defek jaringan yang besar secara intrinsic memiliki volume debris nekrotik, eksudat dan fibrin. Secara konsekuen, reaksi inflamasi lebih intens, dengan potensi sekunder, media-inflamasi dan luka yang lebih besar. Terbentuk jaringan granulasi yang lebih banyak. Volume jaringan granulasi yang lebih besar secara menyeluruh menghasilkan masa jaringan parut yang lebih besar. Penyembuhan sekunder menampakan fenomena kontraksi luka.

Satu minggu, daya luka mendekati 10 % dari kulit yang tidak luka

Sintesa kolagen
Meningkat secara cepat setelah 4 minggu

Modifikasi structural kolagen

Daya luka mencapai hampir 70 %-80 % dari normal dalam 3 bulan

PATHOLOGIC ASPECTS OF REPAIR

Factors that influence the wound healing : Infection The type (and volume) of tissue injured

The location of the injury or the character of the tissue

in which the injury occurs, is also important. Aberrations of the cell growth and ECM production may

occurs even in what begins as normal wound healing.

The mechanism underlying the disabling fibrosis associated with chronic inflammatory dissease such as

rhematoid arthritis, pulmonary fibrosis, and cirrhosis

are essentialy identical to those that are involved in normal wound healing.

Normal wound healing

PLATELET GRANULES AND MEDIATORS OF PLATELET AGGREGATION

PLATELET GRANULES a. Granules: Contain MEDIATORS OF Platelet-Specific Proteins PLATELET Platelet factor 4 AGGREGATION b-Thromboglobulin Thromboxane A2 Platelet-derived growth factor Thrombin Transforming growth Platelet factor 4 factor b. Dense Granules Adenosine diphosphate Serotonin Calcium

Open wound healing

Factors that retard wound healing

Local Factors
Blood supply Mechanical stress

Denervation
Local infection

Necrotic tissue
Protection (dressings)

Foreign body
Hematoma

Surgical techniques
Type of tissue

Factors that retard wound healing

Systemic Factors
Age Anemia Drugs (steroids, cytotoxic medications, intensive antibiotic therapy) Malnutrition Obesity Systemic infection Temperature Trauma, hypovolemia, and hypoxia Genetic disorders (osteogenesis imperfecta, Ehlers-Danlos syndromes, Marfan syndrome) Hormones Diabetes Malignant disease Uremia Vitamin deficiency (vitamin C) Trace metal deficiency (zinc, copper)

Chronic Wound
Fails to heal within 3 months Classification :
pressure sores,diabetic foot, leg ulcers

Most have the potential to heal Due to inadequate cleansing, debridement, edema control, treatment of ischaemia, & achievement of moist wound healing. Increased proteases & collagenase, but decreased growth factors

Four general components of this process. Formation of new blood vessels (angiogenesis) Migration and proliferation of fibroblasts Deposition of EMC Maturation and reorganization of the fibrous

tissue (remodeling)

Proses fibrosis terjadi dalam dua tahap: (1) Emigrasi dan proliferasi fibroblast ke dalam daerah luka (1) Deposisi ECM oleh sel-sel ini