1. Inflammation

2. Proliferation

3. Remodeling

24hrs: a clot begins to form around the wound; neutrophils gather at the wound site

1-7d: The tissue around the wound begins to re-epithelialize (triggered by macrophage-released factors); granulation tissue forms; a new capillary is formed to connect the healing tissue and an adjacent blood vessel (angiogenesis)

>1 wk: Regeneration is basically finished; the wound site contracts

1) Dermal wound

2) Granulation Tissue Formation

3) Random orientation of collagen III around the wound

4) Collagen III is replaced with Collagen I

5) Angiogenesis

6) Collagen accumulates for 2-3 mos.

7) Some blood vessels resorb, scab becomes pale (prim. composed of fibroblasts, ECM. collagen

1) Epidermal wound

2) Epithelial cells flatten, release from ECM, and migrate towards center of wound, contacting other epithelial cells

3) ECM reattaches, regains cuboidal shape with the same mechanical properties as before

1) Endothelial cells activate and survive due to VEGF (vascular-endothelial growth factor)

2) MMPs break down basement membrane, ECM

3) VEGFs cause endothelial cells to proliferate and migrate

4) Integrins form, elongate, and remodel tubes

5) Ang-1 TGF alpha causes maturation of pericytes and smooth muscle vasculature cells

Vasculogenesis: No pre-existing cells (likely differentiated from bone marrow stem cells)

Angiogenesis: Sprouting of new blood vessels from pre-existing vessels

FBGCs - fused macrophages attempting to phagocytose the matl; undergo frustrated phagocytosis

Formation affected by surface topography/chemistry, surface area/volume ratio

More roughness, porosity = higher FBGC formation (higher SA:V ratio)

End stage of healing response in non-degradable biomatls (~4wks post-implantation)

An acellular fibrous capsule (spindle-shaped fibroblasts, a small number of macrophages) forms around the material

Presence of neutrophils suggests persisting inflammation

Presence of FBGCs suggests production of small particles by corrosion, dissolution, wear (unresolved active inflammation/ attempted degradation)

Capsule thickness enhanced by: injury during implant, particulates, motion, edges, current

Can result in granulomas (layer of FBGCs surrounded by modified macrophages and lymphocytes)

Caused by motion around implant and physiochemical implant properties

Can trigger an aquired immune response

After normal wound healing, myofibroblasts disappear by apoptosis

Continuous collagen secretion, remodeling and contraction leads to connective tissue contraction

Examples: hypertrophic scars, keloids, fibrotic diseases

1) Extrustion - formation of a pouch contiguous with the newly formed epithelium; pouch forces material out of the body

2) Resorption - Only occurs with biodegradable materials; the fibrous capsule is collapsed or replaced by appropriate tissue; success for tissue engineering

3) Integration - Relatively rare; material is directly in contact with host material (electrode in the brain, bone implant); success for tissue engineering

4) Encapsulation - Formation of a fibrous capsule around the material; does not resolve, but can reach a steady state; failure for tissue engineering, typical response for non-degradable biomaterials

1) Animal choice (start small, use animals comparable to humans)

2) Implant site

3) Study length: Acute (0-24h), Subacute (14-28d), Subchronic (<90d), Chronic (>90d)

3) Dose and administration

4) Controls (sham surgery)

5) Assesment - visual, histology, electron microscopy, mechanical testing

1) Materials used

2) Intended additives, procces contamination, residues from fabrication

3) Leachable substances

4) Degradation products (designed to degrade, enter body environment)

5) Properties, characteristics of 'final product'

6) Alternation in load or strain in the area surrounding the implant