372 Future Directions
injuries, did not form a clot between the rup-
tured tissue ends; consequently, there was no
scaffold for cell migration and tissue repair
(Murrayet al. 2000a). This inability to form a
clot may be attributed to high intra-articular
levels of plasminogen after cruciate injury
(Brommeret al. 1992; Roscet al. 2002) (Figure
45.1). The observation that the provisional scaf-
fold is insufficient for the CrCL to heal has led to
new lines of inquiry into substitute provisional
scaffolds designed for intra-articular use.
The biomaterial
Extracellular matrix (ECM) proteins, including
collagen, have a long-standing record as bio-
compatible, biodegradable, and safe materials
for orthopaedic applications. Studies of human
and bovinein vitromodels have demonstrated
that fibroblasts are capable of migrating from
the stump of the torn cruciate ligament into
such an ECM biomaterial; hence, it may not be
necessary to add exogenous cultured cells to the
repair site (Murrayet al. 2000b; Murray & Spec-
tor 2001; Murrayet al. 2002).
Signaling
Platelets are the first common factor in phys-
iologic wound healing, and thus represent a
potentially valuable source of growth factor
delivery. They are activated upon contact with
collagen (Fufaet al. 2008), making their combi-
nation with ECM scaffolds logical. Recent stud-
ies have noted that the application of platelets in
physiologic concentrations, rather than the high
concentrations found in platelet-rich plasma
(PRP), may result in improved ligament heal-
ing. Recent studies have shown that reduc-
ing the concentration of PRP to a physiologic
level does not deteriorate the outcome after
bridge-enhanced CrCL repair in pigs (Mas-
trangeloet al. 2011), and that higher concentra-
tions of platelets inhibit ligament cell function
in a three-dimensional culture (Yoshidaet al.
2014). In addition, the inclusion of white blood
cells can result in improved cell proliferation
(Yoshida & Murray 2013), and the inclusion of
red blood cells can improve collagen production
by CrCL fibroblasts (Harrisonet al. 2011). How-
ever, the addition of mesenchymal stem cells, in
turn, does not produce better functional results(A)(B)FibrinogenFibrinogenFibrinFibrinSimultaneously occurringThrombinThrombinPlasminPlasminIntra-articular
PlasminogenuPAHours
after injuryWeeks
after injuryDegradation
ProductsDegradation
ProductsFigure 45.1 (A) The provisional clot formation process for tissues outside of joints. When the tissue is injured,
fibrinogen is cleaved by thrombin into fibrin which serves as a provisional scaffold. (B) The early wound-healing process
for tissues within joints (intra-articular, such as the cranial cruciate ligament). For these tissues, when the injury occurs,
there is an immediate increase in plasmin activation. The plasmin then degrades the fibrin clot, thus effectively
preventing the development of the provisional scaffold. Source: Murray & Spindler 2005. Reproduced with permission
from Wolters Kluwer Health, Inc.